Regional trends in diagnosis of advanced lung cancer in Michigan over 33 years.

Background: Lung cancer is the most common cancer killer worldwide. Nearly 80 percent of lung cancers are diagnosed at advanced stages. Lack of access to medical care and undwerutilized lung cancer screening are key reasons for advanced diagnoses. We sought to understand the regional differences in presentation of lung cancer across Michigan. Utilizing a comprehensive cancer registry over 33 years, our goal was to examine associations between sociodemographic patient factors and diagnoses at advanced stages. Methods: The Michigan Cancer Registry was queried from 1985 to 2018 to include all new diagnoses of non-small cell lung cancer (NSCLC) using International Classification of Diseases for Oncology (ICD-O) version 3 codes. NSCLC was categorized as early, regional and distant disease. Advanced disease was considered to be any disease that was regional or distant. NSCLC rates were calculated and mapped at the zip code level using the 2010 population as the denominator and spatial empirical Bayes methodology. Regional hospital service areas were constructed using travel time to treatment from the patient's zip code centroid. Logistic regression models were estimated to investigate the significance of rural vs. urban and travel time on level of disease at presentation. Kaplan-Meier and multivariate survival analysis was performed to evaluate the association between distance from the nearest medical center and length of survival controlling for known risk factors for lung cancer. Results: From 1985 to 2018, there were 141,977 patients in Michigan diagnosed with NSCLC. In 1985, men were 2.2 times more likely than women to be diagnosed but by 2018 women and men developed disease at equal rates. Mean age was 67.8 years. Among all patients with known stage of disease, 72.5% of patients were diagnosed with advanced disease. Regional and distant NSCLC rates were both higher in the northern parts of the state. Longer drive times in rural regions also significantly increased the likelihood of advanced NSCLC diagnoses, in particular regional lung cancer. Patients with longer drive times also experienced overall worse survival after controlling for other factors. Conclusions: Regional disparities exist in Michigan for diagnoses of NSCLC at advanced stages. Factors such as lack of screening in urban regions and distances to treating institutions in rural areas likely contribute to the increased likelihood of advanced NSCLC. Future interventions should target the specific needs of residents to detect disease at earlier stages and improve overall outcomes.

Lung Cancer and Air Quality in a Large Urban County in the United States.

Lung cancer is the leading cancer-related killer in the United States. The incidence varies geographically and may be affected by environmental pollutants. Our goal was to determine associations within time series for specific air pollutants and lung cancer cases over a 33-year period in Wayne County, Michigan, controlling for population change. Lung cancer data for Wayne County were queried from the Michigan Cancer Registry from 1985 to 2018. Air pollutant data were obtained from the United States Environmental Protection Agency from 1980 to 2018. Autoregressive distributed lag (ARDL) models were estimated to investigate time lags in years between specific air pollution levels and lung cancer development. A total of 58,866 cases of lung cancer were identified. The mean age was 67.8 years. Females accounted for 53 percent of all cases in 2018 compared to 44 percent in 1985. Three major clusters of lung cancer incidence were detected with the most intense clusters in downtown Detroit and the heavily industrialized downriver area. Sulfur dioxide (SO2) had the strongest statistically significant relationship with lung cancer, showing both short- and long-term effects (lag range, 1-15 years). Particulate matter (PM2.5) (lag range, 1-3 years) and nitrogen dioxide (NO2) (lag range, 2-4 years) had more immediate effects on lung cancer development compared to carbon monoxide (CO) (lag range, 5-6 years), hazardous air pollutants (HAPs) (lag range, 9 years) and lead (Pb) (lag range, 10-12 years), which had more long-term effects on lung cancer development. Areas with poor air quality may benefit from targeted interventions for lung cancer screening and reductions in environmental pollution.

The mitochondrial multi-omic response to exercise training across rat tissues.

Mitochondria have diverse functions critical to whole-body metabolic homeostasis. Endurance training alters mitochondrial activity, but systematic characterization of these adaptations is lacking. Here, the Molecular Transducers of Physical Activity Consortium mapped the temporal, multi-omic changes in mitochondrial analytes across 19 tissues in male and female rats trained for 1, 2, 4, or 8 weeks. Training elicited substantial changes in the adrenal gland, brown adipose, colon, heart, and skeletal muscle. The colon showed non-linear response dynamics, whereas mitochondrial pathways were downregulated in brown adipose and adrenal tissues. Protein acetylation increased in the liver, with a shift in lipid metabolism, whereas oxidative proteins increased in striated muscles. Exercise-upregulated networks were downregulated in human diabetes and cirrhosis. Knockdown of the central network protein 17-beta-hydroxysteroid dehydrogenase 10 (HSD17B10) elevated oxygen consumption, indicative of metabolic stress. We provide a multi-omic, multi-tissue, temporal atlas of the mitochondrial response to exercise training and identify candidates linked to mitochondrial dysfunction.

Sexual dimorphism and the multi-omic response to exercise training in rat subcutaneous white adipose tissue.

Subcutaneous white adipose tissue (scWAT) is a dynamic storage and secretory organ that regulates systemic homeostasis, yet the impact of endurance exercise training (ExT) and sex on its molecular landscape is not fully established. Utilizing an integrative multi-omics approach, and leveraging data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we show profound sexual dimorphism in the scWAT of sedentary rats and in the dynamic response of this tissue to ExT. Specifically, the scWAT of sedentary females displays -omic signatures related to insulin signaling and adipogenesis, whereas the scWAT of sedentary males is enriched in terms related to aerobic metabolism. These sex-specific -omic signatures are preserved or amplified with ExT. Integration of multi-omic analyses with phenotypic measures identifies molecular hubs predicted to drive sexually distinct responses to training. Overall, this study underscores the powerful impact of sex on adipose tissue biology and provides a rich resource to investigate the scWAT response to ExT.

An economic assessment of alternative antimicrobial use scenarios on pig farms.

This paper explores the theoretical economic outcome of management changes that result in different levels of antimicrobial use (AMU) in two types of UK pig farm. A static farm economic pig production model (FEPM) was used on a representative 'Top-third' most profitable farm and a representative 'Mid-range' profitable farm. Three AMU theoretical management scenarios were investigated; (a) management changes leading to a reduction of AMU by 35% (AMU35); (b) more extensive management changes leading to a reduction of AMU by 95% (AMU95); and (c) implementing depopulation of the herd (AMU Depop). A sensitivity analysis was conducted to determine the effect of increases or decreases in pig revenue and feed price on farm gross margin under these scenarios. Over a single year, the AMU35 scenario was estimated to have a small positive impact (+3%) on both farm types. The other two AMU reduction scenarios had higher AMU reduction on farms but required higher variable cost and hence they resulted in lower farm profitability. There was a substantial reduction (up to -50%) in farm gross margin under these two AMU reduction scenarios in the modeled short-term time-period. The impact of the alternative AMU scenarios was slightly higher on a farm representing the 'Top-third' farm type, reducing farm gross margin further by 7% compared to the 'Mid-range' farm. Nevertheless, both farm types stay profitable under all three AMU scenarios. The results showed that in the modeled short-term implementing management changes that result in a reduction of on-farm AMU by 35% had a good economic outcome. In practice, the other two scenarios would be considered as longer-term strategies. Although both require higher initial costs to implement, the improved biosecurity and hygiene will benefit from lower disease occurrence for a longer term. Farm gross margins were, however, found to be highly sensitive to changes on market prices especially increasing feed prices. An increase of more than 15% in feed price moved a profitable farm into a loss-making farm. It will be economically challenging for uptakes of these, or similar, AMU reduction scenarios on farms if the market prices become un-favorable to pig farmers.

Intimate Partner Violence and Human Trafficking Screening and Services in Primary Care Across Underserved Communities in the United States-Initial Examination of Trends, 2020-2021.

OBJECTIVES: The Health Resources and Services Administration (HRSA) began collecting data on intimate partner violence (IPV) and human trafficking (HT) in the 2020 Uniform Data System (UDS). We examined patients affected by IPV and HT served by HRSA-funded health centers in medically underserved US communities during the COVID-19 pandemic. METHODS: We established a baseline and measured trends in patient care by analyzing data from the 2020 (N = 28 590 897) and 2021 (N = 30 193 278) UDS. We conducted longitudinal ordinal logistic regression analyses to assess the association of care trends and organization-level and patient characteristics using proportional odds ratios (PORs) and 95% CIs. RESULTS: The number of clinical visits for patients affected by IPV and HT decreased by 29.4% and 88.3%, respectively, from 2020 to 2021. Health centers serving a higher (vs lower) percentage of pediatric patients were more likely to continuously serve patients affected by IPV (POR = 2.58; 95% CI, 1.01-6.61) and HT (POR = 6.14; 95% CI, 2.06-18.29). Health centers serving (vs not serving) patients affected by IPV were associated with a higher percentage of patients who had limited English proficiency (POR = 1.77; 95% CI, 1.02-3.05) and Medicaid beneficiaries (POR = 2.88; 95% CI, 1.48-5.62), whereas health centers serving (vs not serving) patients affected by HT were associated with a higher percentage of female patients of reproductive age (POR = 15.89; 95% CI, 1.61-157.38) and urban settings (POR = 1.74; 95% CI, 1.26-2.37). CONCLUSIONS: The number of clinical visits for patients affected by IPV and HT during the COVID-19 pandemic declined. Delayed care will pose challenges for future health care needs of these populations.

Tackling Brain and Muscle Dysfunction in Acute Respiratory Distress Syndrome Survivors: NHLBI Workshop Report.

Acute respiratory distress syndrome (ARDS) is associated with long-term impairments in brain and muscle function that significantly impact the quality of life of those who survive the acute illness. The mechanisms underlying these impairments are not yet well understood, and evidence-based interventions to minimize the burden on patients remain unproved. The NHLBI of the NIH assembled a workshop in April 2023 to review the state of the science regarding ARDS-associated brain and muscle dysfunction, to identify gaps in current knowledge, and to determine priorities for future investigation. The workshop included presentations by scientific leaders across the translational science spectrum and was open to the public as well as the scientific community. This report describes the themes discussed at the workshop as well as recommendations to advance the field toward the goal of improving the health and well-being of ARDS survivors.

Phage resistance in Klebsiella pneumoniae and bidirectional effects impacting antibiotic susceptibility.

OBJECTIVES: Bacteriophage (phage) therapy is a promising anti-infective option to combat antimicrobial resistance. However, the clinical utilization of phage therapy has been severely compromised by the potential emergence of phage resistance. Although certain phage resistance mechanisms can restore bacterial susceptibility to certain antibiotics, a lack of knowledge of phage resistance mechanisms hinders optimal use of phages and their combination with antibiotics. METHODS: Genome-wide transposon screening was performed with a mutant library of Klebsiella pneumoniae MKP103 to identify phage pKMKP103_1-resistant mutants. Phage-resistant phenotypes were evaluated by time-kill kinetics and efficiency of plating assays. Phage resistance mechanisms were investigated with adsorption, one-step growth, and mutation frequency assays. Antibiotic susceptibility was determined with broth microdilution and population analysis profiles. RESULTS: We observed a repertoire of phage resistance mechanisms in K pneumoniae, such as disruption of phage binding (fhuA::Tn and tonB::Tn), extension of the phage latent period (mnmE::Tn and rpoN::Tn), and increased mutation frequency (mutS::Tn and mutL::Tn). Notably, in contrast to the prevailing view that phage resistance re-sensitizes antibiotic-resistant bacteria, we observed a bidirectional steering effect on bacterial antibiotic susceptibility. Specifically, rpoN::Tn increased susceptibility to colistin while mutS::Tn and mutL::Tn increased resistance to rifampicin and colistin. DISCUSSION: Our findings demonstrate that K pneumoniae employs multiple strategies to overcome phage infection, which may result in enhanced or reduced antibiotic susceptibility. Mechanism-guided phage steering should be incorporated into phage therapy to better inform clinical decisions on phage-antibiotic combinations.

Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2024 Update by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM).

The critical nature of the microbiology laboratory in infectious disease diagnosis calls for a close, positive working relationship between the physician and the microbiologists who provide enormous value to the health care team. This document, developed by experts in both adult and pediatric laboratory and clinical medicine, provides information on which tests are valuable and in which contexts, and on tests that add little or no value for diagnostic decisions. Sections are divided into anatomic systems, including Bloodstream Infections and Infections of the Cardiovascular System, Central Nervous System Infections, Ocular Infections, Soft Tissue Infections of the Head and Neck, Upper Respiratory Infections, Lower Respiratory Tract infections, Infections of the Gastrointestinal Tract, Intraabdominal Infections, Bone and Joint Infections, Urinary Tract Infections, Genital Infections, and Skin and Soft Tissue Infections; or into etiologic agent groups, including arboviral Infections, Viral Syndromes, and Blood and Tissue Parasite Infections. Each section contains introductory concepts, a summary of key points, and detailed tables that list suspected agents; the most reliable tests to order; the samples (and volumes) to collect in order of preference; specimen transport devices, procedures, times, and temperatures; and detailed notes on specific issues regarding the test methods, such as when tests are likely to require a specialized laboratory or have prolonged turnaround times. In addition, the pediatric needs of specimen management are also addressed. There is redundancy among the tables and sections, as many agents and assay choices overlap. The document is intended to serve as a reference to guide physicians in choosing tests that will aid them to diagnose infectious diseases in their patients.

Spatial and spatio-temporal clusters of lung cancer incidence by stage of disease in Michigan, United States 1985-2018.

Lung cancer is the most common cause of cancer-related death in Michigan. Most patients are diagnosed at advanced stages of the disease. There is a need to detect clusters of lung cancer incidence over time, to generate new hypotheses about causation and identify high-risk areas for screening and treatment. The Michigan Cancer Surveillance database of individual lung cancer cases, 1985 to 2018 was used for this study. Spatial and spatiotemporal clusters of lung cancer and level of disease (localized, regional and distant) were detected using discrete Poisson spatial scan statistics at the zip code level over the study time period. The approach detected cancer clusters in cities such as Battle Creek, Sterling Heights and St. Clair County that occurred prior to year 2000 but not afterwards. In the northern area of the lower peninsula and the upper peninsula clusters of late-stage lung cancer emerged after year 2000. In Otter Lake Township and southwest Detroit, late-stage lung cancer clusters persisted. Public and patient education about lung cancer screening programs must remain a health priority in order to optimize lung cancer surveillance. Interventions should also involve programs such as telemedicine to reduce advanced stage disease in remote areas. In cities such as Detroit, residents often live near industry that emits air pollutants. Future research should therefore, continue to focus on the geography of lung cancer to uncover place-based risks and in response, the need for screening and health care services.

A Specialized Centrosome-Proteasome Axis Mediates Proteostasis and Influences Cardiac Stress through Txlnb.

Background: Centrosomes localize to perinuclear foci where they serve multifunctional roles, arranging the microtubule organizing center (MTOC) and anchoring ubiquitin-proteasome system (UPS) machinery. In mature cardiomyocytes, centrosomal proteins redistribute into a specialized perinuclear cage-like structure, and a potential centrosome-UPS interface has not been studied. Taxilin-beta (Txlnb), a cardiomyocyte-enriched protein, belongs to a family of centrosome adapter proteins implicated in protein quality control. We hypothesize that Txlnb plays a key role in centrosomal-proteasomal crosstalk in cardiomyocytes. Methods: Integrative bioinformatics assessed centrosomal gene dysregulation in failing hearts. Txlnb gain/loss-of-function studies were conducted in cultured cardiomyocytes and mice. Txlnb's role in cardiac proteotoxicity and hypertrophy was examined using CryAB-R120G mice and transverse aortic constriction (TAC), respectively. Molecular modeling investigated Txlnb structure/function. Results: Human failing hearts show consistent dysregulation of many centrosome-associated genes, alongside UPS-related genes. Txlnb emerged as a candidate regulator of cardiomyocyte proteostasis that localizes to the perinuclear centrosomal compartment. Txlnb's interactome strongly supports its involvement in cytoskeletal, microtubule, and UPS processes, particularly centrosome-related functions. Overexpressing Txlnb in cardiomyocytes reduced ubiquitinated protein accumulation and enhanced proteasome activity during hypertrophy. Txlnb-knockout (KO) mouse hearts exhibit proteasomal insufficiency and altered cardiac growth, evidenced by ubiquitinated protein accumulation, decreased 26Sß5 proteasome activity, and lower mass with age. In Cryab-R120G mice, Txlnb loss worsened heart failure, causing lower ejection fractions. After TAC, Txlnb-KO mice also showed reduced ejection fraction, increased heart mass, and elevated ubiquitinated protein accumulation. Investigations into the molecular mechanisms revealed that Txlnb-KO did not affect proteasomal subunit expression but led to the upregulation of Txlna and several centrosomal proteins (Cep63, Ofd1, and Tubg) suggesting altered centrosomal dynamics. Structural predictions support Txlnb's role as a specialized centrosomal-adapter protein bridging centrosomes with proteasomes, confirmed by microtubule-dependent perinuclear localization. Conclusions: Together, these data provide initial evidence connecting Txlnb to cardiac proteostasis, hinting at the potential importance of functional bridging between specialized centrosomes and UPS in cardiomyocytes.

Bovine mortality: the utility of two data sources for the provision of population-level surveillance intelligence.

Introduction: The use of existing data to provide surveillance intelligence is widely advocated but often presents considerable challenges. Two data sources could be used as proxies for the mortality experienced by the Scottish cattle population: deaths recorded in the mandatory register [Cattle Tracing System (CTS)] and fallen stock collections by the National Fallen Stock Company (NSFCo) with a nationwide voluntary membership. Methods: Data for the period 2011-2016 were described and compared to establish their strengths and limitations. Similarities and differences in their temporal, seasonal and spatial patterns were examined overall, at postcode area level and for different age groups. Temporal aberration detection algorithms (TADA) were fitted. Results: Broadly, similar patterns were observed in the two datasets; however, there were some notable differences. The observed seasonal, annual and spatial patterns match expectations, given knowledge of Scottish cattle production systems. The registry data provide more comprehensive coverage of all areas of Scotland, while collections data provide a more comprehensive measure of the mortality experienced in 0-1-month-old calves. Discussion: Consequently, estimates of early calf mortality and their impact on the livestock sector made using CTS, or successor registers, will be under-estimates. This may apply to other registry-based systems. Fitted TADA detected points of deviations from expected norms some of which coincided in the two datasets; one with a known external event that caused increased mortality. We have demonstrated that both data sources do have the potential to be utilized to provide measures of mortality in the Scottish cattle population that could inform surveillance activities. While neither is perfect, they are complementary. Each has strengths and weaknesses, so ideally, a system where they are analyzed and interpreted in parallel would optimize the information obtained for surveillance purposes for epidemiologists, risk managers, animal health policy-makers and the wider livestock industry sector. This study provides a foundation on which to build an operational system. Further development will require improvements in the timeliness of data availability and further investment of resources.

ATF4-dependent increase in mitochondrial-endoplasmic reticulum tethering following OPA1 deletion in skeletal muscle.

Mitochondria and endoplasmic reticulum (ER) contact sites (MERCs) are protein- and lipid-enriched hubs that mediate interorganellar communication by contributing to the dynamic transfer of Ca2+, lipid, and other metabolites between these organelles. Defective MERCs are associated with cellular oxidative stress, neurodegenerative disease, and cardiac and skeletal muscle pathology via mechanisms that are poorly understood. We previously demonstrated that skeletal muscle-specific knockdown (KD) of the mitochondrial fusion mediator optic atrophy 1 (OPA1) induced ER stress and correlated with an induction of Mitofusin-2, a known MERC protein. In the present study, we tested the hypothesis that Opa1 downregulation in skeletal muscle cells alters MERC formation by evaluating multiple myocyte systems, including from mice and Drosophila, and in primary myotubes. Our results revealed that OPA1 deficiency induced tighter and more frequent MERCs in concert with a greater abundance of MERC proteins involved in calcium exchange. Additionally, loss of OPA1 increased the expression of activating transcription factor 4 (ATF4), an integrated stress response (ISR) pathway effector. Reducing Atf4 expression prevented the OPA1-loss-induced tightening of MERC structures. OPA1 reduction was associated with decreased mitochondrial and sarcoplasmic reticulum, a specialized form of ER, calcium, which was reversed following ATF4 repression. These data suggest that mitochondrial stress, induced by OPA1 deficiency, regulates skeletal muscle MERC formation in an ATF4-dependent manner.

Quantitative computed tomography analysis of body composition changes in paediatric patients with acute lymphoblastic leukaemia.

Children with acute lymphoblastic leukaemia (ALL) are at risk for obesity and cardiometabolic diseases. To gain insight into body composition changes among children with ALL, we assessed quantitative computed tomography (QCT) data for specific body compartments (subcutaneous adipose tissue [SAT], visceral adipose tissue [VAT], total adipose tissue [TAT], lean tissue [LT], LT/TAT and VAT/SAT at lumbar vertebrae L1 and L2) at diagnosis and at off-therapy for 189 children with ALL and evaluated associations between body mass index (BMI) Z-score and clinical characteristics. BMI Z-score correlated positively with SAT, VAT and TAT and negatively with LT/TAT and VAT/SAT. At off-therapy, BMI Z-score, SAT, VAT and TAT values were higher than at diagnosis, but LT, LT/TAT and VAT/SAT were lower. Patients aged ≥10 years at diagnosis had higher SAT, VAT and TAT and lower LT and LT/TAT than patients aged 2.0-9.9 years. Female patients had lower LT and LT/TAT than male patients. Black patients had less VAT than White patients. QCT analysis showed increases in adipose tissue and decreases in LT during ALL therapy when BMI Z-scores increased. Early dietary and physical therapy interventions should be considered, particularly for patients at risk for obesity.

Lessons Learned From Adolescent COVID-19 Vaccine Administration in Medically Underserved Communities.

OBJECTIVES: In May 2021, the Health Resources and Services Administration Health Center COVID-19 Vaccine Program (HCCVP) began supporting the national adolescent vaccination rollout for a safe return to in-person learning for children and adolescents from medically underserved communities. To understand the initial implementation of adolescent vaccinations, we estimated the number of vaccines administered through the HCCVP at the national and state level to adolescents aged 12-17 years, and we examined challenges and solutions in vaccine deployment. METHODS: We analyzed data on vaccine administration, challenges, and solutions from the Health Center COVID-19 Survey during May 14-August 27, 2021, and we analyzed data on patients served from the 2019 Uniform Data System. National adolescent COVID-19 vaccination and population data came from CDC's COVID Data Tracker and the US Census Bureau's 2019 Current Population Survey. RESULTS: HCCVP health centers administered >485 000 COVID-19 vaccine doses to adolescents during the study period, with variations across states. Health centers in 13 states and territories (Arizona, California, Colorado, Connecticut, Delaware, Maine, Massachusetts, Missouri, Nebraska, Nevada, Oregon, Virginia, and Puerto Rico) vaccinated more adolescents than their share of prepandemic adolescent patients. The most frequently reported challenges in vaccine administration were vaccine confidence and staffing availability. CONCLUSIONS: This assessment of the initial months of COVID-19 vaccine administration among adolescent health center patients suggests rapid response by health centers in several states, reaching beyond their adolescent patient population to support state-level pandemic response. Future research could examine processes to optimize strategic activation of health centers in public health emergency responses.

Uncovering the mechanisms of MuRF1-induced ubiquitylation and revealing similarities with MuRF2 and MuRF3.

MuRF1 (Muscle-specific RING finger protein 1; gene name TRIM63) is a ubiquitin E3 ligase, associated with the progression of muscle atrophy. As a RING (Really Interesting New Gene) type E3 ligase, its unique activity of ubiquitylation is driven by a specific interaction with a UBE2 (ubiquitin conjugating enzyme). Our understanding of MuRF1 function remains unclear as candidate UBE2s have not been fully elucidated. In the present study, we screened human ubiquitin dependent UBE2s in vitro and found that MuRF1 engages in ubiquitylation with UBE2D, UBE2E, UBE2N/V families and UBE2W. MuRF1 can cause mono-ubiquitylation, K48- and K63-linked polyubiquitin chains in a UBE2 dependent manner. Moreover, we identified a two-step UBE2 dependent mechanism whereby MuRF1 is monoubiquitylated by UBE2W which acts as an anchor for UBE2N/V to generate polyubiquitin chains. With the in vitro ubiquitylation assay, we also found that MuRF2 and MuRF3 not only share the same UBE2 partners as MuRF1 but can also directly ubiquitylate the same substrates: Titin (A168-A170), Desmin, and MYLPF (Myosin Light Chain, Phosphorylatable, Fast Skeletal Muscle; also called Myosin Light Regulatory Chain 2). In summary, our work presents new insights into the mechanisms that underpin MuRF1 activity and reveals overlap in MuRF-induced ubiquitylation which could explain their partial redundancy in vivo.

A Twin Study of Altered White Matter Heritability in Youth With Autism Spectrum Disorder.

OBJECTIVE: White matter alterations are frequently reported in autism spectrum disorder (ASD), yet the etiology is currently unknown. The objective of this investigation was to examine, for the first time, the impact of genetic and environmental factors on white matter microstructure in twins with ASD compared to control twins without ASD. METHOD: Diffusion-weighted MRIs were obtained from same-sex twin pairs (6-15 years of age) in which at least 1 twin was diagnosed with ASD or neither twin exhibited a history of neurological or psychiatric disorders. Fractional anisotropy (FA) and mean diffusivity (MD) were examined across different white matter tracts in the brain, and statistical and twin modeling were completed to assess the proportion of variation associated with additive genetic (A) and common/shared (C) or unique (E) environmental factors. We also developed a novel Twin-Pair Difference Score analysis method that produces quantitative estimates of the genetic and environmental contributions to shared covariance between different brain and behavioral traits. RESULTS: Good-quality data were available from 84 twin pairs, 50 ASD pairs (32 concordant for ASD [16 monozygotic; 16 dizygotic], 16 discordant for ASD [3 monozygotic; 13 dizygotic], and 2 pairs in which 1 twin had ASD and the other exhibited some subthreshold symptoms [1 monozygotic; 1 dizygotic]) and 34 control pairs (20 monozygotic; 14 dizygotic). Average FA and MD across the brain, respectively, were primarily genetically mediated in both control twins (A = 0.80, 95% CI [0.57, 1.02]; A = 0.80 [0.55, 1.04]) and twins concordant for having ASD (A = 0.71 [0.33, 1.09]; A = 0.84 [0.32,1.36]). However, there were also significant tract-specific differences between groups. For instance, genetic effects on commissural fibers were primarily associated with differences in general cognitive abilities and perhaps some diagnostic differences for ASD because Twin-Pair Difference-Score analysis indicated that genetic factors may have contributed to ∼40% to 50% of the covariation between IQ scores and FA of the corpus callosum. Conversely, the increased impact of environmental factors on some projection and association fibers were primarily associated with differences in symptom severity in twins with ASD; for example, our analyses suggested that unique environmental factors may have contributed to ∼10% to 20% of the covariation between autism-related symptom severity and FA of the cerebellar peduncles and external capsule. CONCLUSION: White matter alterations in youth with ASD are associated with both genetic contributions and potentially increased vulnerability or responsivity to environmental influences. DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. One or more of the authors of this paper self-identifies as living with a disability. The author list of this paper includes contributors from the location and/or community where the research was conducted and they participated in the data collection, design, analysis, and/or interpretation of the work.

Evaluation of oncology infusion pharmacy practices: A nationwide survey.

PURPOSE: Oncology care continues to evolve at a rapid pace including provision of infusion-based care. There is currently a lack of robust metrics around oncology infusion centers and pharmacy practice. The workgroup completed a nationwide survey to learn about oncology-based infusion pharmacy services offered. The objective was to highlight consistent, measureable oncology-based infusion pharmacy metrics that will provide a foundation to describe overall productivity including emphasis on high patient-safety standards. METHODS: A nationwide survey was developed via a workgroup within the Vizient Pharmacy Cancer Care Group beginning in April 2019 and conducted electronically via the Vizient Pharmacy Network from September to November 2020. The survey was designed to capture a number of key metrics related to oncology-based infusion pharmacy services. RESULTS: Forty-one sites responded to the survey. Responses highlighted hours of operation (median = 11.5), number of infusion chairs (median = 45). Staffing metrics included 7.1 pharmacist full-time equivalent (FTE) and 7.6 technician FTE per week. 80.5% of sites had cleanrooms and 95.1% reported both hazardous and nonhazardous compounding hoods. 68.3% of sites reported using intravenous (IV) technology, 50.0% measured turnaround time, and 31.4% prepared treatment medications in advance. CONCLUSION: There was variability among oncology infusion pharmacy practices in regard to survey responses among sites. The survey results highlight the need for standardization of established productivity metrics across oncology infusion pharmacies in order to improve efficiency and contain costs in the changing oncology landscape. The survey provides insight into oncology infusion pharmacy practices nationwide and provides information for pharmacy leaders to help guide their practices.

A critical discussion on the relationship between E3 ubiquitin ligases, protein degradation, and skeletal muscle wasting: it's not that simple.

Ubiquitination is an important post-translational modification (PTM) for protein substrates, whereby ubiquitin is added to proteins through the coordinated activity of activating (E1), ubiquitin-conjugating (E2), and ubiquitin ligase (E3) enzymes. The E3s provide key functions in the recognition of specific protein substrates to be ubiquitinated and aid in determining their proteolytic or nonproteolytic fates, which has led to their study as indicators of altered cellular processes. MuRF1 and MAFbx/Atrogin-1 were two of the first E3 ubiquitin ligases identified as being upregulated in a range of different skeletal muscle atrophy models. Since their discovery, the expression of these E3 ubiquitin ligases has often been studied as a surrogate measure of changes to bulk protein degradation rates. However, emerging evidence has highlighted the dynamic and complex regulation of the ubiquitin proteasome system (UPS) in skeletal muscle and demonstrated that protein ubiquitination is not necessarily equivalent to protein degradation. These observations highlight the potential challenges of quantifying E3 ubiquitin ligases as markers of protein degradation rates or ubiquitin proteasome system (UPS) activation. This perspective examines the usefulness of monitoring E3 ubiquitin ligases for determining specific or bulk protein degradation rates in the settings of skeletal muscle atrophy. Specific questions that remain unanswered within the skeletal muscle atrophy field are also identified, to encourage the pursuit of new research that will be critical in moving forward our understanding of the molecular mechanisms that govern protein function and degradation in muscle.