Impact of unitary synaptic inhibition on spike timing in ventral tegmental area dopamine neurons.

Midbrain dopamine neurons receive convergent synaptic input from multiple brain areas, which perturbs rhythmic pacemaking to produce the complex firing patterns observed in vivo. This study investigated the impact of single and multiple inhibitory inputs on ventral tegmental area (VTA) dopamine neuron firing in mice of both sexes using novel experimental measurements and modeling. We first measured unitary inhibitory postsynaptic currents (uIPSCs) produced by single axons using both minimal electrical stimulation and minimal optical stimulation of rostromedial tegmental nucleus (RMTg) and ventral pallidum (VP) afferents. We next determined the phase resetting curve (PRC), the reversal potential for GABAA receptor-mediated IPSCs, and the average inter-spike membrane potential trajectory during pacemaking. We combined these data in a phase oscillator model of a VTA dopamine neuron, simulating the effects of unitary inhibitory postsynaptic conductances (uIPSGs) on spike timing and rate. The effect of a uIPSG on spike timing was predicted to vary according to its timing within the inter-spike interval (ISI), or phase. Simulations were performed to predict the pause duration resulting from synchronous arrival of multiple uIPSGs, and the changes in firing rate and regularity produced by asynchronous uIPSGs. The model data suggest that asynchronous inhibition is more effective than synchronous inhibition, because it tends to hold the neuron at membrane potentials well positive to the IPSC reversal potential. Our results indicate that small fluctuations in the inhibitory synaptic input arriving from the many afferents to each dopamine neuron are sufficient to produce highly variable firing patterns like those observed in vivo.Significance Statement This study dissects the input-output relationship of VTA dopamine neurons receiving inputs from single presynaptic inhibitory neurons. We measured unitary IPSCs from two major inhibitory inputs (the RMTg and VP) and simulated their impact on dopamine neuron firing based on new experimental data including the phase resetting curve (PRC) and the reversal potential of the GABAA receptor-mediated currents. The results predict the impact of single and multiple unitary inhibitory postsynaptic conductances (uIPSGs) on spike timing and suggest that asynchronous, low-frequency inhibition can summate in a supralinear manner to powerfully slow or halt a dopamine neuron's firing.

New-onset diabetes is a predictive risk factor for pancreatic lesions in high-risk individuals: An observational cohort study.

Background and Objectives: Pancreatic cancer (PC) is the third cause of cancer-related deaths. Early detection and interception of premalignant pancreatic lesions represent a promising strategy to improve outcomes. We evaluated risk factors of focal pancreatic lesions (FPLs) in asymptomatic individuals at hereditary high risk for PC. Methods: This is an observational single-institution cohort study conducted over a period of 5 years. Surveillance was performed through imaging studies (EUS or magnetic resonance imaging/magnetic resonance cholangiopancreatography) and serum biomarkers. We collected demographic characteristics and used univariate and multivariate logistic regression models to evaluate associations between potential risk factors and odd ratios (ORs) for FPL development. Results: A total of 205 patients completed baseline screening. Patients were followed up to 53 months. We detected FPL in 37 patients (18%) at baseline; 2 patients had lesions progression during follow-up period, 1 of them to PC. Furthermore, 13 patients developed new FPLs during the follow-up period. Univariate and multivariate analyses revealed that new-onset diabetes (NOD) is strongly associated with the presence of FPL (OR, 10.94 [95% confidence interval, 3.01-51.79; P < 0.001]; OR, 9.98 [95% confidence interval, 2.15-46.33; P = 0.003]). Follow-up data analysis revealed that NOD is also predictive of lesions progression or development of new lesions during screening (26.7% vs. 2.6%; P = 0.005). Conclusions: In a PC high-risk cohort, NOD is significantly associated with presence of FPL at baseline and predictive of lesions progression or new lesions during surveillance.

Incorporating social determinants of health into transmission modeling of COVID-19 vaccine in the US: a scoping review.

During COVID-19 in the US, social determinants of health (SDH) have driven health disparities. However, the use of SDH in COVID-19 vaccine modeling is unclear. This review aimed to summarize the current landscape of incorporating SDH into COVID-19 vaccine transmission modeling in the US. Medline and Embase were searched up to October 2022. We included studies that used transmission modeling to assess the effects of COVID-19 vaccine strategies in the US. Studies' characteristics, factors incorporated into models, and approaches to incorporate these factors were extracted. Ninety-two studies were included. Of these, 11 studies incorporated SDH factors (alone or combined with demographic factors). Various sets of SDH factors were integrated, with occupation being the most common (8 studies), followed by geographical location (5 studies). The results show that few studies incorporate SDHs into their models, highlighting the need for research on SDH impact and approaches to incorporating SDH into modeling. Funding: This research was funded by the Centers for Disease Control and Prevention (CDC).

Effect of surgical approach on early return to intended oncologic therapy after resection for pancreatic ductal adenocarcinoma.

BACKGROUND: Although robotic pancreatectomy may facilitate an earlier functional recovery, the impact of a robotic pancreatectomy program during its early experience on the timing of return to intended oncologic therapy (RIOT) after surgery is unknown. METHODS: In this retrospective cohort study, we used propensity score matching with a 1:2 ratio to compare patients who underwent robotic or open surgery (distal pancreatectomy or pancreatoduodenectomy) for pancreatic ductal adenocarcinoma (PDAC) during the first 3 years of our robotic pancreatectomy experience (January 2018-December 2021). Generalized estimating equations modeling was used to evaluate the effect of surgical approach on early RIOT, defined as adjuvant chemotherapy initiation within 8 weeks after surgery, and late RIOT, defined as initiation within 12 weeks after surgery. RESULTS: The matched cohort included 26 patients who underwent robotic pancreatectomy and 52 patients who underwent open pancreatectomy. Rates of receipt of adjuvant chemotherapy were 96.2% and 78.9%, respectively. Rate of early RIOT in the robotic group (73.1% was higher than that in the open group (44.2%; P = 0.018). In multivariable analysis, a robotic approach was associated with early RIOT (odds ratio, 3.54; 95% confidence interval 1.08-11.62; P = 0.038). Surgical approach did not impact late RIOT (odds ratio, 3.21; 95% confidence interval 0.71-14.38; P = 0.128). CONCLUSIONS: Compared with open pancreatectomy, robotic pancreatectomy did not delay RIOT. In fact, odds of early RIOT were increased, which supports the oncological safety of our robotic pancreatectomy program during its implementation.

A Wireless, Multicolor Fluorescence Image Sensor Implant for Real-Time Monitoring in Cancer Therapy.

Real-time monitoring of dynamic biological processes in the body is critical to understanding disease progression and treatment response. This data, for instance, can help address the lower than 50% response rates to cancer immunotherapy. However, current clinical imaging modalities lack the molecular contrast, resolution, and chronic usability for rapid and accurate response assessments. Here, we present a fully wireless image sensor featuring a 2.5×5 mm2 CMOS integrated circuit for multicolor fluorescence imaging deep in tissue. The sensor operates wirelessly via ultrasound (US) at 5 cm depth in oil, harvesting energy with 221 mW/cm2 incident US power density (31% of FDA limits) and backscattering data at 13 kbps with a bit error rate <10-6. In-situ fluorescence excitation is provided by micro-laser diodes controlled with a programmable on-chip driver. An optical frontend combining a multi-bandpass interference filter and a fiber optic plate provides >6 OD excitation blocking and enables three-color imaging for detecting multiple cell types. A 36×40-pixel array captures images with <125 µm resolution. We demonstrate wireless, dual-color fluorescence imaging of both effector and suppressor immune cells in ex vivo mouse tumor samples with and without immunotherapy. These results show promise for providing rapid insight into therapeutic response and resistance, guiding personalized medicine.

Preliminary assessment of blood mercury contamination in four African crocodile species.

Heavy metal contamination in the environment is an increasingly pervasive threat to the long-term persistence of wildlife. As high trophic level consumers, crocodylians are at substantial risk from bioaccumulation of mercury (Hg). Despite that they are generally well-studied and the focal species of many conservation efforts around the world, little is known about Hg contamination levels in most crocodylians. Here we preliminarily evaluate blood Hg contamination in four African species - Central African slender-snouted crocodile (Mecistops leptorhynchus), African dwarf crocodile (Osteolaemus tetraspis), West African crocodile (Crocodylus suchus), and Nile crocodile (Crocodylus niloticus) - from a diversity of sites and habitats across 5 different countries representing varying degrees of environmental pollution. All of our sampled crocodiles were Hg contaminated and, worryingly, these African crocodiles generally showed the highest levels of Hg contamination of any crocodylian species examined to date. Of most concern was that Hg concentrations were not only highest in M. leptorhynchus, the most threatened amongst our study species, but also in individuals sampled in what are believed to be some of the most remote and pristine natural areas left in Africa - Gabon's national parks. Our results underscore the need to better understand the impact of longstanding petroleum, mining, forestry, and agricultural industries on the entire aquatic food chain throughout much of Africa, including on the threatened species in these habitats and the human populations that depend on them for their subsistence and livelihoods.

Development and qualification of 3 L scale-down model for large scale vaccine process on vero cell culture using microcarriers.

Scale-down models (SDM) are pivotal tools for process understanding and improvement to accelerate the development of vaccines from laboratory research to global commercialization. In this study, a 3 L SDM representing a 50 L scale Vero cell culture process of a live-attenuated virus vaccine using microcarriers was developed and qualified based on the constant impeller power per volume principle. Both multivariate data analysis (MVDA) and the traditional univariate data analysis showed comparable and equivalent cell growth, metabolic activity, and product quality results across scales. Computational fluid dynamics simulation further confirmed similar hydrodynamic stress between the two scales.

CSF1R Inhibition in Patients With Advanced Solid Tumors or Tenosynovial Giant Cell Tumor: A Phase 1 Study of Vimseltinib.

PURPOSE: Tenosynovial giant cell tumor (TGCT) is a locally aggressive neoplasm caused by dysregulation of the colony-stimulating factor 1 (CSF1) gene and overexpression of the CSF1 ligand. Surgery is the standard of care for most patients, but there are limited treatment options for patients with TGCT not amenable to surgery. This study evaluates vimseltinib, an investigational, oral, switch-control tyrosine kinase inhibitor designed to selectively and potently inhibit the CSF1 receptor. PATIENTS AND METHODS: This first-in-human, multicenter, open-label, phase 1/2 study of vimseltinib in patients with malignant solid tumors (N = 37) or TGCT not amenable to surgery (N = 32) followed a pharmacologically guided 3 + 3 study design (NCT03069469). The primary objectives were to assess safety and tolerability, determine the recommended phase 2 dose (RP2D), and characterize the pharmacokinetics (PK); exploratory objectives included pharmacodynamics and efficacy. RESULTS: Vimseltinib was well tolerated; the majority of non-laboratory treatment-emergent adverse events were grade 1/2. There was no evidence of cholestatic hepatotoxicity or drug-induced liver injury. The RP2D was determined to be 30 mg twice weekly (no loading dose), and vimseltinib plasma exposure increased with the dose. In patients with TGCT, the median treatment duration was 25.1 months (range, 0.7 to 46.9), and the objective response rate as assessed by independent radiological review using Response Evaluation Criteria in Solid Tumors version 1.1 was 72%. CONCLUSIONS: Vimseltinib demonstrated long-term tolerability, manageable safety, dose-dependent exposure, and robust antitumor activity in patients with TGCT whose disease is not amenable to surgery.

AI-based abdominal CT measurements of orthotopic and ectopic fat predict mortality and cardiometabolic disease risk in adults.

OBJECTIVES: To evaluate the utility of CT-based abdominal fat measures for predicting the risk of death and cardiometabolic disease in an asymptomatic adult screening population. METHODS: Fully automated AI tools quantifying abdominal adipose tissue (L3 level visceral [VAT] and subcutaneous [SAT] fat area, visceral-to-subcutaneous fat ratio [VSR], VAT attenuation), muscle attenuation (L3 level), and liver attenuation were applied to non-contrast CT scans in asymptomatic adults undergoing CT colonography (CTC). Longitudinal follow-up documented subsequent deaths, cardiovascular events, and diabetes. ROC and time-to-event analyses were performed to generate AUCs and hazard ratios (HR) binned by octile. RESULTS: A total of 9223 adults (mean age, 57 years; 4071:5152 M:F) underwent screening CTC from April 2004 to December 2016. 549 patients died on follow-up (median, nine years). Fat measures outperformed BMI for predicting mortality risk-5-year AUCs for muscle attenuation, VSR, and BMI were 0.721, 0.661, and 0.499, respectively. Higher visceral, muscle, and liver fat were associated with increased mortality risk-VSR > 1.53, HR = 3.1; muscle attenuation < 15 HU, HR = 5.4; liver attenuation < 45 HU, HR = 2.3. Higher VAT area and VSR were associated with increased cardiovascular event and diabetes risk-VSR > 1.59, HR = 2.6 for cardiovascular event; VAT area > 291 cm2, HR = 6.3 for diabetes (p < 0.001). A U-shaped association was observed for SAT with a higher risk of death for very low and very high SAT. CONCLUSION: Fully automated CT-based measures of abdominal fat are predictive of mortality and cardiometabolic disease risk in asymptomatic adults and uncover trends that are not reflected in anthropomorphic measures. CLINICAL RELEVANCE STATEMENT: Fully automated CT-based measures of abdominal fat soundly outperform anthropometric measures for mortality and cardiometabolic risk prediction in asymptomatic patients. KEY POINTS: Abdominal fat depots associated with metabolic dysregulation and cardiovascular disease can be derived from abdominal CT. Fully automated AI body composition tools can measure factors associated with increased mortality and cardiometabolic risk. CT-based abdominal fat measures uncover trends in mortality and cardiometabolic risk not captured by BMI in asymptomatic outpatients.

Effectiveness and Safety of an Emergency Department Code Sepsis Protocol: A Pragmatic Clinical Trial.

RATIONALE: Sepsis care delivery - including initiation of prompt, appropriate antimicrobials - remains suboptimal. OBJECTIVE: Determine direct and off-target effects of emergency department (ED) sepsis care reorganization. METHODS: This pragmatic pilot trial enrolled adult patients presenting November 2019 to February 2021 to an ED in Utah before and after implementation of a multimodal, team-based "Code Sepsis" protocol. Patients presenting to two other EDs where usual care was continued served as contemporaneous controls. The primary outcome was door-to-antimicrobial time among patients meeting Sepsis-3 criteria before ED departure. Secondary and safety outcomes included all-cause 30-day mortality, antimicrobial utilization and overtreatment, and antimicrobial-associated adverse events. Multivariable regression analyses employed difference-in-differences methods to account for trends in outcomes unrelated to the studied intervention. RESULTS: Code Sepsis protocol activation (N=307) exhibited 8.5% sensitivity and 66% positive predictive value for patients meeting sepsis criteria before ED departure. Among 10,151 patients meeting sepsis criteria during the study, adjusted difference-in-differences analysis demonstrated a 13-minute (95% CI 7-19-minute) decrease in door-to-antimicrobial time associated with Code Sepsis implementation (p<0.001). Mortality and clinical safety outcomes were unchanged, but Code Sepsis implementation was associated with increased false-positive presumptive infection diagnosis among patients meeting sepsis criteria in the ED and increased antimicrobial utilization. CONCLUSIONS: Implementation of a team-based protocol for rapid sepsis evaluation and treatment during the COVID-19 pandemic's first year was associated with decreased ED door-to-antimicrobial time but also increased antimicrobial utilization. Measurement of both patient-centered and off-target effects of sepsis care improvement interventions is essential to comprehensive assessment of their value. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT04148989) This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Clinical and molecular characteristics of patients with brain metastasis secondary to pancreatic ductal adenocarcinoma.

BACKGROUND: The prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) is poor. Secondary brain metastasis (Br-M) occurs in less than 1% of patients. Clinical characteristics and molecular alterations have not been characterized in this rare patients' subset. MATERIALS AND METHODS: The Foundry software platform was used to retrospectively query electronic health records for patients with Br-M secondary to PDAC from 2005 to 2023; clinical, molecular, and overall survival (OS) data were analyzed. RESULTS: Br-M was diagnosed in 44 patients with PDAC. Median follow-up was 78 months; median OS from initial PDAC diagnosis was 47 months. Median duration from PDAC diagnosis to Br-M detection was 24 months; median OS from Br-M diagnosis was 3 months. At Br-M diagnosis, 82% (n = 36) of patients had elevated CA19-9. Lung was the most common preexisting metastatic location (71%) with Br-M, followed by liver (66%). Br-M were most frequently observed in the frontal lobe (34%, n = 15), cerebellar region (23%, n = 10), and leptomeninges (18%, n = 8). KRAS mutations were detected in 94.1% (n = 16) of patients who had molecular data available (n = 17) with KRASG12V being the most frequent subtype 47% (n = 8); KRASG12D in 29% (n = 5); KRASG12R in 18% (n = 3). Patients who underwent Br-M surgical resection (n = 5) had median OS of 8.6 months, while median OS following stereotactic radiosurgery only (n = 11) or whole-brain radiation only (n = 20) was 3.3 and 2.8 months, respectively. CONCLUSION: Br-M is a late PDAC complication, resulting in an extremely poor prognosis especially in leptomeningeal disease. KRAS was mutated in 94.1% of the patients and the KRASG12V subtype was prevalent.

The Effect of Patient Resilience on Postoperative Scores After One and Two-level Anterior Cervical Discectomy and Fusion.

OBJECTIVE: The purpose is to investigate the association between resilience and outcomes of pain and neck-related disability after single- and two-level anterior cervical discectomy and fusion (ACDF). METHODS: Patients who underwent single- or two-level ACDF were sent a survey between six months and two years following surgery. The survey included the Brief Resilience Scale (BRS), Visual Analogue Scale (VAS) for pain, Neck Disability Index (NDI), and Pain Self-Efficacy Questionnaire (PSEQ-2). Patients completed the VAS and NDI twice, once describing preoperative pain and disability and once describing current pain and disability. Respondents were classified as high resilience (HR), medium resilience (MR), or low resilience (LR). Demographics, PSEQ-2 scores, pre- and postoperative VAS and NDI scores, and change in VAS (ΔVAS) and NDI (ΔNDI) scores were compared between groups. RESULTS: Thirty-three patients comprised the HR group, 273 patients comprised the MR group, and 47 patients comprised the LR group. All groups demonstrated postoperative improvement in VAS and NDI scores that exceeded previously established MCID values. The HR group demonstrated greater improvement in pain compared to the LR group (ΔVAS: -5.8 for HR vs -4.4 for LR, p=0.05). Compared to the MR group, the LR group demonstrated greater postoperative pain (VAS: 3.2 for LR vs 2.5 for MR, p=0.02) and disability (NDI: 11.9 for LR vs 8.6 for MR, p=0.02). CONCLUSIONS: Patients demonstrated improvement in pain and neck-related disability after single- and two-level ACDF, regardless of resilience score. Patients with greater resilience may be expected to demonstrate more improvement in pain after ACDF.

Rational tuning of the concentration-independent enrichment of prion-like domains in stress granules.

Stress granules (SGs) are large ribonucleoprotein assemblies that form in response to acute stress in eukaryotes. SG formation is thought to be initiated by liquid-liquid phase separation (LLPS) of key proteins and RNA. These molecules serve as a scaffold for recruitment of client molecules. LLPS of scaffold proteins in vitro is highly concentration-dependent, yet biomolecular condensates in vivo contain hundreds of unique proteins, most of which are thought to be clients rather than scaffolds. Many proteins that localize to SGs contain low-complexity, prion-like domains (PrLDs) that have been implicated in LLPS and SG recruitment. The degree of enrichment of proteins in biomolecular condensates such as SGs can vary widely, but the underlying basis for these differences is not fully understood. Here, we develop a toolkit of model PrLDs to examine the factors that govern efficiency of PrLD recruitment to stress granules. Recruitment was highly sensitive to amino acid composition: enrichment in SGs could be tuned through subtle changes in hydrophobicity. By contrast, SG recruitment was largely insensitive to PrLD concentration at both a population level and single-cell level. These observations point to a model wherein PrLDs are enriched in SGs through either simple solvation effects or interactions that are effectively non-saturable even at high expression levels.

Genome-wide association study of major anxiety disorders in 122,341 European-ancestry cases identifies 58 loci and highlights GABAergic signaling.

The major anxiety disorders (ANX; including generalized anxiety disorder, panic disorder, and phobias ) are highly prevalent, often onset early, persist throughout life, and cause substantial global disability. Although distinct in their clinical presentations, they likely represent differential expressions of a dysregulated threat-response system. Here we present a genome-wide association meta-analysis comprising 122,341 European ancestry ANX cases and 729,881 controls. We identified 58 independent genome-wide significant ANX risk variants and 66 genes with robust biological support. In an independent sample of 1,175,012 self-report ANX cases and 1,956,379 controls, 51 of the 58 associated variants were replicated. As predicted by twin studies, we found substantial genetic correlation between ANX and depression, neuroticism, and other internalizing phenotypes. Follow-up analyses demonstrated enrichment in all major brain regions and highlighted GABAergic signaling as one potential mechanism underlying ANX genetic risk. These results advance our understanding of the genetic architecture of ANX and prioritize genes for functional follow-up studies.

Postoperative Adverse Events Following Neoadjuvant Therapy and Surgery for Borderline Resectable Pancreatic Cancer in a Phase 2 Clinical Trial (Alliance A021501).

BACKGROUND: Postoperative adverse events (AEs) in patients with borderline resectable pancreatic ductal adenocarcinoma (BR-PC) treated with neoadjuvant therapy and pancreatectomy in the national cooperative group setting have not been previously characterized. We conducted a preplanned secondary analysis of patients enrolled on the Alliance A021501 clinical trial to quantify perioperative AE rates. METHODS: The A021501 phase 2 trial randomized patients with BR-PC to receive 8 doses of mFOLFIRINOX (Arm 1) or 7 doses of mFOLFIRINOX and hypofractionated radiotherapy (Arm 2), followed by pancreatectomy (December 31, 2016 to May 31, 2019). Adverse events were assessed 90 days after pancreatectomy. RESULTS: Of 126 enrolled patients, 51 (40%) underwent pancreatectomy (n = 32, Arm 1; n = 19, Arm 2) at 28 institutions. Five (10%) patients required reoperation within 90 days; 56% of patients (n = 27/48) experienced at least one grade 3 or higher AE (50% vs. 67%, p = 0.37). Ninety-day mortality was 2.0%. Readmission was less frequent in Arm 1 (16% vs. 42%, p = 0.05), but there were no differences between study arms in rates of reoperation (13% vs. 5%), pancreatic fistula or intra-abdominal abscess requiring drainage (9% vs. 16%), or wound infection (6% vs. 16%). Pancreatic fistula or intra-abdominal abscess requiring drainage was associated with receipt of adjuvant therapy (p = 0.012). No difference in overall survival was observed based on occurrence of postoperative AEs (hazard ratio = 1.1; 95% confidence interval 0.5-2.6). CONCLUSIONS: In this multicenter study, rates of postoperative AEs were consistent with those previously reported. Multimodality trials of preoperative therapy for BR-PC may be performed in the cooperative group setting with careful quality assurance and safety monitoring. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02839343.

Enhancement of erythropoietic output by Cas9-mediated insertion of a natural variant in haematopoietic stem and progenitor cells.

Some gene polymorphisms can lead to monogenic diseases, whereas other polymorphisms may confer beneficial traits. A well-characterized example is congenital erythrocytosis-the non-pathogenic hyper-production of red blood cells-that is caused by a truncated erythropoietin receptor. Here we show that Cas9-mediated genome editing in CD34+ human haematopoietic stem and progenitor cells (HSPCs) can recreate the truncated form of the erythropoietin receptor, leading to substantial increases in erythropoietic output. We also show that combining the expression of the cDNA of a truncated erythropoietin receptor with a previously reported genome-editing strategy to fully replace the HBA1 gene with an HBB transgene in HSPCs (to restore normal haemoglobin production in cells with a ß-thalassaemia phenotype) gives the edited HSPCs and the healthy red blood cell phenotype a proliferative advantage. Combining knowledge of human genetics with precise genome editing to insert natural human variants into therapeutic cells may facilitate safer and more effective genome-editing therapies for patients with genetic diseases.

Differences in Volatile Organic Compounds Between Concussed and Non-concussed Division I Athletes.

Introduction Diagnosing a concussion is challenging because of complex and variable symptoms. Establishing a viable biomarker of injury may rely on physiologic measurements rather than symptomology. Volatile organic compounds (VOCs) such as breath acetone have been identified as potential physiological markers that can capture changes in the utilization of energy substrates post-concussion. Here, we aimed to explore whether differences in VOCs exist between concussed and non-concussed athletes at the initial and later stages of injury recovery. Methods Six (N=6) non-concussed athletes were enrolled as control participants prior to the competitive season. Control participants' breath acetone, heart rate, and anthropometric measures were obtained at rest and throughout a single exercise challenge by breathalyzer. Six (N=6) athletes diagnosed with concussion during the competitive season had breath acetone measured daily until cleared to return to activity or approximately four weeks following enrollment where they participated in an exit exercise challenge having breath acetone, heart rate, and anthropometric measures obtained. Comparisons were made between at-rest measures of concussed and non-concussed participants at multiple time points during the recovery period. Paired t-test comparisons with individuals serving as their own control were used to determine individual differences in recovery. Visual graphs were used to demonstrate differences in obtained measures amongst individuals and between groups during the exercise challenges. Results Results demonstrated statistically significant differences in breath acetone between concussed and control participants when the highest day measured during the first week of concussion was compared to the control participant's resting values (P=0.017). Additionally, when the concussed participants served as their own control and their highest measured day of the first week post-concussion was compared to values when cleared to return to activity or at 26 days post-concussion, there was a significant difference in breath acetone (P=0.028). Comparing breath acetone during exercise between non-concussed and cleared concussed participants or four weeks post-injury, demonstrated no significant differences throughout the challenge or at rest prior. Visual graph comparisons in a single participant before and after concussion suggest differences may appear following exercise during the recovery period. Discussion These results suggest VOCs, particularly breath acetone, have the potential to serve as diagnostic markers of concussion. However, longitudinal research within larger cohorts and with equipment able to expel VOCs other than acetone from measures are needed to make informed recommendations.

Intra-neighborhood associations between residential greenness and blood pressure.

INTRODUCTION: Previous investigations have reported that individuals living in greener neighborhoods have better cardiovascular health. It is unclear whether the effects reported at large geographic scales persist when examined at an intra-neighborhood level. The effects of greenness have not been thoroughly examined using high-resolution metrics of greenness exposure, and how they vary with spatial scales of assessment or participant characteristics. METHODS: We conducted a cross-sectional assessment of associations between blood pressure and multiple high-resolution measures of residential area greenness in spatially concentrated HEAL Study cohort of the Green Heart Project. We employed generalized linear models, accounting for individual-level covariates, to examine associations between different high-resolution measures of greenness and blood pressure among 667 participants in a 4 sq. mile contiguous neighborhood area in Louisville, KY. RESULTS: In adjusted models, we observed significant inverse associations between residential greenness, measured by leaf area index (LAI), and systolic blood pressure (SBP) within 150-250 m and 500 m of homes, but not for Normalized Difference Vegetation Index (NDVI) or grass cover. Weaker associations were also found with diastolic blood pressure (DBP). Significant positive associations were observed between LAI and SBP among participants who reported being female, White, without obesity, non-exercisers, non-smokers, younger age, of lower income, and who had high nearby roadway traffic. We found few significant associations between grass cover and SBP, but an inverse association in those with obesity, but positive associations for those without obesity. CONCLUSIONS: We found that leaf surface area of trees around participants home is strongly associated with lower blood pressure, with little association with grass cover. These effects varied with participant characteristics and spatial scales. More research is needed to test causative links between greenspace types and cardiovascular health and to develop population-, typology-, and place-based evidence to inform greening interventions.

Escalated-dose radiotherapy for unresected locally advanced pancreatic cancer: Patterns of care and survival in the United States.

INTRODUCTION: With locally advanced pancreatic cancer (LAPC), uncontrolled local tumor growth frequently leads to mortality. Advancements in radiotherapy (RT) techniques have enabled conformal delivery of escalated-dose RT (EDR), which may have potential local control and overall survival (OS) benefits based on retrospective and early prospective studies. With evidence for EDR emerging, we characterized the adoption of EDR across the United States and its associated outcomes. METHODS: We searched the National Cancer Database for nonsurgically managed LAPC patients diagnosed between 2004 and 2019. Pancreas-directed RT with biologically effective doses (BED10) ≥39 and ≤70 Gy was labeled conventional-dose RT (CDR), and BED10 >70 and ≤132 Gy was labeled EDR. We identified associations of EDR and OS using logistic and Cox regressions, respectively. RESULTS: Among the definitive therapy subset (n = 54,115) of the entire study cohort (n = 91,493), the most common treatments were chemotherapy alone (69%), chemotherapy and radiation (29%), and RT alone (2%). For the radiation therapy subset (n = 16,978), use of pancreas-directed RT remained between 13% and 17% over the study period (ptrend > 0.999). Using multivariable logistic regression, treatment at an academic/research facility (adjusted odds ratio [aOR] 1.46, p < 0.001) and treatment between 2016 and 2019 (aOR 2.54, p < 0.001) were associated with greater receipt of EDR, whereas use of chemotherapy (aOR 0.60, p < 0.001) was associated with less receipt. Median OS estimates for EDR and CDR were 14.5 months and 13.0 months (p < 0.0001), respectively. For radiation therapy subset patients with available survival data (n = 13,579), multivariable Cox regression correlated EDR (adjusted hazard ratio 0.85, 95% confidence interval 0.80-0.91; p < 0.001) with longer OS versus CDR. DISCUSSION AND CONCLUSIONS: Utilization of EDR has increased since 2016, but overall utilization of RT for LAPC has remained at less than one in five patients for almost two decades. These real-world results additionally provide an estimate of effect size of EDR for future prospective trials.