Discovery of AK-1690: A Potent and Highly Selective STAT6 PROTAC Degrader.

STAT6 is an attractive therapeutic target for human cancers and other human diseases. Starting from a STAT6 ligand with Ki = 3.5 µM binding affinity, we obtained AK-068 with Ki = 6 nM to STAT6 and at least >85-fold binding selectivity over STAT5. Using AK-068 and cereblon ligands, we discovered AK-1690 as the first, potent and selective PROTAC STAT6 degrader. AK-1690 effectively induces degradation of STAT6 protein in cells with DC50 values of as low as 1 nM while showing minimal effect on other STAT members up to 10 µM. A single dose of AK-1690 effectively depletes STAT6 in mouse tissues. Determination of the first cocrystal structure of STAT6 in complex with AK-1690 provides a structural basis for their interactions. AK-1690 is a powerful tool with which to investigate the roles of STAT6 in human diseases and biological processes and a promising lead compound for further optimization.

Myeloid-Specific JAK2 Contributes to Inflammation and Salt Sensitivity of Blood Pressure.

BACKGROUND: Salt sensitivity of blood pressure (SSBP), characterized by acute changes in blood pressure with changes in dietary sodium intake, is an independent risk factor for cardiovascular disease and mortality in people with and without hypertension. We previously found that elevated sodium concentration activates antigen-presenting cells (APCs), resulting in high blood pressure, but the mechanisms are unknown. Here, we hypothesized that APC-specific JAK2 (Janus kinase 2) through STAT3 (signal transducer and activator of transcription 3) and SMAD3 (small mothers against decapentaplegic homolog 3) contributes to SSBP. METHOD: We performed bulk or single-cell transcriptomic analyses following in vitro monocytes exposed to high salt and in vivo high sodium treatment in humans using a rigorous salt-loading/depletion protocol to phenotype SSBP. We also used a myeloid cell-specific CD11c+ JAK2 knockout mouse model and measured blood pressure with radiotelemetry after N-omega-nitro-L-arginine-methyl ester and a high salt diet treatment. We used flow cytometry for immunophenotyping and measuring cytokine levels. Fluorescence in situ hybridization and immunohistochemistry were performed to spatially visualize the kidney's immune cells and cytokine levels. Echocardiography was performed to assess cardiac function. RESULTS: We found that high salt treatment upregulates gene expression of the JAK/STAT/SMAD pathway while downregulating inhibitors of this pathway, such as suppression of cytokine signaling and cytokine-inducible SH2, in human monocytes. Expression of the JAK2 pathway genes mirrored changes in blood pressure after salt loading and depletion in salt-sensitive but not salt-resistant humans. Ablation of JAK2, specifically in CD11c+ APCs, attenuated salt-induced hypertension in mice with SSBP. Mechanistically, we found that SMAD3 acted downstream of JAK2 and STAT3, leading to increased production of highly reactive isolevuglandins and proinflammatory cytokine IL (interleukin)-6 in renal APCs, which activate T cells and increase production of IL-17A, IL-6, and TNF-α (tumor necrosis factor-alpha). CONCLUSIONS: Our findings reveal the APC JAK2 signaling pathway as a potential target for the diagnosis and treatment of SSBP in humans.

Demographics of Adults With Obstructive Sleep Apnea Who Undergo Nasal Surgery.

Objective: To assess the demographic characteristics between adult obstructive sleep apnea (OSA) patients who did and did not undergo nasal surgery (NS). Study Design: Retrospective cohort study. Setting: Kaiser Permanente Northern California clinical database. Methods: Retrospective study of adult patients with ≥1 OSA diagnoses linked to clinical encounters from 2009 to 2016. Qualifying NS procedures performed on or after cohort entry through 2017 were ascertained. Demographic and clinical characteristics were compared; multivariable logistic regression examined associations of these characteristics with undergoing NS. Results: A total of 174,821 patients had an OSA diagnosis. Among these, 3518 (2.0%) underwent NS, including septoplasty (61.9%), sinus-related (12.9%), turbinate (14.2%), and rhinoplasty (11.1%) procedures. Compared to the nonsurgery group, NS patients were more likely to be male (75.5% vs 62.1%), younger (48.2 ± 13.0 vs 54.7 ± 14.1), have lower body mass index (31.8 ± 6.4 vs 34.3 ± 8.1), and no comorbid conditions (63.1% vs 53.5%), P < .001. After adjusting for sex, age, body mass index (BMI), neighborhood deprivation, and comorbidities, black and Asian/Pacific Islander adults with OSA had 42% and 46% decreased odds of undergoing NS compared with non-Hispanic white patients (odds ratio, OR [95% confidence interval, CI]: 0.58 [0.50-0.67] and 0.54 [0.49-0.61]), while Hispanic patients had similar odds (OR [95% CI]: 1.02 [0.93-1.12]). Patients living in neighborhoods of highest deprivation had 18% lower odds of undergoing NS, compared with patients from neighborhoods corresponding to areas of lowest deprivation (adjusted odds ratio [95% CI]: 0.82 [0.75-0.91]). Conclusion: These findings suggest that younger age, male sex, lower BMI, and higher SES may be associated with a higher likelihood of undergoing NS in OSA patients.

Statistically Significant Associations Between HPV33, HPV35, and HPV56 With Anal HSIL in a Population of MSMLWH.

OBJECTIVE: The aim of the study is to determine the prevalence of high-risk human papillomavirus (hrHPV) genotypes in men who have sex with other men and are living with HIV and the factors associated with anal high-grade squamous intraepithelial lesions (HSIL). METHODS: Anal swabs were collected for hrHPV genotyping from a cross-sectional group (N = 163) of eligible men who have sex with other men and are living with HIV attending a high-resolution anoscopy clinic. Persistent hrHPV infections were studied in a longitudinal subset (n = 37). Association of anal HSIL with specific hrHPV genotype(s) and with HIV-1 suppression was assessed. Pearson's χ2 test with continuity correction or Fisher's exact test was used to determine statistical significance (alpha = 0.05). RESULTS: Overall prevalence of hrHPV anal infections was 93.3% (152/163). Higher numbers of hrHPV genotypes were detected per sample in the HSIL group compared with less than or Low-grade squamous intraepithelial lesion (≤LSIL) group (p < .001). Proportion of participants infected with HPV33 was higher in the HSIL group (66.7%) than in ≤LSIL group (33.3%, p < .001), as was HPV35 (61.1% vs. 38.9%, p = .001) and HPV56 (56.7% vs. 43.3%, p = .022). HPV33 persistence was highly associated with HSIL (100%; 8/8) compared with ≤LSIL (0%; 0/8) (p < .001). Proportion of HIV-1 suppression (<200 cp/mL) was significantly lower among the HSIL group (80%; 48/60) compared with ≤LSIL group (95.1%; 97/102) (p = .006). CONCLUSIONS: Statistically significant associations existed between anal HSIL and HPV33, HPV35, and HPV56 infections, with HPV33 persistence, and with the lack of HIV-1 suppression. These findings emphasize the critical need for genotyping assays that differentiate more than just HPV16, HPV18 and a pool of "other" hrHPV genotypes and that have an intended use with anal specimens. Globally, this highest-risk population would benefit from the 9-valent vaccine to prevent infections and reduce anal cancer risk.

Prevalence of low vitamin D levels among older US Asian and Pacific Islander adults.

While US Asian and Pacific Islander adults have lower 25-hydroxyvitamin D (25(OH)D) levels than White adults, ethnic subgroup data remain limited. In a large California population, the adjusted prevalence of 25(OH)D < 20 ng/mL (50 nmol/L) was 1.5- to 2.7-fold higher for Asian/Pacific Islander compared to White adults, with substantial variation by ethnicity. PURPOSE: US Asian and Pacific Islander (PI) adults generally have lower 25-hydroxyvitamin D [25(OH)D] levels than non-Hispanic White (NHW) adults, but subgroup data remain limited. We compared sex- and ethnicity-specific prevalence of low 25(OH)D among older Asian/PI and NHW adults. METHODS: Data from 102,556 Asian/PI and 381,724 NHW adults aged 50-89 years with measured 25(OH)D in 2012-2019 and body mass index (BMI, within ± 1 year) were examined in a California healthcare system. Low 25(OH)D < 20 ng/mL (50 nmol/L) was examined by race and ethnicity. Covariates included age, smoking, BMI, and season of measurement. Modified Poisson regression was used to estimate prevalence ratios (aPR), adjusting for covariates. RESULTS: Among 31,287 Asian/PI men and 71,269 Asian/PI women, the prevalence of low 25(OH)D was 22.6% and 14.7%, respectively, significantly higher than observed for 122,162 NHW men (12.3%) and 259,562 NHW women (9.9%). Within Asian/PI subgroups, low 25(OH)D prevalence ranged from 17 to 18% (Korean, Japanese, Filipino), 22 to 24% (Chinese, Vietnamese), 28% (South Asian), and 35% (Native Hawaiian/PI) among men and 11 to 14% (Japanese, Filipina, Chinese, Korean), 17 to 18% (South Asian, Vietnamese), and 26% (Native Hawaiian/PI) among women. The corresponding aPRs (NHW reference) for men and women were as follows: Native Hawaiian/PI, 2.70 and 2.34; South Asian, 2.56 and 2.07; Vietnamese, 2.17 and 2.31; Chinese, 2.04 and 1.89; Korean, 1.60 and 1.85; Filipino, 1.58 and 1.52; and Japanese, 1.58 and 1.49 (p < 0.001). CONCLUSION: In a large US healthcare population of older Asian/PI adults, low 25(OH)D prevalence was 1.5- to 2.7-fold higher for Asian/PI compared to NHW adults, with substantial variation by sex and ethnicity.

The lucidity in dementia experience: perspectives from family and professional caregivers.

BACKGROUND: Family and professional caregivers of individuals with dementia often witness care-receiver's lucidity events. OBJECTIVE: A qualitative data analysis was performed of documented family and professional caregivers' experiences and their respective appraisals of lucidity events. RESEARCH DESIGN AND METHODS: Using a reduction method of selection, data from 10 in-home family caregivers and 20 professional caregivers to long-term care residents was content-coded and analysed. Framed by a priori research questions, a summative approach to qualitative content analysis guided the interpretation of findings. RESULTS: Eight of 10 family- and 15 of 20 staff caregivers gave an example of what they believed was a witnessed lucid event; 88% of family- and 40% of staff caregivers' provided examples that appeared to fit the conceptual definition of lucidity. The emotional impact that the events had on both sets of caregivers was reported. Family caregivers' characterization of lucidity events reflected appraisals of a puzzling occurrence while staff caregivers depicted elements associated with dementia, and lucidity descriptors. The enhanced verbal communication followed by the brief, unexpected quality of lucidity, were the main elements highlighted by both sets of caregivers in their description of lucidity to others. The variability and complexity of the lucidity phenomenon and the potential challenges it poses for both sets of caregivers were characterized. Commonalities and divergences across responses were highlighted. DISCUSSION: Findings validated previous studies' results. The notions introduced by both types of caregivers were thought-provoking and borne practical, clinical, ethical, and assessment (measurement) applicability.

Exploring Overt Racial and Ethnic Conflict in Resident-to-Resident Aggression in Long-Term Care Facilities.

Objectives: Resident-to-resident aggression (RRA) in long-term care facilities is gaining recognition as a serious problem. Racial/ethnic conflict may be a contributing factor to RRA incidents, but it remains insufficiently studied. Our goal was to explore overt racial/ethnic conflict in RRA. Design: We used quantitative and qualitative secondary analyses of existing data from a large, rigorously conducted study of RRA to describe the involved residents and patterns of overt racial/ethnic conflicts. Setting and Participants: The parent study included information of 2011 residents in 10 randomly selected New York State nursing homes with a wide range of racial/ethnic minority residents (4.2%-63.2%). A subset of 407 residents were involved in RRA. Methods: We re-examined data from the parent study, which used an innovative approach to identify RRA incidents by reconstructing each incident based on residents' self-reports, staff interviews, field observations, and medical chart review. Resident and facility information was collected. Results: A total of 35 residents (8.6% of those involved in RRA incidents) were identified as involved in overt racial/ethnic conflicts. These residents were more likely to have had less education than residents involved in other types of RRA but not in overt racial/ethnic conflicts. More than half (56.9%) of the 51 incidents of RRA involving overt racial/ethnic conflict between a specific pair of residents occurred repeatedly. Manifestation of racial/ethnic conflicts included physical violence, discrimination, racial/ethnic slurs, stereotypes, and microaggression. Acute precipitants of these incidents included various communal-living challenges and unmet needs at the facility, relational, and individual levels. Psychological and behavioral consequences were also described. Conclusion and Implications: We found a broad range of manifestations, acute precipitants, circumstances surrounding, and consequences of overt racial/ethnic conflicts in RRA. Additional research is needed to improve understanding of this phenomenon and how staff may effectively intervene and prevent it.

Comprehensive Analyses of the Effects of the Small-Molecule Inhibitor of the UHM Domain in the Splicing Factor U2AF1 in Leukemia Cells.

Mutations in RNA splicing factor genes including SF3B1, U2AF1, SRSF2, and ZRSR2 have been reported to contribute to development of myeloid neoplasms including myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (sAML). Chemical tools targeting cells carrying these mutant genes remain limited and underdeveloped. Among the four proteins, mutant U2AF1 (U2AF1mut) acquires an altered 3' splice site selection preference and co-operates with the wild-type U2AF1 (U2AF1wt) to change various gene isoform patterns to support MDS cells survival and proliferation. U2AF1 mutations in MDS cells are always heterozygous and the cell viability is reduced when exposed to additional insult affecting U2AF1wt function. To investigate if the pharmacological inhibition of U2AF1wt function can provoke drug-induced vulnerability of cells harboring U2AF1 mut , we conducted a fragment-based library screening campaign to discover compounds targeting the U2AF homology domain (UHM) in U2AF1 that is required for the formation of the U2AF1/U2AF2 complex to define the 3' splice site. The most promising hit (SF1-8) selectively inhibited growth of leukemia cell lines overexpressingU2AF1 mut and human primary MDS cells carrying U2AF1 mut . RNA-seq analysis of K562-U2AF1mut following treatment with SF1-8 further revealed alteration of isoform patterns for a set of proteins that impair or rescue pathways associated with endocytosis, intracellular vesicle transport, and secretion. Our data suggested that further optimization of SF1-8 is warranted to obtain chemical probes that can be used to evaluate the therapeutic concept of inducing lethality to U2AF1 mut cells by inhibiting the U2AF1wt protein.

Human SIRT5 variants with reduced stability and activity do not cause neuropathology in mice.

SIRT5 is a sirtuin deacylase that removes negatively charged lysine modifications, in the mitochondrial matrix and elsewhere in the cell. In benign cells and mouse models, under basal conditions, the phenotypes of SIRT5 deficiency are quite subtle. Here, we identify two homozygous SIRT5 variants in patients suspected to have mitochondrial disease. Both variants, P114T and L128V, are associated with reduced SIRT5 protein stability and impaired biochemical activity, with no evidence of neomorphic or dominant negative properties. The crystal structure of the P114T enzyme was solved and shows only subtle deviations from wild-type. Via CRISPR-Cas9, we generated a mouse model that recapitulates the human P114T mutation; homozygotes show reduced SIRT5 levels and activity, but no obvious metabolic abnormalities, neuropathology, or other gross phenotypes. We conclude that these human SIRT5 variants most likely represent severe hypomorphs, but are likely not by themselves the primary pathogenic cause of the neuropathology observed in the patients.

Myeloid Cell Glucocorticoid, Not Mineralocorticoid Receptor Signaling, Contributes to Salt-Sensitive Hypertension in Humans via Cortisol.

BACKGROUND: Salt sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular morbidity and mortality, yet the etiology is poorly understood. We previously found that serum/glucocorticoid-regulated kinase 1 (SGK1) and epoxyeicosatrienoic acids (EETs) regulate epithelial sodium channel (ENaC)-dependent sodium entry into monocyte-derived antigen-presenting cells (APCs) and activation of NADPH oxidase, leading to the formation of isolevuglandins (IsoLGs) in SSBP. Whereas aldosterone via the mineralocorticoid receptor (MR) activates SGK1 leading to hypertension, our past findings indicate that levels of plasma aldosterone do not correlate with SSBP, and there is little to no MR expression in APCs. Thus, we hypothesized that cortisol acting via the glucocorticoid receptor (GR), not the MR in APCs mediates SGK1 actions to induce SSBP. METHODS: We performed cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq) analysis on peripheral blood mononuclear cells of humans rigorously phenotyped for SSBP using an inpatient salt loading/depletion protocol to determine expression of MR, GR, and SGK1 in immune cells. In additional experiments, we performed bulk transcriptomic analysis on isolated human monocytes following in vitro treatment with high salt from a separate cohort. We then measured urine and plasma cortisol, cortisone, renin, and aldosterone. Subsequently, we measured the association of these hormones with changes in systolic, diastolic, mean arterial pressure and pulse pressure as well as immune cell activation via IsoLG formation. RESULTS: We found that myeloid APCs predominantly express the GR and SGK1 with no expression of the MR. Expression of the GR in APCs increased after salt loading and decreased with salt depletion in salt-sensitive but not salt-resistant people and was associated with increased expression of SGK1. Moreover, we found that plasma and urine cortisol/cortisone but not aldosterone/renin correlated with SSBP and APCs activation via IsoLGs. We also found that cortisol negatively correlates with EETs. CONCLUSION: Our findings suggest that renal cortisol signaling via the GR but not the MR in APCs contributes to SSBP via cortisol. Urine and plasma cortisol may provide an important currently unavailable feasible diagnostic tool for SSBP. Moreover, cortisol-GR-SGK1-ENaC signaling pathway may provide treatment options for SSBP.

Home Blood Pressure Telemonitoring and Nurse Case Management in Black and Hispanic Patients With Stroke: A Randomized Clinical Trial.

Importance: Black and Hispanic patients have high rates of recurrent stroke and uncontrolled hypertension in the US. The effectiveness of home blood pressure telemonitoring (HBPTM) and telephonic nurse case management (NCM) among low-income Black and Hispanic patients with stroke is unknown. Objective: To determine whether NCM plus HBPTM results in greater systolic blood pressure (SBP) reduction at 12 months and lower rate of stroke recurrence at 24 months than HBPTM alone among Black and Hispanic stroke survivors with uncontrolled hypertension. Design, Setting, and Participants: Practice-based, multicenter, randomized clinical trial in 8 stroke centers and ambulatory practices in New York City. Black and Hispanic study participants were enrolled between April 18, 2014, and December 19, 2017, with a final follow-up visit on December 31, 2019. Interventions: Participants were randomly assigned to receive either HBPTM alone (12 home BP measurements/week for 12 months, with results transmitted to a clinician; n = 226) or NCM plus HBPTM (20 counseling calls over 12 months; n = 224). Main Outcomes and Measures: Primary outcomes were change in SBP at 12 months and rate of recurrent stroke at 24 months. Final statistical analyses were completed March 14, 2024. Results: Among 450 participants who were enrolled and randomized (mean [SD] age, 61.7 [11.0] years; 51% were Black [n = 231]; 44% were women [n = 200]; 31% had ≥3 comorbid conditions [n = 137]; 72% had household income <$25 000/y [n = 234/324]), 358 (80%) completed the trial. Those in the NCM plus HBPTM group had a significantly greater SBP reduction than those in the HBPTM alone group at 12 months (-15.1 mm Hg [95% CI, -17.2 to -13.0] vs -5.8 mm Hg [95% CI, -7.9 to -3.7], respectively; P < .001). The between-group difference in SBP reduction at 12 months, adjusted for primary care physician clustering, was -8.1 mm Hg (95% CI, -11.2 to -5.0; P < .001) at 12 months. The rate of recurrent stroke was similar between both groups at 24 months (4.0% in the NCM plus HBPTM group vs 4.0% in the HBPTM alone group, P > .99). Conclusions and Relevance: Among predominantly low-income Black and Hispanic stroke survivors with uncontrolled hypertension, addition of NCM to HBPTM led to greater SBP reduction than HBPTM alone. Additional studies are needed to understand the long-term clinical outcomes, cost-effectiveness, and generalizability of NCM-enhanced telehealth programs among low-income Black and Hispanic stroke survivors with significant comorbidity. Trial Registration: Clinical Trials.gov Identifier: NCT02011685.

Estimated Prevalence of Resident-to-Resident Aggression in Assisted Living.

Importance: Resident-to-resident aggression in assisted living facilities can result in physical and psychological harm, but its prevalence is unknown. Objective: To estimate the prevalence of resident-to-resident aggression, including physical, verbal, and sexual, among residents in assisted living facilities. Design, Setting, and Participants: This study used cross-sectional, observational data from a clinical trial, in which residents of assisted living facilities were monitored for events over a 1-month period. All residents of 14 large facilities randomly selected from 2 geographic locations (N = 1067), except those receiving hospice care (n = 11), were invited to participate; 93 died or moved prior to enrollment. There were 33 family and resident refusals; 930 residents were enrolled. Data were collected between May 30, 2018, and August 11, 2022. Main Outcomes and Measures: The data are from a clinical trial testing the effectiveness of an intervention to reduce resident-to-resident aggression. In addition, the study was designed to assess prevalence using the Time 1 (baseline) data, using a probability sample of facilities to allow for this analysis. Resident-to-resident aggression was identified using a mixed-method, case-finding strategy involving 6 sources: (1) cognitively capable resident reports regarding 22 possible events, (2) direct care staff report, (3) staff member reports collected from event-reporting forms, (4) research assistant observation of events in real time, (5) facility accident or incident reports, and (6) resident records. Results: The prevalence of resident-to-resident aggression among the 930 participants (mean [SD] age, 88.0 [7.2] years; 738 women [79.4%]) during the past month was estimated to be 15.2% (141 of 930 residents; 95% CI, 12.1%-18.8%). The most common forms of aggression included verbal (11.2% [104 of 930 residents; 95% CI, 8.8%-14.2%]), physical (41 of 930 residents; 4.4% [95% CI, 3.1%-6.3%]), sexual (0.8% [7 of 930 residents; 95% CI, 0.4%-1.6%]), and other (70 of 930 residents; 7.5% [95% CI, 5.5%-10.2%]). These categories are not mutually exclusive as residents could be involved with more than 1 type of aggressive behavior. Conclusions and Relevance: In this cross-sectional, observational prevalence study, resident-to-resident aggression in assisted living facilities was highly prevalent. Verbal aggression was the most common form, and physical aggression also occurred frequently. The effects of resident-to-resident aggression can be both morbid and mortal; therefore, intervention research is needed to prevent it and to treat it when it occurs.

Measurement of Allostatic Load in Caregivers of Older Hispanic People With Alzheimer Disease and Related Disorders.

BACKGROUND: Allostatic load (AL) has been studied in the context of biomarkers that may be affected by environmental and contextual stressors, including social determinants of health. The specific stressor studied here is the provision of caregiving to older persons with Alzheimer disease and related disorders. The aims were to examine the factor structure of stress and nonstress biomarkers, different methods for calculating AL, and the relationship of AL with other variables. METHODS: Latent variable models were used to examine biomarkers. Regression analyses were performed with the outcomes: AL calculated as percentile-based and clinically-based for both stress and nonstress components. The sample was 187 Hispanic caregivers to individuals with dementia. RESULTS: The results of the confirmatory factor analyses (CFAs) suggested defining 2 factors: nonstress and stress-related. Performance was better for the CFA results and the associations with covariates when stress and nonstress components were examined separately. Despite some limitations, this is one of the first studies of biomarkers in Hispanic caregivers to patients with dementia. It was possible to explain almost 30% of the variance in the nonstress AL component. CONCLUSION: It may be important to differentiate among biomarkers indicative of cardiovascular, metabolic, and immune response as contrasted with the more stress-related biomarkers.

Evaluation of microbial occurrence in reusable robotic instruments for minimally invasive surgery: A pilot study.

In recent decades, minimally invasive surgery has become the favoured surgical technique, with increasing utilisation of robotic surgery to enhance patient outcomes. However, the design complexity of surgical robotic instruments can pose challenges in maintaining adequate cleaning, disinfection and sterilisation-particularly of the device's interior. In our hospital, robotic instruments are reused for a maximum of ten successive patients, following the manufacturer's guidelines. To the best of our knowledge, neither the manufacturer nor ISO standards have specified any methods to determine the sterility of robotic instruments after cleaning, disinfection and sterilisation procedures. In a small pilot study, we used a locally developed protocol to evaluate the sterility of 20 da Vinci SI robotic instruments, with the aim of determining whether the recommended cleaning, disinfection and sterilisation process is adequate to achieve safe usage in subsequent patients. None of the 20 instruments showed viable micro-organisms, therefore the robotic instruments were considered sterile, and suitable for re-use. We recommend our protocol to other hospitals, to be used as an essential control element in the assessment of their unique reprocessing technique for robotic instruments.

FIGO Preconception Checklist: Preconception care for mother and baby.

The preconception period is a unique and opportunistic time in a woman's life when she is motivated to adopt healthy behaviors that will benefit her and her child, making this time period a critical "window of opportunity" to improve short- and long-term health. Improving preconception health can ultimately improve both fetal and maternal outcomes. Promoting health before conception has several beneficial effects, including an increase in seeking antenatal care and a reduction in neonatal mortality. Preconception health is a broad concept that encompasses the management of chronic diseases, including optimal nutrition, adequate consumption of folic acid, control of body weight, adoption of healthy lifestyles, and receipt of appropriate vaccinations. Use of the FIGO Preconception Checklist, which includes the key elements of optimal preconception care, will empower women and their healthcare providers to better prepare women and their families for pregnancy.

Alanine aminotransferase elevation varies by ethnicity among Asian and Pacific Islander children with overweight or obesity.

BACKGROUND: Limited research on alanine aminotransferase (ALT) screening for metabolic dysfunction-associated steatotic liver disease (MASLD) among US Asian/Pacific Islander (PI) children necessitates investigation in this heterogeneous population. OBJECTIVE: Examine ALT elevation among Asian/PI children with overweight or obesity. METHODS: Elevated ALT prevalence (clinical threshold) and association with body mass index ≥85th percentile were compared among 18 402 Asian/PI and 25 376 non-Hispanic White (NHW) children aged 9-17 years using logistic regression. RESULTS: ALT elevation was more prevalent among Asian/PI (vs. NHW) males with overweight (4.0% vs. 2.7%), moderate (7.8% vs. 5.3%) and severe obesity (16.6% vs. 11.5%), and females with moderate (5.1% vs. 3.0%) and severe obesity (10.2% vs. 5.2%). Adjusted odds of elevated ALT were 1.6-fold and ~2-fold higher for Asian/PI (vs. NHW) males and females (with obesity), respectively. Filipino, Chinese and Southeast Asian males had 1.7-2.1-fold higher odds, but Native Hawaiian/PI (NHPI) and South Asian males did not significantly differ (vs. NHW). Filipina and Chinese females with obesity had >2-fold higher odds, Southeast and South Asian females did not differ and NHPI findings were mixed (vs. NHW). CONCLUSION: High elevated ALT prevalence among Asian/PI children with overweight and obesity emphasizes the need for MASLD risk assessment and examination of ethnic subgroups.

Remote submerged banks and mesophotic ecosystems can provide key habitat for endangered marine megafauna.

The importance of some ecosystems remains poorly understood. We showed that mesophotic ecosystems (30 to 150 m) are a key habitat for a critically endangered species, with strong evidence that a globally important population of adult hawksbill turtles (Eretmochelys imbricata) almost exclusively foraged at these depths on remote submerged banks. This discovery highlights the need for such areas to be included in conservation planning, for example, as part of the United Nations High Seas Treaty. We equipped nesting turtles with Fastloc-GPS (Global Positioning System) satellite tags at an Indian Ocean breeding area and they all traveled to deep foraging sites (6765 days of tracking data across 22 individuals including 183,921 dive-depth measurements) rather than shallow coral reef sites. Both chart depths and depth data relayed from the tags indicated that turtles foraged at mesophotic depths, the modal dive depths being between 35 and 40 m. We calculate that 55,554 km2 of the western Indian Ocean alone consists of submerged banks between 30 and 60 m.

Hypertension Related Co-Morbidities and Complications in Women of Sub-Saharan Africa: A Brief Review.

Hypertension is the leading cause of cardiovascular disease in women, and sub-Saharan African (SSA) countries have some of the highest rates of hypertension in the world. Expanding knowledge of causes, management, and awareness of hypertension and its co-morbidities worldwide is an effective strategy to mitigate its harms, decrease morbidities and mortality, and improve individual quality of life. Hypertensive disorders of pregnancy (HDPs) are a particularly important subset of hypertension, as pregnancy is a major stress test of the cardiovascular system and can be the first instance in which cardiovascular disease is clinically apparent. In SSA, women experience a higher incidence of HDP compared with other African regions. However, the region has yet to adopt treatment and preventative strategies for HDP. This delay stems from insufficient awareness, lack of clinical screening for hypertension, and lack of prevention programs. In this brief literature review, we will address the long-term consequences of hypertension and HDP in women. We evaluate the effects of uncontrolled hypertension in SSA by including research on heart disease, stroke, kidney disease, peripheral arterial disease, and HDP. Limitations exist in the number of studies from SSA; therefore, we will use data from countries across the globe, comparing and contrasting approaches in similar and dissimilar populations. Our review highlights an urgent need to prioritize public health, clinical, and bench research to discover cost-effective preventative and treatment strategies that will improve the lives of women living with hypertension in SSA.

Recent Advances in Understanding Peripheral and Gut Immune Cell-Mediated Salt-Sensitive Hypertension and Nephropathy.

Hypertension is the primary modifiable risk factor for cardiovascular, renal, and cerebrovascular diseases and is considered the main contributing factor to morbidity and mortality worldwide. Approximately 50% of hypertensive and 25% of normotensive people exhibit salt sensitivity of blood pressure, which is an independent risk factor for cardiovascular disease. Human and animal studies demonstrate that the immune system plays an important role in the etiology and pathogenesis of salt sensitivity of blood pressure, kidney damage, and vascular diseases. Antigen-presenting and adaptive immune cells are implicated in salt-sensitive hypertension and salt-induced renal and vascular injury. Elevated sodium activates antigen-presenting cells to release proinflammatory cytokines including IL (interleukin) 6, tumor necrosis factor-α, IL-1ß, and accumulate isolevuglandin-protein adducts. In turn, these activate T cells release prohypertensive cytokines including IL-17A. Moreover, high-salt intake is associated with gut dysbiosis, leading to inflammation, oxidative stress, and blood pressure elevation but the mechanistic contribution to salt-sensitivity of blood pressure is not clearly understood. Here, we discuss recent advances in research investigating the cause, potential biomarkers, and therapeutic targets for salt-sensitive hypertension as they pertain to the gut microbiome, immunity, and inflammation.