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Multiple morbidities in pregnancy: Time for research, innovation, and action

Ma, 25/09/2018 - 23:00

by James G. Beeson, Caroline S. E. Homer, Christopher Morgan, Clara Menendez

In a Guest Editorial, James Beeson and colleagues discuss the contribution of nonobstetric morbidity to mortality during and around pregnancy and what needs to be done to address this global health challenge.

Variations in the quality of tuberculosis care in urban India: A cross-sectional, standardized patient study in two cities

Ma, 25/09/2018 - 23:00

by Ada Kwan, Benjamin Daniels, Vaibhav Saria, Srinath Satyanarayana, Ramnath Subbaraman, Andrew McDowell, Sofi Bergkvist, Ranendra K. Das, Veena Das, Jishnu Das, Madhukar Pai

Background

India has the highest burden of tuberculosis (TB). Although most patients with TB in India seek care from the private sector, there is limited evidence on quality of TB care or its correlates. Following our validation study on the standardized patient (SP) method for TB, we utilized SPs to examine quality of adult TB care among health providers with different qualifications in 2 Indian cities.

Methods and findings

During 2014–2017, pilot programs engaged the private health sector to improve TB management in Mumbai and Patna. Nested within these projects, to obtain representative, baseline measures of quality of TB care at the city level, we recruited 24 adults to be SPs. They were trained to portray 4 TB “case scenarios” representing various stages of disease and diagnostic progression. Between November 2014 and August 2015, the SPs visited representatively sampled private providers stratified by qualification: (1) allopathic providers with Bachelor of Medicine, Bachelor of Surgery (MBBS) degrees or higher and (2) non-MBBS providers with alternative medicine, minimal, or no qualifications.Our main outcome was case-specific correct management benchmarked against the Standards for TB Care in India (STCI). Using ANOVA, we assessed variation in correct management and quality outcomes across (a) cities, (b) qualifications, and (c) case scenarios. Additionally, 2 micro-experiments identified sources of variation: first, quality in the presence of diagnostic test results certainty and second, provider consistency for different patients presenting the same case.A total of 2,652 SP–provider interactions across 1,203 health facilities were analyzed. Based on our sampling strategy and after removing 50 micro-experiment interactions, 2,602 interactions were weighted for city-representative interpretation. After weighting, the 473 Patna providers receiving SPs represent 3,179 eligible providers in Patna; in Mumbai, the 730 providers represent 7,115 eligible providers. Correct management was observed in 959 out of 2,602 interactions (37%; 35% weighted; 95% CI 32%–37%), primarily from referrals and ordering chest X-rays (CXRs). Unnecessary medicines were given to nearly all SPs, and antibiotic use was common. Anti-TB drugs were prescribed in 118 interactions (4.5%; 5% weighted), of which 45 were given in the case in which such treatment is considered correct management.MBBS and more qualified providers had higher odds of correctly managing cases than non-MBBS providers (odds ratio [OR] 2.80; 95% CI 2.05–3.82; p < 0.0001). Mumbai non-MBBS providers had higher odds of correct management than non-MBBS in Patna (OR 1.79; 95% CI 1.06–3.03), and MBBS providers’ quality of care did not vary between cities (OR 1.15; 95% CI 0.79–1.68; p = 0.4642). In the micro-experiments, improving diagnostic certainty had a positive effect on correct management but not across all quality dimensions. Also, providers delivered idiosyncratically consistent care, repeating all observed actions, including mistakes, approximately 75% of the time. The SP method has limitations: it cannot account for patient mix or care-management practices reflecting more than one patient–provider interaction.

Conclusions

Quality of TB care is suboptimal and variable in urban India’s private health sector. Addressing this is critical for India’s plans to end TB by 2025. For the first time, we have rich measures on representative levels of care quality from 2 cities, which can inform private-sector TB interventions and quality-improvement efforts.

Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial

Lu, 24/09/2018 - 23:00

by Brian Lawlor, Ricardo Segurado, Sean Kennelly, Marcel G. M. Olde Rikkert, Robert Howard, Florence Pasquier, Anne Börjesson-Hanson, Magda Tsolaki, Ugo Lucca, D. William Molloy, Robert Coen, Matthias W. Riepe, János Kálmán, Rose Anne Kenny, Fiona Cregg, Sarah O'Dwyer, Cathal Walsh, Jessica Adams, Rita Banzi, Laetitia Breuilh, Leslie Daly, Suzanne Hendrix, Paul Aisen, Siobhan Gaynor, Ali Sheikhi, Diana G. Taekema, Frans R. Verhey, Raffaello Nemni, Flavio Nobili, Massimo Franceschi, Giovanni Frisoni, Orazio Zanetti, Anastasia Konsta, Orologas Anastasios, Styliani Nenopoulou, Fani Tsolaki-Tagaraki, Magdolna Pakaski, Olivier Dereeper, Vincent de la Sayette, Olivier Sénéchal, Isabelle Lavenu, Agnès Devendeville, Gauthier Calais, Fiona Crawford, Michael Mullan, for the NILVAD Study Group

Background

This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti-inflammatory and anti-tau activity in preclinical studies, properties that could have disease-modifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease.

Methods and findings

NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of ≥12 and <27. Participants were randomly assigned to 8 mg sustained-release nilvadipine or matched placebo. The a priori defined primary outcome was progression on the Alzheimer's Disease Assessment Scale Cognitive Subscale-12 (ADAS-Cog 12) in the modified intention-to-treat (mITT) population (n = 498), with the Clinical Dementia Rating Scale sum of boxes (CDR-sb) as a gated co-primary outcome, eligible to be promoted to primary end point conditional on a significant effect on the ADAS-Cog 12. The analysis set had a mean age of 73 years and was 62% female. Baseline demographic and Alzheimer disease–specific characteristics were similar between treatment groups, with reported mean of 1.7 years since diagnosis and mean SMMSE of 20.4. The prespecified primary analyses failed to show any treatment benefit for nilvadipine on the co-primary outcome (p = 0.465). Decline from baseline in ADAS-Cog 12 on placebo was 0.79 (95% CI, −0.07–1.64) at 13 weeks, 6.41 (5.33–7.49) at 52 weeks, and 9.63 (8.33–10.93) at 78 weeks and on nilvadipine was 0.88 (0.02–1.74) at 13 weeks, 5.75 (4.66–6.85) at 52 weeks, and 9.41 (8.09–10.73) at 78 weeks. Exploratory analyses of the planned secondary outcomes showed no substantial effects, including on the CDR-sb or the Disability Assessment for Dementia. Nilvadipine appeared to be safe and well tolerated. Mortality was similar between groups (3 on nilvadipine, 4 on placebo); higher counts of adverse events (AEs) on nilvadipine (1,129 versus 1,030), and serious adverse events (SAEs; 146 versus 101), were observed. There were 14 withdrawals because of AEs. Major limitations of this study were that subjects had established dementia and the likelihood that non-Alzheimer subjects were included because of the lack of biomarker confirmation of the presence of brain amyloid.

Conclusions

The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease.

Trial registration

Clinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.

Type 2 diabetes genetic loci informed by multi-trait associations point to disease mechanisms and subtypes: A soft clustering analysis

Ve, 21/09/2018 - 23:00

by Miriam S. Udler, Jaegil Kim, Marcin von Grotthuss, Sílvia Bonàs-Guarch, Joanne B. Cole, Joshua Chiou, Christopher D. Anderson on behalf of METASTROKE and the ISGC , Michael Boehnke, Markku Laakso, Gil Atzmon, Benjamin Glaser, Josep M. Mercader, Kyle Gaulton, Jason Flannick, Gad Getz, Jose C. Florez

Background

Type 2 diabetes (T2D) is a heterogeneous disease for which (1) disease-causing pathways are incompletely understood and (2) subclassification may improve patient management. Unlike other biomarkers, germline genetic markers do not change with disease progression or treatment. In this paper, we test whether a germline genetic approach informed by physiology can be used to deconstruct T2D heterogeneity. First, we aimed to categorize genetic loci into groups representing likely disease mechanistic pathways. Second, we asked whether the novel clusters of genetic loci we identified have any broad clinical consequence, as assessed in four separate subsets of individuals with T2D.

Methods and findings

In an effort to identify mechanistic pathways driven by established T2D genetic loci, we applied Bayesian nonnegative matrix factorization (bNMF) clustering to genome-wide association study (GWAS) results for 94 independent T2D genetic variants and 47 diabetes-related traits. We identified five robust clusters of T2D loci and traits, each with distinct tissue-specific enhancer enrichment based on analysis of epigenomic data from 28 cell types. Two clusters contained variant-trait associations indicative of reduced beta cell function, differing from each other by high versus low proinsulin levels. The three other clusters displayed features of insulin resistance: obesity mediated (high body mass index [BMI] and waist circumference [WC]), “lipodystrophy-like” fat distribution (low BMI, adiponectin, and high-density lipoprotein [HDL] cholesterol, and high triglycerides), and disrupted liver lipid metabolism (low triglycerides). Increased cluster genetic risk scores were associated with distinct clinical outcomes, including increased blood pressure, coronary artery disease (CAD), and stroke. We evaluated the potential for clinical impact of these clusters in four studies containing individuals with T2D (Metabolic Syndrome in Men Study [METSIM], N = 487; Ashkenazi, N = 509; Partners Biobank, N = 2,065; UK Biobank [UKBB], N = 14,813). Individuals with T2D in the top genetic risk score decile for each cluster reproducibly exhibited the predicted cluster-associated phenotypes, with approximately 30% of all individuals assigned to just one cluster top decile. Limitations of this study include that the genetic variants used in the cluster analysis were restricted to those associated with T2D in populations of European ancestry.

Conclusion

Our approach identifies salient T2D genetically anchored and physiologically informed pathways, and supports the use of genetics to deconstruct T2D heterogeneity. Classification of patients by these genetic pathways may offer a step toward genetically informed T2D patient management.

Community delivery of antiretroviral drugs: A non-inferiority cluster-randomized pragmatic trial in Dar es Salaam, Tanzania

Me, 19/09/2018 - 23:00

by Pascal Geldsetzer, Joel M. Francis, David Sando, Gerda Asmus, Irene A. Lema, Eric Mboggo, Happiness Koda, Sharon Lwezaula, Ramya Ambikapathi, Wafaie Fawzi, Nzovu Ulenga, Till Bärnighausen

Background

With the increase in people living with HIV in sub-Saharan Africa and expanding eligibility criteria for antiretroviral therapy (ART), there is intense interest in the use of novel delivery models that allow understaffed health systems to successfully deal with an increasing demand for antiretroviral drugs (ARVs). This pragmatic randomized controlled trial in Dar es Salaam, Tanzania, evaluated a novel model of ARV community delivery: lay health workers (home-based carers [HBCs]) deliver ARVs to the homes of patients who are clinically stable on ART, while nurses and physicians deliver standard facility-based care for patients who are clinically unstable. Specifically, the trial aimed to assess whether the ARV community delivery model performed at least equally well in averting virological failure as the standard of care (facility-based care for all ART patients).

Methods and findings

The study took place from March 1, 2016, to October 27, 2017. All (48) healthcare facilities in Dar es Salaam that provided ART and had an affiliated team of public-sector HBCs were randomized 1:1 to either (i) ARV community delivery (intervention) or (ii) the standard of care (control). Our prespecified primary endpoint was the proportion of adult non-pregnant ART patients with virological failure at the end of the study period. The prespecified margin of non-inferiority was a risk ratio (RR) of 1.45. The mean follow-up period was 326 days. We obtained intent-to-treat (ITT) RRs using a log-binomial model adjusting standard errors for clustering at the level of the healthcare facility. A total of 2,172 patients were enrolled at intervention (1,163 patients) and control (1,009 patients) facilities. Of the 1,163 patients in the intervention arm, 516 (44.4%) were both clinically stable on ART and opted to receive ARVs in their homes or at another meeting point of their choosing in the community. At the end of the study period, 10.9% (95/872) of patients in the control arm and 9.7% (91/943) in the intervention arm were failing virologically. The ITT RR for virological failure demonstrated non-inferiority of the ARV community delivery model (RR 0.89 [1-sided 95% CI 0.00–1.18]). We observed no significant difference between study arms in self-reported patient healthcare expenditures over the last 6 months before study exit. Of those who received ARVs in the community, 97.2% (95% CI 94.7%–98.7%) reported being either “satisfied” or “very satisfied” with the program. Other than loss to follow-up (18.9% in the intervention and 13.6% in the control arm), the main limitation of this trial was that substantial decongestion of healthcare facilities was not achieved, thus making the logic for our preregistered ITT approach (which includes those ineligible to receive ARVs at home in the intervention sample) less compelling.

Conclusions

In this study, an ARV community delivery model performed at least as well as the standard of care regarding the critical health indicator of virological failure. The intervention did not significantly reduce patient healthcare expenditures, but satisfaction with the program was high and it is likely to save patients time. Policy-makers should consider piloting, evaluating, and scaling more ambitious ARV community delivery programs that can reach higher proportions of ART patients.

Trial registration

ClinicalTrials.gov NCT02711293.

Nutritional quality of food as represented by the FSAm-NPS nutrient profiling system underlying the Nutri-Score label and cancer risk in Europe: Results from the EPIC prospective cohort study

Ma, 18/09/2018 - 23:00

by Mélanie Deschasaux, Inge Huybrechts, Neil Murphy, Chantal Julia, Serge Hercberg, Bernard Srour, Emmanuelle Kesse-Guyot, Paule Latino-Martel, Carine Biessy, Corinne Casagrande, Mazda Jenab, Heather Ward, Elisabete Weiderpass, Christina C. Dahm, Kim Overvad, Cecilie Kyrø, Anja Olsen, Aurélie Affret, Marie-Christine Boutron-Ruault, Yahya Mahamat-Saleh, Rudolf Kaaks, Tilman Kühn, Heiner Boeing, Lukas Schwingshackl, Christina Bamia, Eleni Peppa, Antonia Trichopoulou, Giovanna Masala, Vittorio Krogh, Salvatore Panico, Rosario Tumino, Carlotta Sacerdote, Bas Bueno-de-Mesquita, Petra H. Peeters, Anette Hjartåker, Charlotta Rylander, Guri Skeie, J. Ramón Quirós, Paula Jakszyn, Elena Salamanca-Fernández, José María Huerta, Eva Ardanaz, Pilar Amiano, Ulrika Ericson, Emily Sonestedt, Ena Huseinovic, Ingegerd Johansson, Kay-Tee Khaw, Nick Wareham, Kathryn E. Bradbury, Aurora Perez-Cornago, Konstantinos K. Tsilidis, Pietro Ferrari, Elio Riboli, Marc J. Gunter, Mathilde Touvier

Background

Helping consumers make healthier food choices is a key issue for the prevention of cancer and other diseases. In many countries, political authorities are considering the implementation of a simplified labelling system to reflect the nutritional quality of food products. The Nutri-Score, a five-colour nutrition label, is derived from the Nutrient Profiling System of the British Food Standards Agency (modified version) (FSAm-NPS). How the consumption of foods with high/low FSAm-NPS relates to cancer risk has been studied in national/regional cohorts but has not been characterized in diverse European populations.

Methods and findings

This prospective analysis included 471,495 adults from the European Prospective Investigation into Cancer and Nutrition (EPIC, 1992–2014, median follow-up: 15.3 y), among whom there were 49,794 incident cancer cases (main locations: breast, n = 12,063; prostate, n = 6,745; colon-rectum, n = 5,806). Usual food intakes were assessed with standardized country-specific diet assessment methods. The FSAm-NPS was calculated for each food/beverage using their 100-g content in energy, sugar, saturated fatty acid, sodium, fibres, proteins, and fruits/vegetables/legumes/nuts. The FSAm-NPS scores of all food items usually consumed by a participant were averaged to obtain the individual FSAm-NPS Dietary Index (DI) scores. Multi-adjusted Cox proportional hazards models were computed. A higher FSAm-NPS DI score, reflecting a lower nutritional quality of the food consumed, was associated with a higher risk of total cancer (HRQ5 versus Q1 = 1.07; 95% CI 1.03–1.10, P-trend < 0.001). Absolute cancer rates in those with high and low (quintiles 5 and 1) FSAm-NPS DI scores were 81.4 and 69.5 cases/10,000 person-years, respectively. Higher FSAm-NPS DI scores were specifically associated with higher risks of cancers of the colon-rectum, upper aerodigestive tract and stomach, lung for men, and liver and postmenopausal breast for women (all P < 0.05). The main study limitation is that it was based on an observational cohort using self-reported dietary data obtained through a single baseline food frequency questionnaire; thus, exposure misclassification and residual confounding cannot be ruled out.

Conclusions

In this large multinational European cohort, the consumption of food products with a higher FSAm-NPS score (lower nutritional quality) was associated with a higher risk of cancer. This supports the relevance of the FSAm-NPS as underlying nutrient profiling system for front-of-pack nutrition labels, as well as for other public health nutritional measures.

Towards national systems for continuous surveillance of antimicrobial resistance: Lessons from tuberculosis

Ve, 14/09/2018 - 23:00

by Amitabh B. Suthar, Patrick K. Moonan, Heather L. Alexander

In a Perspective on the research article from Jacobson and colleagues, Amitabh Suthar and colleagues from the Centers for Disease Control and Prevention discuss the importance of and considerations for developing real-time and large-scale reporting systems for tracking and controlling antimicrobial resistance.

Associations of device-measured physical activity across adolescence with metabolic traits: Prospective cohort study

Ma, 11/09/2018 - 23:00

by Joshua A. Bell, Mark Hamer, Rebecca C. Richmond, Nicholas J. Timpson, David Carslake, George Davey Smith

Background

Multiple occasions of device-measured physical activity have not been previously examined in relation to metabolic traits. We described associations of total activity, moderate-to-vigorous physical activity (MVPA), and sedentary time from three accelerometry measures taken across adolescence with detailed traits related to systemic metabolism.

Methods and findings

There were 1,826 male and female participants recruited at birth in 1991–1992 via mothers into the Avon Longitudinal Study of Parents and Children offspring cohort who attended clinics in 2003–2005, 2005–2006, and 2006–2008 who were included in ≥1 analysis. Waist-worn uniaxial accelerometers measured total activity (counts/min), MVPA (min/d), and sedentary time (min/d) over ≥3 d at mean age 12y, 14y, and 15y. Current activity (at age 15y), mean activity across occasions, interaction by previous activity, and change in activity were examined in relation to systolic and diastolic blood pressure, insulin, C-reactive protein, and 230 traits from targeted metabolomics (nuclear magnetic resonance spectroscopy), including lipoprotein cholesterol and triglycerides, amino and fatty acids, glycoprotein acetyls, and others, at age 15y. Mean current total activity was 477.5 counts/min (SD = 164.0) while mean MVPA and sedentary time durations were 23.6 min/d (SD = 17.9) and 522.1 min/d (SD = 66.0), respectively. Mean body mass index at age 15y was 21.4 kg/m2 (SD = 3.5). Correlations between first and last activity measurement occasions were low (e.g., r = 0.40 for counts/min). Current activity was most strongly associated with cholesterol and triglycerides in high-density lipoprotein (HDL) and very low-density lipoprotein (VLDL) particles (e.g., −0.002 mmol/l or −0.18 SD units; 95% CI −0.24–−0.11 for triglycerides in chylomicrons and extremely large very low-density lipoprotein [XL VLDL]) and with glycoprotein acetyls (−0.02 mmol/l or −0.16 SD units; 95% CI −0.22–−0.10), among others. Associations were similar for mean activity across 3 occasions. Attenuations were modest with adjustment for fat mass index based on dual-energy X-ray absorptiometry (DXA). In mutually adjusted models, higher MVPA and sedentary time were oppositely associated with cholesterol and triglycerides in VLDL and HDL particles (MVPA more strongly with glycoprotein acetyls and sedentary time more strongly with amino acids). Associations appeared less consistent for sedentary time than for MVPA based on longer-term measures and were weak for change in all activity types from age 12y–15y. Evidence was also weak for interaction between activity types at age 15y and previous activity measures in relation to most traits (minimum P = 0.003; median P = 0.26 for counts/min) with interaction coefficients mostly positive. Study limitations include modest sample sizes and relatively short durations of accelerometry measurement on each occasion (3–7 d) and of time lengths between first and last accelerometry occasions (<4 years), which can obscure patterns from chance variation and limit description of activity trajectories. Activity was also recorded using uniaxial accelerometers which predated more sensitive triaxial devices.

Conclusions

Our results support associations of physical activity with metabolic traits that are small in magnitude and more robust for higher MVPA than lower sedentary time. Activity fluctuates over time, but associations of current activity with most metabolic traits do not differ by previous activity. This suggests that the metabolic effects of physical activity, if causal, depend on most recent engagement.

Risk of adverse outcomes following urinary tract infection in older people with renal impairment: Retrospective cohort study using linked health record data

Lu, 10/09/2018 - 23:00

by Haroon Ahmed, Daniel Farewell, Nick A. Francis, Shantini Paranjothy, Christopher C. Butler

Background

Few studies have investigated the risk of adverse outcomes in older people with renal impairment presenting to primary care with a urinary tract infection (UTI). The aim of this study was to determine the risk of adverse outcomes in patients aged ≥65 years presenting to primary care with a UTI, by estimated glomerular filtration rate (eGFR) and empirical prescription of nitrofurantoin versus trimethoprim.

Methods and findings

This was a retrospective cohort study using linked health record data from 795,484 patients from 393 general practices in England, who were aged ≥65 years between 2010 and 2016. Patients were entered into the cohort if they presented with a UTI and had a creatinine measurement in the 24 months prior to presentation. We calculated an eGFR to estimate risk of adverse outcomes by renal function, and propensity-score matched patients with eGFRs <60 mL/minute/1.73 m2 to estimate risk of adverse outcomes between those prescribed trimethoprim and nitrofurantoin. Outcomes were 14-day risk of reconsultation for urinary symptoms and same-day antibiotic prescription (proxy for treatment nonresponse), hospitalisation for UTI, sepsis, or acute kidney injury (AKI), and 28-day risk of death. Of 123,607 eligible patients with a UTI, we calculated an eGFR for 116,945 (95%). Median age was 76 (IQR, 70–83) years and 32,428 (28%) were male. Compared to an eGFR of >60 mL/minute/1.73 m2, patients with an eGFR of <60 mL/minute/1.73 m2 had greater odds of hospitalisation for UTI (adjusted odds ratios [ORs] ranged from 1.14 [95% confidence interval (CI) 1.01–1.28, p = 0.028], for eGFRs of 45–59, to 1.68 [95% CI 1.01–2.82, p < 0.001] for eGFRs <15) and AKI (adjusted ORs ranged from 1.57 [95% CI 1.29–1.91, p < 0.001], for eGFRs of 45–59, to 4.53 [95% CI 2.52–8.17, p < 0.001] for eGFRs <15). Compared to an eGFR of >60 mL/minute/1.73 m2, patients with an eGFR <45 had significantly greater odds of hospitalisation for sepsis, and those with an eGFR <30 had significantly greater odds of death. Compared to trimethoprim, nitrofurantoin prescribing was associated with lower odds of hospitalisation for AKI (ORs ranged from 0.62 [95% CI 0.40–0.94, p = 0.025], for eGFRs of 45–59, to 0.45 [95% CI 0.25–0.81, p = 0.008] for eGFRs <30). Nitrofurantoin was not associated with greater odds of any adverse outcome. Our study lacked data on urine microbiology and antibiotic-related adverse events. Despite our design, residual confounding may still have affected some of our findings.

Conclusions

Older patients with renal impairment presenting to primary care with a UTI had an increased risk of UTI-related hospitalisation and death, suggesting a need for interventions that reduce the risk of these adverse outcomes. Nitrofurantoin prescribing was not associated with an increased risk of adverse outcomes in patients with an eGFR <60 mL/minute/1.73 m2 and could be used more widely in this population.

Correction: Suppression of GATA-3 Nuclear Import and Phosphorylation: A Novel Mechanism of Corticosteroid Action in Allergic Disease

Ve, 07/09/2018 - 23:00

by Kittipong Maneechotesuwan, Xin Yao, Kazuhiro Ito, Elen Jazrawi, Omar S. Usmani, Ian M. Adcock, Peter J. Barnes

Seasonal plasticity of cognition and related biological measures in adults with and without Alzheimer disease: Analysis of multiple cohorts

Ma, 04/09/2018 - 23:00

by Andrew S. P. Lim, Chris Gaiteri, Lei Yu, Shahmir Sohail, Walter Swardfager, Shinya Tasaki, Julie A. Schneider, Claire Paquet, Donald T. Stuss, Mario Masellis, Sandra E. Black, Jacques Hugon, Aron S. Buchman, Lisa L. Barnes, David A. Bennett, Philip L. De Jager

Background

There are few data concerning the association between season and cognition and its neurobiological correlates in older persons—effects with important translational and therapeutic implications for the diagnosis and treatment of Alzheimer disease (AD). We aimed to measure these effects.

Methods and findings

We analyzed data from 3,353 participants from 3 observational community-based cohort studies of older persons (the Rush Memory and Aging Project [MAP], the Religious Orders Study [ROS], and the Minority Aging Research Study [MARS]) and 2 observational memory-clinic-based cohort studies (Centre de Neurologie Cognitive [CNC] study at Lariboisière Hospital and the Sunnybrook Dementia Study [SDS]). We performed neuropsychological testing and, in subsets of participants, evaluated cerebrospinal fluid AD biomarkers, standardized structured autopsy measures, and/or prefrontal cortex gene expression by RNA sequencing. We examined the association between season and these variables using nested multiple linear and logistic regression models. There was a robust association between season and cognition that was replicated in multiple cohorts (amplitude = 0.14 SD [a measure of the magnitude of seasonal variation relative to overall variability; 95% CI 0.07–0.23], p = 0.007, in the combined MAP, ROS, and MARS cohorts; amplitude = 0.50 SD [95% CI 0.07–0.66], p = 0.017, in the SDS cohort). Average composite global cognitive function was higher in the summer and fall compared to winter and spring, with the difference equivalent in cognitive effect to 4.8 years’ difference in age (95% CI 2.1–8.4, p = 0.002). Further, the odds of meeting criteria for mild cognitive impairment or dementia were higher in the winter and spring (odds ratio 1.31 [95% CI 1.10–1.57], p = 0.003). These results were robust against multiple potential confounders including depressive symptoms, sleep, physical activity, and thyroid status and persisted in cases with AD pathology. Moreover, season had a marked effect on cerebrospinal fluid Aβ 42 level (amplitude 0.30 SD [95% CI 0.10–0.64], p = 0.003), which peaked in the summer, and on the brain expression of 4 cognition-associated modules of co-expressed genes (m6: amplitude = 0.44 SD [95% CI 0.21–0.65], p = 0.0021; m13: amplitude = 0.46 SD [95% CI 0.27–0.76], p = 0.0009; m109: amplitude = 0.43 SD [95% CI 0.24–0.67], p = 0.0021; and m122: amplitude 0.46 SD [95% CI 0.20–0.71], p = 0.0012), which were in phase or anti-phase to the rhythms of cognition and which were in turn associated with binding sites for several seasonally rhythmic transcription factors including BCL11A, CTCF, EGR1, MEF2C, and THAP1. Limitations include the evaluation of each participant or sample once per annual cycle, reliance on self-report for measurement of environmental and behavioral factors, and potentially limited generalizability to individuals in equatorial regions or in the southern hemisphere.

Conclusions

Season has a clinically significant association with cognition and its neurobiological correlates in older adults with and without AD pathology. There may be value in increasing dementia-related clinical resources in the winter and early spring, when symptoms are likely to be most pronounced. Moreover, the persistence of robust seasonal plasticity in cognition and its neurobiological correlates, even in the context of concomitant AD pathology, suggests that targeting environmental or behavioral drivers of seasonal cognitive plasticity, or the key transcription factors and genes identified in this study as potentially mediating these effects, may allow us to substantially improve cognition in adults with and without AD.

Addition of a polygenic risk score, mammographic density, and endogenous hormones to existing breast cancer risk prediction models: A nested case–control study

Ma, 04/09/2018 - 23:00

by Xuehong Zhang, Megan Rice, Shelley S. Tworoger, Bernard A. Rosner, A. Heather Eliassen, Rulla M. Tamimi, Amit D. Joshi, Sara Lindstrom, Jing Qian, Graham A. Colditz, Walter C. Willett, Peter Kraft, Susan E. Hankinson

Background

No prior study to our knowledge has examined the joint contribution of a polygenic risk score (PRS), mammographic density (MD), and postmenopausal endogenous hormone levels—all well-confirmed risk factors for invasive breast cancer—to existing breast cancer risk prediction models.

Methods and findings

We conducted a nested case–control study within the prospective Nurses’ Health Study and Nurses’ Health Study II including 4,006 cases and 7,874 controls ages 34–70 years up to 1 June 2010. We added a breast cancer PRS using 67 single nucleotide polymorphisms, MD, and circulating testosterone, estrone sulfate, and prolactin levels to existing risk models. We calculated area under the curve (AUC), controlling for age and stratified by menopausal status, for the 5-year absolute risk of invasive breast cancer. We estimated the population distribution of 5-year predicted risks for models with and without biomarkers. For the Gail model, the AUC improved (p-values < 0.001) from 55.9 to 64.1 (8.2 units) in premenopausal women (Gail + PRS + MD), from 55.5 to 66.0 (10.5 units) in postmenopausal women not using hormone therapy (HT) (Gail + PRS + MD + all hormones), and from 58.0 to 64.9 (6.9 units) in postmenopausal women using HT (Gail + PRS + MD + prolactin). For the Rosner–Colditz model, the corresponding AUCs improved (p-values < 0.001) by 5.7, 6.2, and 6.5 units. For estrogen-receptor-positive tumors, among postmenopausal women not using HT, the AUCs improved (p-values < 0.001) by 14.3 units for the Gail model and 7.3 units for the Rosner–Colditz model. Additionally, the percentage of 50-year-old women predicted to be at more than twice 5-year average risk (≥2.27%) was 0.2% for the Gail model alone and 6.6% for the Gail + PRS + MD + all hormones model. Limitations of our study included the limited racial/ethnic diversity of our cohort, and that general population exposure distributions were unavailable for some risk factors.

Conclusions

In this study, the addition of PRS, MD, and endogenous hormones substantially improved existing breast cancer risk prediction models. Further studies will be needed to confirm these findings and to determine whether improved risk prediction models have practical value in identifying women at higher risk who would most benefit from chemoprevention, screening, and other risk-reducing strategies.

Science Without Publication Paywalls: cOAlition S for the Realisation of Full and Immediate Open Access

Ma, 04/09/2018 - 23:00

by Marc Schiltz

In this Perspective, a group of national funders, joined by the European Commission and the European Research Council, announce plans to make Open Access publishing mandatory for recipients of their agencies’ research funding.

Breastfeeding in low-resource settings: Not a “small matter”

Ma, 28/08/2018 - 23:00

by Lars Åke Persson

Despite its clear biological benefits, many infants globally do not receive exclusive breastfeeding. In a Guest Editorial, Lars Åke Persson discusses what is needed to make breastfeeding the social norm.

Crowdsourcing to expand HIV testing among men who have sex with men in China: A closed cohort stepped wedge cluster randomized controlled trial

Ma, 28/08/2018 - 23:00

by Weiming Tang, Chongyi Wei, Bolin Cao, Dan Wu, Katherine T. Li, Haidong Lu, Wei Ma, Dianmin Kang, Haochu Li, Meizhen Liao, Katie R. Mollan, Michael G. Hudgens, Chuncheng Liu, Wenting Huang, Aifeng Liu, Ye Zhang, M. Kumi Smith, Kate M. Mitchell, Jason J. Ong, Hongyun Fu, Peter Vickerman, Ligang Yang, Cheng Wang, Heping Zheng, Bin Yang, Joseph D. Tucker

Background

HIV testing rates are suboptimal among at-risk men. Crowdsourcing may be a useful tool for designing innovative, community-based HIV testing strategies to increase HIV testing. The purpose of this study was to use a stepped wedge cluster randomized controlled trial (RCT) to evaluate the effect of a crowdsourced HIV intervention on HIV testing uptake among men who have sex with men (MSM) in eight Chinese cities.

Methods and findings

An HIV testing intervention was developed through a national image contest, a regional strategy designathon, and local message contests. The final intervention included a multimedia HIV testing campaign, an online HIV testing service, and local testing promotion campaigns tailored for MSM. This intervention was evaluated using a closed cohort stepped wedge cluster RCT in eight Chinese cities (Guangzhou, Shenzhen, Zhuhai, and Jiangmen in Guangdong province; Jinan, Qingdao, Yantai, and Jining in Shandong province) from August 2016 to August 2017. MSM were recruited through Blued, a social networking mobile application for MSM, from July 29 to August 21 of 2016. The primary outcome was self-reported HIV testing in the past 3 months. Secondary outcomes included HIV self-testing, facility-based HIV testing, condom use, and syphilis testing. Generalized linear mixed models (GLMMs) were used to analyze primary and secondary outcomes. We enrolled a total of 1,381 MSM. Most were ≤30 years old (82%), unmarried (86%), and had a college degree or higher (65%). The proportion of individuals receiving an HIV test during the intervention periods within a city was 8.9% (95% confidence interval [CI] 2.2–15.5) greater than during the control periods. In addition, the intention-to-treat analysis showed a higher probability of receiving an HIV test during the intervention periods as compared to the control periods (estimated risk ratio [RR] = 1.43, 95% CI 1.19–1.73). The intervention also increased HIV self-testing (RR = 1.89, 95% CI 1.50–2.38). There was no effect on facility-based HIV testing (RR = 1.00, 95% CI 0.79–1.26), condom use (RR = 1.00, 95% CI 0.86–1.17), or syphilis testing (RR = 0.92, 95% CI 0.70–1.21). A total of 48.6% (593/1,219) of participants reported that they received HIV self-testing. Among men who received two HIV tests, 32 individuals seroconverted during the 1-year study period. Study limitations include the use of self-reported HIV testing data among a subset of men and non-completion of the final survey by 23% of participants. Our study population was a young online group in urban China and the relevance of our findings to other populations will require further investigation.

Conclusions

In this setting, crowdsourcing was effective for developing and strengthening community-based HIV testing services for MSM. Crowdsourced interventions may be an important tool for the scale-up of HIV testing services among MSM in low- and middle-income countries (LMIC).

Trial registration

ClinicalTrials.gov NCT02796963

Relationship between very low low-density lipoprotein cholesterol concentrations not due to statin therapy and risk of type 2 diabetes: A US-based cross-sectional observational study using electronic health records

Ma, 28/08/2018 - 23:00

by QiPing Feng, Wei-Qi Wei, Cecilia P. Chung, Rebecca T. Levinson, Alexandra C. Sundermann, Jonathan D. Mosley, Lisa Bastarache, Jane F. Ferguson, Nancy J. Cox, Dan M. Roden, Joshua C. Denny, MacRae F. Linton, Digna R. Velez Edwards, C. Michael Stein

Background

Observations from statin clinical trials and from Mendelian randomization studies suggest that low low-density lipoprotein cholesterol (LDL-C) concentrations may be associated with increased risk of type 2 diabetes mellitus (T2DM). Despite the findings from statin clinical trials and genetic studies, there is little direct evidence implicating low LDL-C concentrations in increased risk of T2DM.

Methods and findings

We used de-identified electronic health records (EHRs) at Vanderbilt University Medical Center to compare the risk of T2DM in a cross-sectional study among individuals with very low (≤60 mg/dl, N = 8,943) and normal (90–130 mg/dl, N = 71,343) LDL-C levels calculated using the Friedewald formula. LDL-C levels associated with statin use, hospitalization, or a serum albumin level < 3 g/dl were excluded. We used a 2-phase approach: in 1/3 of the sample (discovery) we used T2DM phenome-wide association study codes (phecodes) to identify cases and controls, and in the remaining 2/3 (validation) we identified T2DM cases and controls using a validated algorithm. The analysis plan for the validation phase was constructed at the time of the design of that component of the study. The prevalence of T2DM in the very low and normal LDL-C groups was compared using logistic regression with adjustment for age, race, sex, body mass index (BMI), high-density lipoprotein cholesterol, triglycerides, and duration of care. Secondary analyses included prespecified stratification by sex, race, BMI, and LDL-C level. In the discovery cohort, phecodes related to T2DM were significantly more frequent in the very low LDL-C group. In the validation cohort (N = 33,039 after applying the T2DM algorithm to identify cases and controls), the risk of T2DM was increased in the very low compared to normal LDL-C group (odds ratio [OR] 2.06, 95% CI 1.80–2.37; P < 2 × 10−16). The findings remained significant in sensitivity analyses. The association between low LDL-C levels and T2DM was significant in males (OR 2.43, 95% CI 2.00–2.95; P < 2 × 10−16) and females (OR 1.74, 95% CI 1.42–2.12; P = 6.88 × 10−8); in normal weight (OR 2.18, 95% CI 1.59–2.98; P = 1.1× 10−6), overweight (OR 2.17, 95% CI 1.65–2.83; P = 1.73× 10−8), and obese (OR 2.00, 95% CI 1.65–2.41; P = 8 × 10−13) categories; and in individuals with LDL-C < 40 mg/dl (OR 2.31, 95% CI 1.71–3.10; P = 3.01× 10−8) and LDL-C 40–60 mg/dl (OR 1.99, 95% CI 1.71–2.32; P < 2.0× 10−16). The association was significant in individuals of European ancestry (OR 2.67, 95% CI 2.25–3.17; P < 2 × 10−16) but not in those of African ancestry (OR 1.09, 95% CI 0.81–1.46; P = 0.56). A limitation was that we only compared groups with very low and normal LDL-C levels; also, since this was not an inception cohort, we cannot exclude the possibility of reverse causation.

Conclusions

Very low LDL-C concentrations occurring in the absence of statin treatment were significantly associated with T2DM risk in a large EHR population; this increased risk was present in both sexes and all BMI categories, and in individuals of European ancestry but not of African ancestry. Longitudinal cohort studies to assess the relationship between very low LDL-C levels not associated with lipid-lowering therapy and risk of developing T2DM will be important.

Influence of puberty timing on adiposity and cardiometabolic traits: A Mendelian randomisation study

Ma, 28/08/2018 - 23:00

by Joshua A. Bell, David Carslake, Kaitlin H. Wade, Rebecca C. Richmond, Ryan J. Langdon, Emma E. Vincent, Michael V. Holmes, Nicholas J. Timpson, George Davey Smith

Background

Earlier puberty is widely linked with future obesity and cardiometabolic disease. We examined whether age at puberty onset likely influences adiposity and cardiometabolic traits independent of childhood adiposity.

Methods and findings

One-sample Mendelian randomisation (MR) analyses were conducted on up to 3,611 white-European female and male offspring from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort recruited at birth via mothers between 1 April 1991 and 31 December 1992. Time-sensitive exposures were age at menarche and age at voice breaking. Outcomes measured at age 18 y were body mass index (BMI), dual-energy X-ray absorptiometry–based fat and lean mass indices, blood pressure, and 230 cardiometabolic traits derived from targeted metabolomics (150 concentrations plus 80 ratios from nuclear magnetic resonance [NMR] spectroscopy covering lipoprotein subclasses of cholesterol and triglycerides, amino acids, inflammatory glycoproteins, and others). Adjustment was made for pre-pubertal BMI measured at age 8 y. For negative control MR analyses, BMI and cardiometabolic trait measures taken at age 8 y (before puberty, and which therefore cannot be an outcome of puberty itself) were used. For replication analyses, 2-sample MR was conducted using summary genome-wide association study data on up to 322,154 adults for post-pubertal BMI, 24,925 adults for post-pubertal NMR cardiometabolic traits, and 13,848 children for pre-pubertal obesity (negative control). Like observational estimates, 1-sample MR estimates in ALSPAC using 351 polymorphisms for age at menarche (explaining 10.6% of variance) among 2,053 females suggested that later age at menarche (per year) was associated with −1.38 kg/m2 of BMI at age 18 y (or −0.34 SD units, 95% CI −0.46, −0.23; P = 9.77 × 10−09). This coefficient attenuated 10-fold upon adjustment for BMI at age 8 y, to −0.12 kg/m2 (or −0.03 SDs, 95% CI −0.13, 0.07; P = 0.55). Associations with blood pressure were similar, but associations across other traits were small and inconsistent. In negative control MR analyses, later age at menarche was associated with −0.77 kg/m2 of pre-pubertal BMI measured at age 8 y (or −0.39 SDs, 95% CI −0.50, −0.29; P = 6.28 × 10−13), indicating that variants influencing menarche also influence BMI before menarche. Cardiometabolic trait associations were weaker and less consistent among males and both sexes combined. Higher BMI at age 8 y (per 1 kg/m2 using 95 polymorphisms for BMI explaining 3.4% of variance) was associated with earlier menarche among 2,648 females (by −0.26 y, 95% CI −0.37, −0.16; P = 1.16 × 10−06), likewise among males and both sexes combined. In 2-sample MR analyses using 234 polymorphisms and inverse variance weighted (IVW) regression, each year later age at menarche was associated with −0.81 kg/m2 of adult BMI (or −0.17 SD units, 95% CI −0.21, −0.12; P = 4.00 × 10−15). Associations were weaker with cardiometabolic traits. Using 202 polymorphisms, later menarche was associated with lower odds of childhood obesity (IVW-based odds ratio = 0.52 per year later, 95% CI 0.48, 0.57; P = 6.64 × 10−15). Study limitations include modest sample sizes for 1-sample MR, lack of inference to non-white-European populations, potential selection bias through modest completion rates of puberty questionnaires, and likely disproportionate measurement error of exposures by sex. The cardiometabolic traits examined were heavily lipid-focused and did not include hormone-related traits such as insulin and insulin-like growth factors.

Conclusions

Our results suggest that puberty timing has a small influence on adiposity and cardiometabolic traits and that preventive interventions should instead focus on reducing childhood adiposity.

Different scientific approaches are needed to generate stronger evidence for population health improvement

Ma, 28/08/2018 - 23:00

by Martin White, Jean Adams

In a Perspective, Martin White and Jean Adams discuss challenges in the evaluation of interventions intended to benefit population health.

Metabolic syndrome and risk of Parkinson disease: A nationwide cohort study

Ma, 21/08/2018 - 23:00

by Ga Eun Nam, Seon Mee Kim, Kyungdo Han, Nan Hee Kim, Hye Soo Chung, Jin Wook Kim, Byoungduck Han, Sung Jung Cho, Ji Hee Yu, Yong Gyu Park, Kyung Mook Choi

Background

The association of metabolic syndrome (MetS) with the development of Parkinson disease (PD) is currently unclear. We sought to determine whether MetS and its components are associated with the risk of incident PD using large-scale cohort data for the whole South Korean population.

Methods and findings

Health checkup data of 17,163,560 individuals aged ≥40 years provided by the National Health Insurance Service (NHIS) of South Korea between January 1, 2009, and December 31, 2012, were included, and participants were followed up until December 31, 2015. The mean follow-up duration was 5.3 years. The hazard ratio (HR) and 95% confidence interval (CI) of PD were estimated using a Cox proportional hazards model adjusted for potential confounders. We identified 44,205 incident PD cases during follow-up. Individuals with MetS (n = 5,848,508) showed an increased risk of PD development compared with individuals without MetS (n = 11,315,052), even after adjusting for potential confounders including age, sex, smoking, alcohol consumption, physical activity, income, body mass index, estimated glomerular filtration rate, and history of stroke (model 3; HR, 95% CI: 1.24, 1.21–1.27). Each MetS component was positively associated with PD risk (HR, 95% CI: 1.13, 1.10–1.16 for abdominal obesity; 1.13, 1.10–1.15 for hypertriglyceridemia; 1.23, 1.20–1.25 for low high-density lipoprotein cholesterol; 1.05, 1.03–1.08 for high blood pressure; 1.21, 1.18–1.23 for hyperglycemia). PD incidence positively correlated with the number of MetS components (log-rank p < 0.001), and we observed a gradual increase in the HR for incident PD with increasing number of components (p < 0.001). A significant interaction between age and MetS on the risk of incident PD was observed (p for interaction < 0.001), and people aged ≥65 years old with MetS showed the highest HR of incident PD of all subgroups compared to those <65 years old without MetS (reference subgroup). Limitations of this study include the possibilities of misdiagnosis of PD and reverse causality.

Conclusions

Our population-based large-scale cohort study suggests that MetS and its components may be risk factors of PD development.

Metabolic syndrome and risk of Parkinson disease: A nationwide cohort study

Ma, 21/08/2018 - 23:00

by Ga Eun Nam, Seon Mee Kim, Kyungdo Han, Nan Hee Kim, Hye Soo Chung, Jin Wook Kim, Byoungduck Han, Sung Jung Cho, Ji Hee Yu, Yong Gyu Park, Kyung Mook Choi

Background

The association of metabolic syndrome (MetS) with the development of Parkinson disease (PD) is currently unclear. We sought to determine whether MetS and its components are associated with the risk of incident PD using large-scale cohort data for the whole South Korean population.

Methods and findings

Health checkup data of 17,163,560 individuals aged ≥40 years provided by the National Health Insurance Service (NHIS) of South Korea between January 1, 2009, and December 31, 2012, were included, and participants were followed up until December 31, 2015. The mean follow-up duration was 5.3 years. The hazard ratio (HR) and 95% confidence interval (CI) of PD were estimated using a Cox proportional hazards model adjusted for potential confounders. We identified 44,205 incident PD cases during follow-up. Individuals with MetS (n = 5,848,508) showed an increased risk of PD development compared with individuals without MetS (n = 11,315,052), even after adjusting for potential confounders including age, sex, smoking, alcohol consumption, physical activity, income, body mass index, estimated glomerular filtration rate, and history of stroke (model 3; HR, 95% CI: 1.24, 1.21–1.27). Each MetS component was positively associated with PD risk (HR, 95% CI: 1.13, 1.10–1.16 for abdominal obesity; 1.13, 1.10–1.15 for hypertriglyceridemia; 1.23, 1.20–1.25 for low high-density lipoprotein cholesterol; 1.05, 1.03–1.08 for high blood pressure; 1.21, 1.18–1.23 for hyperglycemia). PD incidence positively correlated with the number of MetS components (log-rank p < 0.001), and we observed a gradual increase in the HR for incident PD with increasing number of components (p < 0.001). A significant interaction between age and MetS on the risk of incident PD was observed (p for interaction < 0.001), and people aged ≥65 years old with MetS showed the highest HR of incident PD of all subgroups compared to those <65 years old without MetS (reference subgroup). Limitations of this study include the possibilities of misdiagnosis of PD and reverse causality.

Conclusions

Our population-based large-scale cohort study suggests that MetS and its components may be risk factors of PD development.