Molecular analysis of persistent and recurrent Barrett's esophagus in the setting of endoscopic therapy.

INTRODUCTION: Early neoplastic progression of Barrett's esophagus (BE) is often treated with endoscopic therapy. While effective, some patients are refractory to therapy or recur after apparent eradication of the BE. The goal of this study was to determine whether genomic alterations within the treated BE may be associated with persistent or recurrent disease. METHODS: We performed DNA sequencing on pre-treatment esophageal samples from 45 patients who were successfully treated by endoscopic therapy and did not recur as well as pre- and post-treatment samples from 40 patients who had persistent neoplasia and 21 patients who had recurrent neoplasia. The genomic alterations were compared between groups. RESULTS: The genomic landscape was similar between all groups. Patients with persistent disease were more likely to have pre-treatment alterations involving the receptor tyrosine kinase pathway (p=0.01), amplifications of oncogenes (p=0.01), and deletions of tumor suppressor genes (p=0.02). These associations were no longer significant after adjusting for patient age and BE length. Over half of patients with persistent (52.5%) or recurrent (57.2%) disease showed pre- and post-treatment samples that shared at least 50% of their driver mutations. CONCLUSION: Pre-treatment samples were genomically similar between those who responded to endoscopic therapy and those who had persistent or recurrent disease, suggesting there is not a strong genomic component to treatment response. While it was expected to find shared driver mutations in pre- and post-treatment samples in patients with persistent disease, the finding that an equal number of patients with recurrent disease also showed this relation suggests that many recurrences represent undetected minimal residual disease.

Intramedullary Fixation Versus Plate Fixation of Distal Fibular Fractures: A Systematic Review.

INTRODUCTION: The purpose of this systematic review and meta-analysis was to provide an update of the recent literature comparing clinical outcomes of surgically treated fibular fractures using intramedullary nailing (IMN) with open reduction and internal plate fixation (ORIF). METHODS: A literature search reporting clinical outcomes after IMN or ORIF of the distal fibula was conducted on PubMed. Inclusion criteria consisted of original studies; studies focusing on clinical outcomes after IMN or IMN and ORIF published before May 11, 2022; studies with at least 5 patients; and studies reporting union rates, complication rates, and patient-reported outcomes such as American Orthopaedic Foot and Ankle Society (AOFAS) and Olerud-Molander scores. RESULTS: Of 2,394 studies identified, a total of 29 studies (4 LOE-I, 2 LOE-II, 6 LOE-III, 17 LOE-IV) were included consisting of 1,850 IMN patients and 514 plate patients. The pooled mean age of IMN patients was 58 years (95% confidence interval [CI], 54 to 62, I2 = 42%) versus 57 years (95% CI, 53 to 62, I2 = 49%) in ORIF. Union rates for IMN patients revealed a 99% union rate (95% CI, 0.98 to 1.00, I2 = 20%) versus 97% union rate for ORIF patients (95% CI, 0.94 to 0.99, I2 = 0%). Studies that compared IMN with ORIF revealed no difference in union rates (risk ratio [RR] = 0.99, 95% CI, 0.96 to 1.02, I2 = 0%). IMN patients showed a 15% complication rate (95% CI, 0.09 to 0.23, I2 = 89%), whereas plate patients had a complication rate of 30% (95% CI, 0.18 to 0.46, I2 = 63%). When comparing studies with both treatments, IMN patients had a significantly lower risk of complications (RR = 0.49, 95% CI, 0.29 to 0.82, I2 = 50%). The IMN group trended toward a higher mean AOFAS and Olerud-Molander score than the plate group by 4.53 (95% CI, -14.58 to 23.65, I2 = 85%) and 3.54 (95% CI, -2.32 to 9.41, I2 = 76%) points, respectively. CONCLUSION: Current literature reveals near equivalence in union rates and a markedly lower risk of complications when comparing IMN with plate fixation. While IMN patients had higher AOFAS and Olerud-Molander scores, these differences were not statistically significant. Notably, subgroup analyses indicated that rates of symptomatic implant and removal of implant were comparable between IMN and ORIF, which may indicate that wound-related complications were reduced in the minimally invasive IMN technique. While the high cost of IMN implants remains a barrier to their widespread adoption, the long-term benefits of reducing complications, specifically associated with wound complications in high-risk populations, may greatly improve quality of care for patients with distal fibula fractures. Additional research and cost-effectiveness analyses are warranted to fully assess the long-term benefits and economic feasibility of using IMN fixation for distal fibula fractures. LEVEL OF EVIDENCE: Therapeutic Level IV.

Tradeoff between speed and robustness in primordium initiation mediated by auxin-CUC1 interaction.

Robustness is the reproducible development of a phenotype despite stochastic noise. It often involves tradeoffs with other performance metrics, but the mechanisms underlying such tradeoffs were largely unknown. An Arabidopsis flower robustly develops four sepals from four precisely positioned auxin maxima. The development related myb-like 1 (drmy1) mutant generates noise in auxin signaling that disrupts robustness in sepal initiation. Here, we find that increased expression of CUP-SHAPED COTYLEDON1 (CUC1), a boundary specification transcription factor, in drmy1 underlies this loss of robustness. CUC1 surrounds and amplifies stochastic auxin noise in drmy1 to form variably positioned auxin maxima and sepal primordia. Removing CUC1 from drmy1 provides time for noisy auxin signaling to resolve into four precisely positioned auxin maxima, restoring robust sepal initiation. However, removing CUC1 decreases the intensity of auxin maxima and slows down sepal initiation. Thus, CUC1 increases morphogenesis speed but impairs robustness against auxin noise. Further, using a computational model, we find that the observed phenotype can be explained by the effect of CUC1 in repolarizing PIN FORMED1 (PIN1), a polar auxin transporter. Lastly, our model predicts that reducing global growth rate improves developmental robustness, which we validate experimentally. Thus, our study illustrates a tradeoff between speed and robustness during development.

Whole genome sequencing refines stratification and therapy of patients with clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer, but a comprehensive description of its genomic landscape is lacking. We report the whole genome sequencing of 778 ccRCC patients enrolled in the 100,000 Genomes Project, providing for a detailed description of the somatic mutational landscape of ccRCC. We identify candidate driver genes, which as well as emphasising the major role of epigenetic regulation in ccRCC highlight additional biological pathways extending opportunities for therapeutic interventions. Genomic characterisation identified patients with divergent clinical outcome; higher number of structural copy number alterations associated with poorer prognosis, whereas VHL mutations were independently associated with a better prognosis. The observations that higher T-cell infiltration is associated with better overall survival and that genetically predicted immune evasion is not common supports the rationale for immunotherapy. These findings should inform personalised surveillance and treatment strategies for ccRCC patients.

Efficient High-Order Space-Angle-Energy Polytopic Discontinuous Galerkin Finite Element Methods for Linear Boltzmann Transport.

We introduce an hp-version discontinuous Galerkin finite element method (DGFEM) for the linear Boltzmann transport problem. A key feature of this new method is that, while offering arbitrary order convergence rates, it may be implemented in an almost identical form to standard multigroup discrete ordinates methods, meaning that solutions can be computed efficiently with high accuracy and in parallel within existing software. This method provides a unified discretisation of the space, angle, and energy domains of the underlying integro-differential equation and naturally incorporates both local mesh and local polynomial degree variation within each of these computational domains. Moreover, general polytopic elements can be handled by the method, enabling efficient discretisations of problems posed on complicated spatial geometries. We study the stability and hp-version a priori error analysis of the proposed method, by deriving suitable hp-approximation estimates together with a novel inf-sup bound. Numerical experiments highlighting the performance of the method for both polyenergetic and monoenergetic problems are presented.

High-dimensional mapping of human CEACAM1 expression on immune cells and association with melanoma drug resistance.

BACKGROUND: Human carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is an inhibitory cell surface protein that functions through homophilic and heterophilic ligand binding. Its expression on immune cells in human tumors is poorly understood. METHODS: An antibody that distinguishes human CEACAM1 from other highly related CEACAM family members was labeled with 159Tb and inserted into a panel of antibodies that included specificity for programmed cell death protein 1 (PD1) and PD-L1, which are targets of immunotherapy, to gain a data-driven immune cell atlas using cytometry by time-of-flight (CyTOF). A detailed inventory of CEACAM1, PD1, and PD-L1 expression on immune cells in metastatic lesions to lymph node or soft tissues and peripheral blood samples from patients with treatment-naive and -resistant melanoma as well as peripheral blood samples from healthy controls was performed. RESULTS: CEACAM1 is absent or at low levels on healthy circulating immune cells but is increased on immune cells in peripheral blood and tumors of melanoma patients. The majority of circulating PD1-positive NK cells, innate T cells, B cells, monocytic cells, dendritic cells, and CD4+ T cells in the peripheral circulation of treatment-resistant disease co-express CEACAM1 and are demonstrable as discrete populations. CEACAM1 is present on distinct types of cells that are unique to the tumor microenvironment and exhibit expression levels that are highest in treatment resistance; this includes tumor-infiltrating CD8+ T cells. CONCLUSIONS: To the best of our knowledge, this work represents the first comprehensive atlas of CEACAM1 expression on immune cells in a human tumor and reveals an important correlation with treatment-resistant disease. These studies suggest that agents targeting CEACAM1 may represent appropriate partners for PD1-related pathway therapies.

Some proteins, such as programmed cell death protein 1 (PD1), can stop the immune system from attacking cancer cells, allowing cancers to grow. Therapies targeting these proteins can be highly effective, but tumors can become resistant. It is important to identify factors involved in this resistance to develop improved cancer therapies. Human carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is a protein that inhibits an immune response and its levels have been associated with poor patient outcomes. We applied a method that allows for the detection of proteins on a single cell to uncover CEACAM1 patterns in melanoma. We found that increased CEACAM1 expression levels on multiple different immune cell types was associated with tumors that were resistant to therapy. These findings may help us to understand the role of CEACAM1 in cancer and to develop better cancer therapies.

Intraoperative Fluoroscopy Versus Navigation to Determine Cup Anteversion in Direct Anterior Total Hip Replacement: A Technical Trick for Obtaining "True" Anteversion.

During acetabular cup positioning, intraoperative measurements of cup anteversion were taken using both fluoroscopy and navigation system. With the C-arm introduced at 40°, an anteroposterior view of the pelvis is taken. The C-arm is then centered over the hip, showing an anteverted cup with an approximate inclination of 40°. The axial C-arm is tilted away until the cup opening is visualized as a straight line, indicating that the beam of the fluoroscopy is aligned with the cup's anteversion. The tilt angle on the C-arm and anteversion reading on the navigation workstation were recorded. The high degree of agreement between fluoroscopic and navigation measurement of acetabular cup anteversion supports the use of fluoroscopy in settings with limited access to navigation systems in direct anterior total hip arthroplasty.

Effect of cross-platform gene-expression, computational methods on breast cancer subtyping in PALOMA-2 and PALLET studies.

Intrinsic breast cancer molecular subtyping (IBCMS) provides significant prognostic information for patients with breast cancer and helps determine treatment. This study compared IBCMS methods on various gene-expression platforms in PALOMA-2 and PALLET trials. PALOMA-2 tumor samples were profiled using EdgeSeq and nanostring and subtyped with AIMS, PAM50, and research-use-only (ruo)Prosigna. PALLET tumor biopsies were profiled using mRNA sequencing and subtyped with AIMS and PAM50. In PALOMA-2 (n = 222), a 54% agreement was observed between results from AIMS and gold-standard ruoProsigna, with AIMS assigning 67% basal-like to HER2-enriched. In PALLET (n = 224), a 69% agreement was observed between results from PAM50 and AIMS. Different IBCMS methods may lead to different results and could misguide treatment selection; hence, a standardized clinical PAM50 assay and computational approach should be used.Trial number: NCT01740427.

Plastic pollution and human pathogens: Towards a conceptual shift in risk management at bathing water and beach environments.

Emerging evidence indicates that micro- and macro-plastics present in water can support a diverse microbial community, including potential human pathogens (e.g., bacteria, viruses). This interaction raises important concerns surrounding the role and suitability of current bathing water regulations and associated pathogen exposure risk within beach environments. In response to this, we critically evaluated the available evidence on plastic-pathogen interactions and identified major gaps in knowledge. This review highlighted the need for a conceptual shift in risk management at public beaches recognising: (i) interconnected environmental risks, e.g., associations between microbial compliance parameters, potential pathogens and both contemporary and legacy plastic pollution; and (ii) an appreciation of risk of exposure to plastic co-pollutants for both water and waterside users. We present a decision-making framework to identify options to manage plastic-associated pathogen risks alongside short- and longer-term research priorities. This advance will help deliver improvements in managing plastic-associated pathogen risk, acknowledging that human exposure potential is not limited to only those who engage in water-based activity. We argue that adopting these recommendations will help create an integrated approach to managing and reducing human exposure to pathogens at bathing, recreational water and beach environments.

The plastisphere can protect Salmonella Typhimurium from UV stress under simulated environmental conditions.

Plastic waste is found with increasing frequency in the environment, in low- and middle-income countries. Plastic pollution has increased concurrently with both economic development and rapid urbanisation, amplifying the effects of inadequate waste management. Distinct microbial communities can quickly colonise plastic surfaces in what is collectively known as the 'plastisphere'. The plastisphere can act as a reservoir for human pathogenic bacteria, including Salmonella enterica sp. (such as S. Typhimurium), which can persist for long periods, retain pathogenicity, and pose an increased public health risk. Through employing a novel mesocosm setup, we have shown here that the plastisphere provides enhanced protection against environmental pressures such as ultraviolet (UV) radiation and allows S. Typhimurium to persist at concentrations (>1 × 103 CFU/ml) capable of causing human infection, for up to 28 days. Additionally, using a Galleria Mellonella model of infection, S. Typhimurium exhibits greater pathogenicity following recovery from the UV-exposed plastisphere, suggesting that the plastisphere may select for more virulent variants. This study demonstrates the protection afforded by the plastisphere and provides further evidence of environmental plastic waste acting as a reservoir for dangerous clinical pathogens. Quantifying the role of plastic pollution in facilitating the survival, persistence, and dissemination of human pathogens is critical for a more holistic understanding of the potential public health risks associated with plastic waste.

Using the Equatorial Talar Line as a Radiographic Predictor of Sanders Type 3 and 4 Calcaneus Fractures and Lateral Wall Blowout.

OBJECTIVE: To assess the equatorial talar line (ETL) as a sensitive radiographic parameter to predict Sanders type III and IV fractures and the presence of lateral wall blowout. METHODS: Reliability of the ETL was assessed using the intraclass correlation coefficient (ICC) and receiver operating curve (ROC) to predict sensitivity. Using lateral ankle radiographs, raters determined whether the calcaneal tuberosity was "above" (predicting Sanders type I or II) or "below" (predicting Sanders type III or IV and lateral wall blowout). RESULTS: In determining the "above" or "below" location of the ETL, the calculated ICC was 1.0 for each session. As a predictor of Sanders fracture classification type, the calculated ICC was 0.93 for the first session and 0.89 for the second session for an overall ICC of 0.91. As a predictor of Sanders fracture type, ROC analysis yielded an overall sensitivity of 0.82. As a predictor of lateral wall blowout, ROC analysis yielded an overall sensitivity of 0.81. CONCLUSION: The ETL is a reproducible radiographic parameter that can be reliably used to crudely predict between Sanders type I or II (ETL is "above") and Sanders type III or IV (ETL is "below") calcaneus fractures as well as the presence of lateral wall blowout.

Outcome of Patients with Locally Advanced Rectal Cancer Pursuing Non-Surgical Strategy in National Cancer Database.

BACKGROUND: Survival data on patients with locally advanced rectal cancer (LARC) undergoing non-operative management (NOM) in a real-world setting are lacking. METHODS: We analyzed LARC patients from the National Cancer Database with the following features: treated between 2010 and 2020, age 18-65 years, Charlson comorbidity index (CCI) ≤ 1, received neoadjuvant multiagent chemotherapy plus radiation ≥ 45 Gray, and underwent surgery or NOM. Patients were stratified into two groups: (A) clinical T1-3 tumors with positive nodes (cT1-3N+) and (B) clinical T4 tumors, N+/- (cT4N+/-). We performed a comparative analysis of overall survival (OS) with NOM versus surgery by the Kaplan-Meier method and propensity score matching. Additionally, a multivariable analysis explored the association between NOM and OS. RESULTS: NOM exhibited significantly lower OS than surgery in both groups. In cT1-3N+ patients, NOM resulted in a 5-year OS of 73.9% (95% confidence interval [CI] = 69.7-77.6%) versus 84.5% (95% CI = 83.6-85.3%) with surgery (p < 0.001). In the cT4N+/- group, NOM yielded a 5-year OS of 44.5% (95% CI = 37.0-51.8%) versus 72.5% (95% CI = 69.9-74.8%) with surgery (p < 0.001). Propensity score matching and multivariable analyses revealed similar conclusions. CONCLUSION: Patients with LARC undergoing NOM versus surgery in real-world settings appear to have inferior survival.

TRPV4 neuromuscular disease registry highlights bulbar, skeletal and proximal limb manifestations.

Dominant missense mutations of the calcium-permeable cation channel TRPV4 cause Charcot-Marie-Tooth disease (CMT) type 2C and two forms of distal spinal muscular atrophy. These conditions are collectively referred to as TRPV4-related neuromuscular disease and share features of motor greater than sensory dysfunction and frequent vocal fold weakness. Pathogenic variants lead to gain of ion channel function that can be rescued by TRPV4 antagonists in cellular and animal models. As small molecule TRPV4 antagonists have proven safe in trials for other disease indications, channel inhibition is a promising therapeutic strategy for TRPV4 patients. However, the current knowledge of the clinical features and natural history of TRPV4-related neuromuscular disease is insufficient to enable rational clinical trial design. To address these issues, we developed a TRPV4 patient database and administered a TRPV4-specific patient questionnaire. Here, we report demographic and clinical information, including CMT examination scores (CMTES), from 68 patients with known pathogenic TRPV4 variants, 40 of whom also completed the TRPV4 patient questionnaire. TRPV4 patients showed a bimodal age of onset, with the largest peak occurring in the first 2 years of life. Compared to CMT1A patients, TRPV4 patients showed distinct symptoms and signs, manifesting more ambulatory difficulties and more frequent involvement of proximal arm and leg muscles. Although patients reported fewer sensory symptoms, sensory dysfunction was often detected clinically. Many patients were affected by vocal fold weakness (55%) and shortness of breath (55%), and 11% required ventilatory support. Skeletal abnormalities were common, including scoliosis (64%), arthrogryposis (33%), and foot deformities. Strikingly, patients with infantile onset of disease showed less sensory involvement and less progression of symptoms. These results highlight distinctive clinical features in TRPV4 patients, including motor-predominant disease, proximal arm and leg weakness, severe ambulatory difficulties, vocal fold weakness, respiratory dysfunction, and skeletal involvement. In addition, patients with infantile onset of disease appeared to have a distinct phenotype with less apparent disease progression based on CMTES. These collective observations indicate that clinical trial design for TRPV4-related neuromuscular disease should include outcome measures that reliably capture non-length dependent motor dysfunction, vocal fold weakness, and respiratory disease.

Patterns of Smoking Cessation Strategies and Perception of E-cigarette Harm Among Bladder Cancer Survivors.

BACKGROUND: Cigarette smoking is the leading preventable cause of bladder cancer (BC). Some proponents of e-cigarettes describe their use as a risk mitigation strategy despite potential carcinogen exposure and uncertain long-term risks. OBJECTIVE: We assessed smoking cessation strategies, including e-cigarette use, and harm perception among patients with BC. METHODS: We performed a cross-sectional study on a convenience sample of patients with BC at a single institution from August 2021 - October 2022. The survey instrument was sourced from the Cancer Patient Tobacco Use Questionnaire (C-TUQ) from the American Association for Cancer Research with standardized questions on tobacco use, cessation questions, and e-cigarette harm perceptions. RESULTS: Of the 104 surveyed BC patients (mean age: 72 years; 27% female; 55% with muscle-invasive disease), 20% were current smokers (median pack years: 40) and 51% were former smokers (median pack years: 20). A minority (9%) had quit smoking at the time of diagnosis. Pharmacotherapy for smoking cessation included nicotine patches (25%), gum (21%), lozenges (8%), e-cigarettes (8%), and Varenicline/Bupropion (4%). Notably, 43% of patients who continued to smoke expressed willingness to switch to e-cigarettes as a cessation aid. E-cigarette users (11%) more commonly perceived e-cigarettes as non-harmful compared to former (4%) and non-smokers (4%) (P = .048), though all groups regarded e-cigarettes as equally addictive as traditional cigarettes. CONCLUSIONS: Despite the prevalence of BC survivors who continue to smoke, a significant proportion perceive e-cigarettes as a viable and less harmful cessation aid. The infrequent use of FDA-approved pharmacotherapies underscores potential implementation gaps. These findings highlight the need for further research and targeted interventions in addressing smoking cessation among BC survivors.

An Age-Stratified Analysis of Early Postoperative Mortality Among Medicare-Eligible Patients With Common Gastrointestinal and Hepato-pancreato-biliary Malignancies.

Background: The frequency of major cancer surgery in the elderly (≥80 years) has increased concomitantly with the rise in average age of the population. We assessed early postoperative mortality following hepato-pancreato-biliary (HPB) and gastrointestinal (GI) procedures for common malignancies stratified by age. Methods: The National Cancer Database (2004-2017) was queried for patients who underwent resection for GI (gastroesophageal and colorectal) or HPB (pancreatic adenocarcinoma, biliary tract, and primary liver) cancers. We compared early postoperative mortality (30 d and 90 d) stratified by age (65-79 vs ≥80 years) and procedure, and compared survival outcomes by age and operative vs nonoperative management. Results: A total of 709,358 patients were included. The 30-day mortality ranged from 1.8% to 5.8% among patients 65-79 years and from 3.2% to 12.4% among patients ≥80 years depending on procedure. The 90-day mortality ranged from 3.6% to 10.6% in patients 65-79 years compared to 8.4%-21.0% among patients ≥80 years. The overall 90-day mortality was 5.2% for patients 65-79 years and 12.0% for patients ≥80 years (P < .001). Age ≥80 was associated with worse survival among operatively managed patients with each upper GI, HPB, and lower GI malignancy relative to younger patients on multivariable analysis. However, operative management of patients ≥80 years was associated with improved survival relative to nonoperative management. Discussion: Elderly patients suffer higher postoperative mortality after major GI and HPB cancer surgery, but operative management is associated with improved survival among patients ≥80 years as compared to nonoperative management. These data are important to contextualize when counseling elderly patients on their treatment options for localized GI and HPB cancers.

Climate Change and Cardiovascular Health: A Systematic Review.

Importance: Climate change may increase the risk of adverse cardiovascular outcomes by causing direct physiologic changes, psychological distress, and disruption of health-related infrastructure. Yet, the association between numerous climate change-related environmental stressors and the incidence of adverse cardiovascular events has not been systematically reviewed. Objective: To review the current evidence on the association between climate change-related environmental stressors and adverse cardiovascular outcomes. Evidence Review: PubMed, Embase, Web of Science, and Cochrane Library were searched to identify peer-reviewed publications from January 1, 1970, through November 15, 2023, that evaluated associations between environmental exposures and cardiovascular mortality, acute cardiovascular events, and related health care utilization. Studies that examined only nonwildfire-sourced particulate air pollution were excluded. Two investigators independently screened 20 798 articles and selected 2564 for full-text review. Study quality was assessed using the Navigation Guide framework. Findings were qualitatively synthesized as substantial differences in study design precluded quantitative meta-analysis. Findings: Of 492 observational studies that met inclusion criteria, 182 examined extreme temperature, 210 ground-level ozone, 45 wildfire smoke, and 63 extreme weather events, such as hurricanes, dust storms, and droughts. These studies presented findings from 30 high-income countries, 17 middle-income countries, and 1 low-income country. The strength of evidence was rated as sufficient for extreme temperature; ground-level ozone; tropical storms, hurricanes, and cyclones; and dust storms. Evidence was limited for wildfire smoke and inadequate for drought and mudslides. Exposure to extreme temperature was associated with increased cardiovascular mortality and morbidity, but the magnitude varied with temperature and duration of exposure. Ground-level ozone amplified the risk associated with higher temperatures and vice versa. Extreme weather events, such as hurricanes, were associated with increased cardiovascular risk that persisted for many months after the initial event. Some studies noted a small increase in cardiovascular mortality, out-of-hospital cardiac arrests, and hospitalizations for ischemic heart disease after exposure to wildfire smoke, while others found no association. Older adults, racial and ethnic minoritized populations, and lower-wealth communities were disproportionately affected. Conclusions and Relevance: Several environmental stressors that are predicted to increase in frequency and intensity with climate change are associated with increased cardiovascular risk, but data on outcomes in low-income countries are lacking. Urgent action is needed to mitigate climate change-associated cardiovascular risk, particularly in vulnerable populations.

Ocular perfusion pressure is not reduced in response to lower body negative pressure.

Lower body negative pressure (LBNP) has been proposed as a countermeasure to mitigate the cephalad fluid shift occurring during spaceflight, which may be associated with the development of Spaceflight Associated Neuro-ocular Syndrome (SANS). This study quantifies the effect of LBNP on intraocular pressure (IOP), mean arterial pressure at eye level (MAPeye), and ocular perfusion pressure (OPP). Twenty-four subjects (12 male, 12 female) were subjected to graded LBNP in 0° supine and 15° head-down tilt (HDT) postures from 0 mmHg to -50 mmHg in 10 mmHg increments. IOP decreased significantly with LBNP pressure in 0° supine (by 0.7 ± 0.09 mmHg per 10 mmHg LBNP pressure, p < 0.001) and in 15° HDT (by 1.0 ± 0.095 mmHg per 10 mmHg of LBNP pressure, p < 0.001). MAPeye significantly decreased by 0.9 ± 0.4 mmHg per 10 mmHg of LBNP pressure in 0° supine (p = 0.016) but did not significantly change with LBNP in 15° HDT (p = 0.895). OPP did not significantly change with LBNP in 0° supine (p = 0.539) but it significantly increased in 15° HDT at 1.0 ± 0.3 mmHg per 10 mmHg of LBNP pressure (p = 0.010). Sex did not have a significant effect on OPP, MAPeye, or IOP in any condition. In 15° HDT, the reduction in IOP during increasing negative pressure, combined with the relatively constant MAPeye, led to the increase in OPP. Furthermore, results suggest that LBNP, while effective in reducing IOP, is not effective in reducing OPP across all postures investigated.

Incidental Finding of an Atypical Cartilaginous Tumor in an Adult Female with Recurrent Patellar Dislocation: Single-stage Extended Curettage using Freezing Nitrogen Ethanol Composite followed by Medial Patello-Femoral Ligament Reconstruction.

Atypical cartilaginous tumor (ACT) refers to a low-grade cartilaginous neoplasm microscopically identical to grade 1 chondrosarcoma, affecting the appendicular skeleton. Treatment with intralesional curettage has been found to provide sufficient local control with less morbidity compared to wide resection. This is the first reported case of a simultaneous medial patello-femoral ligament (MPFL) reconstruction with extended curettage for ACT on the ipsilateral femur. A 45-year-old female presented with chronic recurrent patellar dislocation of the right knee. Magnetic resonance imaging revealed a tear of the MPFL, with an incidental epi-metaphyseal chondroid lesion. After biopsy confirmed an ACT, single-stage extended curettage using freezing nitrogen ethanol composite (FNEC) and MPFL reconstruction was performed, followed by augmentation with bone cement and a distal femoral plate. Currently, the patient is independently ambulatory, with full range of motion about the knee. Following histologic confirmation of an ACT in the setting of a concurrent MCL tear, a single-stage procedure to address both conditions is a viable option that can reduce complications associated with multiple surgeries. Extended curettage using FNEC has been shown to produce good short-term oncologic outcomes while maximizing function.

Characterization of adverse events in injured patients at risk of hemorrhagic shock: a secondary analysis of three harmonized prehospital randomized clinical trials.

Background: The reporting of adverse events (AEs) is required and well defined in the execution of clinical trials, but is poorly characterized particularly in prehospital trials focusing on traumatic injury. In the setting of prehospital traumatic injury trials, no literature currently exists analyzing the clinical implications of AEs and their associations with mortality and morbidity. We sought to analyze AEs from three prehospital hemorrhagic shock trials and characterize their time course, incidence, severity, associated clinical outcomes, and relatedness. Methods: We performed a secondary analysis of three prehospital randomized clinical trials. We analyzed AEs at both the patient level as well as the individual AE level. We categorized patients who had no AEs, a single documented AE and those with multiple events (>1 AE). We characterized AE timing, severity, relatedness and attributable mortality outcomes. Results: We included 1490 patients from the three harmonized clinical trials, with 299 (20.1%) individual patients having at least a single AE documented with 529 AEs documented overall as a proportion of patients had multiple events. Over 44% of patients had a death-related misclassified AE. Patients with at least a single documented AE had a significantly higher 28-day mortality (log-rank χ2=81.27, p<0.001) compared with those without an AE documented. Patients with a single AE had a significant higher mortality than those with multiple AEs, potentially due to survival bias (log-rank χ2=11.80, p=0.006). When relatedness of each individual AE was characterized, over 97% of AEs were classified as 'definitely not related' or 'probably not related' to the intervention. Conclusions: AEs in hemorrhagic shock trials are common, occur early and are associated with mortality and survival bias. The potential for inaccurate reporting exists, and education and training remain essential for appropriate treatment arm comparison. The current results have important relevance to injury-related clinical trials. Trial registration numbers: NCT01818427, NCT02086500 and NCT03477006. Level of evidence: II.