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1.  Shallow Encoding and Forgetting Are Associated with Dependence in Instrumental Activities of Daily Living Among Older Adults Living with HIV Infection 
Aging and HIV are both risk factors for memory deficits and declines in real-world functioning. However, we know little about the profile of memory deficits driving instrumental activities of daily living (IADL) declines across the lifespan in HIV. This study examined 145 younger (<50 years) and 119 older (≥50 years) adults with HIV who completed the California Verbal Learning Test-Second Edition (CVLT-II), the Wechsler Memory Scale-Third Edition Logical Memory subtest (WMS-III LM), and a modified Lawton and Brody ADL questionnaire. No memory predictors of IADL dependence emerged in the younger cohort. In the older group, IADL dependence was uniquely associated with worse performance on all primary CVLT-II variables, as well as elevated recency effects. Poorer immediate and delayed recall of the WMS-III LM was also associated with IADL dependence, although recognition was intact. Findings suggest older HIV-infected adults with shallow encoding and forgetting are at risk for IADL dependence.
doi:10.1093/arclin/acu009
PMCID: PMC4000232  PMID: 24695591
Aging; Disability; Everyday functioning; Learning and memory
2.  Effectiveness of 7-Valent Pneumococcal Conjugate Vaccine Against Invasive Pneumococcal Disease in HIV-Infected and -Uninfected Children in South Africa: A Matched Case-Control Study 
Cohen, Cheryl | von Mollendorf, Claire | de Gouveia, Linda | Naidoo, Nireshni | Meiring, Susan | Quan, Vanessa | Nokeri, Vusi | Fortuin-de Smit, Melony | Malope-Kgokong, Babatyi | Moore, David | Reubenson, Gary | Moshe, Mamokgethi | Madhi, Shabir A. | Eley, Brian | Hallbauer, Ute | Kularatne, Ranmini | Conklin, Laura | O'Brien, Katherine L. | Zell, Elizabeth R. | Klugman, Keith | Whitney, Cynthia G. | von Gottberg, Anne | Moore, David | Verwey, Charl | Varughese, Sheeba | Archary, Moherndran | Naby, Fathima | Dawood, Khathija | Naidoo, Ramola | Elliott, Gene | Hallbauer, Ute | Eley, Brian | Nuttall, James | Cooke, Louise | Finlayson, Heather | Rabie, Helena | Whitelaw, Andrew | Perez, Dania | Jooste, Pieter | Naidoo, Dhamiran | Kularatne, Ranmini | Reubenson, Gary | Cohen, Cheryl | de Gouveia, Linda | du Plessis, Mignon | Govender, Nevashan | Meiring, Susan | Quan, Vanessa | von Mollendorf, Claire | Fortuin-de Smidt, Melony | Naidoo, Nireshni | Malope-Kgokong, Babatyi | Nokeri, Vusi | Ncha, Relebohile | Lindani, Sonwabo | von Gottberg, Anne | Spies, Barry | Sono, Lino | Maredi, Phasweni | Hamese, Ken | Moshe, Mamokgethi | Nchabeleng, Maphosane | Ngcobo, Ntombenhle | van den Heever, Johann | Madhi, Shabir | Conklin, Laura | Verani, Jennifer | Whitney, Cynthia | Zell, Elizabeth | Loo, Jennifer | Nelson, George | Klugman, Keith | O'Brien, Katherine
A 2 + 1 seven-valent pneumococcal conjugate vaccine schedule is effective against vaccine-serotype invasive pneumococcal disease (IPD) in HIV-uninfected children and HIV-exposed but -uninfected children and against all-serotype multidrug-resistant IPD in HIV-uninfected children.
Background. South Africa introduced 7-valent pneumococcal conjugate vaccine (PCV7) in April 2009 using a 2 + 1 schedule (6 and 14 weeks and 9 months). We estimated the effectiveness of ≥2 PCV7 doses against invasive pneumococcal disease (IPD) in human immunodeficiency virus (HIV)–infected and -uninfected children.
Methods. IPD (pneumococcus identified from a normally sterile site) cases were identified through national laboratory-based surveillance. Specimens were serotyped by Quellung or polymerase chain reaction. Four controls, matched for age, HIV status, and hospital were sought for each case. Using conditional logistic regression, we calculated vaccine effectiveness (VE) as 1 minus the adjusted odds ratio for vaccination.
Results. From March 2010 through November 2012, we enrolled 187 HIV-uninfected (48 [26%] vaccine serotype) and 109 HIV-infected (43 [39%] vaccine serotype) cases and 752 HIV-uninfected and 347 HIV-infected controls aged ≥16 weeks. Effectiveness of ≥2 PCV7 doses against vaccine-serotype IPD was 74% (95% confidence interval [CI], 25%–91%) among HIV-uninfected and −12% (95% CI, −449% to 77%) among HIV-infected children. Effectiveness of ≥3 doses against vaccine-serotype IPD was 90% (95% CI, 14%–99%) among HIV-uninfected and 57% (95% CI, −371% to 96%) among HIV-infected children. Among HIV-exposed but -uninfected children, effectiveness of ≥2 doses was 92% (95% CI, 47%–99%) against vaccine-serotype IPD. Effectiveness of ≥2 doses against all-serotype multidrug-resistant IPD was 96% (95% CI, 62%–100%) among HIV-uninfected children.
Conclusions. A 2 + 1 PCV7 schedule was effective in preventing vaccine-serotype IPD in HIV-uninfected and HIV-exposed, uninfected children. This finding supports the World Health Organization recommendation for this schedule as an alternative to a 3-dose primary series among HIV-uninfected individuals.
doi:10.1093/cid/ciu431
PMCID: PMC4144265  PMID: 24917657
children; HIV; pneumococcus; pneumococcal conjugate vaccine; South Africa
3.  Cigarette Smoking, Passive Smoking, Alcohol Consumption, and Hearing Loss 
The objective of this large population-based cross-sectional study was to evaluate the association between smoking, passive smoking, alcohol consumption, and hearing loss. The study sample was a subset of the UK Biobank Resource, 164,770 adults aged between 40 and 69 years who completed a speech-in-noise hearing test (the Digit Triplet Test). Hearing loss was defined as speech recognition in noise in the better ear poorer than 2 standard deviations below the mean with reference to young normally hearing listeners. In multiple logistic regression controlling for potential confounders, current smokers were more likely to have a hearing loss than non-smokers (odds ratio (OR) 1.15, 95 % confidence interval (CI) 1.09–1.21). Among non-smokers, those who reported passive exposure to tobacco smoke were more likely to have a hearing loss (OR 1.28, 95 %CI 1.21–1.35). For both smoking and passive smoking, there was evidence of a dose-response effect. Those who consume alcohol were less likely to have a hearing loss than lifetime teetotalers. The association was similar across three levels of consumption by volume of alcohol (lightest 25 %, OR 0.61, 95 %CI 0.57–0.65; middle 50 % OR 0.62, 95 %CI 0.58–0.66; heaviest 25 % OR 0.65, 95 %CI 0.61–0.70). The results suggest that lifestyle factors may moderate the risk of hearing loss. Alcohol consumption was associated with a protective effect. Quitting or reducing smoking and avoiding passive exposure to tobacco smoke may also help prevent or moderate age-related hearing loss.
doi:10.1007/s10162-014-0461-0
PMCID: PMC4141428  PMID: 24899378
age-related hearing loss; presbycusis; smoking; passive smoking; alcohol
4.  A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement 
Brain  2014;137(8):2329-2345.
Using whole-exome sequencing, Bannwarth et al. identify a missense mutation in the mitochondrial gene, CHCHD10, in two families with frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS). CHCHD10 helps to maintain the morphology of mitochondrial cristae and the stability of mitochondrial DNA. Other cases of FTD-ALS may be mitochondrial in origin.
Mitochondrial DNA instability disorders are responsible for a large clinical spectrum, among which amyotrophic lateral sclerosis-like symptoms and frontotemporal dementia are extremely rare. We report a large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy. In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V. The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder. Patient fibroblasts present with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network. Interestingly, expression of matrix-targeted photoactivatable GFP showed that mitochondrial fusion was not inhibited in patient fibroblasts. Using whole-exome sequencing we identified a missense mutation (c.176C>T; p.Ser59Leu) in the CHCHD10 gene that encodes a coiled-coil helix coiled-coil helix protein, whose function is unknown. We show that CHCHD10 is a mitochondrial protein located in the intermembrane space and enriched at cristae junctions. Overexpression of a CHCHD10 mutant allele in HeLa cells led to fragmentation of the mitochondrial network and ultrastructural major abnormalities including loss, disorganization and dilatation of cristae. The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis. We identified the same missense p.Ser59Leu mutation in one of these families. This work opens a novel field to explore the pathogenesis of the frontotemporal dementia-amyotrophic lateral sclerosis clinical spectrum by showing that mitochondrial disease may be at the origin of some of these phenotypes.
doi:10.1093/brain/awu138
PMCID: PMC4107737  PMID: 24934289
CHCHD10; mitochondrial DNA instability; mitochondrial disorder; FTD-ALS
6.  Lack of Effectiveness of Antiretroviral Therapy in Preventing HIV Infection in Serodiscordant Couples in Uganda: An Observational Study 
PLoS ONE  2015;10(7):e0132182.
Background
We examined the real-world effectiveness of ART as an HIV prevention tool among HIV serodiscordant couples in a programmatic setting in a low-income country.
Methods
We enrolled individuals from HIV serodiscordant couples aged ≥18 years of age in Jinja, Uganda from June 2009 – June 2011. In one group of couples the HIV positive partner was receiving ART as they met clinical eligibility criteria (a CD4 cell count ≤250 cells/ μL or WHO Stage III/IV disease). In the second group the infected partner was not yet ART-eligible. We measured HIV incidence by testing the uninfected partner every three months. We conducted genetic linkage studies to determine the source of new infections in seroconverting participants.
Results
A total of 586 couples were enrolled of which 249 (42%) of the HIV positive participants were receiving ART at enrollment, and an additional 99 (17%) initiated ART during the study. The median duration of follow-up was 1.5 years. We found 9 new infections among partners of participants who had been receiving ART for at least three months and 8 new infections in partners of participants who had not received ART or received it for less than three months, for incidence rates of 2.09 per 100 person-years (PYRs) and 2.30 per 100 PYRs, respectively. The incidence rate ratio for ART-use was 0.91 (95% confidence interval 0.31-2.70; p=0.999). The hazard ratio for HIV seroconversion associated with ART-use by the positive partner was 1.07 (95% CI 0.41-2.80). A total of 5/7 (71%) of the transmissions on ART and 6/7 (86%) of those not on ART were genetically linked.
Conclusion
Overall HIV incidence was low in comparison to previous studies of serodiscordant couples. However, ART-use was not associated with a reduced risk of HIV transmission in this study.
doi:10.1371/journal.pone.0132182
PMCID: PMC4501729  PMID: 26171777
7.  Vision impairment and dual sensory problems in middle age 
Purpose
Vision and hearing impairments are known to increase in middle age. In this study we describe the prevalence of vision impairment and dual sensory impairment in UK adults aged 40 to 69 years in a very large and recently ascertained data set. The associations between vision impairment, age, sex, socioeconomic status, and ethnicity are reported.
Methods
This research was conducted using the UK Biobank Resource, with subsets of UK Biobank data analysed with respect to self-report of eye problems and glasses use. Better-eye visual acuity with habitually worn refractive correction was assessed with a logMAR chart (n = 116,682). Better-ear speech reception threshold was measured with an adaptive speech in noise test, the Digit Triplet Test (n = 164,770). Prevalence estimates were weighted with respect to UK 2001 Census data.
Results
Prevalence of mild visual impairment and low vision was estimated at 15.2% (95% CI 14.9–15.5%) and 0.9% (95% CI 0.8–1.0%), respectively. Use of glasses was 88.0% (95% CI 87.9–88.1%). The prevalence of dual sensory impairment was 3.1% (95% CI 3.0–3.2%) and there was a nine-fold increase in the prevalence of dual sensory problems between the youngest and oldest age groups. Older adults, those from low socioeconomic and ethnic minority backgrounds were most at risk for vision problems.
Conclusions
Mild vision impairment is common in middle aged UK adults, despite widespread use of spectacles. Possible barriers to optometric care for those from low socioeconomic and ethnic minority backgrounds may require attention. A higher than expected prevalence of dual impairment suggests that hearing and vision problems share common causes. Optometrists should consider screening for hearing problems, particularly among older adults.
doi:10.1111/opo.12138
PMCID: PMC4273649  PMID: 24888710
vision impairment; dual sensory problems
9.  Transmission of Multidrug-Resistant and Drug-Susceptible Tuberculosis within Households: A Prospective Cohort Study 
PLoS Medicine  2015;12(6):e1001843.
Background
The “fitness” of an infectious pathogen is defined as the ability of the pathogen to survive, reproduce, be transmitted, and cause disease. The fitness of multidrug-resistant tuberculosis (MDRTB) relative to drug-susceptible tuberculosis is cited as one of the most important determinants of MDRTB spread and epidemic size. To estimate the relative fitness of drug-resistant tuberculosis cases, we compared the incidence of tuberculosis disease among the household contacts of MDRTB index patients to that among the contacts of drug-susceptible index patients.
Methods and Findings
This 3-y (2010–2013) prospective cohort household follow-up study in South Lima and Callao, Peru, measured the incidence of tuberculosis disease among 1,055 household contacts of 213 MDRTB index cases and 2,362 household contacts of 487 drug-susceptible index cases.
A total of 35/1,055 (3.3%) household contacts of 213 MDRTB index cases developed tuberculosis disease, while 114/2,362 (4.8%) household contacts of 487 drug-susceptible index patients developed tuberculosis disease. The total follow-up time for drug-susceptible tuberculosis contacts was 2,620 person-years, while the total follow-up time for MDRTB contacts was 1,425 person-years. Using multivariate Cox regression to adjust for confounding variables including contact HIV status, contact age, socio-economic status, and index case sputum smear grade, the hazard ratio for tuberculosis disease among MDRTB household contacts was found to be half that for drug-susceptible contacts (hazard ratio 0.56, 95% CI 0.34–0.90, p = 0.017). The inference of transmission in this study was limited by the lack of genotyping data for household contacts. Capturing incident disease only among household contacts may also limit the extrapolation of these findings to the community setting.
Conclusions
The low relative fitness of MDRTB estimated by this study improves the chances of controlling drug-resistant tuberculosis. However, fitter multidrug-resistant strains that emerge over time may make this increasingly difficult.
In this prospective cohort study, Louis Grandjean and colleagues examine the relative fitness of multidrug-resistant versus drug-susceptible tuberculosis for transmission among household contacts in South Lima and Callao, Peru.
Editors' Summary
Background
Tuberculosis—a contagious bacterial disease that usually infects the lungs—is a global public health problem. Every year, 8.6 million people develop active tuberculosis (tuberculosis disease), and at least 1.3 million people die as a result, mainly in resource-limited countries. Mycobacterium tuberculosis, the bacterium that causes tuberculosis, is spread in airborne droplets when people with tuberculosis disease cough or sneeze. Consequently, an individual’s risk of contracting tuberculosis increases with his/her frequency of contact with people who have the disease; people who live in the same household as someone with tuberculosis disease are at particularly high risk. Other risk factors for contracting tuberculosis include living in crowded or insanitary conditions and being immunocompromised because of, for example, infection with HIV. The characteristic symptoms of tuberculosis disease are persistent cough, fever, weight loss, and night sweats. Diagnostic tests for the disease include sputum smear microscopy (microscopic analysis of mucus coughed up from the lungs), the growth of M. tuberculosis from sputum samples, and chest X-rays.
Why Was This Study Done?
Taking several antibiotics (including rifampicin and isoniazid) daily for six months can cure tuberculosis, but the emergence of multidrug-resistant tuberculosis (MDRTB) is making the disease increasingly hard to treat. How badly MDRTB will affect tuberculosis control efforts is likely to depend on the relative “fitness” of multi-drug resistant and drug-susceptible M. tuberculosis strains. The fitness of a pathogen (infectious organism) is its ability to survive, reproduce, be transmitted, and cause disease in another host. Animal and laboratory studies indicate that drug-resistant M. tuberculosis strains are less fit than drug-susceptible strains, but these studies do not account for the clinical, environmental, and socio-economic variables that influence a patient’s ability to cause tuberculosis disease in a contact, and may not accurately measure the relative fitness of M. tuberculosis strains. In this prospective cohort study, the researchers estimate the fitness of drug-resistant tuberculosis relative to drug-susceptible tuberculosis by comparing the incidence of additional cases of tuberculosis disease in households with an MDRTB index case and the incidence in households with a drug-susceptible tuberculosis index case. A prospective cohort study follows a group of people over time to see whether specific baseline characteristics are associated with specific outcomes. The incidence of a disease is the number of new cases in a population over a given time period.
What Did the Researchers Do and Find?
The researchers enrolled 1,055 household contacts of 213 MDRTB index cases (individuals whose disease was resistant to at least rifampicin and isoniazid) and 2,362 household contacts of 487 drug-susceptible tuberculosis index cases living in South Lima and Callao, Peru. During three years of follow-up, 35 (3.3%) of the household contacts of the MDRTB index cases and 114 (4.8%) of the household contacts of the drug-susceptible tuberculosis index cases developed tuberculosis disease. After adjusting for factors likely to affect the transmission of tuberculosis, such as HIV status, socio-economic status, and sputum smear grade of the index case (higher smear grades are associated with a higher risk of tuberculosis transmission), the hazard ratio for tuberculosis disease for household contacts of MDRTB index cases was half that of the household contacts of drug-susceptible tuberculosis index cases. That is, the household contacts of MDRTB index cases contracted tuberculosis disease half as often as those of drug-susceptible tuberculosis index cases.
What Do These Findings Mean?
These findings indicate that, within households, MDRTB has a relatively low fitness compared to drug-susceptible tuberculosis. That is, at least during the first three years following exposure, individuals with MDRTB are less likely to transmit disease to their household contacts than individuals with drug-susceptible tuberculosis. These findings agree with those of previous animal and laboratory studies and with the findings of molecular epidemiology studies that have used genetic methods to estimate M. tuberculosis fitness within populations. Because the researchers did not genetically compare M. tuberculosis strains isolated from the index cases with strains isolated from the household contacts who developed tuberculosis disease, some of these contacts may have become infected outside the household. Moreover, it may not be possible to extrapolate these findings to the community setting. Nevertheless, the low relative fitness of MDRTB reported here improves our chances of controlling the spread of drug-resistant tuberculosis, with the proviso that the emergence of fitter MDRTB strains over time might yet threaten global tuberculosis control efforts.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001843.
The World Health Organization provides information (in several languages) on tuberculosis and on multidrug-resistant tuberculosis; the Global Tuberculosis Report 2014 provides information about tuberculosis around the world; a supplement to the report entitled Drug-Resistant TB—Surveillance and Response is available
The Stop TB Partnership is working towards tuberculosis elimination and provides personal stories about tuberculosis (in English and Spanish); the Tuberculosis Vaccine Initiative (a not-for-profit organization) also provides personal stories about tuberculosis
The US Centers for Disease Control and Prevention provides information about tuberculosis and about drug-resistant tuberculosis (in English and Spanish)
The US National Institute of Allergy and Infectious Diseases also has detailed information on all aspects of tuberculosis
MedlinePlus has links to further information about tuberculosis (in English and Spanish)
doi:10.1371/journal.pmed.1001843
PMCID: PMC4477882  PMID: 26103620
10.  Investigating the effectiveness of different aspirin dosing regimens and the timing of aspirin intake in primary and secondary prevention of cardiovascular disease: protocol for a systematic review 
Systematic Reviews  2015;4:88.
Background
Once-daily low-dose aspirin is routinely used for the prevention of secondary events in cardiovascular disease (CVD). The routine use of aspirin in primary prevention of CVD is less clear due to a finer balance between benefits and harms. In addition, the variability in benefit achievable from the prescription of aspirin has led to a growing interest in considering whether there are more effective aspirin regimens than once-daily dosing or whether effectiveness is influenced by the time of day aspirin is taken (chronotherapy). The proposed systematic review will evaluate the evidence on the effects of different aspirin regimens used in terms of number of doses (e.g. split or alternate dosing) or dosing time of aspirin (e.g. morning versus evening) in primary and secondary prevention of CVD.
Methods/design
Standard systematic review methodology will be employed for study identification, selection and data extraction. Electronic databases will be searched incorporating terms relating to population and the intervention. No date or language limitations will apply. Systematic reviews and controlled studies comparing different aspirin regimens—in terms of frequency or timing—for primary and/or secondary prevention of CVD will be included. No restrictions on outcome will apply. Quality assessment will be appropriate for each study design. The data will be tabulated and narratively synthesised. Meta-analysis may be undertaken where clinical and methodological homogeneity exists.
Discussion
There are a number of published and ongoing primary studies that investigate the cardiovascular protective effect of different aspirin regimens. However, no systematic review to date has attempted to review the evidence pertaining to aspirin dosing regimens differing in frequency and/or in timing. The proposed systematic review will cover both the above questions and could potentially be beneficial for reconsidering the current practice of managing patients with aspirin in primary care.
Systematic review registration
PROSPERO CRD42014010596
Electronic supplementary material
The online version of this article (doi:10.1186/s13643-015-0078-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s13643-015-0078-3
PMCID: PMC4475616  PMID: 26088608
Aspirin; Aspirin doses; Split dosing; Aspirin regimens; Timing; Primary prevention; Secondary prevention; Cardiovascular disease; Systematic review
11.  Prognostic Factors for Response to Cisplatin-based Chemotherapy in Advanced Cervical Carcinoma: a Gynecologic Oncology Group Study 
Gynecologic oncology  2009;116(1):44-49.
Purpose
Cisplatin-based combination chemotherapy is considered standard treatment for advanced/recurrent cervical carcinoma; however, the majority of patients do not respond. This study was undertaken to identify the prognostic factors and develop a model predictive of (non-) response to chemotherapy.
Methods
Four-hundred twenty-eight patients with advanced cervical cancer who received a cisplatin-containing combination in three Gynecologic Oncology Group (GOG) protocols (110, 169 and 179) were evaluated for baseline clinical characteristics and multivariate analysis was conducted to identify factors independently prognostic predictive of response using a Logistic regression model. A predictive model was developed and externally validated using an independent GOG protocol (149) data.
Results
Multivariate analysis identified five factors (African-American, performance status [PS] > 0, pelvic disease, prior radiosensitizer and time interval from diagnosis to first recurrence ≤ one year) independently prognostic of poor response. A simple prognostic index was derived based on the total number of risk factors. When patients were classified into three risk groups (low risk: 0–1 factor; mid risk: 2–3 factors; high risk: 4–5 factors), patients with 4–5 risk factors were estimated to have a response rate of only 13%, and median progression-free and overall survival of 2.8 months and 5.5 months, respectively. The accuracy of the index was supported by both internal and external datasets.
Conclusions
A simple index based on five prognostic factors may have utility in clinical practice to identify the women who are not likely to respond to the cisplatin-containing regimens. This subgroup of patients should be considered for non-cisplatin chemotherapy or investigational trials.
doi:10.1016/j.ygyno.2009.09.006
PMCID: PMC4470610  PMID: 19853287
cervical cancer; cisplatin; tumor response; prognostic factor
12.  Prolonged Infectiousness of Tuberculosis Patients in a Directly Observed Therapy Short-Course Program with Standardized Therapy 
Background
Effective tuberculosis control is compromised by a lack of clarity about the timeframe of viable Mycobacterium tuberculosis shedding after treatment initiation under programmatic conditions. This study quantifies time to conversion from smear and culture positivity to negativity in unselected tuberculosis patients receiving standardized therapy in a directly observed therapy short-course (DOTS) program.
Methods
Longitudinal cohort study following up 93 adults initiating tuberculosis therapy in Lima, Peru. Baseline culture and drug susceptibility tests (DSTs) were performed using the MBBacT, proportion, and microscopic observation drug susceptibility (MODS) methods. Smear microscopy and MODS liquid culture were performed at baseline and weekly for 4 weeks then every other week for 26 weeks.
Results
Median conversion time from culture positivity to culture negativity of 38.5 days was unaffected by baseline smear status. Patients with fully susceptible tuberculosis had a median time to culture conversion of 37 days; 10% remained culture positive at day 60. Delayed culture conversion was associated with multidrug resistance, regardless of DST method used; non–multidrug resistance as defined by the proportion method and MODS (but not MBBacT) was also associated with delay. Persistent day 60 smear positivity yielded positive and negative predictive values of 67% and 92%, respectively, for detecting multidrug resistance.
Conclusions
Smear and culture conversion in treated tuberculosis patients takes longer than is conventionally believed, even with fully susceptible disease, and must be accounted for in tuberculosis treatment and prevention programs. Persistent day 60 smear positivity is a poor predictor of multidrug resistance. The industrialized-world convention of universal baseline DST for tuberculosis patients should become the standard of care in multidrug resistance–affected resource-limited settings.
doi:10.1086/655127
PMCID: PMC4465448  PMID: 20624064
13.  Risk of tuberculosis in patients with diabetes: population based cohort study using the UK Clinical Practice Research Datalink 
BMC Medicine  2015;13:135.
Background
Previous cohort studies demonstrate diabetes as a risk factor for tuberculosis (TB) disease. Public Health England has identified improved TB control as a priority area and has proposed a primary care-based screening program for latent TB.
We investigated the association between diabetes and risk of tuberculosis in a UK General Practice cohort in order to identify potential high-risk groups appropriate for latent TB screening.
Methods
Using data from the UK Clinical Practice Research Datalink we constructed a cohort of patients with incident diabetes. We included 222,731 patients with diabetes diagnosed from 1990–2013 and 1,218,616 controls without diabetes at index date who were matched for age, sex and general practice. The effect of diabetes was explored using a Poisson analysis adjusted for age, ethnicity, body mass index, socioeconomic status, alcohol intake and smoking. We explored the effects of age, diabetes duration and severity. The effects of diabetes on risk of incident TB were explored across strata of chronic disease care defined by cholesterol and blood pressure measurement and influenza vaccination rates.
Results
During just under 7 million person-years of follow-up, 969 cases of TB were identified. The incidence of TB was higher amongst patients with diabetes compared with the unexposed group: 16.2 and 13.5 cases per 100,000 person-years, respectively. After adjustment for potential confounders the association between diabetes and TB remained (adjusted RR 1.30, 95 % CI 1.01 to 1.67, P = 0.04). There was no evidence that age, time since diagnosis and severity of diabetes affected the association between diabetes and TB. Diabetes patients with the lowest and highest rates of chronic disease management had a higher risk of TB (P <0.001 for all comparisons).
Conclusions
Diabetes as an independent risk factor is associated with only a modest overall increased risk of TB in our UK General Practice cohort and is unlikely to be sufficient cause to screen for latent TB. Across different consulting patterns, diabetes patients accessing the least amount of chronic disease care are at highest risk for TB.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-015-0381-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-015-0381-9
PMCID: PMC4470065  PMID: 26048371
Tuberculosis; Diabetes; CPRD; Epidemiology; Cohort
14.  Nutrient Sensing Nuclear Receptors Coordinate Autophagy 
Nature  2014;516(7529):112-115.
Autophagy is an evolutionally conserved catabolic process that recycles nutrients upon starvation and maintains cellular energy homeostasis1–3. Its acute regulation by nutrient sensing signaling pathways is well described, but its longer-term transcriptional regulation is not. The nuclear receptors PPARα and FXR are activated in the fasted or fed liver, respectively4,5. Here we show that both regulate hepatic autophagy. Pharmacologic activation of PPARα reverses the normal suppression of autophagy in the fed state, inducing autophagic lipid degradation, or lipophagy. This response is lost in PPARα knockout (PPARα−/−) mice, which are partially defective in the induction of autophagy by fasting. Pharmacologic activation of the bile acid receptor FXR strongly suppresses the induction of autophagy in the fasting state, and this response is absent in FXR knockout (FXR−/−) mice, which show a partial defect in suppression of hepatic autophagy in the fed state. PPARα and FXR compete for binding to shared sites in autophagic gene promoters, with opposite transcriptional outputs. These results reveal complementary, interlocking mechanisms for regulation of autophagy by nutrient status.
doi:10.1038/nature13961
PMCID: PMC4267857  PMID: 25383539
15.  An Active Lifestyle is Associated with Better Neurocognitive Functioning in Adults Living with HIV-infection 
Journal of neurovirology  2014;20(3):233-242.
Studies of healthy adults show that engagement in physical, social, and mental activities is associated with better cognitive outcomes, suggesting these activities may increase cognitive reserve. Given the prevalence and real-world impact of HIV-associated neurocognitive disorders (HAND), the present study examined the association between neurocognitive outcomes and self-reported proxies for physical exercise, social activity, and mental activity (employment was used as a proxy for mental activity) among 139 HIV-infected adults (Mage = 48.7; 48% age 50+). Participants completed a neuromedical and neuropsychological battery and were classified based on the number of self-reported active lifestyle factors (ALFs; 0 to 3), including physical exercise, social activity, and current employment. The association between ALFs and both demographically-adjusted average neuropsychological T-scores and HAND diagnoses were examined. Results revealed that an increased number of ALFs was associated with better global neurocognitive performance as well as a lower prevalence of HAND. These cross-sectional findings suggest that an active engagement in life may bolster neurocognitive functioning, perhaps by enhancing cognitive and/or brain reserve. However, an alternative explanation might be that persons with better neurocognitive functioning are more inclined and able to engage in these life activities. Future studies should utilize neuroimaging methodology, longitudinal data, and interventional approaches to establish cause-effect relationships and uncover the neural mechanisms whereby physical, social, and mental stimulation may protect neurocognition via cognitive reserve among those living with HIV.
doi:10.1007/s13365-014-0240-z
PMCID: PMC4040153  PMID: 24554483
cognitive reserve; neuroAIDS; cognitive impairment; protective factors
16.  HIV protease inhibitor exposure predicts cerebral small vessel disease 
AIDS (London, England)  2014;28(9):1297-1306.
Objective
HIV-associated neurocognitive disorders (HAND) remain prevalent in patients who receive highly active antiretroviral therapy (HAART) and may be associated with cumulative exposure to antiretroviral medications and other factors. We proposed that chronic toxic effects of antiretroviral drugs could contribute to cerebral small vessel disease (CSVD), which might be one of the key underpinnings of HAND.
Design
Clinicopathological cross-sectional study of HIV-infected adults in the California NeuroAIDS Tissue Network.
Methods
We employed multivariable logistic regression methods to determine associations between HAART exposure (protease inhibitor [PI]-based, non-PI-based, or no HAART) and CSVD occurrence (standard histopathology: moderate/severe, mild, or absent). We also associated HAND (relative to normal cognition) with CSVD, HIV-related neuropathologic changes, older age at death (≥50 years), sex, or hepatitis C virus infection.
Results
We found that both mild and moderate/severe CSVD were associated with PI-based HAART exposure after adjusting for diabetes mellitus [odds ratio (OR) 2.8 [95% confidence interval (CI) 1.03, 7.9] and 2.6 [95% CI 1.03, 6.7], respectively, n=134]. Moderate/severe CSVD was associated with diabetes after adjusting for HAART exposure (OR 7.4 [95% CI 1.6, 70.7], n=134). Notably, HAND was associated with mild CSVD (OR 4.8 [95% CI 1.1, 21.2], n=63), which remained statistically significant after adjusting for vessel mineralization, HIV encephalitis, microglial nodular lesions, white matter lesions, or older age.
Conclusion
PI-based HAART exposure may increase the risk of CSVD and thereby neurocognitive impairment in HIV-infected adults. Besides the possible direct toxicity to cerebral small vessels, PI-based HAART may contribute indirectly to CSVD by inducing metabolic abnormalities.
doi:10.1097/QAD.0000000000000262
PMCID: PMC4071161  PMID: 24637542
aging; antiretroviral; cognition; HIV dementia; protease inhibitor; small vessel disease
17.  Successful Cognitive Aging and Health-Related Quality of Life in Younger and Older Adults Infected with HIV 
AIDS and behavior  2014;18(6):1186-1197.
OBJECTIVE
Neurocognitive impairments commonly occur and adversely impact everyday functioning in older adults infected with HIV, but little is known about successful cognitive aging (SCA) and its health-related quality of life (HRQoL) correlates.
METHOD
Seventy younger (≤ 40 years) and 107 older (≥ 50 years) HIV+ adults, as well as age-matched seronegative comparison groups of younger (N=48) and older (N=77) subjects completed a comprehensive battery of neuropsychological, psychiatric, medical, and HRQoL assessments. SCA was operationalized as the absence of both performance-based neurocognitive deficits and self-reported symptoms (SCA-ANDS) as determined by published normative standards.
RESULTS
A stair-step decline in SCA-ANDS was observed in accordance with increasing age and HIV serostatus, with the lowest rates of SCA-ANDS found in the older HIV+ group (19%). In both younger and older HIV+ adults, SCA-ANDS was strongly related to better mental HRQoL.
CONCLUSION
HIV infection has additive adverse effects on SCA, which may play a unique role in mental well-being among HIV-infected persons across the lifespan.
doi:10.1007/s10461-014-0743-x
PMCID: PMC4020963  PMID: 24633788
Successful aging; well-being; neuropsychological assessment; AIDS-related dementia
18.  Robust and Reproducible Quantification of the Extent of Chest Radiographic Abnormalities (And It’s Free!) 
PLoS ONE  2015;10(5):e0128044.
Rationale
Objective, reproducible quantification of the extent of abnormalities seen on a chest radiograph would improve the user-friendliness of a previously proposed severity scoring system for pulmonary tuberculosis and could be helpful in monitoring response to therapy, including in clinical trials.
Methods
In this study we report the development and evaluation of a simple tool using free image editing software (GIMP) to accurately and reproducibly quantify the area of affected lung on the chest radiograph of tuberculosis patients. As part of a pharmacokinetic study in Lima, Peru, a chest radiograph was performed on patients with pulmonary tuberculosis and this was subsequently photographed using a digital camera. The GIMP software was used by two independent and trained readers to estimate the extent of affected lung (expressed as a percentage of total lung area) in each radiograph and the resulting radiographic SCORE.
Results
56 chest radiographs were included in the reading analysis. The Intraclass correlation coefficient (ICC) between the 2 observers was 0.977 (p<0.001) for the area of lung affected and was 0.955 (p<0.001) for the final score; and the kappa coefficient of Interobserver agreement for both the area of lung affected and the score were 0.9 (p<0.001) and 0.86 (p<0.001) respectively.
Conclusions
This high level of between-observer agreement suggests that this freely available software could constitute a simple and useful tool for robust evaluation of individual and serial chest radiographs.
doi:10.1371/journal.pone.0128044
PMCID: PMC4440724  PMID: 25996917
19.  The Association between Mycobacterium Tuberculosis Genotype and Drug Resistance in Peru 
PLoS ONE  2015;10(5):e0126271.
Background
The comparison of Mycobacterium tuberculosis bacterial genotypes with phenotypic, demographic, geospatial and clinical data improves our understanding of how strain lineage influences the development of drug-resistance and the spread of tuberculosis.
Methods
To investigate the association of Mycobacterium tuberculosis bacterial genotype with drug-resistance. Drug susceptibility testing together with genotyping using both 15-loci MIRU-typing and spoligotyping, was performed on 2,139 culture positive isolates, each from a different patient in Lima, Peru. Demographic, geospatial and socio-economic data were collected using questionnaires, global positioning equipment and the latest national census.
Results
The Latin American Mediterranean (LAM) clade (OR 2.4, p<0.001) was significantly associated with drug-resistance and alone accounted for more than half of all drug resistance in the region. Previously treated patients, prisoners and genetically clustered cases were also significantly associated with drug-resistance (OR's 2.5, 2.4 and 1.8, p<0.001, p<0.05, p<0.001 respectively).
Conclusions
Tuberculosis disease caused by the LAM clade was more likely to be drug resistant independent of important clinical, genetic and socio-economic confounding factors. Explanations for this include; the preferential co-evolution of LAM strains in a Latin American population, a LAM strain bacterial genetic background that favors drug-resistance or the "founder effect" from pre-existing LAM strains disproportionately exposed to drugs.
doi:10.1371/journal.pone.0126271
PMCID: PMC4435908  PMID: 25984723
20.  Lysosomal Signaling Molecules Regulate Longevity in Caenorhabditis elegans 
Science (New York, N.Y.)  2015;347(6217):83-86.
Lysosomes are crucial cellular organelles for human health that function in digestion and recycling of extracellular and intracellular macromolecules. We describe a signaling role for lysosomes that affects aging. In the worm, Caenorhabditis elegans, the lysosomal acid lipase LIPL-4 triggered nuclear translocalization of a lysosomal lipid chaperone LBP-8, consequently promoting longevity by activating the nuclear hormone receptors NHR-49 and NHR-80. We used high-throughput metabolomic analysis to identify several lipids whose abundance was increased in worms constitutively over-expressing LIPL-4. Among them, oleoylethanolamide directly bound to LBP-8 and NHR-80 proteins, activated transcription of target genes of NHR-49 and NHR-80, and promoted longevity in C. elegans. These findings reveal a lysosome-to-nucleus signaling pathway that promotes longevity and suggest a function of lysosomes as signaling organelles in metazoans.
doi:10.1126/science.1258857
PMCID: PMC4425353  PMID: 25554789
21.  The orphan nuclear receptor small heterodimer partner is required for thiazolidinedione effects in leptin-deficient mice 
Background
Small heterodimer partner (SHP, NR0B2) is involved in diverse metabolic pathways, including hepatic bile acid, lipid and glucose homeostasis, and has been implicated in effects on the peroxisome proliferator-activated receptor γ (PPARγ), a master regulator of adipogenesis and the receptor for antidiabetic drugs thiazolidinediones (TZDs). In this study, we aim to investigate the role of SHP in TZD response by comparing TZD-treated leptin-deficient (ob/ob) and leptin-, SHP-deficient (ob/ob;Shp−/−) double mutant mice.
Results
Both ob/ob and double mutant ob/ob;Shp−/− mice developed hyperglycemia, insulin resistance, and hyperlipidemia, but hepatic fat accumulation was decreased in the double mutant ob/ob;Shp−/− mice. PPARγ2 mRNA levels were markedly lower in ob/ob;Shp−/− liver and decreased to a lesser extent in adipose tissue. The TZD troglitazone did not reduce glucose or circulating triglyceride levels in ob/ob;Shp−/− mice. Expression of the adipocytokines, such as adiponectin and resistin, was not stimulated by troglitazone treatment. Expression of hepatic lipogenic genes was also reduced in ob/ob;Shp−/− mice. Moreover, overexpression of SHP by adenovirus infection increased PPARγ2 mRNA levels in mouse primary hepatocytes.
Conclusions
Our results suggest that SHP is required for both antidiabetic and hypolipidemic effects of TZDs in ob/ob mice through regulation of PPARγ expression.
doi:10.1186/s12929-015-0133-3
PMCID: PMC4489392  PMID: 25951943
SHP; Troglitazone; PPARγ; Thiazolidinedione
22.  Feedback Valence Affects Auditory Perceptual Learning Independently of Feedback Probability 
PLoS ONE  2015;10(5):e0126412.
Previous studies have suggested that negative feedback is more effective in driving learning than positive feedback. We investigated the effect on learning of providing varying amounts of negative and positive feedback while listeners attempted to discriminate between three identical tones; an impossible task that nevertheless produces robust learning. Four feedback conditions were compared during training: 90% positive feedback or 10% negative feedback informed the participants that they were doing equally well, while 10% positive or 90% negative feedback informed them they were doing equally badly. In all conditions the feedback was random in relation to the listeners’ responses (because the task was to discriminate three identical tones), yet both the valence (negative vs. positive) and the probability of feedback (10% vs. 90%) affected learning. Feedback that informed listeners they were doing badly resulted in better post-training performance than feedback that informed them they were doing well, independent of valence. In addition, positive feedback during training resulted in better post-training performance than negative feedback, but only positive feedback indicating listeners were doing badly on the task resulted in learning. As we have previously speculated, feedback that better reflected the difficulty of the task was more effective in driving learning than feedback that suggested performance was better than it should have been given perceived task difficulty. But contrary to expectations, positive feedback was more effective than negative feedback in driving learning. Feedback thus had two separable effects on learning: feedback valence affected motivation on a subjectively difficult task, and learning occurred only when feedback probability reflected the subjective difficulty. To optimize learning, training programs need to take into consideration both feedback valence and probability.
doi:10.1371/journal.pone.0126412
PMCID: PMC4422442  PMID: 25946173
23.  All-trans-Retinoic Acid Ameliorates Hepatic Steatosis in Mice via a Novel Transcriptional Cascade 
Hepatology (Baltimore, Md.)  2014;59(5):1750-1760.
Mice deficient small heterodimer partner (SHP) are protected from diet induced hepatic steatosis due to increased fatty acid oxidation and decreased lipogenesis. The decreased lipogenesis appears to be a direct consequence of very low expression of peroxisome proliferator activated receptor gamma 2 (PPARγ2), a potent lipogenic transcription factor, in the SHP−/− liver. The current study focuses on the identification of a SHP dependent regulatory cascade that controls PPARγ2 gene expression, thereby regulating hepatic fat accumulation. Illumina BeadChip array and real-time polymerase chain reaction were used to identify genes responsible for the linkage between SHP and PPARγ2 using hepatic RNAs isolated from SHP−/− and SHP-overexpressing mice. The initial efforts identify that hairy and enhancer of split 6 (Hes6), a novel transcriptional repressor, is an important mediator of the regulation of PPARγ2 transcription by SHP. The Hes6 promoter is specifically activated by the retinoic acid receptor (RAR) in response to its natural agonist ligand all-trans retinoic acid (atRA), and is repressed by SHP. Hes6 subsequently represses hepatocyte nuclear factor 4 alpha (HNF4α) activated-PPARγ2 gene expression via direct inhibition of the HNF4α transcriptional activity. Furthermore, we provide evidences that atRA treatment or adenovirus-mediated RARα overexpression significantly reduced hepatic fat accumulation in obese mouse models as observed in earlier studies and the beneficial effect is achieved via the proposed transcriptional cascade.
Conclusions
Our study describes a novel transcriptional regulatory cascade controlling hepatic lipid metabolism that identifies retinoic acid signaling as a new therapeutic approach to non-alcoholic fatty liver diseases.
doi:10.1002/hep.26699
PMCID: PMC4008145  PMID: 24038081
Lipid homeostasis; Nuclear Hormone Receptors; Fsp27; SHP; Hes6
24.  Hearing in middle age: a population snapshot of 40–69 year olds in the UK 
Ear and hearing  2014;35(3):e44-e51.
Objective
To report population-based prevalence of hearing impairment based on speech recognition in noise testing in a large and inclusive sample of UK adults aged 40 to 69 years. The present study is the first to report such data. Prevalence of tinnitus and use of hearing aids is also reported.
Design
The research was conducted using the UK Biobank resource. The better-ear unaided speech reception threshold was measured adaptively using the Digit Triplet Test (n = 164,770). Self-report data on tinnitus, hearing aid use, noise exposure as well as demographic variables were collected.
Results
Overall, 10.7% of adults (95%CI 10.5–10.9%) had significant hearing impairment. Prevalence of tinnitus was 16.9% (95%CI 16.6–17.1%) and hearing aid use was 2.0% (95%CI 1.9–2.1%). Odds of hearing impairment increased with age, with a history of work- and music-related noise exposure, for lower socioeconomic background and for ethnic minority backgrounds. Males were at no higher risk of hearing impairment than females.
Conclusion
Around 1 in 10 adults aged 40 to 69 years have substantial hearing impairment. The reasons for excess risk of hearing impairment particularly for those from low socioeconomic and ethnic minority backgrounds require identification, as this represents a serious health inequality. The underutilization of hearing aids has altered little since the 1980s, and is a major cause for concern.
doi:10.1097/AUD.0000000000000010
PMCID: PMC4264521  PMID: 24518430
25.  Good Quality Locally Procured Drugs Can Be as Effective as Internationally Quality Assured Drugs in Treating Multi-Drug Resistant Tuberculosis 
PLoS ONE  2015;10(4):e0126099.
Background
Owing toGiven the high costs of drugs to treat multi-drug resistant tuberculosis (MDR-TB), the Green Light Committee (GLC) initiative enables TB programs to procure quality-assured drugs at reduced prices. Despite price reductions, internationally quality assured (IQA) drugs can be more expensive than locally procured drugs. There is little evidence to inform decision-makers about whether IQA drugs are more effective than local drugs. This is the first study to compare outcomes between MDR-TB patients treated using IQA, and locally procured drugs in the same hospitals during the same time period.
Methods/Findings
A retrospective cohort study was conducted in three hospitals across Pakistan. Data on baseline characteristics and treatment outcomes during the first six months of treatment were extracted from hospital records of adult culture-positive pulmonary MDR-TB patients starting treatment between January 2011 and June 2012. Two cohorts were defined: patients receiving IQA drugs, and patients receiving locally procured non-IQA drugs. Data were analysed using Kaplan-Meier curves and Cox proportional hazards regression. The primary outcome compared between cohorts was time to culture conversion. Of 231 patients, 90 were in the IQA and 141 in the non-IQA cohorts. Baseline characteristics were similar except for higher frequency of quinolone resistance in the IQA cohort. Overall, 193 patients (84%) culture converted. Culture conversion was not faster in the IQA cohort; the median time was 81 and 68 days in the IQA and non-IQA cohorts, respectively. Unadjusted and adjusted hazard ratios for culture conversion in IQA verses non-IQA cohorts were 0.82 (95%-CI, 0.62-1.10) and 0.95 (95%-CI, 0.66-1.36) respectively.
Conclusions
Use of good quality, locally procured drugs can be effective in treating MDR-TB, may involve lower costs than using IQA drugs and could strengthen developing country drug quality assurance systems. This may be a suitable alternative in lieu of or whilst awaiting arrival of internationally procured medicines.
doi:10.1371/journal.pone.0126099
PMCID: PMC4414548  PMID: 25923538

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