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Abstract Background There is a lack of up-to-date information on the prevalence and burden of headache in Norway. Here we describe the methods and validation of the diagnostic tool of the PopHEAD study, a study designed to determine the prevalence and burden of migraine, tension-type headache, and medication-overuse headache. Method PopHEAD is a Norwegian population-based cross-sectional study conducted in Vestfold and Telemark County in 2023. A random sample of 28,753 individuals aged 18 to 70 was invited to participate. The study used a digital version of the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) questionnaire, translated into Norwegian using the Lifting The Burden translation protocol. A subsample of participants was contacted by telephone within four weeks for an interview with a headache neurologist blinded to the questionnaire responses. Headache disorders were diagnosed according to the criteria of the International Classification of Headache Disorders version 3. Validity was expressed by sensitivity, specificity and Cohen’s kappa (κ). Results In total, 8,265 (3,344 men and 4,921 women) responded. Most men (75.0%) and women (89.7%) reported having had a headache in the past year. Of 667 participants contacted for a telephone interview, 505 responded. The sensitivity and specificity of the questionnaire-based diagnoses were 97% and 72% for self-reported headache in the previous year (Cohen’s kappa κ = 0.72), 77% and 85% for migraine (κ = 0.61), 77% and 74% for tension-type headache (κ = 0.51), and 58% and 99% for medication-overuse headache (κ = 0.63), respectively. Conclusion The PopHEAD questionnaire is a valid tool for identifying individuals with lifetime headache, migraine, tension-type headache, and medication overuse headache.

Abstract Introduction Disengagement from HIV care during the perinatal period remains a challenge. Improving engagement in HIV care requires monitoring engagement across multiple indicators, including retention in HIV care, visit adherence, clinic transfers, and viral suppression to support improved clinical and programmatic outcomes. Methods We enrolled a prospective cohort of pregnant WHIV across a network of five urban clinics in Lilongwe, Malawi from February 2020-February 2021. WHIV were followed from their first antenatal care visit through 9 months postpartum across all study sites using biometric fingerprint scanning. Study visits occurred at enrollment into antenatal care, 6 weeks’, 6 months, and 9 months postpartum. In addition, all usual care HIV visits were captured via medical records. Participants who missed a study visit or usual care visit were traced. We evaluated determinants of multiple indicators of engagement in care, including retention in HIV care (attending a scheduled visit or self-reported recent visit when traced), HIV visit adherence (missed scheduled HIV visits and HIV visit coverage), clinic transfers, and viral load suppression (

IntroductionRespiratory syncytial virus (RSV) is the leading cause of hospitalization among US infants. Characterizing service utilization during infant RSV hospitalizations may provide important information for prioritizing resources and interventions.ObjectiveThe objective of this study was to describe the procedures and services received by infants hospitalized during their first RSV episode in their first RSV season, in addition to what proportion of infants died during this hospitalization.MethodsIn this retrospective observational study, we analyzed three different administrative claims datasets to examine healthcare service utilization during RSV hospitalizations among infants. The study population included infants born between July 2016 and February 2020 who experienced an RSV episode during their first RSV season and had an associated inpatient hospitalization. We stratified infants into three comorbidity groups: healthy term, palivizumab-eligible, and other comorbidities. Outcomes included extracorporeal membrane oxygenation, supplemental oxygen use (in-hospital and post-discharge), mechanical ventilation (invasive and non-invasive), chest imaging, infant mortality, length of inpatient stay, intensive care unit (ICU) admission, and number of days in the ICU.ResultsChest imaging was the most frequently administered procedure during RSV-associated hospitalizations, with approximately 34-38% of infants receiving it. Around one-quarter of infants were admitted to the ICU during their first RSV hospitalization. Median lengths of stay in the hospital were 3-4 days, extending to 4-6 days in the presence of ICU admission. Palivizumab-eligible infants had higher utilization of healthcare services and spent more time in the hospital or ICU compared to healthy infants or those with other comorbidities.ConclusionsThis study provides insights into the utilization of healthcare services during RSV hospitalizations among infants. Understanding service utilization patterns can aid in improved management and resource allocation for infants in the United States, ultimately contributing to better outcomes and reduced healthcare costs overall. However, likely under-ascertainment of ventilation and oxygen-related services in insurance claims remains an impediment to studying these outcomes.

ABSTRACT Mitchella repens (partridgeberry; family Rubiaceae) is a creeping, understory plant native to eastern North America. The twinned, tubular flowers of this distylous plant are bright white and produce volatile organic compounds (VOCs). Partridgeberry has intermorph incompatibility and thus requires pollinators to move pollen from one morph to the other. Despite partridgeberry being a common member of forest communities, little is known about its pollination syndrome. Using headspace solid‐phase microextraction (HS‐SPME) coupled with gas chromatography–mass spectrometry (GC–MS) analysis the floral VOCs were identified, with the four predominant molecules being α‐pinene, camphene, D‐limonene, and verbenone. The VOC profile contained 27 molecules consisting mostly of monoterpenes. Two independent sample t‐tests confirmed that each morph produced statistically similar floral VOC profiles (p > 0.1). Additionally, two of the predominant VOC molecules, α‐pinene and D‐limonene, were measured throughout the 5‐day flowering cycle. Simple linear regressions of these compound levels versus days after flowering (DAF) confirmed that α‐pinene and D‐limonene both decreased with flower age. Insect visits were observed to correlate with α‐pinene and D‐limonene concentrations, peaking at 1–2 DAF and then declining through 5 DAF.

The enzyme deoxyhypusine synthase (DHS) catalyzes the first step in the post-translational modification of the eukaryotic translation factor 5A (eIF5A). This is the only protein known to contain the amino acid hypusine, which results from this modification. Both eIF5A and DHS are essential for cell viability in eukaryotes, and inhibiting DHS is a promising strategy to develop new therapeutic alternatives. DHS proteins from many are sufficiently different from their human orthologs for selective targeting against infectious diseases; however, no DHS inhibitor selective for parasite orthologs has previously been reported. Here, we established a yeast surrogate genetics platform to identify inhibitors of DHS from Plasmodium vivax, one of the major causative agents of malaria. We constructed genetically modified Saccharomyces cerevisiae strains expressing DHS genes from Homo sapiens (HsDHS) or P. vivax (PvDHS) in place of the endogenous DHS gene from S. cerevisiae. Compared with a HsDHS complemented strain with a different genetic background that we previously generated, this new strain background was ~60-fold more sensitive to an inhibitor of human DHS. Initially, a virtual screen using the ChEMBL-NTD database was performed. Candidate ligands were tested in growth assays using the newly generated yeast strains expressing heterologous DHS genes. Among these, two showed promise by preferentially reducing the growth of the PvDHS-expressing strain. Further, in a robotized assay, we screened 400 compounds from the Pathogen Box library using the same S. cerevisiae strains, and one compound preferentially reduced the growth of the PvDHS-expressing yeast strain. Western blot revealed that these compounds significantly reduced eIF5A hypusination in yeast. The compounds showed antiplasmodial activity in the asexual erythrocyte stage; EC50 in high nM to low μM range, and low cytotoxicity. Our study demonstrates that this yeast-based platform is suitable for identifying and verifying candidate small molecule DHS inhibitors, selective for the parasite over the human ortholog.

Background Option B+ aims to prevent mother-to-child transmission of HIV by providing lifelong antiretroviral therapy (ART) to pregnant and breastfeeding women living with HIV (PBWHIV). Identifying and reengaging PBWHIV who disengage or fail to initiate ART is essential for the success of Option B+. However, the process is often suboptimal, leading to challenges such as misclassification of patients as lost to follow-up. Healthcare workers (HCWs) are pivotal for monitoring engagement, but little is known about their monitoring practices. This study aimed to explore how HCWs monitor women's engagement in Option B+ services. Methods A qualitative study was conducted in five high-volume health facilities in Lilongwe, Malawi. Thirty HCWs responsible for monitoring women in Option B+ were purposively selected as key informants. Semistructured interviews were conducted between March and June 2021. Thematic analysis employing deductive and inductive coding methods was utilized. The Consolidated Framework for Implementation Research was used to map gaps, strategies, barriers, and facilitators of monitoring. Results Monitoring was described as tracking a PBWHIV from HIV diagnosis to initiation of ART to subsequent ART visits for up to 2 years postpartum. The gaps included timing variations in tracing. No procedures to follow up formal transfer-outs or management of silent transfers during emergency ART refills were identified. Strategies identified included interfacility collaboration, record review, tracing, escorting women during initial visits, and self-reports. Technological innovations, such as WhatsApp groups, were highlighted as game changers in interfacility collaboration when tracking women's movements. Barriers included resource constraints (human and operational), poor work attitudes, and challenges faced by women (partner support, stigma, and HCW rapport). The facilitators included implementing partner support, leadership, and strategies such as education and tracing. Conclusion Addressing resource constraints, women's relationship dynamics for self-management, HCWs’ attitudes, and standardizing tracing protocols are crucial for effective monitoring. Leveraging instant messaging for clinic coordination may enhance tracing. Further research and interventions should target identified gaps to promote effective monitoring in similar settings.

Abstract Option B + provides lifelong ART to pregnant and breastfeeding women with HIV to reduce mother-to-child transmission of HIV (eMTCT) and improve maternal health. The effectiveness of Option B + relies on continuous engagement, but suboptimal monitoring of HIV care hinders our measurements of engagement. Process mapping and quality improvement (PROMAQI) is a quality improvement strategy for healthcare workers (HCWs) to optimize complex processes such as monitoring HIV care. We assessed the acceptability and feasibility of the PROMAQI among HCWs and identified barriers and facilitators for PROMAQI implementation. A cross-sectional study using a mixed method approach was conducted from August 2021 to March 2022 across five urban health facilities participating in PROMAQI implementation n the Lilongwe district, Malawi. We assessed PROMAQI acceptability and feasibility at the end of the study. A 5-point Likert (1 = worst to 5 = best) scale tool was administered to 110 HCWs (n = 15–33 per facility) involved in PROMAQI implementationThese data were analysed using descriptive statistics Among the 110 HCWs, twenty-two (QI team (n = 11) and QI implementers (n = 11)) were purposively selected for in-depth interviews. Thematic analysis was conducted using deducted and inductive approaches. The theoretical framework for acceptability (TFA) was used to identify reasons for acceptability. The Consolidated Framework for Implementation Research (CFIR) was used to characterize the barriers and facilitators of PROMAQI implementation. HCWs recruited had a median age of 37 (32–43) years, 82.0% of whom were female. Most (42%) had completed secondary education, and 84% were nurses and community health workers. The median (IQR) acceptability and feasibility scores for the PROMAQI were 5 (IQR 4–5) and 4 (IQR 4–5), respectively. Reasons for high PROMAQI acceptability included addressing a relevant gap and improving performance. Perceived implementation barriers included poor work attitudes, time constraints, resource limitations, knowledge gaps, and workbook difficulties. The facilitators included communication, mentorship, training, and financial incentives. PROMAQI is a highly acceptable and feasible tool for monitoring engagement of women in Option B + . Addressing these barriers may optimize the implementation of PROMAQI. Scaling up PROMAQI may enhance retention in the Option B + program and facilitate eMTCT.

Abstract The I148M variant of PNPLA3 is closely associated with hepatic steatosis. Recent evidence indicates that the I148M mutant functions as an inhibitor of PNPLA2/ATGL-mediated lipolysis, leaving the role of wild-type PNPLA3 undefined. Despite showing a triglyceride hydrolase activity in vitro, PNPLA3 has yet to be established as a lipase in vivo. Here, we show that PNPLA3 preferentially hydrolyzes polyunsaturated triglycerides, mobilizing polyunsaturated fatty acids for phospholipid desaturation and enhancing hepatic secretion of triglyceride-rich lipoproteins. Under lipogenic conditions, mice with liver-specific knockout or acute knockdown of PNPLA3 exhibit aggravated liver steatosis and reduced plasma VLDL-triglyceride levels. Similarly, I148M-knockin mice show decreased hepatic triglyceride secretion during lipogenic stimulation. Our results highlight a specific context whereby the wild-type PNPLA3 facilitates the balance between hepatic triglyceride storage and secretion, and suggest the potential contribution of a loss-of-function by the I148M variant to the development of fatty liver disease in humans.

During neuronal differentiation, neuroprogenitor cells become polarized, change shape, extend axons, and form complex dendritic trees. While growing, axons are guided by molecular cues to their final destination, where they establish synaptic connections with other neuronal cells. Several layers of regulation are integrated to control neuronal development properly. Although control of mRNA translation plays an essential role in mammalian gene expression, how it contributes temporarily to the modulation of later stages of neuronal differentiation remains poorly understood. Here, we investigated how translation control affects pathways and processes essential for neuronal maturation, using H9-derived human neuro progenitor cells differentiated into neurons as a model. Through Ribosome Profiling (Riboseq) combined with RNA sequencing (RNAseq) analysis, we found that translation control regulates the expression of critical hub genes. Fundamental synaptic vesicle secretion genes belonging to SNARE complex, Rab family members, and vesicle acidification ATPases are strongly translationally regulated in developing neurons. Translational control also participates in neuronal metabolism modulation, particularly affecting genes involved in the TCA cycle and glutamate synthesis/catabolism. Importantly, we found translation regulation of several critical genes with fundamental roles regulating actin and microtubule cytoskeleton pathways, critical to neurite generation, spine formation, axon guidance, and circuit formation. Our results show that translational control dynamically integrates important signals in neurons, regulating several aspects of its development and biology.

The purpose of this study was to examine administrators' use of data, their perceptions of data, and what their expectations were in terms of teacher use of data. In conjunction with this examination will be a closer look at the new Professional Standards for Educational Leaders (PSEL) to determine the connections as well as the disconnections to the way school leaders currently use data in their everyday practice and the standards of practice called for by the PSEL. A qualitative approach using interviews, focus groups, and document review was used to answer a question about the adequacy of current data-driven decision practices of school leaders in light of the new Professional Standards for Educational Leaders. Findings suggest that the participants in this study used data to inform their practice as it relates to the four PSEL standards focusing on instructional leadership. However, there was little evidence that administrators used data to inform their practice related to the other six PSEL standards related to cultural awareness, organizational culture and climate, and community awareness. As a result, we suggest that the new PSEL standards demand a broader view of data and its use in decision making.

Abstract Anticipating and managing the impacts of sea‐level rise for nations astride active tectonic margins requires understanding of rates of sea surface elevation change in relation to coastal land elevation. Vertical land motion (VLM) can either exacerbate or reduce sea‐level changes with impacts varying significantly along a coastline. Determining rate, pattern, and variability of VLM near coasts leads to a direct improvement of location‐specific relative sea level (RSL) estimates for coastal hazard risk assessment. Here, we utilize vertical velocity field from interferometric synthetic aperture radar (InSAR) data, calibrated with campaign and continuous Global Navigation Satellite System data, to determine the VLM for the entire coastline of New Zealand. Guided by available knowledge of the seismic cycle, the VLM data infer secular, interseismic rates of land surface deformation. Using the Framework for Assessing Changes to Sea‐level (FACTS), we build probabilistic RSL projections using the same emissions scenarios employed in IPCC Assessment Report 6 and local VLM data at 8,179 sites, thereby enhancing spatial coverage that was previously limited to four tide gauges. We present ensembles of probability distributions of RSL for each scenario to 2150, and for low confidence sea‐level processes to 2300. Where land subsidence is occurring at rates >2 mm/y VLM makes a significant contribution to RSL projections for all scenarios out to 2150. Our approach can be applied to similar locations across the world and has significant implications for adaptation planning, as timing of threshold exceedance for coastal inundation can be brought forward (or delayed) by decades.

Abstract Introduction Outside of pregnancy, evidence shows that persons with HIV initiating or switching to dolutegravir (DTG)‐based antiretroviral therapy (ART) experience greater weight gain compared to those on other ART classes. However, there are few data on the impact of DTG‐based ART on gestational weight gain (GWG) in sub‐Saharan Africa where HIV is most common. According to the National Academy of Medicine (NAM), GWG below and above NAM guidelines is associated with adverse birth outcomes. Therefore, the objective of this study was to describe GWG by HIV status and ART regimen, and examine the associations with adverse birth outcomes. Methods We enrolled pregnant women with HIV (WHIV) and without HIV (≥18 years) in a peri‐urban primary healthcare facility in Cape Town, South Africa between 2019 and 2022. GWG was study‐measured at 24–28 (baseline) and 33–38 weeks gestation and converted to GWG rate (kg/week) in accordance with NAM guidelines. GWG z‐scores were generated using the INTEGROWTH‐21 and US standards to account for differing lengths of gestation. Birth outcome data were obtained from medical records. Associations of GWG z‐score with adverse birth outcomes were assessed using multivariable linear or log‐binomial regression. Results Among 292 participants (48% WHIV), median age was 29 years (IQR, 25–33), median pre‐pregnancy body mass index (BMI) was 31 kg/m2 (IQR, 26–36) and 20% were primiparous at baseline. The median weekly rate of GWG was 0.30 kg/week (IQR, 0.12–0.50), 35% had GWG below NAM standards (59% WHIV) and 48% had GWG above NAM standards (36% WHIV). WHIV gained weight more slowly (0.25 vs. 0.37 kg/week, p4000 g (RR = 2.18 95% CI 1.18, 4.01). Conclusions Despite slower GWG among WHIV, nearly half of all women gained weight faster than recommended by the NAM. GWG was positively associated with infant birth weight. Interventions to support healthy GWG in sub‐Saharan Africa are urgently needed.

Michael Bogart,1 Lindsay GS Bengtson,2 Mary G Johnson,2 Scott H Bunner,2 Noelle N Gronroos,2 Kristi K DiRocco3 1US Value Evidence & Outcomes, R&D US, GSK, Research Triangle Park, NC, USA; 2Health Economics and Outcomes Research, Optum, Eden Prairie, MN, USA; 3USA, Medical Affairs, GSK, Collegeville, PA, USACorrespondence: Kristi K DiRocco, US Medical Affairs, GSK, 1250 S. Collegeville Road, Collegeville, PA, 19426, USA, Tel +1 610-412-7175, Email kristi.k.dirocco@gsk.comPurpose: Patients with chronic obstructive pulmonary disease (COPD) have been shown to benefit from triple therapy commonly delivered by multiple-inhaler triple therapy (MITT); however, the complexity of MITT regimens may decrease patient adherence. Fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI), a once-daily single-inhaler triple therapy (SITT), became available in the United States (US) in 2017, but real-world data comparing outcomes for SITT versus MITT are currently limited. This study compared outcomes among patients with COPD initiating MITT versus SITT with FF/UMEC/VI who were either Medicare Advantage with Part D (MAPD) beneficiaries or commercial enrollees in the US.Methods: Retrospective study using administrative claims data from the Optum Research Database for patients with COPD who initiated FF/UMEC/VI or MITT between September 1, 2017, and March 31, 2019 (index date: first pharmacy claim for FF/UMEC/VI cohort; earliest day of ≥ 30 consecutive days-long period of overlap in the day’s supply of all triple therapy components for MITT cohort). COPD exacerbations, adherence to triple therapy, and all-cause and COPD-related health care resource utilization (HCRU) and costs were compared between FF/UMEC/VI and MITT initiators.Results: In total, 4659 FF/UMEC/VI initiators and 9845 MITT initiators for the MAPD population, and 821 FF/UMEC/VI initiators and 1893 MITT initiators for the commercial population were included in the study. MAPD beneficiaries initiating FF/UMEC/VI had a significantly lower annual rate of severe exacerbations compared to MITT initiators (0.26 vs 0.29; p=0.014). They also had a significantly higher mean adherence (proportion of days covered) (0.51 vs 0.37; p< 0.001) and significantly lower all-cause and COPD-related inpatient stays compared to MITT initiators ([32.02% vs 34.27%; p=0.017], [16.09% vs 17.72%; p=0.037]). Trends were similar among the commercial population, but the results were not statistically significant.Conclusion: FF/UMEC/VI initiators had significantly fewer severe exacerbations, higher triple therapy adherence, and lower HCRU costs compared to MITT initiators for MAPD beneficiaries.Plain language summary: Triple therapy for chronic obstructive pulmonary disease (COPD) includes the use of several inhalers daily in a respiratory therapy combination known as multiple-inhaler triple therapy (MITT), which can be challenging for patients. However, treatment can be simplified by combining these therapies into just one inhaler, in a respiratory therapy combination known as single-inhaler triple therapy (SITT). As there is currently limited information comparing treatment outcomes in patients using SITT versus those using MITT in the real world, in this study we included Medicare Advantage with Part D (MAPD) beneficiaries and commercial enrollees with COPD who started using either an SITT combination of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) or MITT. More specifically, we looked at flare-ups in COPD symptoms (known as exacerbations), percentage of days that a patient had their medication on hand (known as treatment adherence), and health care utilization and costs. The study was conducted using administrative claims data between September 1, 2016, and March 31, 2020 from the Optum Research Database. For patients who had MAPD insurance, individuals who started FF/UMEC/VI experienced fewer severe exacerbations and increased treatment adherence, as compared to those who started MITT. They also had lower health care utilization and costs compared to those using MITT. Similar results were observed for patients who were commercially enrolled, albeit lacking statistical significance. Overall, the findings of this study indicate that triple therapy with FF/UMEC/VI can improve exacerbations and treatment adherence in patients with COPD and decrease health care utilization and associated costs.Keywords: chronic obstructive pulmonary disease, triple therapy, multiple-inhaler triple therapy, single-inhaler triple therapy, adherence, exacerbations

Abstract Background Muscles in the post-stroke arm commonly demonstrate abnormal reflexes that result in increased position- and velocity-dependent resistance to movement. We sought to develop a reliable way to quantify mechanical consequences of abnormal neuromuscular mechanisms throughout the reachable workspace in the hemiparetic arm post-stroke. Methods Survivors of hemiparetic stroke (HS) and neurologically intact (NI) control subjects were instructed to relax as a robotic device repositioned the hand of their hemiparetic arm between several testing locations that sampled the arm's passive range of motion. During transitions, the robot induced motions at either the shoulder or elbow joint at three speeds: very slow (6°/s), medium (30°/s), and fast (90°/s). The robot held the hand at the testing location for at least 20 s after each transition. We recorded and analyzed hand force and electromyographic activations from selected muscles spanning the shoulder and elbow joints during and after transitions. Results Hand forces and electromyographic activations were invariantly small at all speeds and all sample times in NI control subjects but varied systematically by transport speed during and shortly after movement in the HS subjects. Velocity-dependent resistance to stretch diminished within 2 s after movement ceased in the hemiparetic arms. Hand forces and EMGs changed very little from 2 s after the movement ended onward, exhibiting dependence on limb posture but no systematic dependence on movement speed or direction. Although each HS subject displayed a unique field of hand forces and EMG responses across the workspace after movement ceased, the magnitude of steady-state hand forces was generally greater near the outer boundaries of the workspace than in the center of the workspace for the HS group but not the NI group. Conclusions In the HS group, electromyographic activations exhibited abnormalities consistent with stroke-related decreases in the stretch reflex thresholds. These observations were consistent across repeated testing days. We expect that the approach described here will enable future studies to elucidate stroke's impact on the interaction between the neural mechanisms mediating control of upper extremity posture and movement during goal-directed actions such as reaching and pointing with the arm and hand.