Tissue-specific genetic variation suggests distinct molecular pathways between body shape phenotypes and colorectal cancer.

It remains unknown whether adiposity subtypes are differentially associated with colorectal cancer (CRC). To move beyond single-trait anthropometric indicators, we derived four multi-trait body shape phenotypes reflecting adiposity subtypes from principal components analysis on body mass index, height, weight, waist-to-hip ratio, and waist and hip circumference. A generally obese (PC1) and a tall, centrally obese (PC3) body shape were both positively associated with CRC risk in observational analyses in 329,828 UK Biobank participants (3728 cases). In genome-wide association studies in 460,198 UK Biobank participants, we identified 3414 genetic variants across four body shapes and Mendelian randomization analyses confirmed positive associations of PC1 and PC3 with CRC risk (52,775 cases/45,940 controls from GECCO/CORECT/CCFR). Brain tissue-specific genetic instruments, mapped to PC1 through enrichment analysis, were responsible for the relationship between PC1 and CRC, while the relationship between PC3 and CRC was predominantly driven by adipose tissue-specific genetic instruments. This study suggests distinct putative causal pathways between adiposity subtypes and CRC.

Multi-Trait Body Shape Phenotypes and Breast Cancer Risk in Postmenopausal Women: A Causal Mediation Analysis in the UK Biobank Cohort.

Body shape phenotypes combining multiple anthropometric traits have been linked to postmenopausal breast cancer (BC). However, underlying biological pathways remain poorly understood. This study investigated to what extent the associations of body shapes with postmenopausal BC risk is mediated by biochemical markers. The study included 176,686 postmenopausal women from UK Biobank. Four body shape phenotypes were derived from principal component (PC) analysis of height, weight, body mass index, waist and hip circumferences, and waist-to-hip ratio (WHR). The four-way decomposition of the total effect was used to estimate mediation and interaction effects simultaneously as well as the mediated proportions. After 10.9 years median follow-up, 6,396 incident postmenopausal BC were diagnosed. There was strong evidence of positive associations between PC1 (general obesity) and PC2 (tall, low WHR), and BC risk. The association of PC1 with BC risk was positively mediated by testosterone and negatively by insulin-like growth factor-1 (IGF-1), with the overall proportion mediated (sum of the mediated interaction and pure indirect effect (PIE)) accounting for 11.4% (95% confidence intervals: 5.1 to 17.8%) and -12.2% (-20.5% to -4.0%) of the total effect, respectively. Small proportions of the association between PC2 and BC were mediated by IGF-1 (PIE: 2.8% (0.6 to 4.9%)), and sex hormone-binding globulin (SHBG) (PIE: -6.1% (-10.9% to -1.3%)). Our findings are consistent with differential pathways linking different body shapes with BC risk, with a suggestive mediation through testosterone and IGF-1 in the relationship of a generally obese body shape and BC risk, while IGF-1 and SHBG may mediate a tall/lean body shape-BC risk association.

Large-scale assessment of physical activity in a population using high-resolution hip-worn accelerometry: the German National Cohort (NAKO).

Large population-based cohort studies utilizing device-based measures of physical activity are crucial to close important research gaps regarding the potential protective effects of physical activity on chronic diseases. The present study details the quality control processes and the derivation of physical activity metrics from 100 Hz accelerometer data collected in the German National Cohort (NAKO). During the 2014 to 2019 baseline assessment, a subsample of NAKO participants wore a triaxial ActiGraph accelerometer on their right hip for seven consecutive days. Auto-calibration, signal feature calculations including Euclidean Norm Minus One (ENMO) and Mean Amplitude Deviation (MAD), identification of non-wear time, and imputation, were conducted using the R package GGIR version 2.10-3. A total of 73,334 participants contributed data for accelerometry analysis, of whom 63,236 provided valid data. The average ENMO was 11.7 ± 3.7 mg (milli gravitational acceleration) and the average MAD was 19.9 ± 6.1 mg. Notably, acceleration summary metrics were higher in men than women and diminished with increasing age. Work generated in the present study will facilitate harmonized analysis, reproducibility, and utilization of NAKO accelerometry data. The NAKO accelerometry dataset represents a valuable asset for physical activity research and will be accessible through a specified application process.

Personality and the use of cancer screenings - Results of the German National Cohort.

Objective: To determine the association between personality characteristics and use of different cancer screenings. Methods: We used data from the German National Cohort (NAKO; mean age was 53.0 years (SD: 9.2 years)) - a population-based cohort study. A total of 132,298 individuals were included in the analyses. As outcome measures, we used (self-reported): stool examination for blood (haemoccult test, early detection of bowel cancer), colonoscopy (screening for colorectal cancer), skin examination for moles (early detection of skin cancer), breast palpation by a doctor (early detection of breast cancer), x-ray examination of the breast ("mammography", early detection of breast cancer), cervical smear test, finger examination of the rectum (early detection of prostate cancer), and blood test for prostate cancer (determination of Prostate-Specific Antigen level). The established Big Five Inventory-SOEP was used to quantify personality factors. It was adjusted for several covariates based on the Andersen model. Unadjusted and adjusted multiple logistic regressions were computed. Results: A higher probability of having a skin examination for moles, for example, was associated with a higher conscientiousness (OR: 1.07, p < 0.001), higher extraversion (OR: 1.03, p < 0.001), higher agreeableness (OR: 1.02, p < 0.001), lower openness to experience (OR: 0.98, p < 0.001) and higher neuroticism (OR: 1.07, p < 0.001) among the total sample. Depending on the outcome used, the associations slightly varied. Conclusions: Particularly higher levels of extraversion, neuroticism and conscientiousness are associated with the use of different cancer screenings. Such knowledge may help to better understand non-participation in cancer screening examinations from a psychological perspective.

Complement C3 as a potential drug target in periodontitis: Evidence from the cis-Mendelian randomization approach.

AIM: Evidence from a Phase IIa trial showed that a complement C3-targeted drug reduced gingival inflammation in patients with gingivitis. Using drug-target Mendelian randomization (MR), we investigated whether genetically proxied C3 inhibition alters the risk of periodontitis. MATERIALS AND METHODS: We used multiple 'cis' instruments from the vicinity of the encoding loci of C3. Instrument selection was restricted to the drug target encoding loci (chromosome 19; 6,677,715-6,730,573 (GRCh37/hg19)). We selected three uncorrelated single-nucleotide polymorphisms (rs141552034, rs145406915, rs11569479) that were associated with serum C3 levels (p value <1 × 10-4 ) from a genome-wide association study (GWAS) of 5368 European descent individuals. We extracted association statistics from a GWAS of 17,353 clinical periodontitis cases and 28,210 European controls. Wald ratios were combined using inverse-variance weighted meta-analysis to estimate the odds ratio (OR) of the genetically proxied inhibition of C3 in relation to periodontitis. RESULTS: MR analysis revealed that the inhibition of C3 reduces the odds of periodontitis (OR 0.91 per 1 standard deviation reduction in C3; 95% confidence interval 0.87-0.96, p value = .0003). CONCLUSIONS: Findings from our MR analysis suggest a potential protective effect of C3 blockade against periodontitis.

Calcium intake in vegan and vegetarian diets: A systematic review and Meta-analysis.

In recent years, plant-based diets have experienced increasing popularity. However, plant-based diets may not always ensure an adequate supply of micronutrients, in particular calcium. We performed a systematic review and meta-analysis of calcium intake in vegan and vegetarian diets as compared to omnivorous diets. We searched PubMed and Web of Science and identified 2,009 potentially relevant articles. Mean calcium intake values were pooled and standardized mean differences (SMD) and 95% confidence intervals (CI) were computed.We analyzed 74 studies, including 7,356 vegan, 51,940 vegetarian, and 107,581 omnivorous participants. Of these, dietary calcium intake was examined in 23 studies of vegans, 60 studies of vegetarians and 74 studies of omnivores. Vegans showed a substantially lower calcium intake than vegetarians (SMD = -0.57; 95%CI = -0.83 to -0.32; p = <0.0001) and omnivores (SMD = -0.70; 95%CI = -0.95 to -0.59; p < 0.0001), whereas no statistically significant difference in calcium intake was noted between vegetarians and omnivores (SMD = 0.07; 95%CI = -0.04 to 0.19; p = 0.1976). In conclusion, vegans show a lower calcium intake than vegetarians and omnivores. This finding emphasizes the need for vegans to monitor their calcium status.

Moderate Intensity Exercise Reduces Side Effects of Cancer Therapy and Maintains Cardiorespiratory Fitness in Male Breast Cancer Patients: Findings from the BRECA Male Crossover Study.

Introduction: There is growing evidence that aerobic exercise mitigates cancer therapy-related side effects and improves cardiorespiratory fitness (CRF). However, to the best of our knowledge, no exercise study has been conducted in male breast cancer (MBC) patients. The aim of this study was to investigate the feasibility and efficacy of different exercise intensities on CRF and self-reported questionnaire items in MBC patients. Methods: Twenty-two MBC patients (60 ± 9 years) participated in this randomized crossover study. After completion of medical treatment, MBC patients were randomly assigned to either moderate (40-50% of heart rate [HR] max. and self-perceived exertion: 11) or vigorous (70-80% of HR max. and self-perceived exertion: 15) exercise intensity during the first 3 months of the study. After a 1-month washout period, participants switched group assignments. Primary endpoints were CRF and questionnaire items. Results: We observed a dropout rate of 36% over 7 months, with the number of participants decreasing from 22 to 14. The results showed significant improvements in "Physical Function" (p = 0.037) and "Social Function" (p = 0.016) after moderate training. A non-significant improvement was also observed in "Breast Symptoms" (p = 0.095), but there was no change in "Fatigue" (p = 0.306). There were no differences observed in cardiovascular fitness (V̇O2 peak) between the treatment groups. Conclusion: This study emphasizes the effectiveness of exercise intervention for an exceedingly rare cancer, highlighting the vital role of moderate intensity aerobic exercise in mitigating treatment side effects. Despite minimal peak V̇O2 differences, both exercise protocols adequately sustain CRF. Future studies are imperative to design optimized, sex-specific rehabilitation strategies tailored to the unique requirements of MBC patients, advancing our understanding of this under explored realm.

Cannabis use and the risk of primary open-angle glaucoma: a Mendelian randomization study.

Several observational studies have investigated the association between cannabis use and intraocular pressure, but its association with primary open-angle glaucoma (POAG) remains unclear. In this study, we leveraged human genetic data to assess through Mendelian randomization (MR) whether cannabis use affects POAG. We used five single-nucleotide polymorphisms (SNPs) associated with lifetime cannabis use (P-value < 5 × 10-8) from a genome-wide association study (GWAS) (N = 184,765) by the International Cannabis Consortium, 23andMe, and UK Biobank and eleven SNPs associated with cannabis use disorder (P-value < 5 × 10-7) from a GWAS meta-analysis of (17,068 cases and 357,219 controls of European descent) from Psychiatric Genomics Consortium Substance Use Disorders working group, Lundbeck Foundation Initiative for Integrative Psychiatric Research, and deCode. We associated the selected five SNPs from the GWAS of lifetime cannabis use and the eleven SNPs from the GWAS of cannabis use disorder, with the largest to date GWAS meta-analysis of POAG (16,677 cases and 199,580 controls). MR analysis suggested no evidence for a causal association of lifetime cannabis use and cannabis use disorder with POAG (odds ratio (OR) of outcome per doubling of the odds of exposure (95% confidence interval): 1.04 (0.88; 1.23) for lifetime cannabis use and 0.97 (0.92; 1.03) for cannabis use disorder). Sensitivity analyses to address pleiotropy and weak instrument bias yielded similar estimates to the primary analysis. In conclusion, our results do not support a causal association between cannabis use and POAG.

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation.

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.

Association between circadian physical activity patterns and mortality in the UK Biobank.

BACKGROUND: The benefit of physical activity (PA) for increasing longevity is well-established, however, the impact of diurnal timing of PA on mortality remains poorly understood. We aimed to derive circadian PA patterns and investigate their associations with all-cause mortality. METHODS: We used 24 h PA time series from 96,351 UK Biobank participants aged between 42 and 79 years at accelerometry in 2013-2015. Functional principal component analysis (fPCA) was applied to obtain circadian PA patterns. Using multivariable Cox proportional hazard models, we related the loading scores of these fPCs to estimate risk of mortality. RESULTS: During 6.9 years of follow-up, 2,850 deaths occurred. Four distinct fPCs accounted for 96% of the variation of the accelerometry data. Using a loading score of zero (i.e., average overall PA during the day) as the reference, a fPC1 score of + 2 (high overall PA) was inversely associated with mortality (Hazard ratio, HR = 0.91; 95% CI: 0.84-0.99), whereas a score of -2 (low overall PA) was associated with higher mortality (1.69; 95% CI: 1.57-1.81; p for non-linearity < 0.001). Significant inverse linear associations with mortality were observed for engaging in midday PA instead of early and late PA (fPC3) (HR for a 1-unit increase 0.88; 95% CI: 0.83-0.93). In contrast, midday and nocturnal PA instead of early and evening PA (fPC4) were positively associated with mortality (HR for a 1-unit increase 1.16; 95% CI: 1.08-1.25). CONCLUSION: Our results suggest that it is less important during which daytime hours one is active but rather, to engage in some level of elevated PA for longevity.

Physical activity and the risk of periodontitis: an instrumental variable study.

OBJECTIVES: Observational studies suggested an inverse association between physical activity and periodontitis. However, observational studies might be subject to unobserved confounding and reverse causation bias. We conducted an instrumental variable study to strengthen the evidence on the relationship between physical activity and periodontitis. MATERIALS AND METHODS: We used genetic variants associated with self-reported and accelerometer-assessed physical activity in 377,234 and 91,084 UK Biobank participants, respectively, as instruments. For these instruments, genetic associations with periodontitis were obtained from 17,353 cases and 28,210 controls in the GeneLifestyle Interactions in Dental Endpoints consortium. RESULTS: We found no evidence for effects of self-reported moderate-to-vigorous physical activity, self-reported vigorous physical activity, accelerometry "average accelerations," and "fraction of accelerations > 425 milli-gravities" on periodontitis. For example, the odds ratio for self-reported moderate-to-vigorous physical activity was 1.07 (95% credible interval: 0.87; 1.34) in Causal Analysis using Summary Effect Estimates. We conducted sensitivity analyses to rule out weak instrument bias and correlated horizontal pleiotropy. CONCLUSIONS: The study does not support an effect of physical activity on the risk of periodontitis. CLINICAL RELEVANCE: This study provides little evidence that recommending physical activity would help prevent periodontitis.

Downregulation of interleukin 6 signaling might reduce the risk of periodontitis: a drug target Mendelian randomization study.

Aim: Interleukin 6 (IL-6) is considered to play a role in the dysbiotic host response in the development of periodontitis. While the inhibition of the IL-6 receptor using monoclonal antibodies is a well-established therapy for some diseases, so far, its potential benefit in patients with periodontitis has not been examined. We tested the association of genetically proxied downregulation of IL-6 signaling with periodontitis to explore whether downregulation of IL-6 signaling could represent a viable treatment target for periodontitis. Materials and methods: As proxies for IL-6 signaling downregulation, we selected 52 genetic variants in close vicinity of the gene encoding IL-6 receptor that were associated with lower circulating C-reactive protein (CRP) levels in a genome-wide association study (GWAS) of 575 531 participants of European ancestry from the UK Biobank and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Associations with periodontitis were tested with inverse-variance weighted Mendelian randomization in a study of 17 353 cases and 28 210 controls of European descent in the Gene-Lifestyle Interactions in Dental Endpoints (GLIDE) consortium. In addition, the effect of CRP reduction independent of the IL-6 pathway was assessed. Results: Genetically proxied downregulation of IL-6 signaling was associated with lower odds of periodontitis (odds ratio (OR) = 0.81 per 1-unit decrement in log-CRP levels; 95% confidence interval (CI): [0.66;0.99]; P = 0.0497). Genetically proxied reduction of CRP independent of the IL-6 pathway had a similar effect (OR = 0.81; 95% CI: [0.68; 0.98]; P = 0.0296). Conclusion: In conclusion, genetically proxied downregulation of IL-6 signaling was associated with lower odds of periodontitis and CRP might be a causal target for the effect of IL-6 on the risk of periodontitis.

Effect of 25-hydroxyvitamin D levels on the internalising dimension as a transdiagnostic risk factor: Mendelian randomisation study.

BACKGROUND: Observational studies indicate a relationship between vitamin D (25-hydroxyvitamin D; 25OHD) deficiency and the development of internalising disorders, especially depression. However, causal inference approaches (e.g. Mendelian randomisation) did not confirm this relationship. Findings from biobehavioural research suggests that new insights are revealed when focusing on psychopathological dimensions rather than on clinical diagnoses. This study provides further evidence on the relationship between 25OHD and the internalising dimension. AIMS: This investigation aimed at examining the causality between 25OHD and internalising disorders including a common internalising factor. METHOD: We performed a two-sample Mendelian randomisation using genome-wide association study (GWAS) summary data for 25OHD (417 580 participants), major depressive disorder (45 591 cases; 97 674 controls), anxiety (5580 cases; 11 730 controls), post-traumatic stress disorder (12 080 cases; 33 446 controls), panic disorder (2248 cases; 7992 controls), obsessive-compulsive disorder (2688 cases; 7037 controls) and anorexia nervosa (16 992 cases; 55 525 controls). GWAS results of the internalising phenotypes were combined to a common factor representing the internalising dimension. We performed several complementary analyses to reduce the risk of pleiotropy and used a second 25OHD GWAS for replication. RESULTS: We found no causal relationship between 25OHD and any of the internalising phenotypes studied, nor with the common internalising factor. Several pleiotropy-robust methods corroborated the null association. CONCLUSIONS: Following current transdiagnostic approaches to investigate mental disorders, our results focused on the shared genetic basis between different internalising phenotypes and provide no evidence for an effect of 25OHD on the internalising dimension.

Relationship between genetically proxied vitamin D and psoriasis risk: a Mendelian randomization study.

BACKGROUND: Observational research suggests that vitamin D levels affect psoriasis. However, observational studies are prone to potential confounding or reverse causation, which complicates interpreting the data and drawing causal conclusions. AIM: To apply Mendelian randomization (MR) methods to comprehensively assess a potential association between vitamin D and psoriasis. METHODS: Genetic variants strongly associated with 25-hydroxyvitamin D (25OHD) in genome-wide association study (GWAS) data from 417 580 and 79 366 individuals from two independent studies served as instrumental variables (used as the discovery and replication datasets, respectively). As the outcome variable, we used GWAS data of psoriasis (13 229 people in the case group, 21 543 in the control group). We used (i) biologically validated genetic instruments, and (ii) polygenic genetic instruments to assess the relationship between genetically proxied vitamin D and psoriasis. We carried out inverse-variance weighted (IVW) MR analyses for the primary analysis. In sensitivity analyses, we used robust MR approaches. RESULTS: MR analyses of both the discovery and replication datasets did not show an effect of 25OHD on psoriasis. Neither the IVW MR analysis of the biologically validated instruments [discovery dataset: odds ratio (OR) 0.99; 95% confidence interval (CI) 0.88-1.12, P = 0.873; replication dataset: OR 0.98, 95% CI 0.66-1.46, P = 0.930] nor that of the polygenic genetic instruments (discovery dataset: OR 1.00, 95% CI 0.81-1.22, P = 0.973; replication dataset: OR 0.94, 95% CI 0.64-1.38, P = 0.737) revealed an impact of 25OHD on psoriasis. CONCLUSION: The present MR study did not support the hypothesis that vitamin D levels, measured by 25OHD, affect psoriasis. This study was conducted on Europeans, so the conclusions may not be applicable to all ethnicities.

Suicide Mortality Risk among Patients with Lung Cancer-A Systematic Review and Meta-Analysis.

The risk for suicide in patients with cancer is higher compared to the general population. However, little is known about patients with lung cancer specifically. We therefore implemented a systematic review and random-effects meta-analysis of retrospective cohort studies on suicide in patients with lung cancer. We searched a high number of common databases up to 02/2021. For the systematic review, a total of 23 studies was included. To exclude bias due to patient sample overlap, the meta-analysis was performed on 12 studies. The pooled standardized mortality ratio (SMR) for suicide was 2.95 (95% Confidence Interval (CI) = 2.42-3.60) for patients with lung cancer as compared to the general population. Subgroups with a pronouncedly higher risk for suicide compared to the general population were found for patients living in the USA (SMR = 4.17, 95% CI = 3.88-4.48), with tumors of late stage (SMR = 4.68, 95% CI = 1.28-17.14), and within one year after diagnosis (SMR = 5.00, 95% CI = 4.11-6.08). An increased risk for suicide was found in patients with lung cancer, with subgroups at particular risk. Patients at increased risk should be monitored more closely for suicidality and should receive specialized psycho-oncological and psychiatric care. Further studies should clarify the role of smoking and depressive symptoms on suicidality among lung cancer patients.

Inhibition of tumor necrosis factor receptor 1 and the risk of periodontitis.

Aim: To investigate the effect of genetically proxied inhibition of tumor necrosis factor receptor 1 (TNFR1) on the risk of periodontitis. Materials and methods: Genetic instruments were selected from the vicinity of TNFR superfamily member 1A (TNFRSF1A) gene (chromosome 12; base pairs 6,437,923-6,451,280 as per GRCh37 assembly) based on their association with C-reactive protein (N= 575,531). Summary statistics of these variants were obtained from a genome-wide association study (GWAS) of 17,353 periodontitis cases and 28,210 controls to estimate the effect of TNFR1 inhibition on periodontitis using a fixed-effects inverse method. Results: Considering rs1800693 as an instrument, we found no effect of TNFR1 inhibition on periodontitis risk (Odds ratio (OR) scaled per standard deviation increment in CRP: 1.57, 95% confidence interval (CI): 0.38;6.46). Similar results were derived from a secondary analysis that used three variants (rs767455, rs4149570, and rs4149577) to index TNFR1 inhibition. Conclusions: We found no evidence of a potential efficacy of TNFR1 inhibition on periodontitis risk.

Effect of interleukin-17 on periodontitis development: An instrumental variable analysis.

BACKGROUND: Circulating levels of interleukin-17 (IL-17) are associated with the presence and severity of periodontitis. However, whether IL-17 is causal for disease development is unknown. We investigated the effect of genetically proxied IL-17 on periodontitis using instrumental variable analysis. METHODS: We identified 12 genetic variants from genome-wide association study (GWAS) of 7760 European descent individuals, used these variants as instrumental variables for IL-17, and linked them to a GWAS of 17,353 clinical periodontitis cases and 28,210 European controls. Generalized weighted least squares analysis accounted for linkage disequilibrium of variants. RESULTS: We found an inverse association of genetically proxied IL-17 and periodontitis (odds ratio, 0.84; 95% confidence interval: 0.75-0.94; p = 0.003), which was corroborated after sensitivity analysis for horizontal pleiotropy. CONCLUSION: The findings suggest that IL-17 protects against initial periodontitis.

Targeted therapies in patients with newly diagnosed glioblastoma-A systematic meta-analysis of randomized clinical trials.

Glioblastoma (GB) is the most common malignant primary brain tumor in adults. The standard of care for newly diagnosed GB involves surgical resection followed by radiochemotherapy with temozolomide, with or without tumor-treating fields. In recent years, various efforts have been made to identify suitable molecularly targeted treatment options for malignant brain tumors. This meta-analysis provides an overview of recently published randomized controlled trials (RCTs) with and without molecular stratification, analyzing targeted agents in patients with newly diagnosed GB. The Cochrane Library, MEDLINE (Ovid), ClinicalTrials.gov, WHO's International Clinical Trials Registry Platform, and Google Scholar were searched for RCTs on targeted therapies in patients with newly diagnosed glioblastoma. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were extracted and pooled in a random-effects meta-analysis. Twelve RCTs (n = 3941 patients) involving protein kinase inhibitors, proteasome and histone deacetylase inhibitors, anti-angiogenic approaches and poly (ADP-ribose) polymerase (PARP) inhibitors were included in the meta-analysis. None of the targeted agents achieved a significant benefit with regard to OS (HR = 0.98 [95% confidence interval (CI) 0.86-1.11, P = .7731]). By comparison, targeted therapy showed a benefit for PFS (HR = 0.83 [95% CI 0.74-0.94, P = .0037]), especially for patients with an unmethylated O6-methylguanine-DNA-methyltransferase (MGMT) promoter (0.75 [95% CI 0.56-0.99, P = .0440]). Prolongation of PFS was largely driven by VEGF inhibition with bevacizumab (HR = 0.70 [95% CI 0.61-0.80, P = .0000]). VEGF inhibition with bevacizumab prolonged PFS in patients with newly diagnosed glioblastoma compared to standard care. However, no improvement in OS was observed with any of the targeted agents.

Association of epidemiological and clinical features with PCR cycle threshold values of SARS-CoV-2 infection: a cross-sectional study.

The cycle threshold (Ct) in quantitative real-time reverse-transcriptase polymerase chain reaction (qRT-PCR) is inversely correlated to the amount of viral nucleic acid or viral load and can be regarded as an indicator of infectivity. We examined the association of socio-demographic and clinical characteristics of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) polymerase chain reaction (PCR) positive cases with PCR cycle threshold (Ct) values at the time of diagnosis. SARS-CoV-2 cases reported between 12 October 2020 and 24 January 2021 in Regensburg were analyzed employing bivariate and multivariable methods. We included 3,029 SARS-CoV-2 cases (31% asymptomatic at diagnosis) and analyzed the association of case characteristics with Ct values in 2,606 cases. Among symptomatic patients, cough (38.0%), rhinitis (32.4%), headache (32.0), and fever/chills (29.9%) were the most frequent complaints. Ct values ≤20 were more frequent in symptomatic cases (20.9% vs. 11.3%), whereas Ct values >30 were more common in asymptomatic cases (32.6% vs. 18.0%). Ct values >20 and ≤30 were most common in symptomatic and asymptomatic cases (48.0% vs 40.7%). We observed lower median Ct values of E and N gene in symptomatic cases. In a random forest model, the total number of symptoms, respiratory symptoms, and age were most strongly associated with low Ct values. In conclusion, certain symptoms and age were associated with lower Ct values. Ct values can be used as a pragmatic approach in estimating infectivity at the first notification of a case and, thus, in guiding containment measures.