Critical-like slowdown in thermal soft-sphere glasses via energy minimization.

Using hybrid molecular dynamics/SWAP Monte Carlo (MD/SMC) simulations, we show that while the terminal relaxation times τ(ϕ) for FIRE energy minimization of soft-sphere glasses can decrease by orders of magnitude as sample equilibration proceeds and the jamming density ϕ_{J} increases, they always scale as τ(ϕ)∼(ϕ_{J}-ϕ)^{-2}∼[Z_{iso}-Z_{ms}(τ)]^{-2}, where Z_{iso}=2d and Z_{ms}(τ) is the average coordination number of particles satisfying a minimal local mechanical stability criterion (Z≥d+1) at the top of the final potential-energy-landscape (PEL) sub-basin the system encounters. This scaling allows us to collapse τ datasets that look very different when plotted as a function of ϕ, and to address a closely related question: how does the character of the PEL basins that dense thermal glasses most typically occupy evolve as the glasses age at constant ϕ and T?

Temporary mechanical support in the peripartum patient as a bridge to postpartum recovery: A report of three cases.

Cardiogenic shock (CS) is a severe complication of peripartum cardiomyopathy (PPCM). Patients with deteriorating CS often require temporary mechanical circulatory support. In PPCM, this can be used as a bridge to postpartum recovery or bridge to decision. The outcomes are unclear, especially if prolonged utilization is required. We present a case series of three patients with PPCM in deteriorating CS who were successfully supported with a ventricular assist device or veno-arterial extracorporeal membrane oxygenation as a bridge to postpartum recovery.

Securement to Prevent Noncuffed Central Venous Catheter Dislodgement in Pediatrics: The SECURED Superiority Randomized Clinical Trial.

Importance: Catheter dislodgement is a common complication for children with tunneled or peripherally inserted noncuffed central venous catheters (CVCs). A subcutaneous anchor securement system (SASS) may reduce this risk compared with traditional adhesive securement. Objective: To compare dislodgement of noncuffed CVCs secured with SASS with dislodgement of noncuffed CVCs secured with sutureless securement devices (SSDs). Design, Setting, and Participants: The SECURED (Securing Central Venous Catheters to Prevent Dislodegment) trial was a pragmatic, multicenter, superiority randomized clinical trial with an internal pilot and was conducted from August 5, 2020, to August 30, 2022, at 2 Australian quaternary pediatric hospitals. Data analysis was performed in January 2023. Patients aged 0 to 18 years requiring a noncuffed CVC (≥3F catheter) were eligible for inclusion. Follow-up duration was 8 weeks or until device removal. Interventions: Patients were randomly assigned 1:1 to receive an SASS or SSD, stratified by hospital and catheter type. Only 1 catheter was studied per patient. Main Outcomes and Measures: The primary outcome was dislodgement (partial or total), defined as movement of the catheter tip by greater than 1 cm (change in external catheter length) at any point during catheter dwell. Dislodgement, reported as a risk ratio (RR), was estimated using a generalized linear model with binomial family and log link. Secondary outcomes were reported as incidence rate ratios and were analyzed using Poission regression. Outcomes reported as mean differences (MDs) were analyzed using linear regression. Results: Of 310 randomized patients, 175 patients (56.5%) were male and median (IQR) patient age was 48 (16-120) months. A total of 307 patients had a catheter device inserted, of which 153 (49.8%) were SASS and 154 (50.2%) were SSD, and were included in the intention-to-treat (ITT) analysis. Device dislodgement was lower with SASS (8 dislodgements in 153 patients [5.2%]) compared with SSD (35 dislodgements in 154 patients [22.7%]) (RR, 0.23; 95% CI, 0.11-0.48; P < .001). The per-protocol analysis was consistent with the ITT analysis. Partial dislodgement accounted for most dislodgement events, including 6 partial dislodgements in the SASS group (3.9%) and 30 partial dislodgements in the SSD group (19.5%) (RR, 0.18; 95% CI, 0.08-0.42). This contributed to fewer complications during dwell in the SASS group (37 reported complications [24.2%]) vs the SSD group (60 reported complications [39.0%]) (RR, 0.62; 95% CI, 0.44-0.87). Staff reported greater difficulty removing devices anchored with SASS vs SSD (mean [SD], 29.1 [31.3] vs 5.3 [17.0], respectively; MD, 23.8; 95% CI, 16.7-31.0). However, use of SASS resulted in reduced per-participant health care costs of A$36.60 (95% credible interval, 4.25-68.95; US $24.36; 95% credible interval, 2.83-45.89). Conclusions and Relevance: In the SECURED trial, noncuffed CVCs secured with SASS had fewer dislodgements compared with SSDs, with a lower cost per patient and an acceptable safety profile. Future efforts should be directed at SASS implementation at the health service level. Trial Registration: anzctr.org.au Identifier: ACTRN12620000783921.

A nationwide study of Stevens-Johnson syndrome and toxic epidermal necrolysis in hospitalized pregnant women in the United States, 2009-2020.

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rarely described in the pregnant population, and knowledge of their impact on the mother/fetus is limited. Objective: To describe SJS/TEN in pregnant women and to investigate the risk factors for developing SJS/TEN in pregnancy. Methods: We utilized hospitalization data from the 2009-2020 National Inpatient Sample. Pregnancy hospitalizations and SJS/TEN involvement were identified by ICD-9/10 codes and analyzed by chi-square and logistic regression. Results: We identified 650 pregnancies complicated by SJS/TEN requiring hospitalization. The median age was 28 years, and most were non-Hispanic White (55.2%). There were ≤10 cases associated with mortality. Most SJS/TEN cases (73.9%) occurred during the third trimester. HIV infection (OR = 9.49; P = .030), herpes simplex virus infection (OR = 2.49; P = .021), genitourinary tract infections (OR = 3.80; P < .001), malignant neoplasm (OR = 8.67; P = .031), and lupus erythematosus (OR = 41.94; P < .001) were associated with increased odds of developing SJS/TEN in pregnancy. Rates of preterm births were higher in the SJS/TEN cohort, 16.9% versus 8.2% (P < .001). Rates of pre-eclampsia, stillbirths, and post-term births were similar between the SJS/TEN versus non-SJS/TEN pregnancy cohorts. Limitations: Limited cohort size. Conclusions: SJS/TEN in pregnancy appears to be mild and is associated with favorable maternal-fetal outcomes, except for increased preterm birth.

invariant Natural Killer T cell therapy as a novel therapeutic approach in hematological malignancies.

Invariant Natural Killer T cell therapy is an emerging platform of immunotherapy for cancer treatment. This unique cell population is a promising candidate for cell therapy for cancer treatment because of its inherent cytotoxicity against CD1d positive cancers as well as its ability to induce host CD8 T cell cross priming. Substantial evidence supports that iNKT cells can modulate myelomonocytic populations in the tumor microenvironment to ameliorate immune dysregulation to antagonize tumor progression. iNKT cells can also protect from graft-versus-host disease (GVHD) through several mechanisms, including the expansion of regulatory T cells (Treg). Ultimately, iNKT cell-based therapy can retain antitumor activity while providing protection against GVHD simultaneously. Therefore, these biological properties render iNKT cells as a promising "off-the-shelf" therapy for diverse hematological malignancies and possible solid tumors. Further the introduction of a chimeric antigen recetor (CAR) can further target iNKT cells and enhance function. We foresee that improved vector design and other strategies such as combinatorial treatments with small molecules or immune checkpoint inhibitors could improve CAR iNKT in vivo persistence, functionality and leverage anti-tumor activity along with the abatement of iNKT cell dysfunction or exhaustion.

A Phase 1 Clinical Trial of NKTR-255 with CD19-22 CAR-T Cell Therapy for Refractory B-cell Acute Lymphoblastic Leukemia.

While chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed / refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, nine of whom successfully received CAR19-22 followed by NKTR-255. There were no dose limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with eight out of nine patients (89%) achieving measurable residual disease negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T-cells in blood and ten-fold increases in CSF CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible and associated with high rates of durable responses (NCT03233854).

Volumetric Analysis: Effect on Diagnosis and Management of Indeterminate Solid Pulmonary Nodules in Routine Clinical Practice.

OBJECTIVE: To evaluate the effect of volumetric analysis on the diagnosis and management of indeterminate solid pulmonary nodules in routine clinical practice. METHODS: This was a retrospective study with 107 computed tomography (CT) cases of solid pulmonary nodules (range, 6-15 mm), 57 pathology-proven malignancies (lung cancer, n = 34; metastasis, n = 23), and 50 benign nodules. Nodules were evaluated on a total of 309 CT scans (average number of CTs/nodule, 2.9 [range, 2-7]). CT scans were from multiple institutions with variable technique. Nine radiologists (attendings, n = 3; fellows, n = 3; residents, n = 3) were asked their level of suspicion for malignancy (low/moderate or high) and management recommendation (no follow-up, CT follow-up, or care escalation) for baseline and follow-up studies first without and then with volumetric analysis data. Effect of volumetry on diagnosis and management was assessed by generalized linear and logistic regression models. RESULTS: Volumetric analysis improved sensitivity (P = 0.009) and allowed earlier recognition (P < 0.05) of malignant nodules. Attending radiologists showed higher sensitivity in recognition of malignant nodules (P = 0.03) and recommendation of care escalation (P < 0.001) compared with trainees. Volumetric analysis altered management of high suspicion nodules only in the fellow group (P = 0.008). κ Statistics for suspicion for malignancy and recommended management were fair to substantial (0.38-0.66) and fair to moderate (0.33-0.50). Volumetric analysis improved interobserver variability for identification of nodule malignancy from 0.52 to 0.66 (P = 0.004) only on the second follow-up study. CONCLUSIONS: Volumetric analysis of indeterminate solid pulmonary nodules in routine clinical practice can result in improved sensitivity and earlier identification of malignant nodules. The effect of volumetric analysis on management recommendations is variable and influenced by reader experience.

Sensitivity and specificity of the Neonatal Visual Assessment to predict motor and cognitive outcomes in infants born very preterm.

BACKGROUND: Very preterm infants are at increased risk of neurodevelopmental impairments. The Neonatal Visual Assessment (NVA) assesses visual function and outcomes and has been used to assess early neurodevelopmental outcomes. This study aimed to compare NVA results of very preterm and term-born infants and to calculate the sensitivity and specificity of the NVA at term equivalent age (TEA) and three months corrected age (CA) to predict motor and cognitive outcomes at 12 months CA in very preterm infants. METHODS: This prospective observational cohort study recruited infants born before 31 weeks gestation and a healthy term-born control group. The NVA was assessed at TEA and three months CA, and neurodevelopmental outcomes (Bayley Scales of Infant and Toddler Development, Third Edition; Neurosensory Motor Developmental Assessment; Alberta Infant Motor Scale) were performed at 12 months CA. The sensitivity and specificity of the NVA to predict outcomes were calculated based on a previously published optimality score. RESULTS: 248 preterm (54 % male) and 46 term-born infants (48 % male) were analysed. The mean NVA scores of preterm and term-born infants were significantly different at TEA (preterm 3.1±2.1; term-born 1.2±1.7, p < 0.001). The NVA had moderate sensitivity (59-78 %) and low specificity (25-27 %) at TEA, and low sensitivity (21-28 %) and high specificity (86-87 %) at three months CA for the prediction of preterm infants' outcomes at 12 months CA. CONCLUSION: The NVA at TEA and three months CA was not a strong predictor of motor and cognitive impairments in this contemporary cohort of very preterm infants.

Blood Stored In EDTA Tubes Provides Accurate Peanut Basophil Activation Test Results For 48 hours.

BACKGROUND: The peanut basophil activation test (BAT) has demonstrated excellent diagnostic accuracy with heparinized blood, but its clinical utility is limited by the short stability of samples stored in this anticoagulant. OBJECTIVE: Using EDTA anticoagulated blood, these investigations determined if Peanut BAT sample stability can be extended to 2 days, the minimum stability requirement for diagnostic tests currently offered through American reference laboratories. METHODS: Peanut non-allergic control (NAC), peanut IgE sensitized (PS), and peanut allergic (PA) children aged 6 months through 17 years were recruited from members of Kaiser Permanente Southern California. EDTA anti-coagulated blood samples were collected from participants, shipped to a centralized laboratory, and stored at 4oC for peanut BAT testing 1 and 2 days later. RESULTS: Peanut BAT results for 23 unblinded participants were used to establish sample rejection and interpretation criteria that were subsequently validated in a prospective double-blind study involving 112 additional children (39-NAC, 36-PS, 37-PA). Of 105 blinded blood samples tested on each study day, 88 (84%) day-1 and 90 (86%) day-2 peanut BAT results were considered interpretable, with diagnostic accuracies of 95.5% and 94.4%, respectively. Moreover, all interpretable PA results were considered positive (100% sensitivity). CONCLUSION: Using EDTA anti-coagulated blood samples collected remotely, 1 and 2 days before testing, study results highlight the favorable diagnostic performance characteristics of the peanut BAT and provide further evidence that the test could be readily operationalized for clinical use by interested commercial reference laboratories.

Composite Pulmonary Embolism Shock Score and Risk of Adverse Outcomes in Patients With Pulmonary Embolism.

BACKGROUND: In hemodynamically stable patients with acute pulmonary embolism (PE), the Composite Pulmonary Embolism Shock (CPES) score predicts normotensive shock. However, it is unknown if CPES predicts adverse clinical outcomes. The objective of this study was to determine whether the CPES score predicts in-hospital mortality, resuscitated cardiac arrest, or hemodynamic deterioration. METHODS: Patients with acute intermediate-risk PE admitted from October 2016 to July 2019 were included. CPES was calculated for each patient. The primary outcome was a composite of in-hospital mortality, resuscitated cardiac arrest, or hemodynamic decompensation. Secondary outcomes included individual components of the primary outcome. The association of CPES with primary and secondary outcomes was evaluated. RESULTS: Among the 207 patients with intermediate-risk PE (64.7% with intermediate-high risk PE), 29 (14%) patients had a primary outcome event. In a multivariable model, a higher CPES score was associated with a worse primary composite outcome (adjusted hazard ratio [aHR], 1.81 [95% CI, 1.29-2.54]; P=0.001). Moreover, a higher CPES score predicted death (aHR, 1.76 [95% CI, 1.04-2.96]; P=0.033), resuscitated cardiac arrest (aHR, 1.99 [95% CI, 1.17-3.38]; P=0.011), and hemodynamic decompensation (aHR, 1.96 [95% CI, 1.34-2.89]; P=0.001). A high CPES score (≥3) was associated with the worse primary outcome when compared with patients with a low CPES score (22% versus 2.4%; P=0.003; aHR, 6.48 [95% CI, 1.49-28.04]; P=0.012). CPES score provided incremental prognostic value for the prediction of primary outcome over baseline demographics and European Society of Cardiology intermediate-risk subcategories (global Χ2 value increased from 0.63 to 1.39 to 13.69; P=0.005). CONCLUSIONS: In patients with acute intermediate-risk PE, the CPES score effectively risk stratifies and prognosticates patients for the prediction of clinical events and provides incremental value over baseline demographics and European Society of Cardiology intermediate-risk subcategories.

Pathogen diversity and antimicrobial resistance transmission of Salmonella enterica serovars Typhi and Paratyphi A in Bangladesh, Nepal, and Malawi: a genomic epidemiological study.

BACKGROUND: Enteric fever is a serious public health concern. The causative agents, Salmonella enterica serovars Typhi and Paratyphi A, frequently have antimicrobial resistance (AMR), leading to limited treatment options and poorer clinical outcomes. We investigated the genomic epidemiology, resistance mechanisms, and transmission dynamics of these pathogens at three urban sites in Africa and Asia. METHODS: S Typhi and S Paratyphi A bacteria isolated from blood cultures of febrile children and adults at study sites in Dhaka (Bangladesh), Kathmandu (Nepal), and Blantyre (Malawi) during STRATAA surveillance were sequenced. Isolates were charactered in terms of their serotypes, genotypes (according to GenoTyphi and Paratype), molecular determinants of AMR, and population structure. We used phylogenomic analyses incorporating globally representative genomic data from previously published surveillance studies and ancestral state reconstruction to differentiate locally circulating from imported pathogen AMR variants. Clusters of sequences without any single-nucleotide variants in their core genome were identified and used to explore spatiotemporal patterns and transmission dynamics. FINDINGS: We sequenced 731 genomes from isolates obtained during surveillance across the three sites between Oct 1, 2016, and Aug 31, 2019 (24 months in Dhaka and Kathmandu and 34 months in Blantyre). S Paratyphi A was present in Dhaka and Kathmandu but not Blantyre. S Typhi genotype 4.3.1 (H58) was common in all sites, but with different dominant variants (4.3.1.1.EA1 in Blantyre, 4.3.1.1 in Dhaka, and 4.3.1.2 in Kathmandu). Multidrug resistance (ie, resistance to chloramphenicol, co-trimoxazole, and ampicillin) was common in Blantyre (138 [98%] of 141 cases) and Dhaka (143 [32%] of 452), but absent from Kathmandu. Quinolone-resistance mutations were common in Dhaka (451 [>99%] of 452) and Kathmandu (123 [89%] of 138), but not in Blantyre (three [2%] of 141). Azithromycin-resistance mutations in acrB were rare, appearing only in Dhaka (five [1%] of 452). Phylogenetic analyses showed that most cases derived from pre-existing, locally established pathogen variants; 702 (98%) of 713 drug-resistant infections resulted from local circulation of AMR variants, not imported variants or recent de novo emergence; and pathogen variants circulated across age groups. 479 (66%) of 731 cases clustered with others that were indistinguishable by point mutations; individual clusters included multiple age groups and persisted for up to 2·3 years, and AMR determinants were invariant within clusters. INTERPRETATION: Enteric fever was associated with locally established pathogen variants that circulate across age groups. AMR infections resulted from local transmission of resistant strains. These results form a baseline against which to monitor the impacts of control measures. FUNDING: Wellcome Trust, Bill & Melinda Gates Foundation, EU Horizon 2020, and UK National Institute for Health and Care Research.

Safety of Breast Liposuction and Oncologic Considerations.

Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Analyzing Racial Disparities in Pediatric Atopic Comorbidity Emergency Department Visitation using Electronic Health Records.

BACKGROUND: Although atopic diseases and associated co-morbidities are prevalent in children, little is known about racial differences in emergency department (ED) visitation. OBJECTIVE: We sought to examine racial differences in ED visitation among children with allergic comorbidities. METHODS: We conducted a retrospective study of patients (<21 years) who visited the ED at a large pediatric hospital for atopic dermatitis (AD), food allergy (FA), asthma, allergic rhinitis (AR), and eosinophilic esophagitis (EoE) from 2015 to 2019. We determined the probability of ED encounter-free using hazard ratios (HR) and time to recurrence (TTR) of ED encounter for patients identified as Black/African American (AA) and White/European American (EA). We assessed potentially underlying allergic, demographic, and place-based factors, and potential interactions between factors. RESULTS: A total of 30,894 patients (38% AA, 62% EA) had 83,078 ED encounters (38,378 first ED encounters, and 44,700 recurrent ED encounters) during the study period. Asthma and AR showed the highest rate of comorbidity in ED encounters in both AA and EA children. AA children exhibited higher HR for encounter following index AD and asthma encounters. We found an interaction between the type of insurance and race in ED encounters for AD, FA, AR, and EoE. In AA children, those insured by Medicaid demonstrated a higher HR for any encounter compared to those with commercial insurance. Conversely, in EA children, those with Medicaid insurance showed a lower HR compared to their commercially insured peers. Regardless of race, allergic comorbidity increased the HR of ED encounter (1.12-1.62) for all allergic diseases. At 5-years follow up, mean differences in TTR were shorter in AA children compared to EA children in AD, FA, and asthma. CONCLUSION: Identification of disease-specific racial disparities in ED visitation related to atopic diseases is a necessary first step toward the design and implementation of interventions capable of equitably reducing emergency care in atopic comorbid children.

Faecal proteomics links neutrophil degranulation with mortality in patients with alcohol-associated hepatitis.

OBJECTIVE: Patients with alcohol-associated hepatitis (AH) have a high mortality. Alcohol exacerbates liver damage by inducing gut dysbiosis, bacterial translocation and inflammation, which is characterised by increased numbers of circulating and hepatic neutrophils. DESIGN: In this study, we performed tandem mass tag (TMT) proteomics to analyse proteins in the faeces of controls (n=19), patients with alcohol-use disorder (AUD; n=20) and AH (n=80) from a multicentre cohort (InTeam). To identify protein groups that are disproportionately represented, we conducted over-representation analysis using Reactome pathway analysis and Gene Ontology to determine the proteins with the most significant impact. A faecal biomarker and its prognostic effect were validated by ELISA in faecal samples from patients with AH (n=70), who were recruited in a second and independent multicentre cohort (AlcHepNet). RESULT: Faecal proteomic profiles were overall significantly different between controls, patients with AUD and AH (principal component analysis p=0.001, dissimilarity index calculated by the method of Bray-Curtis). Proteins that showed notable differences across all three groups and displayed a progressive increase in accordance with the severity of alcohol-associated liver disease were predominantly those located in neutrophil granules. Over-representation and Reactome analyses confirmed that differentially regulated proteins are part of granules in neutrophils and the neutrophil degranulation pathway. Myeloperoxidase (MPO), the marker protein of neutrophil granules, correlates with disease severity and predicts 60-day mortality. Using an independent validation cohort, we confirmed that faecal MPO levels can predict short-term survival at 60 days. CONCLUSIONS: We found an increased abundance of faecal proteins linked to neutrophil degranulation in patients with AH, which is predictive of short-term survival and could serve as a prognostic non-invasive marker.

Effects of protein restriction on insulin-like growth factor (IGF)-1 in men with prostate cancer: results from a randomized clinical trial.

BACKGROUND: Insulin-like growth factor (IGF)-1 and its binding proteins are important in cancer growth, especially in prostate cancer. Observational studies suggest that protein restriction can lower IGF-1 levels. However, it is unclear whether an isocaloric protein-restricted diet affects IGF-1 and IGFBPs in men with prostate cancer. METHODS: In this academic, single-center, parallel-group, prospective, randomized, open-label, blinded end-point trial, 38 consenting overweight (BMI 30.5 ± 5.5 kg/m2) men with localized prostate cancer, aged 43-72 years, were randomized (1:1) with permuted blocks to 4-6 weeks of customized isocaloric PR diets (0.8 g protein/kg lean body mass) or their usual diet. Biomarkers influencing cancer biology, including serum IGF-1 and its binding proteins were measured longitudinally. RESULTS: Contrary to our hypothesis, feeding individuals an isocaloric protein-restricted diet did not result in a significant reduction in serum IGF-1. Moreover, there was no observed increase in serum IGFBP-1 or IGFBP-3 concentration. CONCLUSION: These findings demonstrate that protein restriction without calorie restriction does not reduce serum IGF-1 concentration or increase IGFBP-1 and IGFBP-3 in men with localized prostate cancer. Further research is needed to identify dietary interventions for safely and effectively reducing IGF-1 in this patient group.

Changes in primary care visits for respiratory illness during the COVID-19 pandemic: a multinational study by the International Consortium of Primary Care Big Data Researchers (INTRePID).

Objectives: The majority of patients with respiratory illness are seen in primary care settings. Given COVID-19 is predominantly a respiratory illness, the INTernational ConsoRtium of Primary Care BIg Data Researchers (INTRePID), assessed the pandemic impact on primary care visits for respiratory illnesses. Design: Definitions for respiratory illness types were agreed on collectively. Monthly visit counts with diagnosis were shared centrally for analysis. Setting: Primary care settings in Argentina, Australia, Canada, China, Norway, Peru, Singapore, Sweden and the United States. Participants: Over 38 million patients seen in primary care settings in INTRePID countries before and during the pandemic, from January 1st, 2018, to December 31st, 2021. Main outcome measures: Relative change in the monthly mean number of visits before and after the onset of the pandemic for acute infectious respiratory disease visits including influenza, upper and lower respiratory tract infections and chronic respiratory disease visits including asthma, chronic obstructive pulmonary disease, respiratory allergies, and other respiratory diseases. Results: INTRePID countries reported a marked decrease in the average monthly visits for respiratory illness. Changes in visits varied from -10.9% [95% confidence interval (CI): -33.1 to +11.3%] in Norway to -79.9% (95% CI: -86.4% to -73.4%) in China for acute infectious respiratory disease visits and - 2.1% (95% CI: -12.1 to +7.8%) in Peru to -59.9% (95% CI: -68.6% to -51.3%) in China for chronic respiratory illness visits. While seasonal variation in allergic respiratory illness continued during the pandemic, there was essentially no spike in influenza illness during the first 2 years of the pandemic. Conclusion: The COVID-19 pandemic had a major impact on primary care visits for respiratory presentations. Primary care continued to provide services for respiratory illness, although there was a decrease in infectious illness during the COVID pandemic. Understanding the role of primary care may provide valuable information for COVID-19 recovery efforts and planning for future global emergencies.

ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma.

Cancer cellular heterogeneity and therapy resistance arise substantially from metabolic and transcriptional adaptations, but how these are interconnected is poorly understood. Here, we show that, in melanoma, the cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) forms an enzymatic partnership with acetyl-coenzyme A (CoA) synthetase 2 (ACSS2) in the nucleus to couple high glucose metabolic flux with acetyl-histone H3 modification of neural crest (NC) lineage and glucose metabolism genes. Importantly, we show that acetaldehyde is a metabolite source for acetyl-histone H3 modification in an ALDH1A3-dependent manner, providing a physiologic function for this highly volatile and toxic metabolite. In a zebrafish melanoma residual disease model, an ALDH1-high subpopulation emerges following BRAF inhibitor treatment, and targeting these with an ALDH1 suicide inhibitor, nifuroxazide, delays or prevents BRAF inhibitor drug-resistant relapse. Our work reveals that the ALDH1A3-ACSS2 couple directly coordinates nuclear acetaldehyde-acetyl-CoA metabolism with specific chromatin-based gene regulation and represents a potential therapeutic vulnerability in melanoma.