Key Genes of the Immune System and Predisposition to Acquired Hemophilia A: Evidence from a Spanish Cohort of 49 Patients Using Next-Generation Sequencing.

Acquired hemophilia A (AHA) is a rare bleeding disorder caused by the presence of autoantibodies against factor VIII (FVIII). As with other autoimmune diseases, its etiology is complex and its genetic basis is unknown. The aim of this study was to identify the immunogenetic background that predisposes individuals to AHA. HLA and KIR gene clusters, as well as KLRK1, were sequenced using next-generation sequencing in 49 AHA patients. Associations between candidate genes involved in innate and adaptive immune responses and AHA were addressed by comparing the alleles, genotypes, haplotypes, and gene frequencies in the AHA cohort with those in the donors' samples or Spanish population cohort. Two genes of the HLA cluster, as well as rs1049174 in KLRK1, which tags the natural killer (NK) cytotoxic activity haplotype, were found to be linked to AHA. Specifically, A*03:01 (p = 0.024; odds ratio (OR) = 0.26[0.06-0.85]) and DRB1*13:03 (p = 6.8 × 103, OR = 7.56[1.64-51.40]), as well as rs1049174 (p = 0.012), were significantly associated with AHA. In addition, two AHA patients were found to carry one copy each of the low-frequency allele DQB1*03:09 (nallele = 2, 2.04%), which was completely absent in the donors. To the best of our knowledge, this is the first time that the involvement of these specific alleles in the predisposition to AHA has been proposed. Further molecular and functional studies will be needed to unravel their specific contributions. We believe our findings expand the current knowledge on the genetic factors involved in susceptibility to AHA, which will contribute to improving the diagnosis and prognosis of AHA patients.

Evidence of resistance to ivermectin in the gastrointestinal nematodes of horses from Mexican southeast.

Gastrointestinal nematodes (GIN) are a major impediment to breeding and exploitation of horses. Traditional control of GIN has generated resistance to main anthelmintics, including ivermectin. An analysis of five ranches with a history of IVM use was done to determine the efficacy and resistance of GIN to IVM treatment in horses from the Mexican southeast. Predesigned questionnaires were applied to collect information on previous treatment protocols. The fecal egg count reduction test (FECRT) was applied to determine resistance. Before IVM application, a McMaster test was used to diagnose GIN infection in horses, and feces cultures were done to identify L3 larvae for Strongylida eggs. Pre-treatment samples showed that 72.7% (80/110) of horses were GIN positive, with cyathostomins being the most frequent (91.8%), followed by Oxyuris equi (7.0%), Parascaris equorum (1.0%), and Strongylus vulgaris (0.2%). Based on the results, the horses at each ranch were divided in control (CG) and experimental (EG) groups with similar eggs per gram of feces (EPG). The EG (40/80) was dewormed with IVM (0.2 mg/kg orally) and the CG (40/80) remained untreated. After 14 days, EPG were measured, and feces cultures were done again to identify L3 larvae. After treatment of EG, 40% (16/40) of horses were positive, the most frequently identified GIN were cyathostomins (98.6%), followed by P. equorum (1.0%) and S. vulgaris (0.2%). Three of the five ranches were classified as resistant, according to the FECRT, with a percentage of reduction from 53 to 68%, all of which used IVM ≥4 times annually. This is the first evidence of resistance in cyathostomins to IVM treatment in horses from the Mexican southeast, adding to the current problem of anthelmintic resistance in equine GIN.

Epidemiological intelligence community network intervention: a community response for COVID-19 community transmission.

BACKGROUND: Expanding and providing access to early detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through testing community-based strategies among socially vulnerable communities (SVC) are critical to reducing health disparities. The Epidemiological Intelligence Community Network (EpI-Net) community-based intervention sought to increase coronavirus 2019 (COVID-19) testing uptake and prevention practices among SVC in Puerto Rico (PR). We evaluated EpI-Net's community leaders' capacity-building component by assessing pre-post COVID-19 public health workshops' tests' score changes and satisfaction among trained community leaders. METHODS: A total of 24 community leaders from SVC in PR have completed four community workshops. Pre- and post-assessments were completed as part of the health promotors training program to evaluate participants' tests score changes and satisfaction outcomes. RESULTS: Preliminary results showed: (1) high intervention retention levels of community leaders (85.7% acceptance rate); (2) change in post-test scores for community engagement strategies (p = 0.012); (3) change in post-test educational scores in COVID-19 prevention practices (p = 0.014); and (4) a change in scores in public health emergency management strategies (p < 0.001). CONCLUSIONS: The overall workshop satisfaction was 99.6%. Community leaders have shown the importance of community capacity building as a key component for intervention feasibility and impact. TRIAL REGISTRATION: Our study was retrospectively registered under the ClinicalTrial.gov ID NCT04910542.

Characterization of Seminal Microbiome of Infertile Idiopathic Patients Using Third-Generation Sequencing Platform.

Since the first description of a commensal seminal microbiome using sequencing, less than a decade ago, interest in the composition of this microbiome and its relationship with fertility has been growing. Articles using next-generation sequencing techniques agree on the identification of the most abundant bacterial phyla. However, at the genus level, there is still no consensus on which bacteria are most abundant in human seminal plasma. This discrepancy may be due to methodological variability such as sample collection, bacterial DNA extraction methodology, which hypervariable regions of 16S rRNA gene have been amplified, or bioinformatic analysis. In the present work, seminal microbiota of 14 control samples and 42 samples of idiopathic infertile patients were characterized based on full-length sequencing of the 16S rRNA gene using MinION platform from Oxford Nanopore. These same samples had been analyzed previously using Illumina's MiSeq sequencing platform. Comparison between the results obtained with the two platforms has been used to analyze the impact of sequencing method on the study of the seminal microbiome's composition. Seminal microbiota observed with MinION were mainly composed of the phyla Firmicutes, Proteobacteria, Bacteroidetes and Actinobacteria, with the most abundant genera being Peptoniphilus, Finegoldia, Staphylococcus, Anaerococcus, Campylobacter, Prevotella, Streptococcus, Lactobacillus, Ezakiella and Enterococcus. This composition was similar to that found by the Illumina platform, since these 10 most abundant genera were also among the most abundant genera detected by the Nanopore platform. In both cases, the top 10 genera represented more than 70% of the classified reads. However, relative abundance of each bacterium did not correlate between these two platforms, with intraindividual variations of up to 50 percentage points in some cases. Results suggest that the effect of the sequencing platform on the characterization of seminal microbiota is not very large at the phylum level, with slightly variances in Firmicutes and Actinobacteria, but presents differences at the genus level. These differences could alter the composition and diversity of bacterial profiles or posterior analyses. This indicates the importance of conducting multi-platform studies to better characterize seminal microbioma.

MOBILE Intervention Pilot Study in College Students With Elevated Blood Pressure.

BACKGROUND: Hypertension is typically recognized in middle-aged and older adults but often overlooked in younger populations. OBJECTIVE: We evaluated a mobile intervention for reducing blood pressure (BP) in college-age students for 28 days. METHODS: Students with elevated BP or undiagnosed hypertension were assigned to an intervention or control group. All subjects completed baseline questionnaires and attended an educational session. For 28 days, intervention subjects sent their BP and motivation levels to the research team and completed assigned BP-reducing tasks. After 28 days, all subjects completed an exit interview. RESULTS: We found a statistically significant decrease in BP in the intervention group only ( P = .001) but no statistical difference in sodium intake for either group. Mean hypertension knowledge increased in both groups but was only significant for the control group ( P = .001). CONCLUSIONS: The results provide preliminary data on BP reduction with greater impact on the intervention group.

Metabolic Overlap between Alzheimer's Disease and Metabolic Syndrome Identifies the PVRL2 Gene as a New Modulator of Diabetic Dyslipidemia.

BACKGROUND: Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) share metabolic alterations such as abnormal insulin and lipid metabolism and have some common genetic factors such as APOE genotype. Taking this into account, we hypothesized that we could identify common genetic factors involved in the development of diabetes and cardiovascular diseases. METHODOLOGY: We first genotyped 48 single nucleotide polymorphisms (SNPs) previously associated with AD in a cohort composed of 330 patients with cognitive impairment (CI) to assess their association with plasma lipids. Second, we conducted pleiotropy-informed conjunctional false discovery rate (FDR) analysis designed to identify shared variants between AD and plasma lipid levels. Finally, we used the SNPs to be found associated with lipid parameters and AD to search for associations with lipoprotein parameters in 281 patients with cardiometabolic risk. RESULTS: Five SNPs were significantly associated with lower levels of cholesterol transported in remnant lipoprotein particles (RLPc) in subjects with CI; among these SNPs was the rs73572039 variant in PVRL2. Stratified QQ-plots were conducted on GWAS designed for AD and triglycerides (TG). The cross-trait analysis resulted in a total of 22 independent genomic loci associated with both AD and TG levels with a conjFDR < 0.05. Among these loci, two pleiotropic variants were located in PVRL2 (rs12978931 and rs11667640). The three SNPs in PVRL2 were significantly associated with RLPc, TG, and number of circulating VLDL and HDL particles in subjects with cardiometabolic risk. CONCLUSIONS: We have identified three variants in PVRL2 that predispose individuals to AD that also influence the lipid profile that confers cardiovascular risk in T2DM subjects. PVRL2 is a potential new modulating factor of atherogenic dyslipidemia.

Identification of decreased intrinsic capacity: Performance of diagnostic measures of the ICOPE Screening tool in community dwelling older people in the VIMCI study.

BACKGROUND: The World Health Organization (WHO) has developed the Integrated Care for Older People (ICOPE) strategy to face the challenges of ageing societies. This strategy is focused on person centered care and the assessment intrinsic capacity (IC). Early identification of five domains of IC (cognition, locomotion, vitality, sensory (hearing and vision), and psychological) has been shown to be related with adverse outcomes and can guide actions towards primary prevention and healthy ageing. IC assessment proposed by the WHO ICOPE guidelines is composed by two steps: First, Screening for decreased IC by the ICOPE Screening tool; second, by the reference standard methods. The aim was to assess the performance of diagnostic measures (sensibility, specificity, diagnostic accuracy, and agreement of the ICOPE Screening tool) compared to the reference standard methods in European community-dwelling older adults. METHODS: Cross-sectional analysis of the baseline of the ongoing VIMCI (Validity of an Instrument to Measure Intrinsic Capacity) cohort study, which was carried out in Primary Care centers and outpatient clinics from 5 rural and urban territories in Catalonia (Spain). Participants were 207community dwelling persons ≥ 70-year-old with Barthel ≥ 90, without dementia or advanced chronic conditions who provided their consent to participate. The 5 IC domains were assessed by the ICOPE Screening tool and the reference methods (SPPB, gait speed, MNA, Snellen chart, audiometry, MMSE, GDS5) during patients' visit. Agreement was assessed with the Gwet AC1 index. RESULTS: ICOPE Screening tool sensitivity was higher for cognition (0.889) and ranged between 0.438 and 0.569 for most domains. Specificity ranged from 0.682 to 0.96, diagnostic accuracy from 0.627 to 0.879, Youden index from 0.12 to 0.619, and Gwet AC1 from 0.275 to 0.842. CONCLUSION: The ICOPE screening tool showed fair performance of diagnostic measures; it was helpful to identify those participants with satisfactory IC and showed a modest ability to identify decreased IC in older people with high degree of autonomy. Since low sensitivities were found, a process of external validation would be recommended to reach better discrimination. Further studies about the ICOPE Screening tool and its performance of diagnostic measures in different populations are urgently required.

Multiallelic Copy Number Variation in ORM1 is Associated with Plasma Cell-Free DNA Levels as an Intermediate Phenotype for Venous Thromboembolism.

Venous thromboembolism (VTE) is a common disease with high heritability. However, only a small portion of the genetic variance of VTE can be explained by known genetic risk factors. Neutrophil extracellular traps (NETs) have been associated with prothrombotic activity. Therefore, the genetic basis of NETs could reveal novel risk factors for VTE. A recent genome-wide association study of plasma cell-free DNA (cfDNA) levels in the Genetic Analysis of Idiopathic Thrombophilia 2 (GAIT-2) Project showed a significant associated locus near ORM1. We aimed to further explore this candidate region by next-generation sequencing, copy number variation (CNV) quantification, and expression analysis using an extreme phenotype sampling design involving 80 individuals from the GAIT-2 Project. The RETROVE study with 400 VTE cases and 400 controls was used to replicate the results. A total of 105 genetic variants and a multiallelic CNV (mCNV) spanning ORM1 were identified in GAIT-2. Of these, 17 independent common variants, a region of 22 rare variants, and the mCNV were significantly associated with cfDNA levels. In addition, eight of these common variants and the mCNV influenced ORM1 expression. The association of the mCNV and cfDNA levels was replicated in RETROVE (p-value = 1.19 × 10-6). Additional associations between the mCNV and thrombin generation parameters were identified. Our results reveal that increased mCNV dosages in ORM1 decreased gene expression and upregulated cfDNA levels. Therefore, the mCNV in ORM1 appears to be a novel marker for cfDNA levels, which could contribute to VTE risk.

First morphological and molecular report of Lagochilascaris minor (Nematoda, Ascarididae) in a domestic cat from Veracruz, Mexico.

The clinical presentation and the morphological and molecular findings of Lagochilascaris minor in a domestic cat from Veracruz, Mexico are described. In the physical examination of the cat, a fistula with purulent exudate was observed in the ventral middle and left lateral region of the neck, with the presence of nematodes inside. Thirty-two worms were recovered from the lesion, which were identified based on their morphological characteristics as Lagochilascaris spp. To determine the species of the nematode, DNA was extracted from the worms and a fragment of the cytochrome C oxidase subunit 1 was amplified. The product obtained was 100% similar with L. minor from Costa Rica. This is the first morphological and molecular report of L. minor parasitizing a domestic cat from Veracruz, Mexico, and emphasizes the circulation of this zoonotic parasite in the country.

Who judges medical practice?

Lawsuits due to patient perception of inappropriate medical actions are a growing reality in medical practice, which entails widespread concern in the medical community. Lawsuits often entail additional circumstances beyond the primary concern of preventing or sanctioning acts of medical negligence. CETREMI proposes various recommendations aimed at legal and medical professionals to improve this circumstance and avoid harming the doctor-patient relationship.

Las demandas judiciales por la percepción del paciente de una actuación médica inadecuada son una realidad creciente en la práctica médica, la cual entraña una preocupación extendida en el gremio médico. Las demandas judiciales frecuentemente conllevan circunstancias adicionales a la primaria preocupación de prevenir o sancionar actos de negligencia médica. CETREMI emite algunas recomendaciones a los profesionales jurídicos y médicos para mejorar esta situación y evitar daños en la relación médico-paciente.

¿Quién juzga la actuación médica? / Who judges medical practice?

Resumen Las demandas judiciales por la percepción del paciente de una actuación médica inadecuada son una realidad creciente en la práctica médica, la cual entraña una preocupación extendida en el gremio médico. Las demandas judiciales frecuentemente conllevan circunstancias adicionales a la primaria preocupación de prevenir o sancionar actos de negligencia médica. CETREMI emite algunas recomendaciones a los profesionales jurídicos y médicos para mejorar esta situación y evitar daños en la relación médico-paciente.

Abstract Lawsuits due to patient perception of inappropriate medical actions are a growing reality in medical practice, which entails widespread concern in the medical community. Lawsuits often entail additional circumstances beyond the primary concern of preventing or sanctioning acts of medical negligence. CETREMI proposes various recommendations aimed at legal and medical professionals to improve this circumstance and avoid harming the doctor-patient relationship.