A comprehensive study of common and rare genetic variants in spermatogenesis-related loci identifies new risk factors for idiopathic severe spermatogenic failure.

Study Question: Can genome-wide genotyping data be analysed using a hypothesis-driven approach to enhance the understanding of the genetic basis of severe spermatogenic failure (SPGF) in male infertility?

Summary Answer: Our findings revealed a significant association between SPGF and the gene and identified three novel genes (, , and ) along with 32 potentially pathogenic rare variants in 30 genes that contribute to this condition.

What Is Known Already: SPGF is a major cause of male infertility, often with an unknown aetiology. SPGF can be due to either multifactorial causes, including both common genetic variants in multiple genes and environmental factors, or highly damaging rare variants.

Pain, mindfulness, and placebo: a systematic review.

Introduction: Pain is a complex phenomenon influenced by psychosocial variables, including the placebo effect. The effectiveness of mindfulness-based interventions (MBIs) for pain has been demonstrated in experimental studies and systematic reviews, but the mechanisms of action are only starting to be established. Whether the expectations of individuals experiencing pain can be manipulated during MBIs remains to be systematically evaluated, and what role placebo effects might play remains to be explored.

AXDND1 is required to balance spermatogonial commitment and for sperm tail formation in mice and humans.

Dynein complexes are large, multi-unit assemblies involved in many biological processes via their critical roles in protein transport and axoneme motility. Using next-generation sequencing of infertile men presenting with low or no sperm in their ejaculates, we identified damaging variants in the dynein-related gene AXDND1. We thus hypothesised that AXDND1 is a critical regulator of male fertility.

Genetic mutation of results in male infertility due to abnormal sperm tail composition.

The transition zone is a specialised gate at the base of cilia/flagella, which separates the ciliary compartment from the cytoplasm and strictly regulates protein entry. We identified a potential new regulator of the male germ cell transition zone, CEP76. We demonstrated that CEP76 was involved in the selective entry and incorporation of key proteins required for sperm function and fertility into the ciliary compartment and ultimately the sperm tail.

Changes in environmental exposures over decades may influence the genetic architecture of severe spermatogenic failure.

Study Question: Do the genetic determinants of idiopathic severe spermatogenic failure (SPGF) differ between generations?

Summary Answer: Our data support that the genetic component of idiopathic SPGF is impacted by dynamic changes in environmental exposures over decades.

What Is Known Already: The idiopathic form of SPGF has a multifactorial etiology wherein an interaction between genetic, epigenetic, and environmental factors leads to the disease onset and progression. At the genetic level, genome-wide association studies (GWASs) allow the analysis of millions of genetic variants across the genome in a hypothesis-free manner, as a valuable tool for identifying susceptibility risk loci.

AXDND1 is required to balance spermatogonial commitment and for sperm tail formation in mice and humans.

Dynein complexes are large, multi-unit assemblies involved in many biological processes including male fertility via their critical roles in protein transport and axoneme motility. Previously we identified a pathogenic variant in the dynein gene in an infertile man. Subsequently we identified an additional four potentially compound heterozygous variants of unknown significance in in two additional infertile men.

Baseline Intraoperative Left Ventricular Diastolic Function Is Associated with Postoperative Atrial Fibrillation after Cardiac Surgery.

Background: Detailed understanding of the association between intraoperative left atrial and left ventricular diastolic function and postoperative atrial fibrillation is lacking. In this post hoc analysis of the Posterior Left Pericardiotomy for the Prevention of Atrial Fibrillation after Cardiac Surgery (PALACS) trial, we aimed to evaluate the association of intraoperative left atrial and left ventricular diastolic function as assessed by transesophageal echocardiography (TEE) with postoperative atrial fibrillation.

Methods: PALACS patients with available intraoperative TEE data (n = 402 of 420; 95.

Non-coding variants in VAMP2 and SNAP25 affect gene expression: potential implications in migraine susceptibility.

Migraine is a common and complex neurological disease potentially caused by a polygenic interaction of multiple gene variants. Many genes associated with migraine are involved in pathways controlling the synaptic function and neurotransmitters release. However, the molecular mechanisms underpinning migraine need to be further explored.

Integrating functional scoring and regulatory data to predict the effect of non-coding SNPs in a complex neurological disease.

Most SNPs associated with complex diseases seem to lie in non-coding regions of the genome; however, their contribution to gene expression and disease phenotype remains poorly understood. Here, we established a workflow to provide assistance in prioritising the functional relevance of non-coding SNPs of candidate genes as susceptibility loci in polygenic neurological disorders. To illustrate the applicability of our workflow, we considered the multifactorial disorder migraine as a model to follow our step-by-step approach.

Aberrant Splicing Caused by a Novel VPS16 Variant Linked to Dystonia Type 30.

Dystonia is a hyperkinetic movement disorder characterized by sustained or intermittent involuntary muscle contractions, causing abnormal postures and/or repetitive movements. In this report, we identified a novel heterozygous splice-site variant in VPS16 (NM_022575.4:c.

Postoperative pericardial effusion, pericardiotomy, and atrial fibrillation: An explanatory analysis of the PALACS trial.

Background: In the Posterior left pericardiotomy for the prevention of atrial fibrillation after cardiac surgery (PALACS) trial, posterior pericardiotomy was associated with a significant reduction in postoperative atrial fibrillation (POAF) after cardiac surgery. We aimed to investigate the mechanisms underlying this effect.

Methods: We included PALACS patients with available echocardiographic data (n = 387/420, 92%).

Diverse monogenic subforms of human spermatogenic failure.

Non-obstructive azoospermia (NOA) is the most severe form of male infertility and typically incurable. Defining the genetic basis of NOA has proven challenging, and the most advanced classification of NOA subforms is not based on genetics, but simple description of testis histology. In this study, we exome-sequenced over 1000 clinically diagnosed NOA cases and identified a plausible recessive Mendelian cause in 20%.

Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility.

We conducted a genome-wide association study in a large population of infertile men due to unexplained spermatogenic failure (SPGF). More than seven million genetic variants were analysed in 1,274 SPGF cases and 1,951 unaffected controls from two independent European cohorts. Two genomic regions were associated with the most severe histological pattern of SPGF, defined by Sertoli cell-only (SCO) phenotype, namely the MHC class II gene HLA-DRB1 (rs1136759, P = 1.

Portuguese Older Persons' Views about Living in a Nursing Home: Challenges to the Rehabilitation of the Image of LTC in Post-Pandemic Times.

This paper addresses the broad topic of what older people think about nursing homes in Portugal. In the aftermath of the COVID-19 pandemic and considering the tragic events taking place in nursing homes, the challenge of reimagining the sector involves not only improving procedures and models of care, making sure they meet what citizens consider adequate, but also rehabilitating the image people have about nursing homes and rebuilding trust. Current and future decisions about how one meets LTC needs is influenced by the extent to which individuals see the alternatives as adequate.

DDB1- and CUL4-associated factor 12-like protein 1 (Dcaf12l1) is not essential for male fertility in mice.

Male infertility is a common condition affecting at least 7% of men worldwide and is often genetic in origin. Using whole exome sequencing, we recently discovered three hemizygous, likely damaging variants in DDB1- and CUL4-associated factor 12-like protein 1 (DCAF12L1) in men with azoospermia. DCAF12L1 is located on the X-chromosome and as identified by single cell sequencing studies, its expression is enriched in human testes and specifically in Sertoli cells and spermatogonia.

Common genetic variation in KATNAL1 non-coding regions is involved in the susceptibility to severe phenotypes of male infertility.

Background: Previous studies in animal models evidenced that genetic mutations of KATNAL1, resulting in dysfunction of its encoded protein, lead to male infertility through disruption of microtubule remodelling and premature germ cell exfoliation. Subsequent studies in humans also suggested a possible role of KATNAL1 single-nucleotide polymorphisms in the development of male infertility as a consequence of severe spermatogenic failure.

Objectives: The main objective of the present study is to evaluate the effect of the common genetic variation of KATNAL1 in a large and phenotypically well-characterised cohort of infertile men because of severe spermatogenic failure.

Common Variation in the PIN1 Locus Increases the Genetic Risk to Suffer from Sertoli Cell-Only Syndrome.

We aimed to analyze the role of the common genetic variants located in the locus, a relevant prolyl isomerase required to control the proliferation of spermatogonial stem cells and the integrity of the blood-testis barrier, in the genetic risk of developing male infertility due to a severe spermatogenic failure (SPGF). Genotyping was performed using TaqMan genotyping assays for three taggers (rs2287839, rs2233678 and rs62105751). The study cohort included 715 males diagnosed with SPGF and classified as suffering from non-obstructive azoospermia (NOA, = 505) or severe oligospermia (SO, = 210), and 1058 controls from the Iberian Peninsula.

A High Methylation Level of a Novel -284 bp CpG Island in the Gene Promoter Is Potentially Associated with Migraine in Women.

Migraine is a complex neurovascular disorder affecting one billion people worldwide, mainly females. It is characterized by attacks of moderate to severe headache pain, with associated symptoms. Receptor activity modifying protein (RAMP1) is part of the Calcitonin Gene-Related Peptide (CGRP) receptor, a pharmacological target for migraine.

Actionable secondary findings following exome sequencing of 836 non-obstructive azoospermia cases and their value in patient management.

Study Question: What is the load, distribution and added clinical value of secondary findings (SFs) identified in exome sequencing (ES) of patients with non-obstructive azoospermia (NOA)?

Summary Answer: One in 28 NOA cases carried an identifiable, medically actionable SF.

What Is Known Already: In addition to molecular diagnostics, ES allows assessment of clinically actionable disease-related gene variants that are not connected to the patient's primary diagnosis, but the knowledge of which may allow the prevention, delay or amelioration of late-onset monogenic conditions. Data on SFs in specific clinical patient groups, including reproductive failure, are currently limited.

Left Atrial Strain Quantification by Intraoperative Transesophageal Echocardiography: Validation With Transthoracic Echocardiography.

Objective: Whereas left atrial (LA) strain has been well-validated using transthoracic echocardiography (TTE), its detection using transesophageal echocardiography (TEE) has not been studied. Conventional transesophageal views are known to be limited due to the posterior location of the LA. Here, the feasibility and accuracy of the deep transgastric long-axis LA focused view for peak atrial longitudinal strain (PALS) quantification was tested.

Influence of PICALM and CLU risk variants on beta EEG activity in Alzheimer's disease patients.

PICALM and CLU genes have been linked to alterations in brain biochemical processes that may have an impact on Alzheimer's disease (AD) development and neurophysiological dynamics. The aim of this study is to analyze the relationship between the electroencephalographic (EEG) activity and the PICALM and CLU alleles described as conferring risk or protective effects on AD patients and healthy controls. For this purpose, EEG activity was acquired from: 18 AD patients and 12 controls carrying risk alleles of both PICALM and CLU genes, and 35 AD patients and 12 controls carrying both protective alleles.