The US Residency Selection Process After the United States Medical Licensing Examination Step 1 Pass/Fail Change: Overview for Applicants and Educators

The United States Medical Licensing Examination (USMLE) Step 1, arguably the most significant assessment in the USMLE examination series, changed from a 3-digit score to a pass/fail outcome in January 2022. Given the rapidly evolving body of literature on this subject, this paper aims to provide a comprehensive review of the historical context and impact of this change on various stakeholders involved in residency selection. For this, relevant keyword-based searches were performed in PubMed, Google Scholar, and Scopus to identify relevant literature. Given the unique history of USMLE Step 1 in the US residency selection process and the score’s correlation with future performance in board-certifying examinations in different specialties, this scoring change is predicted to significantly impact US Doctor of Medicine students, US Doctor of Osteopathic Medicine students, international medical graduates, and residency program directors, among others. The significance and the rationale of the pass/fail change along with the implications for both residency applicants and educators are also summarized in this paper. Although medical programs, academic institutions, and residency organizing bodies across the United States have swiftly stepped up to ensure a seamless transition and have attempted to ensure equity for all, the conversion process carries considerable uncertainty for residency applicants. For educators, the increasing number of applications conflicts with holistic application screening, leading to the expected greater use of objective measures, with USMLE Step 2 Clinical Knowledge likely becoming the preferred screening tool in lieu of Step 1

Effect of selected postemergence herbicides on growth, nodulation, and nitrogen fixation of soybeans (Glycine max)

Call number: LD2668 .T4 1983 C43Master of Scienc

MGMT Methylation and Differential Survival Impact by Sex in Glioblastoma

Introduction: Sex differences in glioblastoma (GBM) have been observed in incidence, genetic and epigenetic alterations, and immune response. These differences have extended to the methylation of the MGMT promoter, which critically impacts temozolomide resistance. However, the association between sex, MGMT methylation, and survival is poorly understood, which this study sought to evaluate. Methods: A retrospective cohort study was conducted and reported following STROBE guidelines, based on adults with newly diagnosed GBM who received their first surgical intervention at Cleveland Clinic (Ohio, USA) between 2012 and 2018. Kaplan-Meier and multivariable Cox proportional hazards models were used to analyze the association between sex and MGMT promoter methylation status on overall survival (OS). MGMT was defined as methylated if the mean of CpG 1-5 ≥ 12. Propensity score matching was performed on a subset of patients to evaluate the effect of individual CpG site methylation. Results: A total of 464 patients had documented MGMT methylation status with a mean age of 63.4 (range 19-93) years. A total of 170 (36.6%) were female, and 133 (28.7%) received gross total resection as a first intervention. A total of 42.5% were MGMT methylated, with females more often having MGMT methylation than males (52.1% vs. 37.4%, p = 0.004). In univariable analysis, OS was significantly longer for MGMT promoter methylated than un-methylated groups for females (2 yr: 36.8% vs. 11.1%; median: 18.7 vs. 9.5 months; p = 0.001) but not for males (2 yr: 24.3% vs. 12.2%; median: 12.4 vs. 11.3 months; p = 0.22, p for MGMT-sex interaction = 0.02). In multivariable analysis, MGMT un-methylated versus methylated promoter females (2.07; 95% CI, 1.45-2.95; p \u3c 0.0001) and males (1.51; 95% CI, 1.14-2.00; p = 0.004) had worse OS. Within the MGMT promoter methylated group, males had significantly worse OS than females (1.42; 95% CI: 1.01-1.99; p = 0.04). Amongst patients with data on MGMT CpG promoter site methylation values (n = 304), the median (IQR) of CpG mean methylation was 3.0% (2.0, 30.5). Females had greater mean CpG methylation than males (11.0 vs. 3.0, p \u3c 0.002) and higher per-site CpG methylation with a significant difference at CPG 1, 2, and 4 (p \u3c 0.008). After propensity score matching, females maintained a significant survival benefit (18.7 vs. 10.0 months, p = 0.004) compared to males (13.0 vs. 13.6 months, p = 0.76), and the pattern of difference was significant (P for CpG-sex interaction = 0.03). Conclusions: In this study, females had higher mean and individual CpG site methylation and received a greater PFS and OS benefit by MGMT methylation that was not seen in males despite equal degrees of CpG methylation

A multicenter, phase 1, Adult Brain Tumor Consortium trial of oral terameprocol for patients with recurrent high-grade glioma (GATOR)

Recurrent high-grade gliomas (rHGGs) have a dismal prognosis, where the maximum tolerated dose (MTD) of IV terameprocol (5 days/month), a transcriptional inhibitor of specificity protein 1 (Sp1)-regulated proteins, is 1,700 mg/day with median area under the plasma concentration-time curve (AUC) of 31.3 μg∗h/mL. Given potentially increased efficacy with sustained systemic exposure and challenging logistics of daily IV therapy, here we investigate oral terameprocol for rHGGs in a multicenter, phase 1 trial (GATOR). Using a 3 + 3 dose-escalation design, we enroll 20 patients, with median age 60 years (range 31-80), 70% male, and median one relapse (range 1-3). Fasting patients tolerate 1,200 mg/day (n = 3), 2,400 mg/day (n = 6), 3,600 mg/day (n = 3), and 6,000 mg/day (n = 2) oral doses without major toxicities. However, increased dosage does not lead to increased systemic exposure, including in fed state (6,000 mg/day, n = 4), with maximal AUC \u3c5 \u3eμg∗h/mL. These findings warrant trials investigating approaches that provide sustained systemic levels of transcription inhibitors to exploit their therapeutic potential. This study was registered at ClinicalTrials.go

Endoglin inhibitor TRC105 with or without bevacizumab for bevacizumab-refractory glioblastoma (ENDOT): a multicenter phase II trial

Background: Glioblastoma (GBM), the most lethal primary brain tumor, has limited treatment options upon recurrence after chemoradiation and bevacizumab. TRC105 (carotuximab), a chimeric anti-endoglin (CD105) antibody, inhibits angiogenesis and potentiates activity of VEGF inhibitor bevacizumab in preclinical models. This study sought to assess safety, pharmacokinetics, and efficacy of TRC105 for bevacizumab-refractory GBM. Methods: We conducted a pre-registered (NCT01564914), multicenter, open-label phase II clinical trial (ENDOT). We administered 10 mg/kg TRC105 monotherapy (first cohort) in adults with GBM and radiographic progression following radiation, temozolomide and bevacizumab therapy. Primary outcome was median time-to-progression (TTP), amended after first cohort\u27s enrollment to median overall survival (mOS). Secondary outcomes were objective response rate, safety and tolerability, and progression-free survival (PFS). Results: 6 patients were enrolled in TRC105 monotherapy cohort. Median TTP and PFS of 5 evaluable patients receiving monotherapy was 1.4 months, in whom plasma VEGF-A levels were elevated post-therapy. Lack of response led to protocol amendment, and second cohort\u27s addition of bevacizumab+TRC105 with primary endpoint of mOS. 16 patients were enrolled in bevacizumab+TRC105 cohort. mOS of 15 evaluable patients was 5.7 (95%CI: 4.2-9.8) months. All 22 patients had measurable disease at baseline. Median PFS of 14 evaluable patients receiving bevacizumab+TRC105 was 1.8 months (95%CI 1.2-2.1). Serum TRC105 was measurable above target concentration of 25 ug/mL in all evaluable patients. Study medications were well-tolerated in both cohorts. Combined administration did not potentiate known toxicities of either medication, with cerebral hemorrhage not observed. Conclusions: Single-agent TRC105 lacks activity in bevacizumab-refractory GBM, possibly secondary to upregulated VEGF-A expression. Meaningful mOS in bevacizumab+TRC105 cohort warrants further trials to investigate efficacy of combination therapy

Novel Therapeutic Approaches in Neoplastic Meningitis

Simple Summary Neoplastic meningitis (NM) is a frequent complication of cancer and is associated with a poor prognosis. The currently available therapies aim to alleviate symptoms and preserve the quality of life. It comprises a multimodal approach, including surgery, intrathecal and systemic chemotherapy, and radiotherapy. The specific treatment is individualized, based on clinical practice guidelines and expert opinion. There are multiple clinical trials undertaken to evaluate the efficacy of novel therapies, including targeted and immunotherapies. This article presents an updated review of treatment approaches in NM. Abstract Central nervous system (CNS) metastasis from systemic cancers can involve the brain parenchyma, leptomeninges, or the dura. Neoplastic meningitis (NM), also known by different terms, including leptomeningeal carcinomatosis and carcinomatous meningitis, occurs due to solid tumors and hematologic malignancies and is associated with a poor prognosis. The current management paradigm entails a multimodal approach focused on palliation with surgery, radiation, and chemotherapy, which may be administered systemically or directly into the cerebrospinal fluid (CSF). This review focuses on novel therapeutic approaches, including targeted and immunotherapeutic agents under investigation, that have shown promise in NM arising from solid tumors

Anxiety, Uncertainty, and Resilience of Medical Students Worldwide during the COVID-19 Pandemic

The COVID-19 pandemic significantly impacted medical education worldwide. While healthcare professionals labored to ensure proper care for COVID-19 patients, medical students suffered from high rates of anxiety, uncertainty, burnout, and depressive symptoms. Whilst students in the pre-clinical phase of education faced disruption of didactic lectures and laboratory training, senior medical students faced uncertainty regarding their clinical rotations and internships, which are vital for practical exposure to healthcare. Several studies across the world demonstrated that clinical learning was significantly affected, with students in many countries completely cut off from in-person rotations. The disruption of the clinical curriculum coupled with a sense of failure to contribute at a time of significant need often led to despair. Reforms proposed and/or implemented by governments, medical advisory boards, medical schools, and other administrative bodies were felt to be insufficient by the medical student fraternity at large. Consequently, these students continue to face high rates of anxiety, depression, and a general sense of cynicism. In this student-authored perspective, we highlight the challenges faced by and the psychological impact on medical students directly or indirectly from the pandemic

Combination of EGFR-Directed Tyrosine Kinase Inhibitors (EGFR-TKI) with Radiotherapy in Brain Metastases from Non-Small Cell Lung Cancer: A 2010-2019 Retrospective Cohort Study

Introduction: Traditionally, brain metastases have been treated with stereotactic radiosurgery (SRS), whole-brain radiation (WBRT), and/or surgical resection. Non-small cell lung cancers (NSCLC), over half of which carry EGFR mutations, are the leading cause of brain metastases. EGFR-directed tyrosine kinase inhibitors (TKI) have shown promise in NSCLC; but their utility in NSCLC brain metastases (NSCLCBM) remains unclear. This work sought to investigate whether combining EGFR-TKI with WBRT and/or SRS improves overall survival (OS) in NSCLCBM. Methods: A retrospective review of NSCLCBM patients diagnosed during 2010–2019 at a tertiary-care US center was performed and reported following the ‘strengthening the reporting of observational studies in epidemiology’ (STROBE) guidelines. Data regarding socio-demographic and histopathological characteristics, molecular attributes, treatment strategies, and clinical outcomes were collected. Concurrent therapy was defined as the combination of EGFR-TKI and radiotherapy given within 28 days of each other. Results: A total of 239 patients with EGFR mutations were included. Of these, 32 patients had been treated with WBRT only, 51 patients received SRS only, 36 patients received SRS and WBRT only, 18 were given EGFR-TKI and SRS, and 29 were given EGFR-TKI and WBRT. Median OS for the WBRT-only group was 3.23 months, for SRS + WBRT it was 3.17 months, for EGFR-TKI + WBRT 15.50 months, for SRS only 21.73 months, and for EGFR-TKI + SRS 23.63 months. Multivariable analysis demonstrated significantly higher OS in the SRS-only group (HR = 0.38, 95% CI 0.17–0.84, p = 0.017) compared to the WBRT reference group. There were no significant differences in overall survival for the SRS + WBRT combination cohort (HR = 1.30, 95% CI = 0.60, 2.82, p = 0.50), EGFR-TKIs and WBRT combination cohort (HR = 0.93, 95% CI = 0.41, 2.08, p = 0.85), or the EGFR-TKI + SRS cohort (HR = 0.46, 95% CI = 0.20, 1.09, p = 0.07). Conclusions: NSCLCBM patients treated with SRS had a significantly higher OS compared to patients treated with WBRT-only. While sample-size limitations and investigator-associated selection bias may limit the generalizability of these results, phase II/III clinicals trials are warranted to investigate synergistic efficacy of EGFR-TKI and SRS

Overseas Medical Students in Ukraine and War-Related Interruption in Education: Global Health Considerations from India

Background: The Russian invasion of Ukraine in 2022 has caused a humanitarian crisis impacting millions of individuals within Ukraine and globally. While war-related healthcare delivery has been discussed in both the academic biomedical literature and in non-peer-reviewed sources, little academic attention has been paid to overseas medical students who have had to abandon their education. These constitute nearly a third of the 80,000 international students in Ukraine and represent a valuable part of the global healthcare workforce. Objective: This article utilizes the illustrative case of the over 18,000 Indian-origin medical students enrolled in Ukraine to review the state of overseas medical students in Ukraine and war-related interruption in education. Methods: Literature, both academic and non-academic, published up until October 1, 2022, pertaining to the conflict, the impact on students, the demands of various stakeholders, and the proposed solutions, was reviewed through the use of appropriate keyword-based searches. Findings: Factors influencing the decision to pursue education in Ukraine and their pre-crisis pathway to home practice are first discussed. Indian-origin students have historically gone on to Ukraine after securing insufficiently competitive ranks in the national medical school entrance exam, thus preventing them from getting a heavily subsidized education at publicly funded institutions in India. In the 2022 Russo-Ukrainian conflict, these students have faced not only actual and potential challenges related to their safety, shelter, food, and home return, they have been considerably impacted by the uncertainty regarding their educational prospects back home. The article then delineates the nuances and challenges in attempting to reintegrate a large potential healthcare workforce in the home country, and discusses possible solutions, especially those being implemented by the government. Conclusion: Urgent need exists for the involvement of all stakeholders and careful consensus-building before the proposed reintegration from an equity-based perspective

DNA Methylation and Histone Modification in Low-Grade Gliomas: Current Understanding and Potential Clinical Targets

Gliomas, the most common type of malignant primary brain tumor, were conventionally classified through WHO Grades I–IV (now 1–4), with low-grade gliomas being entities belonging to Grades 1 or 2. While the focus of the WHO Classification for Central Nervous System (CNS) tumors had historically been on histopathological attributes, the recently released fifth edition of the classification (WHO CNS5) characterizes brain tumors, including gliomas, using an integration of histological and molecular features, including their epigenetic changes such as histone methylation, DNA methylation, and histone acetylation, which are increasingly being used for the classification of low-grade gliomas. This review describes the current understanding of the role of DNA methylation, demethylation, and histone modification in pathogenesis, clinical behavior, and outcomes of brain tumors, in particular of low-grade gliomas. The review also highlights potential diagnostic and/or therapeutic targets in associated cellular biomolecules, structures, and processes. Targeting of MGMT promoter methylation, TET-hTDG-BER pathway, association of G-CIMP with key gene mutations, PARP inhibition, IDH and 2-HG-associated processes, TERT mutation and ARL9-associated pathways, DNA Methyltransferase (DNMT) inhibition, Histone Deacetylase (HDAC) inhibition, BET inhibition, CpG site DNA methylation signatures, along with others, present exciting avenues for translational research. This review also summarizes the current clinical trial landscape associated with the therapeutic utility of epigenetics in low-grade gliomas. Much of the evidence currently remains restricted to preclinical studies, warranting further investigation to demonstrate true clinical utility