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Graphical Abstract Highlight Research • The results of this research showed that allometric growth in males and females had negative allometric growth characteristics. • The growth condition index in male and female fish is dominated by thin and fat body shapes.The maximum length growth (L∞) and growth speed of males is higher than that of females. • Total mortality and fishing mortality for males is higher than for females, but natural mortality for females is higher than for males. • The exploitation rate of males and females is in the Under-exploitation category because the E value is

Background:. We evaluate the performance of plastic surgeons in converting National Institutes of Health K grants in early career to R grants intended for established investigators. We also investigate characteristics that may positively predict successful transition from K to R grants. Methods:. K08, K23, and R01 (or equivalent) grants awarded to plastic surgeons and physicians within the departments of ophthalmology, dermatology, and neurosurgery were collected. Analyses of successful conversion rates from a K to an R grant between plastic surgeons and physicians within the selected departments were performed. Cross-sectional analysis of characteristics among identified plastic surgeons was completed via logistic regression to elucidate possible predictors of successful conversion. Results:. Comparison of pathway initiation rates demonstrate that plastic surgeons receive significantly fewer K grants relative to the size of their field when compared with other specialties (all P < 0.01). Of the analyzed plastic surgeons, 52.9% successfully converted to an R-series grant within 5.4 years of beginning their K-series grant. Conversion rates were not significantly different between plastic surgeons and physicians within the selected departments. Logistic regression analyses revealed that the time-adjusted mean relative citation ratio of K series–associated publications is a positive predictor of successful conversion (P = 0.047). Conclusions:. With regard to increasing National Institutes of Health funding via the K-to-R pathway, we believe the field of plastic surgery could benefit from an increased effort to pursue a pathway of K-to-R conversion with a focus on quality over quantity when publishing articles associated with a K-series grant.

Background:. Although long-term benefits of reduction mammaplasty have been proven, the appropriate age for adolescent reduction mammaplasty has been highly debated due to possible need for revision surgery. Practitioners often delay offering breast reduction to adolescents below age 18 based on presumed insurance denial. We reviewed trends in insurance denial at a single children’s hospital to analyze whether age and/or insurance carriers have a significant impact on coverage of breast reduction. Methods:. A retrospective chart review from 2012 to 2022 of cisgender female patients with macromastia aged 12–20 years at the time of diagnosis was analyzed for differences in breast reduction insurance coverage based on age and body mass index at the time of diagnosis, referral to plastic surgery, and surgery. Results:. A total of 121 cisgender women were included. There were no significant differences in the mean ages of patients who underwent breast reduction versus those who did not (16.46 years versus 16.96 years, respectively; P = 0.089), or in the mean body mass index for patients who did versus those who did not receive breast reduction (28.58 kg/m² versus 29.05kg/m², P = 0.382). Furthermore, there were no significant differences in the proportion of patients undergoing breast reduction by age (P = 0.200) or by insurance class (P = 0.403). Conclusion:. Although insurance varies with carrier, the present findings suggest that surgeons need not delay in facilitating preauthorization for breast reduction in symptomatic patients presenting anytime during their teenage years.

Abstract The shared functions of the skull are thought to result in common evolutionary patterns in mammalian cranial shape. Craniofacial evolutionary allometry (CREA) is a particularly prominent pattern where larger species display proportionally elongate facial skeletons and smaller braincases. It was recently proposed that CREA arises from biomechanical effects of cranial scaling when diets are similar. Thus, deviations from CREA should occur with changes in cranial biomechanics, for example due to dietary change. Here, we test this using 3D geometric morphometric analysis in a dataset of Australian murine crania, which are highly allometric. We contrast allometric and non‐allometric variation in the cranium by comparing evolutionary mode, allometry, ordinations, as well as allometry, integration, and modularity in functional modules. We found evidence of stabilising selection in allometry‐containing and size‐free shape, and substantial non‐allometric variation aligned with dietary specialisation in parallel with CREA. Integration among cranial modules was higher, and modularity lower, with size included, but integration between rostrum and cranial vault, which are involved in the CREA pattern, dropped dramatically after size removal. Our results thus support the hypothesis that CREA is a composite arising from selection on cranial function, with substantial non‐allometric shape variation occurring alongside CREA where dietary specialisation impacts selection on gnawing function. This emphasises the need to research mammalian cranial evolution in the context of allometric and non‐allometric selection on biomechanical function.

Academic departments have been highlighted as key targets to sustainably transform the learning environments of postsecondary science, technology, engineering, and mathematics (STEM) courses in the United States. Despite STEM department chairs playing a critical role in shaping their unit, few studies have characterized how chairs view the teaching culture within their department and how cultural features influence instructional change. This study addressed this gap by applying the four-frames model for organizational change to analyze interviews conducted with 14 STEM department chairs at one research-intensive institution in the United States. The department chairs identified several challenges to supporting and advancing teaching culture. These challenges were mostly related to the structures and symbols frames and included an institutional emphasis on research over teaching, inadequate methods to evaluate effective teaching, and weak teaching feedback mechanisms available to faculty. The chairs also described how they leverage their power to affect people and thereby influence the teaching culture. For example, they strategically position teaching as an important aspect of the departmental culture during hiring processes and elevate certain groups of faculty who have demonstrated interest and efficacy in teaching. This study contributes to the literature by providing a rich description of the teaching culture in STEM departments at a research-intensive institution from the perspective of department chairs. This unique focus on department chairs helps identify opportunities for instructional reforms that are grounded in the reality of the departmental environment and provides a framework for considering how change might occur in STEM departments at research-intensive institutions. The opportunities identified emphasize the importance for department chairs to consider and leverage all four frames to enact instructional change.

Abstract Introduction Typically, oncology is not a structured part of the curriculum in Brazilian medical schools. Furthermore, sarcomas, which are uncommon tumors, are seldom covered in depth. A lack of comprehensive education on sarcomas might result in medical professionals being ill-equipped to care for patients with this condition. Objectives To assess medical students' understanding and awareness of sarcomas and the specific principles related to these tumors. Materials and methods A quantitative, cross-sectional study was conducted using a questionnaire, applied to medical students, focusing on the epidemiology, pathophysiology, and treatments of bone and soft tissue sarcomas. In all tests, the significance level adopted was 5%. The SPSS version 25.0 software was used. Results Of the 825 questionnaires distributed, 325 were returned. Educational sessions on sarcomas did not appear to significantly improve the student's knowledge. Only 29.5% of students identified the lack of pain as an indicator of potential malignancy in soft tissue sarcomas, while 73.8% correctly recognized pain as a symptom of bone sarcomas. Limb amputation as the optimal surgical method for patient recovery was incorrectly reported by 39.1% of the sample. Conclusion A great part of the surveyed population does not have adequate knowledge about the basic concepts associated with limb sarcomas. The minority of them are satisfied with the knowledge gained during their medical education about these tumors. Inadequate medical academic training may initially lead to the wrong clinical management of patients with bone and soft tissue tumor lesions. An educational effort is needed to enhance oncology education for medical students, especially concerning sarcomas.

Background & Aims: Breast regression protein 39 (BRP39) (Chi3L1) and its human homolog YKL-40, is an established biomarker of liver fibrosis in nonalcoholic steatohepatitis (NASH) patients, but its role in NASH pathogenesis remains unclear. We recently identified Chi3L1 as one of the top up-regulated genes in mice with inducible gain-of-function NOD-like receptor protein 3 (NLRP3) activation that mimics several liver features of NASH. This study aimed to investigate the effects of BRP39 deficiency on NLRP3-induced liver inflammation using tamoxifen-inducible Nlrp3 knockin mice sufficient (Nlrp3A350V CRT) and deficient for BRP39 (Nlrp3A350V/BRP-/- CRT). Methods: Using Nlrp3A350V CRT mice and Nlrp3A350V BRP-/- CRT, we investigated the consequences of BRP39 deficiency influencing NLRP3-induced liver inflammation. Results: Our results showed that BRP39 deficiency in NLRP3-induced inflammation improved body weight and liver weight. Moreover, liver inflammation, fibrosis, and hepatic stellate cell activation were reduced significantly, corresponding to significantly decreased Ly6C+ infiltrating macrophages, CD68+ osteopontin-positive hepatic lipid-associated macrophages, and activated Lymphocyte antigen 6 complex locus G6D positive (Ly6G+) and citrullinated histone H3 postivie (H3Cit+) neutrophil accumulation in the liver. Further investigation showed that circulatory neutrophils from NLRP3-induced BRP39-deficient mice have impaired chemotaxis and migration ability, and this was confirmed by RNA bulk sequencing showing reduced immune activation, migration, and signaling responses in neutrophils. Conclusions: These data showcase the importance of BRP39 in regulating the NLRP3 inflammasome during liver inflammation and fibrotic NASH by altering cellular activation, recruitment, and infiltration during disease progression, and revealing BRP39 to be a potential therapeutic target for future treatment of inflammatory NASH and its associated diseases.

Highly pathogenic avian influenza (HPAI) is a highly contagious viral disease that represents a significant threat to poultry production worldwide. Variants of the HPAI virus (HPAIV) H5A/Goose/GuangDong/1/96 (H5 Gs/GD/96) lineage have caused five intercontinental epizootic waves, with the most recent, clade 2.3.4.4b, reaching Argentina in February 2023. Initially detected in wild birds, the virus quickly spread to backyard and commercial poultry farms, leading to economic losses, including the loss of influenza-free status (IFS). By March/April 2023 the epidemic had peaked and vaccination was seriously considered. However, the success of strict stamping-out measures dissuaded the National Animal Health Authority (SENASA) from authorizing any vaccine. Suspected cases sharply declined by May, and the last detection in commercial poultry was reported in June. The effective control and potential eradication of HPAIV in Argentina were due to SENASA’s early detection and rapid response, supported by private companies, veterinarians, and other stakeholders. Stamping-out measures have been effective for virus elimination and reduced farm-to-farm transmission; however, as the virus of this clade may remain present in wild birds, the risk of reintroduction into poultry production is high. Therefore, maintaining continuous active surveillance will be crucial for promptly detecting any new HPAIV incursion and taking appropriate action to contain virus dissemination.

Abstract COVID-19 vaccines were originally designed based on the ancestral Spike protein, but immune escape of emergent Variants of Concern (VOC) jeopardized their efficacy, warranting variant-proof vaccines. Here, we used preclinical rodent models to establish the cross-protective and cross-neutralizing capacity of adenoviral-vectored vaccines expressing VOC-matched Spike. CoroVaxG.3-D.FR, matched to Delta Plus Spike, displayed the highest levels of nAb to the matched VOC and mismatched variants. Cross-protection against viral infection in aged K18-hACE2 mice showed dramatic differences among the different vaccines. While Delta-targeted vaccines fully protected mice from a challenge with Gamma, a Gamma-based vaccine offered only partial protection to Delta challenge. Administration of CorovaxG.3-D.FR in a prime/boost regimen showed that a booster was able to increase the neutralizing capacity of the sera against all variants and fully protect aged K18-hACE2 mice against Omicron BA.1, as a BA.1-targeted vaccine did. The neutralizing capacity of the sera diminished in all cases against Omicron BA.2 and BA.5. Altogether, the data demonstrate that a booster with a vaccine based on an antigenically distant variant, such as Delta or BA.1, has the potential to protect from a wider range of SARS-CoV-2 lineages, although careful surveillance of breakthrough infections will help to evaluate combination vaccines targeting antigenically divergent variants yet to emerge.

Abstract Background Ultra-hypofractionated regimens for definitive prostate cancer (PCa) radiotherapy are increasingly utilized due in part to promising safety and efficacy data complemented by greater patient convenience from a treatment course requiring fewer sessions. As such, stereotactic body radiation therapy (SBRT) is rapidly emerging as a standard definitive treatment option for patients with localized PCa. The commercially available magnetic resonance linear accelerator (MR-LINAC) integrates MR imaging with radiation delivery, providing several theoretical advantages compared to computed tomography (CT)-guided radiotherapy. MR-LINAC technology facilitates improved visualization of the prostate, real-time intrafraction tracking of prostate and organs-at-risk (OAR), and online adaptive planning to account for target movement and anatomical changes. These features enable reduced treatment volume margins and improved sparing of surrounding OAR. The theoretical advantages of MR-guided radiotherapy (MRgRT) have recently been shown to significantly reduce rates of acute grade ≥ 2 GU toxicities as reported in the prospective randomized phase III MIRAGE trial, which compared MR-LINAC vs CT-based 5 fraction SBRT in patients with localized PCa (Kishan et al. JAMA Oncol 9:365-373, 2023). Thus, MR-LINAC SBRT–utilizing potentially fewer treatments–is warranted and clinically relevant for men with low or intermediate risk PCa electing for radiotherapy as definitive treatment. Methods/Design A total of 136 men with treatment naïve low or intermediate risk PCa will be randomized in a 1:1 ratio to 5 or 2 fractions of MR-guided SBRT using permuted block randomization. Randomization is stratified by baseline Expanded PCa Index Composite (EPIC) bowel and urinary domain scores. Patients undergoing 5 fractions will receive 37.5 Gy to the prostate over 10–14 days and patients undergoing 2 fractions will receive 25 Gy to the prostate over 7–10 days. The co-primary endpoints are GI and GU toxicities as measured by change scores in the bowel and urinary EPIC domains, respectively. The change scores will be calculated as pre-treatment (baseline) score subtracted from the 2-year score. Discussion FORT is an international, multi-institutional prospective randomized phase II trial evaluating whether MR-guided SBRT delivered in 2 fractions versus 5 fractions is non-inferior from a gastrointestinal (GI) and genitourinary (GU) toxicity standpoint at 2 years post-treatment in men with low or intermediate risk PCa. Trial registration Clinicaltrials.gov identifier: NCT04984343 . Date of registration: July 30, 2021. Protocol version: 4.0, Nov 8, 2022.

Abstract Background Ultra-hypofractionated image-guided stereotactic body radiotherapy (SBRT) is increasingly used for definitive treatment of localized prostate cancer. Magnetic resonance imaging-guided radiotherapy (MRgRT) facilitates improved visualization, real-time tracking of targets and/or organs-at-risk (OAR), and capacity for adaptive planning which may translate to improved targeting and reduced toxicity to surrounding tissues. Given promising results from NRG-GU003 comparing conventional and moderate hypofractionation in the post-operative setting, there is growing interest in exploring ultra-hypofractionated post-operative regimens. It remains unclear whether this can be done safely and whether MRgRT may help mitigate potential toxicity. SHORTER (NCT04422132) is a phase II randomized trial prospectively evaluating whether salvage MRgRT delivered in 5 fractions versus 20 fractions is non-inferior with respect to gastrointestinal (GI) and genitourinary (GU) toxicities at 2-years post-treatment. Methods A total of 136 patients will be randomized in a 1:1 ratio to salvage MRgRT in 5 fractions or 20 fractions using permuted block randomization. Patients will be stratified according to baseline Expanded Prostate Cancer Index Composite (EPIC) bowel and urinary domain scores as well as nodal treatment and androgen deprivation therapy (ADT). Patients undergoing 5 fractions will receive a total of 32.5 Gy over 2 weeks and patients undergoing 20 fractions will receive a total of 55 Gy over 4 weeks, with or without nodal coverage (25.5 Gy over 2 weeks and 42 Gy over 4 weeks) and ADT as per the investigator’s discretion. The co-primary endpoints are change scores in the bowel and the urinary domains of the EPIC. The change scores will reflect the 2-year score minus the pre-treatment (baseline) score. The secondary endpoints include safety endpoints, including change in GI and GU symptoms at 3, 6, 12 and 60 months from completion of treatment, and efficacy endpoints, including time to progression, prostate cancer specific survival and overall survival. Discussion The SHORTER trial is the first randomized phase II trial comparing toxicity of ultra-hypofractionated and hypofractionated MRgRT in the salvage setting. The primary hypothesis is that salvage MRgRT delivered in 5 fractions will not significantly increase GI and GU toxicities when compared to salvage MRgRT delivered in 20 fractions. Trial registration ClinicalTrials.gov Identifier: NCT04422132. Date of registration: June 9, 2020.

Abstract The NLRP3 inflammasome is an intracellular, multiprotein complex that promotes the auto-catalytic activation of caspase-1 and the subsequent maturation and secretion of the pro-inflammatory cytokines, IL-1β and IL-18. Persistent activation of the NLRP3 inflammasome has been implicated in the pathophysiology of a number of inflammatory and autoimmune diseases, including neuroinflammation, cardiovascular disease, non-alcoholic steatohepatitis, lupus nephritis and severe asthma. Here we describe the preclinical profile of JT002, a novel small molecule inhibitor of the NLRP3 inflammasome. JT002 potently reduced NLRP3-dependent proinflammatory cytokine production across a number of cellular assays and prevented pyroptosis, an inflammatory form of cell death triggered by active caspase-1. JT002 demonstrated in vivo target engagement at therapeutically relevant concentrations when orally dosed in mice and prevented body weight loss and improved inflammatory and fibrotic endpoints in a model of Muckle–Wells syndrome (MWS). In two distinct models of neutrophilic airway inflammation, JT002 treatment significantly reduced airway hyperresponsiveness and airway neutrophilia. These results provide a rationale for the therapeutic targeting of the NLRP3 inflammasome in severe asthma and point to the use of JT002 in a variety of inflammatory disorders.

ABSTRACTFocal radiation therapy (RT) has attracted considerable attention as a combinatorial partner for immunotherapy (IT), largely reflecting a well-defined, predictable safety profile and at least some potential for immunostimulation. However, only a few RT-IT combinations have been tested successfully in patients with cancer, highlighting the urgent need for an improved understanding of the interaction between RT and IT in both preclinical and clinical scenarios. Every year since 2016, ImmunoRad gathers experts working at the interface between RT and IT to provide a forum for education and discussion, with the ultimate goal of fostering progress in the field at both preclinical and clinical levels. Here, we summarize the key concepts and findings presented at the Sixth Annual ImmunoRad conference.

Abstract The increase in mineral and ash-rich waste biomass (MWB) generation in emerging economies poses critical environmental problems and bottlenecks the solid waste and wastewater treatment systems. Transforming these MWB such as sewage sludge from wastewater treatment (SSW) to biochar can be a sustainable method for their disposal and resource recovery. However, such biochar has limited applicability due to the relatively low organic content and possibly contaminated nature of SSW. This may be offset through combined pyrolysis with other MWB, which can also support municipal solid waste management. Studies on this MWB co-pyrolysis are lacking and have not yet seen successful long-term implementation. This work is the second part of authors’ research encompassing an analytical and lab-scale investigation of biochar production from MWB through pyrolysis for the case of Chennai city, India. Here, the physicochemical properties of biochar derived from lab-scale co-pyrolysis of SSW with other MWB such as anaerobic digestate from waste to energy plants of food, kitchen or market waste fermentation, and banana peduncles (BP) collected from vegetable markets and their thermolysis mechanism are comprehensively investigated for purpose of carbon sequestration. Also, a novel preliminary investigation of the effect of sample weight (scaling effect) on the analytical pyrolysis of biomass (BP as model substrate) is undertaken to elucidate its impact on the heat of pyrolysis and carbon distribution in resultant biochar. The maximum carbon sequestration potential of the derived biochar types is 0.22 kg CO2 kg−1 biomass. The co-pyrolysis of MWB is exothermic and governed by the synergetic effects of the components in blends with emission profiles following the order CO2 > CH4 > CO > NH3. Co-pyrolysis reduced the heavy metal enrichment in SSW biochar. The derived biochars can be an immediate source of N, P and S in nutrient-deficient acidic soils. The biochar has only up to 4-ring polyaromatic compounds and a residence time longer than 1 h at 500 °C is necessary to improve carbonization. The heat released during analytical pyrolysis of the model biomass and distribution of carbon in the resultant biochar are significantly influenced by scaling effects, drawing attention to the need for a more detailed scaling investigation of biomass pyrolysis.

OBJECTIVES/GOALS: Prostate cancer treatment is associated with significant genitourinary side effects. There is a critical need for treatment with decreased morbidity. We report the development of a novel treatment paradigm combining irreversible electroporation and lower dose radiation to provide prostate cancer patients with a less morbid treatment. METHODS/STUDY POPULATION: Intermediate risk prostate cancer patients will undergo focal irreversible electroporation followed by low dose, whole gland radiation therapy. The primary endpoint is freedom from clinically significant cancer on biopsy at 12-month follow up. Secondary endpoints include safety profile, oncologic efficacy, effectiveness of RT and need for secondary treatment. This trial (NCT05345444) and currently actively recruiting patients after initial feasibility trial. Sample size is calculated to detect an increase in the proportion of patients who are cancer free at 1-year, from 0.80 to 0.95. An exact binomial test with a 10% one-sided significance level will have 94.3% power to detect the difference between the null and alternative hypothesis when the sample size is 42. RESULTS/ANTICIPATED RESULTS: This is a clinical trial in progress. DISCUSSION/SIGNIFICANCE: Combined irreversible electroporation (IRE) and a lower dose radiotherapy (RTIRE) may provide prostate cancer patients a treatment with minimal side effects.

Cell death is crucial for maintaining tissue balance and responding to diseases. However, under pathological conditions, the surge in dying cells results in an overwhelming presence of cell debris and the release of danger signals. In the liver, this gives rise to hepatic inflammation and hepatocellular cell death, which are key factors in various liver diseases caused by viruses, toxins, metabolic issues, or autoimmune factors. Both clinical and in vivo studies strongly affirm that hepatocyte death serves as a catalyst in the progression of liver disease. This advancement is characterized by successive stages of inflammation, fibrosis, and cirrhosis, culminating in a higher risk of tumor development. In this review, we explore pivotal forms of cell death, including apoptosis, pyroptosis, and necroptosis, examining their roles in both acute and chronic liver conditions, including liver cancer. Furthermore, we discuss the significance of cell death in liver surgery and ischemia-reperfusion injury. Our objective is to illuminate the molecular mechanisms governing cell death in liver diseases, as this understanding is crucial for identifying therapeutic opportunities aimed at modulating cell death pathways.

Abstract Salt-tolerant halophytes have shown potential for biorefinery and agricultural use in salt-affected soils, increasing the value of marginal lands. They could provide a bio-based source for compounds obtained from the petrochemical industry or an alternative for biomass currently imported overseas. Salicornia europaea, Tripolium pannonicum and Crithmum maritimum were cultivated in hydroponic systems under various salinity conditions, harvested green but not food-grade, and fractionated to green juice and fibre residue. Obtained fractions were characterised for contents of carbohydrates, Klason lignin, crude protein, organic acids, lipids, and minerals to evaluate the biomass’ suitability for biorefinery. Significant differences were observed in the biomass yield and the composition of the biomass fractions from different cultivation salinities. High concentrations of crude protein were found. Thus, these species could have the potential for green protein production. Fractions rich in carbohydrates could be used for lignocellulose processing and processes utilising micro-organisms.

In recent years, there has been a rapid expansion in our understanding of regulated cell death, leading to the discovery of novel mechanisms that govern diverse cell death pathways. One recently discovered type of cell death is pyroptosis, initially identified in the 1990s as a caspase-1-dependent lytic cell death. However, further investigations have redefined pyroptosis as a regulated cell death that relies on the activation of pore-forming proteins, particularly the gasdermin family. Among the key regulators of pyroptosis is the inflammasome sensor NOD-like receptor 3 (NLRP3), a critical innate immune sensor responsible for regulating the activation of caspase-1 and gasdermin D. A deeper understanding of pyroptosis and its interplay with other forms of regulated cell death is emerging, shedding light on a complex regulatory network controlling pore-forming proteins and cell fate. Cell death processes play a central role in diseases such as metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis, autoinflammatory disorders, and cancer. Cell death often acts as a starting point in these diseases, making it an appealing target for drug development. Yet, the complete molecular mechanisms are not fully understood, and new discoveries reveal promising novel avenues for therapeutic interventions. In this review, we summarize recent evidence on pathways and proteins controlling pyroptosis and gasdermins. Furthermore, we will address the role of pyroptosis and the gasdermin family in metabolic dysfunction-associated steatotic liver disease and steatohepatitis. Additionally, we highlight new potential therapeutic targets for treating metabolic dysfunction-associated steatohepatitis and other inflammatory-associated diseases.

Among 209 surgical specimens of resectable colorectal adenocarcinomas, nine mucinous carcinomas arising in nonulcerated villous adenoma (MA VA) were identified. They showed infUtration in the colorectal muscillaris própria or through it. However, their morphology was similar to the so-called pseudocarcinomatous submucous foci of villous adenomas. Only one of these tumors had lymph-node metastasis. We suggest that the mechanism of invasion of the colorectal wall in MAMA is diferent from that of the common adenocarcinoma, not implying an authentic carcinomatous transformation at cellular level.

Purpose: This analysis investigates whether research productivity during medical school predicts future research productivity during radiation oncology residency. Methods and Materials: At our institution, there have been 20 medical students who graduated between 2005 and 2015 and subsequently completed their residency training in radiation oncology. We built a database of all PubMed-indexed publications in which these former students were the first author or coauthor. Mean publication rates with 95% confidence intervals (95% CI) were computed. The paired t test and McNemar-Bowker test of symmetry were used to examine differences in first-author and coauthor publications between the medical school and residency periods. An ordinal logistic regression model was employed to measure the odds ratio of publishing during residency versus during medical school. A Spearman correlation coefficient was calculated for the relationship between the number of publications during medical school and the number during residency. Results: A total of 14 and 60 first-author publications (46 and 117 coauthor publications) were identified for 20 individuals during medical school and residency, respectively. There was an average of 0.7 (95% CI, 0.17-1.23) first-author publications during medical school and 3.08 (95% CI, 1.56-4.44) first-author publications during residency (P = .003). Only 15% (3/20) had ≥2 publications during medical school, and 50% (10/20) had ≥2 publications during residency (P = .012). The Spearman correlation coefficient between research publications before and during residency was .457 (P = .043). The mean number of coauthor publications during medical school and residency was 2.3 (95% CI, 0.92-3.68) and 5.85 (95% CI, 3.50-8.20), respectively (P = .004). Conclusions: Based on this retrospective analysis from our institution, student research productivity during medical school, as defined by the number of first-author publications, does correlate with future research productivity during radiation oncology residency.

Purpose: Pelvic reirradiation (re-RT) for patients with gynecologic cancers remains a challenge because of toxicity concerns. Given the dosimetric advantages of proton therapy, we aimed to assess oncologic and toxicity outcomes of patients with re-RT to the pelvis/abdomen with intensity modulated proton therapy (IMPT) for gynecologic cancers. Methods and Materials: We performed a retrospective analysis of all patients with gynecologic cancer treated at a single institution between 2015 and 2021 with IMPT re-RT. Patients were included for analysis if the IMPT plan had at least partial overlap with the treated volume of a previous radiation treatment. Results: A total of 29 patients were included for analysis, with 30 total courses of re-RT. The majority of patients had been treated previously with conventional fractionation to a median dose of 49.2 Gy (30-61.6 Gy). With a median follow-up of 23 months, 1-year local control was 83.5% and overall survival was 65.7%. Three patients (10%) developed acute and late grade 3 toxicity. One-year freedom from late grade 3+ toxicity was 96.3%. Conclusions: This is the first complete analysis of clinical outcomes for re-RT with IMPT for gynecologic malignancies. We demonstrate excellent local control and acceptable acute and late toxicity. IMPT should strongly be considered for treatments requiring re-RT for gynecologic malignancies.

Instructors’ interactions can foster knowledge sharing around teaching and the use of research-based instructional strategies (RBIS). Coordinated teaching presents an impetus for instructors’ interactions and creates opportunities for instructional improvement but also potentially limits an instructor’s autonomy. In this study, we sought to characterize the extent of coordination present in introductory undergraduate courses and to understand how departments and instructors implement and experience course coordination. We examined survey data from 3,641 chemistry, mathematics, and physics instructors at three institution types and conducted follow-up interviews with a subset of 24 survey respondents to determine what types of coordination existed, what factors led to coordination, how coordination constrained instruction, and how instructors maintained autonomy within coordinated contexts. We classified three approaches to coordination at both the overall course and course component levels: independent (i.e., not coordinated), collaborative (decision-making by instructor and others), controlled (decision-making by others, not instructor). Two course components, content coverage and textbooks, were highly coordinated. These curricular components were often decided through formal or informal committees, but these decisions were seldom revisited. This limited the ability for instructors to participate in the decision-making process, the level of interactions between instructors, and the pedagogical growth that could have occurred through these conversations. Decision-making around the other two course components, instructional methods and exams, was more likely to be independently determined by the instructors, who valued this autonomy. Participants in the study identified various ways in which collaborative coordination of courses can promote but also inhibit pedagogical growth. Our findings indicate that the benefits of collaborative course coordination can be realized when departments develop coordinated approaches that value each instructor’s autonomy, incorporate shared and ongoing decision-making, and facilitate collaborative interactions and knowledge sharing among instructors.

Abstract Primary sclerosing cholangitis (PSC) is an idiopathic and heterogenous cholestatic liver disease characterized by chronic inflammation and fibrosis of the biliary tree. Currently, no effective therapies are available for this condition, whose incidence is rising. At present, specificity and sensitivity of current serum markers used to diagnose PSC are limited and often unreliable. In this study, we characterize circulating extracellular vesicles and provide supporting data on their potential use as novel surrogate biomarkers for PSC. EVs are membrane surrounded structures, 100–1000 nm in size, released by cells under various conditions and which carry a variety of bioactive molecules, including small non-coding RNAs, lipids and proteins. In recent years, a large body of evidence has pointed to diagnostic implications of EVs and relative cargo in various human diseases. We isolated EVs from serum of well-characterized patients with PSC or control subjects by differential centrifugation and size-exclusion chromatography. A complete characterization identified elevated levels of circulating EVs in PSC patients compared to healthy control subjects (2000 vs. 500 Calcein-FITC + EVs/μL). Tissue and cell specificity of circulating EVs was assessed by identification of liver-specific markers and cholangiocyte marker CK-19. Further molecular characterization identified 282 proteins that were differentially regulated in PSC-derived compared to healthy control-EVs. Among those, IL-13Ra1 was the most significantly and differentially expressed protein in PSC-derived EVs and correlated with the degree of liver fibrosis. In addition to protein profiling, we performed a miRNA-sequencing analysis which identified 11 among established, liver-specific (e.g., miR-122 and miR-192) and novel miRNAs. One of the newly identified miRNAs, miR-4645-3p, was significantly up-regulated fourfold in PSC-derived EVs compared to circulating EVs isolated from healthy controls. This study provides supporting evidence of the potential role of circulating EVs and associated protein and miRNA cargo as surrogate noninvasive and reliable biomarker for PSC.

Background and Aims: Fecal microbiota transplant (FMT) via colonoscopy is highly effective treatment for Clostridioides difficile infection (CDI). We aimed to determine baseline patient characteristics that predict failure to respond to colonoscopy-based FMT. Methods: We evaluated adult patients who received FMT for CDI not responding to standard therapies at a single tertiary center between 2014 and 2018 in this retrospective cohort study. We defined clinical success as formed stool or C difficile–negative diarrhea at 2 months after FMT. If patients required a second FMT, follow-up was extended 2 months after repeat infusion. We performed multivariate logistic regression and a random forest model to identify variables predictive of response to FMT. Results: Clinical success was attained in 87.3% of 103 patients who underwent FMT for CDI. In the multivariate model, the odds of FMT failure for family donation compared with stool bank were odds ratio 4.13 (1.00–7.01 P = .049). Diarrhea while taking anti-CDI antibiotics was common (37.8% of patients) and did not predict failure (odds ratio 0.64, 0.19–2.11 P = .46) in the univariate model. A machine learning model to predict response using clinical factors only achieved a sensitivity of 70%, specificity of 77%, and negative predictive value of 96%. Conclusion: Colonoscopy-based FMT was highly effective for CDI, even in a population where immunosuppression and proton pump inhibitor use were common. Family stool donation was associated with FMT failure, compared with the use of a stool bank. The study suggests that the use of a stool bank may not only improve access to FMT but also its efficacy.

El estreñimiento crónico (EC) es una condición común que afecta a la población mundial (12 al 19%), con una mayor predilección por las mujeres, con una proporción estimada M: H de 2.2:1.

Abstract Inflammatory changes in the liver represent a key feature of non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease (NAFLD). Innate immune activation including hepatic neutrophilic infiltration acts as an important inflammatory trigger as well as a potential mediator of inflammation resolution. In this study, we dissected the effects of neutrophil depletion via anti-lymphocyte antigen 6 complex locus G6D (Ly6G) antibodies administration during ongoing high fat-fructose-cholesterol (FFC) diet-induced murine NASH and during inflammation resolution by switching into a low-fat control diet. During NASH progression, protective effects were shown as HSC activation, cell infiltration and activation of pro-inflammatory macrophages were ameliorated. Furthermore, these changes were contrasted with the effects observed when neutrophil depletion was performed during the resolution phase. Impaired resolving mechanisms, such as a failure to balance the pro and anti-inflammatory cytokines ratio, deficient macrophage phenotypic switch into a pro-restorative profile, and defective repair and remodeling processes were observed when neutrophils were depleted in this scenario. This study described phase-dependent contrasting roles of neutrophils as triggers and pro-resolutive mediators of liver injury and fibrosis associated with diet-induced NASH in mice. These findings have important translational implications at the time of designing NASH therapeutic strategies.

During the last two decades, nonalcoholic fatty liver disease (NAFLD) has emerged as the most common hepatic disease in pediatrics, mainly owing to the rising prevalence of pediatric obesity. Epidemiological studies have shown that the progressive increase in NAFLD prevalence is associated not only with obesity but also with changes in dietary habits experienced by all age groups, characterized by the increased intake of added sugars and certain fatty acids. In this review article, we focus on the effect of oxidized fatty acids deriving from linoleic acid and arachidonic acid on the pathogenesis and progression of NAFLD in youth.

Neurons in sensory cortex exhibit a remarkable capacity to maintain stable firing rates despite large fluctuations in afferent activity levels. However, sudden peripheral deafferentation in adulthood can trigger an excessive, non-homeostatic cortical compensatory response that may underlie perceptual disorders including sensory hypersensitivity, phantom limb pain, and tinnitus. Here, we show that mice with noise-induced damage of the high-frequency cochlear base were behaviorally hypersensitive to spared mid-frequency tones and to direct optogenetic stimulation of auditory thalamocortical neurons. Chronic two-photon calcium imaging from ACtx pyramidal neurons (PyrNs) revealed an initial stage of spatially diffuse hyperactivity, hyper-correlation, and auditory hyperresponsivity that consolidated around deafferented map regions three or more days after acoustic trauma. Deafferented PyrN ensembles also displayed hypersensitive decoding of spared mid-frequency tones that mirrored behavioral hypersensitivity, suggesting that non-homeostatic regulation of cortical sound intensity coding following sensorineural loss may be an underlying source of auditory hypersensitivity. Excess cortical response gain after acoustic trauma was expressed heterogeneously among individual PyrNs, yet 40% of this variability could be accounted for by each cell’s baseline response properties prior to acoustic trauma. PyrNs with initially high spontaneous activity and gradual monotonic intensity growth functions were more likely to exhibit non-homeostatic excess gain after acoustic trauma. This suggests that while cortical gain changes are triggered by reduced bottom-up afferent input, their subsequent stabilization is also shaped by their local circuit milieu, where indicators of reduced inhibition can presage pathological hyperactivity following sensorineural hearing loss.

Abiotic stress conditions, such as salinity, affect plant development and productivity and threaten the sustainability of agricultural production. Salt has been proven to accumulate in soil and water over time as a result of various anthropogenic activities and climatic changes. Species of the genus Salicornia thrive in the most saline environments and have a wide climatic tolerance. They can be found in a variety of subtropical, oceanic, and continental environments. This study aims to establish Salicornia europaea as a novel source of plant-based compounds that can grow in areas unsuitable for other crops. The morphological and compositional changes in the tissues of S. europaea in different consecutive developmental stages have not been investigated so far. Therefore, a comprehensive study of changes during the lifecycle of S. europaea was carried out, following changes in the plant’s composition, including biomass yield, and soluble and insoluble compounds. For this, plants were cultivated in hydroponics for 15 weeks and harvested weekly to analyze biomass production, to determine soluble and insoluble compounds, protein content, and polyphenols. According to the results, glucan, xylan, and lignin increase with plant age, while water extractives decrease. Protein content is higher in young plants, while flavonoid content depends on the phenological stage, decreasing in the early flowering stage and then increasing as plants enter early senescence. Our results can aid in finding the optimal harvesting stage of S. europaea, depending on the component of interest.

In the present study, the levels of serum and airway soluble chemokines, pro-inflammatory/regulatory cytokines, and growth factors were quantified in critically ill COVID-19 patients (total n=286) at distinct time points (D0, D2-6, D7, D8-13 and D>14-36) upon Intensive Care Unit (ICU) admission. Augmented levels of soluble mediators were observed in serum from COVID-19 patients who progress to death. An opposite profile was observed in tracheal aspirate samples, indicating that systemic and airway microenvironment diverge in their inflammatory milieu. While a bimodal distribution was observed in the serum samples, a unimodal peak around D7 was found for most soluble mediators in tracheal aspirate samples. Systems biology tools further demonstrated that COVID-19 display distinct eccentric soluble mediator networks as compared to controls, with opposite profiles in serum and tracheal aspirates. Regardless the systemic-compartmentalized microenvironment, networks from patients progressing to death were linked to a pro-inflammatory/growth factor-rich, highly integrated center. Conversely, patients evolving to discharge exhibited networks of weak central architecture, with lower number of neighborhood connections and clusters of pro-inflammatory and regulatory cytokines. All in all, this investigation with robust sample size landed a comprehensive snapshot of the systemic and local divergencies composed of distinct immune responses driven by SARS-CoV-2 early on severe COVID-19.

Nonalcoholic fatty liver disease (NAFLD) is currently one of most common forms of chronic liver disease globally. NAFLD represents a wide spectrum of liver involvement from nonprogressive isolated steatosis to nonalcoholic steatohepatitis (NASH), characterized by liver necroinflammation and fibrosis and currently one of the top causes of end‐stage liver disease and hepatocellular carcinoma. At present, there is a lack of effective treatments, and a central barrier to the development of therapies is the requirement for an invasive liver biopsy for diagnosis of NASH. Discovery of reliable, noninvasive biomarkers are urgently needed. In this study, we tested whether circulating extracellular vesicles (EVs), cell‐derived small membrane‐surrounded structures with a rich cargo of bioactive molecules, may serve as reliable noninvasive “liquid biopsies” for NASH diagnosis and assessment of disease severity. Total circulating EVs and hepatocyte‐derived EVs were isolated by differential centrifugation and size‐exclusion chromatography from serum samples of healthy individuals, patients with precirrhotic NASH, and patients with cirrhotic NASH. EVs were further characterized by flow cytometry, electron microscopy, western blotting, and dynamic light scattering assays before performing a proteomics analysis. Our findings suggest that levels of total and hepatocyte‐derived EVs correlate with NASH clinical characteristics and disease severity. Additionally, using proteomics data, we developed understandable, powerful, and unique EV‐based proteomic signatures for potential diagnosis of advanced NASH. Conclusion: Our study shows that the quantity and protein constituents of circulating EVs provide strong evidence for EV protein–based liquid biopsies for NAFLD/NASH diagnosis.

Abstract Multidimensional analysis of traits are now common in ecology and evolution and are based on trait spaces in which each dimension summarizes the observed trait combination (a morphospace or an ecospace). Observations of interest will typically occupy a subset of this space, and researchers will calculate one or more measures to quantify how organisms inhabit that space. In macroevolution and ecology, these measures called disparity or dissimilarity metrics are generalized as space occupancy measures. Researchers use these measures to investigate how space occupancy changes through time, in relation to other groups of organisms, or in response to global environmental changes. However, the mathematical and biological meaning of most space occupancy measures is vague with the majority of widely used measures lacking formal description. Here, we propose a broad classification of space occupancy measures into three categories that capture changes in size, density, or position. We study the behavior of 25 measures to changes in trait space size, density, and position on simulated and empirical datasets. We find that no measure describes all of trait space aspects but that some are better at capturing certain aspects. Our results confirm the three broad categories (size, density, and position) and allow us to relate changes in any of these categories to biological phenomena. Because the choice of space occupancy measures is specific to the data and question, we introduced https://tguillerme.shinyapps.io/moms/moms, a tool to both visualize and capture changes in space occupancy for any measurement. https://tguillerme.shinyapps.io/moms/moms is designed to help workers choose the right space occupancy measures, given the properties of their trait space and their biological question. By providing guidelines and common vocabulary for space occupancy analysis, we hope to help bridging the gap in multidimensional research between ecology and evolution.

Abstract Background Categorization of topographical features into landform type is a long-standing method for understanding physiographic patterns in the environment. Differences in forest composition between landform types are driven primarily by concurrent differences in soil composition and moisture, but also disturbance regime. Many studies have focused on the interaction between fire disturbance, succession, and landforms, but the effects of hurricane disturbance on compositional differences between landforms are poorly understood. In the study presented here, we assess compositional and structural differences between landform types in the tree community of a young sub-tropical forest that is frequently subjected to hurricanes. Specifically, we ask whether the tree community (1) changed structurally over the study period, (2) experienced compositional change over the study period, (3) is compositionally different between landform types, and (4) exhibits compositional change mediated by landform type. Results The tree community experienced significant structural change over the course of our study, but compositional change was only significant for some landforms. Conclusion Despite large-scale, intense, and frequent hurricane disturbance to our study system, compositional change in the tree community was localized and only significant for some landform types.

This review covers some important new aspects of the alcohol-induced communications between liver parenchymal and non-parenchymal cells leading to liver injury development. The information exchange between various cell types may promote end-stage liver disease progression and involves multiple mechanisms, such as direct cell-to-cell interactions, extracellular vesicles (EVs) or chemokines, cytokines, and growth factors contained in extracellular fluids/cell culture supernatants. Here, we highlighted the role of EVs derived from alcohol-exposed hepatocytes (HCs) in activation of non-parenchymal cells, liver macrophages (LM), and hepatic stellate cells (HSC). The review also concentrates on EV-mediated crosstalk between liver parenchymal and non-parenchymal cells in the settings of HIV- and alcohol co-exposure. In addition, we overviewed the literature on the crosstalk between cell death pathways and inflammasome activation in alcohol-activated HCs and macrophages. Furthermore, we covered highly clinically relevant studies on the role of non-inflammatory factors, sinusoidal pressure (SP), and hepatic arterialization in alcohol-induced hepatic fibrogenesis. We strongly believe that the review will disclose major mechanisms of cell-to-cell communications pertained to alcohol-induced liver injury progression and will identify therapeutically important targets, which can be used for alcohol-associated liver disease (ALD) prevention.

Nonalcoholic fatty liver disease (NAFLD) is common in children and may progress to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and even cirrhosis in childhood or early adulthood, indicating the need for pharmacologic treatment in this age group. Multiple trials are evaluating different therapeutic targets for NASH with fibrosis in adults, and the U.S. Food and Drug Administration has recently provided clear guidance to the pharmaceutical industry on developing drugs for the treatment of noncirrhotic NASH with liver fibrosis. Pediatric NAFLD has several unique aspects that distinguish it from the adult disease in terms of histology, our understanding of the natural history, and the utility of noninvasive tests. These differences have the potential to impact the design of clinical trials to test different drugs in the pediatric population. The aim of this article is to provide a review of common misconceptions regarding pediatric NAFLD and key differences from adult NAFLD. We have provided our recommendations on the design of early proof‐of‐concept and late phase 2 trials based on lessons learned from previous clinical trials. We believe that clinical drug development for children with NAFLD should happen in parallel with ongoing adult trials.

Health education is an important topic in high school given its lasting effect on learners. Medical students are in a unique position to deliver this curriculum as they can provide information from a relatable standpoint. Ten medical students created a health education program, The Healthier Nevada Project (HNVP), designed for high school students using four modules focused on adolescent public health concerns: substance use and addiction, exercise, personal relationships, and stress and mental health. The curriculum was administered to over 700 health class students at three schools in Reno, Nevada, U.S.A., from August 2019–March 2020. This cross-sectional study measured whether the modules increased students’ comfort level, familiarity, and likelihood of discussing each topic with a healthcare provider. The method of evaluation was pre- and post-Likert scale surveys with 7–10 questions regarding students’ understanding of each topic, knowledge of related resources, and likelihood of future discussions with healthcare providers. Linear regression analysis showed significant increases in mean scores (in all cases p

Summary: Gene regulatory networks (GRNs), consisting of transcription factors and their target sites, control neurogenesis and cell-fate specification in the developing central nervous system. In this study, we use integrated single-cell RNA and single-cell ATAC sequencing (scATAC-seq) analysis in developing mouse and human retina to identify multiple interconnected, evolutionarily conserved GRNs composed of cell-type-specific transcription factors that both activate genes within their own network and inhibit genes in other networks. These GRNs control temporal patterning in primary progenitors, regulate transition from primary to neurogenic progenitors, and drive specification of each major retinal cell type. We confirm that NFI transcription factors selectively activate expression of genes promoting late-stage temporal identity in primary retinal progenitors and identify other transcription factors that regulate rod photoreceptor specification in postnatal retina. This study inventories cis- and trans-acting factors that control retinal development and can guide cell-based therapies aimed at replacing retinal neurons lost to disease.

A preliminary vaccination trial against the emergent pathogen, SARS-CoV-2, was completed in captive black-footed ferrets (Mustela nigripes; BFF) to assess safety, immunogenicity, and anti-viral efficacy. Vaccination and boosting of 15 BFF with purified SARS-CoV-2 S1 subunit protein produced a nearly 150-fold increase in mean antibody titers compared to pre-vaccination titers. Serum antibody responses were highest in young animals, but in all vaccinees, antibody response declined rapidly. Anti-viral activity from vaccinated and unvaccinated BFF was determined in vitro, as well as in vivo with a passive serum transfer study in mice. Transgenic mice that received BFF serum transfers and were subsequently challenged with SARS-CoV-2 had lung viral loads that negatively correlated (p < 0.05) with the BFF serum titer received. Lastly, an experimental challenge study in a small group of BFF was completed to test susceptibility to SARS-CoV-2. Despite viral replication and shedding in the upper respiratory tract for up to 7 days post-challenge, no clinical disease was observed in either vaccinated or naive animals. The lack of morbidity or mortality observed indicates SARS-CoV-2 is unlikely to affect wild BFF populations, but infected captive animals pose a potential risk, albeit low, for humans and other animals.