The piRNA-pathway factor FKBP6 is essential for spermatogenesis but dispensable for control of meiotic LINE-1 expression in humans.

Infertility affects around 7% of the male population and can be due to severe spermatogenic failure (SPGF), resulting in no or very few sperm in the ejaculate. We initially identified a homozygous frameshift variant in FKBP6 in a man with extreme oligozoospermia. Subsequently, we screened a total of 2,699 men with SPGF and detected rare bi-allelic loss-of-function variants in FKBP6 in five additional persons. All six individuals had no or extremely few sperm in the ejaculate, which were not suitable for medically assisted reproduction. Evaluation of testicular tissue revealed an arrest at the stage of round spermatids. Lack of FKBP6 expression in the testis was confirmed by RT-qPCR and immunofluorescence staining. In mice, Fkbp6 is essential for spermatogenesis and has been described as being involved in piRNA biogenesis and formation of the synaptonemal complex (SC). We did not detect FKBP6 as part of the SC in normal human spermatocytes, but small RNA sequencing revealed that loss of FKBP6 severely impacted piRNA levels, supporting a role for FKBP6 in piRNA biogenesis in humans. In contrast to findings in piRNA-pathway mouse models, we did not detect an increase in LINE-1 expression in men with pathogenic FKBP6 variants. Based on our findings, FKBP6 reaches a "strong" level of evidence for being associated with male infertility according to the ClinGen criteria, making it directly applicable for clinical diagnostics. This will improve patient care by providing a causal diagnosis and will help to predict chances for successful surgical sperm retrieval.

Beyond tobacco: genomic disparities in lung cancer between smokers and never-smokers.

BACKGROUND: Tobacco use is one of the main risk factors for Lung Cancer (LC) development. However, about 10-20% of those diagnosed with the disease are never-smokers. For Non-Small Cell Lung Cancer (NSCLC) there are clear differences in both the clinical presentation and the tumor genomic profiles between smokers and never-smokers. For example, the Lung Adenocarcinoma (LUAD) histological subtype in never-smokers is predominately found in young women of European, North American, and Asian descent. While the clinical presentation and tumor genomic profiles of smokers have been widely examined, never-smokers are usually underrepresented, especially those of a Latin American (LA) background. In this work, we characterize, for the first time, the difference in the genomic profiles between smokers and never-smokers LC patients from Chile. METHODS: We conduct a comparison by smoking status in the frequencies of genomic alterations (GAs) including somatic mutations and structural variants (fusions) in a total of 10 clinically relevant genes, including the eight most common actionable genes for LC (EGFR, KRAS, ALK, MET, BRAF, RET, ERBB2, and ROS1) and two established driver genes for malignancies other than LC (PIK3CA and MAP2K1). Study participants were grouped as either smokers (current and former, n = 473) or never-smokers (n = 200) according to self-report tobacco use at enrollment. RESULTS: Our findings indicate a higher overall GA frequency for never-smokers compared to smokers (58 vs. 45.7, p-value < 0.01) with the genes EGFR, KRAS, and PIK3CA displaying the highest prevalence while ERBB2, RET, and ROS1 the lowest. Never-smokers present higher frequencies in seven out of the 10 genes; however, smokers harbor a more complex genomic profile. The clearest differences between groups are seen for EGFR (15.6 vs. 21.5, p-value: < 0.01), PIK3CA (6.8 vs 9.5) and ALK (3.2 vs 7.5) in favor of never-smokers, and KRAS (16.3 vs. 11.5) and MAP2K1 (6.6 vs. 3.5) in favor of smokers. Alterations in these genes are comprised almost exclusively by somatic mutations in EGFR and mainly by fusions in ALK, and only by mutations in PIK3CA, KRAS and MAP2K1. CONCLUSIONS: We found clear differences in the genomic landscape by smoking status in LUAD patients from Chile, with potential implications for clinical management in these limited-resource settings.

Phasing of de novo mutations using a scaled-up multiple amplicon long-read sequencing approach.

De novo mutations (DNMs) play an important role in severe genetic disorders that reduce fitness. To better understand their role in disease, it is important to determine the parent-of-origin and timing of mutational events that give rise to these mutations, especially in sex-specific developmental disorders such as male infertility. However, currently available short-read sequencing approaches are not ideally suited for phasing, as this requires long continuous DNA strands that span both the DNM and one or more informative single-nucleotide polymorphisms. To overcome these challenges, we optimized and implemented a multiplexed long-read sequencing approach using Oxford Nanopore technologies MinION platform. We focused on improving target amplification, integrating long-read sequenced data with high-quality short-read sequence data, and developing an anchored phasing computational method. This approach handled the inherent phasing challenges of long-range target amplification and the normal accumulation of sequencing error associated with long-read sequencing. In total, 77 of 109 DNMs (71%) were successfully phased and parent-of-origin identified. The majority of phased DNMs were prezygotic (90%), the accuracy of which is highlighted by an average mutant allele frequency of 49.6% and standard error of 0.84%. This study demonstrates the benefits of employing an integrated short-read and long-read sequencing approach for large-scale DNM phasing.

The ubiquitin E3 ligase Parkin regulates neuronal CaV1.3 channel functional expression.

Neuronal L-type Ca2+ channels of the CaV1.3 subclass are transmembrane protein complexes that contribute to the pacemaker activity in the adult substantia nigra dopaminergic neurons. The altered function of these channels may play a role in the development and progress of neurodegenerative mechanisms implicated in Parkinson's disease (PD). Although L-type channel expression is precisely regulated, an increased functional expression has been observed in PD. Previously, we showed that Parkin, an E3 enzyme of the ubiquitin-proteasome system (UPS) interacts with neuronal CaV2.2 channels promoting their ubiquitin-mediated degradation. In addition, previous studies show an increase in CaV1.3 channel activity in dopaminergic neurons of the SNc and that Parkin expression is reduced in PD. These findings suggest that the decrease in Parkin may affect the proteasomal degradation of CaV1.3, which helps explain the increase in channel activity. Therefore, the present report aims to gain insight into the degradation mechanisms of the neuronal CaV1.3 channel by the UPS. Immunoprecipitation assays showed the interaction between Parkin and the CaV1.3 channels expressed in HEK-293 cells and neural tissues. Likewise, Parkin overexpression reduced the total and membrane channel levels and decreased the current density. Consistent with this, patch-clamp recordings in the presence of an inhibitor of the UPS, MG132, prevented the effects of Parkin, suggesting enhanced channel proteasomal degradation. In addition, the half-life of the pore-forming CaV1.3α1 protein was significantly reduced by Parkin overexpression. Finally, electrophysiological recordings using a PRKN knockout HEK-293 cell line generated by CRISPR/Cas9 showed increased current density. These results suggest that Parkin promotes the proteasomal degradation of CaV1.3, which may be a relevant aspect for the pathophysiology of PD.NEW & NOTEWORTHY The increased expression of CaV1.3 calcium channels is a crucial feature of Parkinson's disease (PD) pathophysiology. However, the mechanisms that determine this increase are not yet defined. Parkin, an enzyme of the ubiquitin-proteasome system, is known to interact with neuronal channels promoting their ubiquitin-mediated degradation. Interestingly, Parkin mutations also play a role in PD. Here, the degradation mechanisms of CaV1.3 channels and their relationship with the pathophysiology of PD are studied in detail.

Biomarkers of mammographic density in premenopausal women.

BACKGROUND: While mammographic density is one of the strongest risk factors for breast cancer, little is known about its determinants, especially in young women. We applied targeted metabolomics to identify circulating metabolites specifically associated with mammographic density in premenopausal women. Then, we aimed to identify potential correlates of these biomarkers to guide future research on potential modifiable determinants of mammographic density. METHODS: A total of 132 metabolites (acylcarnitines, amino acids, biogenic amines, glycerophospholipids, sphingolipids, hexose) were measured by tandem liquid chromatography/mass spectrometry in plasma samples from 573 premenopausal participants in the Mexican Teachers' Cohort. Associations between metabolites and percent mammographic density were assessed using linear regression models, adjusting for breast cancer risk factors and accounting for multiple tests. Mean concentrations of metabolites associated with percent mammographic density were estimated across levels of several lifestyle and metabolic factors. RESULTS: Sphingomyelin (SM) C16:1 and phosphatidylcholine (PC) ae C30:2 were inversely associated with percent mammographic density after correction for multiple tests. Linear trends with percent mammographic density were observed for SM C16:1 only in women with body mass index (BMI) below the median (27.4) and for PC ae C30:2 in women with a BMI over the median. SM C16:1 and PC ae C30:2 concentrations were positively associated with cholesterol (total and HDL) and inversely associated with number of metabolic syndrome components. CONCLUSIONS: We identified new biomarkers associated with mammographic density in young women. The association of these biomarkers with mammographic density and metabolic parameters may provide new perspectives to support future preventive actions for breast cancer.

Landscape of Germline Genetic Variants in AGT, MGMT, and TP53 in Mexican Adult Patients with Astrocytoma.

Astrocytoma is the most common type of primary brain tumor. The risk factors for astrocytoma are poorly understood; however, germline genetic variants account for 25% of the risk of developing gliomas. In this study, we assessed the risk of astrocytoma associated with variants in AGT, known by its role in angiogenesis, TP53, a well-known tumor suppressor and the DNA repair gene MGMT in a Mexican population. A case-control study was performed in 49 adult Mexican patients with grade II-IV astrocytoma. Sequencing of exons and untranslated regions of AGT, MGMT, and TP53 from was carried in an Ion Torrent platform. Individuals with Mexican Ancestry from the 1000 Genomes Project were used as controls. Variants found in our cohort were then assessed in a The Cancer Genome Atlas astrocytoma pan-ethnic validation cohort. Variants rs1926723 located in AGT (OR 2.74, 1.40-5.36 95% CI), rs7896488 in MGMT (OR 3.43, 1.17-10.10 95% CI), and rs4968187 in TP53 (OR 2.48, 1.26-4.88 95% CI) were significantly associated with the risk of astrocytoma after multiple-testing correction. This is the first study where the AGT rs1926723 variant, TP53 rs4968187, and MGMT rs7896488 were found to be associated with the risk of developing an astrocytoma.

The challenges facing indigenous communities in Latin America as they confront the COVID-19 pandemic.

The coronavirus disease 2019 (COVID-2019) pandemic struck Latin America in late February and is now beginning to spread across the rural indigenous communities in the region, home to 42 million people. Eighty percent of this highly marginalized population is concentrated in Bolivia, Guatemala, Mexico and Peru. Health care services for these ethnic groups face distinct challenges in view of their high levels of marginalization and cultural differences from the majority. Drawing on 30 years of work on the responses of health systems in the indigenous communities of Latin America, our group of researchers believes that countries in the region must be prepared to combat the epidemic in indigenous settings marked by deprivation and social disparity. We discuss four main challenges that need to be addressed by governments to guarantee the health and lives of those at the bottom of the social structure: the indigenous peoples in the region. More than an analysis, our work provides a practical guide for designing and implementing a response to COVID-19 in indigenous communities.

A systematic review and standardized clinical validity assessment of male infertility genes.

STUDY QUESTION: Which genes are confidently linked to human monogenic male infertility? SUMMARY ANSWER: Our systematic literature search and clinical validity assessment reveals that a total of 78 genes are currently confidently linked to 92 human male infertility phenotypes. WHAT IS KNOWN ALREADY: The discovery of novel male infertility genes is rapidly accelerating with the availability of next-generating sequencing methods, but the quality of evidence for gene-disease relationships varies greatly. In order to improve genetic research, diagnostics and counseling, there is a need for an evidence-based overview of the currently known genes. STUDY DESIGN, SIZE, DURATION: We performed a systematic literature search and evidence assessment for all publications in Pubmed until December 2018 covering genetic causes of male infertility and/or defective male genitourinary development. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two independent reviewers conducted the literature search and included papers on the monogenic causes of human male infertility and excluded papers on genetic association or risk factors, karyotype anomalies and/or copy number variations affecting multiple genes. Next, the quality and the extent of all evidence supporting selected genes was weighed by a standardized scoring method and used to determine the clinical validity of each gene-disease relationship as expressed by the following six categories: no evidence, limited, moderate, strong, definitive or unable to classify. MAIN RESULTS AND THE ROLE OF CHANCE: From a total of 23 526 records, we included 1337 publications about monogenic causes of male infertility leading to a list of 521 gene-disease relationships. The clinical validity of these gene-disease relationships varied widely and ranged from definitive (n = 38) to strong (n = 22), moderate (n = 32), limited (n = 93) or no evidence (n = 160). A total of 176 gene-disease relationships could not be classified because our scoring method was not suitable. LARGE SCALE DATA: Not applicable. LIMITATIONS, REASONS FOR CAUTION: Our literature search was limited to Pubmed. WIDER IMPLICATIONS OF THE FINDINGS: The comprehensive overview will aid researchers and clinicians in the field to establish gene lists for diagnostic screening using validated gene-disease criteria and help to identify gaps in our knowledge of male infertility. For future studies, the authors discuss the relevant and important international guidelines regarding research related to gene discovery and provide specific recommendations for the field of male infertility. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a VICI grant from The Netherlands Organization for Scientific Research (918-15-667 to J.A.V.), the Royal Society, and Wolfson Foundation (WM160091 to J.A.V.) as well as an investigator award in science from the Wellcome Trust (209451 to J.A.V.). PROSPERO REGISTRATION NUMBER: None.

Improved detection of CFTR variants by targeted next-generation sequencing in male infertility: a case series.

RESEARCH QUESTION: Congenital bilateral absence of vas deferens (CBAVD) is characterized by 'obstructive azoospermia' in male patients with primary infertility. In the routine clinical workup of infertile men, patients with an absence of vas deferens are screened for CFTR variants. However, current genetic testing panels do not cover all variants, missing some CBAVD cases. Here, CFTR testing was explored by targeted next-generation sequencing (NGS) to improve variant detection. DESIGN: Five individuals with heterozygous pathogenic CFTR variants were identified using targeted NGS in a cohort of 1112 idiopathic infertile men with azoospermia or severe oligozoospermia. Pre-screening exclusion criteria were CBAVD by clinical examination with positive CFTR sequence analysis as part of routine fertility workup. RESULTS: Cases 1, 2 and 3 presented with CBAVD after which CFTR screening by mutation panel analysis was negative. Case 4 presented with congenital unilateral absence of vas deferens, after which CFTR panel analysis identified a heterozygous p.(Phe508del) variant. Case 5 presented with a palpable vas deferens so CFTR panel analysis was not offered. In all five men, targeted NGS revealed additional pathogenic variants: p.(Arg117Cys) and p.(Arg1158*) (case 1); p.(Asp110His) and p.(Ser945Leu) (case 2); p.(Arg248Thr) and p.(Phe508Cys) (case 3); p.(Gly463Ser) (case 4); p.(Phe508del) (case 4 and 5); and p.(Arg117His) (case 5). CONCLUSIONS: Targeted NGS led to the detection of five infertile men with CFTR variants who would otherwise have remained undiagnosed after routine genetic screening during the fertility workup for azoospermia or severe oligozoospermia. Given the wide availability of affordable targeted NGS, the data suggest that full gene analysis, and not mutation panels, should be considered to screen CFTR in azoospermic men.

Renin angiotensin system and its role in biomarkers and treatment in gliomas.

Gliomas are the most common primary intrinsic tumor in the brain and are classified as low- or high-grade according to the World Health Organization (WHO). Patients with high-grade gliomas (HGG) who undergo surgical resection with adjuvant therapy have a mean overall survival of 15 months and 100% recurrence. The renin-angiotensin system (RAS), the primary regulator of cardiovascular circulation, exhibits local action and works as a paracrine system. In the context of this local regulation, the expression of RAS peptides and receptors has been detected in different kinds of tumors, including gliomas. The dysregulation of RAS components plays a significant role in the proliferation, angiogenesis, and invasion of these tumors, and therefore in their outcomes. The study and potential application of RAS peptides and receptors as biomarkers in gliomas could bring advantages against the limitations of current tumoral markers and should be considered in the future. The targeting of RAS components by RAS blockers has shown potential of being protective against cancer and improving immunotherapy. In gliomas, RAS blockers have shown a broad spectrum for beneficial effects and are being considered for use in treatment protocols. This review aims to summarize the background behind how RAS plays a role in gliomagenesis and explore the evidence that could lead to their use as biomarkers and treatment adjuvants.

Validation and application of a novel integrated genetic screening method to a cohort of 1,112 men with idiopathic azoospermia or severe oligozoospermia.

Microdeletions of the Y chromosome (YCMs), Klinefelter syndrome (47,XXY), and CFTR mutations are known genetic causes of severe male infertility, but the majority of cases remain idiopathic. Here, we describe a novel method using single molecule Molecular Inversion Probes (smMIPs), to screen infertile men for mutations and copy number variations affecting known disease genes. We designed a set of 4,525 smMIPs targeting the coding regions of causal (n = 6) and candidate (n = 101) male infertility genes. After extensive validation, we screened 1,112 idiopathic infertile men with non-obstructive azoospermia or severe oligozoospermia. In addition to five chromosome YCMs and six other sex chromosomal anomalies, we identified five patients with rare recessive mutations in CFTR as well as a patient with a rare heterozygous frameshift mutation in SYCP3 that may be of clinical relevance. This results in a genetic diagnosis in 11-17 patients (1%-1.5%), a yield that may increase significantly when more genes are confidently linked to male infertility. In conclusion, we developed a flexible and scalable method to reliably detect genetic causes of male infertility. The assay consolidates the detection of different types of genetic variation while increasing the diagnostic yield and detection precision at the same or lower price compared with currently used methods.

Molecular Biology In Young Women With Breast Cancer: From Tumor Gene Expression To DNA Mutations.

Young women with breast cancer (YWBC) represent roughly 15% of breast cancer (BC) cases in Latin America and other developing regions. Breast tumors occurring at an early age are more aggressive and have an overall worse prognosis compared to breast tumors in postmenopausal women. The expression of relevant proliferation biomarkers such as endocrine receptors and human epidermal growth factor receptor 2 appears to be unique in YWBC. Moreover, histopathological, molecular, genetic, and genomic studies have shown that YWBC exhibit a higher frequency of aggressive subtypes, differential tumor gene expression, increased genetic susceptibility, and specific genomic signatures, compared to older women with BC. This article reviews the current knowledge on tumor biology and genomic signatures in YWBC.

Influence of paternal age on ongoing pregnancy rate at eight weeks' gestation in assisted reproduction.

A retrospective cohort study was performed with the followings aims: to evaluate the influence of paternal age on best embryo quality available for embryo transfer on the third day; biochemical pregnancy rate; miscarriage rate and ongoing pregnancy rate at 8 weeks' gestational age, after IVF or intracytoplasmic sperm injection (ICSI) treatment, respectively, including treatment with non-ejaculated spermatozoa. In total, 7051 first IVF/ICSI cycles in Radboud university medical center, between 1 January 2001 and 1 June 2013 were included in this study. A statistical model was used to analyse the effect of paternal age and maternal age. No statistically significant differences between the paternal age groups were found with respect to the probability of an ongoing pregnancy after the first cycle (35-44 years: odds ratio [OR] = 0.97 [95% confidence interval [CI]: 0.86 to 1.10] and ≥45 years: OR = 1.01 [95% CI: 0.82 to 1.26]), respectively, compared with <35 years of age (control). Similar results were found with respect to paternal age and the availability of a top quality embryo for transfer, biochemical pregnancy and miscarriage. However, live birth was not taken into account. In conclusion, paternal age did not affect ongoing pregnancy rates in first IVF/ICSI cycles.

Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome.

To gain insight into the function of DNA methylation at cis-regulatory regions and its impact on gene expression, we measured methylation, RNA polymerase occupancy and histone modifications at 16,000 promoters in primary human somatic and germline cells. We find CpG-poor promoters hypermethylated in somatic cells, which does not preclude their activity. This methylation is present in male gametes and results in evolutionary loss of CpG dinucleotides, as measured by divergence between humans and primates. In contrast, strong CpG island promoters are mostly unmethylated, even when inactive. Weak CpG island promoters are distinct, as they are preferential targets for de novo methylation in somatic cells. Notably, most germline-specific genes are methylated in somatic cells, suggesting additional functional selection. These results show that promoter sequence and gene function are major predictors of promoter methylation states. Moreover, we observe that inactive unmethylated CpG island promoters show elevated levels of dimethylation of Lys4 of histone H3, suggesting that this chromatin mark may protect DNA from methylation.

Chromosome-wide nucleosome replacement and H3.3 incorporation during mammalian meiotic sex chromosome inactivation.

In mammalian males, the first meiotic prophase is characterized by formation of a separate chromatin domain called the sex body. In this domain, the X and Y chromosomes are partially synapsed and transcriptionally silenced, a process termed meiotic sex-chromosome inactivation (MSCI). Likewise, unsynapsed autosomal chromatin present during pachytene is also silenced (meiotic silencing of unsynapsed chromatin, MSUC). Although it is known that MSCI and MSUC are both dependent on histone H2A.X phosphorylation mediated by the kinase ATR, and cause repressive H3 Lys9 dimethylation, the mechanisms underlying silencing are largely unidentified. Here, we demonstrate an extensive replacement of nucleosomes within unsynapsed chromatin, depending on and initiated shortly after induction of MSCI and MSUC. Nucleosomal eviction results in the exclusive incorporation of the H3.3 variant, which to date has primarily been associated with transcriptional activity. Nucleosomal exchange causes loss and subsequent selective reacquisition of specific histone modifications. This process therefore provides a means for epigenetic reprogramming of sex chromatin presumably required for gene silencing in the male mammalian germ line.

Diagnostic Yield of Video Capsule Endoscopy for Small Bowel Bleeding: Eight Consecutive Years of Experience at the VA Caribbean Healthcare System.

OBJECTIVE: To evaluate the diagnostic yield of video capsule endoscopy (VCE) in patients with small bowel gastrointestinal bleeding and examine the impact of this diagnostic technology on the clinical management of this complaint. METHODS: This was a retrospective study in which all patients who underwent VCE (May 7, 2003 - December 31, 2011) were included. Records were reviewed for the type of bleeding (overt vs. occult; when present), demographic data, lab results, and capsule endoscopy findings. Information regarding medical treatment (i.e., endoscopic intervention, surgical therapy, or both) was also recorded. RESULTS: A total of 229 subjects were included in the study. Most were men; the mean age of all the subjects was 69.8 years. Of the 229 VCEs, 154 (67.3%) were done because of occult bleeding and 75 (32%) because of overt bleeding. VCEs were normal in 34 (14.9%) cases and non-diagnostic in 15 (6.6%). Angiodysplasia, erosions, and ulcers were the most common findings (48.5%, 24.5%, and 10.92% respectively). Active bleeding was reported in 7 cases (3%). Nearly 20% of the 229 cases required either endoscopic or surgical intervention. CONCLUSION: In our study, VCE achieved a diagnostic yield of 78.6%. In 1 of every 5 subjects, video capsule endoscopy led to the identification of small bowel lesions that required either endoscopic or surgical resection, rather than conservative treatment with iron replacement. VCE proved to be a very useful investigative tool, not only for establishing the source of bleeding but also, most importantly, for directing the appropriate therapy for lesions that would otherwise have been missed by conventional studies.

The influence of sperm motility and cryopreservation on the treatment outcome after intracytoplasmic sperm injection following testicular sperm extraction.

INTRODUCTION: It is already known that embryo quality is a major contributing factor to the outcome of assisted reproduction techniques. This study focuses on treatment variables that might be of importance to the outcome of intracytoplasmic sperm injection following testicular sperm extraction (TESE-ICSI) in non-obstructive azoospermia. MATERIAL AND METHODS: A retrospective cohort study was conducted at a Dutch tertiary care academic training hospital between July 2009 and December 2013. With logistic regression analysis we explored the influence of treatment variables, including testicular sperm parameters - (i) motile or tail touch spermatozoa, and (ii) use of fresh or frozen testicular semen-samples - on biochemical and ongoing pregnancy rates after single (n = 393) and double embryo transfer (n = 352). RESULTS: Multivariate logistic regression analysis identified the rank of the TESE-ICSI attempt [odds ratio (OR) 0.8, 95% confidence interval (95% CI) 0.70-0.93], the number of embryos available for transfer (OR 1.1, 95% CI 1.06-1.19) and quality of the embryo(s) transferred (OR 12.8, 95% CI 5.00-32.67) as possible predictors of biochemical pregnancy, whereas only embryo quality (OR 16.9, 95% CI 5.23-54.87) was independently associated with ongoing pregnancy. CONCLUSIONS: The use of cryopreserved testicular sperm does not negatively influence the ongoing pregnancy and live birth rate after TESE-ICSI. However, sperm motility seems to increase the pregnancy rate through its influence on embryo quality. Therefore, fresh TESE has no added value when there is still cryopreserved testicular sperm available. Motile sperm is preferred for injection, but the use of tail touch sperm results in an acceptable treatment outcome.

Nutritional status according to the stages of Alzheimer's disease.

OBJECTIVE: To assess the nutritional status of Alzheimer's disease (AD) patients with no other associated dementia, according to disease stage. DESIGN: Cross-sectional observational study. SETTING: Neurobehavioral Diseases Outpatient Clinic, Clinical Hospital, Ribeirao Preto Medical School (University of São Paulo). PARTICIPANTS: The sample consisted of 36 individuals of both genders with AD diagnosis, and no other associated type of dementia, in various stages of the disease, according to the Clinical Dementia Rating (CDR 0.5-3). MEASUREMENTS: Nutritional status was evaluated using the Mini Nutritional Assessment (MNA) and anthropometric measurements such as weight, body mass index (BMI) and arm, waist, abdomen and hip circumferences. In addition, body composition was assessed by bioelectrical impedance analysis (BIA). RESULTS: The mean age of the group was 74.2 ± 10.1 years, 72.2 % of them were women. The MNA showed that most of these individuals were at risk for malnutrition (55.5 %) and many of them (43.7 %) were underweight according to BMI. Data from BIA analysis revealed that 41.7 % of these individuals had a quantity of body fat classified as malnutrition and 11.1 % had a phase angle (PA) below recommended values for age group. There was a negative and significant correlation of lean mass and PA with age, and of global MNA evaluation with CDR, as well as a positive correlation of MNA total score with fat mass and BMI. Worse classifications of nutritional status obtained by MNA scores were also observed in the more severe stages of the disease, according to the CDR. CONCLUSION: Patients with AD are mostly elderly with changes in body composition that are typical of aging, with signs of peripheral malnutrition and preservation of abdominal fat. However, greater impairment of general nutritional status was observed in the more advanced stages of AD, creating a situation of greater vulnerability for these patients.

Improved phenotypic classification of male infertility to promote discovery of genetic causes.

An increasing number of genes are being described in the context of non-syndromic male infertility. Linking the underlying genetic causes of non-syndromic male infertility with clinical data from patients is important to establish new genotype-phenotype correlations. This process can be facilitated by using universal nomenclature, but no standardized vocabulary is available in the field of non-syndromic male infertility. The International Male Infertility Genomics Consortium aimed at filling this gap, providing a standardized vocabulary containing nomenclature based on the Human Phenotype Ontology (HPO). The "HPO tree" was substantially revised compared with the previous version and is based on the clinical work-up of infertile men, including physical examination and hormonal assessment. Some causes of male infertility can already be suspected based on the patient's clinical history, whereas in other instances, a testicular biopsy is needed for diagnosis. We assembled 49 HPO terms that are linked in a logical hierarchy and showed examples of morphological features of spermatozoa and testicular histology of infertile men with identified genetic diagnoses to describe the phenotypes. This work will help to record patients' phenotypes systematically and facilitate communication between geneticists and andrologists. Collaboration across institutions will improve the identification of patients with the same phenotypes, which will promote the discovery of novel genetic causes for non-syndromic male infertility.

Associations of Nativity and the Role of the Hispanic Paradox on the Cognitive Health of Older Latinos Living in the United States.

Background: US-based Latinos have lower education and income combined with higher health risks than non-Latino whites, but often 'paradoxically' evidence better health-related outcomes. Less work has investigated this paradox for cognitive-related outcomes despite nativity diversity. Objective: We evaluated cognitive aging within older Latinos of diverse nativity currently living in the US and participating in Rush Alzheimer's Disease Center studies. Methods: Participants without baseline dementia, who completed annual neuropsychological assessments (in English or Spanish) were grouped by US-born (n = 117), Mexico-born (n = 173), and born in other Latin American regions (LAr-born = 128). Separate regression models examined associations between nativity and levels of (N = 418) or change in (n = 371; maximum follow-up ∼16 years) global and domain-specific cognition. Results: Demographically-adjusted linear regression models indicated that foreign-born nativity was associated with lower levels of global cognition and select cognitive domains compared to US-born Latinos. No associations of nativity with cognitive decline emerged from demographically-adjusted mixed-effects models; however, Mexico-born nativity appeared associated with slower declines in working memory compared to other nativity groups (p-values ≥ 0.051). Mexico-born Latinos had relatively higher vascular burden and lower education levels than other nativity groups; however, this did not alter results. Conclusions: Nativity differences in baseline cognition may be due, in part, to accumulated stressors related to immigration and acculturation experienced by foreign-born Latinos which may hasten meeting criteria for dementia later in life. In contrast, Mexico-born participants' slower working memory declines, taken in the context of other participant characteristics including vascular burden, suggests the Hispanic Paradox may relate to factors with the potential to affect cognition.