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Post-COVID conditions (PCCs) are common and have significant morbidity. Risk factors for PCC include advancing age, female sex, obesity, and diabetes mellitus. Little is known about treatment, inflammation, and PCC. Among 882 individuals with confirmed SARS-CoV-2 infection participating in a randomized trial of COVID-19 convalescent plasma (CCP) vs control plasma with available biospecimens and symptom data, the association between early CCP treatment, cytokine levels, and PCC was evaluated. Cytokine and chemokine levels were assessed at baseline, day 14, and day 90 using a multiplexed sandwich immunoassay (Meso Scale Discovery). Presence of any self-reported PCC symptoms was assessed at day 90. Associations between CCP treatment, cytokine levels, and PCC were examined using multivariate logistic regression models. One third of the 882 participants had day 90 PCC symptoms, with fatigue (14.5%) and anosmia (14.5%) being most common. Cytokine levels decreased from baseline to day 90. In a multivariable analysis, female sex (adjusted odds ratio [AOR] = 2.69 [1.93-3.81]), older age (AOR = 1.32 [1.17-1.50]), and elevated baseline levels of IL-6 (AOR = 1.59 [1.02-2.47]) were independently associated with development of PCC. Those who received early CCP treatment (≤5 days after symptom onset) compared to late CCP treatment had statistically significant lower odds of PCC. IMPORTANCE Approximately 20% of individuals infected with SARS-CoV-2 experienced long-term health effects, as defined PCC. However, it is unknown if there are any early biomarkers associated with PCC or whether early intervention treatments may decrease the risk of PCC. In a secondary analysis of a randomized clinical trial, this study demonstrates that among outpatients with SARS-CoV-2, increased IL-6 at time of infection is associated with increased odds of PCC. In addition, among individuals treated early, within 5 days of symptom onset, with COVID-19 convalescent plasma, there was a trend for decreased odds of PCC after adjusting for other demographic and clinical characteristics. Future treatment studies should be considered to evaluate the effect of early treatment and anti-IL-6 therapies on PCC development.

BACKGROUND: The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000). METHODS: This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch. RESULTS: Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal sentinel surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. CONCLUSIONS: The consortiums aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies. FUNDING: No specific funding was awarded for this meta-analysis. Coordinators were supported by fellowships from the European Union (ZAD received funding from the European Unions Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 845681), the Wellcome Trust (SB, Wellcome Trust Senior Fellowship), and the National Health and Medical Research Council (DJI is supported by an NHMRC Investigator Grant [GNT1195210]).

BACKGROUND: COVID-19 convalescent plasma (CCP) is an important therapeutic option for outpatients at high risk of hospitalization from SARS-CoV-2 infection. We assessed the safety of outpatient CCP transfusions administered during clinical trials. STUDY DESIGN AND METHODS: We analyzed data pertaining to transfusion-related reactions from two randomized controlled trials in the U.S. that evaluated the efficacy of CCP versus control plasma in various ambulatory settings. Multivariable logistic regression was used to assess whether CCP was associated with transfusion reactions, after adjusting for potential confounders. RESULTS: The combined study reported 79/1351 (5.9%) adverse events during the transfusion visit, with the majority 62/1351 (4.6%) characterized by mild, allergic-type findings of urticaria, and/or pruritus consistent with minor allergic transfusion reactions; the other reported events were attributed to the patients underlying disease, COVID-19, or vasovagal in nature. We found no difference in the likelihood of allergic transfusion reactions between those receiving CCP versus control plasma (adjusted odds ratio [AOR], 0.75; 95% CI, 0.43-1.31). Risk of urticaria and/or pruritus increased with a pre-existing diagnosis of asthma (AOR, 2.33; 95% CI, 1.16-4.67). We did not observe any CCP-attributed antibody disease enhancement in participants with COVID-19 or increased risk of infection. There were no life-threatening severe transfusion reactions and no patients required hospitalization related to transfusion-associated complications. DISCUSSION: Outpatient plasma administration was safely performed for nearly 1400 participants. CCP is a safe therapeutic option for outpatients at risk of hospitalization from COVID-19.

Stress triggers anticipatory physiological responses that promote survival, a phenomenon termed allostasis. However, the chronic activation of energy-dependent allostatic responses results in allostatic load, a dysregulated state that predicts functional decline, accelerates aging, and increases mortality in humans. The energetic cost and cellular basis for the damaging effects of allostatic load have not been defined. Here, by longitudinally profiling three unrelated primary human fibroblast lines across their lifespan, we find that chronic glucocorticoid exposure increases cellular energy expenditure by ∼60%, along with a metabolic shift from glycolysis to mitochondrial oxidative phosphorylation (OxPhos). This state of stress-induced hypermetabolism is linked to mtDNA instability, non-linearly affects age-related cytokines secretion, and accelerates cellular aging based on DNA methylation clocks, telomere shortening rate, and reduced lifespan. Pharmacologically normalizing OxPhos activity while further increasing energy expenditure exacerbates the accelerated aging phenotype, pointing to total energy expenditure as a potential driver of aging dynamics. Together, our findings define bioenergetic and multi-omic recalibrations of stress adaptation, underscoring increased energy expenditure and accelerated cellular aging as interrelated features of cellular allostatic load.

BACKGROUND: Cytokines and chemokines play a critical role in the response to infection and vaccination. We aimed to assess the longitudinal association of COVID-19 vaccination with cytokine and chemokine concentrations and trajectories among people with SARS-CoV-2 infection. METHODS: In this longitudinal, prospective cohort study, blood samples were used from participants enrolled in a multi-centre randomised trial assessing the efficacy of convalescent plasma therapy for ambulatory COVID-19. The trial was conducted in 23 outpatient sites in the USA. In this study, participants (aged ≥18 years) were restricted to those with COVID-19 before vaccination or with breakthrough infections who had blood samples and symptom data collected at screening (pre-transfusion), day 14, and day 90 visits. Associations between COVID-19 vaccination status and concentrations of 21 cytokines and chemokines (measured using multiplexed sandwich immunoassays) were examined using multivariate linear mixed-effects regression models, adjusted for age, sex, BMI, hypertension, diabetes, trial group, and COVID-19 waves (pre-alpha or alpha and delta). FINDINGS: Between June 29, 2020, and Sept 30, 2021, 882 participants recently infected with SARS-CoV-2 were enrolled, of whom 506 (57%) were female and 376 (43%) were male. 688 (78%) of 882 participants were unvaccinated, 55 (6%) were partly vaccinated, and 139 (16%) were fully vaccinated at baseline. After adjusting for confounders, geometric mean concentrations of interleukin (IL)-2RA, IL-7, IL-8, IL-15, IL-29 (interferon-λ), inducible protein-10, monocyte chemoattractant protein-1, and tumour necrosis factor-α were significantly lower among the fully vaccinated group than in the unvaccinated group at screening. On day 90, fully vaccinated participants had approximately 20% lower geometric mean concentrations of IL-7, IL-8, and vascular endothelial growth factor-A than unvaccinated participants. Cytokine and chemokine concentrations decreased over time in the fully and partly vaccinated groups and unvaccinated group. Log10 cytokine and chemokine concentrations decreased faster among participants in the unvaccinated group than in other groups, but their geometric mean concentrations were generally higher than fully vaccinated participants at 90 days. Days since full vaccination and type of vaccine received were not correlated with cytokine and chemokine concentrations. INTERPRETATION: Initially and during recovery from symptomatic COVID-19, fully vaccinated participants had lower concentrations of inflammatory markers than unvaccinated participants suggesting vaccination is associated with short-term and long-term reduction in inflammation, which could in part explain the reduced disease severity and mortality in vaccinated individuals. FUNDING: US Department of Defense, National Institutes of Health, Bloomberg Philanthropies, State of Maryland, Mental Wellness Foundation, Moriah Fund, Octapharma, HealthNetwork Foundation, and the Shear Family Foundation.

Using DNA methylation profiles (n = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in HOXL subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors. The methylation state of some modules responds to perturbations such as caloric restriction, ablation of growth hormone receptors, consumption of high-fat diets, and expression of Yamanaka factors. This study reveals an intertwined evolution of the genome and epigenome that mediates the biological characteristics and traits of different mammalian species.

BackgroundPatients with acute myeloid leukemia (AML) who have tumor protein p53 (TP53) mutations or a complex karyotype have a poor prognosis, and hypomethylating agents are often used. The authors evaluated the efficacy of entospletinib, an oral inhibitor of spleen tyrosine kinase, combined with decitabine in this patient population.MethodsThis was a multicenter, open-label, phase 2 substudy of the Beat AML Master Trial (ClinicalTrials.gov identifier NCT03013998) using a Simon two-stage design. Eligible patients aged 60 years or older who had newly diagnosed AML with mutations in TP53 with or without a complex karyotype (cohort A; n = 45) or had a complex karyotype without TP53 mutation (cohort B; n = 13) received entospletinib 400 mg twice daily with decitabine 20 mg/m2 on days 1-10 every 28 days for up to three induction cycles, followed by up to 11 consolidation cycles, in which decitabine was reduced to days 1-5. Entospletinib maintenance was given for up to 2 years. The primary end point was complete remission (CR) and CR with hematologic improvement by up to six cycles of therapy.ResultsThe composite CR rates for cohorts A and B were 13.3% (95% confidence interval, 5.1%-26.8%) and 30.8% (95% confidence interval, 9.1%-61.4%), respectively. The median duration of response was 7.6 and 8.2 months, respectively, and the median overall survival was 6.5 and 11.5 months, respectively. The study was stopped because the futility boundary was crossed in both cohorts.ConclusionsThe combination of entospletinib and decitabine demonstrated activity and was acceptably tolerated in this patient population; however, the CR rates were low, and overall survival was short. Novel treatment strategies for older patients with TP53 mutations and complex karyotype remain an urgent need.

Earth system models (ESMs) typically simplify the representation of land surface spectral albedo to two values, which correspond to the photosynthetically active radiation (PAR, 400–700 nm) and the near infrared (NIR, 700–2,500 nm) spectral bands. However, the availability of hyperspectral observations now allows for a more direct retrieval of ecological parameters and reduction of uncertainty in surface reflectance. To investigate sensitivity and quantify biases of incorporating hyperspectral albedo information into ESMs, we examine how shortwave soil albedo affects surface radiative forcing and simulations of the carbon and water cycles. Results reveal that the use of two broadband values to represent soil albedo can introduce systematic radiative-forcing differences compared to a hyperspectral representation. Specifically, we estimate soil albedo biases of ±0.2 over desert areas, which can result in spectrally integrated radiative forcing divergences of up to 30 W m−2, primarily due to discrepancies in the blue (404–504 nm) and far-red (702–747 nm) regions. Furthermore, coupled land-atmosphere simulations indicate a significant difference in net solar flux at the top of the atmosphere (>3.3 W m−2), which can impact global energy fluxes, rainfall, temperature, and photosynthesis. Finally, simulations show that considering the hyperspectrally resolved soil reflectance leads to increased maximum daily temperatures under current and future CO2 concentrations.

Forecasts about future emotion are often inaccurate, so why do people rely on them to make decisions? People may forecast some features of their emotional experience better than others, and they may report relying on forecasts that are more accurate to make decisions. To test this, four studies assessed the features of emotion people reported forecasting to make decisions about their careers, education, politics, and health. In Study 1, graduating medical students reported relying more on forecast emotional intensity than frequency or duration to decide how to rank residency programs as part of the process of being matched with a program. Similarly, participants reported relying more on forecast emotional intensity than frequency or duration to decide which universities to apply to (Study 2), which presidential candidate to vote for (Study 3), and whether to travel as Covid-19 rates declined (Study 4). Studies 1 and 3 also assessed forecasting accuracy. Participants forecast emotional intensity more accurately than frequency or duration. People make better decisions when they can anticipate the future. Thus, people's reports of relying on forecast emotional intensity to guide life-changing decisions, and the greater accuracy of these forecasts, provide important new evidence of the adaptive value of affective forecasts.

BACKGROUND: Influenza vaccination is recommended for adults regardless of human immunodeficiency virus (HIV) status. There may be facilitators or barriers to vaccinating people with HIV (PWH) that differ from people without HIV (PWoH). We sought to describe the uptake of influenza vaccination by HIV status and identify factors associated with vaccination. METHODS: We abstracted data from the electronic health records of PWH and PWoH in Kaiser Permanente Northern California during 6 influenza seasons (2013-2018). We determined vaccination uptake and used Poisson regression models to evaluate factors associated with vaccination in PWH and PWoH. RESULTS: 9272 PWH and 194 393 PWoH matched by age, sex, and race/ethnicity were included (mean age: 48 vs 49 years; men: 91% vs 90%; White race: 53% for both groups). PWH were more likely to receive the influenza vaccine (65-69% across years for PWH and 37-41% for PWoH) with an adjusted risk ratio for all years of 1.48 (95% CI: 1.46-1.50). For PWH, lower vaccination uptake was associated with several factors that suggested more complex health needs, such as lower CD4 cell counts, higher HIV viral loads, prior depression diagnoses, having Medicare insurance, and having a higher number of comorbidities. Associations with vaccination uptake were attenuated in PWH, compared with PWoH, for smoking, alcohol, and demographic factors. CONCLUSIONS: PWH had an almost 50% higher uptake of influenza vaccination than PWoH, possibly reflecting greater engagement with the healthcare system. We also found that PWH with more complex health needs had reduced vaccination uptake. Findings may inform outreach strategies to increase influenza vaccination in PWH.

BackgroundCancer-related cognitive impairment (CRCI) is a common symptom in patients with breast cancer. In our previous study of 397 women with breast cancer, we identified 3 groups of patients with distinct CRCI profiles (ie, high, moderate, and low-moderate attentional function). Compared with the other 2 classes, the low-moderate class was younger, had more comorbidities, and with lower functional status.ObjectivesIn this study, we expand on this work and evaluate for differences among these latent classes in the severity of psychological (depression and anxiety) and physical (fatigue, decrements in energy, sleep disturbance, and pain) symptoms before surgery.MethodsCancer-related cognitive impairment was assessed using the Attentional Functional Index from before through 6 months after surgery. Lower Attentional Functional Index scores indicate higher levels of CRCI. Psychological and physical symptoms were assessed with valid instruments. Parametric and nonparametric tests were used to evaluate for differences in symptom severity scores among the latent classes.ResultsApproximately 60% of patients experienced CRCI (ie, moderate and low-moderate classes). Significant differences were found among the 3 classes in the severity of trait and state anxiety, depressive symptoms, fatigue, and sleep disturbance (ie, high < moderate < low-moderate). In addition, compared with the other 2 classes, the low-moderate class reported higher pain interference scores.ConclusionsThese findings suggest that women with clinically meaningful levels of persistent CRCI have a relatively high symptom burden before surgery.Implications for practiceClinicians need to routinely perform preoperative assessments of CRCI and associated symptoms and initiate therapeutic interventions.

BACKGROUND: Morning and evening fatigue are distinct and distressing symptoms experienced during chemotherapy that demonstrate a large amount of interindividual variability. OBJECTIVES: The objectives of this study were to identify subgroups of patients with distinct morning and evening fatigue co-occurrence profiles and evaluate for differences among these subgroups in demographic, clinical, and symptom characteristics and quality of life. METHODS: Oncology patients ( n = 1,334) completed the Lee Fatigue Scale to self-report morning and evening fatigue, six times over two cycles of chemotherapy. Latent profile analysis was used to identify subgroups of patients with distinct morning and evening physical fatigue profiles. RESULTS: Four distinct morning and evening fatigue profiles were identified (i.e., Both Low, Low Morning + Moderate Evening, Both Moderate, and Both High). Compared to the Both Low profile, the Both High profile was significantly younger, less likely to be married or partnered, more likely to live alone, had a higher comorbidity burden, and lower functional status. The Both High profile had higher levels of anxiety, depressive symptoms, sleep disturbance, and pain and lower levels of quality of life. DISCUSSION: The variability in the morning and evening severity scores among the four profiles supports the hypothesis that morning and evening fatigue are distinct but related symptoms. Clinically meaningful levels of both morning and evening fatigue were reported by 50.4% of our sample, which suggests that the co-occurrence of these two symptoms is relatively common. Patients in Both Moderate and Both High profiles experienced an extremely high symptom burden that warrants ongoing assessments and aggressive symptom management interventions.

BackgroundUp to 45% of patients report cancer-related cognitive impairment (CRCI). A variety of characteristics are associated with the occurrence and/or severity of CRCI. However, an important gap in knowledge of risk factors for CRCI is the relative contribution of each factor. The multifactorial model of cancer-related cognitive impairment (MMCRCI) is a conceptual model of CRCI that can be used to evaluate the strength of relationships between various factors and CRCI.ObjectivesThe purpose of this study was to use structural regression methods to evaluate the MMCRCI using data from a large sample of outpatients receiving chemotherapy ( n = 1,343). Specifically, the relationships between self-reported CRCI and four MMCRCI concepts (i.e., social determinants of health, patient-specific factors, treatment factors, and co-occurring symptoms) were examined. The goals were to determine how well the four concepts predicted CRCI and determine the relative contribution of each concept to deficits in perceived cognitive function.MethodsThis study is part of a larger, longitudinal study that evaluated the symptom experience of oncology outpatients receiving chemotherapy. Adult patients were diagnosed with breast, gastrointestinal, gynecological, or lung cancer; had received chemotherapy within the preceding 4 weeks; were scheduled to receive at least two additional cycles of chemotherapy; were able to read, write, and understand English; and gave written informed consent. Self-reported CRCI was assessed using the attentional function index. Available study data were used to define the latent variables.ResultsOn average, patients were 57 years of age, college educated, and with a mean Karnofsky Performance Status score of 80. Of the four concepts evaluated, whereas co-occurring symptoms explained the largest amount of variance in CRCI, treatment factors explained the smallest amount of variance. A simultaneous structural regression model that estimated the joint effect of the four exogenous latent variables on the CRCI latent variable was not significant.DiscussionThese findings suggest that testing individual components of the MMCRCI may provide useful information on the relationships among various risk factors, as well as refinements of the model. In terms of risk factors for CRCI, co-occurring symptoms may be more significant than treatment factors, patient-specific factors, and/or social determinants of health in patients receiving chemotherapy.

Genome-wide association studies (GWAS) of Alzheimer's disease are predominantly carried out in European ancestry individuals despite the known variation in genetic architecture and disease prevalence across global populations. We leveraged published GWAS summary statistics from European, East Asian, and African American populations, and an additional GWAS from a Caribbean Hispanic population using previously reported genotype data to perform the largest multi-ancestry GWAS meta-analysis of Alzheimer's disease and related dementias to date. This method allowed us to identify two independent novel disease-associated loci on chromosome 3. We also leveraged diverse haplotype structures to fine-map nine loci with a posterior probability >0.8 and globally assessed the heterogeneity of known risk factors across populations. Additionally, we compared the generalizability of multi-ancestry- and single-ancestry-derived polygenic risk scores in a three-way admixed Colombian population. Our findings highlight the importance of multi-ancestry representation in uncovering and understanding putative factors that contribute to risk of Alzheimer's disease and related dementias.

For more than a century, the Supreme Court has applied the unconstitutional conditions doctrine in many contexts, scrutinizing government efforts to condition the tradeoff of rights for benefits with regard to speech, funding, and takings, among others. The Court has declined, however, to invoke the doctrine in the area of criminal procedure, where people accused of crime are often asked to--and often do--surrender their constitutional rights under the Fourth, Fifth, and Sixth Amendments in return for some benefit. Despite its insistence that the unconstitutional conditions doctrine applies broadly across the Bill of Rights, the Court's jurisprudence demonstrates that the doctrine functions as a selective shield that offers no support for certain rightsholders. We argue that the Court's approach undermines vital rights, with especially harmful consequences for people who most need judicial protection. Since individuals accused of crime are often extremely vulnerable to coercive government measures, the important safeguards offered by the unconstitutional conditions doctrine should be at their height in the criminal procedure setting. Indeed, lower federal courts and some state courts have applied the doctrine to criminal procedure issues, demonstrating the doctrine's utility in this domain. We conclude that the Supreme Court's aversion to leveraging the unconstitutional conditions doctrine in its criminal procedure docket rests not on a principled doctrinal distinction, but on a failure to take seriously the constitutional predicaments facing those charged with crimes. In accordance with its obligation to render equal justice under law, the Court must apply the unconstitutional conditions doctrine in this most critical area., ARTICLE CONTENTS INTRODUCTION 1405 I. CURRENT SCHOLARSHIP ON THE UNCONSTITUTIONAL CONDITIONS DOCTRINE 1412 II. THE UNCONSTITUTIONAL CONDITIONS LANDSCAPE IN SUPREME COURT JURISPRUDENCE 1415 A. First Amendment Unconstitutional Conditions 1417 Jurisprudence: [...]

PURPOSE Physically or psychologically distressing birth experiences can influence postpartum health, parenting efficacy, and future pregnancy plans. Communication deficits contribute to negative birth experiences. This qualitative analysis explored themes related to communication and negative birth experiences among Black birthing people who experienced preterm birth. METHODS We conducted qualitative interviews with non-Hispanic Black, English language-proficient birthing people with Medicaid-insured preterm infants. Interviews were designed to explore experiences with health care access and well-being after birth. Interviews were audio recorded, transcribed, and coded following an integrated approach where we applied a priori codes and captured emergent themes from the data. RESULTS We interviewed 30 participants from October 2018 to July 2021. Median gestational age at birth was 30 weeks (range 22-36 weeks). Interviews occurred a median of 7 months postpartum (range 2-34 months). Themes emerged related to negative birth experiences and communication: (1) communication gaps during urgent or emergent intrapartum procedures contributed to negative birth experiences; (2) postpartum opportunities to share birth experiences, particularly with peers, sometimes mitigated the psychological consequences of negative birth experiences; (3) participants did not consistently discuss concerns about future pregnancy risk related to negative birth experiences with clinical teams. CONCLUSIONS Themes from this sample of Black birthing people who experienced preterm birth suggest 3 ways health systems might intervene to improve communication to mitigate the consequences of negative birth experiences. Improvement efforts in these areas may improve postpartum health, future pregnancy outcomes, and long-term health. Key words: African American; birth trauma; Black; Black birthing people; interconception care; intrapartum care; negative birth experience; preconception care; reproductive justice; health communication; postpartum care, INTRODUCTION Birth experiences sometimes cause psychological distress, persistent feelings of anger or loss, or depression and posttraumatic stress disorder. (1-4) These negative birth experiences and their sequelae can influence women's [...]