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Objectives This study aims to show whether correlation exists between pediatric residency applicants’ quantitative scores on the United States Medical Licensing Exam Step 2 Clinical Knowledge examination and their subsequent performance in residency training based on the Accreditation Council for Graduate Medical Education Milestones, which are competency-based assessments that aim to determine residents’ ability to work unsupervised after postgraduate training. No previous literature has correlated Step 2 Clinical Knowledge scores with pediatric residency performance assessed by Milestones. Methods In this retrospective cohort study, the United States Medical Licensing Exam Step 2 Clinical Knowledge Scores and Milestones data were collected from all 188 residents enrolled in a single categorical pediatric residency program from 2012 - 2017. Pearson correlation coefficients were calculated amongst available test and milestone data points to determine correlation between test scores and clinical performance. Results Using Pearson correlation coefficients, no significant correlation was found between quantitative scores on the Step 2 Clinical Knowledge exam and average Milestones ratings (r = -0.1 for post-graduate year 1 residents and r = 0.25 for post-graduate year 3 residents). Conclusions These results demonstrate that Step 2 scores have no correlation to success in residency training as measured by progression along competency-based Milestones. This information should limit the importance residency programs place on quantitative Step 2 scores in their ranking of residency applicants. Future studies should include multiple residency programs across multiple specialties to help make these findings more generalizable.

Abstract Patients with prostate cancer (PC) generally do not respond favorably to immune checkpoint inhibitors, which may be due to a low abundance of tumor-infiltrating lymphocytes even when mutational load is high. Here, we identified a patient who presented with high-grade primary prostate cancer with two adjacent tumor nodules. While both nodules were mismatch repair-deficient (MMRd), exhibited pathogenic MSH2 and MSH6 alterations, had a high tumor mutational burden (TMB), and demonstrated high microsatellite instability (MSI), they had markedly distinct immune phenotypes. The first displayed a dense infiltrate of lymphocytes (“hot nodule”), while the second displayed significantly fewer infiltrating lymphocytes (“cold nodule”). Whole-exome DNA analysis found that both nodules shared many identical mutations, indicating that they were derived from a single clone. However, the cold nodule appeared to be sub-clonal relative to the hot nodule, suggesting divergent evolution of the cold nodule from the hot nodule. Whole-transcriptome RNA analysis found that the cold nodule demonstrated lower expression of genes related to antigen presentation (HLA) and, paradoxically, classical tumor immune tolerance markers such as PD-L1 (CD274) and CTLA-4. Immune cell deconvolution suggested that the hot nodule was enriched not only in CD8+ and CD4 + T lymphocytes, but also in M1 macrophages, activated NK cells, and γδ T cells compared to the cold nodule. This case highlights that MMRd/TMB-high PC can evolve to minimize an anti-tumor immune response, and nominates downregulation of antigen presentation machinery (HLA loss) as a potential mechanism of adaptive immune evasion in PC.

People for whom English is a second language, such as the deaf population, often have unequal access to health information and low health literacy. In the context of a wider study on risk of tick-borne illness in deaf communities, we explored barriers, opportunities, and nuances to accessible health information and communication among deaf people. Semi-structured qualitative individual and group interviews were conducted with 40 deaf people in upstate New York, to explore factors associated with health literacy and health information accessibility. Interviews were conducted in American Sign Language (ASL) by a deaf researcher fluent in ASL. Data analysis included the translation of ASL signs into English words, systematic coding, and generation of themes. A total of 21 interview events (mean time per interview = 41 minutes) were conducted. Two main themes and multiple sub-themes emerged from the data: 1) Layers of obstacles faced by deaf people confirms (or reinforces) exclusion; and 2) preventive information is unavailable or inaccessible to deaf people. Sub- themes identified in the results were perceptions of the deaf community and deaf culture, complex layers of obstacles faced by deaf individuals, the digital divide, the culture of communication, awareness of tick and tick-borne disease (TBD) diseases, importance of using certified deaf interpreters (CDI), health information dissemination strategies and collaborations with the education system, and physical/virtual community engagement. The data suggested several challenges to health literacy in the deaf population, including healthcare and education inequalities and negative perceptions of deaf people by both deaf and hearing people. Improving health literacy in the deaf population requires more interpreters who themselves are deaf ("certified deaf interpreters"), provision of health information in ASL, and a greater engagement with the deaf population by education and healthcare systems.

Many flies have specially evolved feeding mechanisms to imbibe liquids of specific viscosities. Observations of feeding on atypical liquids are notable because of their rarity.We report the first record of intrusive fluid feeding on vertebrate carrion by Philoliche rondani.

Abstract Agrivoltaic (AV) systems are designed to coproduce photovoltaic (PV) energy on lands simultaneously supporting agriculture (food/forage production). PV infrastructure in agroecosystems alters resources critical for plant growth, and water‐limited agroecosystems such as grasslands are likely to be particularly sensitive to the unique spatial and temporal patterns of incident sunlight and soil water inherent within AV systems. However, the impact of resource alteration on forage production, the primary ecosystem service from managed grasslands, is poorly resolved. Here, we evaluated seasonal patterns of soil moisture (SM) and diurnal variation in incident sunlight (photosynthetic photon flux density [PPFD]) in a single‐axis‐tracking AV system established in a formerly managed semiarid C3 grassland in Colorado. Our goals were to (1) quantify dynamic patterns of PPFD and SM within a 1.2 MW PV array in a perennial grassland, and (2) determine how aboveground net primary production (ANPP) and photosynthetic parameters responded to the resource patterns created by the PV array. We hypothesized that spatial variability in ANPP would be strongly related to SM patterns, typical of most grasslands. We measured significant reductions in ANPP directly beneath PV panels, where SM and PPFD were both low. However, in locations with significantly increased SM from the shedding and redistribution of precipitation by PV panels, ANPP was not increased. Instead, ANPP was greatest in locations where plants were shaded in the afternoon but received high levels of PPFD in the morning hours, when air temperatures and vapor pressure deficits were relatively low. Thus, contrary to expectations, we found relatively weak relationships between SM and ANPP despite significant spatial variability in both. Further, there was little evidence that light‐saturated photosynthesis (Asat) and quantum yield of CO2 assimilation (ϕCO2) differed for plants growing directly beneath (lowest PPFD) versus between (highest PPFD) PV panels. Overall, the AV system established in this semiarid managed grassland did not alter patterns of ANPP in ways predictable from past studies of controls of ANPP in open grasslands. However, our results suggest that the diurnal timing of low versus high periods of PPFD incident on plants is an important determinant of productivity patterns in grasslands.

BackgroundSarcomas are a diverse group of neoplasms that vary greatly in clinical presentation and responsiveness to treatment. Given the differences in the sites of involvement, rarity, and treatment modality, a multidisciplinary approach is required. Previous literature suggests patients with sarcoma suffer from poorer quality of life (QoL) especially physical and functional wellbeing. Adolescent and young adult (AYA) patients are an underrepresented population in cancer research and have differing factors influencing QoL.MethodsRetrospective analysis of Young Adult patients (age 18–39) enrolled in the Sarcoma Tissue Repository at University of Iowa. QoL was assessed using the self-report FACT-G questionnaire at enrollment and 12 months post-diagnosis; overall scores and the 4 wellbeing subscales (Physical, Emotional, Social, Functional) were calculated. Linear mixed effects models were used to measure the association between the rate of change in FACT-G subscale scores and baseline clinical, comorbidity, and treatment characteristics.Results49 patients were identified. 57.1% of patients had a malignancy involving an extremity. Mean FACT-G scores of overall wellbeing improved from baseline to 12 months (76.4 vs. 85.4, p < 0.01). Social and emotional wellbeing did not differ significantly between baseline and 12 months. Physical wellbeing (18.8 vs. 23.9, p < 0.01) and functional wellbeing (16.8 vs. 20.0, p< 0.01) scores improved from baseline to 12 months. No difference was seen for FACT-G overall scores for age, sex, laterality, marital status, performance status, having children, clinical stage, limb surgery, chemotherapy, or tumor size. A difference was demonstrated in physical wellbeing scores for patients with baseline limitation (ECOG 1-3) compared to those with no baseline limitation (ECOG 0) (p = 0.03). A difference was demonstrated in social wellbeing based on anatomical site (p = 0.02).ConclusionYoung adults with sarcoma treated at a tertiary center had improvements in overall reported QoL at 12 months from diagnosis. Overall baseline QoL scores on FACT-G were lower than the general adult population for YA patients with sarcoma but at 12 months became in line with general population norms. The improvements seen merit further investigation to evaluate how these change over the continuum of care. Quality of life changes may be useful outcomes of interest in sarcoma trials.

The Fern Cave System, developed in the western escarpment of the Southern Cumberland Plateau of the Interior Low Plateau karst region in Northeastern Alabama, USA, is a global hotspot of cave-limited biodiversity as well as home to the largest winter hibernaculum for the federally endangered Gray Bat (Myotis grisescens). We combined the existing literature, museum accessions, and database occurrences with new observations from bioinventory efforts conducted in 2018–2022 to generate an updated list of troglobiotic and stygobiotic species for the Fern Cave System. Our list of cave-limited fauna totals twenty-seven species, including nineteen troglobionts and eight stygobionts. Two pseudoscorpions are endemic to the Fern Cave System: Tyrannochthonius torodei and Alabamocreagris mortis. The exceptional diversity at Fern Cave is likely associated with several factors, such as the high dispersal potential of cave fauna associated with expansive karst exposures along the Southern Cumberland Plateau, high surface productivity, organic input from a large bat colony, favorable climate throughout the Pleistocene, and location within a larger regional hotspot of subterranean biodiversity. Nine species are of conservation concern, including the recently discovered Alabama cave shrimp Palaemonias alabamae, because of their small range sizes, few occurrences, and several potential threats.

Introduction: Eculizumab has transformed outcomes for patients with atypical hemolytic uremic syndrome (aHUS). Its efficacy and safety profile was well characterized in the clinical trial program. The long-term safety profile was not previously assessed or compared against nontreated patients in an observational registry setting. Methods: The Global aHUS Registry recruits patients with clinical diagnoses of aHUS. This analysis includes baseline characteristics and targeted safety events from adult and pediatric patients who were “ever treated” versus “never treated” with eculizumab in the first 5 years of the registry, through January 26, 2017. Results: Overall, 1321 patients (adult, n = 842; pediatric, n = 479; ever treated, n = 865; never treated, n = 456) were enrolled. A higher proportion of ever-treated versus never-treated adult and pediatric patients had renal, cardiovascular, pulmonary, central nervous system, gastrointestinal symptoms, and hepatic impairment. No differences in safety event rates between ever-treated and never-treated patients were observed, except serious infections in pediatric patients (5.15 versus 1.12 events/100 patient-years for ever- and never-treated patients, respectively). Deaths were more frequent in adult (4.7% and 9.9% of ever- and never-treated patients) compared with pediatric patients (1.8% of ever-treated patients; no deaths in never-treated patients).Three meningococcal infections were reported in ever-treated patients; 1 infection led to a fatal outcome. Conclusion: In this large observational dataset covering 5 years of registry enrollment, no new safety concerns were identified for adult or pediatric eculizumab-treated patients with aHUS, confirming a positive benefit−risk profile in a real-world setting. Keywords: atypical hemolytic uremic syndrome, complement, thrombotic microangiopathy, safety

The Alabama Cave Shrimp Palaemonias alabamae Smalley, 1961 is a federally endangered cave shrimp endemic to just four cave systems within and near the greater Huntsville metropolitan area in Madison County, Alabama USA. It is one of two described atyid cave shrimp in the Interior Low Plateau karst region. Here we report the discovery of a new population of P. alabamae from the Fern Cave system in western Jackson County, Alabama. We observed four cave shrimp in August 2018 in an isolated pool in the base-level stream passage of the longest cave system in Alabama. Two cave shrimp were observed during a subsequent survey in July 2019: one in the same isolated pool and a second shrimp in a pool in the main stream passage. Morphological and genetic analyses confirm that this population is closely allied with other populations in Madison County. This new population expands the known distribution of the species into a new county and watershed (Lower Paint Rock River). The potential exists to discover additional populations in Paint Rock River valley and other nearby regions.

Abstract Background Hyperdynamic therapy, also called triple-H therapy, is the standard treatment and prophylaxis for aneurysmal-associated vasospasm. In patients who are able to tolerate cardiopulmonary stressors induced by this therapy, it is of benefit as a modality for prevention and treatment of delayed ischemic neurologic deficit. However, it can be a cause of significant cardiopulmonary or neurologic sequelae. In rare cases, it can be associated with posterior reversible encephalopathy syndrome (PRES), secondary to prolonged vasopressor and hypertensive therapies. Case presentation We present the case of a patient with right-sided aneurysmal-associated vasospasm who, after 10 days of triple-H therapy, experienced a seizure and was found to have left-sided PRES. Right-sided vasospasm served as a protective mechanism from triple-H therapy-associated PRES. It presented a treatment conundrum due to contradictory perfusion requirements. Hypertensive therapy was curtailed and in efforts to preserve local cerebral perfusion and vasodilation, local therapy with intrathecal nicardipine was initiated. We present our case, a review of the literature, and management considerations. Conclusions Therapies that have conventionally functioned as second line treatments for aneurysmal subarachnoid hemorrhage (intra-arterial vasodilators and intrathecal vasodilators) may be beneficial as earlier treatments in the setting of vasospasm given the systemic difficulties and complications associated with HHH therapy in patients with PRES.

Objectives To determine the proportion of patients with extremity sarcoma who would be willing to participate in a clinical trial in which they would be randomised to one of four different postoperative sarcoma surveillance regimens. Additionally, we assessed patients’ perspectives on the burden of cancer care, factors that influence comfort with randomisation and the importance of cancer research.Design Prospective, cross-sectional patient survey.Setting Outpatient sarcoma clinics in Canada, the USA and Spain between May 2017 and April 2020. Survey data were entered into a study-specific database.Participants Patients with extremity sarcoma who had completed definitive treatment from seven clinics across Canada, the USA and Spain.Main outcome measures The proportion of patients with extremity sarcoma who would be willing to participate in a randomised controlled trial (RCT) that evaluates varying postoperative cancer surveillance regimens.Results One hundred thirty complete surveys were obtained. Respondents reported a wide range of burdens related to clinical care and surveillance. The majority of patients (85.5%) responded that they would agree to participate in a cancer surveillance RCT if eligible. The most common reason to participate was that they wanted to help future patients. Those that would decline to participate most commonly reported that participating in research would be too much of a burden for them at a time when they are already feeling overwhelmed. However, most patients agreed that cancer research will help doctors better understand and treat cancer.Conclusions These results demonstrate that most participants would be willing to participate in an RCT that evaluates varying postoperative cancer surveillance regimens. Participants’ motivation for trial participation included altruistic reasons to help future patients and deterrents to trial participation included the overwhelming burden of a cancer diagnosis. These results will help inform the development of patient-centred RCT protocols in sarcoma surveillance research.Level of evidence V.

Composite hemangioendothelioma (CHE) is a rare neoplastic disorder of vascular origin and consists of admixture of benign, intermediate and malignant vascular histological components. It is first described in 2000 and ever since composite hemangioendothelioma has been described in various soft tissue locations of the body and internal organs in various case reports. Here we present two rare cases of composite hemangioendothelioma of bone and what we believe are the first reported presentation of primary composite hemangioendothelioma in the bones of the lower extremities. Immunohistochemistry in composite hemagioendothelioma shows markers of endothelial origin and many cases have large vacuolated endothelial cells giving a pseudolipoblastic appearance to cells. Treatment is mainly surgical as it a locally aggressive tumor and metastasize is rare. Both of patients in our presentation are treated with lower extremity amputation and it is sometimes unfortunate given composite hemangioendothelioma is known to happen in younger to middle age group such as our patients. This would require psychological counseling and support through the process. Further adjuvant treatments are undefined given the rarity of the diagnosis.

The COVID-19 pandemic has had innumerable profound impacts, many of which have resulted in irrevocable changes to both the practice of medicine and the teaching of medicine. Medical educators have adapted to the need for social distancing by providing virtual educational opportunities for their learners, often without training or experience in online teaching. Because these educators require both professional development and technical support for their online teaching to be sustainable and effective, departments need to provide immediate help and support. These twelve tips are designed for those in leadership roles who have recognized the need for investment in online education and are interested in strategies to ensure the success of their educational programs.

Objective: Immunoglobulin G4-related disease (IgG4-RD) is an increasingly recognised cause of various systemic fibro-inflammatory conditions. However, laryngeal involvement as a primary feature is extremely rare. We aimed to report on a case series of such patients and examine the global literature relating to laryngeal involvement. Methods: Having previously reported a case of IgG4-RD laryngeal pseudotumour, we describe a case series of further 4 patients with primary laryngeal IgG4-RD managed by our UK quaternary airway service and provide a brief overview of laryngeal IgG4-RD. Results: Including our cases, 14 cases of primary laryngeal IgG4-RD have been reported. Vocal cord involvement is relatively uncommon. Repeat biopsies may be required to achieve histological diagnosis. Remission is achievable by commencement of immunomodulatory treatment, following which laryngeal reconstruction may be necessary. Conclusion: Laryngeal involvement is a rare presentation of IgG4-RD, itself a rare and difficult-to-diagnose condition. A high and prolonged index of suspicion is necessary from both surgical and pathological specialists for correct diagnosis and management.

Abstract Background The prevalence of antimicrobial resistance among gram-negative pathogens in complicated intra-abdominal infections (cIAIs) has increased. In the absence of timely information on the infecting pathogens and their susceptibilities, local or regional epidemiology may guide initial empirical therapy and reduce treatment failure, length of stay and mortality. The objective of this study was to assess the cost-effectiveness of ceftolozane/tazobactam + metronidazole compared with piperacillin/tazobactam in the treatment of hospitalized US patients with cIAI at risk of infection with resistant pathogens. Methods We used a decision-analytic Monte Carlo simulation model to compare the costs and quality-adjusted life years (QALYs) of persons infected with nosocomial gram-negative cIAI treated empirically with either ceftolozane/tazobactam + metronidazole or piperacillin/tazobactam. Pathogen isolates were randomly drawn from the Program to Assess Ceftolozane/Tazobactam Susceptibility (PACTS) database, a surveillance database of non-duplicate bacterial isolates collected from patients with cIAIs in medical centers in the USA from 2011 to 2013. Susceptibility to initial therapy was based on the measured susceptibilities reported in the PACTS database determined using standard broth micro-dilution methods as described by the Clinical and Laboratory Standards Institute (CLSI). Results Our model results, with baseline resistance levels from the PACTS database, indicated that ceftolozane/tazobactam + metronidazole dominated piperacillin/tazobactam, with lower costs ($44,226/patient vs. $44,811/patient respectively) and higher QALYs (12.85/patient vs. 12.70/patient, respectively). Ceftolozane/tazobactam + metronidazole remained the dominant choice in one-way and probabilistic sensitivity analyses. Conclusions Based on surveillance data, ceftolozane/tazobactam is more likely to be an appropriate empiric therapy for cIAI in the US. Results from a decision-analytic simulation model indicate that use of ceftolozane/tazobactam + metronidazole would result in cost savings and improves QALYs, compared with piperacillin/tazobactam.

Abstract Background A challenge in the empiric treatment of complicated urinary tract infection (cUTI) is identifying the initial appropriate antibiotic therapy (IAAT), which is associated with reduced length of stay and mortality compared with initial inappropriate antibiotic therapy (IIAT). We evaluated the cost-effectiveness of ceftolozane/tazobactam compared with piperacillin/tazobactam (one of the standard of care antibiotics), for the treatment of hospitalized patients with cUTI. Methods A decision-analytic Monte Carlo simulation model was developed to compare the costs and effectiveness of empiric treatment with either ceftolozane/tazobactam or piperacillin/tazobactam in hospitalized adult patients with cUTI infected with Gram-negative pathogens in the US. The model applies the baseline prevalence of resistance as reported by national in-vitro surveillance data. Results In a cohort of 1000 patients, treatment with ceftolozane/tazobactam resulted in higher total costs compared with piperacillin/tazobactam ($36,413 /patient vs. $36,028/patient, respectively), greater quality-adjusted life years (QALYs) (9.19/patient vs. 9.13/patient, respectively) and an incremental cost-effectiveness ratio (ICER) of $6128/QALY. Ceftolozane/tazobactam remained cost-effective at a willingness to pay of $100,000 per QALY compared to piperacillin/tazobactam over a range of input parameter values during one-way and probabilistic sensitivity analysis. Conclusions Model results show that ceftolozane/tazobactam is likely to be cost-effective compared with piperacillin/tazobactam for the empiric treatment of hospitalized cUTI patients in the United States.

An intensive coordinated airborne and ground-based measurement study was conducted in the Fayetteville Shale in northwestern Arkansas during September and October 2015 to compare and explain potential discrepancies between top-down and bottom-up estimates of regional natural gas (NG) methane (CH4) emissions. In situ mobile downwind measurements are used to document the ethane to methane enhancement ratios (ERs) in emission plumes from NG operations in the region. Enhancement ratios are low (

Sarcoma is a widely varied and devastating oncological subtype, with overall five-year survival of 65% that drops to 16% with the presence of metastatic disease at diagnosis. Standard of care for localized sarcomas is predicated on local control with wide-local resection and radiation therapy, or, less commonly, chemotherapy, depending on tumor subtype. Verteporfin has the potential to be incorporated into this standard of care due to its unique molecular properties: inhibition of the upregulated Hippo pathway that frequently drives soft tissue sarcoma and photodynamic therapy-mediated necrosis due to oxidative damage. The initial anti-proliferative effect of verteporfin is mediated via binding and dissociation of YAP/TEAD proteins from the nucleus, ultimately leading to decreased cell proliferation as demonstrated in multiple in vitro studies. This effect has the potential to be compounded with use of photodynamic therapy to directly induce cellular necrosis with use of a clinical laser. Photodynamic therapy has been incorporated into multiple malignancies and has the potential to be incorporated into sarcoma treatment.

At the annual Iditarod Race, Alaskan Huskies repeatedly run for up to 8 hours at 16 km/h to complete 1600 km. We previously demonstrated high rates of mitochondrial protein synthesis in Alaskan Huskies, which we suspected allowed rapid remodeling of mitochondrial proteins in response to energetic stress. The purpose of this study was to examine mitochondrial respiration in permeabilized skeletal muscle fibers of Alaskan Huskies in the offseason (Non-raced) and following the 1600 km Iditarod Sled Dog Race (Raced). We hypothesized that compared to Non-raced Huskies, raced Huskies that completed a 1600 km race would have greater mitochondrial respiratory capacities, and improvements in capacities of oxidative phosphorylation (OXPHOS) based on NADH-generating substrates as compared to fatty acids. Using high-resolution respirometry (HRR) we investigated the respiration of permeabilized muscle fibers from Alaskan Huskies. Maximum capacities were 254±26 pmol.s-1.mg-1 for OXPHOS (coupled, P) and 254±37 pmol.s-1.mg-1 for the electron transfer system (ETS; non-coupled, E). After racing respiratory capacities from NADH-linked substrates, but not fat-derived substrates increased. Finally, the OXPHOS to ETS capacity ratio (P/E) increased after racing from 0.90±0.03 to 0.97±0.02. From our previous studies and the current study, we conclude that Alaskan Huskies maintain high mitochondrial protein turnover to facilitate rapid adaptation to environmental extremes and energetic challenges.

Conventional disease surveillance mechanisms that rely on passive reporting may be too slow and insensitive to rapidly detect a large-scale infectious disease outbreak; the reporting time from a patient’s initial symptoms to specific disease diagnosis takes days to weeks. To meet this need, new surveillance methods are being developed. Referred to as nontraditional or syndromic surveillance, these new systems typically rely on prediagnostic data to rapidly detect infectious disease outbreaks, such as those caused by bioterrorism. Using data from a large health maintenance organization, we discuss the development, implementation, and evaluation of a time-series syndromic surveillance detection algorithm for influenzalike illness in Minnesota.