Mutations in SCNM1 cause orofaciodigital syndrome due to minor intron splicing defects affecting primary cilia.

Orofaciodigital syndrome (OFD) is a genetically heterogeneous ciliopathy characterized by anomalies of the oral cavity, face, and digits. We describe individuals with OFD from three unrelated families having bi-allelic loss-of-function variants in SCNM1 as the cause of their condition. SCNM1 encodes a protein recently shown to be a component of the human minor spliceosome. However, so far the effect of loss of SCNM1 function on human cells had not been assessed. Using a comparative transcriptome analysis between fibroblasts derived from an OFD-affected individual harboring SCNM1 mutations and control fibroblasts, we identified a set of genes with defective minor intron (U12) processing in the fibroblasts of the affected subject. These results were reproduced in SCNM1 knockout hTERT RPE-1 (RPE-1) cells engineered by CRISPR-Cas9-mediated editing and in SCNM1 siRNA-treated RPE-1 cultures. Notably, expression of TMEM107 and FAM92A encoding primary cilia and basal body proteins, respectively, and that of DERL2, ZC3H8, and C17orf75, were severely reduced in SCNM1-deficient cells. Primary fibroblasts containing SCNM1 mutations, as well as SCNM1 knockout and SCNM1 knockdown RPE-1 cells, were also found with abnormally elongated cilia. Conversely, cilia length and expression of SCNM1-regulated genes were restored in SCNM1-deficient fibroblasts following reintroduction of SCNM1 via retroviral delivery. Additionally, functional analysis in SCNM1-retrotransduced fibroblasts showed that SCNM1 is a positive mediator of Hedgehog (Hh) signaling. Our findings demonstrate that defective U12 intron splicing can lead to a typical ciliopathy such as OFD and reveal that primary cilia length and Hh signaling are regulated by the minor spliceosome through SCNM1 activity.

Processing speed mediates the relationship between DDR1 and psychosocial functioning in euthymic patients with bipolar disorder presenting psychotic symptoms.

The DDR1 locus is associated with the diagnosis of schizophrenia and with processing speed in patients with schizophrenia and first-episode psychosis. Here, we investigated whether DDR1 variants are associated with bipolar disorder (BD) features. First, we performed a case‒control association study comparing DDR1 variants between patients with BD and healthy controls. Second, we performed linear regression analyses to assess the associations of DDR1 variants with neurocognitive domains and psychosocial functioning. Third, we conducted a mediation analysis to explore whether neurocognitive impairment mediated the association between DDR1 variants and psychosocial functioning in patients with BD. Finally, we studied the association between DDR1 variants and white matter microstructure. We did not find any statistically significant associations in the case‒control association study; however, we found that the combined genotypes rs1264323AA-rs2267641AC/CC were associated with worse neurocognitive performance in patients with BD with psychotic symptoms. In addition, the combined genotypes rs1264323AA-rs2267641AC/CC were associated with worse psychosocial functioning through processing speed. We did not find correlations between white matter microstructure abnormalities and the neurocognitive domains associated with the combined genotypes rs1264323AA-rs2267641AC/CC. Overall, the results suggest that DDR1 may be a marker of worse neurocognitive performance and psychosocial functioning in patients with BD, specifically those with psychotic symptoms.

Variant characterisation and clinical profile in a large cohort of patients with Ellis-van Creveld syndrome and a family with Weyers acrofacial dysostosis.

BACKGROUND: Ellis-van Creveld syndrome (EvC) is a recessive disorder characterised by acromesomelic limb shortening, postaxial polydactyly, nail-teeth dysplasia and congenital cardiac defects, primarily caused by pathogenic variants in EVC or EVC2. Weyers acrofacial dysostosis (WAD) is an ultra-rare dominant condition allelic to EvC. The present work aimed to enhance current knowledge on the clinical manifestations of EvC and WAD and broaden their mutational spectrum. METHODS: We conducted molecular studies in 46 individuals from 43 unrelated families with a preliminary clinical diagnosis of EvC and 3 affected individuals from a family with WAD and retrospectively analysed clinical data. The deleterious effect of selected variants of uncertain significance was evaluated by cellular assays. MAIN RESULTS: We identified pathogenic variants in EVC/EVC2 in affected individuals from 41 of the 43 families with EvC. Patients from each of the two remaining families were found with a homozygous splicing variant in WDR35 and a de novo heterozygous frameshift variant in GLI3, respectively. The phenotype of these patients showed a remarkable overlap with EvC. A novel EVC2 C-terminal truncating variant was identified in the family with WAD. Deep phenotyping of the cohort recapitulated 'classical EvC findings' in the literature and highlighted findings previously undescribed or rarely described as part of EvC. CONCLUSIONS: This study presents the largest cohort of living patients with EvC to date, contributing to better understanding of the full clinical spectrum of EvC. We also provide comprehensive information on the EVC/EVC2 mutational landscape and add GLI3 to the list of genes associated with EvC-like phenotypes.

Novel genes and sex differences in COVID-19 severity.

Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10-22 and P = 8.1 × 10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10-8) and ARHGAP33 (P = 1.3 × 10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

Ocular Mucous Membrane Pemphigoid: The Effect of Risk Factors at Presentation on Treatment Outcomes.

PURPOSE: Analyze the influence of risk factors at presentation in the long-term immunosuppressive therapy (IMT) outcomes of ocular mucous membrane pemphigoid (OMMP). DESIGN: Retrospective multicenter study. PARTICIPANTS: Patients with OMMP seen at the Duke Eye Center, Tecnologico de Monterrey, and Hospital Clinic of Barcelona from 1990 to 2022. METHODS: Data at presentation on demographics, direct immunofluorescence, ocular findings, sites of extraocular manifestations (EOMs), and previous treatments in patients with a clinical or laboratory diagnosis of OMMP, were analyzed with multivariable analysis and Kaplan-Meier plots to identify factors associated with adverse outcomes. MAIN OUTCOME MEASURES: (1) Inflammatory control (no conjunctival inflammation in both eyes at 3 months on IMT); (2) relapse (new-onset inflammation after absolute control in either eye); (3) progression (≥ 1 cicatrizing stage progression in either eye); and (4) vision loss (≥ 2 Snellen lines). RESULTS: A total of 117 patients (234 eyes), 61% (71/117) of whom were women, with a mean age of 66.6 (SD: 12.4) years (range: 37-97 years) and median follow-up of 34 months (interquartile range: 16-66 months; range: 3-265 months), were enrolled. Inflammatory control was achieved in 57% of patients (67/117), with high-risk EOM (HR-EOM), including esophageal, nasopharyngeal, and/or genital involvement (adjusted odds ratio [aOR]: 12.51; 95% confidence interval [CI]: 2.61-59.99; P = 0.002) and corneal scarring (aOR: 3.06; 95% CI, 1.15-8.14; P = 0.025), as significant risk factors for persistent inflammation. Disease relapse, progression, and vision loss occurred in 20% of patients (23/117), 12% of patients (14/117), and 27% of patients (32/117), respectively. Baseline corneal scarring was a risk factor for relapse (adjusted hazard ratio: 4.14; 95% CI: 1.61-10.62; P = 0.003), progression (aOR: 11.46; 95% CI: 1.78-73.75; P = 0.010), and vision loss (aOR: 3.51; 95% CI: 1.35-9.10; P = 0.010). HR-EOM was associated with stage progression (aOR, 34.57; 95% CI, 6.57-181.89; P<0.001) and vision loss (aOR, 8.42; 95% CI, 2.50-28.42; P = 0.001). No significant differences were found between IMT regimes and relapse (P = 0.169). CONCLUSIONS: Ocular mucous membrane pemphigoid presenting with HR-EOMs and corneal scarring has an increased risk of stage progression and vision loss. Corneal scarring and severe inflammation at baseline were associated with an increased risk of relapse. A disease progression staging system incorporating both the HR-EOMs and corneal involvement is required to predict the visual outcome of OMMP better. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Non-immune hydrops fetalis is associated with bi-allelic pathogenic variants in the MYB Binding Protein 1a (MYBBP1A) gene.

Non-immune hydrops fetalis (NIHF) is a rare entity characterized by excessive accumulation of fluid within the fetal extravascular compartments and body cavities. Here we present two intrauterine fetal demises with NIHF presenting with oligohydramnios, cystic hygroma, pleural effusion, and generalized hydrops with predominance of subcutaneous edema. The fetuses also presented with ascites, severe and precocious IUGR and skeletal anomalies. Whole exome sequencing was applied in order to screen for a possible genetic cause. The results identified biallelic variants in MYBBP1A in both fetuses. A previous report described another case with a similar phenotype having compound heterozygous variants in the same gene. The protein encoded by MYBBP1A is involved in several cellular processes including the synthesis of ribosomal DNA, the response to nucleolar stress, and tumor suppression. Our functional protein analysis through immunohistochemistry indicates that MYBBP1A is a gene expressed during fetal stages. Altogether, we concluded that MYBBP1A is associated with the development of hydrops fetalis. More cases and further studies are necessary to understand the role of this gene and the mechanism associated with NIHF.

Decoding load or selection in visuospatial working memory?

Flexible updating of information in Visual Working Memory (VWM) is crucial to deal with its limited capacity. Previous research has shown that the removal of no longer relevant information takes some time to complete. Here, we sought to study the time course of such removal by tracking the accompanying drop in load through behavioral and neurophysiological measures. In the first experimental session, participants completed a visuospatial retro-cue task in which the Cue-Target Interval (CTI) was manipulated. The performance revealed that it takes about half a second to make full use of the retro-cue. In a second session, we sought to study the dynamics of load-related electroencephalographic (EEG) signals to track the removal of information. We applied Multivariate Pattern Analysis (MVPA) to EEG data from the same task. Right after encoding, results replicated previous research using MVPA to decode load. However, especially after the retro-cue, results suggested that classifiers were mainly sensitive to a selection component, and not so much to load per se. Additionally, visual cue variations, as well as eye movements that accompany load manipulations can also contribute to decoding. These findings advise caution when using MVPA to decode VWM load, as classifiers may be sensitive to confounding operations.

Testing the modulation of self-related automatic and others-related controlled processing by chronotype and time-of-day.

We assessed whether self-related automatic and others-related controlled processes are modulated by chronotype and time-of-day. Here, a shape-label matching task composed of three geometrical shapes arbitrarily associated with you, friend, and stranger was used. Twenty Morning-types, and twenty Evening-types performed the task at the optimal and non-optimal times of day (i.e., 8 AM, or 8:30 PM). Morning-types did not exhibit noticeable synchrony effects, thus proving the better adaptation of these participants to non-optimal moments of the day as compared to Evening-types. Contrary to our predictions regarding the absence of automatic-processing modulation and the presence of controlled-processing influences by time-of-day, we found an influence on self-related but not others-related processing only in Evening-type participants. Although brain structures are not directly tackled, we argue that such modulation may be due to the dependence of the activation of the ventromedial prefrontal cortex (VMPFC), an essential component of the self-attention network on circadian rhythms.

Self-prioritization effect in the attentional blink paradigm: Attention-based or familiarity-based effect?

The self-prioritization effect (SPE) refers to the advantage in processing stimuli associated with oneself. Here, we addressed the SPE in an attentional blink (AB) task. In Experiment 1, shapes associated to you, friend, or stranger served as T1, and letter X as T2. The AB effect was larger for you than the other label conditions, and larger for friend condition than for stranger condition. We suggest that self-associated shape increased its perceptual salience, producing greater attentional capture. In Experiment 2 participants trained with a shape-label matching task to increase familiarity with the shape-label associations before performing the AB task. The difference between friend and stranger conditions disappeared, suggesting that the difference between the two conditions observed in Experiment 1 was mainly due to differences in familiarity or frequency of use. Importantly, the advantage of you over friend and stranger conditions remained, suggesting that the SPE is a genuine effect.

Consolidating the association of biallelic MAPKAPK5 pathogenic variants with a distinct syndromic neurodevelopmental disorder.

BACKGROUND: MAPK-activated protein kinase 5 (MAPKAPK5) is an essential enzyme for diverse cellular processes. Dysregulation of the pathways regulated by MAPKAPK enzymes can lead to the development of variable diseases. Recently, homozygous loss-of-function variants in MAPKAPK5 were reported in four patients from three families presenting with a recognisable neurodevelopmental disorder, so-called 'neurocardiofaciodigital' syndrome. OBJECTIVE AND METHODS: In order to improve characterisation of the clinical features associated with biallelic MAPKAPK5 variants, we employed a genotype-first approach combined with reverse deep-phenotyping of three affected individuals. RESULTS: In the present study, we identified biallelic loss-of-function and missense MAPKAPK5 variants in three unrelated individuals from consanguineous families. All affected individuals exhibited a syndromic neurodevelopmental disorder characterised by severe global developmental delay, intellectual disability, characteristic facial morphology, brachycephaly, digital anomalies, hair and nail defects and neuroradiological findings, including cerebellar hypoplasia and hypomyelination, as well as variable vision and hearing impairment. Additional features include failure to thrive, hypotonia, microcephaly and genitourinary anomalies without any reported congenital heart disease. CONCLUSION: In this study, we consolidate the causality of loss of MAPKAPK5 function and further delineate the molecular and phenotypic spectrum associated with this new ultra-rare neurodevelopmental syndrome.

Vascular Surgery Education and Training in the American Continent: Current Status and Future Directions.

OBJECTIVE: Despite the increasing burden of cardiovascular diseases, there is a shortage of vascular surgeons worldwide, with a higher scarcity in low and middle-income countries. The objective of the present study was to report the current status of vascular surgery education and training on the American continent. MATERIALS AND METHODS: Official government, postgraduate medical schools, and medical associations' websites were searched for data regarding vascular surgery training positions, programs, and pathways available in the 35 countries of the American continent. RESULTS: There are 707 annual positions for training in vascular surgery offered by 367 training programs. Of the 35 countries in America, only 17 (48.5%) offer vascular surgery training as an independent specialty. In one (2.8%) country, Peru, vascular surgery is mixed with cardiothoracic surgery. There is no vascular surgery training in the remaining 17 (48.5%) countries. Brazil has the highest number of training positions, offering 292 (41.3%) positions per year, followed by the United States, with 214 (30.2%) positions per year, and Mexico, with 69 (9.7%) positions per year. The country with more positions per 1,000,000 inhabitants is Cuba (3.93), followed by Brazil (1.34) and Uruguay (0.87). Brazil, Canada, Mexico, and the United States are the only four countries that have vascular surgery board exams. CONCLUSION: This is the first report presenting a large-scale picture of vascular surgery education and training in the American continent. Brazil is the country that offers more vascular surgery training opportunities, followed by the United States and Mexico. Disseminating vascular surgery training in America is of utmost importance to help fight the cardiovascular diseases pandemic the world faces.

Influence of a football match on landing biomechanics and jump performance in female football players.

This study aimed to assess the acute effect of a competitive football match on jump performance and kinematic parameters during jump landing in semiprofessional female football players. Twenty-two semiprofessional players (20 ± 3 years) underwent a drop jump task for a posterior video analysis of the landing phase. These measurements were obtained at (1) baseline, (2) after, and (3) 48 h after a competitive football match. A one-way ANOVA with repeated measures was employed to detect differences over the time. There was a main effect of time for maximal knee flexion angle during drop landing (p = 0.001). In comparison with baseline, maximal knee flexion angle was reduced immediately post-match and was still reduced 48 h after the match (63.4 ± 8.6 vs 57.0 ± 11.7 vs 48.9 ± 19.1, p ≤ 0.038). There was also a main effect of time for drop jump height (p < 0.001). Drop jump height was reduced immediately post-match and remained low 48 h after the match in comparison with baseline (27.3 ± 3.6 vs 24.5 ± 2.8 ~ 25.5 ± 3.0 cm, p ≤ 0.002). There was a main effect of time on hip flexion angle during landing (p = 0.001), but the pairwise comparison revealed that this variable was not affected immediately post-match but was lower 48 h after the match than at baseline (50.1 ± 10.1 ~ 50.8 ± 13.2 vs 38.1 ± 17.8 °, p ≤ 0.005). A competitive football match worsened jump performance and several landing biomechanical parameters in female football players, which were still decreased in comparison with baseline even 48 h after the match.

Comparison of male and female non-refugee immigrants with psychosis: clinical, sociodemographic, and migration-related differences and impact on stress.

PURPOSE: To compare social, clinical, and migration-related factors between male and female immigrants with psychotic disorders and to determine the association between these variables and stress in the last year. METHODS: We administered the Holmes and Rahe Social Readjustment Scale to evaluate psychological stress in 99 non-refugee immigrants (26 women, 73 men) who presented ≥ one psychotic episode (ICD-10 criteria). We compared the two groups in terms of sociodemographic, clinical, cultural, and migration-related variables. A multivariable analysis using a linear regression model (stepwise method) was performed to evaluate potential associations between these variables and stress. RESULTS: Women were more likely to be married and divorced, had less access to welfare payments, and lower unemployment and homeless rates than men. The most common psychiatric diagnosis was psychosis not otherwise specified with more women being affected (61.5% in women vs. 45.2% in men), but the diagnosis of schizophrenia was more common in men (38.4% vs 15.4%). Both groups exhibited very high levels of stress in the past year (mean total distress score > 300). In women, stress was significantly associated with age at first migration and be a racialized person. By contrast, among men stress was significantly associated with language barrier and comorbidity with a physical disorder. CONCLUSIONS: The results of this study reveal important differences between men and women immigrants. These findings underscore the importance of understanding how gender-specific roles and social expectations intersect with the timing and nature of migration to influence stress levels differently in immigrant women and men with psychotic disorders.

Misophonia matters: A case study of the role of brain imaging in debates over new diagnoses.

Misophonia has gained attention in scientific circles that utilise brain imaging to validate diagnoses. The condition is promoted as not merely a symptom of other psychiatric diagnoses but as a discrete clinical entity. We illustrate the social construction of the diagnostic category of misophonia through examining prominent claims in research studies that use brain imaging to substantiate the diagnosis. We show that brain images are insufficient to establish the 'brain basis for misophonia' due to both technical and logical limitations of imaging data. Often misunderstood as providing direct access to the matter of the body, brain images are mediated and manipulated numerical data (Joyce, 2005, Social Studies of Science 35(3), p. 437). Interpretations of brain scans are further shaped by social expectations and attributes considered salient to the data. Causal inferences drawn from these studies are problematic because 'misophonics' are clinically pre-diagnosed before participating. We argue that imaging cannot replace the social process of diagnosis in the case of misophonia, nor validate diagnostic measures or otherwise substantiate the condition. More broadly, we highlight both the cultural authority and inherent limitations of brain imaging in the social construction of contested diagnoses while also illustrating its role in the disaggregation of symptoms into new diagnoses.

Depressive-Like Effects of Foreclosing: A Cross-Sectional Study of Hair Cortisol Concentration.

INTRODUCTION: Foreclosing and home eviction have been associated with various negative health outcomes, probably due to exposure to such stressful circumstance, but there is no evidence about foreclosure and home eviction to elicit cortisol responses. METHODS: Participants who recently had received a court eviction notice were compared to subjects suffering a depressive disorder and to healthy controls in terms of hair cortisol concentrations. RESULTS: Subjects under the stressful circumstance of foreclosure and patients with depression showed comparable concentrations in most of the hair segments while healthy subjects displayed the lowest levels of cortisol. CONCLUSION: The findings show that foreclosure and home eviction are associated with increased cumulative hair cortisol and with depressive-like symptoms. Foreclosing procedures yielded to maintain high levels of cortisol which may increase the risk to develop major depression.

White shark comparison reveals a slender body for the extinct megatooth shark, Otodus megalodon (Lamniformes: Otodontidae).

The megatooth shark, †Otodus megalodon, which likely reached at least 15 m in total length, is an iconic extinct shark represented primarily by its gigantic teeth in the Neogene fossil record. As one of the largest marine carnivores to ever exist, understanding the biology, evolution, and extinction of †O. megalodon is important because it had a significant impact on the ecology and evolution of marine ecosystems that shaped the present-day oceans. Some attempts inferring the body form of †O. megalodon have been carried out, but they are all speculative due to the lack of any complete skeleton. Here we highlight the fact that the previous total body length estimated from vertebral diameters of the extant white shark (Carcharodon carcharias) for an †O. megalodon individual represented by an incomplete vertebral column is much shorter than the sum of anteroposterior lengths of those fossil vertebrae. This factual evidence indicates that †O. megalodon had an elongated body relative to the body of the modern white shark. Although its exact body form remains unknown, this proposition represents the most parsimonious empirical evidence, which is a significant step towards deciphering the body form of †O. megalodon.

Lessons Learned From Ocular Graft versus Host Disease: An Ocular Surface Inflammatory Disease of Known Time of Onset.

ABSTRACT: The ocular surface inflammatory disorders (OSIDs) comprise a group of conditions characterized by persistent inflammation of the ocular surface and adnexal tissues. Systemic autoimmune diseases and hypersensitivity reactions cause them, and, if left untreated, can result in severe inflammatory dry eye, corneal damage, and vision loss. Ocular graft-versus-host disease (oGVHD) forms part of the ocular surface inflammatory disease umbrella. It is a condition occurring after allogeneic hematopoietic stem cell or bone marrow transplantation, usually in chronic graft-versus-host disease. oGVHD can virtually affect any ocular adnexal tissue, especially the meibomian glands, and cause persistent inflammation, tissue fibrosis, and subsequent chronic, severe dry eye disease. Among the OSIDs, oGVHD has the particularity that it has a "time zero," meaning we know when the disease started. As such, preclinical models have leveraged this to investigate the molecular mechanisms involved in the damage oGVHD causes to the ocular surface. In oGVHD, establishing a "time zero" allows for predicting the clinical course and establishing adequate treatment. This is also possible because the inflammatory infiltration occurs in ocular surface tissues, which are readily accessible. Using oGVHD, we might be able to understand the immune response mechanisms in other OSIDs better (i.e., Sjögren syndrome, Stevens-Johnson syndrome, among others). This review presents an up-to-date overview of the pathogenesis, clinical presentation, and treatment of oGVHD. In addition, we will discuss the value of the "time zero" concept in the study of oGVHD.

Evaluation of gender-affirming care experiences of transgender and gender diverse patients within a LGBTQ+ community pharmacy.

BACKGROUND: Transgender and gender diverse (TGD) populations require personalized care. Lived experiences and needs TGD populations express, compounded by limited care access, negatively shape health care involvement. Manifestations from these barriers may present as health care avoidance, identity concealment, or preventive care hinderance. Community pharmacies remain engagement points for TGD patients, but gender diverse services remain limited. What remains unknown is how TGD pharmacy perceptions and behaviors are influenced with gender-affirming care (GAC) accessibility. OBJECTIVES: The primary objective is to assess how TGD patient perceptions and behaviors toward community pharmacy experiences are affected through a lesbian, gay, bisexual, transgender, queer/questioning, and others (LGBTQ+) community-based health system. METHODS: A cross-sectional, multisite, reflective survey was conducted at 4 LGBTQ+ community pharmacies in central and southwest Ohio. Nine 5-point Likert-item questions and one ordinal question were used to analyze perception and behavior. Participants responded for LGBTQ+ and external pharmacy experiences respectively. Data were analyzed through descriptive methods, paired Student's t test, and Fisher's exact test or c2 test where appropriate. RESULTS: In total, 267 surveys were completed with 96 TGD submissions qualifying for analysis. Perceptions toward pharmacy experience saw statistically significant differences among all evaluations of perception. Behavioral assessment demonstrated statistically significant improvements in pharmacy outreach except for seeking medications from outside sources. Respondents indicated more involvement with the LGBTQ+ pharmacies versus external pharmacies in discussing medications (96.9% vs. 60.4%), care plans (64.6% vs. 41.6%), disclosure of pronouns or gender (97.9% vs. 43.8%), and feeling needs were understood (96.8% vs. 51%). CONCLUSION: Inclusive community pharmacies may positively affect pharmacy perceptions and behaviors of TGD patients. These findings call attention to barriers in the provision of care for TGD patients while highlighting the change community pharmacies can have when providing these services. Community pharmacies should be encouraged to incorporate inclusive environments to improve TGD patient care involvement and access.

Unveiling Novel Urease Inhibitors for Helicobacter pylori: A Multi-Methodological Approach from Virtual Screening and ADME to Molecular Dynamics Simulations.

Helicobacter pylori (Hp) infections pose a global health challenge demanding innovative therapeutic strategies by which to eradicate them. Urease, a key Hp virulence factor hydrolyzes urea, facilitating bacterial survival in the acidic gastric environment. In this study, a multi-methodological approach combining pharmacophore- and structure-based virtual screening, molecular dynamics simulations, and MM-GBSA calculations was employed to identify novel inhibitors for Hp urease (HpU). A refined dataset of 8,271,505 small molecules from the ZINC15 database underwent pharmacokinetic and physicochemical filtering, resulting in 16% of compounds for pharmacophore-based virtual screening. Molecular docking simulations were performed in successive stages, utilizing HTVS, SP, and XP algorithms. Subsequent energetic re-scoring with MM-GBSA identified promising candidates interacting with distinct urease variants. Lys219, a residue critical for urea catalysis at the urease binding site, can manifest in two forms, neutral (LYN) or carbamylated (KCX). Notably, the evaluated molecules demonstrated different interaction and energetic patterns in both protein variants. Further evaluation through ADMET predictions highlighted compounds with favorable pharmacological profiles, leading to the identification of 15 candidates. Molecular dynamics simulations revealed comparable structural stability to the control DJM, with candidates 5, 8 and 12 (CA5, CA8, and CA12, respectively) exhibiting the lowest binding free energies. These inhibitors suggest a chelating capacity that is crucial for urease inhibition. The analysis underscores the potential of CA5, CA8, and CA12 as novel HpU inhibitors. Finally, we compare our candidates with the chemical space of urease inhibitors finding physicochemical similarities with potent agents such as thiourea.

Optimization of methane gas-liquid mass transfer during biogas-based ectoine production in bubble column bioreactors.

Nowadays, the utilization of biogas for energy generation is hindered by the declining production costs of solar and wind power. A shift towards the valorization of biogas into ectoine, a highly valuable bioproduct priced at 1000 €â¸±kg-1, offers a novel approach to fostering a more competitive biogas market while contributing to carbon neutrality. This study evaluated the optimization of CH4 gas-liquid mass transfer in 10 L bubble column bioreactors for CH4 conversion into ectoine and hydroxyectoine using a mixed methanotrophic culture. The influence of the empty bed residence time (EBRTs of 27, 54, and 104 min) at different membrane diffuser pore sizes (0.3 and 0.6 mm) was investigated. Despite achieving CH4 elimination capacities (CH4-ECs) of 10-12 g⸱m-3⸱h-1, an EBRT of 104 min mediated CH4 limitation within the cultivation broth, resulting in a negligible biomass growth. Reducing the EBRT to 54 min entailed CH4-ECs of 21-24 g⸱m-3⸱h-1, concomitant to a significant increase in biomass growth (up to 0.17 g⸱L⸱d-1) and reaching maximum ectoine and hydroxyectoine accumulation of 79 and 13 mg⸱gVSS-1, respectively. Conversely, process operation at an EBRT of 27 min lead to microbial inhibition, resulting in a reduced biomass growth of 0.09 g⸱L⸱d-1 and an ectoine content of 47 mg⸱gVSS-1. While the influence of diffuser pore size was less pronounced compared to EBRT, the optimal process performance was observed with a diffuser pore size of 0.6 mm.