Medicine Milestones Research Articles

KRAS-Driven Tumorigenesis and KRAS-Driven Therapy in Pancreatic Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is associated with significant morbidity and mortality and is projected to be the second leading cause of cancer-related deaths by 2030. Mutations in KRAS are found in the vast majority of PDAC cases and plays an important role in the development of the disease. KRAS drives tumor cell proliferation and survival through activating the MAPK pathway to drive cell cycle progression and to lead to MYC-driven cellular programs. Moreover, activated KRAS promotes a protumorigenic microenvironment through forming a desmoplastic stroma and by impairing antitumor immunity. Secretion of granulocyte-macrophage colony-stimulating factor and recruitment of myeloid-derived suppressor cells and protumorigenic macrophages results in an immunosuppressive environment while secretion of secrete sonic hedgehog and TGFβ drive fibroblastic features characteristic of PDAC. Recent development of several small molecules to directly target KRAS marks an important milestone in precision medicine. Many molecules show promise in preclinical models of PDAC and in early phase clinical trials. In this review, we discuss the underlying cell intrinsic and extrinsic roles of KRAS in PDAC tumorigenesis, the pharmacologic development of KRAS inhibition, and therapeutic strategies to target KRAS in PDAC.

Dr. Subhas Mukhopadhyay (1931-1981): A Pioneer in the Field of Reproductive Medicine.

Dr. Subhas Mukhopadhyay achieved a significant milestone in reproductive medicine by creating India's first test-tube baby, just 67 days after British researchers made a similar breakthrough. Despite this remarkable achievement, Dr. Mukhopadhyay faced substantial discredit, ridicule, and forced silence, which tragically led to his untimely death by suicide. It was only through the persistent efforts of Dr. T. C. Anand Kumar that Dr. Mukhopadhyay's pioneering work was eventually recognized, and he was credited with this groundbreaking accomplishment in India.

Emergency Medicine Milestones Final Ratings Are Often Subpar.

The emergency medicine (EM) milestones are objective behaviors that are categorized into thematic domains called "subcompetencies" (eg, emergency stabilization). The scale for rating milestones is predicated on the assumption that a rating (level) of 1.0 corresponds to an incoming EM-1 resident and a rating of 4.0 is the "target rating" (albeit not an expectation) for a graduating resident. Our aim in this study was to determine the frequency with which graduating residents received the target milestone ratings. This retrospective, cross-sectional study was a secondary analysis of a dataset used in a prior study but was not reported previously. We analyzed milestone subcompetency ratings from April 25-June 24, 2022 for categorical EM residents in their final year of training. Ratings were dichotomized as meeting the expected level at the time of program completion (ratings of ≥3.5) and not meeting the expected level at the time of program completion (ratings of ≤3.0). We calculated the number of residents who did not achieve target ratings for each of the subcompetencies. In Spring 2022, of the 2,637 residents in the spring of their last year of training, 1,613 (61.2%) achieved a rating of ≥3.5 on every subcompetency and 1,024 (38.8%) failed to achieve that rating on at least one subcompetency. There were 250 residents (9.5%) who failed to achieve half of their expected subcompetency ratings and 105 (4.0%) who failed to achieve the expected rating (ie, rating was ≤3.0) on every subcompetency. When using an EM milestone rating threshold of 3.5, only 61.2% of physicians achieved the target ratings for program graduation; 4.0% of physicians failed to achieve target ratings for any milestone subcompetency; and 9.5% of physicians failed to achieve the target ratings for graduating residents in half of the subcompetencies.

Innovative cell transplant advancement A Research breakthrough by Chinese doctors for diabetes management

This study presents a groundbreaking advancement in diabetes treatment achieved by Chinese scientists through an innovative cell transplant technique. Traditional diabetes management, typically involving regular insulin injections and constant monitoring, imposes a significant burden on patients. However, this new therapy promises to revolutionize diabetes care. A team of researchers from Shanghai Changzheng Hospital, the Centre for Excellence in Molecular Cell Science under the Chinese Academy of Sciences, and Renji Hospital successfully cured a 59-year-old patient with type-2 diabetes using cell therapy. The patient, whose blood sugar levels remained uncontrolled despite regular insulin injections, underwent a cell transplant in July 2021. Peripheral blood mononuclear cells from the patient were reprogrammed into "seed cells" that act like pancreatic islet cells and then implanted. Within eleven weeks, the patient no longer required insulin injections, and after a year, he stopped all diabetes-related medications. Follow-up examinations confirmed the restoration of pancreatic islet function, and the patient has been insulin-free for 33 months, highlighting the long-term efficacy of the treatment. This therapy harnesses the body's regenerative capabilities, marking a significant milestone in regenerative medicine. The innovative approach not only cures the patient but also offers the potential for preventing diabetes. With China facing a substantial healthcare burden due to its high diabetes prevalence, this technique could significantly alleviate the burden by reducing dependency on lifelong insulin injections.

Early Emergency Medicine Milestone Assessment for Predicting First-Year Resident Performance.

The Accreditation Council for Graduate Medical Education (ACGME) requires emergency medicine (EM) residency training programs to monitor residents' progress using standardized milestones. The first assessment of PGY 1 resident milestones occurs midway through the first year and could miss initial deficiencies. Early assessment of PGY 1 EM resident milestones has potential to identify at-risk residents prior to standard midyear evaluations. We developed an orientation syllabus for PGY 1 residents followed by a milestone assessment. Assessment scores helped predict future milestone scores and American Board of Emergency Medicine (ABEM) In-Training Examination (ITE) scores for PGY 1 residents. From 2013 to 2020, we developed and implemented Milestone Evaluation Day (MED), a simulation-based day and written exam assessing PGY 1 EM residents during their first month on the 23 ACGME 1.0 milestones. MED stations included a history and physical with verbal presentation, patient simulation, vascular access, wound management, and airway management. MED, Clinical Competency Committee-generated (CCC-generated) milestone, and ABEM ITE scores were averaged and compared utilizing Pearson's correlation coefficient. Of 112 PGY 1 EM residents, 110 (98%) were analyzed over an 8-year period. We observed a moderate positive correlation of MED and CCC-generated milestone scores (r = .34, p < .001). There was a nonstatistically significant weak positive correlation of MED and ABEM ITE scores (r = .13, p = .17). An early assessment of EM milestones in the PGY 1 year can assist in the prediction of CCC-generated milestone scores for PGY 1 residents.

Impact of anesthetics on rat hippocampus and neocortex: A comprehensive proteomic study based on label-free mass spectrometry

Anesthesia is regarded as an important milestone in medicine. However, the negative effect on memory and learning has been observed. In addition, the impact of anesthetics on postoperative cognitive functions is still discussed. In this work, in vivo experiment simulating a general anesthesia and ICU sedation was designed to assess the impact of two intravenous (midazolam, dexmedetomidine) and two inhalational (isoflurane, desflurane) agents on neuronal centers for cognition (neocortex), learning, and memory (hippocampus). More than 3600 proteins were quantified across both neocortex and hippocampus. Proteomic study revealed relatively mild effects of anesthetics, nevertheless, protein dysregulation uncovered possible different effect of isoflurane (and midazolam) compared to desflurane (and dexmedetomidine) to neocortical and hippocampal proteins. Isoflurane induced the upregulation of hippocampal NMDAR and other proteins of postsynaptic density and downregulation of GABA signaling, whereas desflurane and dexmedetomidine rather targeted mitochondrial VDAC isoforms and protein regulating apoptotic activity.

Integrating Hospice and Palliative Medicine Education Within the American Board of Emergency Medicine Model.

Hospice and palliative medicine (HPM) is a board-certified subspecialty within emergency medicine (EM), but prior studies have shown that EM residents do not receive sufficient training in HPM. Experts in HPM-EM created a consensus list of competencies for HPM training in EM residency. We evaluated how the HPM competencies integrate within the American Board of Emergency Medicine Milestones, which include the Model of the Clinical Practice of Emergency Medicine (EM Model) and the knowledge, skills, and abilities (KSA) list. Three emergency physicians independently mapped the HPM-EM competencies onto the 2019 EM Model items and the 2021 KSAs. Discrepancies were resolved by a fourth independent reviewer, and the final mapping was reviewed by all team members. The EM Model included 78% (18/23) of the HPM competencies as a direct match, and we identified recommended areas for incorporating the other five. The KSAs included 43% (10/23). Most HPM competencies included in the KSAs mapped onto at least one level B (minimal necessary for competency) KSA. Three HPM competencies were not clearly included in the EM Model or in the KSAs (treating end-of-life symptoms, caring for the imminently dying, and caring for patients under hospice care). The majority of HPM-EM competencies are included in the current EM Model and KSAs and correspond to knowledge needed to be competent in EM. Programs relying on the EM Milestones to plan their curriculums may miss training in symptom management and care for patients at the end of life or who are on hospice.

(O-D1) Simulation-based Assessment for the Emergency Medicine Milestones

(O-D1) Simulation-based Assessment for the Emergency Medicine Milestones

• Education • Simulation-based assessment for the emergency medicine milestones: a national survey of simulation experts and program directors.

• Education • Simulation-based assessment for the emergency medicine milestones: a national survey of simulation experts and program directors.

Adoption of Internal Medicine Milestone Ratings and Changes in Bias Against Black, Latino, and Asian Internal Medicine Residents.

The 2014 adoption of the Milestone ratings system may have affected evaluation bias against minoritized groups. To assess bias in internal medicine (IM) residency knowledge ratings against Black or Latino residents-who are underrepresented in medicine (URiM)-and Asian residents before versus after Milestone adoption in 2014. Cross-sectional and interrupted time-series comparisons. U.S. IM residencies. 59 835 IM residents completing residencies during 2008 to 2013 and 2015 to 2020. Adoption of the Milestone ratings system. Pre-Milestone (2008 to 2013) and post-Milestone (2015 to 2020) bias was estimated as differences in standardized knowledge ratings between U.S.-born and non-U.S.-born minoritized groups versus non-Latino U.S.-born White (NLW) residents, with adjustment for performance on the American Board of Internal Medicine IM certification examination and other physician characteristics. Interrupted time-series analysis measured deviations from pre-Milestone linear bias trends. During the pre-Milestone period, ratings biases against minoritized groups were large (-0.40 SDs [95% CI, -0.48 to -0.31 SDs; P < 0.001] for URiM residents, -0.24 SDs [CI, -0.30 to -0.18 SDs; P < 0.001] for U.S.-born Asian residents, and -0.36 SDs [CI, -0.45 to -0.27 SDs; P < 0.001] for non-U.S.-born Asian residents). These estimates decreased to less than -0.15 SDs after adoption of Milestone ratings for all groups except U.S.-born Black residents, among whom substantial (though lower) bias persisted (-0.26 SDs [CI, -0.36 to -0.17 SDs; P < 0.001]). Substantial deviations from pre-Milestone linear bias trends coincident with adoption of Milestone ratings were also observed. Unobserved variables correlated with ratings bias and Milestone ratings adoption, changes in identification of race/ethnicity, and generalizability to Milestones 2.0. Knowledge ratings bias against URiM and Asian residents was ameliorated with the adoption of the Milestone ratings system. However, substantial ratings bias against U.S.-born Black residents persisted. None.

OPAL trial: challenging the use of opioid analgesics for acute low back pain and neck pain: a milestone in evidence-based medicine.

OPAL trial: challenging the use of opioid analgesics for acute low back pain and neck pain: a milestone in evidence-based medicine.

Bone Marrow Transplantation: Pre and after care

Worldwide, Hematopoietic stem cell transplantation is one of the curative options of treatment for hematological malignancies and other hematological diseases. In few recent years, in Bangladesh, Hematopoietic stem cell transplantation (HSCT) has started and improved significantly, especially in patients with hematological malignancies &amp; nonmalignant hematological diseases. As one of the leading BMT Center, CMH Dhaka has started BMT 8 years ago with the successful case of Allogeneic Bone Marrow Transplantation (Allo-HSCT) which was first time in Bangladesh. It was a historic event and landmark achievements in the history of Medical Science of Bangladesh as Allo-HSCT Bone Marrow Transplantation comparatively have a higher risk of life-threatening complications than Auto-HSCT. Till date, Dhaka CMH BMT Center has successfully completed 65 Bone Marrow Transplantation (48 Auto- HSCT &amp; 17 Allo-HSCT). It is an amazing milestone and advancement in medicine of Bangladesh. A series of tests (Like-Hematological profile, Extensive infection screening, Heart function test, Lung function test, Bone Marrow Study, Bone density scan, PET-scan, CT-scan, Chest X-ray, HLA Typing etc.) and procedures can assess general health and the status of patient‘s condition. The tests and procedures also ensure that patient is physically prepared for the transplant. The evaluation may take several days or more. In the days and weeks after bone marrow transplant, BMT specialists do blood tests and other tests to monitor patient‘s condition. They may need medicine to manage complications, such as nausea and diarrhea. After bone marrow transplant, the patient remains under close medical care. If a patient experiencing infections or other complications, he/ she may need to stay in the hospital for several days or longer for close monitoring. Patients may need periodic transfusions of red blood cells and platelets until bone marrow begins producing enough of those cells on its own. Patient needs follow up and Transplant Physician supervision till death. Bangladesh J Medicine 2023; Vol. 34, No. 2(1) Supplement: 191

A new era of assessment for neonatal-perinatal medicine trainees: milestones 2.0.

To optimize post-graduate competency-based assessment for medical trainees, the Accreditation Council for Graduate Medical Education initiated a sub-specialty-specific revision of the existing Milestones 1.0 assessment framework in 2016. This effort was intended to increase both the effectiveness and accessibility of the assessment tools by incorporating specialty-specific performance expectations for medical knowledge and patient care competencies; decreasing item length and complexity; minimizing inconsistencies across specialties through the development of common "harmonized" milestones; and providing supplemental materials, including examples of expected behaviors at each developmental level, suggested assessment strategies, and relevant resources. This manuscript describes the efforts of the Neonatal-Perinatal Medicine Milestones 2.0 Working Group, outlines the overall intent of Milestones 2.0, compares the novel Milestones to the original version, and details the materials contained in the novel supplemental guide. This new tool should enhance NPM fellow assessment and professional development while maintaining consistent performance expectations across specialties.

Abstract CT083: Tumor-agnostic efficacy and safety of dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: ROAR basket study

Abstract Beyond melanoma, BRAFV600E alterations are prevalent across multiple tumors. We conducted a basket trial (NCT02034110) to assess efficacy and safety of oral BRAF inhibitor dabrafenib (150 mg BD) plus MEK inhibitor trametinib (2 mg OD) in 206 patients (eight cohorts) with BRAFV600E-mutated advanced rare cancers. Patients with anaplastic carcinoma thyroid, biliary tract cancer, gastrointestinal stromal tumor, adenocarcinoma of small intestine, low-grade (eight histologies)/high-grade (seven histologies) glioma, hairy cell leukemia, and multiple myeloma were treated until unacceptable toxicity, disease progression, or death. Overall, median duration of exposure to dabrafenib and trametinib was 12.5 (1–82) and 12.0 (1–84) months, respectively. Primary endpoint was tumor response; secondary endpoints were duration of response, progression free and overall survival, and safety (investigator-assessed). Overall response rate was 56% (38.1%, 72.1%), 53% (37.7%, 68.8%), 0%, 67% (9.4%, 99.2%), 54% (25.1%, 80.8%), 33% (20.0%, 49.0%), 89% (77.8%, 95.9%), and 50% (18.7%, 81.3%), respectively. Median (95% confidence interval) duration of response was 14.4 (7.4, not reached), 8.9 (5.6, 13.7), not reached, 7.7 (not reached, not reached), not reached (5.5, not reached), 31.2 (7.4, 44.2), not reached, and 11.1 (5.6, not reached) months, respectively. Durable and clinically meaningful responses were observed in solid and hematological malignancies (21 histologies). Safety profile was acceptable; most frequent (≥20% patients) treatment-related adverse events were pyrexia (40.8%), fatigue (25.7%), chills (25.7%), nausea (23.8%), and rash (20.4%). The encouraging tumor-agnostic activity of dabrafenib plus trametinib is a promising approach in patients with BRAFV600E-mutated advanced rare cancers. These results supported the accelerated FDA approval for a tumor-agnostic BRAF+MEK inhibitor combination representing a precision medicine milestone. Median progression free and overall survival in BRAFV600E-mutated advanced rare cancer patients ATC(N=36) BTC(N=43) LGG(N=13) HGG(N=45) ASI (N=3) HCL(N=55) MM(N=10) PFS 6.7 (4.7, 13.8) 9.0 (5.5, 9.4) NE 5.5 (1.8, 13.7) 9.5 NE 6.3 (2.3, 12.9) OS 14.5 (6.8, 23.2) 13.5 (10.4, 17.6) 17.6 (9.5, 32.2) NE 21.8 (3.4, NR) NE 33.9 (2.9, 44.6) Patient in the GIST cohort (n=1) did not attain a complete or partial response. ASI, adenocarcinoma of small intestine; ATC, anaplastic thyroid cancer; BTC, biliary tract cancer; GIST, gastrointestinal stromal tumor; HCL, hairy cell leukemia; HGG, high grade (WHO G3/G4) glioma; LGG, low (WHO G1/G2) grade glioma; MM, multiple myeloma; NE, not evaluable; NR, not reached; OS, overall survival; PFS, progression free survival; WHO, World Health Organization. Citation Format: Vivek Subbiah, Robert J. Kreitman, Zev A. Wainberg, Anas Gazzah, Ulrik Lassen, Alexander Stein, Patrick Y. Wen, Sascha Dietrich, Maja JA Jonge, Jean-Yves Blay, Antoine Italiano, Kan Yonemori, Daniel C. Cho, Filip YFL de Vos, Philippe Moreau, Elena Elez Fernandez, Jan H. Schellens, Christoph C. Zielinski, Suman Redhu, Vanessa Q. Passos, Palanichamy Ilankumaran, Yung-Jue Bang. Tumor-agnostic efficacy and safety of dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: ROAR basket study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT083.

A New Milestone in Traditional Medicine: The Recognition of CCRAS-NIIMH as India’s First WHO Collaborating Center for Fundamental and Literary Research in Traditional Medicine

A New Milestone in Traditional Medicine: The Recognition of CCRAS-NIIMH as India’s First WHO Collaborating Center for Fundamental and Literary Research in Traditional Medicine

What to know about 2.0: Revisions to the pediatric emergency medicine milestones.

The Accreditation Council for Graduate Medical Education (ACGME) adopted educational milestones for trainee assessment in 2013, as a key component of the Next Accreditation System. Two years later, the ACGME, American Board of Pediatrics (ABP), and American Board of Emergency Medicine (ABEM) collaborated to create specialty-specific subcompetencies in pediatric emergency medicine (PEM). Since that time, emerging data have demonstrated the need to revise specialty milestones. Consequently, the ACGME summoned a working group to revise the original PEM milestones. The PEM Milestones 2.0 Working Group convened in April 2021, comprising diverse representation from ACGME staff, PEM and EM attendings, PEM fellowship program directors, PEM fellows, and community members, overseen by the ACGME's vice president for milestones development. The group met virtually six times over 3 months, with concurrent independent and subgroup work, to draft the PEM Milestones 2.0 and supplemental guide. The working group's revisions generated concise descriptions of behavioral anchors to define skill acquisition more accurately; attention to the transition from residency to fellowship training; incorporation of harmonized milestones for non-patient care and non-medical knowledge domains; and increased emphasis on diversity, equity, and inclusion. A supplemental guide was also designed to aid programs in designing programmatic assessment related to specialty-specific milestones. The PEM Milestones 2.0 provide an updated, specialty-specific framework to guide the development and assessment of PEM fellows and training programs. Future work may focus on faculty and learner development, advancing validity evidence, strengthening content expertise, and integrating milestones with specialty-specific entrustable professional activities.

Pain Medicine Milestones 2.0: a step into the future.

To describe the process of revising the Pain Medicine Milestones 1.0 and implementing changes into the Pain Medicine Milestones 2.0 along with implications for pain medicine trainees. Competency-based medical education has been implemented in graduate medical education, including pain medicine. Milestones 1.0, introduced by the Accreditation Council for Graduate Medical Education (ACGME), has been used to assess learners in six competencies and respective sub-competencies. Recognizing areas for improvement in Milestones 1.0, the ACGME initiated the process of Milestones 2.0 and a working group was created to execute this task for pain medicine. The working group discussed revisions; consensus was sought when changes were introduced. Final milestones were agreed upon and made available for public comment prior to publication. Redundant sub-competencies were either merged or eliminated, reducing the number of sub-competencies. A maximum of three rows representing skill, knowledge, behavior and attitude were included for each sub-competency. Harmonized Milestones, aligning with other specialties in a predetermined ACGME framework, were adopted and modified to meet the needs of pain medicine. A supplemental guide was developed to assist educators in implementation of Milestones 2.0 and assessment of trainees. The intent of the Milestones 2.0 was to create an improved tool that is comprehensive, easier to utilize, and of increased value for pain medicine training programs. It is expected that implementation of Milestones 2.0 will streamline pain medicine trainee assessments by educators and prepare trainees for the future practice of pain medicine while serving to be the foundation of an iterative process to match the evolution of the specialty.

Acute Chest Syndrome.

Acute Chest Syndrome.

Gender Differences in Emergency Medicine Attending Physician Comments to Residents: A Qualitative Analysis

Prior studies have revealed gender differences in the milestone and clinical competency committee assessment of emergency medicine (EM) residents. To explore gender disparities and the reasons for such disparities in the narrative comments from EM attending physicians to EM residents. This multicenter qualitative analysis examined 10 488 narrative comments among EM faculty and EM residents between 2015 to 2018 in 5 EM training programs in the US. Data were analyzed from 2019 to 2021. Differences in narrative comments by gender and study site. Qualitative analysis included deidentification and iterative coding of the data set using an axial coding approach, with double coding of 20% of the comments at random to assess intercoder reliability (κ, 0.84). The authors reviewed the unmasked coded data set to identify emerging themes. Summary statistics were calculated for the number of narrative comments and their coded themes by gender and study site. χ2 tests were used to determine differences in the proportion of narrative comments by gender of faculty and resident. In this study of 283 EM residents, of whom 113 (40%) identified as women, and 277 EM attending physicians, of whom 95 (34%) identified as women, there were notable gender differences in the content of the narrative comments from faculty to residents. Men faculty, compared with women faculty, were more likely to provide either nonspecific comments (115 of 182 [63.2%] vs 40 of 95 [42.1%]), or no comments (3387 of 10 496 [32.3%] vs 1169 of 4548 [25.7%]; P < .001) to men and women residents. Compared with men residents, more women residents were told that they were performing below level by men and women faculty (36 of 113 [31.9%] vs 43 of 170 [25.3%]), with the most common theme including lack of confidence with procedural skills. In this qualitative study of narrative comments provided by EM attending physicians to residents, multiple modifiable contributors to gender disparities in assessment were identified, including the presence, content, and specificity of comments. Among women residents, procedural competency was associated with being conflated with procedural confidence. These findings can inform interventions to improve parity in assessment across graduate medical education.

Transplant immunology I: mechanisms of rejection in solid organ transplants

Non-identical transplants (allogeneic) have been a modern medicine milestone; however, the major pitfall for completed succeed is the recognition of foreign organ by the immune system. The myriad variations in sequence of the molecules of the major histocompatibility complex (MHC) or human leukocyte antigen (HLA) between individuals are the major cause of allograft rejection. Thus, the recognition by the B or T lymphocytes of the receptor occurs in the hypervariable regions of the HLA molecules that triggers to the graft 3 types of rejection: hyperacute, acute, and chronic. In addition, the rejection could be cause antibody-mediated (ABMR), T-cell-mediated (TCMR), or both, which depends on the main branch is cause of rejection. This review will explore the mechanisms mentioned above and give an introductory insight into transplant immunology; thus, preparer the reader to delve into further reviews in a Histocompatibility or Immunogenetics laboratory purpose.