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1.  Ectopic Lymphoid Structures Support Ongoing Production of Class-Switched Autoantibodies in Rheumatoid Synovium 
PLoS Medicine  2009;6(1):e1.
Background
Follicular structures resembling germinal centres (GCs) that are characterized by follicular dendritic cell (FDC) networks have long been recognized in chronically inflamed tissues in autoimmune diseases, including the synovium of rheumatoid arthritis (RA). However, it is debated whether these ectopic structures promote autoimmunity and chronic inflammation driving the production of pathogenic autoantibodies. Anti-citrullinated protein/peptide antibodies (ACPA) are highly specific markers of RA, predict a poor prognosis, and have been suggested to be pathogenic. Therefore, the main study objectives were to determine whether ectopic lymphoid structures in RA synovium: (i) express activation-induced cytidine deaminase (AID), the enzyme required for somatic hypermutation and class-switch recombination (CSR) of Ig genes; (ii) support ongoing CSR and ACPA production; and (iii) remain functional in a RA/severe combined immunodeficiency (SCID) chimera model devoid of new immune cell influx into the synovium.
Methods and Findings
Using immunohistochemistry (IHC) and quantitative Taqman real-time PCR (QT-PCR) in synovial tissue from 55 patients with RA, we demonstrated that FDC+ structures invariably expressed AID with a distribution resembling secondary lymphoid organs. Further, AID+/CD21+ follicular structures were surrounded by ACPA+/CD138+ plasma cells, as demonstrated by immune reactivity to citrullinated fibrinogen. Moreover, we identified a novel subset of synovial AID+/CD20+ B cells outside GCs resembling interfollicular large B cells. In order to gain direct functional evidence that AID+ structures support CSR and in situ manufacturing of class-switched ACPA, 34 SCID mice were transplanted with RA synovium and humanely killed at 4 wk for harvesting of transplants and sera. Persistent expression of AID and Iγ-Cμ circular transcripts (identifying ongoing IgM-IgG class-switching) was observed in synovial grafts expressing FDCs/CD21L. Furthermore, synovial mRNA levels of AID were closely associated with circulating human IgG ACPA in mouse sera. Finally, the survival and proliferation of functional B cell niches was associated with persistent overexpression of genes regulating ectopic lymphoneogenesis.
Conclusions
Our demonstration that FDC+ follicular units invariably express AID and are surrounded by ACPA-producing plasma cells provides strong evidence that ectopic lymphoid structures in the RA synovium are functional and support autoantibody production. This concept is further confirmed by evidence of sustained AID expression, B cell proliferation, ongoing CSR, and production of human IgG ACPA from GC+ synovial tissue transplanted into SCID mice, independently of new B cell influx from the systemic circulation. These data identify AID as a potential therapeutic target in RA and suggest that survival of functional synovial B cell niches may profoundly influence chronic inflammation, autoimmunity, and response to B cell–depleting therapies.
Costantino Pitzalis and colleagues show that lymphoid structures in synovial tissue of patients with rheumatoid arthritis support production of anti-citrullinated peptide antibodies, which continues following transplantation into SCID mice.
Editors' Summary
Background.
More than 1 million people in the United States have rheumatoid arthritis, an “autoimmune” condition that affects the joints. Normally, the immune system provides protection against infection by responding to foreign antigens (molecules that are unique to invading organisms) while ignoring self-antigens present in the body's own tissues. In autoimmune diseases, this ability to discriminate between self and non-self fails for unknown reasons and the immune system begins to attack human tissues. In rheumatoid arthritis, the lining of the joints (the synovium) is attacked, it becomes inflamed and thickened, and chemicals are released that damage all the tissues in the joint. Eventually, the joint may become so scarred that movement is no longer possible. Rheumatoid arthritis usually starts in the small joints in the hands and feet, but larger joints and other tissues (including the heart and blood vessels) can be affected. Its symptoms, which tend to fluctuate, include early morning joint pain, swelling, and stiffness, and feeling generally unwell. Although the disease is not always easy to diagnose, the immune systems of many people with rheumatoid arthritis make “anti-citrullinated protein/peptide antibodies” (ACPA). These “autoantibodies” (which some experts believe can contribute to the joint damage in rheumatoid arthritis) recognize self-proteins that contain the unusual amino acid citrulline, and their detection on blood tests can help make the diagnosis. Although there is no cure for rheumatoid arthritis, the recently developed biologic drugs, often used together with the more traditional disease-modifying therapies, are able to halt its progression by specifically blocking the chemicals that cause joint damage. Painkillers and nonsteroidal anti-inflammatory drugs can reduce its symptoms, and badly damaged joints can sometimes be surgically replaced.
Why Was This Study Done?
Before scientists can develop a cure for rheumatoid arthritis, they need to know how and why autoantibodies are made that attack the joints in this common and disabling disease. B cells, the immune system cells that make antibodies, mature in structures known as “germinal centers” in the spleen and lymph nodes. In the germinal centers, immature B cells are exposed to antigens and undergo two genetic processes called “somatic hypermutation” and “class-switch recombination” that ensure that each B cell makes an antibody that sticks as tightly as possible to just one antigen. The B cells then multiply and enter the bloodstream where they help to deal with infections. Interestingly, the inflamed synovium of many patients with rheumatoid arthritis contains structures that resemble germinal centers. Could these ectopic (misplaced) lymphoid structures, which are characterized by networks of immune system cells called follicular dendritic cells (FDCs), promote autoimmunity and long-term inflammation by driving the production of autoantibodies within the joint itself? In this study, the researchers investigate this possibility.
What Did the Researchers Do and Find?
The researchers collected synovial tissue from 55 patients with rheumatoid arthritis and used two approaches, called immunohistochemistry and real-time PCR, to investigate whether FDC-containing structures in synovium expressed an enzyme called activation-induced cytidine deaminase (AID), which is needed for both somatic hypermutation and class-switch recombination. All the FDC-containing structures that the researchers found in their samples expressed AID. Furthermore, these AID-containing structures were surrounded by mature B cells making ACPAs. To test whether these B cells were derived from AID-expressing cells resident in the synovium rather than ACPA-expressing immune system cells coming into the synovium from elsewhere in the body, the researchers transplanted synovium from patients with rheumatoid arthritis under the skin of a special sort of mouse that largely lacks its own immune system. Four weeks later, the researchers found that the transplanted human lymphoid tissue was still making AID, that the level of AID expression correlated with the amount of human ACPA in the blood of the mice, and that the B cells in the transplant were proliferating.
What Do These Findings Mean?
These findings show that the ectopic lymphoid structures present in the synovium of some patients with rheumatoid arthritis are functional and are able to make ACPA. Because ACPA may be responsible for joint damage, the survival of these structures could, therefore, be involved in the development and progression of rheumatoid arthritis. More experiments are needed to confirm this idea, but these findings may explain why drugs that effectively clear B cells from the bloodstream do not always produce a marked clinical improvement in rheumatoid arthritis. Finally, they suggest that AID might provide a new target for the development of drugs to treat rheumatoid arthritis.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0060001.
This study is further discussed in a PLoS Medicine Perspective by Rene Toes and Tom Huizinga
The MedlinePlus Encyclopedia has a page on rheumatoid arthritis (in English and Spanish). MedlinePlus provides links to other information on rheumatoid arthritis (in English and Spanish)
The UK National Health Service Choices information service has detailed information on rheumatoid arthritis
The US National Institute of Arthritis and Musculoskeletal and Skin Diseases provides Fast Facts, an easy to read publication for the public, and a more detailed Handbook on rheumatoid arthritis
The US Centers for Disease Control and Prevention has an overview on rheumatoid arthritis that includes statistics about this disease and its impact on daily life
doi:10.1371/journal.pmed.0060001
PMCID: PMC2621263  PMID: 19143467
2.  Non-Specialist Psychosocial Interventions for Children and Adolescents with Intellectual Disability or Lower-Functioning Autism Spectrum Disorders: A Systematic Review 
PLoS Medicine  2013;10(12):e1001572.
In a systematic review, Brian Reichow and colleagues assess the evidence that non-specialist care providers in community settings can provide effective interventions for children and adolescents with intellectual disabilities or lower-functioning autism spectrum disorders.
Please see later in the article for the Editors' Summary
Background
The development of effective treatments for use by non-specialists is listed among the top research priorities for improving the lives of people with mental illness worldwide. The purpose of this review is to appraise which interventions for children with intellectual disabilities or lower-functioning autism spectrum disorders delivered by non-specialist care providers in community settings produce benefits when compared to either a no-treatment control group or treatment-as-usual comparator.
Methods and Findings
We systematically searched electronic databases through 24 June 2013 to locate prospective controlled studies of psychosocial interventions delivered by non-specialist providers to children with intellectual disabilities or lower-functioning autism spectrum disorders. We screened 234 full papers, of which 34 articles describing 29 studies involving 1,305 participants were included. A majority of the studies included children exclusively with a diagnosis of lower-functioning autism spectrum disorders (15 of 29, 52%). Fifteen of twenty-nine studies (52%) were randomized controlled trials and just under half of all effect sizes (29 of 59, 49%) were greater than 0.50, of which 18 (62%) were statistically significant. For behavior analytic interventions, the best outcomes were shown for development and daily skills; cognitive rehabilitation, training, and support interventions were found to be most effective for improving developmental outcomes, and parent training interventions to be most effective for improving developmental, behavioral, and family outcomes. We also conducted additional subgroup analyses using harvest plots. Limitations include the studies' potential for performance bias and that few were conducted in lower- and middle-income countries.
Conclusions
The findings of this review support the delivery of psychosocial interventions by non-specialist providers to children who have intellectual disabilities or lower-functioning autism spectrum disorders. Given the scarcity of specialists in many low-resource settings, including many lower- and middle-income countries, these findings may provide guidance for scale-up efforts for improving outcomes for children with developmental disorders or lower-functioning autism spectrum disorders.
Protocol Registration
PROSPERO CRD42012002641
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Newborn babies are helpless, but over the first few years of life, they acquire motor (movement) skills, language (communication) skills, cognitive (thinking) skills, and social (interpersonal interaction) skills. Individual aspects of these skills are usually acquired at specific ages, but children with a development disorder such as an autism spectrum disorder (ASD) or intellectual disability (mental retardation) fail to reach these “milestones” because of impaired or delayed brain maturation. Autism, Asperger syndrome, and other ASDs (also called pervasive developmental disorders) affect about 1% of the UK and US populations and are characterized by abnormalities in interactions and communication with other people (reciprocal socio-communicative interactions; for example, some children with autism reject physical affection and fail to develop useful speech) and a restricted, stereotyped, repetitive repertoire of interests (for example, obsessive accumulation of facts about unusual topics). About half of individuals with an ASD also have an intellectual disability—a reduced overall level of intelligence characterized by impairment of the skills that are normally acquired during early life. Such individuals have what is called lower-functioning ASD.
Why Was This Study Done?
Most of the children affected by developmental disorders live in low- and middle-income countries where there are few services available to help them achieve their full potential and where little research has been done to identify the most effective treatments. The development of effective treatments for use by non-specialists (for example, teachers and parents) is necessary to improve the lives of people with mental illnesses worldwide, but particularly in resource-limited settings where psychiatrists, psychologists, and other specialists are scarce. In this systematic review, the researchers investigated which psychosocial interventions for children and adolescents with intellectual disabilities or lower-functioning ASDs delivered by non-specialist providers in community settings produce improvements in development, daily skills, school performance, behavior, or family outcomes when compared to usual care (the control condition). A systematic review identifies all the research on a given topic using predefined criteria; psychosocial interventions are defined as therapy, education, training, or support aimed at improving behavior, overall development, or specific life skills without the use of drugs.
What Did the Researchers Do and Find?
The researchers identified 29 controlled studies (investigations with an intervention group and a control group) that examined the effects of various psychosocial interventions delivered by non-specialist providers to children (under 18 years old) who had a lower-functioning ASD or intellectual disability. The researchers retrieved information on the participants, design and methods, findings, and intervention characteristics for each study, and calculated effect sizes—a measure of the effectiveness of a test intervention relative to a control intervention—for several outcomes for each intervention. Across the studies, three-quarters of the effect size estimates were positive, and nearly half were greater than 0.50; effect sizes of less than 0.2, 0.2–0.5, and greater than 0.5 indicate that an intervention has no, a small, or a medium-to-large effect, respectively. For behavior analytic interventions (which aim to improve socially significant behavior by systematically analyzing behavior), the largest effect sizes were seen for development and daily skills. Cognitive rehabilitation, training, and support (interventions that facilitates the relearning of lost or altered cognitive skills) produced good improvements in developmental outcomes such as standardized IQ tests in children aged 6–11 years old. Finally, parental training interventions (which teach parents how to provide therapy services for their child) had strong effects on developmental, behavioral, and family outcomes.
What Do These Findings Mean?
Because few of the studies included in this systematic review were undertaken in low- and middle-income countries, the review's findings may not be generalizable to children living in resource-limited settings. Moreover, other characteristics of the included studies may limit the accuracy of these findings. Nevertheless, these findings support the delivery of psychosocial interventions by non-specialist providers to children who have intellectual disabilities or a lower-functioning ASD, and indicate which interventions are likely to produce the largest improvements in developmental, behavioral, and family outcomes. Further studies are needed, particularly in low- and middle-income countries, to confirm these findings, but given that specialists are scarce in many resource-limited settings, these findings may help to inform the implementation of programs to improve outcomes for children with intellectual disabilities or lower-functioning ASDs in low- and middle-income countries.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001572.
This study is further discussed in a PLOS Medicine Perspective by Bello-Mojeed and Bakare
The US Centers for Disease Control and Prevention provides information (in English and Spanish) on developmental disabilities, including autism spectrum disorders and intellectual disability
The US National Institute of Mental Health also provides detailed information about autism spectrum disorders, including the publication “A Parent's Guide to Autism Spectrum Disorder”
Autism Speaks, a US non-profit organization, provides information about all aspects of autism spectrum disorders and includes information on the Autism Speaks Global Autism Public Health Initiative
The National Autistic Society, a UK charity, provides information about all aspects of autism spectrum disorders and includes personal stories about living with these conditions
The UK National Health Service Choices website has an interactive guide to child development and information about autism and Asperger syndrome, including personal stories, and about learning disabilities
The UK National Institute for Health and Care Excellence provides clinical guidelines for the management and support of children with autism spectrum disorders
The World Health Organization provides information on its Mental Health Gap Action Programme (mhGAP), which includes recommendations on the management of developmental disorders by non-specialist providers; the mhGAP Evidence Resource Center provides evidence reviews for parent skills training for management of children with intellectual disabilities and pervasive developmental disorders and interventions for management of children with intellectual disabilities
PROSPERO, an international prospective register of systematic reviews, provides more information about this systematic review
doi:10.1371/journal.pmed.1001572
PMCID: PMC3866092  PMID: 24358029
3.  Measuring the Population Burden of Injuries—Implications for Global and National Estimates: A Multi-centre Prospective UK Longitudinal Study 
PLoS Medicine  2011;8(12):e1001140.
Ronan Lyons and colleagues compared the population burden of injuries using different approaches from the UK Burden of Injury and Global Burden of Disease studies and find that the absolute UK burden of injury is higher than previously estimated.
Background
Current methods of measuring the population burden of injuries rely on many assumptions and limited data available to the global burden of diseases (GBD) studies. The aim of this study was to compare the population burden of injuries using different approaches from the UK Burden of Injury (UKBOI) and GBD studies.
Methods and Findings
The UKBOI was a prospective cohort of 1,517 injured individuals that collected patient-reported outcomes. Extrapolated outcome data were combined with multiple sources of morbidity and mortality data to derive population metrics of the burden of injury in the UK. Participants were injured patients recruited from hospitals in four UK cities and towns: Swansea, Nottingham, Bristol, and Guildford, between September 2005 and April 2007. Patient-reported changes in quality of life using the EQ-5D at baseline, 1, 4, and 12 months after injury provided disability weights used to calculate the years lived with disability (YLDs) component of disability adjusted life years (DALYs). DALYs were calculated for the UK and extrapolated to global estimates using both UKBOI and GBD disability weights. Estimated numbers (and rates per 100,000) for UK population extrapolations were 750,999 (1,240) for hospital admissions, 7,982,947 (13,339) for emergency department (ED) attendances, and 22,185 (36.8) for injury-related deaths in 2005. Nonadmitted ED-treated injuries accounted for 67% of YLDs. Estimates for UK DALYs amounted to 1,771,486 (82% due to YLDs), compared with 669,822 (52% due to YLDs) using the GBD approach. Extrapolating patient-derived disability weights to GBD estimates would increase injury-related DALYs 2.6-fold.
Conclusions
The use of disability weights derived from patient experiences combined with additional morbidity data on ED-treated patients and inpatients suggests that the absolute burden of injury is higher than previously estimated. These findings have substantial implications for improving measurement of the national and global burden of injury.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Injuries—resulting from traffic collisions, drowning, poisoning, falls or burns, and violence from assault, self-inflicted violence, or acts of war—kill more than 5 million people worldwide every year and cause harm to millions more. Injuries account for at least 9% of global mortality and are a threat to health in every country of the world. Furthermore, for every death-related injury, dozens of injured people are admitted to hospitals, hundreds visit emergency rooms, and thousands go to see their doctors by appointment. A large proportion of people surviving their injuries will be left with temporary or permanent disabilities.
The Global Burden of Diseases, Injuries and Risk Factors (GBD) Studies are instrumental in quantifying the burden of injuries placed on society and are essential for the public health response, priority setting, and policy development. Central to the GBD methodology is the concept of Disability Adjusted Life years (DALYs), and a combination of premature mortality, referred to as years of life lost and years lived with disability. However, rather than evidence and measurements, the GBD Study used panel studies and expert opinion to estimate weights and durations of disability. Therefore, although the GBD has been a major development, it may have underestimated the population burden.
Why Was This Study Done?
Accurate measurement of the burden of injuries is essential to ensure adequate policy responses to prevention and treatment. In this study, the researchers aimed to overcome the limitations of previous studies and for the first time, measured the population burden of injuries in the UK using a combination of disability and morbidity metrics, including years of life lost, and years lived with disabilities.
What Did the Researchers Do and Find?
The researchers recruited patients aged over 5 years with a wide range of injuries (including fractures and dislocations, lacerations, bruises and abrasions, sprains, burns and scalds, and head, eye, thorax, and abdominal injuries) from hospitals in four English cities—Swansea, Nottingham, Bristol, and Guildford—between September 2005 and April 2007. The researchers collected data on injury-related mortality, hospital admissions, and attendances to emergency rooms. They also invited patients (or their proxy, if participants were young children) to complete a self-administered questionnaire at recruitment and at 1, 4, and 12 months postinjury to allow data collection on injury characteristics, use of health and social services, time off work, and recovery from injury, in addition to sociodemographic and economic and occupational characteristics. The researchers also used standardized tools to measure health-related quality of life and work problems. Then, the researchers used these patient-reported changes to calculate DALYs for the UK and then extrapolated these results to calculate global estimates.
In the four study sites, a total of 1,517 injured people (median age of 37.4 years and 53.9% male) participated in the study. The researchers found that the vast majority of injuries were unintentional and that the home was the most frequent location of injury. Using the data and information collected from the questionnaires, the researchers extrapolated their results and found that in 2005, there were an estimated 750,999 injury-related hospital admissions, 7,982,947 emergency room attendances, and 22,185 injury-related deaths, translating to a rate per 100,000 of 1,240, 13,339, and 36.8, respectively. The researchers estimated UK DALYs related to injury to be 1,771,486 compared with 669,822 using the GBD approach. Furthermore, the researchers found that extrapolating patient-derived disability weights to GBD estimates would increase injury-related DALYs 2.6-fold.
What Do These Findings Mean?
The findings of this study suggest that, when using data and information derived from patient experiences, combined with additional morbidity data on patients treated in emergency rooms and those, admitted to hospital, the absolute burden of injury is higher than previously estimated. While this study was carried out in the UK the principal findings are relevant to other countries. However, measurement of the population burden of injuries requires access to high quality data, which may be difficult in less affluent countries, and these data rely on access to health facilities, which is often restricted in resource-limited settings. Despite these concerns, these findings have substantial implications for improving measurements of the national and global burden of injury.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001140.
The World Health Organization website provides detailed information about injuries and also details the work of the Global Burden of Disease Study
The Global Burden of Injury's website is a portal to websites run by groups conducting ongoing research into the measurement of global injury metrics
doi:10.1371/journal.pmed.1001140
PMCID: PMC3232198  PMID: 22162954
4.  A New Arthritis Therapy with Oxidative Burst Inducers 
PLoS Medicine  2006;3(9):e348.
Background
Despite recent successes with biological agents as therapy for autoimmune inflammatory diseases such as rheumatoid arthritis (RA), many patients fail to respond adequately to these treatments, making a continued search for new therapies extremely important. Recently, the prevailing hypothesis that reactive oxygen species (ROS) promote inflammation was challenged when polymorphisms in Ncf1, that decrease oxidative burst, were shown to increase disease severity in mouse and rat arthritis models. Based on these findings we developed a new therapy for arthritis using oxidative burst-inducing substances.
Methods and Findings
Treatment of rats with phytol (3,7,11,15-tetramethyl-2-hexadecene-1-ol) increased oxidative burst in vivo and thereby corrected the effect of the genetic polymorphism in arthritis-prone Ncf1DA rats. Importantly, phytol treatment also decreased the autoimmune response and ameliorated both the acute and chronic phases of arthritis. When compared to standard therapies for RA, anti-tumour necrosis factor-α and methotrexate, phytol showed equally good or better therapeutic properties. Finally, phytol mediated its effect within hours of administration and involved modulation of T cell activation, as injection prevented adoptive transfer of disease with arthritogenic T cells.
Conclusions
Treatment of arthritis with ROS-promoting substances such as phytol targets a newly discovered pathway leading to autoimmune inflammatory disease and introduces a novel class of therapeutics for treatment of RA and possibly other chronic inflammatory diseases.
Treatment of arthritis in rats with phytol, a reactive oxygen species promoting substance, suggests a novel pathway of autoimmune inflammatory disease and possibly a novel therapeutic strategy.
Editors' Summary
Background.
Rheumatoid arthritis (RA) is a chronic illness that affects between 0.3% and 1% of people worldwide, causing pain and swelling in joints, tendons, and other tissues, and frequently leading to permanent deformity and disability. RA involves an abnormal attack by cells of the immune system against the body's own connective tissues (so-called autoimmunity). Current drugs for RA work by counteracting the molecules that cause the pain and swelling (inflammation). By reducing the severity of autoimmune inflammation, these drugs may also reduce the disease's long-term damage to joints.
Inflammation is not always abnormal, but in fact plays an important part in the body's defense against infection. As part of their activity against disease-causing bacteria, the white blood cells known as granulocytes generate reactive oxygen species (ROS), sometimes known as “free radicals.” After engulfing invading bacteria, neutrophils release an “oxidative burst” of ROS—essentially the subcellular equivalent of pouring hydrogen peroxide on a wound to disinfect it. A complex of molecules known collectively as the NADPH oxidase complex has the specific function of generating ROS to fuel the oxidative burst. Interestingly, recent experiments in arthritis-prone rats found that animals with an altered form of one of the subunits of this complex, Ncf1, that decreased the production of ROS also had greater susceptibility to arthritis. This finding was surprising because free radicals have generally been associated with inflammation and long-term damage to cells, so that a reduction in ROS might have been expected to decrease susceptibility to an inflammatory disease like RA.
Why Was This Study Done?
Because many patients with autoimmune inflammatory illnesses like RA do not respond to currently available therapies, new approaches to treatment merit investigation. Based on the observed association between reduced ROS and increased susceptibility to arthritis, the researchers wanted to find out whether treatment with a compound that increases ROS production by the NADPH oxidase complex would cause an improvement in arthritis.
What Did the Researchers Do and Find?
The researchers tested a compound called phytol in arthritis-prone rats to see how it affected inflammation. It is known that arthritis can be induced in these rats by injecting them with an oil called pristane. The researchers found that phytol caused a strong oxidative burst in human granulocyte cells grown in the laboratory, but did not cause arthritis in rats; whereas pristane, which does cause arthritis, caused a lower oxidative burst in the granulocytes.
They then studied whether phytol prevented arthritis in rats. They found that rats injected with phytol were protected from arthritis following a later injection of pristane. Given this result, they wanted to know if phytol increased ROS in the rats as it did in laboratory cell cultures. Studying granulocytes taken from rats that had been treated with phytol, they found that the oxidative burst of these cells was indeed increased, and remained increased for several weeks after treatment. They went on to test phytol as a treatment for active arthritis, and found that it dramatically reduced swollen joints and destruction of cartilage when given to rats with acute pristane-induced arthritis.
The beneficial effects of phytol were seen not only in rats bred with a form of Ncf1 that produces abnormally low amounts of ROS, but also in rats whose granulocytes produce normal oxidative bursts. When compared (in rats) to drugs licensed for RA (etanercept and methotrexate), phytol appeared to be at least as effective. The activity of phytol against arthritis was shown to involve T lymphocytes, as injection of phytol inhibited transfer of pristane-induced arthritis with these cells.
What Do These Findings Mean?
These experiments raise the intriguing possibility of an entirely new modality for treating autoimmune diseases; namely, through drugs designed to increase the production of ROS. This study raises a number of practical and scientific issues. For example, it is not known whether reduced capacity to produce ROS is a significant factor in human RA. Also, the connection between ROS production (by granulocytes) and autoimmune arthritis (which involves activity by T lymphocytes) remains to be clarified. Finally, the destructive effects typically associated with free radicals (such as damage to DNA and blockage of blood vessels) could complicate the use of this approach in humans, and like any new drugs, those that increase ROS production might have other, unanticipated side effects. Whatever the outcome of drug development efforts, however, this study is an excellent reminder that there are no “good” or “evil” biochemicals—in the intricacies of cellular metabolism, it's all a matter of balance.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030348.
The Arthritis Foundation: Rheumatoid Arthritis pages
Medical Inflammation Research pages (R. Holmdahl research group)
Wikipedia chapter on Rheumatoid Arthritis (note: Wikipedia is a free Internet encyclopedia that anyone can edit)
Wikipedia chapter on Reactive Oxygen Species (note: Wikipedia is a free Internet encyclopedia that anyone can edit)
doi:10.1371/journal.pmed.0030348
PMCID: PMC1564167  PMID: 16968121
5.  Measuring the meaning of disability in rheumatoid arthritis: the Personal Impact Health Assessment Questionnaire (PI HAQ) 
Annals of the Rheumatic Diseases  2002;61(11):986-993.
Background: Measurement of disability in rheumatoid arthritis is often used to support treatment decisions and outcome assessments, but is used without reference to the impact of disability on individual patients.
Objective: To develop and validate a scale to measure individual values for functions, which is used to weight the level of an individual patient's functional loss and thus calculate the personal impact of disability.
Methods: In four linked studies, first the phraseology for values was explored to develop a stem question for the value scale couched in terms patients understand (face validity). Then short and long versions of the value scale were compared (content validity) and tests of internal consistency and short term reliability undertaken (criterion validity). Finally, the value scale was examined for long term reliability and agreement with expected variables (criterion and construct validity), after which personal impact scores were calculated and their construct validity examined.
Results: Patients understand the concept of values, and a positively phrased stem question was developed for the value scale, for which a short version was reasonably equivalent to a long version. The value scale was reliable over one week (96% changed by <1 point) with positive interitem correlation. Reasonable six and 12 month reliability was shown (52% changed by <0.5 points), and the value scale was independent of disability and clinical, psychological, personality, and social support variables. Personal impact scores were then calculated by using the value scores to weight disability scores. Impact scores varied widely between patients of similar disability. Personal impact for disability showed convergent validity with dissatisfaction with disability, perceived increase in disability, increased disease activity, worse psychological status, low social support, and time trade off for disability. It discriminated between patients with low and high dissatisfaction with disability, life satisfaction, depression, pain, and helplessness.
Conclusion: This individualised personal impact scale should lend meaning to disability scores, improving the interpretation of clinical and research data.
doi:10.1136/ard.61.11.986
PMCID: PMC1753935  PMID: 12379521
6.  Disability Transitions and Health Expectancies among Adults 45 Years and Older in Malawi: A Cohort-Based Model 
PLoS Medicine  2013;10(5):e1001435.
Collin Payne and colleagues investigated development of disabilities and years expected to live with disabilities in participants 45 years and older participating in the Malawi Longitudinal Survey of Families and Health.
Please see later in the article for the Editors' Summary
Background
Falling fertility and increasing life expectancy contribute to a growing elderly population in sub-Saharan Africa (SSA); by 2060, persons aged 45 y and older are projected to be 25% of SSA's population, up from 10% in 2010. Aging in SSA is associated with unique challenges because of poverty and inadequate social supports. However, despite its importance for understanding the consequences of population aging, the evidence about the prevalence of disabilities and functional limitations due to poor physical health among older adults in SSA continues to be very limited.
Methods and Findings
Participants came from 2006, 2008, and 2010 waves of the Malawi Longitudinal Survey of Families and Health, a study of the rural population in Malawi. We investigate how poor physical health results in functional limitations that limit the day-to-day activities of individuals in domains relevant to this subsistence-agriculture context. These disabilities were parameterized based on questions from the SF-12 questionnaire about limitations in daily living activities. We estimated age-specific patterns of functional limitations and the transitions over time between different disability states using a discrete-time hazard model. The estimated transition rates were then used to calculate the first (to our knowledge) microdata-based health expectancies calculated for SSA. The risks of experiencing functional limitations due to poor physical health are high in this population, and the onset of disabilities happens early in life. Our analyses show that 45-y-old women can expect to spend 58% (95% CI, 55%–64%) of their remaining 28 y of life (95% CI, 25.7–33.5) with functional limitations; 45-y-old men can expect to live 41% (95% CI, 35%–46%) of their remaining 25.4 y (95% CI, 23.3–28.8) with such limitations. Disabilities related to functional limitations are shown to have a substantial negative effect on individuals' labor activities, and are negatively related to subjective well-being.
Conclusions
Individuals in this population experience a lengthy struggle with disabling conditions in adulthood, with high probabilities of remitting and relapsing between states of functional limitation. Given the strong association of disabilities with work efforts and subjective well-being, this research suggests that current national health policies and international donor-funded health programs in SSA inadequately target the physical health of mature and older adults.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The population of the world is getting older. In almost every country, the over-60 age group is growing faster than any other age group. In 2000, globally, there were about 605 million people aged 60 years or more; by 2050, 2 billion people will be in this age group. Much of this increase in the elderly population will be in low-income countries. In sub-Saharan Africa, for example, 10% of the population is currently aged 45 years or more, but by 2060, a quarter of the population will be so-called mature adults. In all countries, population aging is the result of women having fewer children (falling fertility) and people living longer (increasing life expectancy). Thus, population aging is a demographic transition, a change in birth and death rates. In low- and middle-income countries, population aging is occurring in parallel with an “epidemiological transition,” a shift from communicable (infectious) diseases to non-communicable diseases (for example, heart disease) as the primary causes of illness and death.
Why Was This Study Done?
Both the demographic and the epidemiological transition have public health implications for low-income countries. Good health is important for the independence and economic productivity of older people. Productive older people can help younger populations financially and physically, and help compensate for the limitations experienced by younger populations infected with HIV. Also, low-income countries lack social safety nets, so disabled older adults can be a burden on younger populations. Thus, the health of older individuals is important to the well-being of people of all ages. As populations age, low-income countries will need to invest in health care for mature and elderly adults and in disease prevention programs to prevent or delay the onset of non-communicable diseases, which can limit normal daily activities by causing disabilities. Before providing these services, national policy makers need to know the proportion of their population with disabilities, the functional limitations caused by poor physical health, and the health expectancies (the number of years a person can expect to be in good health) of older people in their country. In this cohort modeling study, the researchers estimate health expectancies and transition rates between different levels of disability among mature adults in Malawi, one of the world's poorest countries, using data collected by the Malawi Longitudinal Survey of Families and Health (MLSFH) on economic, social, and health conditions in a rural population. Because Malawi has shorter life expectancies and earlier onset of disability than wealthier countries, the authors considered individuals aged 45 and older as mature adults at risk for disability.
What Did the Researchers Do and Find?
The researchers categorized the participants in the 2006, 2008, and 2010 waves of the MLSFH into three levels of functional limitation (healthy, moderately limited, and severely limited) based on answers to questions in the SF-12 health survey questionnaire that ask about disabilities that limit daily activities that rural Malawians perform. The researchers estimated age–gender patterns of functional limitations and transition rates between different disability states using a discrete-time hazard model, and health expectancies by running a microsimulation to model the aging of synthetic cohorts with various starting ages but the same gender and functional limitation distributions as the study population. These analyses show that the chance of becoming physically disabled rises sharply with age, with 45-year-old women in rural Malawi expected to spend 58% of their estimated remaining 28 years with functional limitations, and 45-year-old men expected to live 41% of their remaining 25.4 years with functional limitations. Also, on average, a 45-year-old woman will spend 2.7 years with moderate functional limitation and 0.6 years with severe functional limitation before she reaches 55; for men the corresponding values are 1.6 and 0.4 years. Around 50% of moderately and 60%–80% of severely limited individuals stated that pain interfered quite a bit or extremely with their normal work during the past four weeks, suggesting that pain treatment may help reduce disability.
What Do These Findings Mean?
These findings suggest that mature adults in rural Malawi will have some degree of disability during much of their remaining lifetime. The risks of experiencing functional limitations are higher and the onset of persistent disabilities happens earlier in Malawi than in more developed contexts—the proportions of remaining life spent with severe limitations at age 45 in Malawi are comparable to those of 80-year-olds in the US. The accuracy of these findings is likely to be affected by assumptions made during modeling and by the quality of the data fed into the models. Nevertheless, these findings suggest that functional limitations, which have a negative effect on the labor activity of individuals, will become more prominent in Malawi (and probably other sub-Saharan countries) as the age composition of populations shifts over the coming years. Older populations in sub-Saharan Africa are not targeted well by health policies and programs at present. Consequently, these findings suggest that policy makers will need to ensure that additional financial resources are provided to improve health-care provision for aging individuals and to lessen the high rates of functional limitation and associated disabilities.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001435.
This study is further discussed in a PLoS Medicine Perspective by Andreas Stuck, et al.
The World Health Organization provides information on many aspects of aging (in several languages); the WHO Study on Global Ageing and Adult Health (SAGE) is compiling longitudinal information on the health and well-being of adult populations and the aging process
The United Nations Population Fund and HelpAge International publication Ageing in the Twenty-First Century is available
HelpAge International is an international nongovernmental organization that helps older people claim their rights, challenge discrimination, and overcome poverty, so that they can lead dignified, secure, and healthy lives
More information on the Malawi Longitudinal Study of Families and Health is available
doi:10.1371/journal.pmed.1001435
PMCID: PMC3646719  PMID: 23667343
7.  Values for function in rheumatoid arthritis: patients, professionals, and public 
Annals of the Rheumatic Diseases  2001;60(10):928-933.
BACKGROUND—Although many disability questionnaires measure fact very efficiently, they do not allow for consideration of the relevance of that disability to the patient. Data suggest that professionals misinterpret the relevance of disability for the patient and thus, also, the outcome of treatment.
OBJECTIVES—Firstly, to examine agreement on levels of importance for the items on a validated disability scale (Health Assessment Questionnaire (HAQ) and Modified HAQ (MHAQ)), within groups of patients with rheumatoid arthritis, health professionals, and controls. Secondly, to see if functional items important to patients are included in the HAQ, and whether the HAQ items are important to patients.
METHODS—25 patients with RA, 25 rheumatology health professionals, and 25 healthy controls were asked to rate the importance of the HAQ (20 items) and MHAQ (eight domains). Before seeing the HAQ, patients were asked to generate items of function important to them.
RESULTS—Only a slight-fair agreement within each group was found for the level of importance of the HAQ and MHAQ, and also within any combination of the groups (κ values <0.38). Most of the functional items valued by patients were contained on the HAQ (70%), and no HAQ items were consistently rated as unimportant.
CONCLUSION—Patients, professionals, and healthy controls do not agree on the importance of disabilities. These data support the need to assess the personal impact of disability, as well as disability itself. Individual importance of disability weighted by level of disability is proposed as a model for calculating the personal impact of disability. A new tool to assess the personal impact of disability is being developed.


doi:10.1136/ard.60.10.928
PMCID: PMC1753375  PMID: 11557648
8.  Short term treatment versus long term management of neck and back disability in older adults utilizing spinal manipulative therapy and supervised exercise: a parallel-group randomized clinical trial evaluating relative effectiveness and harms 
Background
Back and neck disability are frequent in older adults resulting in loss of function and independence. Exercise therapy and manual therapy, like spinal manipulative therapy (SMT), have evidence of short and intermediate term effectiveness for spinal disability in the general population and growing evidence in older adults. For older populations experiencing chronic spinal conditions, long term management may be more appropriate to maintain improvement and minimize the impact of future exacerbations. Research is limited comparing short courses of treatment to long term management of spinal disability.
The primary aim is to compare the relative effectiveness of 12 weeks versus 36 weeks of SMT and supervised rehabilitative exercise (SRE) in older adults with back and neck disability.
Methods/Design
Randomized, mixed-methods, comparative effectiveness trial conducted at a university-affiliated research clinic in the Minneapolis/St. Paul, Minnesota metropolitan area.
Participants
Independently ambulatory community dwelling adults ≥ 65 years of age with back and neck disability of minimum 12 weeks duration (n = 200).
Interventions
12 weeks SMT + SRE or 36 weeks SMT + SRE.
Randomization
Blocked 1:1 allocation; computer generated scheme, concealed in sequentially numbered, opaque, sealed envelopes.
Blinding
Functional outcome examiners are blinded to treatment allocation; physical nature of the treatments prevents blinding of participants and providers to treatment assignment.
Primary endpoint
36 weeks post-randomization.
Data collection
Self-report questionnaires administered at 2 baseline visits and 4, 12, 24, 36, 52, and 78 weeks post-randomization. Primary outcomes include back and neck disability, measured by the Oswestry Disability Index and Neck Disability Index. Secondary outcomes include pain, general health status, improvement, self-efficacy, kinesiophobia, satisfaction, and medication use. Functional outcome assessment occurs at baseline and week 37 for hand grip strength, short physical performance battery, and accelerometry. Individual qualitative interviews are conducted when treatment ends. Data on expectations, falls, side effects, and adverse events are systematically collected.
Primary analysis
Linear mixed-model method for repeated measures to test for between-group differences with baseline values as covariates.
Discussion
Treatments that address the management of spinal disability in older adults may have far reaching implications for patient outcomes, clinical guidelines, and healthcare policy.
Trial registry
www.ClinicalTrials.gov; Identifier: NCT01057706.
doi:10.1186/s12998-014-0026-7
PMCID: PMC4255336  PMID: 25478141
Neck disability; Back disability; Spinal manipulative therapy; Exercise therapy; Older adults; Mixed-methods; Comparative effectiveness
9.  Work disability remains a major problem in rheumatoid arthritis in the 2000s: data from 32 countries in the QUEST-RA Study 
Introduction
Work disability is a major consequence of rheumatoid arthritis (RA), associated not only with traditional disease activity variables, but also more significantly with demographic, functional, occupational, and societal variables. Recent reports suggest that the use of biologic agents offers potential for reduced work disability rates, but the conclusions are based on surrogate disease activity measures derived from studies primarily from Western countries.
Methods
The Quantitative Standard Monitoring of Patients with RA (QUEST-RA) multinational database of 8,039 patients in 86 sites in 32 countries, 16 with high gross domestic product (GDP) (>24K US dollars (USD) per capita) and 16 low-GDP countries (<11K USD), was analyzed for work and disability status at onset and over the course of RA and clinical status of patients who continued working or had stopped working in high-GDP versus low-GDP countries according to all RA Core Data Set measures. Associations of work disability status with RA Core Data Set variables and indices were analyzed using descriptive statistics and regression analyses.
Results
At the time of first symptoms, 86% of men (range 57%-100% among countries) and 64% (19%-87%) of women <65 years were working. More than one third (37%) of these patients reported subsequent work disability because of RA. Among 1,756 patients whose symptoms had begun during the 2000s, the probabilities of continuing to work were 80% (95% confidence interval (CI) 78%-82%) at 2 years and 68% (95% CI 65%-71%) at 5 years, with similar patterns in high-GDP and low-GDP countries. Patients who continued working versus stopped working had significantly better clinical status for all clinical status measures and patient self-report scores, with similar patterns in high-GDP and low-GDP countries. However, patients who had stopped working in high-GDP countries had better clinical status than patients who continued working in low-GDP countries. The most significant identifier of work disability in all subgroups was Health Assessment Questionnaire (HAQ) functional disability score.
Conclusions
Work disability rates remain high among people with RA during this millennium. In low-GDP countries, people remain working with high levels of disability and disease activity. Cultural and economic differences between societies affect work disability as an outcome measure for RA.
doi:10.1186/ar2951
PMCID: PMC2888189  PMID: 20226018
10.  Self report functional disability scores and the use of devices: two distinct aspects of physical function in rheumatoid arthritis. 
Annals of the Rheumatic Diseases  1993;52(7):497-502.
OBJECTIVES--Self report scores of physical disability and the use of devices or assistance in performing activities are sometimes integrated in one index of physical function, although they are aimed at measuring different dimensions of physical disability. The properties of both parameters were evaluated in two groups of patients with rheumatoid arthritis (RA). METHODS--A group of patients with RA of recent onset was compared with a group with established disease on four parameters of disability: use of devices, use of personal assistance, and scores on a validated Dutch version of the Health Assessment Questionnaire Disability Index, with and without integrating the use of devices or assistance. Correlation coefficients among disability parameters were calculated. In multiple regression analysis the influence of disease duration on the disability parameters was determined after disease activity, psychological wellbeing, and demographical characteristics had been controlled. RESULTS--Functional disability scores were mainly related to inflammatory activity and psychological wellbeing, whereas the uses of devices had a strong relation with disease duration, independent of current disease activity. Integrating these parameters of disability yielded a parameter that was still mainly associated with disease activity. CONCLUSION--Self report scores of functional disability and the use of devices represent distinct dimensions of physical function in RA. Integrating both parameters into one measure of physical disability does not provide an index adequately reflecting both dimensions. The use of both parameters to measure outcome in long term clinical studies is recommended.
PMCID: PMC1005087  PMID: 8346977
11.  A pilot study of yoga as self-care for arthritis in minority communities 
Background
While arthritis is the most common cause of disability, non-Hispanic blacks and Hispanics experience worse arthritis impact despite having the same or lower prevalence of arthritis compared to non-Hispanic whites. People with arthritis who exercise regularly have less pain, more energy, and improved sleep, yet arthritis is one of the most common reasons for limiting physical activity. Mind-body interventions, such as yoga, that teach stress management along with physical activity may be well suited for investigation in both osteoarthritis and rheumatoid arthritis. Yoga users are predominantly white, female, and college educated. There are few studies that examine yoga in minority populations; none address arthritis. This paper presents a study protocol examining the feasibility and acceptability of providing yoga to an urban, minority population with arthritis.
Methods/design
In this ongoing pilot study, a convenience sample of 20 minority adults diagnosed with either osteoarthritis or rheumatoid arthritis undergo an 8-week program of yoga classes. It is believed that by attending yoga classes designed for patients with arthritis, with racially concordant instructors; acceptability of yoga as an adjunct to standard arthritis treatment and self-care will be enhanced. Self-care is defined as adopting behaviors that improve physical and mental well-being. This concept is quantified through collecting patient-reported outcome measures related to spiritual growth, health responsibility, interpersonal relations, and stress management. Additional measures collected during this study include: physical function, anxiety/depression, fatigue, sleep disturbance, social roles, and pain; as well as baseline demographic and clinical data. Field notes, quantitative and qualitative data regarding feasibility and acceptability are also collected. Acceptability is determined by response/retention rates, positive qualitative data, and continuing yoga practice after three months.
Discussion
There are a number of challenges in recruiting and retaining participants from a community clinic serving minority populations. Adopting behaviors that improve well-being and quality of life include those that integrate mental health (mind) and physical health (body). Few studies have examined offering integrative modalities to this population. This pilot was undertaken to quantify measures of feasibility and acceptability that will be useful when evaluating future plans for expanding the study of yoga in urban, minority populations with arthritis.
Trial registration
ClinicalTrials.gov: NCT01617421
doi:10.1186/1477-7525-11-55
PMCID: PMC3637098  PMID: 23548052
Yoga; Complementary and alternative medicine; Minority; Osteoarthritis; Rheumatoid arthritis; Self-efficacy
12.  Development of a functional scoring system for rheumatoid arthritis patients with cervical myelopathy. 
Annals of the Rheumatic Diseases  1996;55(12):901-906.
OBJECTIVE: To be able to measure disability objectively in rheumatoid arthritis complicated by cervical myelopathy. METHODS: The responses to the Stanford health assessment questionnaire disability index were recorded from 250 consecutive patients (group 1) referred to our unit for spinal surgery. Using principal components analysis the questionnaire was reduced from 20 questions to 10 questions. In the second part of the study, the results of the questionnaire for those patients undergoing surgery from the original group of 250 patients were analysed with respect to outcome. RESULTS: The reduction in the number of questions results in no significant loss of information, reliability (internal consistency Cronbach's alpha = 0.968) or sensitivity. The new scale, the myelopathy disability index, measures only one dimension (Eigen value 6.97) and may be more finely tuned to the measurement of disability in these myelopathic patients. When administered to the 194 patients undergoing cervical spine (group 2) surgery the myelopathy disability index was an accurate predictor of neurological and functional outcome, as well as survival following surgery (P < 0.0001). CONCLUSIONS: The myelopathy disability index provides a much needed objective and reliable means of assessing disability in patients with rheumatoid involvement of the cervical spine and also in predicting outcome following surgical intervention. It also provides information for both the patient and surgeon alike, on what to realistically expect from surgery. Its adoption should facilitate comparisons between different forms of surgical intervention.
PMCID: PMC1010342  PMID: 9014584
13.  Cohort Differences and Chronic Disease Profiles of Differential Disability Trajectories 
Objectives.
Research shows declining disability rates, but little is known about whether cohort differences are due to delayed onset, increased recovery, or reduced severity of impairment. Furthermore, disease is considered the proximate cause of disability yet chronic conditions rates are increasing, making it unclear whether the conditions predicting specific disability trajectories are changing.
Methods.
We use a latent class analysis of disability trajectories and corresponding mortality with three birth cohorts of the National Long-Term Care Survey to determine how long-term experiences of disablement differ by cohort and chronic conditions.
Results.
More recent cohorts were more likely to experience a decade free of disablement compared with all other disability trajectories. Sensory problems and hypertension correspond to trajectories of non-disablement, whereas hip fracture, stroke, arthritis, and diabetes predict more disabled experiences.
Discussion.
Later life disability is measured nonparametrically to distinguish patterns among long-term trajectories. Findings suggest that more recent cohorts are more likely to forego or delay disability over a decade rather than experience prolonged periods of mild to severe disablement. Serious health events such as stroke, along with diabetes, characterize trajectories of high impairment, warranting future research.
doi:10.1093/geronb/gbr104
PMCID: PMC3198246  PMID: 21968385
Chronic conditions; Cohort; Disability; Trajectories
14.  Expectations for Recovery Important in the Prognosis of Whiplash Injuries 
PLoS Medicine  2008;5(5):e105.
Background
Individuals' expectations on returning to work after an injury have been shown to predict the duration of time that a person with work-related low back pain will remain on benefits; individuals with lower recovery expectations received benefits for a longer time than those with higher expectations. The role of expectations in recovery from traumatic neck pain, in particular whiplash-associated disorders (WAD), has not been assessed to date to our knowledge. The aim of this study was to investigate if expectations for recovery are a prognostic factor after experiencing a WAD.
Methods and Findings
We used a prospective cohort study composed of insurance claimants in Sweden. The participants were car occupants who filed a neck injury claim (i.e., for WAD) to one of two insurance companies between 15 January 2004 and 12 January 2005 (n = 1,032). Postal questionnaires were completed shortly (average 23 d) after the collision and then again 6 mo later. Expectations for recovery were measured with a numerical rating scale (NRS) at baseline, where 0 corresponds to “unlikely to make a full recovery” and 10 to “very likely to make a full recovery.” The scale was reverse coded and trichotomised into NRS 0, 1–4, and 5–10. The main outcome measure was self-perceived disability at 6 mo postinjury, measured with the Pain Disability Index, and categorised into no/low, moderate, and high disability. Multivariable polytomous logistic regression was used for the analysis. There was a dose response relationship between recovery expectations and disability. After controlling for severity of physical and mental symptoms, individuals who stated that they were less likely to make a full recovery (NRS 5–10), were more likely to have a high disability compared to individuals who stated that they were very likely to make a full recovery (odds ratio [OR] 4.2 [95% confidence interval (CI) 2.1 to 8.5]. For the intermediate category (NRS 1–4), the OR was 2.1 (95% CI 1.2 to 3.2). Associations between expectations and disability were also found among individuals with moderate disability.
Conclusions
Individuals' expectations for recovery are important in prognosis, even after controlling for symptom severity. Interventions designed to increase patients' expectations may be beneficial and should be examined further in controlled studies.
Lena Holm and colleagues show that in people who had a whiplash injury after a car crash there was an association between expectation of disability and actual disability six months later.
Editors' Summary
Background
The disability associated with injury is a major source of distress for patients, and can be costly to the health care system and employers when persons fail to recover quickly and are unable to return to work. Finding ways to help people recover quickly and get back to optimal health is important. Some of the most common injuries causing disability and time off work result from whiplash—the sudden hyperextension or “whipping” of the neck, which can occur from a motor vehicle crash. It has long been recognized that psychological factors (such as the ability to cope, how “in control” one feels about one's life) are as important as physical symptoms in how disabling an injury can be. There is now growing evidence that a person's feelings about their ability to recover from injury plays a part in actual recovery. Studies from Europe and North America have shown with conditions like low back pain and minor head injury that a patient's feelings about the possibility of getting better are related to how well they do. Less is known about how important these psychological factors are in recovery from disorders due to whiplash associated disorders.
Why Was This Study Done?
The authors wanted to find out whether there was a relationship between people's expectations for their recovery from whiplash associated disorders and their actual recovery six months later. So, for example, they wondered if a person with whiplash who felt they were very unlikely to recover from their injury, actually did not recover (and vice versa).
What Did the Researchers Do and Find?
The authors had access to an unusual set of health information—insurance claims by people who had been involved in car collisions to two insurance companies in Sweden. They identified about 1,000 adult insurance claimants over one year and mailed them a questionnaire that asked for details about the collision as well as information about the claimant: their demographic profile, health history, and the types of pain and symptoms experienced since the crash. The questionnaire also asked the claimant how likely they thought they were to make a full recovery from their injuries.
For those who said they had whiplash associated disorders, the authors followed up with another questionnaire six months later, which asked for information about any disability, pain, or other symptoms that the claimant was still experiencing because of the injury. Of those who had completed the first questionnaire, 82% were followed up.
Only about a quarter of claimants with whiplash associated disorders said they expected to make a full recovery. Perhaps not surprisingly, those with only mild pain, compared to those with intense pain, were more likely to think so. Persons who said they were less likely to make a full recovery were four times more likely to report high levels of disability six months later. Even for persons (or individuals) people with moderate levels of disability six months after injury, their expectations for recovery were similarly linked to how well they did: the lower the expectations for recovery, the higher the disability. These findings were true even after taking into account how severe signs and symptoms the person had, and how well the person was coping psychologically.
What Do These Findings Mean?
The findings indicate that those with the lowest expectations for recovery after their whiplash injury will have the poorest recovery, and those with the highest expectations will have the best recovery. They also suggest that a patient's expectations about getting better are as important as his or her physical symptoms. The authors say that the more we can influence patients to believe they will make a full recovery, the better chance they will have to recover completely. This means that it may be beneficial for healthcare providers to give support and/or education to patients with whiplash associated disorders that increases their positive feelings toward recovery. The authors call for more studies into whether these types of targeted interventions would be of benefit.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050105.
Information about research on injuries and rehabilitation can be found at the Web sites of organisations devoted to studying the health of workers, such as the Institute for Work and Health in Canada, the Finnish Institute of Occupational Health, and the US National Institute for Occupational Safety and Health
The Wikipedia entry for medical aspects of whiplash describes the four grades of whiplash disorder, but does not cover the debate about the credibility of whiplash disorder (please note that Wikipedia is an online encyclopedia that anyone can edit)
The Sjukvardsradgivningen Web site provides information about whiplash-related disorders, common signs and symptoms, recovery and prognosis, and treatments (in Swedish)
doi:10.1371/journal.pmed.0050105
PMCID: PMC2375948  PMID: 18479182
15.  Multidisciplinary Prospective Study of Mother-to-Child Chikungunya Virus Infections on the Island of La Réunion 
PLoS Medicine  2008;5(3):e60.
Background
An outbreak of chikungunya virus affected over one-third of the population of La Réunion Island between March 2005 and December 2006. In June 2005, we identified the first case of mother-to-child chikungunya virus transmission at the Groupe Hospitalier Sud-Réunion level-3 maternity department. The goal of this prospective study was to characterize the epidemiological, clinical, biological, and radiological features and outcomes of all the cases of vertically transmitted chikungunya infections recorded at our institution during this outbreak.
Methods and Findings
Over 22 mo, 7,504 women delivered 7,629 viable neonates; 678 (9.0%) of these parturient women were infected (positive RT-PCR or IgM serology) during antepartum, and 61 (0.8%) in pre- or intrapartum. With the exception of three early fetal deaths, vertical transmission was exclusively observed in near-term deliveries (median duration of gestation: 38 wk, range 35–40 wk) in the context of intrapartum viremia (19 cases of vertical transmission out of 39 women with intrapartum viremia, prevalence rate 0.25%, vertical transmission rate 48.7%). Cesarean section had no protective effect on transmission. All infected neonates were asymptomatic at birth, and median onset of neonatal disease was 4 d (range 3–7 d). Pain, prostration, and fever were present in 100% of cases and thrombocytopenia in 89%. Severe illness was observed in ten cases (52.6%) and mainly consisted of encephalopathy (n = 9; 90%). These nine children had pathologic MRI findings (brain swelling, n = 9; cerebral hemorrhages, n = 2), and four evolved towards persistent disabilities.
Conclusions
Mother-to-child chikungunya virus transmission is frequent in the context of intrapartum maternal viremia, and often leads to severe neonatal infection. Chikungunya represents a substantial risk for neonates born to viremic parturients that should be taken into account by clinicians and public health authorities in the event of a chikungunya outbreak.
In a prospective study on the island of La Réunion, Marc Lecuit and colleagues find frequent transmission of Chikungunya virus by viremic mothers giving birth during an outbreak, resulting in serious infant illness.
Editors' Summary
Background.
Chikungunya virus, an emerging infectious agent that is transmitted by day-biting mosquitoes, was first isolated from a patient in Tanzania in the early 1950s. Since then, major outbreaks of chikungunya fever have occurred throughout sub-Saharan Africa and in Southeast Asia, India, and the Western Pacific, usually at intervals of about 7–8 years. The virus causes fever, rash, severe joint and muscle pains, and sometimes arthritis (joint inflammation). These symptoms develop within 3–7 days of being bitten by an infected mosquito. Most people recover fully within a few weeks, but joint pain can sometimes continue for years. There is no treatment for chikungunya fever, but the symptoms can be eased with anti-inflammatory drugs. Preventative measures include covering arms and legs and using insecticides to avoid insect bites and depriving the mosquitoes of their breeding sites by draining standing water from man-made containers near human dwellings.
Why Was This Study Done?
In 2005, chikungunya fever appeared for the first time on several islands in the Indian Ocean. On La Réunion Island, the disease affected 300,000 people—more than one-third of the population—between March 2005 and December 2006. In June 2005, clinicians identified the first case of mother-to-child chikungunya virus transmission (vertical transmission). Public-health officials and clinicians need to know more about how often vertical transmission occurs and its clinical implications to help them prepare for future chikungunya fever outbreaks. In this study, the researchers identify and characterize all the cases of vertical chikungunya virus transmission that occurred at the largest hospital on La Réunion Island during the 2005–6 outbreak.
What Did the Researchers Do and Find?
The researchers enrolled all 7,504 women who gave birth at the hospital during the outbreak and their 7,629 children into their study. They then used “RT-PCR” (which detects the genome of virus particles during an active infection) and “IgM serology” (which looks for an immune response to recent infection) to determine which women had been infected with chikungunya virus during their pregnancy. 678 of the new mothers had been infected sometime between conception and a week before delivery, 22 mothers had been infected between 7 and 3 days before delivery, and 39 had been infected 2 days either side of delivery (the “intrapartum” period). Except for three early fetal deaths that were associated with chikungunya virus infections, vertical transmission was seen only in babies born to mothers infected with the virus intrapartum. 19 of the babies born to these women were infected with the virus—a vertical transmission rate of nearly 50%. The women who transmitted the virus to their offspring had more virus in their placenta than those who did not transmit the infection. Delivery by emergency cesarean section did not prevent transmission. All the infected babies were born healthy but developed fever, weakness, and pain within 3–7 days. In many of them, the number of platelets (clot-forming particles) in their blood also dropped dramatically. Ten babies became seriously ill—nine of them developed brain swelling; two had bleeding into their brain. Four children had lasting disabilities at the end of the study.
What Do These Findings Mean?
These findings show that mother-to-child transmission of chikungunya virus occurs frequently when women are infected with the virus at the time of delivery and that newborn children infected by this route can become very ill. Although these results do not find that cesarean section reduces infection rates, 90% of cesarean sections involving infected infants were performed urgently, rather than planned. The study also provides no information about whether delaying delivery, provided that no fetal distress is observed, until the mother's viral load has decreased might be beneficial. More studies are needed to provide a complete description of both the short-term and long-term effects of chikungunya virus infection in newborn babies, but it is clear that clinicians should monitor babies exposed to chikungunya virus during delivery for a week after their birth. Most importantly, clinicians and public-health officials will need to take account of the threat that the chikungunya virus poses to newborn children whenever and wherever it emerges.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050060.
Read the related PLoS Medicine 10.1371/journal.pmed.0050068
The World Health Organization provides information about chikungunya fever and a brief description of the recent chikungunya outbreak in the Indian Ocean (in English, French, Spanish, Arabic, Chinese, and Russian)
The US Centers for Disease Control and Prevention has a fact sheet on chikungunya fever
The UK Health Protection Agency also provides information about chikungunya virus, including news on recent outbreaks
The French Institut de Veille Sanitaire (Institute for Public Health Surveillance) has a Web page on chikungunya (in French)
The Institut Pasteur has a Web page on chikungunya research (in French and English)
doi:10.1371/journal.pmed.0050060
PMCID: PMC2267812  PMID: 18351797
16.  Potential Role of Decoy B7-H4 in the Pathogenesis of Rheumatoid Arthritis: A Mouse Model Informed by Clinical Data 
PLoS Medicine  2009;6(10):e1000166.
Finding an association between soluble B7-H4 and rheumatoid arthritis severity, Lieping Chen and colleagues use a mouse model to show that the soluble form blocks the inhibitory function of cell-surface B7-H4.
Background
A pathogenic hallmark of rheumatoid arthritis (RA) is persistent inflammatory responses in target tissues and organs. Immune responses mediated by T cells and autoantibodies are known to play pivotal roles. A possible interpretation for this observation is a loss of negative regulation of autoimmune responses. Here we sought to investigate whether B7-H4, a cell surface inhibitory molecule of the B7-CD28 signaling pathway, may play a role in the pathogenesis of RA.
Methods and Findings
In a cross-sectional study of a clinical convenience sample using monoclonal antibodies against human B7-H4 molecules, we detected high levels of the soluble form of B7-H4 (sH4) in the sera of 65% of patients with RA (n = 68) versus only 13% of healthy donors (n = 24). Elevated sH4 was associated with an increased disease severity score (DAS28) in a cross-sectional analysis. In a mouse model of RA, transgenic expression of sH4 or genetic deletion of B7-H4 accelerated the progression of collagen-induced arthritis, accompanied by enhanced T and B cell–mediated autoimmune responses as well as increased activity of neutrophils. Expression in vivo of an agonist, a B7-H4-immunoglobulin Fc fusion protein, profoundly suppressed disease progression in the mouse model.
Conclusions
Our findings in mice indicate that sH4 acts as a decoy molecule to block the inhibitory functions of cell-surface B7-H4, leading to exacerbation of collagen-induced arthritis. If the preliminary correlation between sH4 levels and disease activity in patients with RA can be confirmed to reflect a similar mechanism, these findings suggest a novel target for treatment approaches.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Rheumatoid arthritis (RA) is a chronic disease caused by abnormal immune responses. In RA, the body's own immune system mainly attacks the joints, causing inflammation in their lining, but can affect other tissues and organs in the body. About 1% of the population in developed countries suffer from RA, and it can result in long-term joint damage, causing significant illness and disability. Sufferers have chronic pain, loss of function of the joint, and loss of mobility. The cause of RA is unknown and there is no known cure. However, neutrophils (an immune cell important for inflammation) are thought to contribute to the initiation of RA. Understanding the primary mechanisms behind the development of RA, and where the body's immune system goes wrong, is fundamental not only to find new treatments for the disease but also to aid diagnosis to help patients get treatment to help control their often debilitating symptoms.
Why Was the Study Done?
Regulation of the immune system is necessary to prevent overactivity. Interruptions to the normal signals that moderate the immune response can lead to destruction of normal tissues. Previous studies have shown that the B7 family of proteins, which interact with CD28 signaling proteins on the surface of immune cells, are important regulators of the immune response. B7 proteins have also been found to exist in soluble forms that have been implicated in the development of rheumatoid diseases, but their exact role is not well understood. In the current study, researchers examined a member of the B7 family, B7-H4, which normally acts as an inhibitor of the immune response, to find out whether this signaling molecule affects the immune response and has a role in the development of RA.
What Did the Researchers Do and Find?
The researchers collected blood from 68 patients with RA and 24 healthy volunteers, and measured levels of soluble B7-H4, also known as sH4. They found sH4 in blood from 65% of patients with RA, compared with only 13% of healthy people. The levels of sH4 were significantly higher in RA patients (96.1 ng/ml) compared to healthy people (<5 ng/ml). Moreover, the highest levels of sH4 were found in patients with the most severe forms of RA, as measured by a standard index score that includes general health, the number of swollen joints, and the amount of inflammation. The researchers then used a mouse model of RA to explore how sH4 might contribute to RA. First, they injected mice with plasmids (circular pieces of DNA that can be used to transfer genes into organisms) carrying the gene for sH4 and looked at how overexpression of sH4 affected the development of arthritis. They also looked at how deleting the B7-H4 gene in mice affected symptoms. Both overexpression of sH4 and deletion of B7-H4 caused inflammation in the mice; symptoms appeared earlier and were more severe. Furthermore, the effects of sH4 were shown to be dependent on neutrophils. Finally, the researchers successfully prevented the development of disease in mice by using a protein to mimic the normal signaling by B7-H4, which inhibits the immune response.
What Do these Findings Mean?
These findings suggest that the signaling molecule B7-H4 may be involved in the development of RA. B7-H4 normally acts as an inhibitor of the immune response to suppress inflammation, but when its action is blocked the immune response is no longer suppressed, and an inappropriate and increased immune reaction occurs. sH4 is thought to act as a decoy that blocks binding of B7-H4 to its receptor, thereby preventing an inhibitory signal to the immune system. Overexpression of sH4 worsens the symptoms in the mouse model of RA. Intriguingly, high levels of sH4 were also present in RA patients and were associated with increased severity of disease. This study does not establish sH4 as a cause of RA but implicates sH4 as a cause in the progression of increased inflammation in this disease. Immune system signaling molecules have potential as novel targets for treatment of RA and other autoimmune disorders. However, further studies are needed to test whether sH4 has a direct role in the development of RA in humans.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000166.
MedlinePlus has a topic page on RA providing extensive information on symptoms and treatment for RA and access to related clinical trials and medical literature
The National Rheumatoid Arthritis Society (UK) is a patient-led charity to provide information, education, and support for people with RA
The Arthritis Foundation (US) is a national not-for-profit organization that supports public health education and research funding, and provides informational resources for people with arthritis http://www.arthritis.org/
doi:10.1371/journal.pmed.1000166
PMCID: PMC2760136  PMID: 19841745
17.  Factors predicting the outcome of customised foot orthoses in patients with rheumatoid arthritis: a prospective cohort study 
Background
Conservative management of foot problems in patients with rheumatoid arthritis (RA) may consist of the prescription of customised foot orthoses. Indications for foot orthoses are not clear and the effectiveness of the intervention is highly variable among patients. Knowledge on which patients benefit the most from foot orthoses can help to select patients eligible for this type of intervention. The objective of the present study was to determine clinical and demographic factors that predict the outcome of customised foot orthoses on pain and disability in patients with RA.
Methods
A total of 135 RA patients who were supplied with customised foot orthoses were included in this prospective cohort study. Pain and disability were measured before and after the intervention period using a Numeric Rating Scale (NRS) for foot pain, the Foot Function Index (FFI), the Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) and a 10-meter walking test. The intervention period consisted of one or more appointments with the podiatrist during which the foot orthoses were customised.
Swollen foot joint count, foot deformity scores, forefoot peak pressure, disease duration, age, gender, body mass index and baseline values of the outcome measures were selected as potential factors predicting outcome. Multivariate linear regression analyses were performed to determine factors associated with change in pain and disability (at P < 0.05).
Results
Disease duration was negatively associated with the change scores in NRS foot pain (P = 0.018), WOMAC pain (P = 0.001), FFI disability (P = 0.003) and WOMAC physical function (P = 0.002). Age was negatively associated with the change score in 10 meter walking time (P = 0.008). For all outcome measures baseline values were positively associated with the change scores (P < 0.001).
Conclusions
Shorter disease duration predicted greater improvements in self-reported foot pain and disability, and younger age predicted greater improvements in walking time after intervention with foot orthoses. Also, higher baseline values of pain and disability predicted greater improvements. Referral for conservative management with foot orthoses in the early stage of RA seems important when aiming to achieve reduction in pain and improvement in daily activities.
doi:10.1186/1757-1146-4-8
PMCID: PMC3050804  PMID: 21310034
18.  CHANGE IN DISABILITY AFTER HOSPITALIZATION OR RESTRICTED ACTIVITY IN OLDER PERSONS 
Context
Disability among older persons is a complex and highly dynamic process, with high rates of recovery and frequent transitions between states of disability. The role of intervening illnesses and injuries (i.e. events) on these transitions is uncertain.
Objectives
To evaluate the relationship between intervening events and transitions among states of no disability, mild disability, severe disability and death, and to determine the association of physical frailty with these transitions.
Design, Setting, and Participants
Prospective cohort study, conducted in greater New Haven, Connecticut, from March 1998 to December 2008, of 754 community-living persons, aged 70 years or older, who were nondisabled at baseline in four essential activities of daily living: bathing, dressing, walking, and transferring. Telephone interviews were completed monthly for more than 10 years to assess disability and ascertain exposure to intervening events, which included illnesses and injuries leading to either hospitalization or restricted activity. Physical frailty (defined as gait speed >10 seconds on the rapid gait test) was assessed every 18 months through 108 months.
Main Outcome Measure
Transitions between no disability, mild disability, and severe disability, and 3 transitions from each of these states to death, were evaluated each month.
Results
Hospitalization was strongly associated with 8 of the 9 possible transitions, with increased multivariable hazard ratios (HR) as high as 168 (95% confidence interval [CI], 118–239) for the transition from no disability to severe disability and decreased HRs as low as 0.41 (95% CI, 0.30–0.54) for the transition from mild disability to no disability. Restricted activity also increased the likelihood of transitioning from no disability to both mild and severe disability (HR [CI]: 2.59 [2.23–3.02] and 8.03 [5.28–12.21]), respectively, and from mild disability to severe disability (1.45 [1.14–1.84]), but was not associated with recovery from mild or severe disability. For all nine of the transitions, the presence of physical frailty accentuated the associations of the intervening events. For example, the absolute risk of transitioning from no disability to mild disability within one month after hospitalization for frail individuals was 12.4% (95% CI, 12.1%–12.7%) vs 4.9% (4.7%–5.1%) for non-frail individuals. Among the possible reasons for hospitalization, fall-related injury conferred the highest likelihood of developing new or worsening disability.
Conclusions
Among older persons, particularly those who were physically frail, intervening illnesses and injuries greatly increased the likelihood of developing new or worsening disability. Only the most potent events, i.e. those leading to hospitalization, reduced the likelihood of recovery from disability.
doi:10.1001/jama.2010.1568
PMCID: PMC3124926  PMID: 21045098
19.  Disability and schizophrenia: a systematic review of experienced psychosocial difficulties 
BMC Psychiatry  2012;12:193.
Background
Schizophrenia is a significantly disabling disease that affects all major areas of life. There is a lack of comprehensive synthesis of research findings on the full extent of psychosocial difficulties (PSDs) experienced by people living with schizophrenia. This paper provides a systematic review of the literature concerning PSDs and their associated factors in schizophrenia. PSDs were conceptualized in accordance with the International Classification of Functioning, Disability and Health (ICF) as disabilities, in particular impairments of mental functions, activity limitations and participation restrictions.
Methods
An electronic search using MEDLINE and PsychINFO plus a manual search of the literature was performed for qualitative and longitudinal studies published in English between 2005 and 2010 that examined PSDs in persons with schizophrenia. The ICF was used as a conceptual framework.
Results
A total of 104 papers were included. The most frequent PSDs addressed in the literature were not specific ones, directly linkable to the ICF categories of mental functions, activity limitations or participation restrictions, but broad areas of psychosocial functioning, such as psychopathological symptoms (53% of papers) or global disability and functioning (37%). Among mental functions, the most extensively studied were cognitive functions (27%) and emotional functions (27%). Within the domain of activities and participation, the most widely investigated were difficulties in relationships with others (31%) and employment (20%). Of the factors associated with the intensity or course of PSDs, the most commonly identified were treatment modalities (56%), psychopathological symptoms (26%), and socio-demographic variables (24%). Medication tended to improve the most relevant PSD, but at the same time was the only consistently reported determinant of onset of PSDs (emerging as unwanted side-effects).
Conclusions
The present review illustrates the remarkably broad scope and diversity of psychosocial areas affected in schizophrenia and shows how these areas are interconnected and how they interact with contextual factors. The need for a shift in focus of schizophrenia research is suggested – from an excessive reliance on global measures of psychopathology and disability for defining outcomes to the creation of profiles of specific PSDs that have a more direct bearing on the disabling experience and real-world functioning of patients and can serve to guide interventions and monitoring over time.
doi:10.1186/1471-244X-12-193
PMCID: PMC3539983  PMID: 23137171
Schizophrenia; Psychosocial difficulties; Disability; Functioning; ICF
20.  Rheumatoid arthritis 
Clinical Evidence  2007;2007:1124.
Introduction
Rheumatoid arthritis usually starts as a symmetrical polyarthritis, and its course is marked by flares and remissions. The aims of treatment are to relieve pain and swelling, and to improve function. In addition, disease-modifying antirheumatic drugs (DMARDs) may reduce disease progression.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments in people with rheumatoid arthritis who have not previously received any disease-modifying antirheumatic drug treatment? How do different drug treatments compare in people with rheumatoid arthritis who have either not responded to or are intolerant of first-line disease-modifying antirheumatic drugs? We searched: Medline, Embase, The Cochrane Library and other important databases up to June 2005 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 62 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adalimumab, anakinra, antimalarial drugs, azathioprine, ciclosporin, corticosteroids, cyclophosphamide, etanercept, infliximab plus methotrexate, leflunomide, methotrexate (alone; or plus sulfasalazine plus hydroxychloroquine), oral gold, parenteral gold, penicillamine, sulfasalazine.
Key Points
Rheumatoid arthritis is a chronic inflammatory disorder that mainly affects the peripheral joints and surrounding tissue. It usually starts as a symmetrical polyarthritis, and its course is marked by flares and remissions.The aims of treatment are to relieve pain and swelling, and to improve function. In addition, disease-modifying antirheumatic drugs (DMARDs) may reduce disease progression.
The DMARD methotrexate is widely used as first-line treatment in people with rheumatoid arthritis because of consensus about its effectiveness in practice. Sulfasalazine and combined treatment with methotrexate and sulfasalazine are as effective as methotrexate in improving pain, joint swelling, and function in people with early rheumatoid arthritis who have not previously received DMARDs. Antimalarials may improve symptoms and function in DMARD-naïve people, and are reasonably well tolerated, but radiological evidence of erosion is more marked with antimalarials than with sulfasalazine.
There is a variety of DMARDs available for second-line treatment of rheumatoid arthritis, and we found no clear evidence that one is superior. Methotrexate, sulfasalazine, penicillamine , and leflunomide cause similar improvements in symptoms and function when given to people as second-line DMARD treatment, although methotrexate causes fewer adverse effects.The combination of methotrexate plus sulfasalazine plus hydroxychloroquine is more effective in reducing measures of disease activity in people receiving second-line treatment than any of the drugs used alone. Adding the cytokine inhibitors infliximab or etanercept to methotrexate is more effective than using methotrexate alone.Although antimalarials and oral gold seem to improve clinical disease activity when given as second-line treatment, they are not as effective as methotrexate or sulfasalazine. Although parenteral gold is more effective than oral gold, it leads to higher levels of toxicity than most of the other commonly used DMARDs. Ciclosporin offers short-term control of rheumatoid arthritis when used as second-line treatment, but is associated with nephrotoxicity.We don′t know whether cyclophosphamide is as effective as other DMARDs for second-line treatment.Cytokine inhibitors may offer an alternative to traditional DMARDs for second line treatment of rheumatoid arthritis, but more research is needed. Etanercept may be as effective as methotrexate in improving symptoms, function, and radiological evidence of progression, but more evidence for its effect is needed Azathioprine is less effective and is less well tolerated than methotrexate.We don't know whether anakinra or adalimumab are as effective as other DMARDs for second-line treatment.Although widely used for the initial short-term relief of clinical disease activity in rheumatoid arthritis, we don't know how corticosteroids compare with other drugs for first or second-line treatment.
PMCID: PMC2943775  PMID: 19454108
21.  The mental health of UK Gulf war veterans: phase 2 of a two phase cohort study 
BMJ : British Medical Journal  2002;325(7364):576.
Objectives
To examine the prevalence of psychiatric disorders in veterans of the Gulf war with or without unexplained physical disability (a proxy measure of ill health) and in similarly disabled veterans who had not been deployed to the Gulf war (non-Gulf veterans).
Design
Two phase cohort study.
Setting
Current and ex-service UK military personnel.
Participants
Phase 1 consisted of three randomly selected samples of Gulf veterans, veterans of the 1992-7 Bosnia peacekeeping mission, and UK military personnel not deployed to the Gulf war (Era veterans) who had completed a postal health questionnaire. Phase 2 consisted of randomly selected subsamples from phase 1 of Gulf veterans who reported physical disability (n=111) or who did not report disability (n=98) and of Bosnia (n=54) and Era (n=79) veterans who reported physical disability.
Main outcome measure
Psychiatric disorders assessed by the schedule for clinical assessment in neuropsychiatry and classified by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition.
Results
Only 24% (n=27) of the disabled Gulf veterans had a formal psychiatric disorder (depression, anxiety, or alcohol related disorder). The prevalence of psychiatric disorders in non-disabled Gulf veterans was 12%. Disability and psychiatric disorders were weakly associated in the Gulf group when confounding was adjusted for (adjusted odds ratio 2.4, 99% confidence interval 0.8 to 7.2, P=0.04). The prevalence of psychiatric disorders was similar in disabled non-Gulf veterans and disabled Gulf veterans ( 19% v 24%; 1.3, 0.5 to 3.4). All groups had rates for post-traumatic stress disorder of between 1% and 3%.
Conclusions
Most disabled Gulf veterans do not have a formal psychiatric disorder. Post-traumatic stress disorder is not higher in Gulf veterans than in other veterans. Psychiatric disorders do not fully explain self reported ill health in Gulf veterans; alternative explanations for persistent ill health in Gulf veterans are needed.
What is already known on this topicGulf veterans report medically unexplained symptoms more often than non-Gulf veteransThe clinical characteristics of ill health in Gulf veterans are not well known, and factors associated with ill health in Gulf veterans are poorly understoodWhat this study addsMost ill Gulf veterans do not have a formal psychiatric disorderThe rates for post-traumatic stress disorder are lowPsychiatric morbidity is not strongly associated with ill health in Gulf veteransThe rates for somatoform disorders are three times greater in disabled Gulf veterans than they are in disabled non-Gulf veterans
PMCID: PMC124552  PMID: 12228134
22.  Assessing function in patients undergoing joint replacement: a study protocol for a cohort study 
Background
Joint replacement is an effective intervention for people with advanced arthritis, although there is an important minority of patients who do not improve post-operatively. There is a need for robust evidence on outcomes after surgery, but there are a number of measures that assess function after joint replacement, many of which lack any clear theoretical basis. The World Health Organisation has introduced the International Classification of Functioning, Disability and Health (ICF), which divides function into three separate domains: Impairment, activity limitations and participation restrictions. The aim of this study is to compare the properties and responsiveness of a selection of commonly used outcome tools that assess function, examine how well they relate to the ICF concepts, and to explore the changes in the measures over time.
Methods/design
Two hundred and sixty three patients listed for lower limb joint replacement at an elective orthopaedic centre have been recruited into this study. Participants attend the hospital for a research appointment prior to surgery and then at 3-months and 1-year after surgery. At each assessment time, function is assessed using a range of measures. Self-report function is assessed using the WOMAC, Aberdeen Impairment, Activity Limitation and Participation Restriction Measure, SF-12 and Measure Yourself Medical Outcome Profile 2. Clinician-administered measures of function include the American Knee Society Score for knee patients and the Harris Hip Score for hip patients. Performance tests include the timed 20-metre walk, timed get up and go, sit-to-stand-to-sit, step tests and single stance balance test. During the performance tests, participants wear an inertial sensor and data from motion analysis are collected. Statistical analysis will include exploring the relationship between measures describing the same ICF concepts, assessing responsiveness, and studying changes in measures over time.
Discussion
There are a range of tools that can be used to assess function before and after joint replacement, with little information about how these various measures compare in their properties and responsiveness. This study aims to provide this data on a selection of commonly used assessments of function, and explore how they relate to the ICF domains.
doi:10.1186/1471-2474-13-220
PMCID: PMC3520823  PMID: 23148591
Joint replacement; Hip; Knee; Disability; Pain; Function; Outcome; Self-report; Performance tests; Motion analysis
23.  Antenatal Syphilis Screening Using Point-of-Care Testing in Sub-Saharan African Countries: A Cost-Effectiveness Analysis 
PLoS Medicine  2013;10(11):e1001545.
Yukari Manabe and colleagues evaluate the cost-effectiveness and budget impact of antenatal syphilis screening for 43 countries in sub-Saharan Africa and estimate the impact of universal screening on averted stillbirths, neonatal deaths, congenital syphilis, and DALYs.
Please see later in the article for the Editors' Summary
Background
Untreated syphilis in pregnancy is associated with adverse clinical outcomes for the infant. Most syphilis infections occur in sub-Saharan Africa (SSA), where coverage of antenatal screening for syphilis is inadequate. Recently introduced point-of-care syphilis tests have high accuracy and demonstrate potential to increase coverage of antenatal screening. However, country-specific cost-effectiveness data for these tests are limited. The objective of this analysis was to evaluate the cost-effectiveness and budget impact of antenatal syphilis screening for 43 countries in SSA and estimate the impact of universal screening on stillbirths, neonatal deaths, congenital syphilis, and disability-adjusted life years (DALYs) averted.
Methods and Findings
The decision analytic model reflected the perspective of the national health care system and was based on the sensitivity (86%) and specificity (99%) reported for the immunochromatographic strip (ICS) test. Clinical outcomes of infants born to syphilis-infected mothers on the end points of stillbirth, neonatal death, and congenital syphilis were obtained from published sources. Treatment was assumed to consist of three injections of benzathine penicillin. Country-specific inputs included the antenatal prevalence of syphilis, annual number of live births, proportion of women with at least one antenatal care visit, per capita gross national income, and estimated hourly nurse wages. In all 43 sub-Saharan African countries analyzed, syphilis screening is highly cost-effective, with an average cost/DALY averted of US$11 (range: US$2–US$48). Screening remains highly cost-effective even if the average prevalence falls from the current rate of 3.1% (range: 0.6%–14.0%) to 0.038% (range: 0.002%–0.113%). Universal antenatal screening of pregnant women in clinics may reduce the annual number of stillbirths by up to 64,000, neonatal deaths by up to 25,000, and annual incidence of congenital syphilis by up to 32,000, and avert up to 2.6 million DALYs at an estimated annual direct medical cost of US$20.8 million.
Conclusions
Use of ICS tests for antenatal syphilis screening is highly cost-effective in SSA. Substantial reduction in DALYs can be achieved at a relatively modest budget impact. In SSA, antenatal programs should expand access to syphilis screening using the ICS test.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Syphilis is a sexually transmitted infection caused by a bacterium called Treponema pallidum. In many countries, the screening and treatment program for syphilis in pregnancy is inadequate, leading to babies being affected. It is estimated that between 2.5% and 17% of pregnant women in sub-Saharan Africa are infected with syphilis; recent estimates suggest that more than 535,000 pregnancies occur in women with active syphilis each year. Maternal syphilis in pregnancy has been estimated to cause approximately half a million adverse outcomes in babies, including stillbirths, neonatal deaths, preterm or low-birth-weight babies, and congenital infections. If a pregnant woman is tested, and given penicillin if positive, then many of these harmful outcomes can be avoided. The best time to screen and treat is in the first half of pregnancy.
Until recently, tests for syphilis were done in a laboratory as an enzyme immunoassay, requiring technical staff. Recently, rapid tests for syphilis became available for use at the point of care. There are considerable advantages to this approach: the tests can be undertaken using a finger prick to obtain a small amount of blood, and require minimal staff training and no specialist laboratory equipment. A result can be given within minutes, avoiding the need for a return visit in settings where antenatal care is infrequent.
Why Was This Study Done?
Although the advantages to the mother and baby of testing seem clear, the cost-effectiveness of a screening and treatment program using rapid point-of-care tests has not previously been assessed for most sub-Saharan African countries. The program has the greatest potential value in settings where syphilis is common. In local guidelines, testing is often recommended, but uncertainty over the costs and technical requirements has meant that antenatal syphilis screening has not been comprehensively introduced. The aim of this study was to assess whether antenatal syphilis screening was cost-effective for 43 countries in sub-Saharan Africa by estimating the extent of infant mortality and disability that could be prevented if maternal syphilis was diagnosed and treated.
What Did the Researchers Do and Find?
The researchers created a model that allowed them to determine the cost-effectiveness of antenatal syphilis screening and treatment. They included many factors including the performance of the test, how common syphilis is in each country, the number of births, the likelihood of harmful outcomes, the effectiveness of penicillin therapy, the cost of an antenatal visit, and the cost of the test and the penicillin treatment, if positive. Then they calculated how many deaths and how much disability could be prevented by screening and treatment. The results were expressed in disability-adjusted life years (DALYs), which give the number of years affected by ill health, disability, or early death. The study found that screening was highly cost-effective, with each DALY prevented on average costing only US$11.
What Do These Findings Mean?
Across sub-Saharan Africa, only about 40% of women are screened for syphilis during one of their antenatal care visits. These findings suggest that it would be an efficient use of health care resources to scale up antenatal screening programs for syphilis using the rapid point-of-care test. Comparing these results to those for other health care interventions in resource-limited settings suggests that screening pregnant women for syphilis in sub-Saharan Africa could achieve a substantial improvement in public health at relatively little cost. The researchers propose that combining HIV and syphilis tests into one antenatal screening package could be an efficient way of introducing a care package into settings where uptake is currently limited.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001545.
The World Health Organization provides information on syphilis in pregnant women
The London School of Hygiene & Tropical Medicine has information on efforts to reduce congenital syphilis and a rapid syphilis test toolkit
The US Centers for Disease Control and Prevention's STD Curriculum includes materials on syphilis
doi:10.1371/journal.pmed.1001545
PMCID: PMC3818163  PMID: 24223524
24.  THE COURSE OF DISABILITY BEFORE AND AFTER A SERIOUS FALL INJURY 
JAMA internal medicine  2013;173(19):10.1001/jamainternmed.2013.9063.
Importance
Although a serious fall injury is often a devastating event, little is known about the course of disability (i.e. functional trajectories) prior to a serious fall injury or the relationship between these trajectories and those that follow the fall.
Objectives
To identify distinct sets of functional trajectories in the year immediately before and after a serious fall injury, to evaluate the relationship between the pre-fall and post-fall trajectories, and to determine whether these results differed based on the type of injury.
Design, Setting, and Participants
Prospective cohort study conducted in greater New Haven, Connecticut, from March 1998 to June 2012 of 754 community-living persons aged 70 or older who were initially nondisabled in their basic activities of daily living. Of the 130 participants who subsequently sustained a serious fall injury, 62 had a hip fracture and 68 had another fall-related injury leading to hospitalization.
Main Outcome Measures
Functional trajectories, based on 13 basic, instrumental and mobility activities that were assessed during monthly interviews, were identified in the year before and after the serious fall injury, respectively.
Results
Before the fall, five distinct trajectories were identified: no disability (n=16, 12.3%), mild disability (n=34, 26.2%), moderate disability (n=34, 26.2%), progressive disability (n=23, 17.7%), and severe disability (n=23, 17.7%). After the fall, four distinct trajectories were identified: rapid recovery (n=12, 9.2%), gradual recovery (n=35, 26.9%), little recovery (n=26, 20.0%), and no recovery (n=57, 43.8%). For both hip fractures and other serious fall injuries, the probabilities of the post-fall trajectories were greatly influenced by the pre-fall trajectories, such that rapid recovery was observed only among persons who had no disability or mild disability, and a substantive recovery, defined as rapid or gradual, was highly unlikely among those who had progressive or severe disability. The post-fall trajectories were consistently worse for hip fractures than for the other serious injuries.
Conclusions and Relevance
The functional trajectories before and after a serious fall injury are quite varied, but highly interconnected, suggesting that the likelihood of recovery is greatly constrained by the pre-fall trajectory.
doi:10.1001/jamainternmed.2013.9063
PMCID: PMC3812391  PMID: 23958741
25.  More relevant, precise, and efficient items for assessment of physical function and disability: moving beyond the classic instruments 
Annals of the Rheumatic Diseases  2006;65(Suppl 3):iii16-iii21.
Objectives
Patient reported outcomes (PROs) have become standard study endpoints. However, little attention has been given to using item improvement to advance PRO performance which could improve precision, clarity, patient relevance, and information content of “physical function/disability” items and thus the performance of resulting instruments.
Methods
The present study included1860 physical function/disability items from 165 instruments. Item formulations were assessed by frequency of use, modified Delphi consensus, respondent judgement of clarity and importance, and item response theory (IRT). Data from 1100 rheumatoid arthritis, osteoarthritis, and normal ageing subjects, using qualitative item review, focus groups, cognitive interviews, and patient survey were used to achieve a unique item pool that was clear, reliable, sensitive to change, readily translatable, devoid of floor and ceiling limitations, contained unidimensional subdomains, and had maximal information content.
Results
A “present tense” time frame was used most frequently, better understood, more readily translated, and more directly estimated the latent trait of disability. Items in the “past tense” had 80–90% false negatives (p<0.001). The best items were brief, clear, and contained a single construct. Responses with four to five options were preferred by both experts and respondents. The term physical function may be preferable to the term disability because of fewer floor effects. IRT analyses of “disability” suggest four independent subdomains (mobility, dexterity, axial, and compound) with factor loadings of 0.81–0.99.
Conclusions
Major improvement in performance of items and instruments is possible, and may have the effect of substantially reducing sample size requirements for clinical trials.
doi:10.1136/ard.2006.059279
PMCID: PMC1798376  PMID: 17038464
disability; physical function; item response theory (IRT); sample sizes; item improvement

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