omicSynth: An open multi-omic community resource for identifying druggable targets across neurodegenerative diseases.

Treatments for neurodegenerative disorders remain rare, but recent FDA approvals, such as lecanemab and aducanumab for Alzheimer disease (MIM: 607822), highlight the importance of the underlying biological mechanisms in driving discovery and creating disease modifying therapies. The global population is aging, driving an urgent need for therapeutics that stop disease progression and eliminate symptoms. In this study, we create an open framework and resource for evidence-based identification of therapeutic targets for neurodegenerative disease. We use summary-data-based Mendelian randomization to identify genetic targets for drug discovery and repurposing. In parallel, we provide mechanistic insights into disease processes and potential network-level consequences of gene-based therapeutics. We identify 116 Alzheimer disease, 3 amyotrophic lateral sclerosis (MIM: 105400), 5 Lewy body dementia (MIM: 127750), 46 Parkinson disease (MIM: 605909), and 9 progressive supranuclear palsy (MIM: 601104) target genes passing multiple test corrections (pSMR_multi < 2.95 × 10-6 and pHEIDI > 0.01). We created a therapeutic scheme to classify our identified target genes into strata based on druggability and approved therapeutics, classifying 41 novel targets, 3 known targets, and 115 difficult targets (of these, 69.8% are expressed in the disease-relevant cell type from single-nucleus experiments). Our novel class of genes provides a springboard for new opportunities in drug discovery, development, and repurposing in the pre-competitive space. In addition, looking at drug-gene interaction networks, we identify previous trials that may require further follow-up such as riluzole in Alzheimer disease. We also provide a user-friendly web platform to help users explore potential therapeutic targets for neurodegenerative diseases, decreasing activation energy for the community.

Functional promiscuity of small multidrug resistance transporters from Staphylococcus aureus, Pseudomonas aeruginosa, and Francisella tularensis.

Small multidrug resistance transporters efflux toxic compounds from bacteria and are a minimal system to understand multidrug transport. Most previous studies have focused on EmrE, the model SMR from Escherichia coli, finding that EmrE has a broader substrate profile than previously thought and that EmrE may perform multiple types of transport, resulting in substrate-dependent resistance or susceptibility. Here, we performed a broad screen to identify potential substrates of three other SMRs: PAsmr from Pseudomonas aeruginosa; FTsmr from Francisella tularensis; and SAsmr from Staphylococcus aureus. This screen tested metabolic differences in E. coli expressing each transporter versus an inactive mutant, for a clean comparison of sequence and substrate-specific differences in transporter function, and identified many substrates for each transporter. In general, resistance compounds were charged, and susceptibility substrates were uncharged, but hydrophobicity was not correlated with phenotype. Two resistance hits and two susceptibility hits were validated via growth assays and IC50 calculations. Susceptibility is proposed to occur via substrate-gated proton leak, and the addition of bicarbonate antagonizes the susceptibility phenotype, consistent with this hypothesis.

xWAS analysis in neuropsychiatric disorders by integrating multi-molecular phenotype quantitative trait loci and GWAS summary data.

BACKGROUND: Integrating quantitative trait loci (QTL) data related to molecular phenotypes with genome-wide association study (GWAS) data is an important post-GWAS strategic approach employed to identify disease-associated molecular features. Various types of molecular phenotypes have been investigated in neuropsychiatric disorders. However, these findings pertaining to distinct molecular features are often independent of each other, posing challenges for having an overview of the mapped genes. METHODS: In this study, we comprehensively summarized published analyses focusing on four types of risk-related molecular features (gene expression, splicing transcriptome, protein abundance, and DNA methylation) across five common neuropsychiatric disorders. Subsequently, we conducted supplementary analyses with the latest GWAS dataset and corresponding deficient molecular phenotypes using Functional Summary-based Imputation (FUSION) and summary data-based Mendelian randomization (SMR). Based on the curated and supplemented results, novel reliable genes and their functions were explored. RESULTS: Our findings revealed that eQTL exhibited superior ability in prioritizing risk genes compared to the other QTL, followed by sQTL. Approximately half of the genes associated with splicing transcriptome, protein abundance, and DNA methylation were successfully replicated by eQTL-associated genes across all five disorders. Furthermore, we identified 436 novel reliable genes, which enriched in pathways related with neurotransmitter transportation such as synaptic, dendrite, vesicles, axon along with correlations with other neuropsychiatric disorders. Finally, we identified ten multiple molecular involved regulation patterns (MMRP), which may provide valuable insights into understanding the contribution of molecular regulation network targeting these disease-associated genes. CONCLUSIONS: The analyses prioritized novel and reliable gene sets related with five molecular features based on published and supplementary results for five common neuropsychiatric disorders, which were missed in the original GWAS analysis. Besides, the involved MMRP behind these genes could be given priority for further investigation to elucidate the pathogenic molecular mechanisms underlying neuropsychiatric disorders in future studies.

Integrated mendelian randomization analyses highlight AFF3 as a novel eQTL-mediated susceptibility gene in renal cancer and its potential mechanisms.

BACKGROUNDS: A growing number of expression quantitative trait loci (eQTLs) have been found to be linked with tumorigenesis. In this article, we employed integrated Mendelian randomization (MR) analyses to identify novel susceptibility genes in renal cancer (RC) and reveal their potential mechanisms. METHODS: Two-sample MR analyses were performed to infer causal relationships between eQTLs, metabolites, and RC risks through the "TwoSampleMR" R package. Sensitivity analyses, such as heterogeneity, pleiotropy, and leave-one-out analysis, were used to assess the stability of our outcomes. Summary-data-based MR (SMR) analyses were used to verify the causal relationships among cis-eQTLs and RC risks via the SMR 1.3.1 software. RESULTS: Our results provided the first evidence for AFF3 eQTL elevating RC risks, suggesting its oncogenic roles (IVW method; odds ratio (OR) = 1.0005; 95% confidence interval (CI) = 1.0001-1.0010; P = 0.0285; heterogeneity = 0.9588; pleiotropy = 0.8397). Further SMR analysis validated the causal relationships among AFF3 cis-eQTLs and RC risks (P < 0.05). Moreover, the TCGA-KIRC, the ICGC-RC, and the GSE159115 datasets verified that the AFF3 gene was more highly expressed in RC tumors than normal control via scRNA-sequencing and bulk RNA-sequencing (P < 0.05). Gene set enrichment analysis (GSEA) analysis identified six potential biological pathways of AFF3 involved in RC. As for the potential mechanism of AFF3 in RC, we concluded in this article that AFF3 eQTL could negatively modulate the levels of the X-11,315 metabolite (IVW method; OR = 0.9127; 95% CI = 0.8530-0.9765; P = 0.0081; heterogeneity = 0.4150; pleiotropy = 0.8852), exhibiting preventive effects against RC risks (IVW method; OR = 0.9987; 95% CI = 0.9975-0.9999; P = 0.0380; heterogeneity = 0.5362; pleiotropy = 0.9808). CONCLUSIONS: We concluded that AFF3 could serve as a novel eQTL-mediated susceptibility gene in RC and reveal its potential mechanism of elevating RC risks via negatively regulating the X-11,315 metabolite levels.

The relationship between innate/adaptive immunity and gastrointestinal cancer : a multi-omics Mendelian randomization study.

BACKGROUND: Innate/adaptive immunity is the key to anti-tumor therapy. However, its causal relationship to Gastrointestinal (GI) cancer remains unclear. METHODS: Immunity genes were extracted from the MSigDB database. The Genome-wide association studies (GWAS) summary data of GI cancer were integrated with expression quantitative trait loci (eQTL) and DNA methylation quantitative trait loci (mQTL) associated with genes. Summary-data-based Mendelian randomization (SMR) and co-localization analysis were used to reveal causal relationships between genes and GI cancer. Two-sample MR analysis was used for sensitivity analysis. Single cell analysis clarified the enrichment of genes. RESULTS: Three-step SMR analysis showed that a putative mechanism, cg17294865 CpG site regulating HLA-DRA expression was negatively associated with gastric cancer risk. HLA-DRA was significantly differentially expressed in monocyte/macrophage and myeloid cells in gastric cancer. CONCLUSION: This study provides evidence that upregulating the expression level of HLA-DRA can reduce the risk of gastric cancer.

Excess mortality in patients with non-functioning pituitary adenoma: a systematic review and meta-analysis.

BACKGROUND: Patients with non-functioning pituitary adenoma (NFPA) often present with a variety of clinical manifestations and comorbidities, mainly determined by the local mass effect of the tumor and by hypopituitarism. Whether this has an impact on overall mortality, however, is still unclear. METHODS: PubMed/Medline, EMBASE, and Cochrane Library databases were systematically searched until May 2023 for studies reporting data either about standardized mortality ratios (SMRs) or about predictors of mortality in patients with NFPA. Effect sizes were pooled through a random-effect model. This systematic review and meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO, #CRD42023417782). RESULTS: Eleven studies were eligible for inclusion in the systematic review; among these, five studies reported data on SMRs, with a total follow-up time of approximately 130,000 person-years. Patients with NFPA showed an increased mortality risk compared to the general population (SMR = 1.57 [95%CI: 1.20-1.99], p < 0.01). Age and sex appeared to act as effect modifiers, with a trend towards higher SMRs in females (SMR = 1.57 [95%CI: 0.91-2.41], p = 0.10) than in males (SMR = 1.00 [95%CI: 0.89-1.11], p = 0.97), and in patients diagnosed at age 40 years or younger (SMR = 3.19 [95%CI: 2.50-3.97], p < 0.01) compared to those with later onset of the disease (SMR = 1.26 [95%CI: 0.93-1.65], p = 0.13). The trend towards excess mortality was similar in patients with normal (SMR = 1.22 [95%CI: 0.94-1.53], p = 0.13) or deficient (SMR = 1.26 [95%CI: 0.82-1.79], p = 0.27) pituitary function. CONCLUSIONS: Excess mortality is observed in patients with NFPA, regardless of pituitary function, especially in women and in patients with a younger age at diagnosis.

Reclaiming mendelian randomization from the deluge of papers and misleading findings.

Mendelian randomization (MR) is a powerful epidemiological method for causal inference. However, its recent surge in popularity has brought two concerning trends. First, the public availability of summary results from genome-wide association studies has led to an explosion of low-quality two-sample mendelian randomization (2SMR) studies. These studies add minimal - if any - value and overwhelm reviewers and journals. Second, the availability of large datasets with individual-level genotype data, like UK Biobank, has spurred the development and use of novel MR methods. However, some methods are being applied without proper testing, leading to misleading results, as exemplified by recent spurious findings that are being retracted and/or corrected relating to vitamin D. What can editors and peer reviewers do to handle the deluge of 2SMR studies and the premature application of highly complex MR methods? We advise editors to simply reject papers that only report 2SMR findings, with no additional supporting evidence. For reviewers receiving such papers, we provide a template for rejection. In addition, reviewers should demand rigorous testing of novel methods, including through the use of positive and negative controls before they are applied. Rejecting non-contributory 2SMR papers and imposing intensive scrutiny to novel methods is crucial if the scientific community is to reclaim MR.

Low skeletal muscle radiodensity is a risk factor for adjuvant chemotherapy discontinuation in colorectal cancer.

BACKGROUND: Previously, we reported SMR (skeletal muscle radiodensity) as a potential prognostic marker for colorectal cancer. However, there have been limited studies on the association between SMR and the continuation of adjuvant chemotherapy in colorectal cancer. METHODS: In this retrospective study, 143 colorectal cancer patients underwent curative surgery and adjuvant chemotherapy using the CAPOX regimen. Patients' SMRs were measured from preoperative CT images and divided into low (bottom quarter) and high (top three quarters) SMR groups. We compared chemotherapy cycles, capecitabine and oxaliplatin doses, and adverse effects in each group. RESULTS: The low SMR group had significantly fewer patients completing adjuvant chemotherapy compared to the high SMR group (44% vs. 68%, P < 0.01). Capecitabine and oxaliplatin doses were also lower in the low SMR group. Incidences of Grade 2 or Grade 3 adverse effects did not differ between groups, but treatment discontinuation due to adverse effects was significantly higher in the low SMR group. Logistic regression analysis revealed Stage III disease (odds ratio 18.09, 95% CI 1.41-231.55) and low SMR (odds ratio 3.26, 95% CI 1.11-9.56) as factors associated with unsuccessful treatment completion. Additionally, a higher proportion of low SMR patients received fewer than 2 cycles of chemotherapy (50% vs. 12%). CONCLUSION: The low SMR group showed higher treatment incompletion rates and received lower drug doses during adjuvant chemotherapy. Low SMR independently contributed to treatment non-completion in colorectal cancer patients.

High cardiovascular mortality risk among older merkel cell carcinoma patients.

OBJECTIVE: Previous research has primarily focused on the incidence and mortality rates of Merkel cell carcinoma (MCC), neglecting the examination of cardiovascular mortality (CVM) risk among survivors, particularly older patients. This study aims to assess the risk of CVM in older individuals diagnosed with MCC. METHODS: Data pertaining to older MCC patients were obtained from the Surveillance, Epidemiology, and End Results database (SEER). CVM risk was measured using standardized mortality ratio (SMR) and cumulative mortality. Multivariate Fine-Gray's competing risk model was utilized to evaluate the risk factors contributing to CVM. RESULTS: Among the study population of 2,899 MCC patients, 465 (16.0%) experienced CVM during the follow-up period. With the prolongation of the follow-up duration, the cumulative mortality rate for CVM reached 27.36%, indicating that cardiovascular disease (CVD) became the second most common cause of death. MCC patients exhibited a higher CVM risk compared to the general population (SMR: 1.69; 95% CI: 1.54-1.86, p < 0.05). Notably, the SMR for other diseases of arteries, arterioles, and capillaries displayed the most significant elevation (SMR: 2.69; 95% CI: 1.16-5.29, p < 0.05). Furthermore, age at diagnosis and disease stage were identified as primary risk factors for CVM, whereas undergoing chemotherapy or radiation demonstrated a protective effect. CONCLUSION: This study emphasizes the significance of CVM as a competing cause of death in older individuals with MCC. MCC patients face a heightened risk of CVM compared to the general population. It is crucial to prioritize cardiovascular health starting from the time of diagnosis and implement personalized CVD monitoring and supportive interventions for MCC patients at high risk. These measures are essential for enhancing survival outcomes.

Do Miniature Eye Movements Affect Neurofeedback Training Performance? A Combined EEG-Eye Tracking Study.

EEG-based neurofeedback is a prominent method to modulate one's own brain activity in a desired direction. However, the EEG signal can be disturbed by artifacts, e.g., eye movements, which can consequently confound the neurofeedback performance. Involuntary miniature eye movements can be hardly detected by conventional EEG correction methods such as recording the electro-oculogram (EOG) and subtracting EOG activity from the EEG signal. However, such miniature eye movements can influence EEG activity, especially in the Gamma frequency range, enormously. In the present study, we investigated whether power in different EEG frequencies can be effectively modulated by self-control of brain signals during neurofeedback training and/or whether changes in EEG power are provoked by miniature eye movements during the training. To this end, 24 participants performed one session of SMR and one session of Gamma neurofeedback training. Additionally, in each training session sham feedback was performed. An eye tracker was used to detect miniature eye movements (< 1°) during neurofeedback training. About two thirds of the participants were able to increase their SMR power over the course of NF training, while one third was able to increase Gamma power. Generally, miniature eye movements induced a strong Gamma power increase. The number of eye movements also increased numerically over the course of the NF training. However, we did not find a significant relationship with the NF training performance. This is a first indication that miniature saccades do not affect NF training performance, but should not be neglected during NF training. Our results have to be confirmed in future studies.

Neurofeedback and epilepsy: Renaissance of an old self-regulation method?

Neurofeedback is a brain-computer interface tool enabling the user to self-regulate their neuronal activity, and ultimately, induce long-term brain plasticity, making it an interesting instrument to cure brain disorders. Although this method has been used successfully in the past as an adjunctive therapy in drug-resistant epilepsy, this approach remains under-explored and deserves more rigorous scientific inquiry. In this review, we present early neurofeedback protocols employed in epilepsy and provide a critical overview of the main clinical studies. We also describe the potential neurophysiological mechanisms through which neurofeedback may produce its therapeutic effects. Finally, we discuss how to innovate and standardize future neurofeedback clinical trials in epilepsy based on evidence from recent research studies.

Do the humeral radiographic changes at 5-year follow-up affect the clinical outcomes of press-fit humeral stems in primary reverse shoulder arthroplasties?

INTRODUCTION: The purposes of this study were to analyze and compare the functional outcomes and radiological changes around the press-fit humeral components in two contemporary medialized reverse total shoulder arthroplasty (RTSA) systems at a minimum of 5-year follow-up. MATERIALS AND METHODS: Between December 2003 and December 2015, 249 consecutive RTSAs were performed at our hospital. Of these, 68 primary uncemented RTSA met our inclusion criteria. The Constant-Murley score (CMS), the modified Constant score, a visual analog scale (VAS) and active shoulder range of motion (ROM) were measured pre- and postoperatively. Radiological assessment was performed by plain radiographs at a minimum of 5 years postoperatively. RESULTS: At a mean follow-up of 80.2 months, there was no significant difference (p = .59) between the postoperative functional scores and range of motion of the two groups (Delta Xtend and Lima SMR). Radiological data of stress-shielding were observed in 38 patients (55.9%) being slightly more frequent in the Lima SMR group (21 patients) than in the Delta Xtend group (17 patients) (p = .62). CONCLUSIONS: Our study shows that the good functional results are similar between the two uncemented RTSA systems used and that they do not depend on the presence of radiological changes (stress-shielding) in the humeral stem at a minimum 5-year follow-up.

Mortality and risk of progression to adult T cell leukemia/lymphoma in HTLV-1-associated myelopathy/tropical spastic paraparesis.

Human T cell leukemia virus 1 (HTLV-1) causes the functionally debilitating disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) as well as adult T cell leukemia lymphoma (ATLL). Although there were concerns that the mortality of HAM/TSP could be affected by the development of ATLL, prospective evidence was lacking in this area. In this 5-y prospective cohort study, we determined the mortality, prevalence, and incidence of ATLL in 527 HAM/TSP patients. The standard mortality ratio of HAM/TSP patients was 2.25, and ATLL was one of the major causes of death (5/33 deaths). ATLL prevalence and incidence in these patients were 3.0% and 3.81 per 1,000 person-y, respectively. To identify patients at a high risk of developing ATLL, flow cytometry, Southern blotting, and targeted sequencing data were analyzed in a separate cohort of 218 HAM/TSP patients. In 17% of the HAM/TSP patients, we identified an increase in T cells positive for cell adhesion molecule 1 (CADM1), a marker for ATLL and HTLV-1-infected cells. Genomic analysis revealed that somatic mutations of HTLV-1-infected cells were seen in 90% of these cases and 11% of them had dominant clone and developed ATLL in the longitudinal observation. In this study, we were able to demonstrate the increased mortality in patients with HAM/TSP and a significant effect of ATLL on their prognosis. Having dominant clonal expansion of HTLV-1-infected cells with ATLL-associated somatic mutations may be important characteristics of patients with HAM/TSP who are at an increased risk of developing ATLL.

Effects of SMR Neurofeedback on Cognitive Functions in an Adult Population with Sleep Problems: A Tele-neurofeedback Study.

A good night's sleep is vital for normal human cognitive performance. We earlier reported that a home-based tele-neurofeedback program effectively reduced sleep problems (Krepel et al. in Appl Psychophysiol Biofeedback, https://doi.org/10.1007/s10484-021-09525-z , 2021). The present article presents a follow-up on this earlier study and investigates improvements in cognitive functions after sensory-motor rhythm (SMR) neurofeedback. Thirty-seven participants reporting sleep problems received SMR neurofeedback. Cognitive measures were assessed pre- and post-treatment. Measurements included a continuous performance/working memory (CPT/WM) task, Stroop task, and Trailmaking A and B test (from the IntegNeuro cognitive test battery). For neurofeedback-Learners relative to non-Learners significantly improved CPT/WM response time (d = 0.50), omission errors (d = 0.67), and Stroop incongruent performance (d = 0.72) were found. A significant time effect for both groups were found for the Stroop, the Trailmaking test part B (d = 0.52), and the Stroop interference score (d = 0.55). No significant correlations between changes in sleep and changes in cognition (p > 0.05) were found for the sample. SMR neurofeedback specifically improved measures of attention (response time and omission errors in a CPT/WM test) and working memory (Stroop incongruent) for SMR Learners compared to non-Learners with medium effect sizes. Furthermore, overall improvements for the whole sample were found on measures of executive function and visual attention, possibly reflecting non-specific or practice effects. Future better powered randomized control trials are needed to investigate if cognitive improvements are a direct effect of SMR neurofeedback or mediated by sleep improvements.

Functional Role of YnfA, an Efflux Transporter in Resistance to Antimicrobial Agents in Shigella flexneri.

Shigella flexneri has become a significant public health concern accounting for the majority of shigellosis cases worldwide. Even though a multitude of efforts is being made into the development of a vaccine to prevent infections, the absence of a licensed global vaccine compels us to enormously depend on antibiotics as the major treatment option. The extensive-unregulated use of antibiotics for treatment along with natural selection in bacteria has led to the rising of multidrug-resistance Shigella strains. Out of the various mechanisms employed by bacteria to gain resistance, efflux transporters are considered to be one of the principal contributors to antimicrobial resistance. The small multidrug-resistance family consists of unique small proteins that act as efflux pumps and are involved in extruding various antimicrobial compounds. The present study aims to demonstrate the role of an efflux transporter YnfA belonging to the SMR family and its functional involvement in promoting antimicrobial resistance in S. flexneri. Employing various genetic, computational, and biochemical techniques, we show how disrupting the YnfA transporter, renders the mutant Shigella strain more susceptible to some antimicrobial compounds tested in this study, and significantly affects the overall transport activity of the bacteria against ethidium bromide and acriflavine when compared with the wild-type Shigella strain. We also assessed how mutating some of the conserved amino acid residues of YnfA alters the resistance profile and efflux activity of the mutant YnfA transporter. This study provides a functional understanding of an uncharacterized SMR transporter YnfA of Shigella.

A TOR-YAK1 signaling axis controls cell cycle, meristem activity and plant growth in Arabidopsis.

TARGET OF RAPAMYCIN (TOR) is a conserved eukaryotic phosphatidylinositol-3-kinase-related kinase that plays a major role in regulating growth and metabolism in response to environment in plants. We performed a genetic screen for Arabidopsis ethylmethane sulfonate mutants resistant to the ATP-competitive TOR inhibitor AZD-8055 to identify new components of the plant TOR pathway. We found that loss-of-function mutants of the DYRK (dual specificity tyrosine phosphorylation regulated kinase)/YAK1 kinase are resistant to AZD-8055 and, reciprocally, that YAK1 overexpressors are hypersensitive to AZD-8055. Significantly, these phenotypes were conditional on TOR inhibition, positioning YAK1 activity downstream of TOR. We further show that the ATP-competitive DYRK1A inhibitor pINDY phenocopies YAK1 loss of function. Microscopy analysis revealed that YAK1 functions to repress meristem size and induce differentiation. We show that YAK1 represses cyclin expression in the different zones of the root meristem and that YAK1 is essential for TOR-dependent transcriptional regulation of the plant-specific SIAMESE-RELATED (SMR) cyclin-dependent kinase inhibitors in both meristematic and differentiating root cells. Thus, YAK1 is a major regulator of meristem activity and cell differentiation downstream of TOR.

Cancer Mortality in People Receiving Dialysis for Kidney Failure: An Australian and New Zealand Cohort Study, 1980-2013.

RATIONALE & OBJECTIVE: Cancer is a significant cause of morbidity in the population with kidney failure; however, cancer mortality in people undergoing dialysis has not been well described. We sought to compare cancer mortality in people on dialysis for kidney failure with cancer mortality in the general population. STUDY DESIGN: A retrospective cohort study using linked health-administrative and dialysis registry data. SETTING & PARTICIPANTS: All people receiving dialysis represented in the Australian and New Zealand Dialysis and Transplantation Registry, 1980-2013. EXPOSURE: Dialysis; hemodialysis (HD) and peritoneal dialysis (PD). OUTCOME: Death and underlying cause of death ascertained using health administrative data and classified using International Classification of Diseases, Tenth Revision, Australian Modification (ICD-10-AM) codes. ANALYTICAL APPROACH: Indirect standardization on age at death, sex, year, and country to estimate standardized mortality ratios (SMR). RESULTS: Over 269,598 person years of observation, 34,100 deaths occurred among 59,648 people on dialysis, including 3,677 cancer deaths. The relative risk of all-site cancer death in dialysis was twice (SMR, 2.4 [95% CI, 2.33-2.49]) that of the general population and highest for oral and pharynx cancers (SMR, 24.3 [95% CI, 18.0-31.5]) and multiple myeloma (SMR, 22.5 [95% CI, 20.3-23.9]). Women on dialysis had a significantly higher risk of all-site cancer mortality (SMR, 2.7 [95% CI, 2.59-2.89]) compared with men (SMR, 2.3 [95% CI, 2.17-2.36]) (P < 0.001). People on HD (SMR, 2.2 [95% CI, 2.11-2.30]) experienced greater excess deaths from all-site cancer compared with people on PD (SMR, 1.3 [95% CI, 1.23-1.44]). Excess deaths have gradually decreased over time for all-site, multiple myeloma, and kidney cancers (P < 0.001) but have not kept up with improvements in the general population. By contrast, among people receiving dialysis, excess deaths increased for colorectal and lung cancers (P < 0.001). LIMITATIONS: Confirmation of cancer diagnoses and population incidence data were not available; inability to exclude pre-existing cancers. CONCLUSIONS: People on dialysis experience excess all-site and site-specific cancer mortality compared with the general population. Mortality differs by modality type, age, and sex. Understanding the role of kidney failure and other morbidities in the treatment of cancer is important for shared decision-making regarding cancer treatments and identifying potential approaches to improve outcomes.

Training the brain to time: the effect of neurofeedback of SMR-Beta1 rhythm on time perception in healthy adults.

The timing ability plays an important role in everyday activities and is influenced by several factors such as the attention and arousal levels of the individuals. The effects of these factors on time perception have been interpreted through psychological models of time, including Attentional Gate Model (AGM). On the other hand, research has indicated that neurofeedback (NFB) training improves attention and increases arousal levels in the clinical and healthy population. Regarding the link between attentional processing and arousal levels and NFB and their relation to time perception, this study is a pilot demonstration of the influence of SMR-Beta1 (12-18 Hz) NFB training on time production and reproduction performance in healthy adults. To this end, 12 (9 female and 3 males; M = 26.3, SD = 3.8) and 12 participants (7 female and 5 males; M = 26.9, SD = 3.1) were randomly assigned into the experimental (with SMR-Beta1 NFB) and control groups (without any NFB training), respectively. The experimental group underwent intensive 10 sessions (3 days a week) of the 12-18 Hz up-training. Time production and reproduction performance were assessed pre and post NFB training for all participants. Three-way mixed ANOVA was carried out on T-corrected scores of reproduction and production tasks. Correlation analysis was also performed between SMR-Beta1 and time perception. While NFB training significantly influenced time production (P < 0.01), no such effect was observed for the time reproduction task. The results of the study are finally discussed within the frameworks of AGM, dual-process and cognitive aspects of time perception. Overall, our results contribute to disentangling the underlying mechanisms of temporal performance in healthy individuals.

Prolonged cortisol elevation alters whole body and tissue metabolism in rainbow trout (Oncorhynchus mykiss).

Chronic elevation of circulating cortisol is known to have deleterious effects on fish, but information about the consequences of prolonged cortisol elevation on the metabolism of fish is scarce. To test the effects of chronic cortisol elevation on the aerobic performance of rainbow trout, we examined how two severities of chronically elevated plasma cortisol levels affected the oxygen uptake during rest and after exhaustive exercise using a high (HC) and a medium cortisol (MC) treatment. High cortisol doses significantly affected standard (SMR) and maximum metabolic rates (MMR) compared to control fish. In comparison, the medium cortisol treatment elevated maximum metabolic rates (MMR) but did not significantly influence SMR compared to a sham group (S) and control group (C). The medium cortisol treatment resulted in a significantly increased metabolic scope due to an elevation of MMR, an effect that was abolished in the HC group due to co-occuring elevations in SMR. The elevated SMR of the HC-treated fish could be explained by increased in vitro oxygen uptake rates (MO2) of specific tissues, indicating that the raised basal metabolism was caused, in part, by an increase in oxygen demand of specific tissues. Haematological results indicated an increased reliance on anaerobic metabolic pathways in cortisol-treated fish under resting conditions.

Mortality and prognostic factors of Bullous Pemphigoid in a Moroccan population.

BACKGROUND: Bullous pemphigoid is a common autoimmune blistering skin disease that is significantly associated with a high rate of morbidity and mortality. OBJECTIVE: Our aim was to determine the 1-, 2- and 3-year mortality rate and standardized mortality ratio of BP in Moroccan patients, as well as to identify risk factors that influence survival both in the 1st and 3rd year of follow-up. METHODS: All patients with BP diagnosed between January 2008 and December 2017 in a tertiary referral centre at the Mohammed V Military Hospital in Morocco were included retrospectively. RESULTS: The 1-year, 2-year and 3-year mortality rates of the cases were 25.8%, 32.3% and 43%, respectively. The median age of onset was 72 years (range, 64 ∼ 80 years), and 51 (54.8%) patients were men. The standardized mortality ratio of patients with BP was 2.6 times higher than that of age- and sex-matched members of the general Moroccan population. Besides advanced age, the presence of diabetes mellitus at the time of diagnosis was associated with increased 3-year mortality in multivariate analysis. CONCLUSION: This is the first study analysing the mortality rate of bullous pemphigoid in Morocco. Our findings confirm a high mortality rate for BP patients compared with the expected mortality rate for age- and sex-adjusted general Moroccan population. Risk factors for increased 3-year mortality include advanced age at the time of diagnosis and diabetes mellitus.