Single-cell transcriptomic profiling of human pancreatic islets reveals genes responsive to glucose exposure over 24 h.

AIMS/HYPOTHESIS: Disruption of pancreatic islet function and glucose homeostasis can lead to the development of sustained hyperglycaemia, beta cell glucotoxicity and subsequently type 2 diabetes. In this study, we explored the effects of in vitro hyperglycaemic conditions on human pancreatic islet gene expression across 24 h in six pancreatic cell types: alpha; beta; gamma; delta; ductal; and acinar. We hypothesised that genes associated with hyperglycaemic conditions may be relevant to the onset and progression of diabetes. METHODS: We exposed human pancreatic islets from two donors to low (2.8 mmol/l) and high (15.0 mmol/l) glucose concentrations over 24 h in vitro. To assess the transcriptome, we performed single-cell RNA-seq (scRNA-seq) at seven time points. We modelled time as both a discrete and continuous variable to determine momentary and longitudinal changes in transcription associated with islet time in culture or glucose exposure. Additionally, we integrated genomic features and genetic summary statistics to nominate candidate effector genes. For three of these genes, we functionally characterised the effect on insulin production and secretion using CRISPR interference to knock down gene expression in EndoC-ßH1 cells, followed by a glucose-stimulated insulin secretion assay. RESULTS: In the discrete time models, we identified 1344 genes associated with time and 668 genes associated with glucose exposure across all cell types and time points. In the continuous time models, we identified 1311 genes associated with time, 345 genes associated with glucose exposure and 418 genes associated with interaction effects between time and glucose across all cell types. By integrating these expression profiles with summary statistics from genetic association studies, we identified 2449 candidate effector genes for type 2 diabetes, HbA1c, random blood glucose and fasting blood glucose. Of these candidate effector genes, we showed that three (ERO1B, HNRNPA2B1 and RHOBTB3) exhibited an effect on glucose-stimulated insulin production and secretion in EndoC-ßH1 cells. CONCLUSIONS/INTERPRETATION: The findings of our study provide an in-depth characterisation of the 24 h transcriptomic response of human pancreatic islets to glucose exposure at a single-cell resolution. By integrating differentially expressed genes with genetic signals for type 2 diabetes and glucose-related traits, we provide insights into the molecular mechanisms underlying glucose homeostasis. Finally, we provide functional evidence to support the role of three candidate effector genes in insulin secretion and production. DATA AVAILABILITY: The scRNA-seq data from the 24 h glucose exposure experiment performed in this study are available in the database of Genotypes and Phenotypes (dbGap; https://www.ncbi.nlm.nih.gov/gap/ ) with accession no. phs001188.v3.p1. Study metadata and summary statistics for the differential expression, gene set enrichment and candidate effector gene prediction analyses are available in the Zenodo data repository ( https://zenodo.org/ ) under accession number 11123248. The code used in this study is publicly available at https://github.com/CollinsLabBioComp/publication-islet_glucose_timecourse .

Helminth induced monocytosis conveys protection from respiratory syncytial virus infection in mice.

BACKGROUND: Respiratory syncytial virus (RSV) infection in infants is a major cause of viral bronchiolitis and hospitalisation. We have previously shown in a murine model that ongoing infection with the gut helminth Heligmosomoides polygyrus protects against RSV infection through type I interferon (IFN-I) dependent reduction of viral load. Yet, the cellular basis for this protection has remained elusive. Given that recruitment of mononuclear phagocytes to the lung is critical for early RSV infection control, we assessed their role in this coinfection model. METHODS: Mice were infected by oral gavage with H. polygyrus. Myeloid immune cell populations were assessed by flow cytometry in lung, blood and bone marrow throughout infection and after secondary infection with RSV. Monocyte numbers were depleted by anti-CCR2 antibody or increased by intravenous transfer of enriched monocytes. RESULTS: H. polygyrus infection induces bone marrow monopoiesis, increasing circulatory monocytes and lung mononuclear phagocytes in a IFN-I signalling dependent manner. This expansion causes enhanced lung mononuclear phagocyte counts early in RSV infection that may contribute to the reduction of RSV load. Depletion or supplementation of circulatory monocytes prior to RSV infection confirms that these are both necessary and sufficient for helminth induced antiviral protection. CONCLUSIONS: H. polygyrus infection induces systemic monocytosis contributing to elevated mononuclear phagocyte numbers in the lung. These cells are central to an anti-viral effect that reduces the peak viral load in RSV infection. Treatments to promote or modulate these cells may provide novel paths to control RSV infection in high risk individuals.

Buried interface molecular hybrid for inverted perovskite solar cells.

Perovskite solar cells (PSCs) with an "inverted" architecture are a key pathway for commercializing this emerging photovoltaic technology due to the better power conversion efficiency (PCE) and operational stability as compared to the "normal" device structure. Specifically, PCEs of the inverted PSCs have exceeded 25% owing to the development of improved self-assembled molecules (SAMs)1-5 and passivation strategies6-8. Nevertheless, poor wettability and agglomerations of SAMs9-12 will cause interfacial losses, impeding further improvement in PCE and stability. Herein, we report on molecular hybrid at the buried interface in inverted PSCs by co-assembling a multiple carboxylic acid functionalized aromatic compound of 4,4',4''-nitrilotribenzoicacid (NA) with a popular SAM of [4-(3,6-dime-thyl-9H-carbazol-9-yl)butyl]phosphonic acid (Me-4PACz) to improve the heterojunction interface. The molecular hybrid of Me-4PACz with NA could substantially improve the interfacial characteristics. The resulting inverted PSCs demonstrated a record-certified steady-state efficiency of 26.54%. Crucially, this strategy aligns seamlessly with large-scale manufacturing, achieving the highest certified PCE for inverted mini-modules at 22.74% (aperture area: 11.1 cm2). Our device also maintained 96.1% of its initial PCE after more than 2,400 hours of 1-sun operation in ambient air.

Pembrolizumab plus Abiraterone Acetate and Prednisone in Patients with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Results from KEYNOTE-365 Cohort D.

BACKGROUND AND OBJECTIVE: Abiraterone acetate (abiraterone) plus prednisone is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Our aim was to evaluate the efficacy and safety of pembrolizumab plus abiraterone in mCRPC. METHODS: In cohort D of the phase 1b/2 KEYNOTE-365 study (NCT02861573), patients were chemotherapy-naïve, had disease progression ≤6 mo before screening, and had either not received prior next-generation hormonal agents for mCRPC or had received prior enzalutamide for mCRPC and had disease progression or became intolerant to enzalutamide. Patients received pembrolizumab 200 mg intravenously every 3 wk plus abiraterone 1000 mg orally once daily and prednisone 5 mg orally twice daily. The primary endpoints were safety, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review (BICR). Secondary endpoints included radiographic progression-free survival (rPFS) according to Prostate Cancer Clinical Trials Working Group 3-modified RECIST v1.1 by BICR and overall survival (OS). KEY FINDINGS AND LIMITATIONS: For the 103 patients who were treated, median follow-up was 28 mo (interquartile range 26-31). The confirmed PSA response rate was 56% (58/103 patients). The ORR for patients with RECIST v1.1-measurable disease was 16% (6/37 patients). Median rPFS was 15 mo (95% confidence interval 9.2-22) and median OS was 30 mo (95% confidence interval 23-not reached); the estimated 24-mo OS rate was 58%. In total, 91% of patients experienced treatment-related adverse events, and 39% experienced grade 3-5 events. Grade 3/4 elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) was observed in 12% and 6.8% of patients, respectively. One patient died due to treatment-related myasthenic syndrome. Study limitations include the single-arm design. CONCLUSIONS: Pembrolizumab plus abiraterone and prednisone demonstrated antitumor activity and acceptable safety in patients with chemotherapy-naïve mCRPC. Higher incidence of grade 3/4 elevated ALT/AST occurred than was reported for the individual agents. PATIENT SUMMARY: For patients with metastatic castratation-resistant prostate cancer, the drug combination of pembrolizumab plus abiraterone and prednisone showed antitumor activity and acceptable safety.

Sex-specific overdominance at the maturation vgll3 gene for reproductive fitness in wild Atlantic salmon.

Linking reproductive fitness with adaptive traits at the genomic level can shed light on the mechanisms that produce and maintain sex-specific selection. Here, we construct a multigenerational pedigree to investigate sex-specific selection on a maturation gene, vgll3, in a wild Atlantic salmon population. The vgll3 locus is responsible for ~40% of the variation in maturation (sea age at first reproduction). Genetic parentage analysis was conducted on 18,265 juveniles (parr) and 685 adults collected at the same spawning ground over eight consecutive years. A high proportion of females (26%) were iteroparous and reproduced two to four times in their lifetime. A smaller proportion of males (9%) spawned at least twice in their lifetime. Sex-specific patterns of reproductive fitness were related to vgll3 genotype. Females showed a pattern of overdominance where vgll3*EL genotypes had three-fold more total offspring than homozygous females. In contrast, males demonstrated that late-maturing vgll3*LL individuals had two-fold more offspring than either vgll3*EE or vgll3*EL males. Taken together, these data suggest that balancing selection in females contributes to the maintenance of variation at this locus via increased fitness of iteroparous vgll3*EL females. This study demonstrates the utility of multigenerational pedigrees for uncovering complex patterns of reproduction, sex-specific selection and the maintenance of genetic variation.

Older adults' perceptions of ageism, discrimination, and racism.

Older adults often experience different forms of discrimination, whether it be on the basis of their age, gender, race, or ethnicity (Rochon et al. 2021). Many older adults have stated they have experienced the health care system differently because of their race or ethnicity . Understanding older adults' experiences and their perceptions of ageism and racism can guide future work. This observational cross-sectional study captured community-dwelling older adults' perceptions about their experiences with ageism and racism. A few opened-ended questions were included in the cross-sectional survey. While results did not yield differences with respect to perceptions of ageism by race; there were statistically significant results in regard to perceived racism, with higher scores on the racism scales for individuals who self-identified as Black. Discussion and implications for practice, policy and research are explored.

Normothermia to Decrease Surgical Site Infection Risk: Silver Bullet or Fool's Gold? A Retrospective Cohort Study.

PURPOSE: Surgical site infection (SSI) is the leading cause of nosocomial infections among surgical patients in the United States. Currently, there is compelling evidence suggesting that temperature dysregulation in surgical patients may be a risk factor for the development of SSI. We examined the relationship between perioperative hypothermia (PH) and SSI in a population of surgical patients with diabetes mellitus (DM). METHODS: This retrospective cohort review was conducted on patients with a history of DM undergoing orthopaedic surgery at our institution between May 1, 2018, and April 1, 2022. Inclusion criteria were age older than 15 years, a history of DM or recent hemoglobin A1c concentration of ≥6.5%, and operation of at least 60 minutes under general anesthesia. Perioperative hypothermia was defined as an intraoperative temperature ≤ 35.5°C. Continuous variables were compared using the t-test and Wilcoxon rank-sum test. Categorical variables were compared using the chi-squared test. We constructed a multivariable logistic regression model to estimate SSI risk while controlling for demographic variables. RESULTS: A total of 236 patients were included in the final analysis. The overall incidence of SSI was 5.93%. 99 patients (42%) experienced PH. No difference was observed in the risk of SSI between the normothermic and hypothermic cohorts. Among the 99 patients who experienced PH, increasing HbA1c was associated with increasing risk of SSI (OR = 2.39, 95% CI = 1.12 to 5.32, P-value = 0.0222). The multivariable logistic regression model had good discriminatory ability (c-statistic 0.74, 95% CI: 0.61 to 0.89) and good predictive accuracy (sensitivity 64%, specificity 73%). DISCUSSION: PH is not an independent risk factor of SSI. However, in the presence of elevated HbA1c, PH may more than double the risk of SSI. Perioperative hypothermia may be an additive risk factor in the setting of poor glycemic control and potentially in the setting of other known risk factors.

Structural basis for IL-33 recognition and its antagonism by the helminth effector protein HpARI2.

IL-33 plays a significant role in inflammation, allergy, and host defence against parasitic helminths. The model gastrointestinal nematode Heligmosomoides polygyrus bakeri secretes the Alarmin Release Inhibitor HpARI2, an effector protein that suppresses protective immune responses and asthma in its host by inhibiting IL-33 signalling. Here we reveal the structure of HpARI2 bound to mouse IL-33. HpARI2 contains three CCP-like domains, and we show that it contacts IL-33 primarily through the second and third of these. A large loop which emerges from CCP3 directly contacts IL-33 and structural comparison shows that this overlaps with the binding site on IL-33 for its receptor, ST2, preventing formation of a signalling complex. Truncations of HpARI2 which lack the large loop from CCP3 are not able to block IL-33-mediated signalling in a cell-based assay and in an in vivo female mouse model of asthma. This shows that direct competition between HpARI2 and ST2 is responsible for suppression of IL-33-dependent responses.

Time to diagnosis among young patients with cancer.

BACKGROUND: Sociodemographic and clinical factors associated with diagnostic delays in pediatric, adolescent, and young adult cancers are poorly understood. METHODS: Using the Optum Labs Data Warehouse's de-identified claims data for commercial health plan enrollees, we identified children (0-14 years) and adolescents/young adults (AYAs) (15-39 years) diagnosed with one of 10 common cancers from 2001 to 2017, who were continuously enrolled for 6 months preceding diagnosis. Time to diagnosis was calculated as days between first medical encounter with possible cancer symptoms and cancer diagnosis date. Median times from first symptom to diagnosis were compared using Wilcoxon rank sum test. Multivariable unconditional logistic regression identified sociodemographic factors associated with longer time (>3 months) to cancer diagnosis (from symptom onset). RESULTS: Of 47,296 patients, 87% presented prior to diagnosis with symptoms. Patients with central nervous system (CNS) tumors were most likely to present with symptoms (93%), whereas patients with cervical cancer were least likely (70%). Symptoms varied by malignancy. Of patients with symptoms, thyroid (105 days [range: 50-154]) and cervical (104 days [range: 41-151]) cancer had the longest median time to diagnosis. Females and patients at either end of the age spectrum were more likely to experience diagnosis delays of more than 3 months. CONCLUSION: In a commercially insured population, time to diagnosis varies by cancer type, age, and sex. Further work is needed to understand the patient, provider, and health system-level factors contributing to time from symptom onset to diagnosis, specifically in the very young children and the young adult patient population going forward.

Physician Specialty Differences in Unprofessional Behaviors Observed and Reported by Coworkers.

Importance: Because unprofessional behaviors are associated with patient complications, malpractice claims, and well-being concerns, monitoring concerns requiring investigation and individuals identified in multiple reports may provide important opportunities for health care leaders to support all team members. Objective: To examine the distribution of physicians by specialty who demonstrate unprofessional behaviors measured through safety reports submitted by coworkers. Design, Setting, and Participants: This retrospective cohort study was conducted among physicians who practiced at the 193 hospitals in the Coworker Concern Observation Reporting System (CORS), administered by the Vanderbilt Center for Patient and Professional Advocacy. Data were collected from January 2018 to December 2022. Exposure: Submitted reports concerning communication, professional responsibility, medical care, and professional integrity. Main Outcomes and Measures: Physicians' total number and categories of CORS reports. The proportion of physicians in each specialty (nonsurgeon nonproceduralists, emergency medicine physicians, nonsurgeon proceduralists, and surgeons) who received at least 1 report and who qualified for intervention were calculated; logistic regression was used to calculate the odds of any CORS report. Results: The cohort included 35 120 physicians: 18 288 (52.1%) nonsurgeon nonproceduralists, 1876 (5.3%) emergency medicine physicians, 6743 (19.2%) nonsurgeon proceduralists, and 8213 (23.4%) surgeons. There were 3179 physicians (9.1%) with at least 1 CORS report. Nonsurgeon nonproceduralists had the lowest percentage of physicians with at least 1 report (1032 [5.6%]), followed by emergency medicine (204 [10.9%]), nonsurgeon proceduralists (809 [12.0%]), and surgeons (1134 [13.8%]). Nonsurgeon nonproceduralists were less likely to be named in a CORS report than other specialties (5.6% vs 12.8% for other specialties combined; difference in percentages, -7.1 percentage points; 95% CI, -7.7 to -6.5 percentage points; P < .001). Pediatric-focused nonsurgeon nonproceduralists (2897 physicians) were significantly less likely to be associated with a CORS report than nonpediatric nonsurgeon nonproceduralists (15 391 physicians) (105 [3.6%] vs 927 [6.0%]; difference in percentages, -2.4 percentage points, 95% CI, -3.2 to -1.6 percentage points; P < .001). Pediatric-focused emergency medicine physicians, nonsurgeon proceduralists, and surgeons had no significant differences in reporting compared with nonpediatric-focused physicians. Conclusions and Relevance: In this cohort study, less than 10% of physicians ever received a coworker report with a concern about unprofessional behavior. Monitoring reports of unprofessional behaviors provides important opportunities for health care organizations to identify and intervene as needed to support team members.

A real-time prognostic model for venous thromboembolic events among hospitalized adults.

Background: Hospital-acquired venous thromboembolism (HA-VTE) is a leading cause of morbidity and mortality among hospitalized adults. Guidelines recommend use of a risk-prediction model to estimate HA-VTE risk for individual patients. Extant models do not perform well for broad patient populations and are not conducive to automation in clinical practice. Objectives: To develop an automated, real-time prognostic model for venous thromboembolism during hospitalization among all adult inpatients using readily available data from the electronic health record. Methods: The derivation cohort included inpatient hospitalizations ("encounters") for patients ≥16 years old at Vanderbilt University Medical Center between 2018 and 2020 (n = 132,330). HA-VTE events were identified using International Classification of Diseases, 10th Revision, codes. The prognostic model was developed using least absolute shrinkage and selection operator regression. Temporal external validation was performed in a validation cohort of encounters between 2021 and 2022 (n = 62,546). Prediction performance was assessed by discrimination accuracy (C statistic) and calibration (integrated calibration index). Results: There were 1187 HA-VTEs in the derivation cohort (9.0 per 1000 encounters) and 864 in the validation cohort (13.8 per 1000 encounters). The prognostic model included 25 variables, with placement of a central line among the most important predictors. Prediction performance of the model was excellent (C statistic, 0.891; 95% CI, 0.882-0.900; integrated calibration index, 0.001). The model performed similarly well across subgroups of patients defined by age, sex, race, and type of admission. Conclusion: This fully automated prognostic model uses readily available data from the electronic health record, exhibits superior prediction performance compared with existing models, and generates granular risk stratification in the form of a predicted probability of HA-VTE for each patient.

To Revise or Not Revise? Isolated Margin Positivity in Localized Pancreatic Ductal Adenocarcinoma.

BACKGROUND: The study determined the proportion of patients with pancreatic adenocarcinoma (PDAC) who had margin-positive disease and no other adverse pathologic findings (APF) using institutional and administrative datasets. METHODS: Patients with clinical stage I or II PDAC in the National Cancer Database (NCDB 2010-2020) and those who underwent pancreatectomy at the authors' institution (2010-2021) were identified. Isolated margin positivity (IMP) was defined as a positive surgical margin with no APF (negative nodes, no lymphovascular/perineural invasion). RESULTS: The study included 225 patients from the authors' institution and 23,598 patients from the NCDB. The margin-positive rates were 21.8% and 20.3%, and the IMP rates were 0.4% and 0.5%, respectively. In the institutional cohort, 68.4% of the patients had recurrence, and most of the patients (65.6%) had distant recurrences. The median recurrence-free survival (RFS) was 63.3 months for no APF, not reached for IMP, 14.8 months for negative margins & 1 APF, 20.3 months for positive margins & 2 APFs, and 12.9 months with all APF positive. The patients in the NCDB with IMP had a lower median OS than the patients with no APF (20.5 vs 390 months), but a higher median OS than those with margin positivity plus 1 APF (20.5 vs 18.0 months) or all those with APF positivity (20.5 vs 15.4 months). Based on institutional rates of IMP, any margin positivity, neck margin positivity (NMP), and no APF, the fraction of patients who might benefit from neck margin revision was 1 in 100,000, and those likely to benefit from any margin revision was 1 in 18,500. In the NCDB, those estimated to derive potential benefit from margin revision was 1 in 25,000. CONCLUSIONS: Isolated margin positivity in resected PDAC is rare, and most patients experience distant recurrence. Revision of IMP appears unlikely to confer benefit to most patients.

Water- and heat-activated dynamic passivation for perovskite photovoltaics.

Further improvements in perovskite solar cells (PSCs) require better control of ionic defects in the perovskite photoactive layer during the manufacturing stage and their usage1-5. Here, we report a living passivation strategy using a hindered urea/thiocarbamate bond6-8 Lewis acid-base material (HUBLA), where dynamic covalent bonds with water and heat-activated characteristics can dynamically heal the perovskite to ensure device performance and stability. Upon exposure to moisture or heat, HUBLA generates new agents and further passivates defects in the perovskite. This passivation strategy achieved high-performance devices with a power conversion efficiency (PCE) of 25.1%. HUBLA devices retained 94% of their initial PCE for approximately 1500 hours of aging at 85 °C in N2 and maintained 88% of their initial PCE after 1000 hours of aging at 85 °C and 30% relative humidity (RH) in air.

The impact of clinical genome sequencing in a global population with suspected rare genetic disease.

There is mounting evidence of the value of clinical genome sequencing (cGS) in individuals with suspected rare genetic disease (RGD), but cGS performance and impact on clinical care in a diverse population drawn from both high-income countries (HICs) and low- and middle-income countries (LMICs) has not been investigated. The iHope program, a philanthropic cGS initiative, established a network of 24 clinical sites in eight countries through which it provided cGS to individuals with signs or symptoms of an RGD and constrained access to molecular testing. A total of 1,004 individuals (median age, 6.5 years; 53.5% male) with diverse ancestral backgrounds (51.8% non-majority European) were assessed from June 2016 to September 2021. The diagnostic yield of cGS was 41.4% (416/1,004), with individuals from LMIC sites 1.7 times more likely to receive a positive test result compared to HIC sites (LMIC 56.5% [195/345] vs. HIC 33.5% [221/659], OR 2.6, 95% CI 1.9-3.4, p < 0.0001). A change in diagnostic evaluation occurred in 76.9% (514/668) of individuals. Change of management, inclusive of specialty referrals, imaging and testing, therapeutic interventions, and palliative care, was reported in 41.4% (285/694) of individuals, which increased to 69.2% (480/694) when genetic counseling and avoidance of additional testing were also included. Individuals from LMIC sites were as likely as their HIC counterparts to experience a change in diagnostic evaluation (OR 6.1, 95% CI 1.1-∞, p = 0.05) and change of management (OR 0.9, 95% CI 0.5-1.3, p = 0.49). Increased access to genomic testing may support diagnostic equity and the reduction of global health care disparities.

The detection of a strong episignature for Chung-Jansen syndrome, partially overlapping with Börjeson-Forssman-Lehmann and White-Kernohan syndromes.

Chung-Jansen syndrome is a neurodevelopmental disorder characterized by intellectual disability, behavioral problems, obesity and dysmorphic features. It is caused by pathogenic variants in the PHIP gene that encodes for the Pleckstrin homology domain-interacting protein, which is part of an epigenetic modifier protein complex. Therefore, we hypothesized that PHIP haploinsufficiency may impact genome-wide DNA methylation (DNAm). We assessed the DNAm profiles of affected individuals with pathogenic and likely pathogenic PHIP variants with Infinium Methylation EPIC arrays and report a specific and sensitive DNAm episignature biomarker for Chung-Jansen syndrome. In addition, we observed similarities between the methylation profile of Chung-Jansen syndrome and that of functionally related and clinically partially overlapping genetic disorders, White-Kernohan syndrome (caused by variants in DDB1 gene) and Börjeson-Forssman-Lehmann syndrome (caused by variants in PHF6 gene). Based on these observations we also proceeded to develop a common episignature biomarker for these disorders. These newly defined episignatures can be used as part of a multiclass episignature classifier for screening of affected individuals with rare disorders and interpretation of genetic variants of unknown clinical significance, and provide further insights into the common molecular pathophysiology of the clinically-related Chung-Jansen, Börjeson-Forssman-Lehmann and White-Kernohan syndromes.

Single nuclei RNA-seq reveals a medium spiny neuron glutamate excitotoxicity signature prior to the onset of neuronal death in an ovine Huntington's disease model.

Huntington's disease (HD) is a neurodegenerative genetic disorder caused by an expansion in the CAG repeat tract of the huntingtin (HTT) gene resulting in behavioural, cognitive, and motor defects. Current knowledge of disease pathogenesis remains incomplete, and no disease course-modifying interventions are in clinical use. We have previously reported the development and characterisation of the OVT73 transgenic sheep model of HD. The 73 polyglutamine repeat is somatically stable and therefore likely captures a prodromal phase of the disease with an absence of motor symptomatology even at 5-years of age and no detectable striatal cell loss. To better understand the disease-initiating events we have undertaken a single nuclei transcriptome study of the striatum of an extensively studied cohort of 5-year-old OVT73 HD sheep and age matched wild-type controls. We have identified transcriptional upregulation of genes encoding N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors in medium spiny neurons, the cell type preferentially lost early in HD. Further, we observed an upregulation of astrocytic glutamate uptake transporters and medium spiny neuron GABAA receptors, which may maintain glutamate homeostasis. Taken together, these observations support the glutamate excitotoxicity hypothesis as an early neurodegeneration cascade-initiating process but the threshold of toxicity may be regulated by several protective mechanisms. Addressing this biochemical defect early may prevent neuronal loss and avoid the more complex secondary consequences precipitated by cell death.

Implementable Prediction of Pressure Injuries in Hospitalized Adults: Model Development and Validation.

Background: Numerous pressure injury prediction models have been developed using electronic health record data, yet hospital-acquired pressure injuries (HAPIs) are increasing, which demonstrates the critical challenge of implementing these models in routine care. Objective: To help bridge the gap between development and implementation, we sought to create a model that was feasible, broadly applicable, dynamic, actionable, and rigorously validated and then compare its performance to usual care (ie, the Braden scale). Methods: We extracted electronic health record data from 197,991 adult hospital admissions with 51 candidate features. For risk prediction and feature selection, we used logistic regression with a least absolute shrinkage and selection operator (LASSO) approach. To compare the model with usual care, we used the area under the receiver operating curve (AUC), Brier score, slope, intercept, and integrated calibration index. The model was validated using a temporally staggered cohort. Results: A total of 5458 HAPIs were identified between January 2018 and July 2022. We determined 22 features were necessary to achieve a parsimonious and highly accurate model. The top 5 features included tracheostomy, edema, central line, first albumin measure, and age. Our model achieved higher discrimination than the Braden scale (AUC 0.897, 95% CI 0.893-0.901 vs AUC 0.798, 95% CI 0.791-0.803). Conclusions: We developed and validated an accurate prediction model for HAPIs that surpassed the standard-of-care risk assessment and fulfilled necessary elements for implementation. Future work includes a pragmatic randomized trial to assess whether our model improves patient outcomes.

Expression profiling of cochlear genes uncovers sex-based cellular function in mouse cochleae.

Sex is a pivotal biological factor that significantly impacts tissue homeostasis and disease susceptibility. In the auditory system, sex differences have been observed in cochlear physiology and responses to pathological conditions. However, the underlying molecular mechanisms responsible for these differences remain elusive. The current research explores the differences in gene expression profiles in the cochlea between male and female mice, aiming to understand the functional implication of sex-biased gene expression in each sex. Using RNA-sequencing analysis on cochlear tissues obtained from male and female mice, we identified a significant number of genes exhibiting sex-biased expression differences. While some of these differentially expressed genes are located on sex chromosomes, most are found on autosomal chromosomes. Further bioinformatic analysis revealed that these genes are involved in several key cellular functions. In males, these genes are notably linked to oxidative phosphorylation and RNA synthesis and processing, suggesting their involvement in mitochondrial energy production and regulatory control of gene expression. In contrast, sex-biased genes are associated with mechano-transduction and synaptic transmission within female cochleae. Collectively, our study provides valuable insights into the molecular differences between the sexes and emphasizes the need for future research to uncover their functional implications and relevance to auditory health and disease development.

Development and Validation of an Automated, Real-Time Predictive Model for Postpartum Hemorrhage.

OBJECTIVE: To develop and validate a predictive model for postpartum hemorrhage that can be deployed in clinical care using automated, real-time electronic health record (EHR) data and to compare performance of the model with a nationally published risk prediction tool. METHODS: A multivariable logistic regression model was developed from retrospective EHR data from 21,108 patients delivering at a quaternary medical center between January 1, 2018, and April 30, 2022. Deliveries were divided into derivation and validation sets based on an 80/20 split by date of delivery. Postpartum hemorrhage was defined as blood loss of 1,000 mL or more in addition to postpartum transfusion of 1 or more units of packed red blood cells. Model performance was evaluated by the area under the receiver operating characteristic curve (AUC) and was compared with a postpartum hemorrhage risk assessment tool published by the CMQCC (California Maternal Quality Care Collaborative). The model was then programmed into the EHR and again validated with prospectively collected data from 928 patients between November 7, 2023, and January 31, 2024. RESULTS: Postpartum hemorrhage occurred in 235 of 16,862 patients (1.4%) in the derivation cohort. The predictive model included 21 risk factors and demonstrated an AUC of 0.81 (95% CI, 0.79-0.84) and calibration slope of 1.0 (Brier score 0.013). During external temporal validation, the model maintained discrimination (AUC 0.80, 95% CI, 0.72-0.84) and calibration (calibration slope 0.95, Brier score 0.014). This was superior to the CMQCC tool (AUC 0.69 [95% CI, 0.67-0.70], P <.001). The model maintained performance in prospective, automated data collected with the predictive model in real time (AUC 0.82 [95% CI, 0.73-0.91]). CONCLUSION: We created and temporally validated a postpartum hemorrhage prediction model, demonstrated its superior performance over a commonly used risk prediction tool, successfully coded the model into the EHR, and prospectively validated the model using risk factor data collected in real time. Future work should evaluate external generalizability and effects on patient outcomes; to facilitate this work, we have included the model coefficients and examples of EHR integration in the article.

Determinants of thermal homeostasis in the preimplantation embryo: a role for the embryo's central heating system?

A number of factors may impinge on thermal homeostasis in the early embryo. The most obvious is the ambient temperature in which development occurs. Physiologically, the temperature in the lumen of the female tract is typically lower than the core body temperature, yet rises at ovulation in the human, while in an IVF setting, embryos are usually maintained at core body temperature. However, internal cellular developmental processes may modulate thermal control within the embryo itself, especially those occurring in the mitochondria which generate intracellular heat through proton leak and provide the embryo with its own 'central heating system'. Moreover, mitochondrial movements may serve to buffer high local intracellular temperatures. It is also notable that the preimplantation stages of development would generate proportionally little heat within their mitochondria until the blastocyst stage as mitochondrial metabolism is comparatively low during the cleavage stages. Despite these data, the specific notion of thermal control of preimplantation development has received remarkably scant consideration. This opinion paper illustrates the lack of reliable quantitative data on these markers and identifies a major research agenda which needs to be addressed with urgency in view of laboratory conditions in which embryos are maintained as well as climate change-derived heat stress which has a negative effect on numerous clinical markers of early human embryo development.