Does smoking cessation reduce other substance use, psychiatric symptoms, and pain symptoms? Results from an emulated hypothetical randomized trial of US veterans.

BACKGROUND: Quitting smoking may lead to improvement in substance use, psychiatric symptoms, and pain, especially among high-risk populations who are more likely to experience comorbid conditions. However, causal inferences regarding smoking cessation and its subsequent benefits have been limited. METHODS: We emulated a hypothetical open-label randomized control trial of smoking cessation using longitudinal observational data of HIV-positive and HIV-negative US veterans from 2003-2015 in the Veterans Aging Cohort Study. We followed individuals from the first time they self-reported current cigarette smoking (baseline). We categorized participants as quitters or non-quitters at the first follow-up visit (approximately 1 year after baseline). Using inverse probability weighting to adjust for confounding and selection bias, we estimated odds ratios for improvement of co-occurring conditions (unhealthy alcohol use, cannabis use, illicit opioid use, cocaine use, depressive symptoms, anxiety symptoms, and pain symptoms) at second follow-up (approximately 2 years after baseline) for those who quit smoking compared to those who did not, among individuals who had the condition at baseline. RESULTS: Of 4,165 eligible individuals (i.e., current smokers at baseline), 419 reported no current smoking and 2,330 reported current smoking at the first follow-up. Adjusted odds ratios (95% confidence intervals) for associations between quitting smoking and improvement of each condition at second follow-up were: 2.10 (1.01, 4.35) for unhealthy alcohol use, 1.75 (1.00, 3.06) for cannabis use, 1.10 (0.58, 2.08) for illicit opioid use, and 2.25 (1.20, 4.24) for cocaine use, 0.78 (0.44, 1.38) for depressive symptoms, 0.93 (0.58, 1.49) for anxiety symptoms, and 1.31 (0.84, 2.06) for pain symptoms. CONCLUSIONS: While a causal interpretation of our findings may not be warranted, we found evidence for decreased substance use among veterans who quit cigarette smoking but none for the resolution of psychiatric conditions or pain symptoms. Findings suggest the need for additional resources combined with smoking cessation to reduce psychiatric and pain symptoms for high-risk populations.

Utility of beta-lactam allergy assessment in patients receiving vancomycin for surgical prophylaxis.

Background: Beta-lactam antibiotics are first-line agents for most patients receiving antimicrobial prophylaxis in surgical procedures. Despite evidence showing low cross-reactivity between penicillins and cephalosporins, patients with beta-lactam allergies commonly receive vancomycin as an alternative to avoid allergic reaction. Methods: Adult patients receiving vancomycin for surgical prophylaxis with a reported beta-lactam allergy at our institution between August 2017 to July 2018 were retrospectively evaluated for potential eligibility for penicillin allergy testing and/or receipt of standard prophylaxis. Results: Among 830 patients who received vancomycin for surgical prophylaxis, 196 reported beta-lactam allergy and were included in the analysis. Approximately 40 % of surgeries were orthopedic. Of patients receiving vancomycin as first-line therapy, 189 (96.4 %) were potentially eligible for beta-lactam prophylaxis. Conclusions: Patients with beta-lactam allergies often qualify for receipt of a first-line antibiotic. An opportunity exists for improved allergy assessment as an antimicrobial stewardship intervention in surgical prophylaxis.

Influence of Antibiotic Exposure Intensity on the Risk of Clostridioides difficile Infection.

BACKGROUND: Antibiotics are a strong risk factor for Clostridioides difficile infection (CDI), and CDI incidence is often measured as an important outcome metric for antimicrobial stewardship interventions aiming to reduce antibiotic use. However, risk of CDI from antibiotics varies by agent and dependent on the intensity (i.e., spectrum and duration) of antibiotic therapy. Thus, the impact of stewardship interventions on CDI incidence is variable, and understanding this risk requires a more granular measure of intensity of therapy than traditionally used measures like days of therapy (DOT). METHODS: We performed a retrospective cohort study to measure the independent association between intensity of antibiotic therapy, as measured by the antibiotic spectrum index (ASI), and hospital-associated CDI (HA-CDI) at a large academic medical center between January 2018 and March 2020. We constructed a marginal Poisson regression model to generate adjusted relative risks for a unit increase in ASI per antibiotic day. RESULTS: We included 35,457 inpatient encounters in our cohort. Sixty-eight percent of patients received at least one antibiotic. We identified 128 HA-CDI cases, which corresponds to an incidence rate of 4.1 cases per 10,000 patient-days. After adjusting for known confounders, each additional unit increase in ASI per antibiotic day is associated with 1.09 times the risk of HA-CDI (Relative Risk = 1.09, 95% Confidence Interval: 1.06 to 1.13). CONCLUSIONS: ASI was strongly associated with HA-CDI and could be a useful tool in evaluating the impact of antibiotic stewardship on HA-CDI rates, providing more granular information than the more commonly used days of therapy.

Mesenchymal stromal cells with chimaeric antigen receptors for enhanced immunosuppression.

Allogeneic mesenchymal stromal cells (MSCs) are a safe treatment option for many disorders of the immune system. However, clinical trials using MSCs have shown inconsistent therapeutic efficacy, mostly owing to MSCs providing insufficient immunosuppression in target tissues. Here we show that antigen-specific immunosuppression can be enhanced by genetically modifying MSCs with chimaeric antigen receptors (CARs), as we show for E-cadherin-targeted CAR-MSCs for the treatment of graft-versus-host disease in mice. CAR-MSCs led to superior T-cell suppression and localization to E-cadherin+ colonic cells, ameliorating the animals' symptoms and survival rates. On antigen-specific stimulation, CAR-MSCs upregulated the expression of immunosuppressive genes and receptors for T-cell inhibition as well as the production of immunosuppressive cytokines while maintaining their stem cell phenotype and safety profile in the animal models. CAR-MSCs may represent a widely applicable therapeutic technology for enhancing immunosuppression.

Historical Redlining and Present-Day Nonsuicide Firearm Fatalities.

BACKGROUND: Redlining began in the 1930s with the Home Owners' Loan Corporation (HOLC); this discriminatory practice limited mortgage availability and reinforced concentrated poverty that still exists today. It is important to understand the potential health implications of this federally sanctioned segregation. OBJECTIVE: To examine the relationship between historical redlining policies and present-day nonsuicide firearm fatalities. DESIGN: Maps from the HOLC were overlaid with incidence of nonsuicide firearm fatalities from 2014 to 2022. A multilevel negative binomial regression model tested the association between modern-day firearm fatalities and HOLC historical grading (A ["best"] to D ["hazardous"]), controlling for year, HOLC area-level demographics, and state-level factors as fixed effects and a random intercept for city. Incidence rates (IRs) per 100 000 persons, incidence rate ratios (IRRs), and adjusted IRRs (aIRRs) for each HOLC grade were estimated using A-rated areas as the reference. SETTING: 202 cities with areas graded by the HOLC in the 1930s. PARTICIPANTS: Population of the 8597 areas assessed by the HOLC. MEASUREMENTS: Nonsuicide firearm fatalities. RESULTS: From 2014 to 2022, a total of 41 428 nonsuicide firearm fatalities occurred in HOLC-graded areas. The firearm fatality rate increased as the HOLC grade progressed from A to D. In A-graded areas, the IR was 3.78 (95% CI, 3.52 to 4.05) per 100 000 persons per year. In B-graded areas, the IR, IRR, and aIRR relative to A areas were 7.43 (CI, 7.24 to 7.62) per 100 000 persons per year, 2.12 (CI, 1.94 to 2.32), and 1.42 (CI, 1.30 to 1.54), respectively. In C-graded areas, these values were 11.24 (CI, 11.08 to 11.40) per 100 000 persons per year, 3.78 (CI, 3.47 to 4.12), and 1.90 (CI, 1.75 to 2.07), respectively. In D-graded areas, these values were 16.26 (CI, 16.01 to 16.52) per 100 000 persons per year, 5.51 (CI, 5.05 to 6.02), and 2.07 (CI, 1.90 to 2.25), respectively. LIMITATION: The Gun Violence Archive relies on media coverage and police reports. CONCLUSION: Discriminatory redlining policies from 80 years ago are associated with nonsuicide firearm fatalities today. PRIMARY FUNDING SOURCE: Fred Lovejoy Housestaff Research and Education Fund.

Experimentally Induced Reductions in Alcohol Consumption and Brain, Cognitive, and Clinical Outcomes in Older Persons With and Those Without HIV Infection (30-Day Challenge Study): Protocol for a Nonrandomized Clinical Trial.

BACKGROUND: Both alcohol consumption and HIV infection are associated with worse brain, cognitive, and clinical outcomes in older adults. However, the extent to which brain and cognitive dysfunction is reversible with reduction or cessation of drinking is unknown. OBJECTIVE: The 30-Day Challenge study was designed to determine whether reduction or cessation of drinking would be associated with improvements in cognition, reduction of systemic and brain inflammation, and improvement in HIV-related outcomes in adults with heavy drinking. METHODS: The study design was a mechanistic experimental trial, in which all participants received an alcohol reduction intervention followed by repeated assessments of behavioral and clinical outcomes. Persons were eligible if they were 45 years of age or older, had weekly alcohol consumption of 21 or more drinks (men) or 14 or more drinks (women), and were not at high risk of alcohol withdrawal. After a baseline assessment, participants received an intervention consisting of contingency management (money for nondrinking days) for at least 30 days followed by a brief motivational interview. After this, participants could either resume drinking or not. Study questionnaires, neurocognitive assessments, neuroimaging, and blood, urine, and stool samples were collected at baseline, 30 days, 90 days, and 1 year after enrollment. RESULTS: We enrolled 57 persons with heavy drinking who initiated the contingency management protocol (mean age 56 years, SD 4.6 years; 63%, n=36 male, 77%, n=44 Black, and 58%, n=33 people with HIV) of whom 50 completed 30-day follow-up and 43 the 90-day follow-up. The planned study procedures were interrupted and modified due to the COVID-19 pandemic of 2020-2021. CONCLUSIONS: This was the first study seeking to assess changes in brain (neuroimaging) and cognition after alcohol intervention in nontreatment-seeking people with HIV together with people without HIV as controls. Study design strengths, limitations, and lessons for future study design considerations are discussed. Planned analyses are in progress, after which deidentified study data will be available for sharing. TRIAL REGISTRATION: ClinicalTrials.gov NCT03353701; https://clinicaltrials.gov/study/NCT03353701. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/53684.

G Protein Activation Occurs via a Largely Universal Mechanism.

Understanding how signaling proteins like G proteins are allosterically activated is a long-standing challenge with significant biological and medical implications. Because it is difficult to directly observe such dynamic processes, much of our understanding is based on inferences from a limited number of static snapshots of relevant protein structures, mutagenesis data, and patterns of sequence conservation. Here, we use computer simulations to directly interrogate allosteric coupling in six G protein α-subunit isoforms covering all four G protein families. To analyze this data, we introduce automated methods for inferring allosteric networks from simulation data and assessing how allostery is conserved or diverged among related protein isoforms. We find that the allosteric networks in these six G protein α subunits are largely conserved and consist of two pathways, which we call pathway-I and pathway-II. This analysis predicts that pathway-I is generally dominant over pathway-II, which we experimentally corroborate by showing that mutations to pathway-I perturb nucleotide exchange more than mutations to pathway-II. In the future, insights into unique elements of each G protein family could inform the design of isoform-specific drugs. More broadly, our tools should also be useful for studying allostery in other proteins and assessing the extent to which this allostery is conserved in related proteins.

Landslide assessment through integrated geoelectrical and seismic methods: A case study in Thungsong site, southern Thailand.

Many landslides can cause significant damage to infrastructure, property, and human life. To study landslide structure and processes, geophysical techniques are most productive when employed in combination with other survey and monitoring tools, such as intrusive sampling. Here, the integration of electrical resistivity tomography (ERT) and seismic refraction tomography (SRT) methods is used to assess landslides in Thungsong district, Nakhon Si Thammarat, the south of Thailand, where is a hilly and seasons of prolonged rainfall region. The 2D cross-plot analysis of P-wave velocity and resistivity values obtained by these two methods is introduced to identify potential landslide-prone zones in this region. The results of the 2D cross-plot model reveal detailed image of the subsurface conditions, highlighting areas of low P-wave velocity (lower than 600 m/s) and low resistivity (lower than 600 Ωm). These areas are indicative of weak zone and are potential to be sliding materials. Moreover, an intrusive sampling data from boreholes is also used for the calibration and validation geophysical data with geological data. This can improve the accuracy of landslide assessment and develop effective mitigation strategies to reduce the risk of landslides in this area. In addition of the 2D cross-plot, the volume of sliding material is also determined from the difference of the surface and slipping plane elevations. The volume calculation of sliding material is roughly 33447.76 m3. This approach provides a preliminary tool for landslide studies and monitoring landslides in this region, thus enabling an improved understanding of slope failure processes in this context, and the basis of a landslide mitigation strategy in the future.

Characterization of per- and polyfluoroalkyl substances (PFAS) concentrations in a community-based sample of infants from Samoa.

Per- and polyfluoroalkyl substances (PFAS) are persistent contaminants with documented harmful health effects. Despite increasing research, little attention has been given to studying PFAS contamination in low- and middle-income countries, including Samoa. Using data and biosamples collected through the Foafoaga o le Ola ("Beginning of Life") Study, which recruited a sample of mothers and infants from Samoa, we conducted an exploratory study to describe concentrations of 40 PFAS analytes in infant cord blood collected at birth (n = 66) and infant dried blood spots (DBS) collected at 4 months post-birth (n = 50). Of the 40 PFAS analytes tested, 19 were detected in cord blood, with 10 detected in >50% of samples (PFBA, PFPeA, PFOA, PFNA, PFDA, PFUnA, PFTrDA, PFHxS, PFOS, and 9Cl-PF3ONS); and 12 analytes were detected in DBS, with 3 detected in >50% of samples (PFBA, PFHxS, and PFOS). PFAS concentrations were generally lower than those reported in existing literature, with the exception of PFHxS, which was detected at higher concentrations. In cord blood, we noted suggestive (p < 0.05) or significant (p < 0.006) associations between higher PFHxS and male sex; higher PFPeA and residence in Northwest 'Upolu (NWU) compared to the Apia Urban Area (AUA); lower PFUnA and 9Cl-PF3ONS and greater socioeconomic resources; lower PFOA and higher parity; higher PFDA and higher maternal age; and lower PFUnA, PFTrDA, and 9Cl-PF3ONS and higher maternal BMI. In DBS, we found suggestive (p < 0.05) or significant (p < 0.025) associations between lower PFBA and residence in NWU versus AUA; lower PFBA and PFHxS and higher maternal age; and higher PFBA and higher maternal BMI. Finally, we observed associations between nutrition source at 4 months and DBS PFBA and PFHxS, with formula- or mixed-fed infants having higher concentrations compared to exclusively breastfed infants. This study represents the first characterization of PFAS contamination in Samoa. Additional work in larger samples is needed to identify potentially modifiable determinants of PFAS concentrations, information that is critical for informing environmental and health policy measures.

Clinical and longitudinal patterns of frequent presenters to emergency departments: A multi-centre data linkage analysis.

OBJECTIVE: To describe clinical characteristics and longitudinal patterns of representation in a cohort of patients who frequently present to EDs for care. METHODS: A retrospective data analysis linking routinely collected ED data across three hospitals. The study population consisted of patients who presented to any ED on 10 or more occasions in any continuous 365-day period from 1 July 2015 to 30 June 2021. Presenting complaints were divided into those with any mental health, drug and alcohol, or social presentations (MHDAS group) and those without (non-MHDAS group). Outcomes of interest were number of presentations as well as temporal and facility clustering of presentations. A per patient regression analysis was performed to identify independent risk factors for increased presentations. RESULTS: Presentations by 1640 frequent ED presenters in the study constituted 4.6% of total ED presentations. MHDAS study group were younger, predominantly English speaking, twice as likely to be married, had lower hospital admission rates and almost three times as many of them did not wait for treatment. Statistically significant differences were also found between these groups regarding presentation clustering, facility entropy, each of the four categories of the number of ED presentations, and Index of Relative Socio-Economic Advantage and Disadvantage. CONCLUSION: Representations associated with MHDAS have a different trajectory of representation episodes compared to non-MHDAS group. Escalating number of presentations and clustering are important predictors of future representation numbers. Those 'did not waits' who appear to be representing would be the highest risk of ongoing and persistent representations in the future and should be the target of early interventions to ensure they are accessing appropriate care before this happens.

Safety and Efficacy Report for the Use of Poly-4-Hydroxybutyrate as a Retropubic Mid-Urethral Sling (MUS) for Stress Urinary Incontinence: A Prospective 24 Months Follow-Up of New Poly-4-Hydroxybutyrate TephaFlex SUI Bioresorbable MUS.

STUDY OBJECTIVE: To investigate the feasibility and safety of the retropubic mid-urethral sling (MUS) procedure with a resorbable mesh implant made of poly-4-hydroxybutyrate (P4HB). DESIGN: A prospective clinical cohort study with 24 months follow-up. SETTING: A tertiary academic hospital. PATIENTS: Seventeen women with moderate to severe stress urinary incontinence (SUI). INTERVENTIONS: A retropubic MUS procedure with P4HB sling. MEASUREMENTS AND MAIN RESULTS: Seventeen women underwent an uncomplicated MUS procedure with a new sling made of resorbable P4HB. Following safety criteria, there has been no need to stop the study before 24 months' end point. Three serious adverse events were reported during follow-up: (1) inability to void urine after 1 week postsurgery, (2) a hysterectomy and bilateral oophorectomy performed due to a precancerous endometrial lesion at 16 months after initial MUS procedure and (3) exposed mesh with a part of device sheath left behind. These participants underwent an uncomplicated reintervention with no additional and/or permanent harm. Reinterventions because of failure of cure contained 3 second MUS procedures and one admission of urethral bulking agent. Seventy-six percent and 47 percent of patients were objectively cured of SUI at 12 and 24 months, respectively. CONCLUSIONS: Preliminary evidence suggests that a sling made of P4HB can be safely used for MUS procedures and could be an alternative for permanent polypropylene slings in patients that prefer the use of nonpermanent material.

Abortion Restrictiveness and Infant Mortality: An Ecologic Study, 2014-2018.

INTRODUCTION: The U.S. has the highest infant mortality rate among peer countries. Restrictive abortion laws may contribute to poor infant health outcomes. This ecological study investigated the association between county-level infant mortality and state-level abortion access legislation in the U.S. from 2014 to 2018. METHODS: A multivariable regression analysis with the outcome of county-level infant mortality rates, controlling for the primary exposure of state-level abortion laws, and county-level factors, county-level distance to an abortion facility, and state Medicaid expansion status was performed. Incidence rate ratios and 95% CIs were reported. Analyses were conducted in 2022-2023. RESULTS: There were 113,397 infant deaths among 19,559,660 live births (infant mortality rate=5.79 deaths/1,000 live births; 95% CI=5.75, 5.82). Black infant mortality rate (10.69/1,000) was more than twice the White infant mortality rate (4.87/1,000). In the multivariable model, increased infant mortality rates were seen in states with ≥8 restrictive laws, with the most restrictive (11-12 laws) having a 16% increased infant mortality level (adjusted incidence rate ratios=1.162; 95% CI=1.103, 1.224). Increased infant mortality rates were associated with increased county-level Black race individuals (adjusted incidence rate ratios=1.031; 95% CI=1.026, 1.037), high school education (adjusted incidence rate ratios=1.018; 95% CI=1.008, 1.029), maternal smoking (adjusted incidence rate ratios=1.025; 95% CI=1.018, 1.033), and inadequate prenatal care (adjusted incidence rate ratios=1.045; 95% CI=1.036, 1.055). CONCLUSIONS: State-level abortion law restrictiveness is associated with higher county-level infant mortality rates. The Supreme Court decision on Dobbs versus Jackson and changes in state laws limiting abortion may affect future infant mortality.

Alcohol Consumption and Illicit Drug Use: Associations With Fall, Fracture, and Acute Health Care Utilization Among People With HIV Infection.

BACKGROUND: Given alcohol and/or other drug (AOD) use occurs among people with HIV (PWH), we examined its association with falls and fall-related outcomes and whether frailty moderates the association. SETTING: Northeastern US city. METHODS: We analyzed an observational cohort of PWH with current or past AOD use. Alcohol measures were any past 14-day heavy use, average alcohol/day, and days with heavy use. Drug use measures were past 30-day illicit use of cocaine, opioids, and sedatives. Repeated cross-sectional associations were estimated with separate multivariable generalized estimating equation regression models for each fall-related outcome. RESULTS: Among PWH (n = 251; mean age 52 [SD = 10]), 35% reported heavy alcohol use, 24% cocaine, 16% illicit opioids, 13% illicit sedatives, and 35% any fall; 27% were frail. Heavy alcohol use was associated with a fall (AOR = 1.49, 95% CI: 1.08 to 2.07), multiple falls (AOR = 1.55 95% CI: 1.10 to 2.19), and fall/fracture-related emergency department visit or hospitalization (AOR = 1.81, 95% CI: 1.10 to 2.97). Higher average alcohol/day and more heavy drinking days were associated with multiple falls. Illicit sedative use was associated with a fall, multiple falls, and emergency department visit/hospitalization and opioid use with fracture. Frailty moderated the association of heavy alcohol use and a fall (AOR = 2.26, 95% CI: 1.28 to 4.01 in those frail) but not in those not frail. CONCLUSION: The effect of AOD use on falls and fall-related outcomes was most pronounced with alcohol, particularly among frail PWH. Heavy alcohol, illicit sedative, and illicit opioid use are high-priority targets for preventing falls and fall-related consequences for PWH.

Changes in the Murine Microbiome and Bacterial Extracellular Vesicle Production in Response to Antibiotic Treatment and Norovirus Infection.

Norovirus infection is influenced by the presence of commensal bacteria, and both human and murine norovirus (MNV) bind to these bacteria. These virus-bacterial interactions, as well as MNV infection, promote the increased production of bacterial extracellular vesicles (bEVs). However, no correlation has been made between specific bacterial groups, their vesicles, and their impact on norovirus infection. The current study evaluated the impact of select bacterial compositions of murine microbiomes using antibiotic (ABX) cocktails on MNV infection and bEV production. The goal of this research was to determine if increases in bEVs following MNV infection in mice were associated with changes in specific bacterial populations. Bacterial taxa were found to be differentially abundant in both ABX-treated and untreated mice, with the greatest change in bacterial taxa seen in mice treated with a broad-spectrum ABX cocktail. Specifically, Lachnospiraeae were found to be differentially abundant between a variety of treatment factors, including MNV infection. Overall, these results demonstrate that MNV infection can alter the abundance of bacterial taxa within the microbiota, as well as their production of extracellular vesicles, and that the use of selective antibiotic treatments can allow the detection of viral impacts on the microbiome that might otherwise be masked.

Racial & ethnic disparities in geographic access to critical care in the United States: A geographic information systems analysis.

OBJECTIVE: It is important to identify gaps in access and reduce health outcome disparities, understanding access to intensive care unit (ICU) beds, especially by race and ethnicity, is crucial. Our objective was to evaluate the race and ethnicity-specific 60-minute drive time accessibility of ICU beds in the United States (US). DESIGN: We conducted a cross-sectional study using road network analysis to determine the number of ICU beds within a 60-minute drive time, and calculated adult intensive care bed ratios per 100,000 adults. We evaluated the US population at the Census block group level and stratified our analysis by race and ethnicity and by urbanicity. We classified block groups into four access levels: no access (0 adult intensive care beds/100,000 adults), below average access (>0-19.5), average access (19.6-32.0), and above average access (>32.0). We calculated the proportion of adults in each racial and ethnic group within the four access levels. SETTING: All 50 US states and the District of Columbia. PARTICIPANTS: Adults ≥15 years old. MAIN OUTCOME MEASURES: Adult intensive care beds/100,000 adults and percentage of adults national and state) within four access levels by race and ethnicity. RESULTS: High variability existed in access to ICU beds by state, and substantial disparities by race and ethnicity. 1.8% (n = 5,038,797) of Americans had no access to an ICU bed, and 26.8% (n = 73,095,752) had below average access, within a 60-minute drive time. Racial and ethnic analysis showed high rates of disparities (no access/below average access): American Indians/Alaskan Native 12.6%/28.5%, Asian 0.7%/23.1%, Black or African American 0.6%/16.5%, Hispanic or Latino 1.4%/23.0%, Native Hawaiian and other Pacific Islander 5.2%/35.0%, and White 2.1%/29.0%. A higher percentage of rural block groups had no (5.2%) or below average access (41.2%), compared to urban block groups (0.2% no access, 26.8% below average access). CONCLUSION: ICU bed availability varied substantially by geography, race and ethnicity, and by urbanicity, creating significant disparities in critical care access. The variability in ICU bed access may indicate inequalities in healthcare access overall by limiting resources for the management of critically ill patients.

Characterization of Per- and Polyfluoroalkyl Substance (PFAS) concentrations in a community-based sample of infants from Samoa.

Per- and polyfluoroalkyl substances (PFAS) are persistent contaminants with documented harmful health effects. Despite increasing research, little attention has been given to studying PFAS contamination in low- and middle-income countries, including Samoa, where there is more recent modernization and potential window to examine earlier stages of PFAS exposure and consequences. Using data and biosamples collected through the Foafoaga o le Ola ("Beginning of Life") Study, which recruited a sample of mothers and infants from Samoa, we conducted an exploratory study to describe concentrations of 40 PFAS analytes in infant cord blood collected at birth (n=66) and dried blood spots (DBS) collected at 4 months post-birth (n=50). Of the 40 PFAS analytes tested, 19 were detected in cord blood, with 11 detected in >10% of samples (PFBA, PFPeA, PFHpA, PFOA, PFNA, PFDA, PFUnA, PFTrDA, PFHxS, PFOS, and 9Cl-PF3ONS); 12 analytes were detected in DBS, with 3 detected in >10% of samples (PFBA, PFHxS, and PFOS). PFAS concentrations were generally lower than those reported in existing literature, with the exception of PFHxS, which was detected at higher concentrations. In cord blood, we noted associations between higher PFHxS and male sex, higher PFPeA and residence in Northwest 'Upolu (NWU) compared to the Apia Urban Area (AUA), and lower PFUnA and 9Cl-PF3ONS with greater socioeconomic resources. In DBS, we found associations between higher PFBA and greater socioeconomic resources, and between lower PFBA and PFHxS and residence in NWU versus AUA. However, the latter association did not hold when controlling for socioeconomic resources. Finally, we observed associations between nutrition source at 4 months and DBS PFBA and PFHxS, with formula- or mixed-fed infants having higher concentrations compared to exclusively breastfed infants. This study presents the first evidence of PFAS contamination in Samoa. Additional work in larger samples is needed to identify potentially modifiable determinants of PFAS concentrations, information that is critical for informing environmental and health policy measures.

Protein Kinase Signaling Networks Driven by Oncogenic Gq/11 in Uveal Melanoma Identified by Phosphoproteomic and Bioinformatic Analyses.

Metastatic uveal melanoma (UM) patients typically survive only 2 to 3 years because effective therapy does not yet exist. Here, to facilitate the discovery of therapeutic targets in UM, we have identified protein kinase signaling mechanisms elicited by the drivers in 90% of UM tumors: mutant constitutively active G protein α-subunits encoded by GNAQ (Gq) or GNA11 (G11). We used the highly specific Gq/11 inhibitor FR900359 (FR) to elucidate signaling networks that drive proliferation, metabolic reprogramming, and dedifferentiation of UM cells. We determined the effects of FR on the proteome and phosphoproteome of UM cells as indicated by bioinformatic analyses with CausalPath and site-specific gene set enrichment analysis. We found that inhibition of oncogenic Gq/11 caused deactivation of PKC, Erk, and the cyclin-dependent kinases CDK1 and CDK2 that drive proliferation. Inhibition of oncogenic Gq/11 in UM cells with low metastatic risk relieved inhibitory phosphorylation of polycomb-repressive complex subunits that regulate melanocytic redifferentiation. Site-specific gene set enrichment analysis, unsupervised analysis, and functional studies indicated that mTORC1 and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 drive metabolic reprogramming in UM cells. Together, these results identified protein kinase signaling networks driven by oncogenic Gq/11 that regulate critical aspects of UM cell biology and provide targets for therapeutic investigation.

Ten Years Later, Alarm Fatigue Is Still a Safety Concern.

Ten years after the publication of a landmark article in AACN Advanced Critical Care, alarm fatigue continues to be an issue that researchers, clinicians, and organizations aim to remediate. Alarm fatigue contributes to missed alarms and medical errors that result in patient death, increased clinical workload and burnout, and interference with patient recovery. Led by the American Association of Critical-Care Nurses, national patient safety organizations continue to prioritize efforts to battle alarm fatigue and have proposed alarm management strategies to mitigate the effects of alarm fatigue. Similarly, clinical efforts now use simulation studies, individualized alarm thresholds, and interdisciplinary teams to optimize alarm use. Finally, engineering research efforts have innovated the standard alarm to convey information more effectively for medical users. By focusing on patient and provider safety, clinical workflow, and alarm technology, efforts to reduce alarm fatigue over the past 10 years have been grounded in an evidence-based and personnel-focused approach.