Barriers and Facilitators to Accessing PrEP and Other Sexual Health Services Among Immigrant Latino Men Who Have Sex with Men in Los Angeles County.

In the United States, immigrant Latino men who have sex with men (ILMSM) are, compared to white MSM, disproportionately burdened by HIV and lack access to highly effective HIV prevention strategies, such as pre-exposure prophylaxis (PrEP). Qualitative research centered on exploring barriers that ILMSM experience in accessing PrEP and other sexual services is extremely limited, despite a high prevalence of HIV in this population. In this study, a purposive sample of ILMSM (n = 25) was recruited to participate in a semi-structured in-depth interview to identify the distinct barriers and facilitators ILMSM experience in accessing sexual health services given their complex intersectional identities of being an immigrant, Latino, and a sexual minority man. Using a thematic analysis approach, nine themes were generated from the data representing barriers and facilitators. Barriers included: (1) cost and a lack of health insurance, (2) complexity of PrEP assistance programs; (3) challenges related to the immigrant experience; (4) impact of gay stigma; and (5) communication challenges. Facilitators included: (1) improving affordability and accessibility of PrEP services; (2) receiving services from LGBT- or Latine LGBT-centered clinics; (3) receiving services from medical providers who are gay and/or Latino; and (4) providing targeted community outreach, education, and promotion of PrEP to ILMSM. While many of the barriers illuminated in the study were structural (e.g., cost and lack of health insurance), and not easy to overcome, the findings highlight a range of facilitators that can support access to PrEP and other sexual health services for ILMSM. Considering these findings, we suggest strategies that may enhance access to needed sexual health services among ILMSM.

Genomic SNPs resolve the phylogeny of an ancient amphibian island radiation from the Seychelles.

Unusually for oceanic islands, the granitic Seychelles host multiple lineages of endemic amphibians. This includes an ancient (likely ca. 60 million years) radiation of eight caecilian species, most of which occur on multiple islands.These caecilians have a complicated taxonomic history and their phylogenetic inter-species relationships have been difficult to resolve. Double-digest RAD sequencing (ddRADseq) has been applied extensively to phylogeography and increasingly to phylogenetics but its utility for resolving ancient divergences is less well established. To address this, we applied ddRADseq to generate a genome-wide SNP panel for phylogenomic analyses of the Seychelles caecilians, whose phylogeny has so far not been satisfactorily resolved with traditional DNA markers. Based on 129,154 SNPs, we resolved deep and shallow splits, with strong support. Our findings demonstrate the capability of genome-wide SNPs for evolutionary inference at multiple taxonomic levels and support the recently proposed synonymy of Grandisonia Taylor, 1968 with Hypogeophis Peters, 1879. We revealed three clades of Hypogeophis (large-, medium- and short-bodied) and identify a single origin of the diminutive, stocky-bodied and pointy-snouted phenotype.

Irreversible Electroporation as a Valid Treatment Option for Hepatic Epithelioid Hemangioendothelioma: An International Multicenter Experience.

PURPOSE: Hepatic epithelioid hemangioendothelioma (HEHE) is a rare tumor with currently no established standard of care. This international multicenter retrospective study assesses the use of percutaneous irreversible electroporation (IRE) as an ablative tool to treat HEHE and provides a clinical overview of the current management and role of IRE in HEHE treatment. MATERIAL AND METHODS: Between 2017 and 2023, 14 patients with 47 HEHE tumors were treated with percutaneous IRE using CT-scan guidance in 23 procedures. Baseline patient and tumor characteristics were evaluated. Primary outcome measures included safety and effectiveness, analyzed using Common Terminology Criteria for Adverse Events (CTCAE) and treatment response by mRECIST criteria. Secondary outcome measures included technical success, post-treatment tumor sizes and length of hospital stay. Technical success was defined as complete ablation with an adequate ablative margin (intentional tumor free ablation margin > 5 mm). RESULTS: IRE treatment resulted in technical success in all tumors. Following a median follow-up of 15 months, 30 tumors demonstrated a complete response according to mRECIST criteria. The average tumor size pre-treatment was 25.8 mm, accompanied by an average reduction in tumor size by 7.5 mm. In 38 out of 47 tumors, there was no evidence of local recurrence. In nine tumors, residual tumor was present. There were no cases of progressive disease. Median length of hospital stay was one day. Only one grade 3 CTCAE event occurred, a pneumothorax requiring chest tube placement. CONCLUSION: The current study provides evidence that IRE is a safe and efficacious minimally invasive treatment option for HEHE.

TERT activation targets DNA methylation and multiple aging hallmarks.

Insufficient telomerase activity, stemming from low telomerase reverse transcriptase (TERT) gene transcription, contributes to telomere dysfunction and aging pathologies. Besides its traditional function in telomere synthesis, TERT acts as a transcriptional co-regulator of genes pivotal in aging and age-associated diseases. Here, we report the identification of a TERT activator compound (TAC) that upregulates TERT transcription via the MEK/ERK/AP-1 cascade. In primary human cells and naturally aged mice, TAC-induced elevation of TERT levels promotes telomere synthesis, blunts tissue aging hallmarks with reduced cellular senescence and inflammatory cytokines, and silences p16INK4a expression via upregulation of DNMT3B-mediated promoter hypermethylation. In the brain, TAC alleviates neuroinflammation, increases neurotrophic factors, stimulates adult neurogenesis, and preserves cognitive function without evident toxicity, including cancer risk. Together, these findings underscore TERT's critical role in aging processes and provide preclinical proof of concept for physiological TERT activation as a strategy to mitigate multiple aging hallmarks and associated pathologies.

Disease relapse in relation to lymph node sampling in lung carcinoid patients.

The predictive value of the extent of peri-operative lymph node (LN) sampling in relation to disease relapse in patients with pulmonary carcinoid (PC) is unknown. Furthermore, post-surgery follow-up recommendations rely on institutional retrospective studies with short follow-ups. We aimed to address these shortcomings by examining the relation between LN sampling and relapse in a population-based cohort with long-term follow-up. By combining the Dutch nationwide pathology and cancer registries, all patients with surgically resected PC (2003-2012) were included in this analysis (last update 2020). The extent of surgical LN dissection was scored for the number of LN samples, location (hilar/mediastinal), and completeness of resection according to European Society of Thoracic Surgeons (ESTS) guidelines. Relapse-free interval (RFI) was evaluated using Kaplan Meier and multivariate regression analysis. 662 patients were included. The median follow-up was 87.5 months. Relapse occurred in 10% of patients, mostly liver (51.8%) and locoregional sites (45%). The median RFI was 48.1 months (95% CI 36.8-59.4). Poor prognostic factors were atypical carcinoid, pN1/2, and R1/R2 resection. In 546 patients LN dissection data could be retrieved; at least one N2 LN was examined in 44% and completeness according to ESTS in merely 7%. In 477 cN0 patients, 5.9% had pN1 and 2.5% had pN2 disease. In conclusion, relapse occurred in 10% of PC patients with a median RFI of 48.1 months thereby underscoring the necessity of long-term follow-up. Extended mediastinal LN sampling was rarely performed but systematic nodal evaluation is recommended as it provides prognostic information on distant relapse.

Acceptability and appropriateness of information sessions to increase knowledge and awareness of PrEP and TelePrEP among Latina Women.

Women of color are disproportionately impacted by HIV. Although PrEP effectively prevents HIV infection, PrEP coverage and knowledge remain low in this population. To address barriers to PrEP, we implemented women-centered and culturally appropriate Information Sessions (IS) delivered by staff from the population they serve to increase knowledge, awareness, and use of PrEP through telemedicine (e.g., PlushCare). Our analysis focuses on Latina women (LW) participants, given the dearth of literature dedicated to the needs of LW. We partnered with a woman-led community-based organization (CBO) to implement the strategy with LW clients. Health educators conducted 26 IS with 94 LW (20 in Spanish and 6 in English). Participants who completed the IS were invited for interviews to assess the acceptability and appropriateness of the IS to increase knowledge and awareness of PrEP and PlushCare. Four themes emerged from the thematic analysis: (1) IS increased knowledge and awareness of PrEP and PlushCare; (2) perceived acceptability and appropriateness of IS; (3) insufficient reasons to warrant use of PrEP; and (4) positive attitudes about PlushCare. Our findings suggest that a women-centered and culturally appropriate IS implemented through a trusted, woman-led CBO is an acceptable and appropriate implementation strategy to inform LW about PrEP.

Generation of human induced pluripotent stem cell lines (LUMCi051-A,B and LUMCi052-A,B,C) of two patients with Spinocerebellar ataxia type 7.

Spinocerebellar Ataxia Type 7 (SCA7) is an autosomal dominantly inherited disorder, primarily characterized by cerebellar ataxia and visual loss. SCA7 is caused by a CAG repeat expansion in exon 3 of the ATXN7 gene. We generated human induced pluripotent stem cells (hiPSCs) from peripheral blood-derived erythroblasts from two SCA7 patients (LUMCi051-A,B and LUMCi052-A,B,C) using integration-free episomal vectors. All hiPSC clones express pluripotency factors, show a normal karyotype, and can differentiate into the three germ layers. These lines can be used for in vitro disease modeling and therapy testing.

In vivo editing of lung stem cells for durable gene correction in mice.

In vivo genome correction holds promise for generating durable disease cures; yet, effective stem cell editing remains challenging. In this work, we demonstrate that optimized lung-targeting lipid nanoparticles (LNPs) enable high levels of genome editing in stem cells, yielding durable responses. Intravenously administered gene-editing LNPs in activatable tdTomato mice achieved >70% lung stem cell editing, sustaining tdTomato expression in >80% of lung epithelial cells for 660 days. Addressing cystic fibrosis (CF), NG-ABE8e messenger RNA (mRNA)-sgR553X LNPs mediated >95% cystic fibrosis transmembrane conductance regulator (CFTR) DNA correction, restored CFTR function in primary patient-derived bronchial epithelial cells equivalent to Trikafta for F508del, corrected intestinal organoids and corrected R553X nonsense mutations in 50% of lung stem cells in CF mice. These findings introduce LNP-enabled tissue stem cell editing for disease-modifying genome correction.

The venom and telopodal defence systems of the centipede Lithobius forficatus are functionally convergent serial homologues.

BACKGROUND: Evolution of novelty is a central theme in evolutionary biology, yet studying the origins of traits with an apparently discontinuous origin remains a major challenge. Venom systems are a well-suited model for the study of this phenomenon because they capture several aspects of novelty across multiple levels of biological complexity. However, while there is some knowledge on the evolution of individual toxins, not much is known about the evolution of venom systems as a whole. One way of shedding light on the evolution of new traits is to investigate less specialised serial homologues, i.e. repeated traits in an organism that share a developmental origin. This approach can be particularly informative in animals with repetitive body segments, such as centipedes. RESULTS: Here, we investigate morphological and biochemical aspects of the defensive telopodal glandular organs borne on the posterior legs of venomous stone centipedes (Lithobiomorpha), using a multimethod approach, including behavioural observations, comparative morphology, proteomics, comparative transcriptomics and molecular phylogenetics. We show that the anterior venom system and posterior telopodal defence system are functionally convergent serial homologues, where one (telopodal defence) represents a model for the putative early evolutionary state of the other (venom). Venom glands and telopodal glandular organs appear to have evolved from the same type of epidermal gland (four-cell recto-canal type) and while the telopodal defensive secretion shares a great degree of compositional overlap with centipede venoms in general, these similarities arose predominantly through convergent recruitment of distantly related toxin-like components. Both systems are composed of elements predisposed to functional innovation across levels of biological complexity that range from proteins to glands, demonstrating clear parallels between molecular and morphological traits in the properties that facilitate the evolution of novelty. CONCLUSIONS: The evolution of the lithobiomorph telopodal defence system provides indirect empirical support for the plausibility of the hypothesised evolutionary origin of the centipede venom system, which occurred through functional innovation and gradual specialisation of existing epidermal glands. Our results thus exemplify how continuous transformation and functional innovation can drive the apparent discontinuous emergence of novelties on higher levels of biological complexity.

Practitioner dashboard feedback improves glycemic but not temperature compliance during cardiac surgery: A single center retrospective analysis.

STUDY OBJECTIVE: To determine the association of practitioner dashboard feedback of intraoperative glycemic and temperature control on maintenance of normoglycemia and normothermia. DESIGN: Retrospective review. SETTING: Single tertiary care institution. PATIENTS: Patients over the age of 18 undergoing cardiac surgery from February 17, 2021 through February 16, 2023. During the study interval, 15 anesthesiologists providing care during 2255 procedures were analyzed: 1114 prior to the individual faculty dashboard distribution and 1141 after commencement of dashboard distribution. INTERVENTIONS: On February 17, 2022, anesthesia faculty members began receiving monthly individualized dashboards indicating their personal intraoperative glycemic and temperature compliance rates. MEASUREMENTS: Baseline patient demographic characteristics, surgical and cardiopulmonary bypass times, perioperative temperature and glucose concentrations, and the incidence of sternal wound infections. Glycemic compliance was defined as final serum glucose between 80 and 180 mg/dL. Temperature compliance was defined as an average temperature during the final 30 min of the surgical procedure between 35 and 37.3 °C inclusive. MAIN RESULTS: Dashboard distribution was associated with a significant decrease in the average glucose concentration (median location shift by -6 mg% (95% confidence interval (CI) -8, -4), p < 0.001) from 157 mg/dL to 152 mg/dL and final glucose concentration (median location shift by -17 mg/dL (95% CI -19, -14, p < 0.001) from 161 mg/dL to 145 mg/dL. The intervention was associated with an improvement in glycemic compliance from 71.4% to 87.1% (odds ratio (OR): 2.71(95% CI 2.19, 3.37, p < 0.001)). There were no significant differences in final temperature (36.3 °C [Q1, Q3: 36.0, 36.6] vs. 36.3 °C [Q1, Q3: 36.0, 36.7] (p = 0.232)) with the intervention nor were there any statistically significant differences in temperature compliance (93.9% vs. 92.9%, OR: 0.79 (95% CI 0.55-1.14, p = 0.25). There were no statistically significant changes in the incidence of superficial, deep, or any wound infections with the intervention. CONCLUSIONS: Individualized practitioner dashboard distribution may be an effective tool to increase intraoperative glycemic control.

DNA Mutational and Copy Number Variation Profiling of Primary Craniofacial Osteosarcomas by Next-Generation Sequencing.

BACKGROUND: Craniofacial osteosarcomas (CFOS) are uncommon malignant neoplasms of the head and neck with different clinical presentation, biological behavior and prognosis from conventional osteosarcomas of long bones. Very limited genetic data have been published on CFOS. METHODS: In the current study, we performed comprehensive genomic studies in 15 cases of high-grade CFOS by SNP array and targeted next generation sequencing. RESULT: Our study shows high-grade CFOS demonstrate highly complex and heterogenous genomic alterations and harbor frequently mutated tumor suppressor genes TP53, CDKN2A/B, and PTEN, similar to conventional osteosarcomas. Potentially actionable gene amplifications involving CCNE1, AKT2, MET, NTRK1, PDGFRA, KDR, KIT, MAP3K14, FGFR1, and AURKA were seen in 43% of cases. GNAS hotspot activating mutations were also identified in a subset of CFOS cases, with one case representing malignant transformation from fibrous dysplasia, suggesting a role for GNAS mutation in the development of CFOS. CONCLUSION: High-grade CFOS demonstrate highly complex and heterogenous genomic alterations, with amplification involving receptor tyrosine kinase genes, and frequent mutations involving tumor suppressor genes.

Safety Assessment of Triphenyl Phosphate as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of Triphenyl Phosphate, which is reported to function as a plasticizer in manicuring products. The Panel reviewed the available data to determine the safety of this ingredient. The Panel concluded that Triphenyl Phosphate is safe in cosmetics in the present practices of use and concentration described in this safety assessment.

Influence of folic acid and vitamin B12 supplementation on arsenic methylation: A double-blinded, placebo-controlled trial in Bangladeshi children.

BACKGROUND: Inorganic arsenic is metabolized to monomethyl- (MMAs) and dimethyl- (DMAs) species via one-carbon metabolism (OCM); this facilitates urinary arsenic elimination. OCM is influenced by folate and vitamin B12 and previous randomized control trials (RCTs) showed that folic acid (FA) supplementation increases arsenic methylation in adults. This RCT investigated the effects of FA + B12 supplementation on arsenic methylation in children, a key developmental stage where OCM supports growth. METHODS: A total of 240 participants (8-11 years, 53 % female) drinking from wells with arsenic concentrations > 50 µg/L, were encouraged to switch to low arsenic wells and were randomized to receive 400 µg FA + 5 µg B12 or placebo daily for 12-weeks. Urine and blood samples were collected at baseline, week 1 (only urine) and week 12. Generalized estimated equation (GEE) models were used to assess treatment effects on arsenic species in blood and urine. RESULTS: At baseline, the mean ± SD total blood and urinary arsenic were 5.3 ± 2.9 µg/L and 91.2 ± 89.5 µg/L. Overall, total blood and urine arsenic decreased by 11.7% and 17.6%, respectively, at the end of follow up. Compared to placebo, the supplementation group experienced a significant increase in the concentration of blood DMAs by 14.0% (95% CI 5.0, 25.0) and blood secondary methylation index (DMAs/MMAs) by 0.19 (95% CI: 0.09, 0.35) at 12 weeks. Similarly, there was a 1.62% (95% CI: 0.43, 20.83) significantly higher urinary %DMAs and -1.10% (95% CI: -1.73, -0.48) significantly lower urinary %MMAs in the supplementatio group compared to the placebo group after 1 week. The direction of the changes in the urinary %iAs, %MMAs, and %DMAs at week 12 were consistent with those at week 1, though estimates were not significant. Treatment effects were stronger among participants with higher baseline blood arsenic concentrations. Results were consistent across males and females, and participants with higher and lower folate and B12 status at baseline. CONCLUSION: This RCT confirms that FA + B12 supplementation increases arsenic methylation in children as reflected by decreased MMAs and increased DMAs in blood and urine. Nutritional interventions may improve arsenic methylation and elimination in children, potentially reducing arsenic toxicity while also improving nutritional status.

Timing-dependent synergies between motor cortex and posterior spinal stimulation in humans.

Volitional movement requires descending input from the motor cortex and sensory feedback through the spinal cord. We previously developed a paired brain and spinal electrical stimulation approach in rats that relies on convergence of the descending motor and spinal sensory stimuli in the cervical cord. This approach strengthened sensorimotor circuits and improved volitional movement through associative plasticity. In humans, it is not known whether posterior epidural spinal cord stimulation targeted at the sensorimotor interface or anterior epidural spinal cord stimulation targeted within the motor system is effective at facilitating brain evoked responses. In 59 individuals undergoing elective cervical spine decompression surgery, the motor cortex was stimulated with scalp electrodes and the spinal cord was stimulated with epidural electrodes, with muscle responses being recorded in arm and leg muscles. Spinal electrodes were placed either posteriorly or anteriorly, and the interval between cortex and spinal cord stimulation was varied. Pairing stimulation between the motor cortex and spinal sensory (posterior) but not spinal motor (anterior) stimulation produced motor evoked potentials that were over five times larger than brain stimulation alone. This strong augmentation occurred only when descending motor and spinal afferent stimuli were timed to converge in the spinal cord. Paired stimulation also increased the selectivity of muscle responses relative to unpaired brain or spinal cord stimulation. Finally, clinical signs suggest that facilitation was observed in both injured and uninjured segments of the spinal cord. The large effect size of this paired stimulation makes it a promising candidate for therapeutic neuromodulation. KEY POINTS: Pairs of stimuli designed to alter nervous system function typically target the motor system, or one targets the sensory system and the other targets the motor system for convergence in cortex. In humans undergoing clinically indicated surgery, we tested paired brain and spinal cord stimulation that we developed in rats aiming to target sensorimotor convergence in the cervical cord. Arm and hand muscle responses to paired sensorimotor stimulation were more than five times larger than brain or spinal cord stimulation alone when applied to the posterior but not anterior spinal cord. Arm and hand muscle responses to paired stimulation were more selective for targeted muscles than the brain- or spinal-only conditions, especially at latencies that produced the strongest effects of paired stimulation. Measures of clinical evidence of compression were only weakly related to the paired stimulation effect, suggesting that it could be applied as therapy in people affected by disorders of the central nervous system.

Miscibility of Amorphous Solid Dispersions: A Rheological and Solid-State NMR Spectroscopy Study.

Miscibility is critical in the prediction of stability against crystallization of amorphous solid dispersions (ASDs) in the solid state. However, currently available approaches for its determination are limited by both theoretical and practical considerations. Recently, a rheological approach guided by the polymer overlap concentration (c*) has been proposed for miscibility quantification of ASDs [J. Pharm. Sci., 112 (2023) 204-212] and shown to be useful in predicting both accelerated and long term physical stability in the absence of moisture. However, this approach can only be performed at high temperatures (slightly above the melting temperature, Tm, of drugs), and little is known about the difference in miscibility between high and low temperatures (e.g., below the glass transition temperature, Tg). Here we compare the miscibility of nifedipine (NIF)/polyvinylpyrrolidone (PVP) ASDs as determined by the rheological approach at 175°C (∼3°C above Tm of NIF) and solid state NMR (ssNMR) 1H T1 and T1ρ relaxation times at -20°C (∼66°C below Tg of NIF). Our results indicate agreement between the two methods. For low molecular weight (Mw) PVP, T1ρ measurements are more consistent with the rheological approach, while T1 measurements are closer for relatively high Mw PVP. Our findings support the use of the c* based rheological approach for inferring miscibility of deeply cooled ASDs.

Analysis of urinary potassium isotopes and association with pancreatic health: healthy, diabetic and cancerous states.

Background: More than 700 million people worldwide suffer from diseases of the pancreas, such as diabetes, pancreatitis and pancreatic cancer. Often dysregulation of potassium (K+) channels, co-transporters and pumps can promote development and progression of many types of these diseases. The role of K+ transport system in pancreatic cell homeostasis and disease development remains largely unexplored. Potassium isotope analysis (δ41K), however, might have the potential to detect minute changes in metabolic processes relevant for pancreatic diseases. Methods: We assessed urinary K isotope composition in a case-control study by measuring K concentrations and δ41K in spot urines collected from patients diagnosed with pancreatic cancer (n=18), other pancreas-related diseases (n=14) and compared those data to healthy controls (n=16). Results: Our results show that urinary K+ levels for patients with diseased pancreas (benign and pancreatic cancer) are significantly lower than the healthy controls. For δ41K, the values tend to be higher for individuals with pancreatic cancer (mean δ41K = -0.58 ± 0.33‰) than for healthy individuals (mean δ41K = -0.78 ± 0.19‰) but the difference is not significant (p=0.08). For diabetics, urinary K+ levels are significantly lower (p=0.03) and δ41K is significantly higher (p=0.009) than for the healthy controls. These results suggest that urinary K+ levels and K isotopes can help identify K disturbances related to diabetes, an associated factors of all-cause mortality for diabetics. Conclusion: Although the K isotope results should be considered exploratory and hypothesis-generating and future studies should focus on larger sample size and δ41K analysis of other K-disrupting diseases (e.g., chronic kidney disease), our data hold great promise for K isotopes as disease marker.

Improved Test Fixture for Collecting Microcontact Performance and Reliability Data.

Microelectromechanical systems (MEMS) ohmic contact switches are considered to be a promising candidate for wireless communication applications. The longevity of MEMS switches is directly related to the reliability and performance of microcontacts. In this work, an improved microcontact test fixture with high actuation rates (KHz) and highly precise position control (nm) and force (nN) control was developed. Here, we collected microcontact performance data from initial contact tests (ICT) and microcontact reliability data from cold switched tests (CST). To perform these tests with our test fixture, we fabricated MEMS microcontact test structures with relatively high Young's modulus electroplated Nickel (Ni)-based, fixed-fixed beam structure with Au/RuO2 bimetallic microcontacts. These structures were characterized for forces ranging from 200-1000 µN in ICT tests. In a CST test, the tested microcontact survived more than 200 million cycles at a 1 KHz cycle rate, with a stable contact resistance value ranging between 3.8-5.2 Ω. These experiments validate the potentiality of our microcontact test fixture, and will facilitate further investigation on advanced microcontacts to enhance the MEMS switch's reliability.