In Vivo Glucose Transporter-2 Regulation of Dorsomedial Versus Ventrolateral VMN Astrocyte Metabolic Sensor and Glycogen Metabolic Enzyme Gene Expression in Female Rat.

Astrocyte glycogenolysis shapes ventromedial hypothalamic nucleus (VMN) regulation of glucostasis in vivo. Glucose transporter-2 (GLUT2), a plasma membrane glucose sensor, controls hypothalamic primary astrocyte culture glycogen metabolism in vitro. In vivo gene silencing tools and single-cell laser-catapult-microdissection/multiplex qPCR techniques were used here to examine whether GLUT2 governs dorsomedial (VMNdm) and/or ventrolateral (VMNvl) VMN astrocyte metabolic sensor and glycogen metabolic enzyme gene profiles. GLUT2 gene knockdown diminished astrocyte GLUT2 mRNA in both VMN divisions. Hypoglycemia caused GLUT2 siRNA-reversible up-regulation of this gene profile in the VMNdm, but down-regulated VMNvl astrocyte GLUT2 transcription. GLUT2 augmented baseline VMNdm and VMNvl astrocyte glucokinase (GCK) gene expression, but increased (VMNdm) or reduced (VMNvl) GCK transcription during hypoglycemia. GLUT2 imposed opposite control, namely stimulation versus inhibition of VMNdm or VMNvl astrocyte 5'-AMP-activated protein kinase-alpha 1 and -alpha 2 gene expression, respectively. GLUT2 stimulated astrocyte glycogen synthase (GS) gene expression in each VMN division. GLUT2 inhibited transcription of the AMP-sensitive glycogen phosphorylase (GP) isoform GP-brain type (GPbb) in each site, yet diminished (VMNdm) or augmented (VMNvl) astrocyte GP-muscle type (GPmm) mRNA. GLUT2 enhanced VMNdm and VMNvl glycogen accumulation during euglycemia, and curbed hypoglycemia-associated VMNdm glycogen depletion. Results show that VMN astrocytes exhibit opposite, division-specific GLUT2 transcriptional responsiveness to hypoglycemia. Data document divergent GLUT2 control of GCK, AMPK catalytic subunit, and GPmm gene profiles in VMNdm versus VMNvl astrocytes. Ongoing studies seek to determine how differential GLUT2 regulation of glucose and energy sensor function and glycogenolysis in each VMN location may affect local neuron responses to hypoglycemia.

A B7-H3-targeted CD28 bispecific antibody enhances the activity of anti-PD1 and CD3 T-cell engager immunotherapies.

T-cell activation is a multistep process requiring T-cell receptor engagement by peptide-major histocompatibility complexes (Signal 1) coupled with CD28-mediated costimulation (Signal 2). Tumors typically lack expression of CD28 ligands, so tumor-specific Signal 1 (e.g., neoepitope presentation) without costimulation may be ineffective or even induce T-cell anergy. We designed the bispecific antibody XmAb808 to co-engage the tumor-associated antigen B7-H3 with CD28 to promote T-cell costimulation within the tumor microenvironment. XmAb808 costimulation was measured by its ability to activate and expand T cells and enhance T cell-mediated cancer cell killing in cocultures of human peripheral blood mononuclear cells (PBMCs) and cancer cells, and in mice engrafted with human PBMCs and tumor xenografts. XmAb808 avidly bound cancer cells and stimulated interleukin (IL)2 and interferon (IFN)γ secretion from T cells cocultured with cancer cells engineered to deliver Signal 1 to T cells via a surface-expressed anti-CD3 antibody. XmAb808 enhanced expression of the anti-apoptotic factor Bcl-xL and CD25, promoting survival and IL2-dependent expansion of T cells coupled with increased T cell-mediated cytotoxicity in vitro. XmAb808 combined with a EpCAM×CD3 bispecific antibody to enhance target cell killing through IL2-dependent expansion of CD25+ T cells. This combination also suppressed pancreatic tumor xenograft growth in mice. Further, XmAb808 combined with an anti-PD1 antibody to suppress breast tumor xenograft growth in mice. XmAb808 as monotherapy and in combination with an anti-PD1 antibody is currently in clinical development in patients with advanced solid tumors. Our results suggest that XmAb808 may also combine with tumor antigen-targeted anti-CD3 (Signal 1) T-cell engagers.

Enhanced Manual Ventilation with a Handheld Audiovisual Device - BENGI - Insights from a Pilot Study in Special Operations Medicine.

BACKGROUND: In emergency casualty and evacuation situations, manual ventilation using self-inflating bags remains a critical skill; however, significant challenges exist in ensuring safety and effectiveness, since inaccurate manual ventilation is associated with life-threatening risks (e.g., gastric insufflation with aspiration, barotrauma, and reduced venous return). METHODS: This study assessed the impact of audiovisual feedback from the bag-valve-mask (BVM) emergency narration guided instrument (BENGI), a handheld manual ventilation guidance device, on improving performance and safety, immediately and 2 weeks after, with no additional manual ventilation training. In a crossover manikin simulation study with 20 participants, BENGI immediately and significantly improved tidal volume and respiratory rate accuracy. RESULTS: Intraand inter-participant variations were lower with BENGI, with Poincaré plot analysis showing improved performance that remained for at least 2 weeks following BENGI training. CONCLUSION: BENGI's audiovisual feedback improves manual immediately and persistently, making it invaluable for training and clinical use in diverse scenarios, from battlespace to civilian emergencies.

Neurotoxic effects associated with chronic inhalation and oral exposure to glyphosate-based herbicide IN adult rats.

The use of glyphosate-based herbicides (GBHs) for agricultural production has increased substantially around the world, as have their residues in the environment. Its effects on the central nervous system and neurotoxicity pathways are still not fully understood. The aim of this study was to evaluate the neurotoxic effect of chronic exposure to a GBH in adult rats. Sixty adult male albino Wistar rats were allocated into 6 groups, 2 control groups, and four GBH exposure groups (n = 10/group). The animals were exposed to two concentrations of GBH, orally and by inhalation: 2.99 × 10-3 grams of active ingredient per hectare (g.a.i./ha) and 7.48 × 10-3 g.a.i./ha. The animals were exposed for six months. Behavioral studies were performed. Brain tissue was collected for histopathological, immunohistochemical, and oxidative stress analyses. Animals exposed by inhalation to GBH spent more time in the central area of the open field test, whereas animals exposed to a high oral concentration of GBH spent less time in the open arms in the elevated plus-maze test. Tissue hyperemia occurred only in animals exposed to high concentrations of GBH. There was a greater thickness of the cerebral cortex and an increase in the expression of the BCL-2 in the animals exposed by inhalation to GBH. There was no difference in the doses of malonaldehyde and protein carbonylation between exposed and unexposed groups. The exposure to GBH caused increased levels of anxiety, regardless of the route, high concentrations caused hyperemia and inhalation exposure cause increased cortex thickness and increased BCl-2 expression.

Trends in dental school faculty: An analysis of the results of the 2021‒2022 ADEA Dental School Faculty Demographic Census and 2018‒2019 ADEA Survey of Dental School Faculty.

PURPOSE/OBJECTIVES: Each year, American Dental Education Association (ADEA) collects data on U.S. dental school faculty demographics, compensation, and vacant and lost positions. One of the purposes of the reports associated with this project is to provide information to U.S. dental schools on national trends on dental school faculty. This report examines the landscape of faculty workforce at U.S.-accredited dental schools in 2021‒2022 and changes relative to the 2018‒2019 academic year. The information contained within this report includes faculty position information, new and separated faculty, open or vacant faculty positions, lost faculty positions, and faculty demographics. METHODS: The report analyzes data from the 2018‒2019 ADEA Survey of Dental School Faculty (representing an estimated 91% of the full-time and part-time faculty) and 2021‒2022 ADEA Dental School Faculty Salary and Demographic Census (an estimated 84% of the faculty). RESULTS: The analysis revealed that more than half of dental school faculty was in the south and northeast in 2021‒2022. Among responding schools, 85% of the faculty concentrated on teaching, research, and training in 2021‒2022, a proportion similar with 2018‒2019. One in five faculty was tenured or on tenure track, similar with 2018‒2019. More than three-quarters of full-time and part-time faculty were clinical faculty in 2021‒2022. There was a 62% increase in open faculty positions between 2018‒2019 and 2021‒2022. Women accounted for four in 10 faculty members in 2021‒2022-more than 3 years before. The median age of dental school faculty declined from 56 to 54 years old between 2019 and 2022. CONCLUSIONS: This study found that dental school faculty was increasingly younger, with more women members and more open positions in 2021‒2022 than in 2018‒2019.

Skin mycosis distribution, and burden of visits over a decade in Colombia: ecological study.

Objectives: To describe the sociodemographic distribution of dermatomycosis and the visits burden over a 10-year period of care. Methods: An ecological study was conducted using data on visits and people treated in the Colombian Health System during 2010-2019 using the International Classification of Diseases, Tenth Revision codes (ICD-10). Departments and geopolitical regions were the units of analysis, and visit burden was reported as frequency, intensity (visits per person), and rate of dermatomycosis visits (per 10,000 visits; 95% confidence interval). Results: A total of 4,570,593 visits were analyzed. The most used ICD-10 codes were B369 (superficial mycosis, unspecified), B360 (pityriasis versicolor), B354 (Tinea corporis), B359 (dermatophytosis), and B351 (Tinea unguium) (56.5%), with visits primarily involving the adult population (27-59 years; 32.2%), women (43.4%), and urban populations (57.3%). Amazonas department had the highest rate of visits (2.36 per 10,000), while Nariño had the highest intensity of visits (1.94 visits per person). Caribbean region had the highest rate of visits (17.0 per 10,000 visits; 17.0-17.0), followed by the Amazon region (16.3 per 10,000 visits; 16.2-16.4). Conclusions: The annual visits burden of dermatomycosis in Colombia is high and concentrated in susceptible geographic areas, possibly due to socio-environmental factors. This health problem is overshadowed by chronic diseases and trauma but is often recurrent, and chronic, and induces out-of-pocket costs for treatment.

What clinicians could consider in providing group interventions for people with cognitive impairments: a scoping review.

This study identified evidence and considerations for allied health clinicians in providing group interventions for people with cognitive impairment. A scoping review was conducted by searching the MEDLINE (Ovid), CINHAL (EBSCOhost), Scopus (Elsevier), Embase (Ovid) and TROVE databases from 2016. Articles of any study design in which group interventions were performed by an allied health professional with participants with cognitive impairment were included. Data on physical, cognitive, psychological, and quality of life measures were extracted from the selected articles. Standardised mean changes (SMC) were calculated. Ten articles were included in the study. No article directly compared group interventions versus one-to-one interventions. The results of the meta-analysis showed significant improvements after the intervention in the physical (SMC = 0.42, P = 0.013), cognitive (SMC = 0.43, P = 0.005), psychological (SMC = 0.14, P = 0.005), and quality of life domains (SMC = 0.28, P = 0.002). This review identified considerations for clinicians when developing group interventions for people with cognitive impairments, including specific participant criteria, increasing support, modifications to intervention difficulty, and environmental considerations. Group intervention for people with cognitive impairments demonstrated moderate effectiveness in improving physical and cognitive domains and a small effect in improving psychological and quality of life domains. Specific considerations are recommended when clinicians provide group interventions for people with cognitive impairments.

Physical and psychological distress amongst patients undergoing neoadjuvant chemotherapy for advanced ovarian cancer.

OBJECTIVE: This study compares baseline clinical characteristics, physical function testing, and patient-reported outcomes for patients undergoing primary cytoreductive surgery versus neoadjuvant chemotherapy, with the goal of better understanding unique patient needs at diagnosis. METHODS: Patients with suspected advanced stage (IIIC/IV) epithelial ovarian cancer undergoing either primary cytoreductive surgery or neoadjuvant chemotherapy were enrolled in a single-institution, non-randomized prospective behavioral intervention trial of prehabilitation. Baseline clinical characteristics were abstracted. Physical function was evaluated using the Short Physical Performance Battery, Fried Frailty Index, gait speed, and grip strength. Patient-reported outcomes were evaluated using Patient-Reported Outcomes Measurement Information System metrics and the Perceived Stress Scale. RESULTS: There were no significant differences in demographics or clinical characteristics between cohorts at enrollment, with the exception of performance status, clinical stage, and albumin. While gait speed and grip strength were lower amongst neoadjuvant chemotherapy patients, there were no significant differences in physical function using the Short Physical Performance Battery and Fried Frailty Index. Patients in the neoadjuvant chemotherapy cohort reported decreased perception of physical function and increased fatigue on Patient-Reported Outcomes Measurement Information System metrics. A larger proportion of patients in the neoadjuvant cohort reported severe levels of emotional distress and anxiety, as well as greater perceived stress at diagnosis. CONCLUSIONS: Our findings suggest that patients undergoing neoadjuvant chemotherapy for advanced ovarian cancer present with increased psychosocial distress and decreased perception of physical function at diagnosis and may benefit most from early introduction of supportive care.

Two new mouse alleles of Ocm and Slc26a5.

The genes Ocm (encoding oncomodulin) and Slc26a5 (encoding prestin) are expressed strongly in outer hair cells and both are involved in deafness in mice. However, it is not clear if they influence the expression of each other. In this study, we characterise the auditory phenotype resulting from two new mouse alleles, Ocmtm1e and Slc26a5tm1Cre. Each mutation leads to absence of detectable mRNA transcribed from the mutant allele, but there was no evidence that oncomodulin regulates expression of prestin or vice versa. The two mutants show distinctive patterns of auditory dysfunction. Ocmtm1e homozygotes have normal auditory brainstem response thresholds at 4 weeks old followed by progressive hearing loss starting at high frequencies, while heterozygotes show largely normal thresholds until 6 months of age, when signs of worse thresholds are detected. In contrast, Slc26a5tm1Cre homozygotes have stable but raised thresholds across all frequencies tested, 3 to 42 kHz, at least from 4 to 8 weeks old, while heterozygotes have raised thresholds at high frequencies. Distortion product otoacoustic emissions and cochlear microphonics show deficits similar to auditory brainstem responses in both mutants, suggesting that the origin of hearing impairment is in the outer hair cells. Endocochlear potentials are normal in the two mutants. Scanning electron microscopy revealed normal development of hair cells in Ocmtm1e homozygotes but scattered outer hair cell loss even at 4 weeks old when thresholds appeared normal, indicating that there is not a direct relationship between numbers of outer hair cells present and auditory thresholds.

Sex-dimorphic effects of glucose transporter-2 gene knockdown on hypothalamic primary astrocyte phosphoinositide-3-kinase (PI3K)/protein kinase B (PKB/Akt)/mammalian target of rapamycin (mTOR) cascade protein expression and phosphorylation.

Glucose transporter-2 (GLUT2), a unique high capacity/low affinity, highly efficient membrane transporter and sensor, regulates hypothalamic astrocyte glucose phosphorylation and glycogen metabolism. The phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway participates in glucose homeostasis, but its sensitivity to glucose-sensory cues is unknown. Current research used a hypothalamic astrocyte primary culture model to investigate whether glucoprivation causes PI3K/Akt/mTOR pathway activation in one or both sexes by GLUT2-dependent mechanisms. Glucoprivation did not alter astrocyte PI3K levels, yet up-regulated both phosphorylated derivatives in female and down-regulated male p60 phosphoprotein expression. GLUT2 siRNA pretreatment diminished glucoprivic patterns of PI3K and phospho-PI3K expression in each sex. Astrocyte Akt and phospho-Akt/Thr308 proteins exhibited divergent, sex-contingent responses to GLUT2 gene knockdown or glucoprivation. GLUT2 siRNA pretreatment exacerbated glucoprivic-associated Akt diminution in the female, and either amplified (male) or reversed (female) glucoprivic regulation of phospho-Akt/Thr308 expression. GLUT2 gene silencing down- (male) or up-(female) regulated mTOR protein, and phospho-mTOR protein in male. Male astrocyte mTOR and phospho-mTOR profile were refractory to glucoprivation, but glucose-deprived females showed GLUT2-independent mTOR inhibition and GLUT2-dependent phospho-mTOR up-augmentation. Results identify a larger number of glucoprivic-sensitive PI3K/Akt/mTOR pathway proteins in female versus male astrocytes, and document divergent responses of common glucose-sensitive targets. GLUT2 stimulates phosphoPI3K protein expression in each sex, but imposes differential control of PI3K, Akt, phospho-Akt/Thr308, mTOR, and phospho-mTOR profiles in male versus female. Data implicate GLUT2 as a driver of distinctive pathway protein responses to glucoprivation in female, but not male.

A systematic review and meta-analysis of randomized controlled trials to reduce burden, stress, and strain in informal stroke caregivers.

OBJECTIVES: To understand the nature and effectiveness of interventions aimed at improving informal stroke caregiver burden, stress, and strain. DATA SOURCES: In line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic search of CENTRAL, CINAHL, MEDLINE, Embase, APA PsycInfo, and Web of Science was conducted in May 2022. REVIEW METHODS: Studies were eligible if they included an intervention designed for informal stroke caregivers, reported on caregiver burden, strain, or stress, were published in English, and used a randomized controlled trial design. An updated search was conducted in June 2024. The methodological quality of studies was appraised using the Cochrane risk-of-bias tool for randomized trials. The data were pooled, and a meta-analysis was completed for caregiver burden and strain outcomes. RESULTS: Nineteen studies met inclusion criteria and were meta-analyzed. Interventions ranged from 4 days to 12 months. Most studies incorporated educational and/or support components. Meta-analyses revealed nonsignificant effects on caregiver burden or strain. Significant between-group differences for caregiver strain and burden were, however, found in seven studies. CONCLUSION: Limited studies, small sample sizes, and conflicting results made definitive conclusions on the most effective intervention characteristics for improving caregiver outcomes difficult. Of the 19 studies, seven found significant between-group differences for caregiver outcomes postintervention, and these tended to incorporate educational components and comprised between seven and nine sessions. Further high-quality research is required to identify optimal format, duration, and frequency for improving caregiver outcomes.

Hyper-diverse antigenic variation and resilience to transmission-reducing intervention in falciparum malaria.

Intervention efforts against falciparum malaria in high-transmission regions remain challenging, with rapid resurgence typically following their relaxation. Such resilience co-occurs with incomplete immunity and a large transmission reservoir from high asymptomatic prevalence. Incomplete immunity relates to the large antigenic variation of the parasite, with the major surface antigen of the blood stage of infection encoded by the multigene and recombinant family known as var. With a stochastic agent-based model, we investigate the existence of a sharp transition in resurgence ability with intervention intensity and identify molecular indicators informative of its proximity. Their application to survey data with deep sampling of var sequences from individual isolates in northern Ghana suggests that the transmission system was brought close to transition by intervention with indoor residual spraying. These results indicate that sustaining and intensifying intervention would have pushed malaria dynamics to a slow-rebound regime with an increased probability of local parasite extinction.

A new mutation of Sgms1 causes gradual hearing loss associated with a reduced endocochlear potential.

Sgms1 encodes sphingomyelin synthase 1, an enzyme in the sphingosine-1-phosphate signalling pathway, and was previously reported to underlie hearing impairment in the mouse. A new mouse allele, Sgms1tm1a, unexpectedly showed normal Auditory Brainstem Response thresholds. We found that the Sgms1tm1a mutation led to incomplete knockdown of transcript to 20 % of normal values, which was enough to support normal hearing. The Sgms1tm1b allele was generated by knocking out exon 7, leading to a complete lack of detectable transcript in the inner ear. Sgms1tm1b homozygotes showed largely normal auditory brainstem response thresholds at first, followed by progressive loss of sensitivity until they showed severe impairment at 6 months old. The endocochlear potential was consistently reduced in Sgms1tm1b mutants at 3, 4 and 8 weeks old, to around 80 mV compared with around 120 mV in control littermates. The stria vascularis showed a characteristic irregularity of marginal cell surfaces and patchy loss of Kcnq1 expression at their apical membrane, and expression analysis of the lateral wall suggested that marginal cells were the most likely initial site of dysfunction in the mutants. Finally, significant association of auditory thresholds with DNA markers within and close to the human SGMS1 gene were found in the 1958 Birth Cohort, suggesting that SGMS1 variants may play a role in the range of hearing abilities in the human population.

Predictors of outcomes after PCI with incomplete revascularization: Impact of CTO and LAD vessel.

BACKGROUND: Incomplete revascularization (ICR) after percutaneous coronary intervention (PCI) is associated with mortality and morbidity. AIM: We sought to investigate whether ICR in the left anterior descending artery (LAD) is worse than ICR of the right coronary artery (RCA) or left circumflex artery (LCX); and whether ICR in patients with a chronic total occlusion (CTO) is worse than in those without. METHODS: In the RIVER-PCI trial, 2651 patients with ICR after PCI were randomly assigned to ranolazine or placebo. Angiograms were assessed at an independent core laboratory in 2501 patients (94.3%). The primary endpoint was the composite of ischemia-driven revascularization or hospitalization. RESULTS: A total of 1664 patients (66.5%) had ICR involving the LAD, whereas 837 (33.5%) had ICR limited to the RCA or LCX. At median follow-up of 643 days, the primary endpoint occurred in 26.9% versus 26.5% of patients (adjusted HR [aHR]: 1.03, 95% confidence interval [CI]: 0.88-1.21). A nonrecanalized CTO was present in 854 patients (34.1%) with ICR after PCI. The primary endpoint occurred in 28.6% versus 25.9% of ICR patients with versus without a CTO (aHR: 1.10, 95% CI: 0.94-1.29). However, patients with a CTO had higher rates of ischemia-driven hospitalization without revascularization (aHR: 1.27, 95% CI: 1.04-1.56), heart failure hospitalization (aHR: 2.69, 95% CI: 1.61-4.59) and myocardial infarction (aHR: 1.46, 95% CI: 1.11-1.92) compared with those without. CONCLUSIONS: The 2-year prognosis was similar in post-PCI patients with ICR whether the LAD was versus was not involved. ICR patients with a CTO had more frequent hospitalizations for ischemia and myocardial infarctions compared with those without.

Steroidogenic Factor-1 Regulation of Dorsomedial Ventromedial Hypothalamic Nucleus Ghrh Neuron Transmitter Marker and Estrogen Receptor Gene Expression in Male Rat.

Ventromedial hypothalamic nucleus (VMN) growth hormone-releasing hormone (Ghrh) neurotransmission shapes counterregulatory hormone secretion. Dorsomedial VMN Ghrh neurons express the metabolic-sensitive transcription factor steroidogenic factor-1/NR5A1 (SF-1). In vivo SF-1 gene knockdown tools were used here to address the premise that in male rats, SF-1 may regulate basal and/or hypoglycemic patterns of Ghrh, co-transmitter biosynthetic enzyme, and estrogen receptor (ER) gene expression in these neurons. Single-cell multiplex qPCR analyses showed that SF-1 regulates basal profiles of mRNAs that encode Ghrh and protein markers for neurochemicals that suppress (γ-aminobutyric acid) or enhance (nitric oxide; glutamate) counterregulation. SF-1 siRNA pretreatment respectively exacerbated or blunted hypoglycemia-associated inhibition of glutamate decarboxylase67 (GAD67/GAD1) and -65 (GAD65/GAD2) transcripts. Hypoglycemia augmented or reduced nitric oxide synthase and glutaminase mRNAs, responses that were attenuated by SF-1 gene silencing. Ghrh and Ghrh receptor transcripts were correspondingly refractory to or increased by hypoglycemia, yet SF-1 knockdown decreased both gene profiles. Hypoglycemic inhibition of ER-alpha and G protein-coupled-ER gene expression was amplified by SF-1 siRNA pretreatment, whereas as ER-beta mRNA was amplified. SF-1 knockdown decreased (corticosterone) or elevated [glucagon, growth hormone (GH)] basal counterregulatory hormone profiles, but amplified hypoglycemic hypercorticosteronemia and -glucagonemia or prevented elevated GH release. Outcomes document SF-1 control of VMN Ghrh neuron counterregulatory neurotransmitter and ER gene transcription. SF-1 likely regulates Ghrh nerve cell receptivity to estradiol and release of distinctive neurochemicals during glucose homeostasis and systemic imbalance. VMN Ghrh neurons emerge as a likely substrate for SF-1 control of glucose counterregulation in the male rat.

Targeted genome editing restores auditory function in adult mice with progressive hearing loss caused by a human microRNA mutation.

Mutations in microRNA-96 (MIR96) cause autosomal dominant deafness-50 (DFNA50), a form of delayed-onset hearing loss. Genome editing has shown efficacy in hearing recovery through intervention in neonatal mice, yet editing in the adult inner ear is necessary for clinical applications, which has not been done. Here, we developed a genome editing therapy for the MIR96 mutation 14C>A by screening different CRISPR systems and optimizing Cas9 expression and the sgRNA scaffold for efficient and specific mutation editing. AAV delivery of the KKH variant of Staphylococcus aureus Cas9 (SaCas9-KKH) and sgRNA to the cochleae of presymptomatic (3-week-old) and symptomatic (6-week-old) adult Mir9614C>A/+ mutant mice improved hearing long term, with efficacy increased by injection at a younger age. Adult inner ear delivery resulted in transient Cas9 expression without evidence of AAV genomic integration, indicating the good safety profile of our in vivo genome editing strategy. We developed a dual-AAV system, including an AAV-sgmiR96-master carrying sgRNAs against all known human MIR96 mutations. Because mouse and human MIR96 sequences share 100% homology, our approach and sgRNA selection for efficient and specific hair cell editing for long-term hearing recovery lay the foundation for the development of treatment for patients with DFNA50 caused by MIR96 mutations.

Epidemiology of work-related hand and wrist injuries in a referral center: A descriptive study.

BACKGROUND: Occupational hand and wrist injuries (OHWIs) account for 25% of work-related accidents in low- and middle-income countries. In Colombia, more than 500000 occupational accidents occurred in 2021, and although the rate declined to less than 5% in 2020 and 2021, at least one in four accidents involved a hand or wrist injury. AIM: To describe the OHWIs in workers seen at the emergency room at a second-level hospital in Colombia. METHODS: An observational study was performed using data from workers who experienced OHWIs and attended a second-level hospital, between June, 2020 and May, 2021. The overall frequency of OHWIs, as well as their distribution by sociodemographic, clinical, and occupational variables, are described. Furthermore, association patterns between sex, anatomical area (fingers, hand, wrist), and type of job were analyzed by correspondence analysis (CA). RESULTS: There were 2.101 workers treated for occupational accidents, 423 (20.3%) were cases of OHWIs, which mainly affected men (93.9%) with a median age of 31 years and who worked mainly in mining (75.9%). OHWIs were more common in the right upper extremity (55.3%) and comprised different types of injuries, such as contusion (42.1%), laceration (27.9%), fracture (18.7%), and crush injury (15.6%). They primarily affected the phalanges (95.2%), especially those of the first finger (25.7%). The CAs showed associations between the injured anatomical area and the worker's job that differed in men and women (explained variance > 90%). CONCLUSION: One out of five workers who suffered occupational accidents in Cundinamarca, Columbia had an OHWI, affecting mainly males employed in mining. This occupational profile is likely to lead to prolonged rehabilitation, and permanent functional limitations. Our results might be useful for adjusting preventive measures in cluster risk groups.

Clinical and demographic features of patients undergoing video-capsule endoscopy management: A descriptive study.

BACKGROUND: Video-capsule endoscopy (VCE) is an efficient tool that has proven to be highly useful in approaching several gastrointestinal diseases. VCE was implemented in Colombia in 2003, however current characterization of patients undergoing VCE in Colombia is limited, and mainly comes from two investigations conducted before the SARS-CoV-2 pandemic period. AIM: To describe the characteristics of patients undergoing VCEs and establish the main indications, findings, technical limitations, and other outstanding features. METHODS: A descriptive study was carried out using data from reports of VCE (PillCam SB3 system) use in a Gastroenterology Unit in Bogotá, Colombia between September 2019 and January 2023. Demographic and clinical variables such as indication for the VCE, gastric and small bowel transit times (GTT, SBTT), endoscopic preparation quality, and limitations were described [n (%), median (IQR)]. RESULTS: A total of 133 VCE reports were analyzed. Most were in men with a median age of 70 years. The majority had good preparation (96.2%), and there were technical limitations in 15.8% of cases. The main indications were unexplained anemia (91%) or occult bleeding (23.3%). The median GTT and SBTT were 14 and 30 minutes, respectively. The frequencies of bleeding stigma (3.79%) and active bleeding (9.09%) were low, and the most frequent abnormal findings were red spots (28.3%), erosions (17.6%), and vascular ectasias (12.5%). CONCLUSION: VCE showed high-level safety. The main indication was unexplained anemia. Active bleeding was the most frequent finding. Combined with artificial intelligence, VCE can improve diagnostic precision and targeted therapeutic interventions.