Search

* Context.--In the early months of the response to the coronavirus disease 2019 (COVID-19) pandemic, the Johns Hopkins University School of Medicine (JHUSOM) (Baltimore, Maryland) leadership reached out to faculty to develop and implement virtual clinical clerkships after all in-person medical student clinical experiences were suspended. Objective.--To develop and implement a digital slide-based virtual surgical pathology (VSP) clinical elective to meet the demand for meaningful and robust virtual clinical electives in response to the temporary suspension of in-person clinical rotations at JHUSOM. Design.--The VSP elective was modeled after the in-person surgical pathology elective to include virtual previewing and sign-out with standardized cases supplemented by synchronous and asynchronous pathology educational content. Results.--Validation of existing Web communications technology and slide-scanning systems was performed by feasibility testing. Curriculum development included drafting of course objectives and syllabus, Blackboard course site design, electronic-lecture creation, communications with JHUSOM leadership, scheduling, and slide curation. Subjectively, the weekly schedule averaged 35 to 40 hours of asynchronous, synchronous, and independent content, approximately 10 to 11 hours of which were synchronous. As of February 2021, VSP has hosted 35 JHUSOM and 8 non-JHUSOM students, who have provided positive subjective and objective course feedback. Conclusions.--The Johns Hopkins VSP elective provided meaningful clinical experience to 43 students in a time of immense online education need. Added benefits of implementing VSP included increased medical student exposure to pathology as a medical specialty and demonstration of how digital slides have the potential to improve standardization of the pathology clerkship curriculum. (Arch Pathol Lab Med. 2021;145:814-820; doi: 10.5858/arpa.2020-0652-SA), On March 10, 2020, Johns Hopkins University (Baltimore, Maryland) President Ronald J. Daniels announced the suspension of in-person classes for all students, with Johns Hopkins University and Johns Hopkins Medicine [...]

ABSTRACT Introduction Methods Results Conclusions Adolescents with psychosis‐spectrum symptoms are at particularly high risk for suicide, however, little is known about how suicidal cognitions manifest in this population. Suicidal cognitions can occur as verbal thoughts and/or mental images of suicide, and mental images may be indicative of a higher risk for suicidal behaviours. Suicidal mental imagery could be a salient and important suicide‐related risk factor for adolescents with hallucinations in particular, however, the co‐occurrence of these phenomena has yet to be studied. In a sample of psychiatrically hospitalised adolescents, we hypothesize that hallucinations will be associated with increased suicidal mental imagery and suicide attempts.This chart review study included data from 219 adolescents admitted to a psychiatric inpatient unit. Adolescents completed an assessment battery probing hallucinations, suicidal cognitions, and suicide attempts.Adolescents with past‐month hallucinations had higher rates of past‐week suicidal verbal thoughts and suicidal mental imagery, but not suicide attempts, compared to those without hallucinations. Adolescents with hallucinations reported a younger onset of suicidal mental imagery, and they endorsed more frequent imagery. Past‐month hallucinations were significantly and positively associated with suicidal mental imagery, beyond the effects of internalising symptoms. Suicidal mental imagery was positively associated with past‐week suicide attempts, but past‐month hallucinations were not.Our findings indicate that hallucinations are linked to suicidal mental imagery, an important yet under‐studied risk factor for suicidal behaviour. These data highlight the need for more research exploring suicidal mental imagery among high‐risk adolescents experiencing hallucinations to inform suicide risk assessment and intervention. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigates the fecal and tumor microbiome as potential biomarkers of tumor response to neoadjuvant immunotherapy in combination with chemoradiation. We performed 16S rRNA amplicon sequencing on fecal and tumor samples, as well as fecal metabolomics, on biosamples collected from patients with resectable esophageal or gastroesophageal junction carcinoma before and during treatment. The fecal microbiome of patients whose tumors achieved a pathologic complete response revealed enrichment in sphingolipid and primary bile acids, with corresponding elevated abundance of several bacterial species: Roseburis inulinivorans, Ruminococcus callidus, and Fusicantenibacter saccharivorans. While these results provide initial insight, further study is necessary to validate these data and determine how microbes alter the immune response with neoadjuvant immunotherapy. Background: Preclinical and clinical data indicate that chemoradiotherapy (CRT) in combination with checkpoint inhibitors may prime an anti-tumor immunological response in esophageal cancer. However, responses to neoadjuvant therapy can vary widely and the key biomarkers to determine response remain poorly understood. The fecal microbiome is a novel and potentially modifiable biomarker of immunotherapy response, and both fecal and tumor microbes have been found to associate with outcomes in esophageal cancer. Methods: Fecal and tumor samples were collected from patients with stage II–III resectable esophageal or gastroesophageal junction carcinoma treated with neoadjuvant immune checkpoint inhibitors (ICIs) plus CRT prior to surgical resection. Microbiome profiles were analyzed by 16S rRNA amplicon sequencing and taxonomic data were integrated with fecal metabolite analysis to assess microbial function. Results: The fecal microbiome of patients with pathological complete response (PCR) grouped in distinct clusters compared to patients with residual viable tumor (RVT) by Bray–Curtis diversity metric. Integrated taxonomic and metabolomic analysis of fecal samples identified a sphingolipid and primary bile acid as enriched in the PCR, the levels of which correlated with several bacterial species: Roseburis inulinivorans, Ruminococcus callidus, and Fusicantenibacter saccharivorans. Analysis of the tumor microbiome profiles identified several bacterial genera previously associated with esophageal tumors, including Streptococcus and Veillonella. Conclusions: These results further characterize the fecal and tumor microbiome of patients with operable esophageal cancer and identify specific microbes and metabolites that may help elucidate how microbes contribute to tumor response with neoadjuvant CRT combined with ICI. [ABSTRACT FROM AUTHOR]

Motor learning involves both explicit and implicit processes that are fundamental for acquiring and adapting complex motor skills. However, stroke may damage the neural substrates underlying explicit and/or implicit learning, leading to deficits in overall motor performance. Although both learning processes are typically used in concert in daily life and rehabilitation, no gait studies have determined how these processes function together after stroke when tested during a task that elicits dissociable contributions from both. Here, we compared explicit and implicit locomotor learning in individuals with chronic stroke to age- and sex-matched neurologically intact controls. We assessed implicit learning using split-belt adaptation (where two treadmill belts move at different speeds). We assessed explicit learning (i.e., strategy-use) using visual feedback during split-belt walking to help individuals explicitly correct for step length errors created by the split-belts. After the first 40 strides of split-belt walking, we removed the visual feedback and instructed individuals to walk comfortably, a manipulation intended to minimize contributions from explicit learning. We used a multirate state-space model to characterize individual explicit and implicit process contributions to overall behavioral change. The computational and behavioral analyses revealed that, compared with controls, individuals with chronic stroke demonstrated deficits in both explicit and implicit contributions to locomotor learning, a result that runs counter to prior work testing each process individually during gait. Since poststroke locomotor rehabilitation involves interventions that rely on both explicit and implicit motor learning, future work should determine how locomotor rehabilitation interventions can be structured to optimize overall motor learning. NEW & NOTEWORTHY: Motor learning involves both implicit and explicit processes, the underlying neural substrates of which could be damaged after stroke. Although both learning processes are typically used in concert in daily life and rehabilitation, no gait studies have determined how these processes function together after stroke. Using a locomotor task that elicits dissociable contributions from both processes and computational modeling, we found evidence that chronic stroke causes deficits in both explicit and implicit locomotor learning. [ABSTRACT FROM AUTHOR]

Background: Cannabinoids such as cannabidiol (CBD) exhibit anti-inflammatory properties and have the potential to act as a therapeutic following mild traumatic brain injury. There is limited evidence available on the pharmacological, physiological and psychological effects of escalating CBD dosages in a healthy, male, university athlete population. Furthermore, no dosing regimen for CBD is available with implications of improving physiological function. This study will develop an optimal CBD dose based on the pharmacokinetic data in contact-sport athletes. The physiological and psychological data will be correlated to the pharmacokinetic data to understand the mechanism(s) associated with an escalating CBD dose. Methods/design: Forty participants will receive escalating doses of CBD ranging from 5 mg CBD/kg/day to 30 mg CBD/kg/day. The CBD dose is escalated every two weeks in increments of 5 mg CBD/kg/day. Participants will provide blood for pharmacological assessments at each of the 10 visits. Participants will complete a physiological assessment at each of the visits, including assessments of cerebral hemodynamics, blood pressure, electrocardiogram, seismocardiogram, transcranial magnetic stimulation, and salivary analysis for genomic sequencing. Finally, participants will complete a psychological assessment consisting of sleep, anxiety, and pain-related questionnaires. Discussion: This study will develop of an optimal CBD dose based on pharmacological, physiological, and psychological properties for future use during contact sport seasons to understand if CBD can help to reduce the frequency of mild traumatic injuries and enhance recovery. Trial registration: Clinicaltrials.gov: NCT06204003. [ABSTRACT FROM AUTHOR]

This Article presents previously underappreciated and underrecognized nationwide developments concerning the transformed and broadly impactful role of subject-specific interlocutory appeal statutes and rules and recommends a broad reset on the use of such appeals to serve the efficiency of and equal-access to the appellate system. Over the last fifty--and particularly over the last twenty-five-years, interlocutory appeals have expanded from a rarely-used, discouraged practice allowed for a limited category of irremediable trial court orders to a dynamically growing area allowing numerous, specific, and often politically or legislatively significant bases for swift appeal. The Article examines this previously unexplored, evolved, and often consequential area--involving centrally provocative legal issues ranging from abortion and gun rights to low-income public housing to sexual violence against children. For the United States appellate system grounded on the final judgment rule, which limits appeals to only final rulings, the changed role and scope of interlocutory appeals--or appeals of non-final orders--represents a reframing and notable extension of the role of appeals of non-final orders in our justice system. The effect includes crowded appellate dockets, allocation of appellate resources to certain orders favored for swift appeal--and resultingly forcing other appeals to the back of the appellate line--and an appellate workload whose pace and accelerated content increasingly reflects political priorities instead of serving case-specific needs. This Article adds three previously unexamined and central aspects to understanding interlocutory appeals' evolution and status, by (1) presenting the first nationwide empirical study of state interlocutory appeal statutes and rules, focusing on their substance as well as change over time; (2) identifying three phases of interlocutory appeals: from the late 1800s to today, which ends with the third phase, from 2000 to 2024 involving a significant, activist expansion in the use of particular interlocutory appeal grounds to often further law- and rule-makers' priorities; and (3) recognizing three different purposes of legislatures and courts in enacting interlocutory appeals: (a) to press forward a broad-based reform agenda, such as tort reform; (b) to further a particular legislative or court priority, or (c) to expedite a higher court's consideration of the constitutionality of a legally questionable law. Recognizing the booming expansion, increased politicization, and case volume pressures caused by these swelling interlocutory appeals, this Article then proposes a revamping of state interlocutory appeals systems to avoid these ills. This proposal would allow only traditional limited types of orders to merit interlocutory appeal automatically--only those that would result in irremediable, imminent harm incurable after trial. All other orders would require trial and appellate court approval to appeal before final judgment. This Article thus displays the transformed, central role played by interlocutory appeals in numerous political and legal issues and aims to inspire informed consideration of scaling back their use to serve judicial efficiency and appellate equity. [ABSTRACT FROM AUTHOR]

The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The syndrome is caused by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene or by a 17q21.31 microdeletion encompassing KANSL1. Herein we describe a novel cohort of 45 individuals with KdVS of whom 33 have a 17q21.31 microdeletion and 12 a single-nucleotide variant (SNV) in KANSL1 (19 males, 26 females; age range 7 months to 50 years). We provide guidance about the potential pitfalls in the laboratory testing and emphasise the challenges of KANSL1 variant calling and DNA copy number analysis in the complex 17q21.31 region. Moreover, we present detailed phenotypic information, including neuropsychological features, that contribute to the broad phenotypic spectrum of the syndrome. Comparison of the phenotype of both the microdeletion and SNV patients does not show differences of clinical importance, stressing that haploinsufficiency of KANSL1 is sufficient to cause the full KdVS phenotype.

Testosterone is the canonical growth factor of prostate cancer but can paradoxically suppress its growth when present at supraphysiological levels. We have previously demonstrated that the cyclical administration of supraphysiological androgen (SPA), termed bipolar androgen therapy (BAT), can result in tumor regression and clinical benefit for patients with castrationresistant prostate cancer. However, predictors and mechanisms of response and resistance have been ill defined. Here, we show that growth inhibition of prostate cancer models by SPA required high androgen receptor (AR) activity and were driven in part by downregulation of MYC. Using matched sequential patient biopsies, we show that high pretreatment AR activity predicted downregulation of MYC, improved clinical response, and prolonged progression-free and overall survival for patients on BAT. BAT induced strong downregulation of AR in all patients, which is shown to be a primary mechanism of acquired resistance to SPA. Acquired resistance was overcome by alternating SPA with the AR inhibitor enzalutamide, which induced adaptive upregulation of AR and resensitized prostate cancer to SPA. This work identifies high AR activity as a predictive biomarker of response to BAT and supports a treatment paradigm for prostate cancer involving alternating between AR inhibition and activation., Introduction Signaling through the androgen receptor (AR) is the primary oncogenic driver of prostate adenocarcinoma. Inhibition of AR signaling by androgen deprivation and AR inhibitors produces significant therapeutic and palliative [...]