An Atlas of Dietary Intakes and Medication Uses on Risk of Bladder Cancer: A Wide-Angle Mendelian Randomization Analysis.

BACKGROUND: Observational studies suggests that diets and medications affect bladder cancer (BC) development, which are subject to confounding and difficult to make causal inference. Here we aimed to investigate whether those observational associations are causal and determining the potential directions and pathways. METHODS: We used 2-sample Mendelian randomization (MR) analysis to assess associations of dietary intakes, medication uses and molecules with BC risk. Genetic summary data were derived from participants of predominantly European ancestry with rigorous instruments selection, where univariable MR, mediation MR and multivariable MR were performed. RESULTS: The results of univariable MR showed 4 dietary intakes and 4 medication uses having a protective effect on BC, while 4 circulating metabolites, 440 circulating proteins and 2 gut microbes were observed to be causally associated with BC risk. Through mediation MR, we found 572 analytes showing consistent mediating effects between dietary intakes or medication uses and BC risk. Furthermore, 9 out of 16 diet-medication pairs showed significant interactions and alterations on BC when consumed jointly. CONCLUSION: In summary, the findings obtained from the current study have important implications for informing prevention strategies that point to potential lifestyle interventions or medication prescriptions to reduce the risk of developing BC.HighlightsThe current study extends observational literature in showing the importance of diets and medications on bladder cancer prevention.The associations of diets and medications on bladder cancer prevention might be through circulating metabolites, circulating proteins and gut microbiotaOur results provide a new understanding of interactions in certain diet-medication pairs which should be taken into account by both physicians and patients during the development of a treatment strategy.

A predictive model for perinatal hypoxic ischemic encephalopathy using linked maternal and neonatal hospital data.

PURPOSE: To build an evidence-based model to estimate case-specific risk of perinatal hypoxic ischemic encephalopathy. METHODS: A retrospective, cross-sectional study of all births in Hawaii, Michigan, and New Jersey between 2010 and 2015, using linked maternal labor/delivery and neonatal birth records. Stepwise logistic regression and competitive Akaike information criterion were used to identify the most parsimonious model. Predictive ability of the model was measured with bootstrapped optimism-adjusted area under the ROC curve. RESULTS: Among 836,216 births there were 376 (0.45 per 1000) cases of hypoxic ischemic encephalopathy. The final model included 28 variables, 24 associated with increased risk, and 4 that were protective. The optimism-adjusted area under the ROC curve was 0.84. Estimated risk in the study population ranged from 1 in ∼323,000 to 1 in 2.5. The final model confirmed known risk factors (e.g., sentinel events and shoulder dystocia) and identified novel risk factors, such as maternal race and insurance status. CONCLUSION: Our study shows that risk of perinatal hypoxic ischemic encephalopathy injury can be estimated with high confidence. Our model fills a notable gap in the study of hypoxic ischemic encephalopathy prevention: the estimation of risk, particularly in the United States population which is unique with respect to racial and socioeconomic disparities.

The Association between Dietary Inflammatory Potential and Urologic Cancers: A Meta-analysis.

A meta-analysis published in 2018 indicated a significant association between the dietary inflammatory index (DII) and risk of urologic cancers (UC). The number of included studies was limited, and more research has been published on this topic since then. The current study aimed to find a more precise estimate of the association between dietary inflammatory potential and risk of UC by updating the previous meta-analysis. The PubMed and Embase databases were searched between January 2015 and April 2023 to identify eligible articles. Combined relative risk (RR) and 95% confidence intervals (CI) were calculated by random-effects model to assess the association between dietary inflammatory potential and risk of UC by comparison of the highest versus the lowest category of the DII/empirical dietary inflammatory pattern (EDIP) or by using the continuous DII/EDIP score. The analysis, including 23 studies with 557,576 subjects, showed different results for UC. There was a significant association for prostate cancer among case-control studies (RR = 1.75, 95% CI: 1.34-2.28), whereas among cohort studies a null association was found (RR = 1.02, 95% CI: 0.96-1.08). For bladder cancer, a nonsignificant association was observed in both case-control (RR = 1.59, 95% CI: 0.95-2.64) and cohort studies (RR = 1.03, 95% CI: 0.86-1.24). Pooled RR from 3 case-control studies displayed a statistically significant association between the DII and risk of kidney cancer (RR = 1.27, 95% CI: 1.03-1.56). Although DII was positively associated with all types of UC, no association was found for EDIP. The present meta-analysis confirmed that an inflammatory diet has a direct effect on the development of prostate cancer and kidney cancer. Large-scale studies are needed to demonstrate the association between dietary inflammatory potential and risk of UC and provide effective nutritional advice for UC prevention. PROTOCOL REGISTRATION: The protocol was registered in the International Prospective Register of Systematic Reviews (CRD42023391204).

Determinants of patient-reported functional mobility in people with Parkinson's disease: A systematic review.

BACKGROUND: Information on determinants of patient-reported functional mobility is lacking but would inform the planning of healthcare, resources and strategies to promote functional mobility in people with Parkinson's disease (PD). RESEARCH QUESTION: To identify the determinants of patient-reported functional mobility of people with PD. METHODS: Eligible: Randomized Controlled Trials, cohort, case-control, or cross-sectional analyses in people PD without date or setting restrictions, published in English, German, or French. Excluded: instruments with under 50 % of items measuring mobility. On August 9th 2023 we last searched Medline, CINAHL and PsychInfo. We assessed risk of bias using the mixed-methods appraisal tool. Results were synthesized by tabulating the determinants by outcomes and study designs. RESULTS: Eleven studies published 2012-2023 were included (most in Swedish outpatient settings). Samples ranged from 9 to 255 participants. Follow-up varied from 1.5 to 36 months with attrition of 15-42 %. Heterogenic study designs complicated results synthesis. However, determinants related to environment seem to associate the strongest with patient-reported functional mobility, although determinants related to body structures and functions were most investigated. We identified disease duration, the ability to drive, caregiving, sex, age, cognitive impairment, postural instability and social participation as determinants of patient-reported functional mobility. DISCUSSION: Methodological quality of the studies was limited. No study reported an a priori power calculation. Three studies controlled for confounders. The included studies lack representativeness of the population of people living with PD. Standardized sets of outcomes could enable more systematic research synthesis. CONCLUSIONS: Future research should focus on activities, participation and environmental factors and improve methodological quality.

Relationship between multimorbidity, functional limitation, and quality of life among middle-aged and older adults: findings from the longitudinal analysis of the 2013-2020 Survey of Health, Ageing, and Retirement in Europe (SHARE).

PURPOSE: The increased burden of multimorbidity is restricting individuals' ability to live autonomously, leading to a poorer quality of life. This study estimated trajectories of functional limitation and quality of life among middle-aged (ages 50 to 64 years) and older (aged 65 years and older) individuals with and without multimorbidity. We also assessed differences in the relationship between these two trajectories by multimorbidity status and separately for each age cohort. METHODS: Data originated from the Survey of Health, Ageing, and Retirement in Europe (SHARE). In Luxembourg, data were obtained between 2013 and 2020, involving 1,585 respondents ≥ 50 years of age. Multimorbidity was defined as a self-reported diagnosis of two or more out of 16 chronic conditions; functional limitation was assessed by a combined (Instrumental) Activities of Daily Living (ADL/IADLI) scale; and to measure quality of life, we used the Control, Autonomy, Self-Realization, and Pleasure (CASP-12) scale. Latent growth curve modelling techniques were used to conduct the analysis where repeated measures of quality of life and functional limitation were treated as continuous and zero-inflated count variables, respectively. The model was assessed separately in each age cohort, controlling for the baseline covariates, and the estimates from the two cohorts were presented as components of a synthetic cohort covering the life course from the age of 50. RESULTS: Middle-aged and older adults living with multimorbidity experienced poorer quality of life throughout the life course and were at a higher risk of functional limitation than those without multimorbidity. At baseline, functional limitation had a negative impact on quality of life. Furthermore, among middle-aged adults without multimorbidity and older adults with multimorbidity, an increase in the number of functional limitations led to a decline in quality of life. These results imply that the impact of multimorbidity on functional limitation and quality of life may vary across the life course. CONCLUSION: Using novel methodological techniques, this study contributes to a better understanding of the longitudinal relationship between functional limitation and quality of life among individuals with and without multimorbidity and how this relationship changes across the life course. Our findings suggest that lowering the risk of having multimorbidity can decrease functional limitation and increase quality of life.

Systematic review search strategies are poorly reported and not reproducible: a cross-sectional metaresearch study.

OBJECTIVES: To determine the reproducibility of biomedical systematic review search strategies. STUDY DESIGN AND SETTING: A cross-sectional reproducibility study was conducted on a random sample of 100 systematic reviews indexed in MEDLINE in November 2021. The primary outcome measure is the percentage of systematic reviews for which all database searches can be reproduced, operationalized as fulfilling six key Preferred Reporting Items for Systematic reviews and Meta-Analyses literature search extension (PRISMA-S) reporting guideline items and having all database searches reproduced within 10% of the number of original results. Key reporting guideline items included database name, multi-database searching, full search strategies, limits and restrictions, date(s) of searches, and total records. RESULTS: The 100 systematic review articles contained 453 database searches. Only 22 (4.9%) database searches reported all six PRISMA-S items. Forty-seven (10.4%) database searches could be reproduced within 10% of the number of results from the original search; six searches differed by more than 1,000% between the originally reported number of results and the reproduction. Only one systematic review article provided the necessary search details to be fully reproducible. CONCLUSION: Systematic review search reporting is poor. To correct this will require a multifaceted response from authors, peer reviewers, journal editors, and database providers.

The role of multimorbidity and socio-economic characteristics as potential risk factors for Long Covid: evidence from the multilevel analysis of the Survey of Health, Ageing and Retirement in Europe's corona surveys (2020-2021).

BACKGROUND: A substantial proportion of individuals continue experiencing persistent symptoms following the acute stage of their Covid-19 illness. However, there is a shortage of population-based studies on Long Covid risk factors. OBJECTIVE: To estimate the prevalence of Long Covid in the population of middle-aged and older Europeans having contracted Covid-19 and to assess the role of multimorbidity and socio-economic characteristics as potential risk factors of Long Covid. METHODS: A population-based longitudinal prospective study involving a sample of respondents 50 years and older (n = 4,004) from 27 countries who participated in the 2020 and 2021 Survey of Health, Ageing and Retirement in Europe (SHARE), in particular the Corona Surveys. Analyses were conducted by a multilevel (random intercept) hurdle negative binomial model. RESULTS: Overall, 71.6% (95% confidence interval = 70.2-73.0%) of the individuals who contracted Covid-19 had at least one symptom of Long Covid up to 12 months after the infection, with an average of 3.06 (standard deviation = 1.88) symptoms. There were significant cross-country differences in the prevalence of Long Covid and number of symptoms. Higher education and being a man were associated with a lower risk of Long Covid, whilst being employed was associated with a higher risk of having Long Covid. Multimorbidity was associated with a higher number of symptoms and older age was associated with a lower number of symptoms. CONCLUSION: Our results provide evidence on the substantial burden of Long Covid in Europe. Individuals who contracted Covid-19 may require long-term support or further medical intervention, putting additional pressure on national health care systems.

Maternal fatty acid status during pregnancy versus offspring inflammatory markers: a canonical correlation analysis of the MEFAB cohort.

The development of inflammatory lung disorders in children may be related to maternal fatty acid intake during pregnancy. We therefore examined maternal fatty acid (FA) status during pregnancy and its associations with inflammatory markers and lung conditions in the child by analyzing data from the MEFAB cohort using multivariate canonical correlation analysis (CCA). In the MEFAB cohort, 39 different phospholipid FAs were measured in maternal plasma at 16, 22 and 32 weeks of pregnancy, and at day of birth. Child inflammatory markers and self-reported doctor diagnosis of inflammatory lung disorders were assessed at 7 years of age. Using CCA, we found that maternal FA levels during pregnancy were significantly associated with child inflammatory markers at 7 years of age and that Mead acid (20:3n-9) was the most important FA for this correlation. To further verify the importance of Mead acid, we examined the relation between maternal Mead acid levels at the day of birth with the development of inflammatory lung disorders in children at age 7. After stratification for the child's sex, maternal Mead acid levels at day of birth were significantly related with self-reported doctor diagnosis of asthma and lung infections in boys, and bronchitis and total number of lung disorders in girls. Future studies should investigate whether the importance of Mead acid in the relation between maternal FA status and inflammation and lung disorders in the child is due to its role as biomarker for essential fatty acid deficiency or due to its own biological function as pro-inflammatory mediator.

Selenium and Vitamin E for Prevention of Non-Muscle-Invasive Bladder Cancer Recurrence and Progression: A Randomized Clinical Trial.

Importance: Selenium and vitamin E have been identified as promising agents for the chemoprevention of recurrence and progression of non-muscle-invasive bladder cancer. Objective: To determine whether selenium and/or vitamin E may prevent disease recurrence in patients with newly diagnosed NMIBC. Design, Setting, and Participants: This multicenter, prospective, double-blinded, placebo-controlled, 2 × 2 factorial randomized clinical trial included patients with newly diagnosed NMIBC recruited from 10 secondary or tertiary care hospitals in the UK. A total of 755 patients were screened for inclusion; 484 did not meet the inclusion criteria, and 1 declined to participate. A total of 270 patients were randomly assigned to 4 groups (selenium plus placebo, vitamin E plus placebo, selenium plus vitamin E, and placebo plus placebo) in a double-blind fashion between July 17, 2007, and October 10, 2011. Eligibility included initial diagnosis of NMIBC (stages Ta, T1, or Tis); randomization within 12 months of first transurethral resection was required. Interventions: Oral selenium (200 µg/d of high-selenium yeast) and matched vitamin E placebo, vitamin E (200 IU/d of d-alfa-tocopherol) and matched selenium placebo, selenium and vitamin E, or placebo and placebo. Main Outcome and Measures: Recurrence-free interval (RFI) on an intention-to-treat basis (analyses completed on November 28, 2022). Results: The study randomized 270 patients (mean [SD] age, 68.9 [10.4] years; median [IQR] age, 69 [63-77] years; 202 male [75%]), with 65 receiving selenium and vitamin E placebo, 71 receiving vitamin E and selenium placebo, 69 receiving selenium and vitamin E, and 65 receiving both placebos. Median overall follow-up was 5.5 years (IQR, 5.1-6.1 years); 228 patients (84%) were followed up for more than 5 years. Median treatment duration was 1.5 years (IQR, 0.9-2.5 years). The study was halted because of slow accrual. For selenium (n = 134) vs no selenium (n = 136), there was no difference in RFI (hazard ratio, 0.92; 95% CI, 0.65-1.31; P = .65). For vitamin E (n = 140) vs no vitamin E (n = 130), there was a statistically significant detriment to RFI (hazard ratio, 1.46; 95% CI, 1.02-2.09; P = .04). No significant differences were observed for progression-free interval or overall survival time with either supplement. Results were unchanged after Cox proportional hazards regression modeling to adjust for known prognostic factors. In total, 1957 adverse events were reported; 85 were serious adverse events, and all were considered unrelated to trial treatment. Conclusions and Relevance: In this randomized clinical trial of selenium and vitamin E, selenium supplementation did not reduce the risk of recurrence in patients with NMIBC, but vitamin E supplementation was associated with an increased risk of recurrence. Neither selenium nor vitamin E influenced progression or overall survival. Vitamin E supplementation may be harmful to patients with NMIBC, and elucidation of the underlying biology is required. Trial Registration: isrctn.org Identifier: ISRCTN13889738.

Micronuclei in human peripheral blood and bone marrow as genotoxicity markers: A systematic review and meta-analysis.

Can human peripheral blood cells be used as a surrogate for bone marrow cells, in evaluating the genotoxic effects of stressors? We searched the Pubmed/Medline and PubChem databases to identify publications relevant to this question. Micronucleus formation was the genotoxicity endpoint. Three publications comparing exposed vs. non-exposed individuals are included in this analysis; the exposures were to ethylene oxide or ionising radiation (atomic bomb, thorotrast, or radioiodine therapy). Information was extracted on the types of exposure, the numbers of participants, and the micronucleus frequencies. Relative differences (odds ratios) and absolute differences (risk differences) in the numbers of micronuclei between exposed and non-exposed persons were calculated separately for individual cell types (peripheral blood and bone marrow). Random effects meta-analyses for the relative differences in cell abnormalities were performed. The results showed very small differences in the frequencies of micronuclei between exposed and non-exposed individuals, as measured in either peripheral blood or bone marrow cell populations, on both absolute and relative scales. No definite conclusion concerning the relative sensitivities of bone marrow and peripheral blood cells can be made, based on these publications.

The relationship between methodological quality and the use of retracted publications in evidence syntheses.

BACKGROUND: Evidence syntheses cite retracted publications. However, citation is not necessarily endorsement, as authors may be criticizing or refuting its findings. We investigated the sentiment of these citations-whether they were critical or supportive-and associations with the methodological quality of the evidence synthesis, reason for the retraction, and time between publication and retraction. METHODS: Using a sample of 286 evidence syntheses containing 324 citations to retracted publications in the field of pharmacy, we used AMSTAR-2 to assess methodological quality. We used scite.ai and a human screener to determine citation sentiment. We conducted a Pearson's chi-square test to assess associations between citation sentiment, methodological quality, and reason for retraction, and one-way ANOVAs to investigate association between time, methodological quality, and citation sentiment. RESULTS: Almost 70% of the evidence syntheses in our sample were of critically low quality. We found that these critically low-quality evidence syntheses were more associated with positive statements while high-quality evidence syntheses were more associated with negative citation of retracted publications. In our sample of 324 citations, 20.4% of citations to retracted publications noted that the publication had been retracted. CONCLUSION: The association between high-quality evidence syntheses and recognition of a publication's retracted status may indicate that best practices are sufficient. However, the volume of critically low-quality evidence syntheses ultimately perpetuates the citation of retracted publications with no indication of their retracted status. Strengthening journal requirements around the quality of evidence syntheses may lessen the inappropriate citation of retracted publications.

Nine human epidemiological studies on synthetic amorphous silica and respiratory health.

The respiratory health effects of Synthetic Amorphous Silica (SAS) have been studied in human epidemiological research. This article presents a historical overview and review of nine occupational worker studies that have been conducted so far on this topic. The combined study population of all of these studies included 1172 employees, and exposure concentrations ranged from < 1 mg/m3 to 100 mg/m3. In two studies with a total of 293 workers, the incidence of silicosis was investigated after long-term exposure to precipitated SAS, and no cases of silicosis were found (Plunkett and Dewitt, 1962; Volk, 1960). In another study, the spirometry results of 40 workers were normal (Vitums et al., 1977). In a study of 28 workers, 4 cases of silicosis were identified, but it is possible that contamination with cristobalite occurred and detailed information about the amorphous silica origin was not provided (Mohrmann and Kahn, 1985). Ferch et al. (1987) found that lung impairment was associated with confounding factors (smoking) but not with exposure to precipitated SAS in a study of 143 workers. Choudat et al. (1990) reported a reduction in forced expiratory flow in a group exposed to precipitated SAS compared to a control group. Still, they found no correlation between the extent of exposure and pulmonary function was found in a study of 131 workers. Wilson et al. (1979) also failed to show a significant association between the degree of exposure to precipitated SAS and annual changes in lung function in a study of 165 workers. In the most recent and most extensive study (Taeger et al., 2016; Yong et al., 2022) in Germany, involving 462 factory workers, no association between inhalable or respirable SAS dust exposure and respiratory health was reported. Based on the available data, there is no evidence-base to support a relationship between SAS and respiratory health in humans.

Injuries Due to Law Enforcement Use of Force in the United States, 2006-2015: Trends in Severity and by Race.

PURPOSE: The purpose of the study was to assess incidence and severity of hospital reported injuries related to law enforcement Use of Force (UoF) in the US over time, and by race. METHODS: Data from the National Emergency Department Sample from the Healthcare Cost and Utilization Project and the National Electronic Injury Surveillance System (NEISS-AIP) from US Consumer Product Safety Commission were queried to identify UoF injuries. Regression analysis, t-tests, and chi-square tests were used in the analysis. RESULTS: Between 2006-15, there were 529,259 emergency department admissions for UoF injury in the NEDS, and 870,779 admissions in the NEISS-AIP. In a model adjusting for year, sex, and age, the Injury Severity Score increased by 1.1% annually (p<0.0001). Black people were 6 times as likely to be admitted to the ED as White people or Native Americans/Alaska Natives, and 25 times as likely as Asians/Pacific Islanders. Black patients were 4 times as likely as White patients to be admitted as inpatients. Per arrest rate by race using FBI uniform crime reporting data, Black arrestees were 2.5-3.1 times as likely as any other race to be hospitalized for UoF injury. CONCLUSION: The results of the study demonstrate that US law enforcement are injuring civilians more frequently and severely over time, and that Black people are disproportionately affected.

Dietary vitamin D intake and the bladder cancer risk: A pooled analysis of prospective cohort studies.

BACKGROUND & AIMS: Diet may play an essential role in the aetiology of bladder cancer (BC). Vitamin D is involved in various biological functions which have the potential to prevent BC development. Besides, vitamin D also influences the uptake of calcium and phosphorus, thereby possibly indirectly influencing the risk of BC. The aim of the present study was to investigate the relation between vitamin D intake and BC risk. METHODS: Individual dietary data were pooled from ten cohort studies. Food item intake was converted to daily intakes of vitamin D, calcium and phosphorus. Pooled multivariate hazard ratios (HRs), with corresponding 95% confidence intervals (CIs) were obtained using Cox-regression models. Analyses were adjusted for gender, age and smoking status (Model 1), and additionally for the food groups fruit, vegetables and meat (Model 2). Dose-response relationships (Model 1) were examined using a nonparametric test for trend. RESULTS: In total, 1994 cases and 518,002 non-cases were included in the analyses. The present study showed no significant associations between individual nutrient intake and BC risk. A significant decreased BC risk was observed for high vitamin D intake with moderate calcium and low phosphorus intake (Model 2: HRhigh vitD, mod Ca, low P: 0.77, 95% CI: 0.59-1.00). No significant dose-response analyses were observed. CONCLUSION: The present study showed a decreased BC risk for high dietary vitamin D intake in combination with low calcium intake and moderate phosphorus intake. The study highlights the importance of examining the effect of a nutrient in combination with complementary nutrients for risk assessment. Future research should focus on nutrients in a wider context and in nutritional patterns.

Validation of a Parkinson's disease questionnaire-39-based functional mobility composite score (FMCS) in people with Parkinson's disease.

INTRODUCTION: Functional mobility is an important outcome for people with Parkinson's disease (PwP). Despite this, there is no established patient-reported outcome measure that serves as a gold standard for assessing patient-reported functional mobility in PwP. We aimed to validate the algorithm calculating the Parkinson's Disease Questionnaire-39 (PDQ-39) based Functional Mobility Composite Score (FMCS). METHODS: We designed a count-based algorithm to measure patient-reported functional mobility in PwP from items of the PDQ-39 subscales mobility and activities of daily living. Convergent validity of the algorithm calculating the PDQ-39-based FMCS was assessed using the objective Timed Up and Go (n = 253) and discriminative validity was assessed by comparing the FMCS with patient-reported (MDS-UPDRS II) and clinician-assessed (MDS-UPDRS III) motor symptoms as well as between disease stages (H&Y) and PIGD phenotypes (n = 736). Participants were between 22 and 92 years old, with a disease duration from 0 to 32 years and 64.9% in a H&Y 1-2 ranging from 1 to 5. RESULTS: Spearman correlation coefficients (rs) ranging from -0.45 to -0.77 (p < 0.001) indicated convergent validity. Hence, a t-test suggested sufficient ability of the FMCS to discriminate (p < 0.001) between patient-reported and clinician-assessed motor symptoms. More specifically, FMCS was more strongly associated with patient-reported MDS-UPDRS II (rs = -0.77) than clinician-reported MDS-UPDRS III (rs = -0.45) and can discriminate between disease stages as between PIGD phenotypes (p < 0.001). CONCLUSION: The FMCS is a valid composite score to assess functional mobility through patient reports in PwP for studying functional mobility in studies using the PDQ-39.

Response to "Scrutinizing the causal link between excited delirium syndrome and restraint - a commentary on: 'The role of restraint in fatal excited delirium: a research synthesis and pooled analysis' by E.M.F. Strömmer, W. Leith, M.P. Zeegers and M.D. Freeman".

de Boer et al. criticize the conclusions in our 2020 paper on the validity of Excited Delirium Syndrome (ExDS) as "egregiously misleading." Our conclusion was that there "is no existing evidence that indicates that ExDS is inherently lethal in the absence of aggressive restraint." The basis for de Boer and colleague's criticism of our paper is that the ExDS literature does not provide an unbiased view of the lethality of the condition, and therefore the true epidemiologic features of ExDS cannot be determined from what has been published. The criticism is unrelated to the goals or methods of the study, however. Our stated purpose was to investigate "how the term ExDS has evolved in the literature and been endowed with a uniquely lethal quality," and whether there is "evidence for ExDS as a unique cause of a death that would have occurred regardless of restraint, or a label used when a restrained and agitated person dies, and which erroneously directs attention away from the role of restraint in explaining the death." We cannot fathom how de Boer et al. missed this clearly stated description of the study rationale, or why they would endorse a series of fallacious and meaningless claims that gave the appearance that they failed to grasp the basic design of the study. We do acknowledge and thank these authors for pointing out 3 minor citation errors and an equally minor table formatting error (neither of which altered the reported results and conclusions in the slightest), however.

Perceptions of effective policy interventions and strategies to address antibiotic misuse within primary healthcare in India: A qualitative study.

Objectives: Antimicrobial resistance poses a major public health threat. Despite Indian retail sector antibiotic consumption per capita increasing by approximately 22% between 2008 and 2016, empirical studies that examine policy or behavioural interventions addressing antibiotic misuse in primary healthcare are scarce. Our study aimed to assess perceptions of interventions and gaps in policy and practice with respect to outpatient antibiotic misuse in India. Methods: We conducted 23 semi-structured, in-depth interviews with a variety of key informants with diverse backgrounds in academia, non-government organisations, policy, advocacy, pharmacy, medicine and others. Data were charted into a framework matrix and analysed using a hybrid, inductive and deductive thematic analysis. Themes were analysed and organised according to the socio-ecological model at various levels ranging from the individual to the enabling environment. Results: Key informants largely focused on the importance of adopting a structural perspective to addressing socio-ecological drivers of antibiotic misuse. There was a recognition that educational interventions targeting individual or interpersonal interactions were largely ineffective, and policy interventions should incorporate behavioural nudge interventions, improve the healthcare infrastructure and embrace task shifting to rectify staffing disparities in rural areas. Conclusions: Prescription behaviour is perceived to be governed by structural issues of access and limitations in public health infrastructure that create an enabling environment for antibiotic overuse. Interventions should move beyond a clinical and individual focus on behaviour change with respect to antimicrobial resistance and aim for structural alignment between existing disease specific programs and between the informal and formal sector of healthcare delivery in India.

Krill oil supplementation's effect on school grades in typically developing adolescents.

Long-chain polyunsaturated fatty acids (LCPUFA) are important for brain development and functioning and with that, possibly school performance. Several cross-sectional studies have shown significant positive associations between fish consumption, an important source of LCPUFA and school grades in adolescents. The effect of LCPUFA supplementation on school grades in adolescents has not been investigated yet. The goal of the current study was to investigate (I) the associations between the Omega-3 Index (O3I) at baseline and after 12 months respectively and school grades and (II) the effect of one year krill oil supplementation (source of LCPUFA) on school grades in adolescents with a low O3I at baseline. A double-blind randomised placebo-controlled trial with repeated measurements was executed. Participants received either 400 mg eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) per day for the first three months in Cohort 1 and the nine months thereafter 800 mg EPA + DHA per day, Cohort 2 started immediately with 800 mg EPA + DHA per day,or a placebo. The O3I was monitored with a finger prick at baseline, three, six and twelve months. Subject grades for English, Dutch and math were collected, a standardised mathematics test was executed at baseline and at 12 months. Data was analysed with (I) explorative linear regressions to investigate associations at baseline and follow-up and (II) mixed model analyses separately for each of the subject grades and the standardised mathematics test to investigate the effect of supplementation after 12 months. The krill oil group had a small significant increase in the mean O3I at all time points. However, very few participants achieved the intended target O3I range of 8-11%. At baseline a significant association between baseline O3I and English grade was show, additionally a trend for an association with Dutch grade was shown. After 12 months no significant associations were found. Additionally, there was no significant effect of krill oil supplementation on subject grades or standardised mathematics test score. In this study, no significant effect of krill oil supplementation on subject grades or standardised mathematics test performance was found. However, as many participants dropped out and/or were non-adherent, results should be interpreted with caution.