Somatic mutations in arteriovenous malformations in hereditary hemorrhagic telangiectasia support a bi-allelic two-hit mutation mechanism of pathogenesis.

Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder of vascular malformations characterized by mucocutaneous telangiectases and arteriovenous malformations (AVMs) in internal organs. HHT is caused by inheritance of a loss of function mutation in one of three genes. Although individuals with HHT are haploinsufficient for one of these genes throughout their entire body, rather than exhibiting a systemic vascular phenotype, vascular malformations occur as focal lesions in discrete anatomic locations. The inconsistency between genotype and phenotype has provoked debate over whether haploinsufficiency or a different mechanism gives rise to the vascular malformations. We previously showed that HHT-associated skin telangiectases develop by a two-hit mutation mechanism in an HHT gene. However, somatic mutations were identified in only half of the telangiectases, raising the question whether a second-hit somatic mutation is a necessary (required) event in HHT pathogenesis. Here, we show that another mechanism for the second hit is loss of heterozygosity across the chromosome bearing the germline mutation. Secondly, we investigate the two-hit mutation mechanism for internal organ AVMs, the source of much of the morbidity of HHT. Here, we identified somatic molecular genetic events in eight liver telangiectases, including point mutations and a loss of heterozygosity event. We also identified somatic mutations in one pulmonary AVM and two brain AVMs, confirming that mucocutaneous and internal organ vascular malformations undergo the same molecular mechanisms. Together, these data argue that bi-allelic loss of function in an HHT gene is a required event in the pathogenesis of HHT-associated vascular malformations.

Endoscopic Robotic Mitral Operating Room as a Microsystem for Safety and Sustainability.

OBJECTIVE: Safety and sustainability are key elements of a robotic mitral valve (MV) program at any stage of development. Challenges include the positioning of the surgeon at the robotic console, increasing patient complexity, and upstream administrative staffing difficulties. We instituted a systems approach to maximize patient safety and maintain robotic service viability. METHODS: A single dedicated robotic operating room (OR) was equipped as a microsystem with team training in the operative steps, ergonomics, digital tools, and an explicit culture of safety. Outcomes of all robotic mitral procedures including concomitant procedures in the microsystem OR by a single surgeon were retrospectively reviewed. RESULTS: From January 2014 through December 2023, 1,529 consecutive MV patients were operated with an endoscopic robotic approach. Ten patients (0.65%) were converted to conventional approaches. Overall, 1,300 MV repairs (85%) were performed with residual MV regurgitation of none to trace in 1,205 patients (92.7%), mild in 92 patients (7.1%), and moderate in 3 patients (0.23%). MV replacements were performed in 229 patients (15%) with no paravalvular leaks. Mortality was 0.08% in the repair group and 0.87% in the replacement group. No deaths have occurred in the last 38 months. Stroke occurred in 0.31% of repair patients and 1.3% of replacement patients. One patient developed transient renal failure. CONCLUSIONS: Organization of the robotic OR as a microsystem is associated with surgical efficacy and very low morbidity and mortality. A comparable microsystem approach using all or select components may promote safety and sustainability for robotic MV programs at all levels.

Impact of regression modeling on the assessment and harmonization of a point-of-care analyzer and commercial laboratory analyzer for feline plasma biochemistry testing.

BACKGROUND: Regression describes the relationship of results from two analyzers, and the generated equation can be used to harmonize results. Point-of-care (POC) analyzers cannot be calibrated by the end user, so regression offers an opportunity for calculated harmonization. Harmonization (uniformity) of laboratory results facilitates the use of common reference intervals and medical decision thresholds. OBJECTIVE: Our aims were to characterize the relationship of results for multiple biochemistry analytes on a POC and a commercial laboratory analyzer (CL) with three regression techniques and to use regression equations to harmonize the POC results with those of the CL. Harmonized results were assessed by recognized quality goals. We used harmonized results to assess the regression techniques. METHODS: After analyzer imprecision assessments, paired clinical samples were assessed with one dataset to calculate regression parameters that were applied to a second dataset. Three regression techniques were performed, and each was used to harmonize the POC results with those from the CL. POC results were assessed for bias and the number of results reaching quality goals before and after harmonization. RESULTS: All regression techniques could be used to harmonize most analytes so that 95% of results were within ASVCP TEa guidelines. Harmonization could be further improved with alternate regression techniques or exclusions. CONCLUSIONS: Regression offers a means to harmonize POC and CL analyzers. Further work is needed to assess how few samples can reliably be used and to assess likely species differences. No regression technique reliably describes the relationship between methods when correlation is poor.

Social media and youth mental health: Simple narratives produce biased interpretations.

Many academics and pundits contend that social media use is the primary cause of an international youth mental health crisis. However, these claims often rely on correlational evidence, ignoring the confounding effects of developmental, environmental, social, and psychological factors that influence mental health. This oversimplifies the complex etiology of mental health problems. We call for a more nuanced understanding of the role of social media in youth mental health that avoids oversimplification. Additionally, we urge researchers to move beyond vague, narrative-driven verbal theories and encode them into precise, testable causal models. Using simulation techniques and specification curve analyses, we show how misspecified models that ignore these confounding factors can lead to biased conclusions about social media's adverse effects. This simplistic focus on social media use diverts attention from the broader factors contributing to youth mental health problems, hindering the development of effective interventions and support. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Redefining Candidates for Deintensification in Locoregionally Advanced P16+ Oropharyngeal Cancer Based on Relative Risk.

BACKGROUND: Randomized trials have found that patients with locoregionally advanced p16+ oropharyngeal squamous cell carcinoma (OPSCC) do not benefit from treatment deintensification, even among favorable risk groups. While various methods have been used to identify candidates for treatment deintensification, the optimal approach is unknown. METHODS: We conducted a multi-institutional cohort study of 444 patients with previously untreated p16+ OPSCC undergoing definitive radiotherapy with or without systemic therapy between 2009-2022. We compared two approaches for identifying candidates for deintensification: (1) favorable vs. unfavorable risk, using NRG-HN005 eligibility criteria, and (2) low vs. high relative risk for cancer events, using the HNCIG predictive classifier ("omega score"). We tested differences in outcomes and systemic therapy allocation by risk group using multivariable Cox models, competing event models, and logistic regression, and compared characteristics of hypothetical deintensification trials using the two approaches. PFS events were defined as cancer recurrence (locoregional or distant) or death from any cause. RESULTS: Median follow-up time was 52 months; 120 patients (27.0%) were favorable risk; a different 120 patients had low omega score; 28 patients (6.3%) met both criteria; 184 patients (41.4%) had discordant classification. On ordinal logistic regression, decreasing omega score was associated with a statistically significantly lower odds of receiving intensive therapy (normalized OR 0.37 per standard deviation; 95% CI: 0.24-0.57), with a greater magnitude than favorable risk group (OR 0.66; 95% CI: 0.44-0.99). Among patients receiving cisplatin and/or platinum-based induction (N=374), favorable risk was associated with significantly improved PFS (HR 0.59, 95% CI 0.36-0.99), whereas lower omega score was associated with a significantly decreased relative hazard for cancer events (RHR 0.18, 95% CI 0.070-0.46). In simulations, selecting patients with low omega scores increased the efficiency of hypothetical non-inferiority trials. CONCLUSIONS: Considering patients' relative risk for cancer events can help define optimal populations for treatment deintensification in p16+ OPSCC.

Novel Pannexin 1 isoform is increased in cancer.

Pannexin 1 (PANX1) is upregulated in many cancers, where its activity and signalling promote tumorigenic properties. Here, we report a novel ∼25 kDa isoform of human PANX1 (hPANX1-25K) which lacks the N-terminus and was detected in several human cancer cell lines including melanoma, osteosarcoma, breast cancer and glioblastoma multiforme. This isoform was increased upon hPANX1 CRISPR/Cas9 deletion targeting the first exon near M1, suggesting a potential alternative translation initiation (ATI) site. hPANX1-25K was confirmed to be a hPANX1 isoform via mass spectrometry, can be N-linked glycosylated at N254, and can interact with both ß-catenin and full length hPANX1. A double deletion of hPANX1 and hPANX1-25K reduces cell growth and viability in cancer cells. hPANX1-25K is prevalent throughout melanoma progression, and its levels are increased in squamous cell carcinoma cells and patient-derived tumours, compared to keratinocytes and normal skin, indicating that it may be differentially regulated in normal and cancer cells.

Substrate interactions guide cyclase engineering and lasso peptide diversification.

Lasso peptides are a diverse class of naturally occurring, highly stable molecules kinetically trapped in a distinctive [1]rotaxane conformation. How the ATP-dependent lasso cyclase constrains a relatively unstructured substrate peptide into a low entropy product has remained a mystery owing to poor enzyme stability and activity in vitro. In this study, we combined substrate tolerance data with structural predictions, bioinformatic analysis, molecular dynamics simulations and mutational scanning to construct a model for the three-dimensional orientation of the substrate peptide in the lasso cyclase active site. Predicted peptide cyclase molecular contacts were validated by rationally engineering multiple, phylogenetically diverse lasso cyclases to accept substrates rejected by the wild-type enzymes. Finally, we demonstrate the utility of lasso cyclase engineering by robustly producing previously inaccessible variants that tightly bind to integrin αvß8, which is a primary activator of transforming growth factor ß and, thus, an important anti-cancer target.

Serum Proteomic Predictors of Calcification of Solitary Cysticercus Granuloma.

Solitary cysticercus granulomas (SCG), prevalent among Indian patients with new-onset seizures, either resolve completely or transform into calcified granulomas. This study aimed to identify serum proteins through liquid chromatography-tandem mass spectrometry that could predict calcification of SCGs in 20 patients with SCG with at least 6-months of follow-up. At a median follow-up of 14 months, the SCG had calcified (n = 5), resolved (n = 11), or persisted (n = 4). Two serum proteins, ECM1 and MST1, were present in significantly higher serum concentrations, and AZGP1 in significantly lower concentration in subjects with calcifying SCGs than in those with lesions that resolved or persisted. On multivariate analysis, only ECM1 (odds ratio: 1.7, 95% CI: 0-2.8) and MST1 (odds ratio: 3.3, 95% CI: 0-4.1) were independent predictors of calcification of SCG. Combining elevated levels of serum ECM1 and MST1 had a sensitivity of 100% and specificity of 100% in differentiating granulomas that calcified from those that resolved/persisted. Increased expression of serum ECM1 and MST1 in patients with SCG might predict calcification.

Robotic mitral surgery: recent advances and outcomes.

PURPOSE OF REVIEW: This review explores recent advancements in robotic cardiac surgery, specifically focusing on its application in diverse mitral valve surgeries. The aim is to provide an overview of current clinical practices and supporting evidence in this evolving field. RECENT FINDINGS: A literature review indicates a 30% surge in robotic mitral valve repair from 2015 to 2021, paralleled by a decline in sternotomy-based repair per the STS database. Robotic mitral valve repair consistently shows effective and safe outcomes, with comparable mortality but lower morbidity risks than sternotomy and thoracotomy. The robotic approach exhibits lower conversion to valve replacement, shorter ICU stays, and reduced 30-day readmissions. For experienced programs, robotic techniques prove versatile in various pathologies, including rheumatic heart valve disease, infective endocarditis, ischemic cardiomyopathy, and mitral annular calcification necessitating valve replacement. Literature supports their selective use in high-risk scenarios, including redo surgeries and elderly patients. SUMMARY: Recent evidence supports the growing use of robotic approaches in mitral valve surgery, highlighting their efficacy with comparable mortality rates but lower morbidity risks. Robotic techniques consistently yield positive outcomes across various pathologies and patient profiles, signaling a potential paradigm shift in mitral valve interventions.

Time Trends and Demographic Disparities in Helicobacter pylori Burden in a Large, Community-Based Population in the United States.

Background and Aims: There are minimal recent population-based data on the epidemiology of Helicobacter pylori (H. pylori) in the United States. Methods: This retrospective cohort study evaluated H. pylori positivity rates in adult members of a large, community-based US population in 2000-2019. Time trends, demographic disparities, and birth cohort effects on H. pylori test positivity rates were analyzed. Results: Among 751,322 individuals tested for H. pylori, the overall nonserological and serological test positivity rates were 18.2% (95% confidence interval [CI], 18.1%-18.4%) and 36.8% (95% CI, 36.6%-36.9%), respectively. Nonserological positivity rate (95% CI) was significantly higher among Asian (23.2% [22.8%-23.6%]), Black (25.1% [24.4%-25.8%]), and Hispanic (28.1% [27.7%-28.5%]) individuals than non-Hispanic White individuals (10.0% [9.8%-10.2%]), and was significantly higher among individuals with a non-English language preference (32.9% [32.3%-33.5%]) than those with English language preference (15.8% [15.6%-15.9%]). Patterns were similar for serological positivity, although with substantially higher rates. Serological positivity rates decreased over 2 decades but nonserological positivity rates initially decreased and then stabilized over the past decade. There was a significant decrease in both nonserological and serological positivity rates from older to younger birth cohorts. Older age, non-White race or Hispanic ethnicity, male sex, and non-English language preference were associated with high odds of H. pylori positivity. Conclusion: The burden of H. pylori decreased over 2 decades, although the rates of active infection plateaued over the past decade in a diverse, community-based US population, likely attributable to birth cohort effects and demographic changes. Asian, Black, and Hispanic individuals had 2-3-fold higher rates of active H. pylori infection than non-Hispanic White individuals. These findings should inform targeted screening and eradication of H. pylori in high-risk US populations.

Nephrolithiasis on the National Stage: The Kidney Stones of President Lyndon B. Johnson.

Lyndon Baines Johnson, the 36th president of the United States, was troubled with kidney stones for most of his adult life. Three times during his political career, he required either endoscopic or open surgical removal of stones. This review will highlight the symptomatic presentation of his stones, his nephrolithiasis' effect on his political career, and the methods used and reasoning for treating his nephrolithiasis.

Salivary and Serum Analytes and Their Associations with Self-rated Health Among Healthy Young Adults.

BACKGROUND: Understanding the biological processes underlying poor self-rated health (SRH) can inform prevention efforts. The COVID-19 pandemic highlighted the importance of using self-reported measures and self-collected biospecimens, such as saliva, to understand physiological functioning and assist with health surveillance and promotion. However, the associations between salivary analytes and SRH remain understudied. The current study addresses this gap. METHODS: In a laboratory-based study, 99 healthy adults (Mage = 23.8 years, SD = 4.5, 55% men, 43% non-Hispanic White) reported their SRH and provided saliva and blood samples that were assayed for adiponectin, C-reactive protein (CRP), uric acid (UA), and cytokines (IL-1ß, IL-6, IL-8, TNF-α). Principal component analyses assessed the component loadings and generated factor scores for saliva and serum analytes. Binary logistic regressions examined the associations between these components and poor SRH. RESULTS: Salivary analytes loaded onto two components (component 1: adiponectin and cytokines; component 2: CRP and UA) explaining 58% of the variance. Serum analytes grouped onto three components (component 1: IL-8 and TNF-α; component 2: CRP, IL-1ß, and IL-6; component 3: adiponectin and UA) explaining 76% of the variance. Higher salivary component 1 scores predicted higher odds of reporting poor SRH (OR 1.53, 95%CI [1.10, 2.11]). Higher serum component 2 scores predicted higher odds of reporting poor SRH (OR 2.37, 95%CI [1.20, 4.67]). When examined in the same model, salivary component 1 (OR 1.79, 95%CI [1.17, 2.75]) and serum component 2 were associated with poorer SRH (OR 7.74, 95%CI [2.18, 27.40]). CONCLUSIONS: In our sample, whether measured in saliva or serum, indices of inflammatory processes were associated with SRH.

Pan-tumor validation of a NGS fraction-based MSI analysis as a predictor of response to Pembrolizumab.

Microsatellite instability high (MSI-H) and mismatch repair deficient (dMMR) tumor status have been demonstrated to predict patient response to immunotherapies. We developed and validated a next-generation sequencing (NGS)-based companion diagnostic (CDx) to detect MSI-H solid tumors via a comprehensive genomic profiling (CGP) assay, FoundationOne®CDx (F1CDx). To determine MSI status, F1CDx calculates the fraction of unstable microsatellite loci across >2000 loci using a fraction-based (FB) analysis. Across solid tumor types, F1CDx demonstrated a high analytical concordance with both PCR (n = 264) and IHC (n = 279) with an overall percent agreement (OPA) of 97.7% and 97.8%, respectively. As part of a retrospective bridging clinical study from KEYNOTE-158 Cohort K and KEYNOTE-164, patients with MSI-H tumors as determined by F1CDx demonstrated an objective response rate (ORR) of 43.0% to pembrolizumab. In real-world cancer patients from a deidentified clinicogenomic database, F1CDx was at least equivalent in assessing clinical outcome following immunotherapy compared with MMR IHC. Demonstrated analytical and clinical performance of F1CDx led to the pan-tumor FDA approval in 2022 of F1CDx to identify MSI-H solid tumor patients for treatment with pembrolizumab. F1CDx is an accurate, reliable, and FDA-approved method for the identification of MSI-H tumors for treatment with pembrolizumab.

Resolving the metabolism of monolignols and other lignin-related aromatic compounds in Xanthomonas citri.

Lignin, a major plant cell wall component, has an important role in plant-defense mechanisms against pathogens and is a promising renewable carbon source to produce bio-based chemicals. However, our understanding of microbial metabolism is incomplete regarding certain lignin-related compounds like p-coumaryl and sinapyl alcohols. Here, we reveal peripheral pathways for the catabolism of the three main lignin precursors (p-coumaryl, coniferyl, and sinapyl alcohols) in the plant pathogen Xanthomonas citri. Our study demonstrates all the necessary enzymatic steps for funneling these monolignols into the tricarboxylic acid cycle, concurrently uncovering aryl aldehyde reductases that likely protect the pathogen from aldehydes toxicity. It also shows that lignin-related aromatic compounds activate transcriptional responses related to chemotaxis and flagellar-dependent motility, which might play an important role during plant infection. Together our findings provide foundational knowledge to support biotechnological advances for both plant diseases treatments and conversion of lignin-derived compounds into bio-based chemicals.

Impact of Cryopreserved Placental Allografts on Biochemical Recurrence in Prostate Cancer.

BACKGROUND: Human placental allografts are widely used to promote wound healing. Placental (or amniotic membrane/umbilical cord) allografts are placed along the neurovascular bundles during radical prostatectomy to improve continence and erectile function recovery. It is unknown whether placental allografts impact biochemical recurrence (BCR). METHODS: This was a single-surgeon retrospective study of 566 robotic radical prostatectomies performed from April 2015 to March 2021. The patients were divided into three groups: the negative control, Brand A, and Brand B. Brand A and Brand B were both cryopreserved amniotic membrane (CAM) allografts. A total of 324 cases were included for BCR Kaplan-Meier and risk-adjusted multivariate analyses (362 for continence analysis). In vitro analyses were performed to determine the effect of CAM allografts on prostate cancer (PCa) cell line growth. RESULTS: For propensity score-matched analysis (adjusting for pre-operative PSA, tumor stage, Gleason Grade, and margin status), (1) the allograft groups did not show differences in time to BCR vs. the negative control group (p = 0.7), and (2) combined allograft treatment groups showed better continence recovery vs. the negative controls (p = 0.01). In vitro, placental allografts reduced PCa cell line growth in co-culture assays. CONCLUSIONS: cryopreserved AM allografts (combined or individual brands) did not show a significant effect on BCR but improved continence recovery for PCa patients.

Rules of river avulsion change downstream.

Avulsing rivers create new pathways on the floodplain and the associated flooding can profoundly affect society1-4. River avulsions are thought to occur when the water column becomes perched above the floodplain5 or when the slope down the flanks of the channel provides a steeper descent than the existing river channel6,7. We test these classical ideas by quantifying the topography around avulsing rivers and show that these mechanisms, historically invoked separately, work together. Near coasts, rivers avulse when the slope away from the channel is steeper, not because they are perched. The opposite is true near mountain fronts; on fans, the alternative paths are similarly steep to the downstream path, so rivers avulse when they are perched above the surrounding landscape. We reconcile these findings and present a new theoretical framework that identifies which rivers are vulnerable to avulsion and predicts the path of an avulsing river. These first-order rules of avulsion suggest that avulsion risks are underestimated in many coastal environments8 and that probabilistic predictions of avulsion pathfinding can efficiently map hazards with minimal information. Applying these principles for risk assessment could particularly benefit the Global South, which is disproportionately affected by avulsions.

Characterizing the Use of Time-Limited Trials in Patients With Acute Respiratory Failure: A Prospective, Single-Center Observational Study.

IMPORTANCE: A time-limited trial (TLT) is a collaborative plan among clinicians, patients, and families to use life-sustaining therapy for a defined duration, after which the patient's response informs whether to continue care directed toward recovery or shift the focus toward comfort. TLTs are a promising approach to help navigate uncertainty in critical illness, yet little is known about their current use. OBJECTIVES: To characterize TLT use in patients with acute respiratory failure (ARF). DESIGN, SETTING, AND PARTICIPANTS: Prospective 12-month observational cohort study at an U.S. academic medical center of adult ICU patients with ARF receiving invasive mechanical ventilation for greater than or equal to 48 hours. MAIN OUTCOMES AND MEASURES: Primary exposure was TLT participation, identified by patients' ICU physician. Patient characteristics, care delivery elements, and hospital outcomes were extracted from the electronic medical record. RESULTS: Among 176 eligible patients, 36 (20.5%) participated in a TLT. Among 18 ICU attending physicians, nine (50%) participated in greater than or equal to 1 TLT (frequency 0-39% of patients cared for). Median TLT duration was 3.0 days (interquartile range [IQR], 3.0-4.5 d). TLT patients had a higher mean age (67.4 yr [sd, 12.0 yr] vs. 60.0 yr [sd, 16.0 yr]; p < 0.01), higher Charlson Comorbidity Index (5.1 [sd, 2.2] vs. 3.8 [sd, 2.6]; p < 0.01), and similar Sequential Organ Failure Assessment score (9.6 [sd, 3.3] vs. 9.5 [sd, 3.7]; p = 0.93), compared with non-TLT patients. TLT patients were more likely to die or be discharged to hospice (80.6% vs. 42.1%; p < 0.05) and had shorter ICU length of stay (median, 5.7 d [IQR, 4.0-9.0 d] vs. 10.3 d [IQR, 5.5-14.5 d]; p < 0.01). CONCLUSIONS AND RELEVANCE: In this study, approximately one in five patients with ARF participated in a TLT. Our findings suggest TLTs are used primarily in patients near end of life but with substantial physician variation, highlighting a need for evidence to guide optimal use.

Association between inspired oxygen fraction and development of postoperative pulmonary complications in thoracic surgery: a multicentre retrospective cohort study.

BACKGROUND: Limited data exist to guide oxygen administration during one-lung ventilation for thoracic surgery. We hypothesised that high intraoperative inspired oxygen fraction during lung resection surgery requiring one-lung ventilation is independently associated with postoperative pulmonary complications (PPCs). METHODS: We performed this retrospective multicentre study using two integrated perioperative databases (Multicenter Perioperative Outcomes Group and Society of Thoracic Surgeons General Thoracic Surgery Database) to study adult thoracic surgical procedures using one-lung ventilation. The primary outcome was a composite of PPCs (atelectasis, acute respiratory distress syndrome, pneumonia, respiratory failure, reintubation, and prolonged ventilation >48 h). The exposure of interest was high inspired oxygen fraction (FiO2), defined by area under the curve of a FiO2 threshold > 80%. Univariate analysis and logistic regression modelling assessed the association between intraoperative FiO2 and PPCs. RESULTS: Across four US medical centres, 141/2733 (5.2%) procedures conducted in 2716 patients (55% female; mean age 66 yr) resulted in PPCs. FiO2 was univariately associated with PPCs (adjusted OR [aOR]: 1.17, 95% confidence interval [CI]: 1.04-1.33, P=0.012). Logistic regression modelling showed that duration of one-lung ventilation (aOR: 1.20, 95% CI: 1.03-1.41, P=0.022), but not the time-weighted average FiO2 (aOR: 1.01, 95% CI: 1.00-1.02, P=0.165), was associated with PPCs. CONCLUSIONS: Our results do not support limiting the inspired oxygen fraction for the purpose of reducing postoperative pulmonary complications in thoracic surgery involving one-lung ventilation.

Stability and Volatility in the Contextual Predictors of Working-Age Mortality in the United States.

The contextual predictors of mortality in the United States are well documented, but the COVID-19 pandemic may have upended those associations. Informed by the social history of disease framework (SHDF), this study examined how the importance of county contexts on adult deaths from all causes, drug poisonings, and COVID-19-related causes fluctuated during the pandemic. Using 2018 to 2021 vital statistics data, for each quarter, we estimated associations between county-level deaths among adults ages 25 to 64 and prepandemic county-level contexts (economic conditions, racial-ethnic composition, population health profile, and physician supply). The pandemic significantly elevated the importance of county contexts-particularly median household income and counties' preexisting health profile-on all-cause and drug poisoning deaths. The elevated importance of household income may be long-lasting. Contextual inequalities in COVID-19-related deaths rose and then fell, as the SHDF predicts, but rose again along with socio-political disruptions. The findings support and extend the SHDF.

Weight-Based Standardized Sugammadex Dosing in Pediatrics: A Quality Improvement Initiative to Improve Compliance with Dosing Guidelines and Reduce Waste and Cost.

Methods: Sugammadex vials were fractionated into 25, 50, or 100 mg aliquots, which would be distributed to anesthesia staff by pharmacy staff in approximate 2 mg/kg of actual body weight doses (±10%). We analyzed changes in sugammadex waste and dosing practices 1/1/2019 to 3/15/2023 pre/postintervention (4/1/2021). We gauged dose appropriateness using last train of four (TOF) prior to sugammadex administration. Results: 7,889 patients 2-17 years (4,771 with documented TOF), ASA 1-4 receiving general anesthesia with a steroidal NMB medication and sugammadex reversal. Pre- and postintervention mean doses were 2.5 mg/kg (SD: 1.2) and 2.4 mg/kg (SD: 0.96), respectively. A smaller proportion of cases received standard 2 or 4 mg/kg doses (pre: 77.6 vs. post: 66.7%). Mean waste per case declined from 4.2 mg/kg (SD: 4.1) to 0.22 mg/kg (SD: 0.38). Among cases with 0 or 1 measured twitches on TOF that should receive at least 4 mg/kg, fewer received at least 3.6 mg/kg (post: 56.7% vs. pre: 66.8%), and a greater proportion received less than 2.2 mg/kg (post: 27.4% vs. pre: 20.7%). Among cases that should have received at least 2 mg/kg by TOF, the proportion of patients receiving more than 3.6 mg/kg declined from 9.5% to 5.2%. Discussion. Fractionating sugammadex vials was associated with decreases in waste, but not dose, and significant underdosing was more likely to occur. While vial fractionation could enable increased access to sugammadex and other costly medications, it may introduce unintended consequences.