Cancer-related cognitive impairment as a key contributor to psychopathology in cancer survivors: implications for prevention, treatment and supportive care.

A significant proportion of cancer survivors will experience some form of mental health compromise across domains including mood, anxiety, psychosis, eating disorders, and substance use. This psychopathology within cancer survivors is related to a range of negative outcomes and can also have a substantial negative impact on quality of life. Along with psychopathology, cognitive impairments are also commonly experienced, resulting in deficits in memory, reasoning, decision-making, speed of processing, and concentration, collectively referred to as cancer-related cognitive impairment (CRCI). Within the non-oncology literature, cognitive deficits are consistently demonstrated to be a key transdiagnostic aetiological feature of psychopathology, functionally contributing to the development and perpetuation of symptoms. Whilst there is an acknowledgement of the role mental health concerns might play in the development of and perception of CRCI, there has been limited acknowledgement and research exploring the potential for CRCI to functionally contribute toward the development of transdiagnostic psychopathology in cancer survivors beyond simply psychosocial distress. Given the theoretical and empirical evidence suggesting cognitive deficits to be an aetiological factor in psychopathology, we provide a rationale for the potential for CRCI to be a factor in the development and perpetuation of transdiagnostic psychopathology in cancer survivors. This potential functional association has significant implications for risk identification, prevention, treatment, and supportive cancer care approaches regarding psychopathology in cancer survivorship. We conclude by providing directions for future research in this area.

Colorado Tick Fever in the United States, 2013-2022.

Colorado tick fever (CTF) virus is an arbovirus maintained in an enzootic cycle between Rocky Mountain wood ticks (Dermacentor andersoni) and rodent species in the western United States. Individuals with CTF typically present with symptoms including fever, headache, myalgia, and lethargy, with a biphasic illness frequently occurring. We reviewed data on CTF cases reported to the national U.S. arboviral disease surveillance system and identified through testing at the CDC to characterize the epidemiology of CTF from 2013-2022. During this period, 148 CTF cases were identified, all likely infected in an endemic area in one of six states (Montana, Wyoming, Oregon, Colorado, Utah, Idaho). A median of 11 cases (range: 5-37) were identified per year, with an average annual national incidence of 0.04 cases per million population. The median age of cases was 55 years (range: 1-84 years), and 96 (65%) were male. Most (n = 145; 98%) cases acquired infection from April through July. The hospitalization rate was 16% (16 of 102 cases with data), and no deaths were reported. These findings substantiate the continued circulation of CTF virus in the western United States, highlighting the importance of implementing approaches to ensure CTF awareness for medical providers and providing education on tick bite prevention strategies for residents and visitors to risk areas.

Utility of Targeted Sequencing Compared to FISH for Detection of Chronic Lymphocytic Leukemia Copy Number Alterations.

Chronic lymphocytic leukemia (CLL) is characterized by multiple copy number alterations (CNAs) and somatic mutations that are central to disease prognosis, risk stratification, and mechanisms of therapy resistance. Fluorescence in situ hybridization (FISH) panels are widely used in clinical applications as the gold standard for screening prognostic chromosomal abnormalities in CLL. DNA sequencing is an alternative approach to identifying CNAs but is not an established method for clinical CNA screening. We sequenced DNA from 509 individuals with CLL or monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, using a targeted sequencing panel of 59 recurrently mutated genes in CLL and additional amplicons across regions affected by clinically relevant CNAs [i.e., del(17p), del(11q), del(13q), and trisomy 12]. We used the PatternCNV algorithm to call CNA and compared the concordance of calling clinically relevant CNAs by targeted sequencing to that of FISH. We found a high accuracy of calling CNAs via sequencing compared to FISH. With FISH as the gold standard, the specificity of targeted sequencing was >95%, sensitivity was >86%, positive predictive value was >90%, and negative predictive value was >84% across the clinically relevant CNAs. Using targeted sequencing, we were also able to identify other common CLL-associated CNAs, including del(6q), del(14q), and gain 8q, as well as complex karyotype, defined as the presence of 3 or more chromosomal abnormalities, in 26 patients. In a single and cost-effective assay that can be performed on stored DNA samples, targeted sequencing can simultaneously detect CNAs, somatic mutations, and complex karyotypes, which are all important prognostic features in CLL.

Backtranslation of human RNA biosignatures of tuberculosis disease risk into the preclinical pipeline is condition dependent.

It is not clear whether human progression to active tuberculosis disease (TB) risk signatures are viable endpoint criteria for evaluations of treatments in clinical or preclinical development. TB is the deadliest infectious disease globally and more efficacious vaccines are needed to reduce this mortality. However, the immune correlates of protection for either preventing infection with Mycobacterium tuberculosis or preventing TB disease have yet to be completely defined, making the advancement of candidate vaccines through the pipeline slow, costly, and fraught with risk. Human-derived correlate of risk (COR) gene signatures, which identify an individual's risk to progressing to active TB disease, provide an opportunity for evaluating new therapies for TB with clear and defined endpoints. Though prospective clinical trials with longitudinal sampling are prohibitively expensive, characterization of COR gene signatures is practical with preclinical models. Using a 3Rs (Replacement, Reduction and Refinement) approach we reanalyzed heterogeneous publicly available transcriptional datasets to determine whether a specific set of COR signatures are viable endpoints in the preclinical pipeline. We selected RISK6, Sweeney3 and BATF2 human-derived blood-based RNA biosignatures because they require relatively few genes to assign a score and have been carefully evaluated across several clinical cohorts. Excitingly, these data provide proof-of-concept that human COR signatures seem to have high fidelity across several tissue types in the preclinical TB model pipeline and show best performance when the model most closely reflected human infection or disease conditions. Human-derived COR signatures offer an opportunity for high-throughput preclinical endpoint criteria of vaccine and drug therapy evaluations. One Sentence Summary: Human-derived biosignatures of tuberculosis disease progression were evaluated for their predictive fidelity across preclinical species and derived tissues using available public data sets.

Acute Kidney Injury in Inflammatory Bowel Disease Patients: A Nationwide Comparative Analysis.

Rationale & Objective: About 25%-40% of patients with inflammatory bowel disease (IBD) may have extraintestinal manifestations, mainly involving the liver, skin, and joints. Kidney involvement in patients with IBD has been reported, but there are no estimates of its prevalence in population-based studies in the United States. We compared the frequency of acute kidney injury (AKI) among hospitalizations with IBD with that among hospitalizations with collagen vascular diseases and hospitalizations with neither condition. Study Design: Retrospective, population-based cohort study. Setting & Participants: Healthcare Cost and Utilization Project-Nationwide Inpatient Sample database. Outcomes: AKI and AKI requiring dialysis. Analytical Approach: Regression models were used to compare the occurrence of AKI among groups. Inverse probability of treatment weighting was applied to balance groups on covariates. Results: The final sample comprised 5,735,804 hospitalizations, including 57,121 with IBD, 159,930 with collagen vascular diseases, and 5,518,753 with neither IBD nor collagen vascular diseases. AKI was observed in 13%, 15%, and 12.2% of hospitalizations with IBD, collagen vascular diseases, and the general population, respectively. When adjusting for demographic, hospital, and clinical characteristics using inverse probability of treatment weighting, hospitalizations with IBD had higher odds of being diagnosed with AKI than both those with collagen vascular diseases (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.27-1.38) and the general population (OR, 1.27; 95% CI, 1.23-1.31) and also had higher odds of being diagnosed with AKI requiring dialysis than those with collagen vascular diseases (OR, 1.59; 95% CI, 1.31-1.94) or than the general population (OR, 1.45; 95% CI, 1.25-1.68). Limitations: Cross-sectional analysis, underreporting of International Classification of Diseases codes, and analyses relevant to in-hospital stays only. Conclusions: The prevalence and risk of AKI among hospitalizations with IBD is greater than that of hospitalizations with collagen vascular diseases and the general population. Coexisting kidney disease should be considered among patients with a known diagnosis of IBD.

As a nephrologist, we have evaluated many patients with inflammatory bowel disease with various forms of kidney disease, both inflammatory and noninflammatory. Based on a multitude of factors, we have always wondered if there are shared immune mechanisms between the gut and kidney that could explain the underlying inflammation in both organs. In addition, based on recent studies of other autoimmune/inflammatory diseases, there is growing interest in the role of the gut microbiome (microorganisms that reside in our gut) and its influence on the immune system as well as how both the altered microbiome and immune system affect the kidneys. As a first step, we wanted to understand if some forms of kidney disease are more prevalent in patients with inflammatory bowel disease than in the general population, which possibly suggests a shared pathogenesis.

HIV Subtypes and Drug-resistance-associated Mutations in US Blood Donors, 2015-2020.

Background: Monitoring genotypes of HIV infections in blood donors may provide insights into infection trends in the general population. Methods: HIV RNA was extracted from plasma samples of blood donors confirmed as HIV positive by blood screening nucleic acid and antibody tests. HIV genome target regions were amplified using nested real time-polymerase chain reaction followed by next-generation sequencing. Sequences were compared to those in the Los Alamos National Laboratory (LANL) database. Sequences were also assessed for drug resistance mutations (DRM) using the Stanford HIV DRM Database. Results: From available HIV-positive donations collected between 1 September 2015 and 31 December 2020, 563 of 743 (75.8%) were successfully sequenced; 4 were subtype A, 543 subtype B, 5 subtype C, 1 subtype G, 5 circulating recombinant forms (CRF), and 2 were subtype B and D recombinants. Overall, no significant differences between blood donor and available LANL genotypes were found, and the genotypes of newly acquired versus prevalent HIV infections in donors were similar. The proportion of non-B subtypes and CRF remained a small fraction, with no other subtype or CRF representing more than 1% of the total. DRM were identified in 122 (21.6%) samples with protease inhibitor, nucleoside reverse transcriptase inhibitor and non-nucleoside reverse transcriptase inhibitor DRMs identified in 4.9%, 4.6% and 14.0% of samples, respectively. Conclusions: HIV genetic diversity and DRM in blood donors appear representative of circulating HIV infections in the US general population and may provide more information on infection diversity than sequences reported to LANL, particularly for recently transmitted infections.

Genetic and multi-omic resources for Alzheimer disease and related dementia from the Knight Alzheimer Disease Research Center.

The Knight-Alzheimer Disease Research Center (Knight-ADRC) at Washington University in St. Louis has pioneered and led worldwide seminal studies that have expanded our clinical, social, pathological, and molecular understanding of Alzheimer Disease. Over more than 40 years, research volunteers have been recruited to participate in cognitive, neuropsychologic, imaging, fluid biomarkers, genomic and multi-omic studies. Tissue and longitudinal data collected to foster, facilitate, and support research on dementia and aging. The Genetics and high throughput -omics core (GHTO) have collected of more than 26,000 biological samples from 6,625 Knight-ADRC participants. Samples available include longitudinal DNA, RNA, non-fasted plasma, cerebrospinal fluid pellets, and peripheral blood mononuclear cells. The GHTO has performed deep molecular profiling (genomic, transcriptomic, epigenomic, proteomic, and metabolomic) from large number of brain (n = 2,117), CSF (n = 2,012) and blood/plasma (n = 8,265) samples with the goal of identifying novel risk and protective variants, identify novel molecular biomarkers and causal and druggable targets. Overall, the resources available at GHTO support the increase of our understanding of Alzheimer Disease.

Protective interplay: Mycobacterium tuberculosis diminishes SARS-CoV-2 severity through innate immune priming.

At the beginning of the COVID-19 pandemic those with underlying chronic lung conditions, including tuberculosis (TB), were hypothesized to be at higher risk of severe COVID-19 disease. However, there is inconclusive clinical and preclinical data to confirm the specific risk SARS-CoV-2 poses for the millions of individuals infected with Mycobacterium tuberculosis (M.tb). We and others have found that compared to singly infected mice, mice co-infected with M.tb and SARS-CoV-2 leads to reduced SARS-CoV-2 severity compared to mice infected with SARS-CoV-2 alone. Consequently, there is a large interest in identifying the molecular mechanisms responsible for the reduced SARS-CoV-2 infection severity observed in M.tb and SARS-CoV-2 co-infection. To address this, we conducted a comprehensive characterization of a co-infection model and performed mechanistic in vitro modeling to dynamically assess how the innate immune response induced by M.tb restricts viral replication. Our study has successfully identified several cytokines that induce the upregulation of anti-viral genes in lung epithelial cells, thereby providing protection prior to challenge with SARS-CoV-2. In conclusion, our study offers a comprehensive understanding of the key pathways induced by an existing bacterial infection that effectively restricts SARS-CoV-2 activity and identifies candidate therapeutic targets for SARS-CoV-2 infection.

Process of Withdrawal of Mechanical Ventilation at End of Life in the ICU: Clinician Perceptions.

BACKGROUND: Nearly one-quarter of all Americans die in the ICU. Many of their deaths are anticipated and occur following the withdrawal of mechanical ventilation (WMV). However, there are few data on which to base best practices for interdisciplinary ICU teams to conduct WMV. RESEARCH QUESTION: What are the perceptions of current WMV practices among ICU clinicians, and what are their opinions of processes that might improve the practice of WMV at end of life in the ICU? STUDY DESIGN AND METHODS: This prospective two-center observational study conducted in Boston, Massachusetts, the Observational Study of the Withdrawal of Mechanical Ventilation (OBSERVE-WMV) was designed to better understand the perspectives of clinicians and experience of patients undergoing WMV. This report focuses on analyses of qualitative data obtained from in-person surveys administered to the ICU clinicians (nurses, respiratory therapists, and physicians) caring for these patients. Surveys assessed a broad range of clinician perspectives on planning, as well as the key processes required for WMV. This analysis used independent open, inductive coding of responses to open-ended questions. Initial codes were reconciled iteratively and then organized and interpreted using a thematic analysis approach. Opinions were assessed on how WMV could be improved for individual patients and the ICU as a whole. RESULTS: Among 456 eligible clinicians, 312 in-person surveys were completed by clinicians caring for 152 patients who underwent WMV. Qualitative analyses identified two main themes characterizing high-quality WMV processes: (1) good communication (eg, mutual understanding of family preferences) between the ICU team and family; and (2) medical management (eg, planning, availability of ICU team) that minimizes patient distress. Team member support was identified as an essential process component in both themes. INTERPRETATION: Clinician perceptions of the appropriateness or success of WMV prioritize the quality of team and family communication and patient symptom management. Both are modifiable targets of interventions aimed at optimizing overall WMV.

Vitamin D and its associations with blood pressure in the Chronic Kidney Disease in Children (CKiD) cohort.

BACKGROUND: Vitamin D (25OHD) can modulate pathways and mechanisms that regulate blood pressure (BP). Observational studies in children and adults have shown an inverse association between 25OHD and BP. Studies evaluating associations between 25OHD and BP in pediatric chronic kidney disease are limited. METHODS: We evaluated the associations between 25OHD and BP using data from the Chronic Kidney Disease in Children (CKiD) study. Clinic or ambulatory BP index was defined as participant's BP divided by 95th age-sex-height-specific BP percentile, an index > 1 suggests hypertension. Primary outcomes of interest were changes in systolic and diastolic clinic and ambulatory BP indices over follow-up. Linear mixed-effects models were used to evaluate associations between BP indices and 25OHD. RESULTS: The study cohort consisted of 370 participants who contributed 970 person-visits. A subset of 194 participants with ambulatory BP data contributed 465 person-visits. There was an association between baseline 25OHD levels and clinic systolic BP index such that for every 10 ng/ml lower 25OHD, clinic systolic BP index was 1.0% higher (95%CI: 0.2-1.8, p = 0.016) between participants. The association between clinic diastolic BP index with baseline 25OHD was not significant. For within-person changes, longitudinal decreases in 25OHD were not significantly associated with concomitant increases in clinic systolic or diastolic BP index. There were no significant associations between 25OHD levels at baseline or longitudinally with 24-h ABPM indices. CONCLUSIONS: Low 25OHD levels were associated with higher clinic systolic BP in children with CKD. Vitamin D supplementation to maintain normal 25OHD levels might be a useful adjunctive treatment in optimizing BP control in these high-risk patients.

Single-cell view into the role of microbiota shaping host immunity in the larynx.

Microbiota play a critical role in the development and training of host innate and adaptive immunity. We present the cellular landscape of the upper airway, specifically the larynx, by establishing a reference single-cell atlas, while dissecting the role of microbiota in cell development and function at single-cell resolution. We highlight the larynx's cellular heterogeneity with the identification of 16 cell types and 34 distinct subclusters. Our data demonstrate that commensal microbiota have extensive impact on the laryngeal immune system by regulating cell differentiation, increasing the expression of genes associated with host defense, and altering gene regulatory networks. We uncover macrophages, innate lymphoid cells, and multiple secretory epithelial cells, whose cell proportions and expressions vary with microbial exposure. These cell types play pivotal roles in maintaining laryngeal and upper airway health and provide specific guidance into understanding the mechanism of immune system regulation by microbiota in laryngeal health and disease.

Airway basal stem cells are necessary for the maintenance of functional intraepithelial airway macrophages.

Adult stem cells play a crucial role in tissue homeostasis and repair through multiple mechanisms. In addition to being able to replace aged or damaged cells, stem cells provide signals that contribute to the maintenance and function of neighboring cells. In the lung, airway basal stem cells also produce cytokines and chemokines in response to inhaled irritants, allergens, and pathogens, which affect specific immune cell populations and shape the nature of the immune response. However, direct cell-to-cell signaling through contact between airway basal stem cells and immune cells has not been demonstrated. Recently, a unique population of intraepithelial airway macrophages (IAMs) has been identified in the murine trachea. Here, we demonstrate that IAMs require Notch signaling from airway basal stem cells for maintenance of their differentiated state and function. Furthermore, we demonstrate that Notch signaling between airway basal stem cells and IAMs is required for antigen-induced allergic inflammation only in the trachea where the basal stem cells are located whereas allergic responses in distal lung tissues are preserved consistent with a local circuit linking stem cells to proximate immune cells. Finally, we demonstrate that IAM-like cells are present in human conducting airways and that these cells display Notch activation, mirroring their murine counterparts. Since diverse lung stem cells have recently been identified and localized to specific anatomic niches along the proximodistal axis of the respiratory tree, we hypothesize that the direct functional coupling of local stem cell-mediated regeneration and immune responses permits a compartmentalized inflammatory response.

Associations between COVID-19 therapies and outcomes in rural and urban America: A multisite, temporal analysis from the Alpha to Omicron SARS-CoV-2 variants.

PURPOSE: To investigate the enduring disparities in adverse COVID-19 events between urban and rural communities in the United States, focusing on the effects of SARS-CoV-2 vaccination and therapeutic advances on patient outcomes. METHODS: Using National COVID Cohort Collaborative (N3C) data from 2021 to 2023, this retrospective cohort study examined COVID-19 hospitalization, inpatient death, and other adverse events. Populations were categorized into urban, urban-adjacent rural (UAR), and nonurban-adjacent rural (NAR). Adjustments included demographics, variant-dominant waves, comorbidities, region, and SARS-CoV-2 treatment and vaccination. Statistical methods included Kaplan-Meier survival estimates, multivariable logistic, and Cox regression. FINDINGS: The study included 3,018,646 patients, with rural residents constituting 506,204. These rural dwellers were older, had more comorbidities, and were less vaccinated than their urban counterparts. Adjusted analyses revealed higher hospitalization odds in UAR and NAR (aOR 1.07 [1.05-1.08] and 1.06 [1.03-1.08]), greater inpatient death hazard (aHR 1.30 [1.26-1.35] UAR and 1.37 [1.30-1.45] NAR), and greater risk of other adverse events compared to urban dwellers. Delta increased, while Omicron decreased, inpatient adverse events relative to pre-Delta, with rural disparities persisting throughout. Treatment effectiveness and vaccination were similarly protective across all cohorts, but dexamethasone post-ventilation was effective only in urban areas. Nirmatrelvir/ritonavir and molnupiravir better protected rural residents against hospitalization. CONCLUSIONS: Despite advancements in treatment and vaccinations, disparities in adverse COVID-19 outcomes persist between urban and rural communities. The effectiveness of some therapeutic agents appears to vary based on rurality, suggesting a nuanced relationship between treatment and geographic location while highlighting the need for targeted rural health care strategies.

Regulatory T cells effectively downregulate the autoimmune anti-MPO response and ameliorate anti-MPO induced glomerulonephritis in mice.

Regulation of autoreactive cells is key for both prevention and amelioration of autoimmune disease. A better understanding of the key cell population(s) responsible for downregulation of autoreactive cells would provide necessary foundational insight for cellular-based therapies in autoimmune disease. Utilizing a mouse model of anti-myeloperoxidase (MPO) glomerulonephritis, we sought to understand which immune cells contribute to downregulation of the anti-MPO autoimmune response. MPO-/- mice were immunized with whole MPO to induce an anti-MPO response. Anti-MPO splenocytes were then transferred into recipient mice (Rag2-/- mice or WT mice). Anti-MPO titers were followed over time. After anti-MPO splenocyte transfer, WT mice are able to downregulate the anti-MPO response while anti-MPO titers persist in Rag2-/- recipients. Reconstitution with WT splenocytes into Rag2-/- recipients prior to anti-MPO splenocyte transfer enabled mice to downregulate the anti-MPO immune response. Therefore, wildtype splenocytes contain a cellular population that is capable of downregulating the autoimmune response. Through splenocyte transfer, antibody depletion experiments, and purified cell population transfers, we confirmed that the regulatory T cell (Treg) population is responsible for the downregulation of the anti-MPO autoimmune response. Further investigation revealed that functional Tregs from WT mice are capable of downregulating anti-MPO antibody production and ameliorate anti-MPO induced glomerulonephritis. These data underscore the importance of functional Tregs for control of autoimmune responses and prevention of end-organ damage due to autoimmunity.

Long-term follow-up of patients with intermediate-risk neuroblastoma treated with response- and biology-based therapy: A report from the Children's Oncology Group study ANBL0531.

BACKGROUND: We previously reported excellent three-year overall survival (OS) for patients with newly diagnosed intermediate-risk neuroblastoma treated with a biology- and response-based algorithm on the Children's Oncology Group study ANBL0531. We now present the long-term follow-up results. METHODS: All patients who met the age, stage, and tumor biology criteria for intermediate-risk neuroblastoma were eligible. Treatment was based on prognostic biomarkers and overall response. Event-free survival (EFS) and OS were estimated by the Kaplan-Meier method. RESULTS: The 10-year EFS and OS for the entire study cohort (n = 404) were 82.0% (95% confidence interval (CI), 77.2%-86.9%) and 94.7% (95% CI, 91.8%-97.5%), respectively. International Neuroblastoma Staging System stage 4 patients (n = 133) had inferior OS compared with non-stage 4 patients (n = 271; 10-year OS: 90.8% [95% CI, 84.5%-97.0%] vs 96.6% [95% CI, 93.9%-99.4%], p = .02). Infants with stage 4 tumors with ≥1 unfavorable biological feature (n = 47) had inferior EFS compared with those with favorable biology (n = 61; 10-year EFS: 66.8% [95% CI, 50.4%-83.3%] vs 86.9% [95% CI, 76.0%-97.8%], p = .02); OS did not differ (10-year OS: 84.4% [95% CI, 71.8%-97.0%] vs 95.0% [95% CI, 87.7%-100.0%], p = .08). Inferior EFS but not OS was observed among patients with tumors with (n = 26) versus without (n = 314) 11q loss of heterozygosity (10-year EFS: 68.4% [95% CI, 44.5%-92.2%] vs 83.9% [95% CI, 78.7%-89.2%], p = .03; 10-year OS: 88.0% [95% CI, 72.0%-100.0%] vs 95.7% [95% CI, 92.8%-98.6%], p = .09). CONCLUSIONS: The ANBL0531 trial treatment algorithm resulted in excellent long-term survival. More effective treatments are needed for subsets of patients with unfavorable biology tumors.

Distribution of COVID-19 mitigation measures by industry and work arrangement-US blood donors, May 2021-December 2021.

OBJECTIVE: To describe coronavirus disease 2019 (COVID-19) mitigation measures in workplaces of employed US blood donors by industry and work arrangement. METHODS: During May-December 2021, blood donors responded to a survey; we describe the distribution of reported workplace mitigation measures by industry and work arrangement, organized using the hierarchy of controls. RESULTS: Of 53,433 respondents representing 21 industries, ventilation upgrades were reported by 4%-38% of respondents (overall: 20%); telework access ranged from 14%-80% (53% overall). Requiring masks (overall: 84%; range: 40%-94%), physical distancing (77%; 51%-86%), paid leave for illness (70%; 38%-87%), and encouraging vaccination (61%; 33%-80%) were common. Independent workers reported fewer mitigation measures than those in traditional employment settings. CONCLUSIONS: Mitigation measures varied by industry and work arrangement. Some mitigation measures may be challenging to implement or irrelevant in certain industries, supporting the idea that mitigation is not a one-size-fits-all strategy. POLICY IMPLICATIONS: Tailored strategies to mitigate workplace risks of disease transmission are vital. Strategies should rely on effective methods for identifying workplace controls (e.g., through the hierarchy of controls) and account for industry-specific characteristics and workplace environments.

Consistency of metabolite associations with measured glomerular filtration rate in children and adults.

Background: There is interest in identifying novel filtration markers that lead to more accurate GFR estimates than current markers (creatinine and cystatin C) and are more consistent across demographic groups. We hypothesize that large-scale metabolomics can identify serum metabolites that are strongly influenced by glomerular filtration rate (GFR) and are more consistent across demographic variables than creatinine, which would be promising filtration markers for future investigation. Methods: We evaluated the consistency of associations between measured GFR (mGFR) and 887 common, known metabolites quantified by an untargeted chromatography- and spectroscopy-based metabolomics platform (Metabolon) performed on frozen blood samples from 580 participants in Chronic Kidney Disease in Children (CKiD), 674 participants in Modification of Diet in Renal Disease (MDRD) Study and 962 participants in African American Study of Kidney Disease and Hypertension (AASK). We evaluated metabolite-mGFR correlation association with metabolite class, molecular weight, assay platform and measurement coefficient of variation (CV). Among metabolites with strong negative correlations with mGFR (r < -0.5), we assessed additional variation by age (height in children), sex, race and body mass index (BMI). Results: A total of 561 metabolites (63%) were negatively correlated with mGFR. Correlations with mGFR were highly consistent across study, sex, race and BMI categories (correlation of metabolite-mGFR correlations between 0.88 and 0.95). Amino acids, carbohydrates and nucleotides were more often negatively correlated with mGFR compared with lipids, but there was no association with metabolite molecular weight, liquid chromatography/mass spectrometry platform and measurement CV. Among 114 metabolites with strong negative associations with mGFR (r < -0.5), 27 were consistently not associated with age (height in children), sex or race. Conclusions: The majority of metabolite-mGFR correlations were negative and consistent across sex, race, BMI and study. Metabolites with consistent strong negative correlations with mGFR and non-association with demographic variables may represent candidate markers to improve estimation of GFR.

International Prescription Drug Price Comparisons: Estimates Using 2022 Data.

Understanding the extent to which prescription drug prices are higher in the United States than in other countries-after accounting for differences in the volume and mix of drugs-is useful when developing and targeting policies to address both growth in drug spending and the financial impact of prescription drugs on consumers. This study summarizes findings from comparisons of drug prices in the United States and other high-income countries based on 2022 data and presents results for specific types of drugs, including brand-name originator drugs and unbranded generic drugs, and from sensitivity analyses.