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1.  Volume 4 issue 1 — Editor’s commentary 
AAPS PharmSciTech  2003;4(1):42.
PMCID: PMC2750302
6.  Commentary: From the Editor's desk 
PMCID: PMC2562808  PMID: 18924658
7.  Commentary: From the Editor's desk 
PMCID: PMC2547291  PMID: 18927762
8.  Commentary: From the Editor's desk 
PMCID: PMC2547232  PMID: 18927713
9.  Commentary by the Editor (see p133) 
Heart  2001;85(2):132.
PMCID: PMC1729605  PMID: 11156659
10.  Commentary: Trailblazing a Research Agenda at the Interface of Pediatrics and Genomic Discovery—a Commentary on the Psychological Aspects of Genomics and Child Health 
Journal of Pediatric Psychology  2009;34(6):662-664.
Unprecedented advances in human genome science are underway with potential to benefit public health. For example, it is estimated that within a decade, geneticists and epidemiologists will complete a catalog of the majority of genes associated with common chronic diseases. Such rapid advances create possibilities, if not the mandate, for translational research in how best to apply these and other anticipated discoveries for both individual and population health benefit. Driving these discoveries are rapid advances in infrastructure (e.g., the International HapMap Project to catalog human genetic variation;, analytical methods, and technology. This expansion in capabilities quickly has taken us from a genetics paradigm—where the influence of individual genes on health outcomes is paramount, to a genomics paradigm—where the complex influence of individual genes is considered in concert with each other and with environmental exposures on health outcomes. We discuss these and similar groundbreaking discoveries with an eye toward understanding their importance to child health and human development, and the role of behavioral science research conducted at the interface of pediatrics and genomic discovery.
PMCID: PMC2722104  PMID: 19129267
11.  Marcus treatment of endergonic reactions: a commentary 
Biochimica et biophysica acta  2007;1767(10):1228-1232.
Two forms of the equation for expression of the rate constant for electron transfer through a Marcus-type treatment are discussed. In the first (exergonic) form, the Arrhenius exponential term was replaced by its classical Marcus term; in the second (endergonic) form, the forward rate constant was replaced by the reverse rate constant (the forward rate constant in the exergonic direction), which was expanded to an equivalent Marcus term and multiplied by the equilibrium constant. When the classical Marcus treatment was used, these two forms of the rate equation give identical curves relating the logarithm of the rate constant to the driving force. The Marcus term for the relation between activation free-energy, ΔG#, reorganization energy, λ, and driving force, ΔGo, derived from parabolas for the reactant and product states, was identical when starting from exergonic or endergonic parabolas. Moser and colleagues introduced a quantum mechanical correction factor to the Marcus term in order to fit experimental data. When the same correction factor was applied in the treatment for the endergonic direction by Page and colleagues, a different curve was obtained from that found than with the exergonic form. We show that the difference resulted from an algebraic error in development of the endergonic equation.
PMCID: PMC2238675  PMID: 17720135
Marcus theory; Moser-Dutton treatment; endergonic reaction; rate constant
12.  Theoretical accounts of spatial learning – a neurobiological view (commentary on Pearce 2009) 
Theories of learning have historically taken, as their starting point, the assumption that learning processes have universal applicability. This position has been argued on grounds of parsimony, but has received two significant challenges: first, from the observation that some kinds of learning, such as spatial learning, seem to obey different rules from others, and second, that some kinds of learning take place in processing modules that are separate from each other. These challenges arose in the behavioural literature but have since received considerable support from neurobiological studies, particularly single neuron studies of spatial learning, confirming that there are indeed separable (albeit highly intercommunicating) processing modules in the brain which may not always interact (within or between themselves) according to classic associative principles. On the basis of these neurobiological data, reviewed here, it is argued that rather than assuming universality of associative rules, it is more parsimonious to assume sets of locally operating rules, each specialised for a particular domain. By this view, although almost all learning is associative in one way or another, the behavioural-level characterization of the rules governing learning may vary depending on which neural modules are involved in a given behavior. Neurobiological studies, in tandem with behavioural studies, can help reveal the nature of these modules and the local rules by which they interact.
PMCID: PMC3160474  PMID: 20204918
associative learning; spatial learning; geometric module; place cells; grid cells
13.  Annual Research Review: The nature and classification of reading disorders – a commentary on proposals for DSM-5 
This article reviews our understanding of reading disorders in children and relates it to current proposals for their classification in DSM-5. There are two different, commonly occurring, forms of reading disorder in children which arise from different underlying language difficulties. Dyslexia (as defined in DSM-5), or decoding difficulty, refers to children who have difficulty in mastering the relationships between the spelling patterns of words and their pronunciations. These children typically read aloud inaccurately and slowly, and experience additional problems with spelling. Dyslexia appears to arise principally from a weakness in phonological (speech sound) skills, and there is good evidence that it can be ameliorated by systematic phonic teaching combined with phonological awareness training. The other major form of reading difficulty is reading comprehension impairment. These children read aloud accurately and fluently, but have difficulty understanding what they have read. Reading comprehension impairment appears to arise from weaknesses in a range of oral language skills including poor vocabulary knowledge, weak grammatical skills and difficulties in oral language comprehension. We suggest that the omission of reading comprehension impairment from DSM-5 is a serious one that should be remedied. Both dyslexia and reading comprehension impairment are dimensional in nature, and show strong continuities with other disorders of language. We argue that recognizing the continuities between reading and language disorders has important implications for assessment and treatment, and we note that the high rates of comorbidity between reading disorders and other seemingly disparate disorders (including ADHD and motor disorders) raises important challenges for understanding these disorders.
PMCID: PMC3492851  PMID: 22141434
Reading disorders; language disorders; dyslexia; reading comprehension impairment; intervention
14.  “ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis”—a critical commentary 
Free radical biology & medicine  2008;45(9):1217-1219.
In a recent publication (K. Ishikawa et al., 2008, Science 320, 661–664), the authors described how replacing the endogenous mitochondrial DNA (mtDNA) in a weakly metastatic mouse tumor cell line with mtDNA from a highly metastatic cell line enhanced tumor progression through enhanced production of reactive oxygen species (ROS). The authors attributed the transformation from a low-metastatic cell line to a high-metastatic phenotype to overproduction of ROS (hydrogen peroxide and superoxide) caused by a dysfunction in mitochondrial complex I protein encoded by mtDNA transferred from the highly metastatic tumor cell line. In this critical evaluation, using the paper by Ishikawa et al. as an example, we bring to the attention of researchers in the free radical field how the failure to appreciate the complexities of dye chemistry could potentially lead to pitfalls, misinterpretations, and erroneous conclusions concerning ROS involvement. Herein we make a case that the authors have failed to show evidence for formation of superoxide and hydrogen peroxide, presumed to be generated from complex I deficiency associated with mtDNA mutations in metastatic cells.
PMCID: PMC3595710  PMID: 18789385
Reactive oxygen species; Fluorescent probes; Metastasis; Mitochondria; Dichlorodihydrofluorescein; Hydroethidine; Hydrogen peroxide; Superoxide; Free radicals
15.  Selective review and commentary on emerging pharmacotherapies for opioid addiction 
Pharmacotherapies for opioid addiction under active development in the US include lofexidine (primarily for managing withdrawal symptoms) and Probuphine®, a distinctive mode of delivering buprenorphine for six months, thus relieving patients, clinicians, and regulatory personnel from most concerns about diversion, misuse, and unintended exposure in children. In addition, two recently approved formulations of previously proven medications are in early phases of implementation. The sublingual film form of buprenorphine + naloxone (Suboxone®) provides a less divertible, more quickly administered, more child-proof version than the buprenorphine + naloxone sublingual tablet. The injectable depot form of naltrexone (Vivitrol®) ensures consistent opioid receptor blockade for one month between administrations, removing concerns about medication compliance. The clinical implications of these developments have attracted increasing attention from clinicians and policymakers in the US and around the world, especially given that human immunodeficiency virus/acquired immunodeficiency syndrome and other infectious diseases are recognized as companions to opioid addiction, commanding more efforts to reduce opioid addiction. While research and practice improvement efforts continue, reluctance to adopt new medications and procedures can be expected, especially considerations in the regulatory process and in the course of implementation. Best practices and improved outcomes will ultimately emerge from continued development efforts that reflect input from many quarters.
PMCID: PMC3846315  PMID: 24474855
buprenorphine; naltrexone; probuphine; lofexidine; implant buprenorphine; buprenorphine film
16.  Invited Commentary: Are Dietary Intakes and Other Exposures in Childhood and Adolescence Important for Adult Cancers? 
American Journal of Epidemiology  2013;178(2):184-189.
In this issue of the Journal, Nimptsch et al. (Am J Epidemiol. 2013;178(2):172–183) report significant associations between female adolescents' poultry consumption in high school and subsequent reduced risk of colorectal adenomas in adulthood. Consumption of red meat or fish was not related to risk, but replacement with poultry reduced the risk of later adenomas. Most epidemiologic studies of adult diseases lack exposure data from the distant past. By focusing on a cancer precursor lesion and using a variety of methods to assess data quality, the investigators address concerns about the quality of distant recall. These findings add to the growing evidence that links childhood and adolescent lifestyle and environmental exposures with subsequent risk of cancers arising in adulthood. Highlights of the literature on this topic and methodological challenges are summarized. Future studies would benefit from incorporating measures of lifestyle, diet, environmental exposures, and other risk factors from early in life and from validation and other data quality checks of such measurements. Sources of historical data on children's and adolescents' exposures should be sought and evaluated in conjunction with subsequent exposures in relationship to adult-onset cancers.
PMCID: PMC3816339  PMID: 23792894
adolescence; diet; distant past; life course; methods; recall
17.  Invited Commentary: Broadening the Evidence for Adolescent Sexual and Reproductive Health and Education in the United States 
Journal of Youth and Adolescence  2014;43(10):1595-1610.
Scientific research has made major contributions to adolescent health by providing insights into factors that influence it and by defining ways to improve it. However, US adolescent sexual and reproductive health policies—particularly sexuality health education policies and programs—have not benefited from the full scope of scientific understanding. From 1998 to 2009, federal funding for sexuality education focused almost exclusively on ineffective and scientifically inaccurate abstinence-only-until-marriage (AOUM) programs. Since 2010, the largest source of federal funding for sexual health education has been the “tier 1” funding of the Office of Adolescent Health’s Teen Pregnancy Prevention Initiative. To be eligible for such funds, public and private entities must choose from a list of 35 programs that have been designated as “evidence-based” interventions (EBIs), determined based on their effectiveness at preventing teen pregnancies, reducing sexually transmitted infections, or reducing rates of sexual risk behaviors (i.e., sexual activity, contraceptive use, or number of partners). Although the transition from primarily AOUM to EBI is important progress, this definition of evidence is narrow and ignores factors known to play key roles in adolescent sexual and reproductive health. Important bodies of evidence are not treated as part of the essential evidence base, including research on lesbian, gay, bisexual, transgender, queer, and questioning (LGBTQ) youth; gender; and economic inequalities and health. These bodies of evidence underscore the need for sexual health education to approach adolescent sexuality holistically, to be inclusive of all youth, and to address and mitigate the impact of structural inequities. We provide recommendations to improve US sexual health education and to strengthen the translation of science into programs and policy.
PMCID: PMC4162986  PMID: 25200033
18.  Pancreas Transplantation—Registry Report and a Commentary 
Western Journal of Medicine  1985;143(6):845-852.
From December 1966 through December 1984, there were 561 pancreas transplants reported to the American College of Surgeons/National Institutes of Health Organ Transplant Registry, including 60 from 1966 through June 1977, 206 from July 1977 through December 1982 and 295 from January 1983 through December 1984. One-year graft function-survival rates (insulin-independent) in each of the three periods were 3%, 20% and 40%, and the corresponding patient survival rates were 40%, 72% and 77%. Currently 140 patients have functioning grafts, 76 for more than one year. Of the transplants since July 1977, one-year graft survival rates according to technique are 41% for enteric drainage (N = 155), 30% for polymer injection (N = 260) and 29% for urinary drainage (N = 47). Pancreas graft survival rates at one year according to whether or not the recipients have had a kidney transplant were 35% for recipients of simultaneous grafts (N = 281), 28% in recipients of a pancreas after a kidney (N = 112) and 26% in recipients of a pancreas only who did not have uremia (N = 106); corresponding patient survival rates were 69%, 83% and 83%. Overall, one-year pancreas graft survival rates according to whether the patients did or did not have end-stage diabetic nephropathy were 33% versus 25% and the corresponding patient survival rates were 73% versus 84% (P < .01). Patient survival rates were significantly higher in those without than in those with end-stage diabetic nephropathy. An analysis of technically successful grafts according to principal immunosuppressant showed one-year function rates of 46% in 258 cyclosporine-treated recipients and 26% in 143 azathioprine-treated recipients.
Pancreas graft survival rates have progressively improved and the procedure has become safer with advances in surgical technique and immunosuppression. Pancreas transplantation is currently applicable to patients with diabetes mellitus whose complications are, or predictably will be, more serious than the possible side effects of long-term immunosuppression.
PMCID: PMC1306497  PMID: 3911597
19.  Cardiovascular and Interventional Radiological Society of Europe Commentary on the Treatment of Chronic Cerebrospinal Venous Insufficiency 
Chronic cerebrospinal venous insufficiency (CCSVI) is a putative new theory that has been suggested by some to have a direct causative relation with the symptomatology associated with multiple sclerosis (MS) [1]. The core foundation of this theory is that there is abnormal venous drainage from the brain due to outflow obstruction in the draining jugular vein and/or azygos veins. This abnormal venous drainage, which is characterised by special ultrasound criteria, called the “venous hemodynamic insufficiency severity score” (VHISS), is said to cause intracerebral flow disturbance or outflow problems that lead to periventricular deposits [2]. In the CCSVI theory, these deposits have a great similarity to the iron deposits seen around the veins in the legs in patients with chronic deep vein thrombosis. Zamboni, who first described this new theory, has promoted balloon dilatation to treat the outflow problems, thereby curing CCSVI and by the same token alleviating MS complaints. However, this theory does not fit into the existing bulk of scientific data concerning the pathophysiology of MS. In contrast, there is increasing worldwide acceptance of CCSVI and the associated balloon dilatation treatment, even though there is no supporting scientific evidence. Furthermore, most of the information we have comes from one source only. The treatment is called “liberation treatment,” and the results of the treatment can be watched on YouTube. There are well-documented testimonies by MS patients who have gained improvement in their personal quality of life (QOL) after treatment. However, there are no data available from patients who underwent unsuccessful treatments with which to obtain a more balanced view. The current forum for the reporting of success in treating CCSVI and thus MS seems to be the Internet. At the CIRCE office and the MS Centre in Amsterdam, we receive approximately 10 to 20 inquiries a month about this treatment. In addition, many interventional radiologists, who are directly approached by MS patients, contact the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) for advice. Worldwide, several centres are actively promoting and performing balloon dilatation, with or without stenting, for CCSVI. Thus far, no trial data are available, and there is currently no randomized controlled trial (RCT) in progress Therefore, the basis for this new treatment rests on anecdotal evidence and successful testimonies by patients on the Internet. CIRSE believes that this is not a sound basis on which to offer a new treatment, which could have possible procedure-related complications, to an often desperate patient population.
PMCID: PMC2816826  PMID: 21136256
20.  Clinicopathologic correlates in the oldest-old Commentary on “No disease in the brain of a 115-year-old woman” 
Neurobiology of Aging  2008;29(8):1137-1139.
den Dunnen et al. [den Dunnen, W.F.A., Brouwer, W.H., Bijlard, E., Kamphuis, J., van Linschoten, K., Eggens-Meijer, E., Holstege, G., 2008. No disease in the brain of a 115-year-old woman. Neurobiol. Aging] had the opportunity to follow up the cognitive functioning of one of the world’s oldest woman during the last 3 years of her life. They performed two neuropsychological evaluations at age 112 and 115 that revealed a striking preservation of immediate recall abilities and orientation. In contrast, working memory, retrieval from semantic memory and mental arithmetic performances declined after age 112. Overall, only a one-point decrease of MMSE score occurred (from 27 to 26) reflecting the remarkable preservation of cognitive abilities. The neuropathological assessment showed few neurofibrillary tangles (NFT) in the hippocampal formation compatible with Braak staging II, absence of amyloid deposits and other types of neurodegenerative lesions as well as preservation of neuron numbers in locus coeruleus. This finding was related to a striking paucity of Alzheimer disease (AD)-related lesions in the hippocampal formation. The present report parallels the early descriptions of rare “supernormal” centenarians supporting the dissociation between brain aging and AD processes. In conjunction with recent stereological analyses in cases aged from 90 to 102 years, it also points to the marked resistance of the hippocampal formation to the degenerative process in this age group and possible dissociation between the occurrence of slight cognitive deficits and development of AD-related pathologic changes in neocortical areas. This work is discussed in the context of current efforts to identify the biological and genetic parameters of human longevity.
PMCID: PMC2911139  PMID: 18534719
Disease; Brain aging; Centenarians; Longevity; Neuronal vulnerability
21.  The development and general morphology of the telencephalon of actinopterygian fishes: synopsis, documentation and commentary 
Brain Structure & Function  2010;215(3-4):141-157.
The Actinopterygii or ray-finned fishes comprise, in addition to the large superorder of teleosts, four other superorders, namely the cladistians, the chondrosteans, the ginglymodes, and the halecomorphs, each with a limited number of species. The telencephalon of actinopterygian fishes differs from that in all other vertebrates in that it consists of a pair of solid lobes. Lateral ventricles surrounded by nervous tissue are entirely lacking. At the end of the nineteenth century, the theory was advanced that the unusual configuration of the forebrain in actinopterygians results from an outward bending or eversion of its lateral walls. This theory was accepted by some authors, rejected or neglected by others, and modified by some other authors. The present paper is based on the data derived from the literature, complemented by new observations on a large collection of histological material comprising specimens of all five actinopterygian superorders. The paper consists of three parts. In the first, a survey of the development of the telencephalon in actinopterygian fishes is presented. The data collected show clearly that an outward bending or eversion of the pallial parts of the solid hemispheres is the principal morphogenetic event in all five actinopterygian superorders. In all of these superorders, except for the cladistians, eversion is coupled with a marked thickening of the pallial walls. In the second part, some aspects of the general morphology of the telencephalon in mature actinopterygians are highlighted. It is pointed out that (1) the degree of eversion varies considerably among the various actinopterygian groups; (2) eversion leads to the transformation of the telencephalic roof plate into a wide membrane or tela choroidea, which is bilaterally attached to the lateral or ventrolateral aspect of the solid hemispheres; (3) the lines of attachment or taeniae of the tela choroidea form the most important landmarks in the telencephalon of actinopterygians, indicating the sites where the greatly enlarged ventricular surface of the hemispheres ends and its reduced meningeal surface begins; (4) the meningeal surface of the telencephalon shows in most actinopterygians bilaterally a longitudinally oriented sulcus externus, the depth of which is generally positively correlated with the degree of eversion; (5) a distinct lateral olfactory tract, occupying a constant topological position close to the taenia, is present in all actinopterygians studied; and (6) this tract is not homologous to the tract of the same name in the evaginated and inverted forebrains of other groups of vertebrates. In the third and final section, the concept that the structural organization of the pallium in actinopterygians can be fully explained by a simple eversion of its walls, and the various theories, according to which the eversion is complicated by extensive shifts of its constituent cell groups, are discussed and evaluated. It is concluded that there are no reasons to doubt that the pallium of actinopterygian fishes is the product of a simple and complete eversion.
PMCID: PMC3041917  PMID: 20976604
Evagination; Eversion; Lateral olfactory tract; Membranous roof; Sulcus externus; Taenia
22.  The relation between smokeless tobacco and cancer in Northern Europe and North America. A commentary on differences between the conclusions reached by two recent reviews 
BMC Cancer  2009;9:256.
Smokeless tobacco is an alternative for smokers who want to quit but require nicotine. Reliable evidence on its effects is needed. Boffetta et al. and ourselves recently reviewed the evidence on cancer, based on Scandinavian and US studies. Boffetta et al. claimed a significant 60–80% increase for oropharyngeal, oesophageal and pancreatic cancer, and a non-significant 20% increase for lung cancer, data for other cancers being "too sparse". We found increases less than 15% for oesophageal, pancreatic and lung cancer, and a significant 36% increase for oropharyngeal cancer, which disappeared in recent studies. We found no association with stomach, bladder and all cancers combined, using data as extensive as that for oesophageal, pancreatic and lung cancer. We explain these differences.
For those cancers Boffetta et al. considered, we compared the methods, studies and risk estimates used in the two reviews.
One major reason for the difference is our more consistent approach in choosing between study-specific never smoker and combined smoker/non-smoker estimates. Another is our use of derived as well as published estimates. We included more studies, and avoided estimates for data subsets. Boffetta et al. also included some clearly biased or not smoking-adjusted estimates. For pancreatic cancer, their review included significantly increased never smoker estimates in one study and combined smoker/non-smoker estimates in another, omitting a combined estimate in the first study and a never smoker estimate in the second showing no increase. For oesophageal cancer, never smoker results from one study showing a marked increase for squamous cell carcinoma were included, but corresponding results for adenocarcinoma and combined smoker/non-smoker results for both cell types showing no increase were excluded. For oropharyngeal cancer, Boffetta et al. included a markedly elevated estimate that was not smoking-adjusted, and overlooked the lack of association in recent studies.
When conducting meta-analyses, all relevant data should be used, with clear rules governing the choice between alternative estimates. A systematic meta-analysis using pre-defined procedures and all relevant data gives a lower estimate of cancer risk from smokeless tobacco (probably 1–2% of that from smoking) than does the previous review by Boffetta et al.
PMCID: PMC3087330  PMID: 19638246
23.  Indian commentary on the 2009 KDIGO clinical practice guideline for the diagnosis, evaluation, and treatment of chronic kidney disease-mineral and bone disorders 
Indian Journal of Nephrology  2011;21(3):143-151.
This commentary presents the view of an Expert Group of Indian nephrologists on adaptation and implementation of the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for evaluation and management of mineral and bone disorder in chronic kidney disease (CKD-MBD) for practice in India. Zonal meetings of nephrologists drawn from the cross-section were convened to discuss the KDIGO guidelines. Recommendations were presented in a central meeting of zonal representatives. The finalized recommendations were reviewed by all the participants. There was a broad agreement on most of the recommendations made by the KDIGO workgroup. Significant departures in the current guidelines from the previous Kidney Disease Outcome Quality Initiative (KDOQI) guidelines were also noted. The participants agreed that the available evidence did not allow more precise recommendations, and the recommended best practice suggestions were often based on relatively weak evidence. There is a remarkable lack of data from Indian patients. We comment on specific areas and amplify certain concepts where we feel that further guidance that goes beyond what is stated in the document might help Indian nephrologists in appropriate implementation of the KDIGO guidelines. This commentary is intended to help define practically implementable best practices based on current disease concepts and available research evidence, thereby positively affecting the quality of management of CKD-MBD in India, and eventually improving patient outcomes.
PMCID: PMC3161429  PMID: 21886971
Chronic kidney disease; guideline; hyperparathyroidism; KDIGO; mineral and bone disorder
24.  Foot Orthoses in Lower Limb Overuse Conditions: A Systematic Review and Meta-Analysis—Critical Appraisal and Commentary 
Journal of Athletic Training  2011;46(1):103-106.
Collins N, Bisset L, McPoil T, Vicenzino B. Foot orthoses in lower limb overuse conditions: a systematic review and meta-analysis. Foot Ankle Int. 2007;28(3):396–412.
Clinical Question:
Among patients with or at risk for musculoskeletal overuse conditions, (1) do foot orthoses provide clinically meaningful improvements, and (2) are foot orthoses cost-effective?
Data Sources:
Studies published through September 28, 2005, were identified by using MEDLINE, EMBASE, CINAHL and Pre-CINAHL, Physiotherapy Evidence Database (PEDro), PubMed, SPORTDiscus, Biological Abstracts, Web of Science, Allied Health and Complementary Medicine Database, and the full Cochrane Library. The authors did not provide the search strategy used. Reference lists of included randomized controlled trials (RCTs) and identified systematic reviews were searched by hand.
Study Selection:
Studies were included if (1) they were RCTs that included the use of foot orthoses (either custom or prefabricated) in 1 of the intervention groups, (2) the clinical problem was an overuse condition as defined by the American College of Foot and Ankle Orthopedics and Medicine guidelines for which foot orthoses were recommended, and (3) at least 1 clinically relevant outcome was measured for a minimum of 1 week. Limits were not placed on year of publication, status of publication, or language.
Data Extraction:
The journal, authors, and author affiliations of included RCTs were masked from 2 of the reviewers who independently assessed the included RCTs for methodologic quality using a modified PEDro scale plus 3 additional items (justification of sample size, use of outcome measures with known validity and reliability, and reporting of adverse or side effects). Disagreements on methodologic quality were resolved with consensus or by a third reviewer. The effect sizes for the included RCTs were represented by relative risk (RR) for dichotomous outcomes and standardized mean difference (SMD) for continuous data. Confidence intervals (CIs) were reported for RR and SMD. Study data were extracted directly from each of the included studies. If provided, data from intention-to-treat analysis were extracted. Study authors were contacted when insufficient data were reported. A meta-analysis (random-effects model) was conducted using Review Manager (version 4.2; The Nordic Cochrane Centre, Copenhagen, Denmark).
Main Results:
The search identified 3192 potentially relevant studies. Full articles were retrieved for 327 studies. Twenty-two of the 327 studies met the inclusion criteria. Because the authors of 1 study used the same methods to report on 2 populations, a total of 23 RCTs were included in the systematic review. Prevention of lower limb overuse conditions with the use of foot orthoses was reported in 8 RCTs (7 studies). The effect of foot orthoses in the treatment of lower limb overuse conditions was reported in 15 RCTs. Of the 23 RCTs, the cost-effectiveness of foot orthoses was reported in 2 and the adverse effects of foot orthoses were reported in 8. Across the prevention RCTs, data were available for analysis for a range of 47 to 417 participants with 8 to 16 weeks of follow-up. Based on 4 RCTs in which the researchers examined prevention of lower limb overuse conditions with foot orthoses versus control in military personnel, the RR was 1.49 (95% CI  =  1.07, 2.08). A clinically beneficial effect size was set a priori at 1.5 or greater for the foot-orthoses group or at 0.7 or less for the comparison group. Based on 2 RCTs reported in 1 study of the use of custom versus prefabricated foot orthoses for prevention of lower limb overuse conditions, no significant difference in risk was found (RR  =  1.14, 95% CI  =  0.90, 1.44). In their calculating and reporting of RR, the authors do not appear to have followed convention. Across the treatment RCTs, data were available for analysis for a range of 18 to 133 participants with 8 to 52 weeks of follow-up. The authors of the treatment RCTs reported a variety of outcome measures. Two of these, patient-perceived treatment effect (PPE) and pain on the visual analog scale (VAS), were used to calculate an overall treatment effect (PPE as RR and VAS as SMD). Based on 2 RCTs examining foot orthoses versus control, no significant difference in PPE was found (RR  =  1.01, 95% CI  =  0.61, 1.68). Based on 2 RCTs in which custom versus prefabricated foot orthoses were examined, no significant difference in PPE was found (RR  =  0.88, 95% CI  =  0.42, 1.81). The VAS data reported in the text appear to contradict the VAS data reported in Figure 2 for foot orthoses versus control for the treatment of lower limb overuse conditions. Specifically, the lower limit of the CI in the text was negative (−0.28) and in Figure 2 was positive. Because of this apparent contradiction, we did not interpret these data. Authors of 2 RCTs reported cost-effectiveness, but the data could not be pooled. Adverse events were reported in 8 of the 22 studies. The most common adverse effect reported was discomfort, which was the main reason for discontinuing foot-orthoses use in 2 studies.
The evidence supports the use of foot orthoses to prevent a first occurrence of lower limb overuse conditions and shows no difference between custom and prefabricated foot orthoses. The evidence was insufficient to recommend foot orthoses (custom or prefabricated) for the treatment of lower limb overuse conditions.
PMCID: PMC3017481  PMID: 21214358
overuse injuries; foot orthotics
25.  Invited Commentary: Epstein-Barr Virus–Based Screening for the Early Detection of Nasopharyngeal Carcinoma—A New Frontier 
American Journal of Epidemiology  2012;177(3):251-253.
Approximately 2 million new cases of cancer are caused by infections each year. For many of these cancers, we have been successful at developing methods for prevention or effective treatment/control. Epstein-Barr virus (EBV), a ubiquitous infection that establishes lifelong latency, was the first infection to be linked to the development of cancers, including nasopharyngeal carcinoma, lymphomas, and gastric cancer. EBV infection is linked to the development of approximately 200,000 new cancers each year, yet there have been no successful efforts to implement EBV-based strategies for the reduction in the burden of EBV-associated cancers. In this issue of the Journal, Liu et al. (Am J Epidemiol. 2013;177(3):242–250) report results from the enrollment phase of a large effort to demonstrate the efficacy of an EBV-based screening strategy to detect nasopharyngeal carcinoma at early stages and hopefully reduce the mortality associated with this disease. In this invited commentary, the design and initial findings from this demonstration project are reviewed, possible ways to enrich the effort are discussed, and populations that might benefit from EBV-based screening in the future are identified.
PMCID: PMC3626052  PMID: 23255781
cancer; Epstein-Barr virus; infections; nasopharyngeal carcinoma; prevention; screening

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