The impacts of sex and the 5xFAD model of Alzheimer's disease on the sleep and spatial learning responses to feeding time.

Introduction: The relationships between the feeding rhythm, sleep and cognition in Alzheimer's disease (AD) are incompletely understood, but meal time could provide an easy-to-implement method of curtailing disease-associated disruptions in sleep and cognition. Furthermore, known sex differences in AD incidence could relate to sex differences in circadian rhythm/sleep/cognition interactions. Methods: The 5xFAD transgenic mouse model of AD and non-transgenic wild-type controls were studied. Both female and male mice were used. Food access was restricted each day to either the 12-h light phase (light-fed groups) or the 12-h dark phase (dark-fed groups). Sleep (electroencephalographic/electromyographic) recording and cognitive behavior measures were collected. Results: The 5xFAD genotype reduces NREM and REM as well as the number of sleep spindles. In wild-type mice, light-fed groups had disrupted vigilance state amounts, characteristics, and rhythms relative to dark-fed groups. These feeding time differences were reduced in 5xFAD mice. Sex modulates these effects. 5xFAD mice display poorer spatial memory that, in female mice, is curtailed by dark phase feeding. Similarly, female 5xFAD mice have decreased anxiety-associated behavior. These emotional and cognitive measures are correlated with REM amount. Discussion: Our study demonstrates that the timing of feeding can alter many aspects of wake, NREM and REM. Unexpectedly, 5xFAD mice are less sensitive to these feeding time effects. 5xFAD mice demonstrate deficits in cognition which are correlated with REM, suggesting that this circadian-timed aspect of sleep may link feeding time and cognition. Sex plays an important role in regulating the impact of feeding time on sleep and cognition in both wild-type and 5xFAD mice, with females showing a greater cognitive response to feeding time than males.

Harnessing Radicals: Advances in Self-Assembly and Molecular Machinery.

Radicals, with their unpaired electrons, exhibit unique chemical and physical properties that have long intrigued chemists. Despite early skepticism about their stability, the discovery of persistent radicals has opened new possibilities for molecular interactions. This review examines the mechanisms and applications of radically driven self-assembly, focusing on key motifs such as naphthalene diimides, tetrathiafulvalenes, and viologens, which serve as models for radical assembly. The potential of radical interactions in the development of artificial molecular machines (AMMs) are also discussed. These AMMs, powered by radical-radical interactions, represent significant advancements in non-equilibrium chemistry, mimicking the functionalities of biological systems. From molecular switches to ratchets and pumps, the versatility and unique properties of radically powered AMMs are highlighted. Additionally, the applications of radical assembly in materials science are explored, particularly in creating smart materials with redox-responsive properties. The review concludes by comparing AMMs to biological molecular machines, offering insights into future directions. This overview underscores the impact of radical chemistry on molecular assembly and its promising applications in both synthetic and biological systems.

Effects of Wind Speed on Size-Dependent Morphology and Composition of Sea Spray Aerosols.

Variable wind speeds over the ocean can have a significant impact on the formation mechanism and physical-chemical properties of sea spray aerosols (SSA), which in turn influence their climate-relevant impacts. Herein, for the first time, we investigate the effects of wind speed on size-dependent morphology and composition of individual nascent SSA generated from wind-wave interactions of natural seawater within a wind-wave channel as a function of size and their particle-to-particle variability. Filter-based thermal optical analysis, atomic force microscopy (AFM), AFM infrared spectroscopy (AFM-IR), and scanning electron microscopy (SEM) were employed in this regard. This study focuses on SSA with sizes within 0.04-1.8 µm generated at two wind speeds: 10 m/s, representing a wind lull scenario over the ocean, and 19 m/s, indicative of the wind speeds encountered in stormy conditions. Filter-based measurements revealed a reduction of the organic mass fraction as the wind speed increases. AFM imaging at 20% relative humidity of individual SSA identified six main morphologies: prism-like, rounded, core-shell, rod, rod inclusion core-shell, and aggregates. At 10 m/s, most SSA were rounded, while at 19 m/s, core-shells became predominant. Based on AFM-IR, rounded SSA at both wind speeds had similar composition, mainly composed of aliphatic and oxygenated species, whereas the shells of core-shells displayed more oxygenated organics at 19 m/s and more aliphatic organics at 10 m/s. Collectively, our observations can be attributed to the disruption of the sea surface microlayer film structure at higher wind speeds. The findings reveal a significant impact of wind speed on morphology and composition of SSA, which should be accounted for accurate assessment of their climate effects.

Abundance, distribution, and dynamics of Anopheles species (Diptera: Culicidae) in Iowa, United States.

Malaria was once endemic in the United States prior to its elimination in 1951. However, due to consistent introductions of travel-associated malaria cases and the presence of several native Anopheles species (Diptera: Culicidae) that are competent vectors of malaria, the potential for local (autochthonous) malaria transmission remains a persistent threat in the United States. While several intermittent cases of local malaria transmission have occurred in the United States in the decades since elimination, the emergence of autochthonous transmission in 4 states in 2023 demonstrates the continued risk for future outbreaks. Moreover, these recent examples also highlight significant gaps in current mosquito surveillance efforts that have predominantly focused on threats of arboviral disease, such that our understanding of Anopheles distributions relies only on historical records and offers limited insight into the ecological factors that influence their abundance. Herein, we summarize mosquito surveillance data collected over the last 20 years (2004-2023) across 59 Iowa counties to provide essential information into the spatial distribution, temporal abundance, and trap preferences of Anopheles species in the state. Further analyses of the 2 most abundant species, Anopheles punctipennis Say and Anopheles quadrimaculatus Say, reveal the additional influence of precipitation and forested habitats in defining An. punctipennis abundance. Together, we believe these results provide an increased understanding of previously neglected Anopheles species that have the potential for autochthonous malaria transmission in Iowa and that can be extended to other regions of the United States to enhance preparedness for future malaria outbreaks.

Loss of the putative Rab GTPase, Ypt7, impairs the virulence of Cryptococcus neoformans.

Small GTPases of the Rab family coordinate multiple membrane fusion and trafficking events in eukaryotes. In fungi, the Rab GTPase, Ypt7, plays a critical role in late endosomal trafficking, and is required for homotypic fusion events in vacuole biogenesis and inheritance. In this study, we identified a putative YPT7 homologue in Cryptococcus neoformans, a fungal pathogen causing life threatening meningoencephalitis in immunocompromised individuals. As part of an ongoing effort to understand mechanisms of iron acquisition in C. neoformans, we established a role for Ypt7 in growth on heme as the sole iron source. Deletion of YPT7 also caused abnormal vacuolar morphology, defective endocytic trafficking and autophagy, and mislocalization of Aph1, a secreted vacuolar acid phosphatase. Ypt7 localized to the vacuolar membrane and membrane contact sites between the vacuole and mitochondria (vCLAMPs), and loss of the protein impaired growth on inhibitors of the electron transport chain. Additionally, Ypt7 was required for robust growth at 39°C, a phenotype likely involving the calcineurin signaling pathway because ypt7 mutants displayed increased susceptibility to the calcineurin-specific inhibitors, FK506 and cyclosporin A; the mutants also had impaired growth in either limiting or high levels of calcium. Finally, Ypt7 was required for survival during interactions with macrophages, and ypt7 mutants were attenuated for virulence in a mouse inhalation model thus demonstrating the importance of membrane trafficking functions in cryptococcosis.

Investigating the Determinants of Nonaccidental Trauma Evaluation in Pediatric Femur Fractures.

BACKGROUND: Femoral fractures in children have the highest probability for abuse after skull fractures and humeral shaft fractures. However, the reported proportion of pediatric femur fractures that result from nonaccidental trauma (NAT) varies in the literature from 2% to 60%. The purpose of this study was to determine the patient characteristics associated with a physician's decision to conduct a NAT workup and challenge universal clinical practice guidelines stating that all children younger than 3 years with a diaphyseal femur fracture be evaluated for NAT. METHODS: A retrospective review was conducted on patients aged 0 to 36 months diagnosed with a femur fracture between January 1, 2004, and April 9, 2019, at our institution. NAT was defined as a diagnosis of trauma that was nonaccidental in the medical chart after a positive workup by skeletal survey, ophthalmological examination, or other appropriate referral made by the institution's child abuse and neglect team. Patients with incomplete medical records were excluded. RESULTS: A total of 299 patients were identified, and 22 were excluded. 71% (197/277) were screened for NAT. Patients younger than 1 year were significantly more likely to undergo a NAT workup (P = 0.009; Odds Ratio [OR], 2.3; 95% CI, 1.2 to 4.4) and receive a positive result from the NAT workup (P < 0.0005; OR, 11.3; 95% CI, 4.6 to 27.4). Additional injuries were also a significant predictor of a positive NAT workup (P < 0.001; OR, 5.3; 95% CI, 2.4 to 11.9). Patient race/ethnicity, sex, and fracture type were not markedly associated with the physician's decision to conduct a NAT workup. CONCLUSIONS: Infants younger than 1 year with a femur fracture and children younger than 3 years presenting with a femur fracture and another injury are at increased risk of possible NAT. While clinical practice guidelines may minimize racial bias in NAT evaluation, this study demonstrates that universal NAT workups for walking-age children in the absence of other evidence of abuse may be unnecessary. LEVEL OF EVIDENCE: This is a Level III retrospective cohort study.

Exploring the Challenges of Distinguishing Punctate Inner Choroidopathy from Multifocal Choroiditis and Panuveitis.

PURPOSE: This retrospective case series aimed to assess the concordance between clinical diagnoses of punctate inner choroidopathy (PIC) and multifocal choroiditis and panuveitis (MCP) using the 2021 Standardization of Uveitis Nomenclature (SUN) Working Group criteria. METHODS: Using the medical records of the patients, we reevaluated 100 eyes of 75 patients with idiopathic multifocal chorioretinal inflammatory lesions based on SUN criteria and compared the result to the clinical diagnosis. RESULTS: Of 100 eyes, 29 eyes (29%) were diagnosed as PIC and 15 eyes (15%) were diagnosed as MCP using SUN criteria, and 56 (56%) eyes could not be diagnosed as either. Clinically diagnosed PIC eyes were significantly more myopic than the clinically diagnosed MCP eyes (mean spherical equivalent -6.65 ± 4.63 vs. -3.85 ± 2.31, P = 0.01). Sixteen eyes with vitreous inflammation were all clinically diagnosed as MCP, but four (25%) could not be diagnosed as MCP using SUN criteria. CONCLUSIONS: The existing diagnostic criteria showed limitations in capturing all clinical cases of PIC or MCP, and adding or revising criteria on features such as vitreous inflammation or myopia, could be considered to enhance diagnostic accuracy.

Fracture Lines and Patterns in Intra-articular Distal Femur Fractures.

INTRODUCTION: Distal femur fractures are complex injuries that often present with multiple fragments, posing notable challenges to fixation. This study aimed to (1) use preoperative CT scans to graphically display fracture lines in intra-articular distal femur fractures and (2) identify common fracture patterns in these injuries. METHODS: All skeletally mature patients that underwent surgical fixation of Orthopaedic Trauma Association type 33C distal femur fractures between 2012 and 2022 were identified across two level 1 trauma centers (n = 63). Preoperative axial, sagittal, and coronal computed tomography scans were obtained. Fracture lines in each plane were traced out and superimposed on standardized distal femur cross-sections, generating a fracture map for each plane. Injury and fracture characteristics were summarized and compared between fracture patterns. RESULTS: On axial scans, 59 of 63 fractures contained a central intercondylar split from the intercondylar notch to the trochlea. On coronal scans, fracture lines originated at the notch and exited laterally and medially in the supracondylar region, creating a Y-shape. One-third of all fractures contained coronal fracture lines, with most involving the lateral condyle. Based on fracture line orientation and location, fractures were divided into four main fracture pattern types. Type 4 fractures (central split and medial coronal fracture line) were associated with lower average medial fracture height and a lower rate of medial metaphyseal comminution. DISCUSSION: We found that C-type distal femur fractures can present with four main fracture patterns. Most fractures contain a central sagittal intercondylar split, and a high proportion of fractures contain either medial or lateral coronal fracture lines. Fracture pattern was associated with mechanism of injury, presence of medial comminution, and medial fracture line height. Future studies should focus on clinical outcomes and surgical management of these distinct fracture patterns. LEVEL OF EVIDENCE: IV.

Prevalence and predictors of problematic tinnitus.

OBJECTIVE: To determine the prevalence and characteristics of problematic tinnitus in a representative United States (US) sample. DESIGN: Cross-sectional study of the NHANES database from 2011-2012 and 2015-2016. STUDY SAMPLE: 8029 records were included for analysis. RESULTS: The prevalence of any tinnitus was 16.32%. Only 1.38% reported tinnitus as a big problem or worse. Univariate analysis revealed a statistically significant relationship between tinnitus constancy and duration with severity, where more constant perception and longer duration was related to increased severity (p < 0.0001). Multivariable models showed a clear relationship of increased odds ratio (OR) of problematic tinnitus with constancy of tinnitus but not duration. Furthermore, multivariable models showed higher Body Mass Index (OR= 1.013, 95% CI: 0.99-1.03), sleep trouble (OR = 2.016, 95% CI: 1.52-2.66) and comorbidities (OR = 1.43, 95%CI: 1.06-1.94) were all associated with increased problematic tinnitus, but not non-problematic tinnitus. CONCLUSIONS: Our study demonstrated that the prevalence of problematic tinnitus is much lower than the prevalence of any tinnitus. There was also a relationship between BMI, sleep trouble, other comorbidities and increased odds of problematic tinnitus. Tinnitus severity was significantly related to constancy of perception but had a less clear relationship to duration.

The Effects of Unitizing Nail-Plate Constructs in Distal Femur Fractures: A Biomechanical Study.

OBJECTIVES: To assess the biomechanical differences between linked and unlinked constructs in young and osteoporotic cadavers in addition to osteoporotic sawbones. METHODS: Intraarticular distal femur fractures with comminuted metaphyseal regions were created in three young matched pair cadavers, three osteoporotic matched pair cadavers, and six osteoporotic sawbones. Precontoured distal femur locking plates were placed in addition to a standardized retrograde nail, with unitized constructs having one 4.5 mm locking screw placed distally through the nail. Nonunitized constructs had seven 4.5 mm locking screws placed through the plate around the nail, with one 5 mm distal interlock placed through the nail alone. Cadaveric specimens were subjected to axial fatigue loads between 150 and 1500 N (R Ratio = 10) with 1 Hx frequency for 10,000 cycles. Sawbones were axially loaded at 50% of the ultimate load for fatigue testing to achieve runout, with testing performed with 30 and 300 N (R Ratio = 10) loads with 1 Hz frequency for 10,000 cycles. RESULTS: In young cadavers, there was no difference in the mean cyclic displacement of the unitized constructs (1.51 ± 0.62mm) compared to the non-unitized constructs (1.34 ± 0.47mm) (Figure 4A), (p = 0.722). In osteoporotic cadavers, there was no difference in the mean cyclic displacement of the unitized constructs (2.46 ± 0.47mm) compared to the non-unitized constructs (2.91 ± 1.49mm) (p =0.639). There was statistically no significant difference in cyclic displacement between the unitized and non-unitized groups in osteoporotic sawbones(p = 0.181). CONCLUSIONS: Linked constructs did not demonstrate increased axial stiffness or decreased cyclical displacement in comparison to unlinked constructs in young cadaveric specimens, osteoporotic cadaveric specimens, or osteoporotic sawbones.

Modeling the mechanochemical feedback for membrane-protein interactions using a continuum mesh model.

The Helfrich free energy is widely used to model the generation of membrane curvature due to different physical and chemical components. The governing equations resulting from the energy minimization procedure are a system of coupled higher order partial differential equations. Simulations of membrane deformation for obtaining quantitative comparisons against experimental observations require computational schemes that will allow us to solve these equations without restrictions to axisymmetric coordinates. Here, we describe one such tool that we developed in our group based on discrete differential geometry to solve these equations along with examples.

Effects of Relative Humidity and Phase on the Molecular Detection of Nascent Sea Spray Aerosol Using Extractive Electrospray Ionization.

Online mass spectrometry techniques, such as extractive electrospray ionization mass spectrometry (EESI-MS), present an attractive alternative for analyzing aerosol molecular composition due to reduced aerosol sample collection and handling times and improved time resolution. Recent studies show a dependence of EESI-MS sensitivity on particle size and mixing state. This study measured authentic sea spray aerosol (SSA) components generated during a phytoplankton bloom, specifically glycerol, palmitic acid, and potassium ions. We demonstrate temporal variability and trends dependent on specific biological processes occurring in seawater. We found that the EESI-MS sensitivity, after adjusting for pressure variations at the inlet and normalizing to the reagent ion, critically depends on the sample's relative humidity. Relevant SSA species exhibited heightened sensitivity at an elevated relative humidity near the deliquescence relative humidity of sea salt and poorer sensitivity with sparse detection below the efflorescence relative humidity. Modeling the reagent ion's diffusive depth demonstrates that the sample aerosol particle viscosity governs the relative humidity dependence because it modulates the particle's coagulation efficiency and distance the reagent ion diffuses and reacts with components in the particle bulk. The effects of particle size and mixing state are discussed, revealing improved sensitivity of phase-separated components present along the particle surface. This work highlights the importance of the particle phase state in detecting and quantifying molecular components within authentic and complex aerosol particles and the utility of EESI-MS for measuring SSA composition.

Pachychoroid Spectrum Disease: Comparison of Patients with Central Serous Chorioretinopathy Complicated with Pachychoroid Neovasculopathy.

PURPOSE: This study aimed to determine the incidence and visual outcomes of pachychoroid neovasculopathy (PNV) in patients initially diagnosed with central serous chorioretinopathy (CSC). METHODS: In this study, 144 patients aged 20 to 55 years with treatment-naive chronic CSC, defined as the persistence of subretinal fluid (SRF) for ≥6 months, were retrospectively enrolled. Patients with PNV at the initial evaluation were categorized as group 1, whereas those who developed new-onset PNV during follow-up were categorized as group 2. Patients without PNV until the end of the follow-up were categorized as group 3. RESULTS: Over a mean follow-up period of 49.9 ± 39.9 months, new-onset PNV was diagnosed in 11.8% of patients with CSC. The time taken to reach the initial resolution was longest in group 1 (group 1, 11.13 ± 10.70 months; group 2, 8.14 ± 7.90 months; group 3, 7.32 ± 9.55 months), although these differences were not statistically significant. The numbers of injections needed to achieve initial resolution were 3.76 ± 5.90, 1.64 ± 2.06, and 1.74 ± 4.33 in groups 1, 2, and 3, respectively, with no significant differences. SRF recurrence was recorded in seven patients (29.2%) in group 1, nine (64.3%) in group 2, and 28 (26.7%) in group 3. The recurrence rates were significantly higher in group 2 than those in group 1 or 3. At the end of the follow-up period, significant improvements in best-corrected visual acuity were achieved in groups 1 and 3, compared with baseline, but not in group 2. CONCLUSIONS: Patients with chronic CSC with new-onset PNV exhibited higher SRF recurrence and worse visual outcomes compared to those with initial PNV or those with chronic CSC without PNV. Our study emphasizes the importance of routine screening for prompt diagnoses of new-onset PNV in individuals with chronic CSC.

Real-World Incidence of Incident Noninfectious Uveitis in Patients Treated With BRAF Inhibitors: A Nationwide Clinical Cohort Study.

PURPOSE: To compare the incidence of noninfectious uveitis in skin melanoma or lung cancer patients who received BRAF inhibitors with that in those who received immune checkpoint inhibitors (ICIs) or conventional cytotoxic chemotherapy. DESIGN: Nationwide population-based retrospective clinical cohort study METHODS: From the Health Insurance Review and Assessment Service database of South Korea, we retrospectively defined 77,323 patients with skin melanoma or lung cancer who received BRAF inhibitor therapy (BRAF inhibitor-exposed group; n = 396), ICIs (ICI-exposed group; n = 22,474), or conventional cytotoxic chemotherapy (unexposed group; n = 54,453). We calculated the 1-year cumulative incidence of noninfectious uveitis in each group from the first day of BRAF inhibitor, ICI, or cytotoxic agent administration. RESULTS: During the first year of treatment initiation, the cumulative incidence of uveitis was 0.33%, 0.35%, and 2.27% in the unexposed, ICI-exposed, and BRAF inhibitor-exposed groups, respectively. Adjusted hazard ratios (aHR) indicated a 7.52-fold and 5.68-fold increased risk of uveitis in the BRAF inhibitor-exposed group compared with that in the unexposed and ICI-exposed groups (95% confidence interval [CI] 3.83-14.75, P < .001 and 95% CI 2.81-11.47, P < .001, respectively). After 1:4 propensity score matching, aHRs showed a 35.51-fold and 15.80-fold increased risk (95% CI 4.49-280.48, P = .001 and 95% CI 1.76-141.00, P = .014) of uveitis and severe uveitis, respectively, in the BRAF inhibitor-exposed versus unexposed patients. Crossover analysis within the BRAF inhibitor-exposed group showed a 3.71-fold increase in uveitis risk during 1-year post index date in comparison with 1-year prior to index date (95% CI 1.03-13.40, P = .046). In the BRAF inhibitor-exposed group, female sex, chronic kidney disease, and melanoma were associated with a trend of increased, albeit nonsignificant, risk of uveitis. CONCLUSIONS: Melanoma or lung cancer patients treated with BRAF inhibitors showed significantly higher risk of noninfectious uveitis than patients treated with conventional cytotoxic drugs or ICIs. These findings emphasize the importance of pretreatment patient education on BRAF-inhibitor-associated uveitis risk to enable prompt ophthalmic evaluation and treatment if symptoms arise during drug administration.

Drivers of Anemia Reduction among Women of Reproductive Age in Senegal: A Country Case Study.

BACKGROUND: In Senegal, anemia prevalence among women of reproductive age (WRA) decreased from 59% in 2005 to 54% in 2017. However, determinants of reduction in disease burden under challenging public health conditions have not been studied. OBJECTIVE: To conduct a systematic in-depth assessment of the quantitative and qualitative determinants of anemia reduction among WRA in Senegal between 2005 and 2017. METHODS: Standard Exemplars in Global Health methodology was used for quantitative analyses using Senegal's Demographic and Health Surveys. Qualitative analyses included a systematic literature review, program/policy analysis, and interviews with key stakeholders. A final Oaxaca-Blinder decomposition analysis (OBDA) evaluated the relative contribution of direct and indirect factors. RESULTS: Among non-pregnant women (NPW), mean hemoglobin (Hb) increased from 11.4 g/dL in 2005 to 11.7 g/dL in 2017 (p<0.0001), corresponding to a 5%-point decline in anemia prevalence (58% to 53%). However, inequities by geographical region, household wealth, women's educational attainment, urban compared to rural residence, and antenatal care (ANC) during last pregnancy continue to persist. During this time period, several indirect nutrition programs were implemented, with stakeholders acknowledging the importance of these programs, but agreeing there needs to be more consistency, evaluation, and oversight for them to be effective. Our OBDA explained 59% of the observed change in mean Hb, with family planning (25%), malaria prevention programs (17%), use of iron and folic acid (IFA) during last pregnancy (17%), and improvement in women's empowerment (12%) emerging as drivers of anemia decline, corroborating our qualitative and policy analyses. CONCLUSIONS: Despite a reduction in anemia prevalence, anemia remains a severe public health problem in Senegal. To protect the gains achieved to date, as well as accelerate reduction in WRA anemia burden, focused efforts to reduce gender and social disparities, and improve coverage of health services, such as family planning, IFA, and antimalarial programs, are needed.

Drivers of Anemia Reduction among Women of Reproductive Age in the Philippines: A Country Case Study.

BACKGROUND: Anemia prevalence among women of reproductive age (WRA) in the Philippines was 25% in 2000, decreasing to 13% in 2018. To date, an in-depth assessment of the determinants associated with this decline has not been conducted. OBJECTIVE: To conduct a systematic in-depth assessment of the quantitative and qualitative determinants of anemia among WRA in the Philippines between 2008 and 2018. METHODS: Employing standard Exemplars methodology, we conducted quantitative analyses using the Philippines' National Nutrition Survey, the Expanded National Nutrition Survey, and the Philippines National Demographic and Health Surveys. Qualitative analyses included a comprehnsive literature review, program/policy analysis, and interviews with stakeholders to understand country-level enablers and barriers to WRA anemia decline in the Philippines. A final Oaxaca-Blinder decomposition analysis (OBDA) evaluated the relative contribution of direct and indirect factors. RESULTS: Among non-pregnant women (NPW), mean hemoglobin (Hb) increased from 12.7 g/dL in 2008 to 13.1 g/dL in 2018 (p<0.01), corresponding to an 11%-point decline in anemia prevalence (23% to 12%). Inequities by geographical region, household wealth, and women's educational attainment narrowed considerably during this time. Important direct and indirect nutrition programs were introduced during our study period, including universal healthcare and food fortification. Country experts interviewed credited programs focused on alleviating micronutrient deficiencies and poverty, and improvements in women's health and well-being, for the country's extraordinary success. OBDA explained ∼50% of the observed change in mean Hb among NPW, with family planning (35%), household socio-demographics (29%), and improvement in women's nutrition (23%) emerging as critical drivers of anemia decline, corroborating our qualitative and policy analyses. CONCLUSIONS: To protect these gains, WRA anemia prevention efforts in the Philippines should continue to focus on universal healthcare access, women's empowerment, and poverty alleviation.

Real-world incidences and risk factors of immune-related adverse events in patients treated with immune checkpoint inhibitors: A nationwide retrospective cohort study.

Immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) are rare but fatal, requiring systemic steroid use. Therefore, to examine the outcomes, incidence, timing, and risk factors of ICI-associated steroid-requiring severe irAEs, we conducted a nationwide, retrospective, cohort study utilizing the Korean Health Insurance and Review Assessment database. We identified 357,010 patients with lung cancer, bladder cancer, or skin melanoma, eligible for ICI reimbursement in Korea between January 2012 to June 2020. Steroid-requiring severe irAEs following ICI treatment or treatment-emergent AEs following cytotoxic chemotherapy were defined as moderate- or high-dose steroid administration for over 2 consecutive days, along with corresponding ICD-10 codes indicating affected organ systems. The ICI-exposed group (N = 10,118) was compared to a matched cohort of 55,436 ICI-unexposed patients treated with cytotoxic chemotherapy. Incidences of acute severe irAEs requiring moderate- and high-dose steroids were higher in the ICI-exposed group (1.95% and 6.42%, respectively). The ICI-exposed group also had a higher risk of developing delayed severe irAEs requiring moderate- and high-dose steroid use (3.89% and 7.39%). Male sex, high comorbidity index, or previously diagnosed autoimmune diseases were associated with an increased risk of severe irAEs. Notably, 27.4-38.8% of the patients experienced recurrent severe irAEs after re-challenge with ICIs following moderate- or high-dose steroid use, with the severity matching the initial episode. Steroid-requiring severe irAEs were significantly more prevalent among patients exposed to ICIs than among those treated with chemotherapy in acute and delayed periods.