TSWIFT, a novel method for iterative staining of embedded and mounted human brain sections.

Comprehensive characterization of protein networks in mounted brain tissue represents a major challenge in brain and neurodegenerative disease research. In this study, we develop a simple staining method, called TSWIFT, to iteratively stain pre-mounted formalin fixed, paraffin embedded (FFPE) brain sections, thus enabling high-dimensional sample phenotyping. We show that TSWIFT conserves tissue architecture and allows for relabeling a single mounted FFPE sample more than 10 times, even after prolonged storage at 4 °C. Our results establish TSWIFT as an efficient method to obtain integrated high-dimensional knowledge of cellular proteomes by analyzing mounted FFPE human brain tissue.

Reconstructing Nasal Defects With Acellular Dermal Matrix After Mohs Micrographic Surgery: A 12-year Experience.

BACKGROUND AND OBJECTIVE: Large defects of the nose after Mohs surgery pose a significant reconstructive challenge to both dermatologic and reconstructive surgeons. The authors present their 12-year experience utilizing acellular dermal matrices for nasal reconstruction. METHODS: A retrospective review of patients undergoing Mohs surgery and alloplastic nasal reconstruction with acellular dermal matrices between 2010 and 2022 was performed. Patients who underwent single-stage reconstruction and dual-stage reconstruction with skin graft with at least 90 days of follow-up were included. RESULTS: Fifty-one patients met criteria with a median age of 77 years. Fifty-three lesions were reconstructed with acellular dermal matrices. The most common lesion location was nasal sidewall (50%) with a mean defect size of 10.8 cm 2 . 30.8% underwent same-day acellular dermal matrix reconstruction, with 69.2% undergoing two-stage reconstruction. Acellular dermal matrices successfully reconstructed acquired defects in 94.2% of lesions. Average time to re-epithelialization was 27.6 + 6.2 days. Average time to repigmentation was 145.35 + 86 days. No recurrences were recorded. Total complication rate was 9.62%. Average size for successful healing was 10.8 cm 2 . Average defect size for complication or failure was 14.7 cm 2 . Seven sites (13.46%) underwent aesthetic improvement procedures. CONCLUSION: Acellular bilayer wound matrix is an adequate reconstructive option for single or dual-stage reconstruction of the nose with low complication and revision rates.

Estimating Tiotropium Wasted Doses After Adding Revefenacin to an Inpatient Formulary: A Single-Center Cross-Sectional Study.

Introduction: Revefenacin is a once-daily nebulized long-acting muscarinic antagonist (LAMA). Revefenacin is supplied as single-use nebulized vials, which may be preferable and less costly for hospital and health-system pharmacies to dispense versus multidose tiotropium inhalers. Estimates of LAMA multidose inhaler wasted doses remains unknown. Methods: This was a single-center descriptive cross-sectional study conducted between January 1 2021 and December 31 2021. Adult patients 18 years and older admitted to a 500-bed academic medical center in the southern United States and were ordered multidose tiotropium packages or single-use revefenacin vials during the study period were included. Results: Among 602 inpatients, there were 705 LAMA orders: 541 tiotropium (76.7%) and 164 revefenacin (23.3%). Four hundred ninety-five tiotropium orders (91.5%) wasted between 20% and 90% of multidose packages. Approximately $24,000 tiotropium doses were wasted versus single-use revefenacin vials. Conclusion: Multidose inhalers of tiotropium dispensed to hospitalized patients contributed to wasted doses compared to nebulized single-use revefenacin vials. Opportunities exist to minimize wasted doses of multidose long-acting inhalers dispensed to hospitalized patients.

IL-1ß Inhibition Partially Negates the Beneficial Effects of Diet-Induced Atherosclerosis Regression in Mice.

BACKGROUND: Thromboembolic events secondary to rupture or erosion of advanced atherosclerotic lesions is the global leading cause of death. The most common and effective means to reduce these major adverse cardiovascular events, including myocardial infarction and stroke, is aggressive lipid lowering via a combination of drugs and dietary modifications. However, we know little regarding the effects of reducing dietary lipids on the composition and stability of advanced atherosclerotic lesions, the mechanisms that regulate these processes, and what therapeutic approaches might augment the benefits of lipid lowering. METHODS: Smooth muscle cell lineage-tracing Apoe-/- mice were fed a high-cholesterol Western diet for 18 weeks and then a zero-cholesterol standard laboratory diet for 12 weeks before treating them with an IL (interleukin)-1ß or control antibody for 8 weeks. We assessed lesion size and remodeling indices, as well as the cellular composition of aortic and brachiocephalic artery lesions, indices of plaque stability, overall plaque burden, and phenotypic transitions of smooth muscle cell and other lesion cells by smooth muscle cell lineage tracing combined with single-cell RNA sequencing, cytometry by time-of-flight, and immunostaining plus high-resolution confocal microscopic z-stack analysis. RESULTS: Lipid lowering by switching Apoe-/- mice from a Western diet to a standard laboratory diet reduced LDL cholesterol levels by 70% and resulted in multiple beneficial effects including reduced overall aortic plaque burden, as well as reduced intraplaque hemorrhage and necrotic core area. However, contrary to expectations, IL-1ß antibody treatment after diet-induced reductions in lipids resulted in multiple detrimental changes including increased plaque burden and brachiocephalic artery lesion size, as well as increasedintraplaque hemorrhage, necrotic core area, and senescence as compared with IgG control antibody-treated mice. Furthermore, IL-1ß antibody treatment upregulated neutrophil degranulation pathways but downregulated smooth muscle cell extracellular matrix pathways likely important for the protective fibrous cap. CONCLUSIONS: Taken together, IL-1ß appears to be required for the maintenance of standard laboratory diet-induced reductions in plaque burden and increases in multiple indices of plaque stability.

Impact of removing ESBL status labelling from culture reports on the use of carbapenems for non-bacteraemic patients diagnosed with ESBL-positive urinary tract infections.

OBJECTIVES: To evaluate carbapenem prescribing rates for initial definitive treatment of urinary tract infections and clinical outcomes before and after removing ESBL status labels on antibiotic susceptibility reports. METHODS: This was a retrospective cohort study of adult patients treated for at least 48 h for an ESBL-producing/ceftriaxone-resistant Enterobacterales urinary tract infection. ESBL status reporting ceased in September 2022 for a network of seven community hospitals within the USA. The primary endpoint was the rate of carbapenem prescribing for initial definitive treatment of urinary tract infections. Secondary endpoints included total days of therapy for initial definitive treatment with carbapenems, clinical cure rates, time to transition to oral antibiotic therapy for initial definitive treatment, rate of guideline-compliant therapy, rate of relapsed infection within 30 days, 30 day readmission rate, and 30 day all-cause in-hospital mortality. RESULTS: Of 3055 patients screened, 199 were included in the pre group and 153 were included in the post group. The rate of carbapenem prescribing for initial definitive treatment was 156 patients (78%) in the pre group, compared with 93 patients (61%) in the post group (P = <0.01). Days of therapy for initial definitive therapy with carbapenem was 620 in the pre group compared with 372 in the post group (P < 0.01). There was no difference between other secondary outcomes. CONCLUSIONS: Removing ESBL status labels from laboratory reports reduced carbapenem use for initial definitive treatment of urinary tract infections from 78% to 61% (P < 0.01) without impacting clinical outcomes.

Improving appropriate use of intravenous albumin: results of a single-centre audit and multifaceted intervention.

BACKGROUND: Intravenous albumin has limited indications supported by randomised controlled trials, yet it is often prescribed for indications not supported by evidence. AIM: To reduce unnecessary transfusion of albumin. INTERVENTIONS: Under the leadership of a multidisciplinary quality improvement team, evidence-based recommendations were disseminated in tandem with a new electronic order set, an educational strategy, qualitative interviews with prescribers and a return policy change to reduce wastage. IMPLEMENTATION AND EVALUATION: Interventions were introduced in a staggered fashion. The primary outcome, appropriate use of albumin, was monitored and quantified using pre-intervention and post-intervention audits. Process measures included statistical process run charts of monthly usage of 5% and 25% albumin and wastage. Data on length of stay (hospital and intensive care), new inpatient starts on kidney replacement and mortality were collected as balancing measures. RESULTS: Appropriate albumin usage based on indication increased from 30% to 50% (p<0.0001). There was significantly less overall albumin usage in the post-intervention period compared with the pre-intervention period (negative coefficient, p<0.0001), driven by a major reduction in the utilisation of the 5% formulation (p<0.0001). Overall albumin usage was significantly lower in the post-intervention period, decreasing from 800 to 450 vials per month. The intervention resulted in significantly less wastage (negative coefficient, p=0.017). Mortality, length of stay and new starts on kidney replacement therapy remained constant throughout the study period. CONCLUSION: Improved prescribing of albumin was achieved with a multifaceted approach. Substantial and sustained reductions in usage were achieved without negatively impacting patient-important outcomes. The estimated annual savings for the purchase cost of albumin was CAN $300 000. We provide a structured process for other organisations to optimise their use of albumin.

Early Experience With Artificial Intelligence Software to Detect Intracranial Occlusive Stroke in Trauma Patients.

Objective Identifying ischemic stroke is a diagnostic challenge in the trauma subpopulation. We describe our early experience with artificial intelligence-assisted image analysis software for automatically identifying acute ischemic stroke in trauma patients.  Methods Patients were retrospectively screened for (i) admission to the trauma service at a level one trauma center between 2020 and 2022, (ii) radiologist-confirmed intracranial occlusion, (iii) occlusion identified on computed tomography angiography performed within 24 hours of admission, (iv) no intracranial hemorrhage, and (v) contemporaneous analysis with the large vessel occlusion (LVO) detection program. Baseline characteristics, stroke detection, response-activation, and outcome data were summarized.  Results Of 9893 trauma patients admitted, 88 (0.89%) patients had a cerebral stroke diagnosis, of which 10 patients (10/88; 11.4%) met inclusion criteria. Most patients were admitted following a fall (8/10; 80%). Six (6/10; 60.0%) patients had LVOs. The program correctly detected 83.3% (5/6) of patients, and these patients were triaged in less than one hour from arrival on average. The program did not falsely identify non-LVOs as LVOs for any patients. Conclusions Identifying adjunct tools to aid timely identification and treatment of ischemic stroke in trauma patients is necessary to increase the chances for meaningful neurological recovery. Our early experience exhibited potential for using automated software to aid occlusion identification and subsequent stroke team mobilization. Future studies in larger cohorts will expand upon these preliminary findings to establish the accuracy and clinical benefit of automated stroke detection tool integration for the trauma population.

Dopamine­iron homeostasis interaction rescues mitochondrial fitness in Parkinson's disease.

Imbalances of iron and dopamine metabolism along with mitochondrial dysfunction have been linked to the pathogenesis of Parkinson's disease (PD). We have previously suggested a direct link between iron homeostasis and dopamine metabolism, as dopamine can increase cellular uptake of iron into macrophages thereby promoting oxidative stress responses. In this study, we investigated the interplay between iron, dopamine, and mitochondrial activity in neuroblastoma SH-SY5Y cells and human induced pluripotent stem cell (hiPSC)-derived dopaminergic neurons differentiated from a healthy control and a PD patient with a mutation in the α-synuclein (SNCA) gene. In SH-SY5Y cells, dopamine treatment resulted in increased expression of the transmembrane iron transporters transferrin receptor 1 (TFR1), ferroportin (FPN), and mitoferrin2 (MFRN2) and intracellular iron accumulation, suggesting that dopamine may promote iron uptake. Furthermore, dopamine supplementation led to reduced mitochondrial fitness including decreased mitochondrial respiration, increased cytochrome c control efficiency, reduced mtDNA copy number and citrate synthase activity, increased oxidative stress and impaired aconitase activity. In dopaminergic neurons derived from a healthy control individual, dopamine showed comparable effects as observed in SH-SY5Y cells. The hiPSC-derived PD neurons harboring an endogenous SNCA mutation demonstrated altered mitochondrial iron homeostasis, reduced mitochondrial capacity along with increased oxidative stress and alterations of tricarboxylic acid cycle linked metabolic pathways compared with control neurons. Importantly, dopamine treatment of PD neurons promoted a rescue effect by increasing mitochondrial respiration, activating antioxidant stress response, and normalizing altered metabolite levels linked to mitochondrial function. These observations provide evidence that dopamine affects iron homeostasis, intracellular stress responses and mitochondrial function in healthy cells, while dopamine supplementation can restore the disturbed regulatory network in PD cells.

Free flap reconstruction of elbow soft tissue defects: Lessons learned from 15 years of experience.

BACKGROUND: The elbow is a complex joint that is vital for proper function of the upper extremity. Reconstruction of soft tissue defects over the joint space remains challenging, and outcomes following free tissue transfer remain underreported in the literature. The purpose of this analysis was to evaluate the rate of limb salvage, joint function, and clinical complications following microvascular free flap coverage of the elbow. METHODS: This retrospective case series utilized surgical logs of the senior authors (Stephen J Kovach and L Scott Levin) to identify patients who underwent microvascular free flap elbow reconstruction between January 2007 and December 2021. Patient demographics and medical history were collected from the medical chart. Operative notes were reviewed to determine the type of flap procedure performed. The achievement of definitive soft tissue coverage, joint function, and limb salvage status at 1 year was determined from postoperative visit notes. RESULTS: Twenty-one patients (14 male, 7 female, median age 43) underwent free tissue transfer for coverage of soft tissue defects of the elbow. The most common indication for free tissue transfer was traumatic elbow fracture with soft tissue loss (n = 12, [57%]). Among the 21 free flaps performed, 71% (n = 15) were anterolateral thigh flaps, 14% (n = 3) were latissimus dorsi flaps, and 5% (n = 1) were transverse rectus abdominis flaps. The mean flap size was 107.5 cm2. Flap success was 100% (n = 21). The following postoperative wound complications were reported: surgical site infection (n = 1, [5%]); partial dehiscence (n = 5, [24%]); seroma (n = 2, [10%]); donor-site hematoma (n = 1, [5%]); and delayed wound healing (n = 5, [24%]). At 1 year, all 21 patients achieved limb salvage and definitive soft tissue coverage. Of the 17 patients with functional data available, 47% (n = 8) had regained at least 120 degrees of elbow flexion/extension. All patients had greater than 1 year of follow-up. CONCLUSION: Microvascular free flap reconstruction is a safe and effective method of providing definitive soft tissue coverage of elbow defects, as evidenced by high rates of limb salvage and functional recovery following reconstruction.

Epigenetic small-molecule screen for inhibition and reversal of acinar ductal metaplasia in mouse pancreatic organoids.

Background: Acinar ductal metaplasia (ADM) is among the earliest initiating events in pancreatic ductal adenocarcinoma (PDAC) development. Methods: We developed a novel morphology-based screen using organoids from wildtype and p48Cre/+ (Cre) mice to discover epigenetic modulators that inhibit or reverse pancreatic ADM more effectively than the broad-spectrum HDAC inhibitor trichostatin A (TSA). Results: Of the 144 compounds screened, nine hits and two additional natural product HDAC inhibitors were validated by dose-response analysis. The class I HDAC inhibitors apicidin and FK228, and the histone methyltransferase inhibitor chaetocin demonstrated pronounced ADM inhibition and reversal without inducing significant cytotoxicity at 1 µM. Thioester prodrug class I HDAC inhibitor largazole attenuated ADM while its disulfide homodimer was effective in both ADM inhibition and reversal. Prioritized compounds were validated for ADM reversal in p48Cre/+; LSL-KrasG12D/+ (KC) mouse organoids using both morphological and molecular endpoints. Molecular index analysis of ADM reversal in KC mouse organoids demonstrated improved activity compared to TSA. Improved prodrug stability translated into a stronger phenotypic and molecular response. RNA-sequencing indicated that angiotensinogen was the top inhibited pathway during ADM reversal. Conclusion: Our findings demonstrate a unique epigenetic mechanism and suggest that the phenotypic screen developed here may be applied to discover potential treatments for PDAC.

Neuronal and behavioral responses to naturalistic texture images in macaque monkeys.

The visual world is richly adorned with texture, which can serve to delineate important elements of natural scenes. In anesthetized macaque monkeys, selectivity for the statistical features of natural texture is weak in V1, but substantial in V2, suggesting that neuronal activity in V2 might directly support texture perception. To test this, we investigated the relation between single cell activity in macaque V1 and V2 and simultaneously measured behavioral judgments of texture. We generated stimuli along a continuum between naturalistic texture and phase-randomized noise and trained two macaque monkeys to judge whether a sample texture more closely resembled one or the other extreme. Analysis of responses revealed that individual V1 and V2 neurons carried much less information about texture naturalness than behavioral reports. However, the sensitivity of V2 neurons, especially those preferring naturalistic textures, was significantly closer to that of behavior compared with V1. The firing of both V1 and V2 neurons predicted perceptual choices in response to repeated presentations of the same ambiguous stimulus in one monkey, despite low individual neural sensitivity. However, neither population predicted choice in the second monkey. We conclude that neural responses supporting texture perception likely continue to develop downstream of V2. Further, combined with neural data recorded while the same two monkeys performed an orientation discrimination task, our results demonstrate that choice-correlated neural activity in early sensory cortex is unstable across observers and tasks, untethered from neuronal sensitivity, and thus unlikely to reflect a critical aspect of the formation of perceptual decisions. Significance statement: As visual signals propagate along the cortical hierarchy, they encode increasingly complex aspects of the sensory environment and likely have a more direct relationship with perceptual experience. We replicate and extend previous results from anesthetized monkeys differentiating the selectivity of neurons along the first step in cortical vision from area V1 to V2. However, our results further complicate efforts to establish neural signatures that reveal the relationship between perception and the neuronal activity of sensory populations. We find that choice-correlated activity in V1 and V2 is unstable across different observers and tasks, and also untethered from neuronal sensitivity and other features of nonsensory response modulation.

Correlating Age and Hematoma Volume with Extent of Midline Shift in Acute Subdural Hematoma Patients: Validation of an Artificial Intelligence Tool for Volumetric Analysis.

OBJECTIVE: Decision for intervention in acute subdural hematoma patients is based on a combination of clinical and radiographic factors. Age has been suggested as a factor to be strongly considered when interpreting midline shift (MLS) and hematoma volume data for assessing critical clinical severity during operative intervention decisions for acute subdural hematoma patients. The objective of this study was to demonstrate the use of an automated volumetric analysis tool to measure hematoma volume and MLS and quantify their relationship with age. METHODS: A total of 1789 acute subdural hematoma patients were analyzed using qER-Quant software (Qure.ai, Mumbai, India) for MLS and hematoma volume measurements. Univariable and multivariable regressions analyzed association between MLS, hematoma volume, age, and MLS:hematoma volume ratio. RESULTS: In comparison to young patients (≤ 70 years), old patients (>70 years) had significantly higher average hematoma volume (old: 62.2 mL vs. young 46.8 mL, P < 0.0001), lower average MLS (old: 6.6 mm vs. young: 7.4 mm, P = 0.025), and lower average MLS:hematoma volume ratio (old: 0.11 mm/mL vs. young 0.15 mm/mL, P < 0.0001). Young patients had an average of 1.5 mm greater MLS for a given hematoma volume in comparison to old patients. With increasing age, the ratio between MLS and hematoma volume significantly decreases (P = 0.0002). CONCLUSIONS: Commercially available, automated, artificial intelligence (AI)-based tools may be used for obtaining quantitative radiographic measurement data in patients with acute subdural hematoma. Our quantitative results are consistent with the qualitative relationship previously established between age, hematoma volume, and MLS, which supports the validity of using AI-based tools for acute subdural hematoma volume estimation.

Discrimination, drinking to cope, protective behavioral strategies, and alcohol-related consequences among university students.

OBJECTIVE: University students who experience more discrimination typically report more negative consequences from alcohol use. The study aimed to assess whether drinking to cope and protective behavioral strategies for alcohol use would help explain the relationship between everyday discrimination and alcohol-related consequences among university student drinkers. METHOD: Data were collected in Fall 2020 and the sample included 707 undergraduate and graduate students from a large public institution in the northeast who reported consuming alcohol in the past month. Participants identified predominantly as women (71.7%; 24.6% men) and White (65.1%; 7.9% Black/African American; 7.2% Asian/Asian American; 7.1% Hispanic/Latinx). A cross-sectional serial mediation analysis using structural equation modeling was conducted using Mplus. RESULTS: Controlling for alcohol use, results supported a serial partial mediation model. More experiences of discrimination predicted a significant increase in alcohol-related consequences, above and beyond the increase attributed to drinking to cope. More frequent use of protective behavioral strategies significantly increased the odds of reporting no alcohol-related consequences. CONCLUSIONS: Drinking to cope and protective behavioral strategies for alcohol use may help explain why university students who report frequent discrimination are more likely to experience alcohol-related consequences, independent of how much alcohol they consume. Findings can inform clinical and prevention practice, advocacy, and training.

From Cognitive Agents to Cognitive Systems: Theoretical, Methodological, and Empirical Developments of van Gelder's (1998) "Dynamical Hypothesis".

Over two decades have passed since the publication of van Gelder's (1998) "dynamical hypothesis." In that paper, van Gelder proposed that cognitive agents were not digital computers-per the representational computational approach-but dynamical systems. The evolution of the dynamical hypothesis was driven by parallel advances in three areas. Theoretically, a deeper understanding of genetics, biology, neuroscience, and cognitive science inspired questions about how systems within each domain dynamically interact and extend their effects across spatiotemporal scales. Methodologically, more sophisticated and domain-general tools allowed researchers to discover, model, and quantify system dynamics, structure, and patterns across multiple scales to generate a more comprehensive system-level understanding of behaviors. Empirically, we can analyze a system's behavior while preserving its natural dynamics, revealing evidence that the reductionist approach leads to an incomplete understanding of the components and the overall system. Researchers have traditionally reduced a complex system into its component processes and assumed that the parts can be recombined to explain the whole. These three advances fundamentally altered our understanding of a "cognitive agent:" How their behaviors are driven by long-range coordination across multiple processes, how the interdependent and nested structure of interacting variables produces behaviors that are greater than the sum of its parts, and how environmental constraints shape adaptive yet stable behavioral patterns.

Use of Cancer-Directed therapy at the end of life among adolescents and young adults.

BACKGROUND: Adolescents and young adults (AYAs) frequently receive chemotherapy near death. We know less about use of targeted agents and immunotherapy or trends over time. METHODS: We conducted a retrospective cohort study of 1,836 AYAs with cancer who died between 2009-2019 after receiving care at one of three sites (Dana-Farber Cancer Institute, Kaiser Permanente Northern California, and Kaiser Permanente Southern California). We reviewed electronic health data and medical records to examine use of cancer-directed therapy in the last 90 days of life, including chemotherapy, targeted therapy, immunotherapy, and investigational drugs. RESULTS: Over the study period, 35% of AYAs received chemotherapy in the last 90 days of life; 24% received targeted therapy, 7% immunotherapy, and 5% investigational drugs. Fifty-six percent received at least one form of systemic cancer-directed therapy in the last 90 days of life. After adjustment for patient sex, race, ethnicity, age, site of care, diagnosis, and years from diagnosis to death, the proportion of AYAs receiving targeted therapy (odds ratio (OR) 1.05 per year of death, 95% confidence interval (CI) 1.02-1.10, P = .006), immunotherapy (OR 1.27, 95%CI 1.18-1.38, P<.0001), and any cancer-directed therapy (OR1.04, 95%CI 1.01-1.08, P=.01) in the last 90 days of life increased over time. CONCLUSIONS: More than half of AYAs receive cancer therapy in the last 90 days of life, and use of novel agents such as targeted therapy and immunotherapy are increasing over time. While some AYAs may wish to continue cancer therapy while living with advanced disease, efforts are needed to ensure that use of cancer-directed therapy meets preferences of AYAs approaching death.

Chemical Composition of Electronic Vaping Products from School Grounds in California.

INTRODUCTION: The use of electronic vaping products (EVPs) containing nicotine, marijuana, and/or other substances remains prominent among youth; with EVPs containing nicotine being the most commonly used tobacco product among youth since 2014. However, a detailed understanding of the chemical composition of these products is limited. METHODS: During February 25th-March 15th, 2019, a total of 576 EVPs, including 233 e-cigarette devices (with 43 disposable vape pens) and 343 e-liquid cartridges/pods/bottled e-liquids, were found or confiscated from a convenience sample of 16 public high schools in California. Liquids inside 251 vape pens and cartridges/pods/bottled e-liquids were analyzed using a gas chromatography/mass spectrometry (GC/MS). For comparison, new JUUL pods, the most commonly used e-cigarette among youth during 2018-2019, with different flavorings and nicotine content were purchased and analyzed. RESULTS: For e-cigarette cartridges/pods/bottled e-liquids, nicotine was detected in 204 of 208 (98.1%) samples. Propylene glycol (PG) and vegetable glycerin (VG) were dominant solvents in nicotine-containing EVPs. Among 43 disposable vape pen devices, cannabinoids such as tetrahydrocannabinol (THC) or cannabidiol (CBD) were identified in 39 of 43 (90.1%) samples, of which 3 contained both nicotine and THC. Differences in chemical compositions were observed between confiscated or collected JUULs and purchased JUULs. Measured nicotine was inconsistent with labels on some confiscated or collected bottled e-liquids. CONCLUSIONS: EVPs from 16 participating schools were found to widely contain substances with known adverse health effects among youth, including nicotine and cannabinoids. There was inconsistency between labeled and measured nicotine on the products from schools. IMPLICATIONS: This study measured the main chemical compositions of EVPs found at 16 California public high schools. Continued efforts are warranted, including at the school-level, to educate, prevent and reduce youth use of EVPs.

Blood product use for radiological/nuclear trauma: product development and US regulatory considerations.

Blood products are likely to be critical components of the medical response to nuclear detonation, as the hematopoietic subsyndrome of acute radiation syndrome (H-ARS) includes depletion of platelets and red blood cells that can lead to lethal hemorrhage and anemia. There is, however, only limited clinical information on the use of blood products to treat H-ARS. As currently configured, the US blood supply cannot meet the predicted surge in blood product demand that is likely to occur short-term and possibly long-term in the event of a large nuclear detonation. As part of the Administration for Strategic Preparedness and Response within the US Department of Health and Human Services, the Biomedical Advanced Research and Development Authority (BARDA) is addressing this preparedness gap by supporting the development of novel blood products and devices with characteristics that improve blood product storage and use in austere operational environments. The US Food and Drug Administration's Center for Drug Evaluation and Research (CDER) recently issued draft guidance on the development of drugs and biologics regulated by CDER to prevent or treat Acute Radiation Syndrome under the provisions of the "Animal Rule." The commentary provided here discusses the unique regulatory scheme for transfusion components and blood products regulated as biological drugs by Center for Biologics Evaluation and Research, including the ambiguity surrounding the evidentiary requirements for their approval for H-ARS, and whether, under certain circumstances, a specific H-ARS indication is necessary if relevant commercial indications are approved.

The Interruption of Rehabilitation Following Anterior Cruciate Ligament Reconstruction due to COVID-19 Restrictions: Association With Return-to-Sport Testing.

CONTEXT: Among many unanticipated changes, access to rehabilitation was disrupted during the onset of the COVID-19 pandemic. It is unclear how the timing of late-stage rehabilitation following anterior cruciate ligament with surgical reconstruction (ACLR) during the initial months of the pandemic affected outcomes. The purpose of this study was to compare physical performance outcome measures in patients following ACLR prior to and following COVID-19-related restrictions. DESIGN: Retrospective cohort study. METHODS: Data from patients who underwent return-to-sport testing following ACLR were analyzed based on date. December 2018 through March of 2020 (n = 66) was defined as the baseline period, and June through October 2020 (n = 27) was defined as the surveillance period. Outcome measures included single leg hop, triple hop, single leg vertical jump, and the lower-extremity functional test (LEFT). Linear mixed models were used to compare outcome measures before and after the onset of pandemic-related restrictions, clustered by sex and sport. A 1-way analysis of variance was performed to analyze the association between the number of virtual rehabilitation visits and outcome measures for subjects in the surveillance period. RESULTS: Subjects in the surveillance period performed significantly worse in the LEFT (+7.88 s; 95% confidence interval, 1.11 to 14.66; P = .02) and single leg vertical jump on the unaffected side (-4.32 cm; 95% confidence interval, -7.44 to -1.19, P < .01), and performed better with single leg vertical jump symmetry (+6.3%; 95% confidence interval, 1.0% to 11.5%; P = .02). There were no other statistically significant differences. There was no significant association between having virtual rehabilitation visits and any of the performance outcomes. CONCLUSIONS: There was a decline in physical performance outcome measures in patients following ACLR who did not attend regular in-person physical therapy sessions in the late-stage rehabilitation due to COVID-19-related restrictions. Other factors during this unique time period, such as access to training facilities or psychosocial stressors, may have also influenced outcomes.

A report of a prospective randomized trial of extended-release tacrolimus versus immediate release tacrolimus after liver transplantation with anti-thymocyte induction in a steroid free protocol.

PURPOSE: Our study hypothesis was that once daily dosing of extended-release tacrolimus (XRT) would be a safe and effective immunosuppression (IS) with the potential to decrease adverse events (AEs) associated with immediate release tacrolimus (IRT) after liver transplantation (LT). METHODS: All patients receiving LT at our center received rabbit anti-thymocyte globulin (RATG) induction therapy. Eligible patients were randomized in a 1:1 fashion to receive either XRT or IRT. Antimicrobial prophylaxis was the same between arms, and both groups received an antimetabolite for the first 6 months following LT. Patients were then followed at pre-determined study intervals for the following year after LT. We administered the RAND-36SF survey to assess patient's health-related quality of life at pre-determined intervals. All analysis was performed with an intention to treat basis. RESULTS: We screened 194 consecutive patients and enrolled 110. Our control and study arms were well matched. Transplant characteristics were similar between groups. At all timepoints, both arms had similar serum creatinine and estimated glomerular filtration rate (eGFR), calculated by MDRD6 equation, with post-transplant GFRs between 60 and 70 mL/min/1.73 m2 . Tacrolimus trough levels were similar between arms. The XRT arm had fewer AEs (166) and fewer serious AEs (70) compared to IRT (201 and 99, respectively). AEs most commonly were renal, infectious, or gastrointestinal in nature. While not statistically significant, XRT was held temporarily (25 vs. 35 cases) or discontinued (3 vs. 11 cases) less frequently than IRT and had fewer instances of rejection (7 vs. 12 cases). CONCLUSION: This analysis showed that XRT is safe and effective as de novo maintenance IS in a steroid-free protocol with RATG.