Institution-Wide Retreats Foster Organizational Learning and Action at a Comprehensive Cancer Center.

Providing safe and informed healthcare for sexual and gender minority (SGM) individuals with cancer is stymied by the lack of sexual orientation and gender identity (SOGI) data reliably available in health records and by insufficient training for staff. Approaches that support institutional learning, especially around sensitive topics, are essential for hospitals seeking to improve practices impacting patient safety and research. We engineered annual institutional retreats to identify and unify stakeholders, promote awareness of gaps and needs, identify initiatives, minimize redundant projects, and coordinate efforts that promote improvements in SGM cancer care, education, and research. The 2022 and 2023 retreats employed a 4-h hybrid format allowing virtual and in-person engagement. Retreat organizers facilitated small-group discussions for brainstorming among participants. We performed descriptive statistics from retreat evaluations. The retreats engaged 104 attendees from distinct departments and roles. Participants expressed robust satisfaction, commending the retreat organization and content quality. Notably, the first retreat yielded leadership endorsement and funding for a Quality Improvement pilot to standardize SOGI data collection and clinical staff training. The second retreat provided a platform for updates on focused efforts across the institution and for receiving direction regarding national best practices for SGM care and research. We report the processes and outcomes of institution-wide retreats, which served as a platform for identifying gaps in organizational healthcare practices and research for SGM individuals with cancer. The strategies described herein may be readily scaled at other cancer hospitals seeking to learn and enact system-wide practice changes that support the needs of SGM patients and families.

Female sex is a risk factor for painful diabetic peripheral neuropathy: the EURODIAB prospective diabetes complications study.

AIMS/HYPOTHESIS: While the risk factors for diabetic peripheral neuropathy (DPN) are now well recognised, the risk factors for painful DPN remain unknown. We performed analysis of the EURODIAB Prospective Complications Study data to elucidate the incidence and risk factors of painful DPN. METHODS: The EURODIAB Prospective Complications Study recruited 3250 participants with type 1 diabetes who were followed up for 7.3±0.6 (mean ± SD) years. To evaluate DPN, a standardised protocol was used, including clinical assessment, quantitative sensory testing and autonomic function tests. Painful DPN (defined as painful neuropathic symptoms in the legs in participants with confirmed DPN) was assessed at baseline and follow-up. RESULTS: At baseline, 234 (25.2%) out of 927 participants with DPN had painful DPN. At follow-up, incident DPN developed in 276 (23.5%) of 1172 participants. Of these, 41 (14.9%) had incident painful DPN. Most of the participants who developed incident painful DPN were female (73% vs 48% painless DPN p=0.003) and this remained significant after adjustment for duration of diabetes and HbA1c (OR 2.69 [95% CI 1.41, 6.23], p=0.004). The proportion of participants with macro- or microalbuminuria was lower in those with painful DPN compared with painless DPN (15% vs 34%, p=0.02), and this association remained after adjusting for HbA1c, diabetes duration and sex (p=0.03). CONCLUSIONS/INTERPRETATION: In this first prospective study to investigate the risk factors for painful DPN, we definitively demonstrate that female sex is a risk factor for painful DPN. Additionally, there is less evidence of diabetic nephropathy in incident painful, compared with painless, DPN. Thus, painful DPN is not driven by cardiometabolic factors traditionally associated with microvascular disease. Sex differences may therefore play an important role in the pathophysiology of neuropathic pain in diabetes. Future studies need to look at psychosocial, genetic and other factors in the development of painful DPN.

The association of burnout with work absenteeism and the frequency of thoughts in leaving their job in a cohort of healthcare workers during the COVID-19 pandemic.

Introduction: During the coronavirus disease 2019 pandemic, high levels of burnout were reported among healthcare workers. This study examines the association of work absenteeism and frequency of thoughts in leaving current job with burnout among a cohort of healthcare workers during the COVID-19 pandemic. Methods: A cross-sectional survey of healthcare workers was conducted from April-May, 2022 on healthcare workers from 10 hospitals, 18 immediate care centers, and 325 outpatient practices in the Chicago area and surrounding Illinois suburbs. Logistic regression models were used to assess the association of burnout scores (Oldenburg Burnout Inventory-OLBI) and its sub-scores (exhaustion and disengagement scores) with work absenteeism and thoughts of leaving work. Results: One-fifth and 60% of respondents (n = 1,825) reported unplanned absenteeism and thoughts of leaving their job, respectively. After adjusting for covariates, higher burnout scores, especially exhaustion scores, were associated with increased odds of unplanned absenteeism (OR = 1.04, 95% CI: 1.01-1.08). Burnout scores and both sub-scores were also positively associated with the frequency of thoughts of leaving work, e.g., each unit increase in the OLBI burnout score was associated with 1.39 (95% CI: 1.34-1.43) times higher odds of thinking about leaving work "a lot/constantly" vs. "never". Discussion: Overall, this study cohort showed a positive association between burnout scores and unplanned work absenteeism (and frequency of thoughts in leaving job) during the COVID-19 pandemic. More research is needed to support healthcare worker well-being during times of stress and direct solutions to addressing unplanned absenteeism in the light of a pandemic.

Identification of Brain-Penetrant ATP-Competitive mTOR Inhibitors for CNS Syndromes.

The allosteric inhibitor of the mechanistic target of rapamycin (mTOR) everolimus reduces seizures in tuberous sclerosis complex (TSC) patients through partial inhibition of mTOR functions. Due to its limited brain permeability, we sought to develop a catalytic mTOR inhibitor optimized for central nervous system (CNS) indications. We recently reported an mTOR inhibitor (1) that is able to block mTOR functions in the mouse brain and extend the survival of mice with neuronal-specific ablation of the Tsc1 gene. However, 1 showed the risk of genotoxicity in vitro. Through structure-activity relationship (SAR) optimization, we identified compounds 9 and 11 without genotoxicity risk. In neuronal cell-based models of mTOR hyperactivity, both corrected aberrant mTOR activity and significantly improved the survival rate of mice in the Tsc1 gene knockout model. Unfortunately, 9 and 11 showed limited oral exposures in higher species and dose-limiting toxicities in cynomolgus macaque, respectively. However, they remain optimal tools to explore mTOR hyperactivity in CNS disease models.

Inflammation Biomarker Response to Oral 2-Hydroxybenzylamine (2-HOBA) Acetate in Healthy Humans.

Inflammation is associated with the formation of reactive oxygen species (ROS) and the formation of lipid-derived compounds, such as isolevuglandins (IsoLGs), malondialdehyde, 4-hydroxy-nonenal, and 4-oxo-nonenal. The most reactive of these are the IsoLGs, which form covalent adducts with lysine residues and other cellular primary amines leading to changes in protein function, immunogenicity, and epigenetic alterations and have been shown to contribute to a number of inflammatory diseases. 2-Hydroxybenzylamine (2-HOBA) is a natural compound found in buckwheat seeds and reacts with all IsoLG adducts preventing adduct formation with proteins and DNA. Therefore, 2-HOBA is well positioned as an agent for the prevention of inflammatory-prone diseases. In this study, we examined the potential beneficial effects of 2-HOBA on oxidative stress and inflammatory biomarkers in two cohorts of healthy younger and older adults. We utilized the Olink® targeted inflammation panel before and after an oral 15-day treatment regimen with 2-HOBA. We found significant relative changes in the plasma concentration of 15 immune proteins that may reflect the in vivo immune targets of 2-HOBA. Treatment of 2-HOBA resulted in significant increased levels of CCL19, IL-12ß, IL-20Rα, and TNFß, whereas levels of TWEAK significantly decreased. Ingenuity Pathway Analysis identified canonical pathways regulated by the differentially secreted cytokines, chemokines, and growth factors upon 2-HOBA treatment and further points to biofunctions related to the recruitment, attraction, and movement of different immune cell types. In conclusion, 2-HOBA significantly altered the protein biomarkers CCL19, IL-12ß, IL-20Rα, TNFß, and TWEAK, and these may be responsible for the protective effects of 2-HOBA against reactive electrophiles, such as IsoLGs, commonly expressed in conditions of excessive oxidative stress. 2-HOBA has a role as a IsoLG scavenger to proactively improve immune health in a variety of conditions.

Impact of COVID-19 on HIV Testing Among AIDS Institute-Funded Providers in New York State-A Time Series Analysis.

BACKGROUND: New York State (NYS) was at the intersection of the HIV epidemic and coronavirus disease 2019 (COVID-19) pandemic leading to a disruption in HIV-preventive services. This study sought to determine the impact of the COVID-19 pandemic and mitigation efforts on HIV-testing trends in NYS among AIDS Institute (AI)-funded providers. METHODS: We analyzed weekly testing data from the AI Reporting System from January 1, 2017, to June 27, 2021, to fit an interrupted time series model that predicted the expected number of HIV tests among AI-funded providers in NYS had the COVID-19 pandemic not occurred. The actual observed numbers of HIV testing that occurred from weeks beginning March 15, 2020, to June 30, 2021, were compared with the number of HIV tests predicted by the model. RESULTS: In the absence of the COVID-19 pandemic, our model predicted that there would have been 45,605 HIV tests among AI-funded providers between the weeks beginning March 15, 2020, to June 27, 2021. We observed 20,742 HIV tests, representing a 54.5% reduction. We observed percent decreases of greater than 50% for HIV testing among AI-funded providers for New York City (52.9%) and rest of state (59.8%) regions, male (50.6%) and female (66.8%) genders, as well as Black (59.2%), Hispanic (52.8%), mixed race (57.5%), other (50.3%), and White (50.1%) race and ethnicities. CONCLUSION: HIV testing among AI-funded providers in NYS has declined substantially following the COVID-19 pandemic, reflecting decreased access to, and/or demand for, testing among persons at elevated risk for HIV. Initiatives to increase HIV testing and maintain access to HIV prevention services need to be explored following COVID-19.

Acid Sphingomyelinase-Ceramide Induced Vascular Injury Determines Colorectal Cancer Stem Cell Fate.

BACKGROUND/AIMS: It is unknown whether cancer stem cells respond differentially to treatment compared with progeny, potentially providing therapeutic vulnerabilities. Our program pioneered use of ultra-high single dose radiotherapy, which cures diverse metastatic diseases at a higher rate (90-95%) than conventional fractionation (~65%). Single dose radiotherapy engages a distinct biology involving microvascular acid sphingomyelinase/ceramide signaling, which, via NADPH oxidase-2-dependent perfusion defects, initiates an adaptive tumor SUMO Stress Response that globally-inactivates homologous recombination repair of double stand breaks, conferring cure. Accumulating data show diverse stem cells display heightened-dependence on homologous recombination repair to repair resolve double stand breaks. METHODS: Here we use colorectal cancer patient-derived xenografts containing logarithmically-increased Lgr5+ stem cells to explore whether optimizing engagement of this acid sphingomyelinase dependent biology enhances stem cell dependent tumor cure. RESULTS: We show radioresistant colorectal cancer patient-derived xenograft CLR27-2 contains radioresistant microvasculature and stem cells, whereas radiosensitive colorectal cancer patient-derived xenograft CLR1-1 contains radiosensitive microvasculature and stem cells. Pharmacologic or gene therapy enhancement of single dose radiotherapy-induced acid sphingomyelinase/ceramide-mediated microvascular dysfunction dramatically sensitizes CLR27-2 homologous recombination repair inactivation, converting Lgr5+ cells from the most resistant to most sensitive patient-derived xenograft population, yielding tumor cure. CONCLUSION: We posit homologous recombination repair represents a vulnerability determining colorectal cancer stem cell fate, approachable therapeutically using single dose radiotherapy.

BaRTv2: a highly resolved barley reference transcriptome for accurate transcript-specific RNA-seq quantification.

Accurate characterisation of splice junctions (SJs) as well as transcription start and end sites in reference transcriptomes allows precise quantification of transcripts from RNA-seq data, and enables detailed investigations of transcriptional and post-transcriptional regulation. Using novel computational methods and a combination of PacBio Iso-seq and Illumina short-read sequences from 20 diverse tissues and conditions, we generated a comprehensive and highly resolved barley reference transcript dataset from the European 2-row spring barley cultivar Barke (BaRTv2.18). Stringent and thorough filtering was carried out to maintain the quality and accuracy of the SJs and transcript start and end sites. BaRTv2.18 shows increased transcript diversity and completeness compared with an earlier version, BaRTv1.0. The accuracy of transcript level quantification, SJs and transcript start and end sites have been validated extensively using parallel technologies and analysis, including high-resolution reverse transcriptase-polymerase chain reaction and 5'-RACE. BaRTv2.18 contains 39 434 genes and 148 260 transcripts, representing the most comprehensive and resolved reference transcriptome in barley to date. It provides an important and high-quality resource for advanced transcriptomic analyses, including both transcriptional and post-transcriptional regulation, with exceptional resolution and precision.

Incident cardiovascular disease by clustering of favourable risk factors in type 1 diabetes: the EURODIAB Prospective Complications Study.

AIMS: The aim of this prospective study was to examine CVD risk reduction in type 1 diabetes (1) for people with favourable cardiovascular health metrics and (2) by clustering of these metrics. METHODS: Data from 2313 participants from the EURODIAB Prospective Complications Study were analysed. All had type 1 diabetes (51% men, mean ± SD age 32 ± 9 years). Seven cardiovascular health metrics were studied-smoking, BMI, physical activity, a diet score, total cholesterol/HDL-cholesterol ratio, combined systolic and diastolic BP and HbA1c-divided into favourable/less favourable categories. Cox proportional hazards models were used to calculate HRs (95% CIs) of incident CVD for each metric. Clusters were made by scoring each individual by the number of favourable metrics. RESULTS: A total of 163 people developed incident CVD during a mean ± SD follow-up of 7.2 ± 1.3 years. Participants with more favourable HbA1c levels of <57 mmol/mol (<7.4%) had a 37% significantly lower CVD risk than those with a less favourable HbA1c (HR [95% CI] 0.63 [0.44, 0.91]), and participants with a more favourable BP (systolic BP <112 mmHg and diastolic BP <70 mmHg) had a 44% significantly lower CVD risk than participants in the less favourable BP group (HR [95% CI] 0.56 [0.34, 0.92]). There was a dose-response relation with a lower HR observed with greater clustering of more favourable metrics: people with four or more favourable metrics had an HR of 0.37 (95% CI 0.18, 0.76), adjusted for sex and age at diabetes diagnosis, compared with those with no favourable metrics. CONCLUSIONS/INTERPRETATION: Low HbA1c and low BP were protective cardiovascular health metrics in our study of people with type 1 diabetes. Targeting all cardiovascular health metrics could be more effective in preventing CVD than targeting single metrics.

Acute dose toxicity evaluation of the food supplement calcium 3-hydroxy-3-methylbutyrate (HMB) in female Sprague Dawley rats.

The leucine metabolite, 3-hydroxy-3-methylbutyrate (HMB), primarily utilized as the calcium salt (CaHMB) has become one of the most widely used supplements and food ingredients to promote muscle health. While both CaHMB and HMB free acid have published sub-chronic toxicity studies, and CaHMB has published studies on genotoxicity, data are lacking on the acute dosing of HMB which is important for regulatory and transportation classification as well as in cases of accidental overconsumption. Therefore, an acute oral toxicity study was conducted with CaHMB following OECD 420 guidelines. One rat was used in the dosage sighting study and four rats were used in the main study. In both studies, rats were given a single oral dose of 2000 mg/kg body weight by gavage and monitored for 14 days following the dosage for changes in body weight, clinical signs as noted in OECD 420, and at the end of the study a necropsy was conducted to determine any gross tissue abnormalities. The dosage of CaHMB administered resulted in no deaths, no significant adverse clinical signs, and no findings of lesions or abnormal tissues. Under the Global Harmonized System of classification, CaHMB was found to be in the least toxic Category 5 or non-toxic.

Posterior approach to the elbow for insertion of the internal joint stabilizer.

Management of unstable injuries was revolutionized by the Internal Joint Stabilizer (IJS). When compared to long-term immobilization, transarticular pinning, and hinge external fixation, the IJS results in decreased complications and improved clinical outcomes. Historically, the IJS was applied via a lateral approach; however, this limited intraoperative visualization and, in some cases, resulted in increased operative times. This technical report describes a posterior approach, for IJS application. The posterior approach involves an 8- to 10-cm incision over the posterior elbow through the deep fascia before identifying the olecranon and lateral capitellum, then proceeding with IJS application through manufacturer instructions. The ulnar and radial nerves must be identified as they could be damaged in this approach. Using the posterior approach at our institution, we have noticed a possible decrease in operative times and an increase in intraoperative visualization of the elbow without a subsequent increase in complications.

Surgical Management of Ulnar Metacarpal Base Fracture-Dislocations: A Systematic Review.

BACKGROUND: Ulnar metacarpal base fractures can destabilize the carpometacarpal (CMC) joint, prompting surgical stabilization. Studies investigating this injury are limited by small case volumes. Our purpose is to review the surgical techniques, outcomes, and complications of ulnar CMC joint stabilization. METHODS: A literature search was performed of all articles published on the surgical treatment and outcomes of ulnar CMC fracture dislocations using PubMed and Google Scholar databases between the years 2014 and 2019. Data were pooled and analyzed, assessing surgical techniques and hand outcome measures: union, recurrent dislocations, range of motion, grip strength, and complications. RESULTS: Six studies met inclusion criteria. All surgical patients, regardless of technique, went on to union with no incidents of recurrent instability. Grip strength was significantly decreased postoperatively (82.7% of uninjured side). Patients with CMC dislocations of both the fourth and fifth ray had similar postoperative outcomes to those with CMC dislocations of the fifth ray alone. One third of plate and screw constructs required plate removal, due to breakage (2) or implant-related pain (4). Plate-related symptoms resolved after removal in all cases. Delayed treatment decreased the effectiveness of nonoperative treatment, and increased the likelihood of postoperative pain, chronic deformity, malunion, and CMC osteoarthritis. CONCLUSIONS: Closed reduction percutaneous pinning, open reduction percutaneous pinning, and open reduction internal fixation with CMC joint bridging or dorsal buttress plating are all well described, safe techniques with low complication rates. Early, accurate diagnosis of fourth and fifth CMC joint fracture-dislocations is crucial for optimizing hand function and postoperative outcomes.

Dose Response of Acute ATP Supplementation on Strength Training Performance.

Background: Chronic oral ATP supplementation benefits cardiovascular health, muscular performance, body composition, and recovery while attenuating muscle breakdown and fatigue. A single 400 mg dose of oral ATP supplementation improved lower body resistance training performance and energy expenditure in recreational resistance trained males, however, the minimal effective dose is currently unknown. Materials and Methods: Twenty recreationally trained men (age 28.6 ± 1.0 years, body mass 81.2 ± 2.0 kg, height 175.2 ± 1.4 cm, 1RM 141.5 ± 5.0 kg) consumed a single dose of either 400 mg, 200 mg, or 100 mg ATP (PEAK ATP®, TSI USA LLC, Missoula, MT, USA) or a placebo in a randomized, placebo-controlled crossover design, separated by a one week wash out between treatments. After warm-up, participants performed 4 sets of half-squats using free-weights until movement failure separated by 2 mins of rest between sets. Results: In comparison to placebo, 400 mg ATP significantly increased the number of set 1 repetitions (+13%, p = 0.04), and numerically increased total repetitions (+7%, p = 0.19) and total weight lifted (+6%, p = 0.22). 200 mg ATP numerically increased set 1 repetitions (+4% p = 0.47), while 100 mg ATP showed no improvements over placebo. 100 mg ATP (-4%, p < 0.05) and 400 mg ATP (-4%, p = 0.11) decreased the perceived rate of exertion compared to placebo. Conclusions: In this study, the effective minimal dose of acute oral ATP supplementation during resistance exercise to increase performance was determined to be 400 mg, while as little as 100 mg showed improvements in perceived exertion.

Inferior vena cava assessment in term pregnant women using ultrasound: A comparison of the subcostal and right upper quadrant views.

Point-of-care ultrasound can be used at the bedside to assess the haemodynamic status and fluid responsiveness of a pregnant woman. Previous studies demonstrated that views from the apical and parasternal windows are readily obtainable in labouring women. However, using the subcostal window to assess the inferior vena cava can be challenging because of the gravid uterus. A potential alternative is the right upper quadrant transhepatic window. We sought to compare visualisation of the inferior vena cava via the subcostal and right upper quadrant windows, in full-term pregnant women. This was a prospective pilot study carried out in a tertiary academic obstetric centre. Thirty pregnant non-labouring women at full term were recruited. In each patient, the inferior vena cava was visualised through both the subcostal and the right upper quadrant windows. Time to acquire each image, acquisition success rates and ease of obtaining images were compared for both approaches. Image quality was then reviewed and rated by two independent expert reviewers. There was a significant difference in the time required to obtain each view; subcostal median (interquartile range): 52 (35-59) seconds, right upper quadrant median (interquartile range): 23 (11-55) seconds (P=0.0045). Operator-defined successful image acquisition was 100% for the right upper quadrant window compared to 80% for the subcostal window. Ease of obtaining the view, as rated by the operator, was significantly easier in the right upper quadrant window compared to the subcostal window (P <0.0001). Both reviewers independently rated image adequacy to be significantly greater in the right upper quadrant window (73% and 57%) compared to the subcostal window (40% and 10%) (P=0.0213 and P=0.0005, respectively). Inter-rater agreement ranged between good (Cohen's kappa coefficient 0.64) for right upper quadrant windows to fair (Cohen's kappa coefficient 0.29) for subcostal windows. Inferior vena cava visualisation in term pregnant patients may take less time, be easier and provide better quality images when the right upper quadrant window is used compared to the subcostal window.

Effects of ß-hydroxy-ß-methylbutyrate supplementation on muscle mass and strength in onabotulinumtoxin type-A-injected and contralateral quadriceps femoris in rabbits.

OBJECTIVE: To determine the effects of the leucine metabolite ß-hydroxy-ß-methylbutyrate (HMB) on strength, muscle mass, and contractile material in muscle wasting induced by onabotulinumtoxin type-A (BoNT-A) injection into the quadriceps femoris muscles of New Zealand white rabbits. METHODS: A total of 21, female rabbits were divided into 3 groups (n=7, each). Group 1 (Control) received intramuscular injection of saline. Groups 2 and 3 received intramuscular injection of BoNT-A (3.5 units/kg), with group 3 receiving supplementation with HMB (120 mg/kg-BW/day). Muscle morphology, mass, and strength were assessed 8 weeks later in both injected and non-injected contralateral limbs. RESULTS: Injected muscle strength of group 2 (BoNT-A) and group 3 (BoNT-A+HMB) was reduced by 63% and 60%, respectively, compared with Controls (p<0.0001). Strength in contralateral muscles of group 2 was reduced by 23% vs Controls (p<0.002), while in group 3, strength was similar to Controls. Muscle mass in the injected muscles of the BoNT-A and BoNT-A+HMB groups was significantly reduced, by 46% and 48%, respectively. CONCLUSION: While HMB did not prevent loss of muscle strength and mass in the BoNT-A-injected musculature, it prevented significant loss of contractile material in the injected musculature and strength loss in the contralateral non-injected musculature.

Public health utility of cause of death data: applying empirical algorithms to improve data quality.

BACKGROUND: Accurate, comprehensive, cause-specific mortality estimates are crucial for informing public health decision making worldwide. Incorrectly or vaguely assigned deaths, defined as garbage-coded deaths, mask the true cause distribution. The Global Burden of Disease (GBD) study has developed methods to create comparable, timely, cause-specific mortality estimates; an impactful data processing method is the reallocation of garbage-coded deaths to a plausible underlying cause of death. We identify the pattern of garbage-coded deaths in the world and present the methods used to determine their redistribution to generate more plausible cause of death assignments. METHODS: We describe the methods developed for the GBD 2019 study and subsequent iterations to redistribute garbage-coded deaths in vital registration data to plausible underlying causes. These methods include analysis of multiple cause data, negative correlation, impairment, and proportional redistribution. We classify garbage codes into classes according to the level of specificity of the reported cause of death (CoD) and capture trends in the global pattern of proportion of garbage-coded deaths, disaggregated by these classes, and the relationship between this proportion and the Socio-Demographic Index. We examine the relative importance of the top four garbage codes by age and sex and demonstrate the impact of redistribution on the annual GBD CoD rankings. RESULTS: The proportion of least-specific (class 1 and 2) garbage-coded deaths ranged from 3.7% of all vital registration deaths to 67.3% in 2015, and the age-standardized proportion had an overall negative association with the Socio-Demographic Index. When broken down by age and sex, the category for unspecified lower respiratory infections was responsible for nearly 30% of garbage-coded deaths in those under 1 year of age for both sexes, representing the largest proportion of garbage codes for that age group. We show how the cause distribution by number of deaths changes before and after redistribution for four countries: Brazil, the United States, Japan, and France, highlighting the necessity of accounting for garbage-coded deaths in the GBD. CONCLUSIONS: We provide a detailed description of redistribution methods developed for CoD data in the GBD; these methods represent an overall improvement in empiricism compared to past reliance on a priori knowledge.

Anti-ceramide single-chain variable fragment mitigates radiation GI syndrome mortality independent of DNA repair.

After 9/11, threat of nuclear attack on American urban centers prompted government agencies to develop medical radiation countermeasures to mitigate hematopoietic acute radiation syndrome (H-ARS) and higher-dose gastrointestinal acute radiation syndrome (GI-ARS) lethality. While repurposing leukemia drugs that enhance bone marrow repopulation successfully treats H-ARS in preclinical models, no mitigator potentially deliverable under mass casualty conditions preserves GI tract. Here, we report generation of an anti-ceramide 6B5 single-chain variable fragment (scFv) and show that s.c. 6B5 scFv delivery at 24 hours after a 90% lethal GI-ARS dose of 15 Gy mitigated mouse lethality, despite administration after DNA repair was complete. We defined an alternate target to DNA repair, an evolving pattern of ceramide-mediated endothelial apoptosis after radiation, which when disrupted by 6B5 scFv, initiates a durable program of tissue repair, permitting crypt, organ, and mouse survival. We posit that successful preclinical development will render anti-ceramide 6B5 scFv a candidate for inclusion in the Strategic National Stockpile for distribution after a radiation catastrophe.

LXH254, a Potent and Selective ARAF-Sparing Inhibitor of BRAF and CRAF for the Treatment of MAPK-Driven Tumors.

PURPOSE: Targeting RAF for antitumor therapy in RAS-mutant tumors holds promise. Herein, we describe in detail novel properties of the type II RAF inhibitor, LXH254. EXPERIMENTAL DESIGN: LXH254 was profiled in biochemical, in vitro, and in vivo assays, including examining the activities of the drug in a large panel of cancer-derived cell lines and a comprehensive set of in vivo models. In addition, activity of LXH254 was assessed in cells where different sets of RAF paralogs were ablated, or that expressed kinase-impaired and dimer-deficient variants of ARAF. RESULTS: We describe an unexpected paralog selectivity of LXH254, which is able to potently inhibit BRAF and CRAF, but has less activity against ARAF. LXH254 was active in models harboring BRAF alterations, including atypical BRAF alterations coexpressed with mutant K/NRAS, and NRAS mutants, but had only modest activity in KRAS mutants. In RAS-mutant lines, loss of ARAF, but not BRAF or CRAF, sensitized cells to LXH254. ARAF-mediated resistance to LXH254 required both kinase function and dimerization. Higher concentrations of LXH254 were required to inhibit signaling in RAS-mutant cells expressing only ARAF relative to BRAF or CRAF. Moreover, specifically in cells expressing only ARAF, LXH254 caused paradoxical activation of MAPK signaling in a manner similar to dabrafenib. Finally, in vivo, LXH254 drove complete regressions of isogenic variants of RAS-mutant cells lacking ARAF expression, while parental lines were only modestly sensitive. CONCLUSIONS: LXH254 is a novel RAF inhibitor, which is able to inhibit dimerized BRAF and CRAF, as well as monomeric BRAF, while largely sparing ARAF.

Long-term Effects of Calcium ß-Hydroxy-ß-Methylbutyrate and Vitamin D3 Supplementation on Muscular Function in Older Adults With and Without Resistance Training: A Randomized, Double-blind, Controlled Study.

The primary aim of this study was to determine whether supplementation with calcium ß-hydroxy-ß-methylbutyrate (HMB) and vitamin D3 (D) would enhance muscle function and strength in older adults. Older adults over 60 years of age with insufficient circulating 25-hydroxy-vitamin D (25OH-D) levels were enrolled in a double-blinded controlled 12-month study. Study participants were randomly assigned to treatments consisting of: (a) Control + no exercise, (b) HMB+D + no exercise, (c) Control + exercise, and (d) HMB+D + exercise. The study evaluated 117 participants via multiple measurements over the 12 months that included body composition, strength, functionality, and questionnaires. HMB+D had a significant benefit on lean body mass within the nonexercise group at 6 months (0.44 ± 0.27 kg, HMB+D vs -0.33 ± 0.28 kg, control, p < .05). In nonexercisers, improvement in knee extension peak torque (60°/s) was significantly greater in HMB+D-supplemented participants than in the nonsupplemented group (p = .04) at 3 months, 10.9 ± 5.7 Nm and -5.2 ± 5.9 Nm, respectively. A composite functional index, integrating changes in handgrip, Get Up, and Get Up and Go measurements, was developed. HMB+D + no exercise resulted in significant increases in the functional index compared with those observed in the control + no exercise group at 3 (p = .03), 6 (p = .04), and 12 months (p = .04). Supplementation with HMB+D did not further improve the functional index within the exercising group. This study demonstrated the potential of HMB and vitamin D3 supplementation to enhance muscle strength and physical functionality in older adults, even in individuals not engaged in an exercise training program.