Physical Principles of Membrane Shape Regulation by the Glycocalyx.

Cells bend their plasma membranes into highly curved forms to interact with the local environment, but how shape generation is regulated is not fully resolved. Here, we report a synergy between shape-generating processes in the cell interior and the external organization and composition of the cell-surface glycocalyx. Mucin biopolymers and long-chain polysaccharides within the glycocalyx can generate entropic forces that favor or disfavor the projection of spherical and finger-like extensions from the cell surface. A polymer brush model of the glycocalyx successfully predicts the effects of polymer size and cell-surface density on membrane morphologies. Specific glycocalyx compositions can also induce plasma membrane instabilities to generate more exotic undulating and pearled membrane structures and drive secretion of extracellular vesicles. Together, our results suggest a fundamental role for the glycocalyx in regulating curved membrane features that serve in communication between cells and with the extracellular matrix.

Climate and Gender: Association Between Droughts and Intimate Partner Violence in India.

Extreme climate events are related to women's exposure to different forms of violence. We examined the relationship between droughts and physical, sexual, and emotional intimate partner violence (IPV) in India by using 2 different definitions of drought: precipitation-based drought and socioeconomic drought. We analyzed data from 2 rounds of a nationally representative survey, the National Family Health Survey, where married women were asked about their experiences of IPV in the previous year (2015-2016 and 2019-2021; n = 122,696). Precipitation-based drought was estimated using remote sensing data and geographic information system (GIS) mapping, while socioeconomic drought status was collected from government records. Logistic regression models showed precipitation-based drought to increase the risk of experiencing physical IPV and emotional IPV. Similar findings were observed for socioeconomic drought; women residing in areas classified as drought-impacted by the government were more likely to report physical IPV, sexual IPV, and emotional IPV. These findings support the growing body of evidence regarding the relationship between climate change and women's vulnerability, and highlight the need for gender responsive strategies for disaster management and preparedness.

Real-Time Identification of Aerosol-Phase Carboxylic Acid Production Using Extractive Electrospray Ionization Mass Spectrometry.

Comprehensive identification of aerosol sources and their constituent organic compounds requires aerosol-phase molecular-level characterization with a high time resolution. While real-time chemical characterization of aerosols is becoming increasingly common, information about functionalization and structure is typically obtained from offline methods. This study presents a method for determining the presence of carboxylic acid functional groups in real time using extractive electrospray ionization mass spectrometry based on measurements of [M - H + 2Na]+ adducts. The method is validated and characterized using standard compounds. A proof-of-concept application to α-pinene secondary organic aerosol (SOA) shows the ability to identify carboxylic acids even in complex mixtures. The real-time capability of the method allows for the observation of the production of carboxylic acids, likely formed in the particle phase on short time scales (<120 min). Our research explains previous findings of carboxylic acids being a significant component of SOA and a quick decrease in peroxide functionalization following SOA formation. We show that the formation of these acids is commensurate with the increase of dimers in the particle phase. Our results imply that SOA is in constant evolution through condensed-phase processes, which lower the volatility of the aerosol components and increase the available condensed mass for SOA growth and, therefore, aerosol mass loading in the atmosphere. Further work could aim to quantify the effect of particle-phase acid formation on the aerosol volatility distributions.

Tools used to measure the impact of comorbidities on surgical outcomes in children with complex chronic conditions: A scoping review.

AIM: To identify and describe assessment tools used to measure the impact of comorbidities on postoperative outcomes in children with complex chronic conditions (CCC). METHOD: This was a scoping review using five electronic databases. The search was conducted in March 2022 by a medical librarian. There were no date or language restrictions. Included studies were full-text articles published in peer-reviewed journals that described a tool used to measure the impact of comorbidities in children with CCC to assess postoperative outcomes. A standardized data charting tool was used. RESULTS: A total of 2157 articles were retrieved. Five studies reporting on six comorbidity measures met inclusion criteria. All were cohort studies and were secondary analyses of data from an administrative database (n = 4) or a patient registry (n = 1). Sample sizes ranged from 645 to 25 747 participants. One paper described the assessment of reliability. Only one form of validity - predictive validity - was assessed in three papers for five measures. INTERPRETATION: Findings from this scoping review revealed a paucity of comorbidity assessment tools validated for use with children with CCC; significant conceptual and measurement challenges exist in the current scientific literature.

Pharmacogenomic testing and prescribing patterns for patients with cancer in a large national precision medicine cohort.

Population databases could help patients with cancer and providers better understand current pharmacogenomic prescribing and testing practices. This retrospective observational study analysed patients with cancer, drugs with pharmacogenomic evidence and related genetic testing in the National Institutes of Health All of Us database. Most patients with cancer (19 633 (88.3%) vs 2590 (11.7%)) received ≥1 drug and 36 (0.2%) received genetic testing, with a significant association between receiving ≥1 drug and age group (p<0.001), but not sex (p=0.612), race (p=0.232) or ethnicity (p=0.971). Drugs with pharmacogenomic evidence-but not genetic testing-were common for patients with cancer, reflecting key gaps preventing precision medicine from becoming standard of care.

Race, Ethnicity, and Intensive Care Utilization for Common Pediatric Diagnoses: U.S. Pediatric Health Information System 2019 Database Study.

OBJECTIVES: Racial and ethnic disparities in healthcare delivery for acutely ill children are pervasive in the United States; it is unknown whether differential critical care utilization exists. DESIGN: Retrospective study of the Pediatric Health Information System (PHIS) database. SETTING: Multicenter database of academic children's hospitals in the United States. PATIENTS: Children discharged from a PHIS hospital in 2019 with one of the top ten medical conditions where PICU utilization was present in greater than or equal to 5% of hospitalizations. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Race and ethnicity categories included Asian, Black, Hispanic, White, and other. Primary outcomes of interest were differences in rate of PICU admission, and for children requiring PICU care, total hospital length of stay (LOS). One-quarter (n = 44,200) of the 178,134 hospital discharges included a PICU admission. In adjusted models, Black children had greater adjusted odds ratio (aOR [95% CI]) of PICU admission in bronchiolitis (aOR, 1.08 [95% CI, 1.02-1.14]; p = 0.01), respiratory failure (aOR, 1.18 [95% CI, 1.10-1.28]; p < 0.001), seizure (aOR, 1.28 [95% CI, 1.08-1.51]; p = 0.004), and diabetic ketoacidosis (DKA) (aOR, 1.18 [95% CI, 1.05-1.32]; p = 0.006). Together, Hispanic, Asian, and other race children had greater aOR of PICU admission in five of the diagnostic categories, compared with White children. The geometric mean (± sd) hospital LOS ranged from 47.7 hours (± 2.1 hr) in croup to 206.6 hours (± 2.8 hr) in sepsis. After adjusting for demographics and illness severity, non-White children had longer LOS in respiratory failure, pneumonia, DKA, and sepsis. CONCLUSIONS: The need for critical care to treat acute illness in children may be inequitable. Additional studies are needed to understand and eradicate differences in PICU utilization based on race and ethnicity.

Hospital Variation and Resource Use for Infants with Craniosynostosis Undergoing Open, Endoscopic, and Distraction Osteogenesis Surgical Techniques.

BACKGROUND: Craniosynostosis is treated with endoscopic, open, and/or distraction surgical techniques. We assessed institutional variation in the use these techniques for craniosynostosis and compared hospital resource use. METHODS: Retrospective analysis of 5249 infants age <18 months old undergoing surgical procedures for all types of craniosynostosis in 2016-2020 in 39 freestanding children's hospitals in the Pediatric Health Information System (PHIS) database. Endoscopic vs. open cranial vault surgery (with and without distraction osteogenesis) was identified using ICD-10-CM codes. Inpatient cost and length of stay (LOS) were compared by surgery type with Wilcoxon Rank Sum. RESULTS: There was significant (p < .001) variation in the percentage of infants who underwent endoscopic repair across hospitals [median 23.6% (interquartile range (IQR): 7.6%-37.5%), range: 0% to 80.4%] and across regions [range: 22.1% (southeast) to 42.5% (northeast)]. For endoscopic procedures, median LOS and inpatient cost were lower (p < .001) without vs. with distraction [1 day (IQR 1-1) vs. 2 days (IQR 2-2); $14,617 (IQR 11,823-22178) vs. $33,599 (IQR 22,800-38,619)]. For open interventions, median LOS and inpatient cost were also lower (p < .001) without vs. with distraction [3 days (IQR 2-4) vs. 5 days (IQR 4-6) and $37,251 (IQR 27,114-50.320) vs. $62,247 (IQR 42,124-91,620)]. CONCLUSIONS: Substantial variation in the surgical approach for craniosynostosis exists across hospitals and regions. Endoscopic repair without distraction had the lowest hospital resource use, while open repair with distraction had the highest hospital resource. Subsequent analysis of short- and long-term outcomes as well as patient-and-family costs is necessary to assess the true cost-effectiveness of each approach.

Sensitivity Constraints of Extractive Electrospray for a Model System and Secondary Organic Aerosol.

The quantification of an aerosol chemical composition is complicated by the uncertainty in the sensitivity of each species detected. Soft-ionization response factors can vary widely from molecule to molecule. Here, we have employed a method to separate molecules by their volatility through systematic evaporation with a thermal denuder (TD). The fraction remaining after evaporation is compared between an extractive electrospray ionization time-of-flight mass spectrometer (EESI-TOF) and a scanning mobility particle sizer (SMPS), which provides a comparison between a quantified mass loss by the SMPS and the signal loss in the EESI-TOF. The sensitivity of the EESI-TOF is determined for both a simplified complex mixture (PEG-300) and also for a complex mixture of α-pinene secondary organic aerosol (SOA). For PEG-300, separation is possible on a molecule-by-molecule level with the TD and provides insights into the molecule-dependent sensitivity of the EESI-TOF, showing a higher sensitivity toward the most volatile molecule. For α-pinene SOA, sensitivity determination for specific classes is possible because of the number of molecular formula observed by the EESI-TOF. These classes are separated by their volatility and are broken down into monomers (O3-5,6-7,8+), dimers (O4-7,8+), and higher order oligomers (e.g., trimers and tetramers). Here, we show that the EESI-TOF initially measures 60.1% monomers, 32.7% dimers, and 7.2% trimers and tetramers in α-pinene SOA, but after sensitivity correction, the distribution of SOA is 37.4% monomers, 56.1% dimers, and 6.4% trimers and tetramers. These results provide a path forward for the quantification of aerosol components with the EESI-TOF in other applications and potentially for atmospheric measurements.

Magnesium homeostasis in deoxygenated sickle erythrocytes is modulated by endothelin-1 via Na+ /Mg2+ exchange.

Painful crises in sickle cell disease (SCD) are associated with increased plasma cytokines levels, including endothelin-1 (ET-1). Reduced red cell magnesium content, mediated in part by increased Na+ /Mg2+ exchanger (NME) activity, contributes to erythrocyte K+ loss, dehydration and sickling in SCD. However, the relationship between ET-1 and the NME in SCD has remained unexamined. We observed increased NME activity in sickle red cells incubated in the presence of 500 nM ET-1. Deoxygenation of sickle red cells, in contrast, led to decreased red cell NME activity and cellular dehydration that was reversed by the NME inhibitor, imipramine. Increased NME activity in sickle red cells was significantly blocked by pre-incubation with 100 nM BQ788, a selective blocker of ET-1 type B receptors. These results suggest an important role for ET-1 and for cellular magnesium homeostasis in SCD. Consistent with these results, we observed increased NME activity in sickle red cells of three mouse models of sickle cell disease greater than that in red cells of C57BL/J6 mice. In vivo treatment of BERK sickle transgenic mice with ET-1 receptor antagonists reduced red cell NME activity. Our results suggest that ET-1 receptor blockade may be a promising therapeutic approach to control erythrocyte volume and magnesium homeostasis in SCD and may thus attenuate or retard the associated chronic inflammatory and vascular complications of SCD.

Time-Resolved Molecular Characterization of Secondary Organic Aerosol Formed from OH and NO3 Radical Initiated Oxidation of a Mixture of Aromatic Precursors.

Aromatic hydrocarbons (ArHCs) and oxygenated aromatic hydrocarbons (ArHC-OHs) are emitted from a variety of anthropogenic activities and are important precursors of secondary organic aerosol (SOA) in urban areas. Here, we analyzed and compared the composition of SOA formed from the oxidation of a mixture of aromatic VOCs by OH and NO3 radicals. The VOC mixture was composed of toluene (C7H8), p-xylene + ethylbenzene (C8H10), 1,3,5-trimethylbenzene (C9H12), phenol (C6H6O), cresol (C7H8O), 2,6-dimethylphenol (C8H10O), and 2,4,6-trimethylphenol (C9H12O) in a proportion where the aromatic VOCs were chosen to approximate day-time traffic-related emissions in Delhi, and the aromatic alcohols make up 20% of the mixture. These VOCs are prominent in other cities as well, including those influenced by biomass combustion. In the NO3 experiments, large contributions from CxHyOzN dimers (C15-C18) were observed, corresponding to fast SOA formation within 15-20 min after the start of chemistry. Additionally, the dimers were a mixture of different combinations of the initial VOCs, highlighting the importance of exploring SOAs from mixed VOC systems. In contrast, the experiments with OH radicals yielded gradual SOA mass formation, with CxHyOz monomers (C6-C9) being the dominant constituents. The evolution of SOA composition with time was tracked and a fast degradation of dimers was observed in the NO3 experiments, with concurrent formation of monomer species. The rates of dimer decomposition in NO3 SOA were ∼2-3 times higher compared to those previously determined for α-pinene + O3 SOA, highlighting the dependence of particle-phase reactions on VOC precursors and oxidants. In contrast, the SOA produced in the OH experiments did not dramatically change over the same time frame. No measurable effects of humidity were observed on the composition and evolution of SOA.

Integrated Assessment of the Leading Paths to Mitigate CO2 Emissions from the Organic Chemical and Plastics Industry.

The chemical industry is a major and growing source of CO2 emissions. Here, we extend the principal U.S.-based integrated assessment model, GCAM, to include a representation of steam cracking, the dominant process in the organic chemical industry today, and a suite of emerging decarbonization strategies, including catalytic cracking, lower-carbon process heat, and feedstock switching. We find that emerging catalytic production technologies only have a small impact on midcentury emissions mitigation. In contrast, process heat generation could achieve strong mitigation, reducing associated CO2 emissions by ∼76% by 2050. Process heat generation is diversified to include carbon capture and storage (CCS), hydrogen, and electrification. A sensitivity analysis reveals that our results for future net CO2 emissions are most sensitive to the amount of CCS deployed globally. The system as defined cannot reach net-zero emissions if the share of incineration increases as projected without coupling incineration with CCS. Less organic chemicals are produced in a net-zero CO2 future than those in a no-policy scenario. Mitigation of feedstock emissions relies heavily on biogenic carbon used as an alternative feedstock and waste treatment of plastics. The only scenario that delivers net-negative CO2 emissions from the organic chemical sector (by 2070) combines greater use of biogenic feedstocks with a continued reliance on landfilling of waste plastic, versus recycling or incineration, which has trade-offs.

Pneumonia after hip surgery in children with neurological complex chronic conditions.

AIM: In children with neurological complex chronic conditions (CCC) undergoing hip surgery we aimed to: estimate the rate of postoperative pneumonia, determine the effect of pneumonia on postoperative hospital resource use, and identify predictors of postoperative pneumonia. METHOD: A retrospective cohort study was conducted utilizing the Pediatric Health Information System database for 2609 children (1081 females, 1528 males) aged 4 years and older with a neurological CCC who underwent hip surgery (i.e. reconstruction surgery or salvage procedure) between 2016 and 2018 in 41 US children's hospitals. Multivariable, mixed-effects logistic regression was used to assess patient characteristics and risk of pneumonia. RESULTS: Mean age at hip surgery was 10 years 1 month (SD 4y 8mo). The postoperative pneumonia rate was 1.6% (n=42). Median length of stay (LOS) was longer for children with pneumonia and the 30-day all-cause unplanned readmission rate and costs were higher. Variability in rates of pneumonia ranged from 1.1% to 2.8% across hospitals. Significant predictors of postoperative pneumonia were osteotomy type (p=0.005) and number of chronic conditions (p≤0.001). INTERPRETATION: Postoperative pneumonia after hip surgery in children with a neurological CCC is associated with longer LOS, readmissions, and higher costs. Children undergoing pelvic osteotomies and who have multimorbidity need additional clinical support to prevent postoperative pneumonia and decrease resource utilization. WHAT THIS PAPER ADDS: Pneumonia is a major postoperative complication in children with neurological complex chronic conditions (CCC). Forty-two (1.6%) children with neurological CCC developed pneumonia after hip surgery. Length of stay, readmissions, and costs were significantly higher in the group with pneumonia. Variability in pneumonia rates existed across hospitals. Predictors of developing pneumonia include osteotomy type and number of CCC.

Assessing the Utility of a Machine-Learning Model to Assist With the Assignment of the American Society of Anesthesiology Physical Status Classification in Pediatric Patients.

BACKGROUND: The American Society of Anesthesiologists Physical Status Classification System (ASA-PS) is used to classify patients' health before delivering an anesthetic. Assigning an ASA-PS Classification score to pediatric patients can be challenging due to the vast array of chronic conditions present in the pediatric population. The specific aims of this study were to (1) suggest an ASA-PS score for pediatric patients undergoing elective surgical procedures using machine-learning (ML) methods; and (2) assess the impact of presenting the suggested ASA-PS score to clinicians when making their final ASA-PS assignment. The intent was not to create a new ASA-PS score but to use ML methods to generate a suggested score, along with information on how the score was generated (ie, historical information on patient comorbidities) to assist clinicians when assigning their final ASA-PS score. METHODS: A retrospective analysis of 146,784 pediatric surgical encounters from January 1, 2016, to December 31, 2019, using eXtreme Gradient Boosting (XGBoost) methods to predict ASA-PS scores using patients' age, weight, and chronic conditions. SHapley Additive exPlanations (SHAP) were used to assess patient characteristics that contributed most to the predicted ASA-PS scores. The predicted ASA-PS model was presented to a prospective cohort study of 28,677 surgical encounters from December 1, 2021, to October 31, 2022. The predicted ASA-PS score was presented to the anesthesiology provider for review before entering the final ASA-PS score. The study focused on summarizing the available information for the anesthesiologist by using ML methods. The goal was to explore the potential for ML to provide assistance to anesthesiologists by highlighting potential areas of discordance between the variables that generated a given ML prediction and the physician's mental model of the patient's medical comorbidities. RESULTS: For the retrospective analysis, the distribution of predicted ASA-PS scores was 22.7% ASA-PS I, 48.5% II, 23.6% III, 5.1% IV, and 0.04% V. The distribution of clinician-assigned ASA-PS scores was 24.3% for ASA-PS I, 44.5% for ASA-PS II, 24.9% for ASA III, 6.1% for ASA-PS IV, and 0.2% for ASA-V. In the prospective analysis, the final ASA-PS score matched the initial ASA-PS 90.7% of the time and 9.3% were revised after viewing the predicted ASA-PS score. When the initial ASA-PS score and the ML ASA-PS score were discrepant, 19.5% of the cases have a final ASA-PS score which is different from the initial clinician ASA-PS score. The prevalence of multiple chronic conditions increased with ASA-PS score: 34.9% ASA-PS I, 73.2% II, 92.3% III, and 94.4% IV. CONCLUSIONS: ML derivation of predicted pediatric ASA-PS scores was successful, with a strong agreement between predicted and clinician-entered ASA-PS scores. Presentation of predicted ASA-PS scores was associated with revision in final scoring for 1-in-10 pediatric patients.

Metopic ridge presenting to pediatric dermatology and vascular anomalies clinics.

Metopic ridge (MeR) is a midline osseous forehead prominence resulting from physiologic closure of the underlying metopic suture. This mass-like ridge can be mistaken for serious conditions such as a craniosynostosis or vascular anomaly, prompting concern and workup. We reviewed patients presenting for a forehead mass to Vascular Anomalies and Dermatology clinics and diagnosed with MeR to increase familiarity with this finding and to encourage MeR in the differential diagnosis of pediatric midline forehead masses.

Evaluating a scalable ARCHES (Addressing Reproductive Coercion in Health Settings) model in government health facilities in Uasin Gishu county, Kenya: study protocol for a cluster-randomized controlled trial.

BACKGROUND: Since 2013, the World Health Organization has recommended that reproductive coercion (RC) and intimate partner violence (IPV) be addressed within reproductive health services and, in 2018, the Lancet Commission on Sexual and Reproductive Health and Rights found that RC and IPV were significant contributors to unmet need for family planning (FP) and unintended pregnancy. In Kenya, the Ministry of Health (MOH) has made reduction of unintended pregnancy and gender-based violence a primary objective. Despite this need and guidance, no clinic-based intervention models outside of the U.S. (apart from the one described here) have demonstrated efficacy to improve FP use and reduce IPV or RC thereby reducing unintended pregnancy. ARCHES (Addressing Reproductive Coercion in Health Settings) is a brief, clinic-based intervention delivered by existing FP providers aiming to: (1) Increase women's ability to use FP without interference, (2) Provide a safe and supportive environment for IPV disclosure and referral to support services, and (3) Improve quality of FP counseling, including addressing RC and IPV. The objective of this study is to generate evidence on scaling integrated FP services (including FP, RC, and IPV) in public sector health facilities in Uasin Gishu county, Kenya via adaptation and implementation of ARCHES in partnership with the Kenya MOH. METHODS: A cluster-randomized controlled trial paired with concurrent implementation science assessments will test effectiveness of the ARCHES model, adapted for scale by the Kenya MOH, in reducing unintended pregnancy. Female FP clients aged 15-49 years at selected sites will complete baseline surveys (immediately prior to receiving care), immediately post-visit exit surveys, and 6-month follow-up surveys. Provider surveys will assess changes in gender-equitable attitudes and self-efficacy to address violence reported by their clients. Costs associated with scaling ARCHES will be tracked and utilized in combination with results of the effectiveness trial to assess costs and cost-effectiveness relative to the standard of care. DISCUSSION: This study will provide evidence of the effectiveness of a facility-based intervention to address RC and IPV within public sector FP services at scale, as adapted and implemented in Uasin Gishu county, Kenya. Trial registration Trial registered on 28 September 2023 with clinicaltrials.gov NCT06059196.

This study will document evidence of the effectiveness of the ARCHES intervention, a brief, clinic-based counselling intervention demonstrated to reduce intimate partner violence and reproductive coercion and promote women's reproductive health, as scaled in government health facilities in Kenya. ARCHES aims to (1) decrease unintended pregnancy, (2) increase family planning uptake and use/continuation, (3) decrease experiences of reproductive coercion and intimate partner violence of women and girls aged 15­49 years seeking family planning services, and to (4) improve quality of care, (5) increase gender equitable attitudes, and (6) increase self-efficacy to provide comprehensive family planning counseling among providers trained in ARCHES.

Effects of the reaching married adolescents program on modern contraceptive use and intimate partner violence: results of a cluster randomized controlled trial among married adolescent girls and their husbands in Dosso, Niger.

BACKGROUND: Niger has the highest rate of adolescent fertility in the world, with early marriage, early childbearing and high gender inequity. This study assesses the impact of Reaching Married Adolescents (RMA), a gender-synchronized social behavioral intervention designed to improve modern contraceptive use and reduce intimate partner violence (IPV) among married adolescent couples in rural Niger. METHODS: We conducted a four-armed cluster-randomized trial in 48 villages across three districts in Dosso region, Niger. Married adolescent girls (ages 13-19) and their husbands were recruited within selected villages. Intervention arms included home visits by gender-matched community health workers (CHWs) (Arm 1), gender-segregated, group discussion sessions (Arm 2), and both approaches (Arm 3). We used multilevel mixed-effects Poisson regression models to assess intervention effects for our primary outcome, current modern contraceptive use, and our secondary outcome, past year IPV. RESULTS: Baseline and 24-month follow-up data were collected April-June 2016 and April-June 2018. At baseline, 1072 adolescent wives were interviewed (88% participation), with 90% retention at follow-up; 1080 husbands were interviewed (88% participation), with 72% retention at follow-up. Adolescent wives had higher likelihood of modern contraceptive use at follow-up relative to controls in Arm 1 (aIRR 3.65, 95% CI 1.41-8.78) and Arm 3 (aIRR 2.99, 95% CI 1.68-5.32); no Arm 2 effects were observed. Relative to those in the control arm, Arm 2 and Arm 3 participants were significantly less likely to report past year IPV (aIRR 0.40, 95% CI 0.18-0.88 for Arm 2; aIRR 0.46, 95% CI 0.21-1.01 for Arm 3). No Arm 1 effects were observed. CONCLUSIONS: The RMA approach blending home visits by CHWs and gender-segregated group discussion sessions is the optimal format for increasing modern contraceptive use and decreasing IPV among married adolescents in Niger. Trial registration This trial is retrospectively registered with ClinicalTrials.gov, Identifier NCT03226730.

Although Niger has both the highest levels of fertility and of child marriage in the world, as well as substantial gender inequity, there have been no high-quality evaluations of public health programs aiming to increase contraceptive use or decrease intimate partner violence. In this study, we conducted a high quality, randomized controlled trial to evaluate whether the Reaching Married Adolescents public health program could increase modern contraceptive use and decrease intimate partner violence among married adolescent girls (13­19 years old) and their husbands in the Dosso region of Niger. The results of this evaluation provide evidence of the value of individual home visits for wives and their husbands in increasing modern contraceptive use, the value of small group discussions in reducing intimate partner violence, and the combined value of receiving both approaches at the same time for both increasing modern contraceptive use and decreasing intimate partner violence. The current study advances the state of evidence regarding contraceptive use and IPV among married adolescents and their husbands in Niger, highlighting the importance of engaging male partners in such public health programs, as well as of using multiple modes of delivery of programs. The success of this intervention in the high-risk context of Niger suggests that other countries in the region may benefit from testing this approach to improve the health and well-being of young wives.

Measuring social norms of intimate partner violence to exert control over wife agency, sexuality, and reproductive autonomy: an item response modelling of the IPV-ASRA scale.

BACKGROUND: The field of violence prevention research is unequivocal that interventions must target contextual factors, like social norms, to reduce gender-based violence. Limited research, however, on the social norms contributing to intimate partner violence or reproductive coercion exists. One of the driving factors is lack of measurement tools to accurately assess social norms. METHODS: Using an item response modelling approach, this study psychometrically assesses the reliability and validity of a social norms measure of the acceptability of intimate partner violence to exert control over wife agency, sexuality, and reproductive autonomy with data from a population-based sample of married adolescent girls (ages 13-18) and their husbands in rural Niger (n = 559 husband-wife dyads) collected in 2019. RESULTS: A two-dimensional Partial Credit Model for polytomous items was fit, showing evidence of reliability and validity. Higher scores on the "challenging husband authority" dimension were statistically associated with husband perpetration of intimate partner violence. CONCLUSIONS: This brief scale is a short (5 items), practical measure with strong reliability and validity evidence. This scale can help identify populations with high-need for social norms-focused IPV prevention and to help measure the impact of such efforts.

Long-term prevention of gender-based violence, like intimate partner violence and reproductive coercion, requires efforts to change the social environment that facilitates violence against women, yet limited research is available on how to change social environments. One reason is that there are few tools to accurately measure social environments, including social norms, which are the unspoken rules about what behavior is acceptable and what behavior is not. The present research assessed a new social norms measurement tool on the acceptability of intimate partner violence to exert control over wife agency, sexuality, and reproductive autonomy using data from a population-based sample of married adolescents and their husbands in rural Niger (n = 559 husband-wife dyads) collected in 2019. We found that this scale had strong reliability and validity, and that the group of questions about challenging husband authority were related to husband perpetration of intimate partner violence against his wife. This brief scale is a short (5 questions), practical measure with strong reliability and validity evidence that can help identify populations with high-need for social norms-focused prevention and to help measure the impact of such efforts. This evidence strengthens the current set of measurement tools on social norms available to researchers and practitioners.

The erythroid K-Cl cotransport inhibitor [(dihydroindenyl)oxy]acetic acid blocks erythroid Ca2+-activated K+ channel KCNN4.

Red cell volume is a major determinant of HbS concentration in sickle cell disease. Cellular deoxy-HbS concentration determines the delay time, the interval between HbS deoxygenation and deoxy-HbS polymerization. Major membrane transporter protein determinants of sickle red cell volume include the SLC12/KCC K-Cl cotransporters KCC3/SLC12A6 and KCC1/SLC12A4, and the KCNN4/KCa3.1 Ca2+-activated K+ channel (Gardos channel). Among standard inhibitors of KCC-mediated K-Cl cotransport, only [(dihydroindenyl)oxy]acetic acid (DIOA) has been reported to lack inhibitory activity against the related bumetanide-sensitive erythroid Na-K-2Cl cotransporter NKCC1/SLC12A2. DIOA has been often used to inhibit K-Cl cotransport when studying the expression and regulation of other K+ transporters and K+ channels. We report here that DIOA at concentrations routinely used to inhibit K-Cl cotransport can also abrogate activity of the KCNN4/KCa3.1 Gardos channel in human and mouse red cells and in human sickle red cells. DIOA inhibition of A23187-stimulated erythroid K+ uptake (Gardos channel activity) was chloride-independent and persisted in mouse red cells genetically devoid of the principal K-Cl cotransporters KCC3 and KCC1. DIOA also inhibited YODA1-stimulated, chloride-independent erythroid K+ uptake. In contrast, DIOA exhibited no inhibitory effect on K+ influx into A23187-treated red cells of Kcnn4-/- mice. DIOA inhibition of human KCa3.1 was validated (IC50 42 µM) by whole cell patch clamp in HEK-293 cells. RosettaLigand docking experiments identified a potential binding site for DIOA in the fenestration region of human KCa3.1. We conclude that DIOA at concentrations routinely used to inhibit K-Cl cotransport can also block the KCNN4/KCa3.1 Gardos channel in normal and sickle red cells.

Purinergic signaling is essential for full Psickle activation by hypoxia and by normoxic acid pH in mature human sickle red cells and in vitro-differentiated cultured human sickle reticulocytes.

Paracrine ATP release by erythrocytes has been shown to regulate endothelial cell function via purinergic signaling, and this erythoid-endothelial signaling network is pathologically dysregulated in sickle cell disease. We tested the role of extracellular ATP-mediated purinergic signaling in the activation of Psickle, the mechanosensitive Ca2+-permeable cation channel of human sickle erythrocytes (SS RBC). Psickle activation increases intracellular [Ca2+] to stimulate activity of the RBC Gardos channel, KCNN4/KCa3.1, leading to cell shrinkage and accelerated deoxygenation-activated sickling.We found that hypoxic activation of Psickle recorded by cell-attached patch clamp in SS RBC is inhibited by extracellular apyrase, which hydrolyzes extracellular ATP. Hypoxic activation of Psickle was also inhibited by the pannexin-1 inhibitor, probenecid, and by the P2 antagonist, suramin. A Psickle-like activity was also activated in normoxic SS RBC (but not in control red cells) by bath pH 6.0. Acid-activated Psickle-like activity was similarly blocked by apyrase, probenecid, and suramin, as well as by the Psickle inhibitor, Grammastola spatulata mechanotoxin-4 (GsMTx-4).In vitro-differentiated cultured human sickle reticulocytes (SS cRBC), but not control cultured reticulocytes, also exhibited hypoxia-activated Psickle activity that was abrogated by GsMTx-4. Psickle-like activity in SS cRBC was similarly elicited by normoxic exposure to acid pH, and this acid-stimulated activity was nearly completely blocked by apyrase, probenecid, and suramin, as well as by GsMTx-4.Thus, hypoxia-activated and normoxic acid-activated cation channel activities are expressed in both SS RBC and SS cRBC, and both types of activation appear to be mediated or greatly amplified by autocrine or paracrine purinergic signaling.

Dispositional hope as a potential outcome parameter among patients with advanced malignancy: An analysis of the ENABLE database.

BACKGROUND: Hopefulness, whether inherently present (dispositional hope) or augmented (by enhancement techniques), may affect outcomes. This study was performed to determine the association of dispositional hope with survival among patients diagnosed with advanced cancer. METHODS: Data from ENABLE (Educate, Nurture, Advise, Before Life Ends), a palliative care intervention, were reanalyzed to determine the association of higher dispositional hope and patient survival. This was a secondary analysis of data combined from the ENABLE II and ENABLE III randomized controlled trials (RCTs) with respect to dispositional hope and survival. A dispositional hope index was created from 3 hope items from 2 validated baseline questionnaires. Dispositional hope and survival data were collected during the 2 RCTs. In ENABLE II, participants were randomly assigned to the ENABLE intervention or to usual care. In ENABLE III, participants were randomly assigned to receive the intervention immediately or 12 weeks after enrollment. RESULTS: In all, 529 persons were included in Cox proportional hazards regression analyses to model the effects of dispositional hope on survival. An initial analysis without covariates yielded a significant effect of hope (Wald statistic, 8.649; hazard ratio, 0.941; confidence interval, 0.904-0.980; P = .003), such that higher dispositional hope was associated with longer survival. In a subsequent analysis that included all covariates, the effect of dispositional hope approached statistical significance (Wald statistic, 2.96; hazard ratio, 0.933; confidence interval, 0.863-1.010; P = .085). CONCLUSIONS: Higher levels of dispositional hope were associated with longer survival in patients with advanced cancer. Prospective trials are needed to determine the effects of dispositional and augmented hope on the outcomes of patients with advanced cancer.