BMC Medicine

It has been well established that the TMEM106B gene rs1990622 variant was a frontotemporal dementia (FTD) risk factor. Until recently, growing evidence highlights the role of TMEM106B in Alzheimer’s disease (AD). However, it remains largely unclear about the role of rs1990622 variant in AD. Here, we conducted comprehensive analyses including genetic association study, gene expression analysis, eQTLs analysis, and colocalization analysis. In stage 1, we conducted a genetic association analysis of rs1990622 using large-scale genome-wide association study (GWAS) datasets from International Genomics of Alzheimer’s Project (21,982 AD and 41,944 cognitively normal controls) and UK Biobank (314,278 participants). In stage 2, we performed a gene expression analysis of TMEM106B in 49 different human tissues using the gene expression data in GTEx. In stage 3, we performed an expression quantitative trait loci (eQTLs) analysis using multiple datasets from UKBEC, GTEx, and Mayo RNAseq Study. In stage 4, we performed a colocalization analysis to provide evidence of the AD GWAS and eQTLs pair influencing both AD and the TMEM106B expression at a particular region. We found (1) rs1990622 variant T allele contributed to AD risk. A sex-specific analysis in UK Biobank further indicated that rs1990622 T allele only contributed to increased AD risk in females, but not in males; (2) TMEM106B showed different expression in different human brain tissues especially high expression in cerebellum; (3) rs1990622 variant could regulate the expression of TMEM106B in human brain tissues, which vary considerably in different disease statuses, the mean ages at death, the percents of females, and the different descents of the selected donors; (4) colocalization analysis provided suggestive evidence that the same variant contributed to AD risk and TMEM106B expression in cerebellum. Our comprehensive analyses highlighted the role of FTD rs1990622 variant in AD risk. This cross-disease approach may delineate disease-specific and common features, which will be important for both diagnostic and therapeutic development purposes. Meanwhile, these findings highlight the importance to better understand TMEM106B function and dysfunction in the context of normal aging and neurodegenerative diseases.

Diagnosis-based risk adjustment is becoming an important issue globally as a result of its implications for payment, high-risk predictive modelling and provider performance assessment. The Taiwanese National Health Insurance (NHI) programme provides universal coverage and maintains a single national computerized claims database, which enables the application of diagnosis-based risk adjustment. However, research regarding risk adjustment is limited. This study aims to examine the performance of the Adjusted Clinical Group (ACG) case-mix system using claims-based diagnosis information from the Taiwanese NHI programme. A random sample of NHI enrollees was selected. Those continuously enrolled in 2002 were included for concurrent analyses (n = 173,234), while those in both 2002 and 2003 were included for prospective analyses (n = 164,562). Health status measures derived from 2002 diagnoses were used to explain the 2002 and 2003 health expenditure. A multivariate linear regression model was adopted after comparing the performance of seven different statistical models. Split-validation was performed in order to avoid overfitting. The performance measures were adjusted R2 and mean absolute prediction error of five types of expenditure at individual level, and predictive ratio of total expenditure at group level. The more comprehensive models performed better when used for explaining resource utilization. Adjusted R2 of total expenditure in concurrent/prospective analyses were 4.2%/4.4% in the demographic model, 15%/10% in the ACGs or ADGs (Aggregated Diagnosis Group) model, and 40%/22% in the models containing EDCs (Expanded Diagnosis Cluster). When predicting expenditure for groups based on expenditure quintiles, all models underpredicted the highest expenditure group and overpredicted the four other groups. For groups based on morbidity burden, the ACGs model had the best performance overall. Given the widespread availability of claims data and the superior explanatory power of claims-based risk adjustment models over demographics-only models, Taiwan's government should consider using claims-based models for policy-relevant applications. The performance of the ACG case-mix system in Taiwan was comparable to that found in other countries. This suggested that the ACG system could be applied to Taiwan's NHI even though it was originally developed in the USA. Many of the findings in this paper are likely to be relevant to other diagnosis-based risk adjustment methodologies.

Nicotine replacement therapy (NRT) and varenicline are both effective in helping smokers quit. There is growing interest in combining the two treatments to improve treatment outcomes, but no experimental data exist on whether this is efficacious. This double-blind randomised controlled trial was designed to evaluate whether adding nicotine patches to varenicline improves withdrawal relief and short-term abstinence rates. 117 participants seeking help to stop smoking were randomly allocated to varenicline plus placebo patch or varenicline plus nicotine patch (15 mg/16 hour). Varenicline use commenced one week prior to the target quit date (TQD), patch use started on the TQD. Ratings of urges to smoke and cigarette withdrawal symptoms were collected weekly over 4 weeks post-TQD. Medication use and smoking status were established at 1, 4 and 12 weeks. Participants lost to follow-up were included as continuing smokers. 92% of participants used both medications during the first week after the TQD. The combination treatment generated no increase in nausea or other adverse effects. It had no overall effect on urges to smoke or on other withdrawal symptoms. The combination treatment did not improve biochemically validated abstinence rates at 1 week and 4 weeks post-TQD (69% vs 59%, p=0.28 and 60% vs 59%, p=0.91, in the nicotine patch and placebo patch arm, respectively), or self reported abstinence rates at 12 weeks (36% vs. 29%, p=0.39, NS). The efficacy of varenicline was not enhanced by the addition of nicotine patches, although further trials would be useful to exclude the possibility of type II error. Clinicaltrials.gov Registration Number: NCT01184664

Poly(ADP-ribose) polymerases (PARP) are enzymes involved in DNA-damage repair. Inhibition of PARPs is a promising strategy for targeting cancers with defective DNA-damage repair, including BRCA1 and BRCA2 mutation-associated breast and ovarian cancers. Several PARP inhibitors are currently in trials in the adjuvant, neoadjuvant, and metastatic settings for the treatment of ovarian, BRCA-mutated breast, and other cancers. We herein review the development of PARP inhibitors and the basis for the excitement surrounding these agents, their use as single agents and in combinations, as well as their toxicities, mechanisms of acquired resistance, and companion diagnostics.

Little is known about the effects of night shifts and their interactions with genetic factors on chronic obstructive pulmonary disease (COPD). In this study, we aim to investigate relationships between long-term night shift work exposure and COPD risk, and assess modification effects of genetic predisposition. A total of 277,059 subjects who were in paid employment or self-employed were included in the UK Biobank. Information on current and lifetime employment was obtained, and a weighted COPD-specific genetic risk score (GRS) was constructed. We used Cox proportional hazard models to investigate associations between night shift work and COPD risk, and their interaction with COPD-specific GRS. The cohort study included 277,059 participants (133,063 men [48.03%]; mean [SD] age, 52.71 [7.08] years). During a median follow-up of 12.87 years, we documented 6558 incidents of COPD. From day work, irregular night shifts to regular night shifts, there was an increased trend in COPD incidence (P for trend < 0.001). Compared with day workers, the hazard ratio (HR) and 95% confidence interval (CI) of COPD was 1.28 (1.20, 1.37) for subjects with rarely/sometimes night shifts and 1.49 (1.35, 1.66) for those with permanent night shifts. Besides, the longer durations (especially in subjects with night shifts ≥ 10 years) and increasing monthly frequency of night shifts (in workers with > 8 nights/month) were associated with a higher COPD risk. Additionally, there was an additive interaction between night shifts and genetic susceptibility on the COPD risk. Subjects with permanent night shifts and high genetic risk had the highest risk of COPD (HR: 1.90 [95% CI: 1.63, 2.22]), with day workers with low genetic risk as a reference. Long-term night shift exposure is associated with a higher risk of COPD. Our findings suggest that decreasing the frequency and duration of night shifts may offer a promising approach to mitigating respiratory disease incidence in night shift workers, particularly in light of individual susceptibility.

In March 2020, the UK implemented the Coronavirus Job Retention Scheme (furlough) to minimise job losses. Our aim was to investigate associations between furlough and diet, physical activity, and sleep during the early stages of the COVID-19 pandemic. We analysed data on 25,092 participants aged 16–66 years from eight UK longitudinal studies. Changes in employment, including being furloughed, were based on employment status before and during the first lockdown. Health behaviours included fruit and vegetable consumption, physical activity, and sleep. Study-specific estimates obtained using modified Poisson regression, adjusting for socio-demographic characteristics and pre-pandemic health and health behaviours, were statistically pooled using random effects meta-analysis. Associations were also stratified by sex, age, and education. Across studies, between 8 and 25% of participants were furloughed. Compared to those who remained working, furloughed workers were slightly less likely to be physically inactive (RR = 0.85; [95% CI 0.75–0.97]; I 2 = 59%) and did not differ overall with respect to low fruit and vegetable consumption or atypical sleep, although findings for sleep were heterogenous (I 2 = 85%). In stratified analyses, furlough was associated with lower fruit and vegetable consumption among males (RR = 1.11; [1.01–1.22]; I 2 = 0%) but not females (RR = 0.84; [0.68–1.04]; I 2 = 65%). Considering changes in quantity, furloughed workers were more likely than those who remained working to report increases in fruit and vegetable consumption, exercise, and hours of sleep. Those furloughed exhibited similar health behaviours to those who remained in employment during the initial stages of the pandemic. There was little evidence to suggest that adoption of such social protection policies in the post-pandemic recovery period and during future economic crises had adverse effects on population health behaviours.

The Kin-Antwerp project aimed at improving the quality of care provided to patients with diabetes in Kinshasa, the Democratic Republic of the Congo in Central Africa, including the digitalisation of routine clinical data to improve patients’ follow-up. We aim to analyse the data of a study population of Kin-Antwerp to characterise their demographic features, assess their achievement of glycemic target over time, and identify groups requiring prioritised attention. We performed a secondary database analysis of routinely collected information from primary care patients with type 2 diabetes followed from 1991 to 2019. Data included demographics (age, sex), anthropometrics (weight, height), clinical parameters (blood pressure, plasma glucose), and anti-diabetic treatments. Achievement of glycemic target, defined as fasting plasma glucose < 126 mg/dL, over time was assessed using a multilevel mixed-effects logistic regression model. Our study population of patients with type 2 diabetes (N = 8976) comprised a higher proportion of women (67%) and patients between 40 and 65 years old (70.4%). At the first follow-up, most patients were on treatment with insulin (56.5%) and had glycemic levels under the target (79.9%). Women presented more often with obesity (27.4%) and high systolic blood pressure (41.8%) than men (8.6% and 37.0%, respectively). Patients had a median follow-up of 1.8 (interquartile range: 0.5–3.4) years. Overall, the odds of achieving glycemic target increased by 18.4% (odds ratio: 1.184, 95% CI: 1.130 to 1.239; p < 0.001) per year of follow-up. Stratified analyses suggested that the odds of achieving glycemic control over time increased among older patients (> 40 years), but not among younger patients (< 40 years). In our study population, an overall poor glycemic control was observed albeit with a modest improvement in the achievement of glycemic target throughout patients’ follow-up. Younger patients may benefit from prioritised attention to achieve glycemic targets. Based on the information provided by the database, continue monitoring and improvement of the project Kin-Antwerp is recommended. Introducing further efforts to improve type 2 diabetes management should include robust glycemia-monitoring tools and haemoglobin A1c, as well as further outlining self-management strategies.

Acute kidney injury (AKI) is independently associated with increased morbidity and mortality. Ischemia is the leading cause of AKI, and short of supportive measures, no currently available therapy can effectively treat or prevent ischemic AKI. This paper discusses recent developments in the understanding of ischemic AKI pathophysiology, the emerging relationship between ischemic AKI and development of progressive chronic kidney disease, and promising novel therapies currently under investigation. On the basis of recent breakthroughs in understanding the pathophysiology of ischemic AKI, therapies that can treat or even prevent ischemic AKI may become a reality in the near future.

Reduced androgen action during early fetal development has been suggested as the origin of reproductive disorders comprised within the testicular dysgenesis syndrome (TDS). This hypothesis has been supported by studies in rats demonstrating that normal male development and adult reproductive function depend on sufficient androgen exposure during a sensitive fetal period, called the masculinization programming window (MPW). The main aim of this study was therefore to examine the effects of manipulating androgen production during different timepoints during early human fetal testis development to identify the existence and timing of a possible window of androgen sensitivity resembling the MPW in rats. The effects of experimentally reduced androgen exposure during different periods of human fetal testis development and function were examined using an established and validated human ex vivo tissue culture model. The androgen production was reduced by treatment with ketoconazole and validated by treatment with flutamide which blocks the androgen receptor. Testicular hormone production ex vivo was measured by liquid chromatography-tandem mass spectrometry or ELISA assays, and selected protein markers were assessed by immunohistochemistry. Ketoconazole reduced androgen production in testes from gestational weeks (GW) 7–21, which were subsequently divided into four age groups: GW 7–10, 10–12, 12–16 and 16–21. Additionally, reduced secretion of testicular hormones INSL3, AMH and Inhibin B was observed, but only in the age groups GW 7–10 and 10–12, while a decrease in the total density of germ cells and OCT4+ gonocytes was found in the GW 7–10 age group. Flutamide treatment in specimens aged GW 7–12 did not alter androgen production, but the secretion of INSL3, AMH and Inhibin B was reduced, and a reduced number of pre-spermatogonia was observed. This study showed that reduced androgen action during early development affects the function and density of several cell types in the human fetal testis, with similar effects observed after ketoconazole and flutamide treatment. The effects were only observed within the GW 7–14 period—thereby indicating the presence of a window of androgen sensitivity in the human fetal testis.