Time-trends in disease characteristics and comorbidities in patients with chronic hepatitis B in the period 1980–2020

Background & aims: The incidence of chronic hepatitis B (CHB) is declining due to successful implementation of vaccination programs and widespread use of antiviral therapy. We aimed to study time-trends in disease characteristics and comorbidities in newly referred CHB patients. Methods: : We collected information on hepatitis B virus (HBV) related disease characteristics (including hepatitis B e-antigen (HBeAg) status, viremia, stage of liver fibrosis and indication for treatment and/or hepatocellular carcinoma (HCC) surveillance) and presence of comorbidities in all CHB patients referred to our center from 1980 through 2020. Patient characteristics were compared according to referral date (before 2000, between 2000 and 2010 and after 2010). Results: : We identified 1515 eligible patients. Patients referred after 2010 were older (36 versus 34 years, p < 0.001), more often non-Caucasian (82.3% versus 55.0%, p < 0.001) and more frequently HBeAg negative (81.5% versus 49.8%, p < 0.001) when compared to patients referred before 2000. Adjusted for ethnicity, sex and age, patients referred after 2010 were less likely to have significant fibrosis (adjusted odds ratio [aOR]:0.178, p < 0.001) or indication for antiviral therapy (aOR:0.342, p < 0.001) but were more likely to be affected by the metabolic syndrome (aOR:1.985, p = 0.013), hepatic steatosis (aOR:1.727, p < 0.001) and metabolic dysfunction associated fatty liver disease (MAFLD) (aOR:1.438, p = 0.013). Conclusions: : The characteristics of the CHB populations are changing. Newly referred patients are older, have less active HBV related liver disease but are more likely to be co-affected by MAFLD. These findings provide guidance for adequate allocation of resources to cope with the changing characteristics of the CHB population

Can the PROPER intervention reduce psychotropic drug prescription in nursing home residents with dementia?:Results of a cluster-randomized controlled trial

Objectives:To evaluate the effect of the PROPER intervention in nursing home residents with dementia on the prevalence of psychotropic drug use and neuropsychiatric symptoms.Design:A cluster-randomized controlled design with two parallel groups (intervention versus usual care) and assessments at 0, 6, 12, and 18 months.Setting:Thirty-one dementia special care units within 13 long-term care organizations in the Netherlands.Participants:Three hundred eighty nursing home residents with dementiaIntervention:The PROPER intervention consisted of a structured and repeated multidisciplinary medication review, supported by education and continuous evaluation.Measurements:Prescriptions of antipsychotics, antidepressants, anxiolytics, and hypnotics, and occurrence of neuropsychiatric symptoms.Results:The prescription of any type of psychotropic drugs increased in the intervention group, and decreased in the control group, with an estimated difference of 3.9 percentage points per 6 months (p = 0.01). Effects for the individual drug groups were minor (differences of 1.6 percentage points and below per 6 months) and not statistically significant. The occurrence of neuropsychiatric symptoms remained stable in both the intervention and control groups during the follow-up of 18 months.Conclusions:The PROPER intervention failed to demonstrate effectiveness in reducing the prevalence of psychotropic drugs. It may be interesting to enrich the intervention with components that address personal attitudes and communication between nursing home professionals, not only with respect to the prescription of psychotropic drugs, but also to neuropsychiatric symptoms

Identification of cancer predisposition variants in apparently healthy individuals using a next-generation sequencing-based family genomics approach

Cancer, like many common disorders, has a complex etiology, often with a strong genetic component and with multiple environmental factors contributing to susceptibility. A considerable number of genomic variants have been previously reported to be causative of, or associated with, an increased risk for various types of cancer. Here, we adopted a next-generation sequencing approach in 11 members of two families of Greek descent to identify all genomic variants with the potential to predispose family members to cancer. Cross-comparison with data from the Human Gene Mutation Database identified a total of 571 variants, from which 47 % were disease-associated polymorphisms, 26 % disease-associated polymorphisms with additional supporting functional evidence, 19 % functional polymorphisms with in vitro/laboratory or in vivo supporting evidence but no known disease association, 4 % putative disease-causing mutations but with some residual doubt as to their pathological significance, and 3 % disease-causing mutations. Subsequent analysis, focused on the latter variant class most likely to be involved in cancer predisposition, revealed two variants of prime interest, namely MSH2 c.2732T>A (p.L911R) and BRCA1 c.2955delC, the first of which is novel. KMT2D c.13895delC and c.1940C>A variants are additionally reported as incidental findings. The next-generation sequencing-based family genomics approach described herein has the potential to be applied to other types of complex genetic disorder in order to identify variants of potential pathological significance

fMRI connectivity as a biomarker of antipsychotic treatment response: A systematic review

Background: Antipsychotic drugs are the first-choice therapy for psychotic episodes, but antipsychotic treatment response (AP-R) is unpredictable and only becomes clear after weeks of therapy. A biomarker for AP-R is currently unavailable. We reviewed the evidence for the hypothesis that functional magnetic resonance imaging functional connectivity (fMRI-FC) is a predictor of AP-R or could serve as a biomarker for AP-R in psychosis. Method: A systematic review of longitudinal fMRI studies examining the predictive performance and relationship between FC and AP-R was performed following PRISMA guidelines. Technical and clinical aspects were critically assessed for the retrieved studies. We addressed three questions: Q1) is baseline fMRI-FC related to subsequent AP-R; Q2) is AP-R related to a change in fMRI-FC; and Q3) can baseline fMRI-FC predict subsequent AP-R? Results: In total, 28 articles were included. Most studies were of good quality. fMRI-FC analysis pipelines included seed-based-, independent component- / canonical correlation analysis, network-based statistics, and graph-theoretical approaches. We found high heterogeneity in methodological approaches and results. For Q1 (N = 17) and Q2 (N = 18), the most consistent evidence was found for FC between the striatum and ventral attention network as a potential biomarker of AP-R. For Q3 (N = 9) accuracy's varied form 50 till 93%, and prediction models were based on FC between various brain regions. Conclusion: The current fMRI-FC literature on AP-R is hampered by heterogeneity of methodological approaches. Methodological uniformity and further improvement of the reliability and validity of fMRI connectivity analysis is needed before fMRI-FC analysis can have a place in clinical applications of antipsychotic treatment

HFrEF subphenotypes based on 4210 repeatedly measured circulating proteins are driven by different biological mechanisms

Background: HFrEF is a heterogenous condition with high mortality. We used serial assessments of 4210 circulating proteins to identify distinct novel protein-based HFrEF subphenotypes and to investigate underlying dynamic biological mechanisms. Herewith we aimed to gain pathophysiological insights and fuel opportunities for personalised treatment. Methods: In 382 patients, we performed trimonthly blood sampling during a median follow-up of 2.1 [IQR:1.1–2.6] years. We selected all baseline samples and two samples closest to the primary endpoint (PEP; composite of cardiovascular mortality, HF hospitalization, LVAD implantation, and heart transplantation) or censoring, and applied an aptamer-based multiplex proteomic approach. Using unsupervised machine learning methods, we derived clusters from 4210 repeatedly measured proteomic biomarkers. Sets of proteins that drove cluster allocation were analysed via an enrichment analysis. Differences in clinical characteristics and PEP occurrence were evaluated. Findings: We identified four subphenotypes with different protein profiles, prognosis and clinical characteristics, including age (median [IQR] for subphenotypes 1–4, respectively:70 [64, 76], 68 [60, 79], 57 [47, 65], 59 [56, 66]years), EF (30 [26, 36], 26 [20, 38], 26 [22, 32], 33 [28, 37]%), and chronic renal failure (45%, 65%, 36%, 37%). Subphenotype allocation was driven by subsets of proteins associated with various biological functions, such as oxidative stress, inflammation and extracellular matrix organisation. Clinical characteristics of the subphenotypes were aligned with these associations. Subphenotypes 2 and 3 had the worst prognosis compared to subphenotype 1 (adjHR (95%CI):3.43 (1.76–6.69), and 2.88 (1.37–6.03), respectively). Interpretation: Four circulating-protein based subphenotypes are present in HFrEF, which are driven by varying combinations of protein subsets, and have different clinical characteristics and prognosis. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT01851538 https://clinicaltrials.gov/ct2/show/NCT01851538. Funding: EU/ EFPIA IMI2JU BigData@Heart grant n° 116074, Jaap Schouten Foundation and Noordwest Academie.</p

Pollitt syndrome patients carry mutation in TTDN1

Complete human genome sequencing was used to identify the causative mutation in a family with Pollitt syndrome (MIM #. 275550), comprising two non-consanguineous parents and their two affected children. The patient's symptoms were reminiscent of the non-photosensitive form of recessively inherited trichothiodystrophy (TTD). A mutation in the TTDN1/. C7orf11 gene, a gene that is known to be involved in non-photosensitive TTD, had been excluded by others by Sanger sequencing. Unexpectedly, we did find a homozygous single-base pair deletion in the coding region of this gene, a mutation that is known to cause non-photosensitive TTD. The deleterious variant causing a frame shift at amino acid 93 (C326delA) followed the right mode of inheritance in the family and was independently validated using conventional DNA sequencing. We expect this novel DNA sequencing technology to help redefine phenotypic and genomic variation in patients with (mono) genetic disorders in an unprecedented manner

GRB 010921: Discovery of the First HETE Afterglow

We report the discovery of the optical and radio afterglow of GRB 010921, the first gamma-ray burst afterglow to be found from a localization by the High Energy Transient Explorer (HETE) satellite. We present optical spectroscopy of the host galaxy which we find to be a dusty and apparently normal star-forming galaxy at z = 0.451. The unusually steep optical spectral slope of the afterglow can be explained by heavy extinction, A_V > 0.5 mag, along the line of sight to the GRB. Dust with similar A_V for the the host galaxy as a whole appears to be required by the measurement of a Balmer decrement in the spectrum of the host galaxy. Thanks to the low redshift, continued observations of the afterglow will enable the strongest constraints, to date, on the existence of a possible underlying supernova.Comment: 16 pages, 3 figures. Submitted to the Astrophsical Journal Letter

Exome-wide meta-analysis identifies rare 3'-UTR variant in ERCC1/CD3EAP associated with symptoms of sleep apnea

Obstructive sleep apnea (OSA) is a common sleep breathing disorder associated with an increased risk of cardiovascular and cerebrovascular diseases and mortality. Although OSA is fairly heritable (~40%), there have been only few studies looking into the genetics of OSA. In the present study, we aimed to identify genetic variants associated with symptoms of sleep apnea by performing a whole-exome sequence meta-analysis of symptoms of sleep apnea in 1,475 individuals of European descent. We identified 17 rare genetic variants with at least suggestive evidence of significance. Replication in an independent dataset confirmed the association of a rare genetic variant (rs2229918; minor allele frequency = 0.3%) with symptoms of sleep apnea (p-valuemeta = 6.98 × 10-9, ßmeta = 0.99). Rs2229918 overlaps with the 3' untranslated regions of ERCC1 and CD3EAP genes on chromosome 19q13. Both genes are expressed in tissues in the neck area, such as the tongue, muscles, cartilage and the trachea. Further, CD3EAP is localized in the nucleus and mitochondria and involved in the tumor necrosis factor-alpha/nuclear factor kappa B signaling pathway. Our results and biological functions of CD3EAP/ERCC1 genes suggest that the 19q13 locus is interesting for further OSA research

Guided self-help on the internet for turkish migrants with depression: the design of a randomized controlled trial

Background The Turkish population living in the Netherlands has a high prevalence of psychological complaints and has a high threshold for seeking professional help for these problems. Seeking help through the Internet can overcome these barriers. This project aims to evaluate the effectiveness of a guided self-help problem-solving intervention for depressed Turkish migrants that is culturally adapted and web-based. Methods This study is a randomized controlled trial with two arms: an experimental condition group and a wait list control group. The experimental condition obtains direct access to the guided web-based self-help intervention, which is based on Problem Solving Treatment (PST) and takes 6 weeks to complete. Turkish adults with mild to moderate depressive symptoms will be recruited from the general population and the participants can choose between a Turkish and a Dutch version. The primary outcome measure is the reduction of depressive symptoms, the secondary outcome measures are somatic symptoms, anxiety, acculturation, quality of life and satisfaction. Participants are assessed at baseline, post-test (6 weeks), and 4 months after baseline. Analysis will be conducted on the intention-to-treat sample. Discussion This study evaluates the effectiveness of a guided problem-solving intervention for Turkish adults living in the Netherlands that is culturally adapted and web-based