Teaching Systems and their Sub-Topics Under Competency-Based Medical Education (CBME) to Undergraduate Medical Students in a Stepwise Approach.

Medical education in India is confronting a charismatic transformation from traditional curriculum to competency-based medical education (CBME). It is more clinically oriented; skill-based and claims to produce competent Indian medical graduates. CBME has divided subjects into competencies and related topics are scattered over different competencies. The intention behind teaching should not be merely students' learning, but contemplation should be towards concept building, imagination, creativity, self-motivated thinking, and the rightful application of knowledge in day-to-day life. Hence a well-formulated, organized, effective, and practically assessable design and an efficient approach are essential not only to link these spread-over pieces of the topic but to teach that topic in a certain flow and rhythm to a medical student also. Therefore, a stepwise approach has been proposed to teach a CBME-driven curriculum to medical students.

An integrative approach for management of post-traumatic dorsal foot wounds - A case report.

Crush injuries to the foot have become increasingly prevalent in contemporary settings, primarily arising from incidents such as the impact of large objects falling onto the foot or involvement in traffic accidents. The complexity of treating these injuries is compounded by the intricate anatomy of the foot. In specific scenarios, the implementation of an integrated management approach could prove advantageous. In this report, we depict the case of a 23-year-old male who visited the Shalya OPD with a wound on his left foot caused by trauma. The wound covered the medial portion of the foot, involving the dorsal area, and measured roughly 20 cm by 9 cm and was unable to walk. We successfully managed the case by adopting an integrative approach. The Ayurvedic treatment included Panchavalkala kashaya for wound irrigation, as well as oral administration of Amalaki rasayana, Triphala guggulu, Shatavari churna and Ashwagandha churna. Jatyadi taila was topically applied. For the first seven days, in addition to these ayurvedic medications, we also employed analgesics and antibiotics to treat infection and pain. To accomplish early closure, we employed a split-thickness skin graft after sufficient granulation tissue had appeared. The wound was completely healed within three months and the patient was able to walk freely without any support. The combined approach yielded a promising result in this case.

An Enzymatic Route to the Synthesis of Tricyclic Fused Hexahydrofuranofuran P2-Ligand for a Series of Highly Potent HIV-1 Protease Inhibitors.

We describe a stereoselective synthesis of an optically active (1R, 3aS, 5R, 6S, 7aR)-octahydro-1,6-epoxy-isobenzo-furan-5-ol derivative. This stereochemically defined heterocycle serves as a high-affinity ligand for a variety of HIV-1 protease inhibitors. The key synthetic steps involve a highly enantioselective enzymatic desymmetrization of meso-1,2(dihydroxymethyl)cyclohex-4-ene and conversion of the resulting optically active alcohol to a methoxy hexahydroisobenzofuran derivative. A substrate controlled stereoselective dihydroxylation afforded syn-1,2-diols. Oxidation of diol provided the substituted 1,2-diketone and L-Selectride reduction provided the corresponding inverted syn-1,2-diols. Acid catalyzed cyclization furnished the ligand alcohol in optically active form.

Genomic Insights into Dementia: Precision Medicine and the Impact of Gene-Environment Interaction.

The diagnosis, treatment, and management of dementia provide significant challenges due to its chronic cognitive impairment. The complexity of this condition is further highlighted by the impact of gene-environment interactions. A recent strategy combines advanced genomics and precision medicine methods to explore the complex genetic foundations of dementia. Utilizing the most recent research in the field of neurogenetics, the importance of precise genetic data in explaining the variation seen in dementia patients can be investigated. Gene-environment interactions are important because they influence genetic susceptibilities and aid in the development and progression of dementia. Modified to each patient's genetic profile, precision medicine has the potential to detect groups at risk and make previously unheard-of predictions about the course of diseases. Precision medicine techniques have the potential to completely transform treatment and diagnosis methods. Targeted medications that target genetic abnormalities will probably appear, providing the possibility for more efficient and customized medical interventions. Investigating the relationship between genes and the environment may lead to preventive measures that would enable people to change their surroundings and minimize the risk of dementia, leading to the improved lifestyle of affected people. This paper provides a comprehensive overview of the genomic insights into dementia, emphasizing the pivotal role of precision medicine, and gene-environment interactions.

Global experience of faricimab in clinical settings - a review.

INTRODUCTION: Faricimab is a bispecific antibody that acts to reduce neoangiogenesis in exudative retinal vascular disorders. It is approved for use in neovascular age-related macular degeneration and diabetic macular edema. We review the published efficacy and safety of faricimab in clinical settings. AREAS COVERED: A comprehensive literature review was conducted. Based on the 14 published real-world studies, 1127 patients (1204 eyes) were treated with faricimab. The majority of studies (14) included pre-treated patients. Most studies (13) showed central macular thickness improvement. However visual acuity improved in only half of the studies analyzed. Four studies demonstrated an extension of the treatment. Only 4 eyes (0.33%) reported intraocular inflammation and 3 eyes (0.24%) reported retinal pigment epithelial tear. EXPERT OPINION: The clinical experience with faricimab to date has the potential to provide a stable visual outcome with reduced treatment burden in cases that are resistant to other approved anti-VEGF agents. There are no major safety concerns based on this data analysis.

Resolvin D2/GPR18 signaling enhances monocytic myeloid-derived suppressor cell function to mitigate abdominal aortic aneurysm formation.

Abdominal aortic aneurysm (AAA) formation is a chronic vascular pathology characterized by inflammation, leukocyte infiltration and vascular remodeling. The aim of this study was to delineate the protective role of Resolvin D2 (RvD2), a bioactive isoform of specialized proresolving lipid mediators, via G-protein coupled receptor 18 (GPR18) receptor signaling in attenuating AAAs. Importantly, RvD2 and GPR18 levels were significantly decreased in aortic tissue of AAA patients compared with controls. Furthermore, using an established murine model of AAA in C57BL/6 (WT) mice, we observed that treatment with RvD2 significantly attenuated aortic diameter, pro-inflammatory cytokine production, immune cell infiltration (neutrophils and macrophages), elastic fiber disruption and increased smooth muscle cell α-actin expression as well as increased TGF-ß2 and IL-10 expressions compared to untreated mice. Moreover, the RvD2-mediated protection from vascular remodeling and AAA formation was blocked when mice were previously treated with siRNA for GPR18 signifying the importance of RvD2/GPR18 signaling in vascular inflammation. Mechanistically, RvD2-mediated protection significantly enhanced infiltration and activation of monocytic myeloid-derived suppressor cells (M-MDSCs) by increasing TGF-ß2 and IL-10 secretions that mitigated smooth muscle cell activation in a GPR18-dependent manner to attenuate aortic inflammation and vascular remodeling via this intercellular crosstalk. Collectively, this study demonstrates RvD2 treatment induces an expansion of myeloid-lineage committed progenitors, such as M-MDSCs, and activates GPR18-dependent signaling to enhance TGF-ß2 and IL-10 secretion that contributes to resolution of aortic inflammation and remodeling during AAA formation.

MerTK-dependent efferocytosis by monocytic-MDSCs mediates resolution of post-lung transplant injury.

Rationale: Patients with end stage lung diseases require lung transplantation (LTx) that can be impeded by ischemia-reperfusion injury (IRI) leading to subsequent chronic lung allograft dysfunction (CLAD) and inadequate outcomes. Objectives: We examined the undefined role of MerTK (receptor Mer tyrosine kinase) on monocytic myeloid-derived suppressor cells (M-MDSCs) in efferocytosis (phagocytosis of apoptotic cells) to facilitate resolution of lung IRI. Methods: Single-cell RNA sequencing of lung tissue and BAL from post-LTx patients was analyzed. Murine lung hilar ligation and allogeneic orthotopic LTx models of IRI were used with Balb/c (WT), cebpb -/- (MDSC-deficient), Mertk -/- or MerTK-CR (cleavage resistant) mice. Lung function, IRI (inflammatory cytokine and myeloperoxidase expression, immunohistology for neutrophil infiltration), and flow cytometry of lung tissue for efferocytosis of apoptotic neutrophils were assessed in mice. Measurements and Main Results: A significant downregulation in MerTK-related efferocytosis genes in M-MDSC populations of CLAD patients compared to healthy subjects was observed. In the murine IRI model, significant increase in M-MDSCs, MerTK expression and efferocytosis was observed in WT mice during resolution phase that was absent in cebpb -/- Land Mertk -/- mice. Adoptive transfer of M-MDSCs in cebpb -/- mice significantly attenuated lung dysfunction, and inflammation leading to resolution of IRI. Additionally, in a preclinical murine orthotopic LTx model, increases in M-MDSCs were associated with resolution of lung IRI in the transplant recipients. In vitro studies demonstrated the ability of M-MDSCs to efferocytose apoptotic neutrophils in a MerTK-dependent manner. Conclusions: Our results suggest that MerTK-dependent efferocytosis by M-MDSCs can significantly contribute to the resolution of post-LTx IRI.

Simultaneous Liver and Kidney Transplantation in a Patient With Telomere Biology Disorder: A Case Study.

Organ transplantation is the primary therapy for organ failure caused by telomere biology disorder (TBD). We describe the first documented case of simultaneous liver and kidney transplantation (SLKTx) for TBD, although the diagnosis of TBD was reached only three months following SLKTx. The patient was born prematurely, displayed growth retardation, and developed chronic kidney and liver diseases. His pre-SLKTx autoimmune, metabolic, and viral assessments were negative, and persistent pancytopenia (bone marrow cellularity 70-80%) was attributed to renal disease-associated bone marrow changes. Following SLKTx, he was discharged with stable graft function on tacrolimus and prednisolone. Although mycophenolate mofetil was discontinued on the second postoperative day, his pancytopenia persisted. Despite extensive evaluations, including drug, immune, nutritional, and viral assessments, all results were negative. A bone marrow biopsy conducted three months post-transplant revealed significant hypocellularity (40-50%). Whole genome sequencing revealed a likely pathogenic variant of the TINF2 gene. The patient was subsequently treated with danazol. At the nine-month follow-up post-SLKTx, he exhibited stable graft function and improved cell counts while maintaining triple-drug immunosuppression. Given the lack of uniform diagnostic criteria for TBD, healthcare providers must be vigilant with patients presenting with multi-organ failure and persistent cytopenias. Effective pre-transplant screening for TBD can lead to timely diagnoses, better management, and improved post-transplant outcomes.

Hydrogenation driven ultra-low lattice thermal conductivity inß12borophene.

Borophene gathered large interest owing to its polymorphism and intriguing properties such as Dirac point, inherent metallicity, etc but oxidation limits its capabilities. Hydrogenated borophene was recently synthesised experimentally to harness its applications. Motivated by experimental work, in this paper, using first-principles calculations and Boltzmann transport theory, we study the freestandingß12borophene nanosheet doped and functionalised with hydrogen (H), lithium (Li), beryllium (Be), and carbon (C) atoms at differentß12lattice sites. Among all possible configurations, we screen two stable candidates, pristine and hydrogenatedß12borophene nanosheets. Both nanosheets possess dynamic and mechanical stability while the hydrogenated sheet has different anisotropic metallicity compared to pristine sheet leading to enhancement in brittle behaviour. Electronic structure calculations reveal that both nanosheets host Dirac cones (DCs), while hydrogenation leads to shift and enhancement in tilt of the DCs. Further hydrogenation leads to the appearance of additional Fermi pockets in the Fermi surface. Transport calculations reveals that the lattice thermal conductivity changes from 12.51 to 0.22 W m-1 K-1(along armchair direction) and from 4.42 to 0.07 W m-1 K-1(along zigzag direction) upon hydrogenation at room temperature (300 K), demonstrating a large reduction by two orders of magnitude. Such reduction is mainly attributed to decreased phonon mean free path and relaxation time along with the enhanced phonon scattering rates stemming from high frequency phonon flat modes in hydrogenated nanosheet. Comparatively larger weighted phase space leads to increased anharmonic scattering in hydrogenated nanosheet contributing to ultra-low lattice thermal conductivity. Consequently, hydrogenatedß12nanosheet exhibits a comparatively higher thermoelectric figure of merit (∼0.75) at room temperature along armchair direction. Our study demonstrates the effects of functionalisation on transport properties of freestandingß12borophene nanosheets which can be utilised to enhance the thermoelectric performance in two-dimensional (2D) systems and expand the applications of boron-based 2D materials.

Spectrum of Pneumonia in Renal Transplant Recipients: An Indian Experience.

OBJECTIVES: Respiratory tract infections are life-threatening infections in solid-organ transplant recipients that pose risk to the graft and to the patient. This study was undertaken to examine the clinical and microbiological spectrum of pneumonia in renal transplant recipients. MATERIALS AND METHODS: Of 400 consecutive renal transplant recipients, 87 recipients (21.8%) were hospitalized between November 2014 and October 2016 with pneumonia. We examined demographic profiles and clinical investigations. RESULTS: The median age of patients was 38 years (range, 19-72 y). The mean time of presentation after renal transplant was 18 months (range, 1-174 mo). Most patients (80.5%) were on maintenance immunosuppression with tacrolimus, mycophenolate mofetil, and steroids; 34% of patients had an induction agent. Chronic hepatitis C and hepatitis B infections were found in 12.6% and 2.2% of patients, respectively, and new-onset diabetes in 19.5% of patients. Fever (88%), cough (87%), shortness of breath (68%), and hypotension (33%) were common presenting symptoms. Diarrhea was the most frequent accompanying symptom, found in 9.2% of patients. Cytopenia and graft dysfunction were present in 38.7% and 80.4% of patients. Among infections, fungal infections were the most frequent (30%) followed by mixed infections (20.7%), tuberculosis (12.6%), bacterial (12.6%), and viral (3.5%) infections. Etiology could not be found in 27.6% patients. Mortality rate was 24.1%, with the highest rates for fungal infections (44%), followed by bacterial (25%) and mixed infections (18%). Presence of hypoxia and hypotension at presentation was associated with increased risk of death, whereas use of induction agents, new-onset diabetes posttransplant, diabetes mellitus, and acute kidney injury were not correlated with death or increased duration of hospital stay. CONCLUSIONS: Pneumonia carries high risk of mortality in renal transplant recipients. Fungal and bacterial infections carry high risk of mortality. Despite invasive investigations, a substantial number of patients had unidentified etiology.

DDIT4L regulates mitochondrial and innate immune activities in early life.

Pattern recognition receptor responses are profoundly attenuated before the third trimester of gestation in the relatively low-oxygen human fetal environment. However, the mechanisms regulating these responses are uncharacterized. Herein, genome-wide transcription and functional metabolic experiments in primary neonatal monocytes linked the negative mTOR regulator DDIT4L to metabolic stress, cellular bioenergetics, and innate immune activity. Using genetically engineered monocytic U937 cells, we confirmed that DDIT4L overexpression altered mitochondrial dynamics, suppressing their activity, and blunted LPS-induced cytokine responses. We also showed that monocyte mitochondrial function is more restrictive in earlier gestation, resembling the phenotype of DDIT4L-overexpressing U937 cells. Gene expression analyses in neonatal granulocytes and lung macrophages in preterm infants confirmed upregulation of the DDIT4L gene in the early postnatal period and also suggested a potential protective role against inflammation-associated chronic neonatal lung disease. Taken together, these data show that DDIT4L regulates mitochondrial activity and provide what we believe to be the first direct evidence for its potential role supressing innate immune activity in myeloid cells during development.

Gut mycobiome dysbiosis after sepsis and trauma.

BACKGROUND: Sepsis and trauma are known to disrupt gut bacterial microbiome communities, but the impacts and perturbations in the fungal (mycobiome) community after severe infection or injury, particularly in patients experiencing chronic critical illness (CCI), remain unstudied. METHODS: We assess persistence of the gut mycobiome perturbation (dysbiosis) in patients experiencing CCI following sepsis or trauma for up to two-to-three weeks after intensive care unit hospitalization. RESULTS: We show that the dysbiotic mycobiome arrays shift toward a pathobiome state, which is more susceptible to infection, in CCI patients compared to age-matched healthy subjects. The fungal community in CCI patients is largely dominated by Candida spp; while, the commensal fungal species are depleted. Additionally, these myco-pathobiome arrays correlate with alterations in micro-ecological niche involving specific gut bacteria and gut-blood metabolites. CONCLUSIONS: The findings reveal the persistence of mycobiome dysbiosis in both sepsis and trauma settings, even up to two weeks post-sepsis and trauma, highlighting the need to assess and address the increased risk of fungal infections in CCI patients.

A hybrid LBP-CNN with YOLO-v5-based fire and smoke detection model in various environmental conditions for environmental sustainability in smart city.

Smart, secure, and environmentally friendly smart cities are all the rage in urban planning. Several technologies, including the Internet of Things (IoT) and edge computing, are used to develop smart cities. Early and accurate fire detection in a Smart city is always desirable and motivates the research community to create a more efficient model. Deep learning models are widely used for fire detection in existing research, but they encounter several issues in typical climate environments, such as foggy and normal. The proposed model lends itself to IoT applications for authentic fire surveillance because of its minimal configuration load. A hybrid Local Binary Pattern Convolutional Neural Network (LBP-CNN) and YOLO-V5 model-based fire detection model for smart cities in the foggy scenario is presented in this research. Additionally, we recommend a two-part technique for extracting features to be applied to YOLO throughout this article. Using a transfer learning technique, the first portion of the proposed approach for extracting features retrieves standard features. The section part is for retrieval of additional valuable information related to the current activity using the LBP (Local Binary Pattern) protective layer and classifications layers. This research utilizes an online Kaggle fire and smoke dataset with 13950 normal and foggy images. The proposed hybrid model is premised on a two-cascaded YOLO model. In the initial cascade, smoke and fire are detected in the normal surrounding region, and the second cascade fire is detected with density in a foggy environment. In experimental analysis, the proposed model achieved a fire and smoke detection precision rate of 96.25% for a normal setting, 93.2% for a foggy environment, and a combined detection average precision rate of 94.59%. The proposed hybrid system outperformed existing models in terms of better precision and density detection for fire and smoke.

miR397b-LAC2 module regulates cadmium stress response by coordinating root lignification and copper homeostasis in Arabidopsis thaliana.

Non-essential heavy metal cadmium (Cd) is toxic to plants and animals. Cadmium affects plant photosynthesis, respiration, and causes water imbalance and may lead to plant death. Cadmium induces toxicity by interfering with the essential metal copper (Cu) homeostasis, which affects plant nutrition. Though root lignin biosynthesis is positively regulated by Cd stress, the underlying mechanisms promoting lignin accumulation and controlling Cd-induced Cu limitation responses are unclear. Here, we elucidated the role of Cu-responsive microRNA (miR397b) in Arabidopsis thaliana plants for Cd stress by targeting the LACCASE2 (LAC2) gene. This study demonstrated the fundamental mechanism of miR397b-mediated Cd stress response by enhancing the lignin content in root tissues. We developed miR397b over-expressing plants, which showed considerable Cd stress tolerance. Plants with knockdown function of LAC2 also showed significant tolerance to Cd stress. miR397b overexpressing and lac2 mutant plants showed root reduction, higher biomass and chlorophyll content, and significantly lower Reactive Oxygen Species (ROS). This study demonstrated the miR397b-mediated Cd stress response in Arabidopsis by enhancing the lignin content in root tissues. We conclude that modulation in miR397b can be potentially used for improving plants for Cd tolerance and Cu homeostasis.

Human Dose and Pharmacokinetic Predictions for Biologics at Boehringer Ingelheim: A Retrospective Analysis.

INTRODUCTION: Accurate predictions of pharmacokinetics and efficacious doses for biologics in humans are critical for selecting appropriate first-in-human starting doses and dose ranges and for estimating clinical material needs and cost of goods. This also impacts clinical feasibility, particularly for subcutaneously administered biologics. METHODS: We performed a comprehensive comparison between predicted and observed clearances and doses in humans for a set of 22 biologic drugs developed at Boehringer Ingelheim (BI) over the last 2 decades. The analysis included biologics across three therapeutic areas comprising a wide variety of modalities: mono- and bispecific monoclonal antibodies (mAbs) and nanobodies and a Fab fragment. RESULTS: Our analysis showed that observed clearances in humans were within twofold of predicted clearances for 17 out of 20 biologics (85%). Six biologics had uncharacteristically high observed human clearances (range 32-280 mL/h) for their respective molecular classes, impacting their clinical developability. For three molecules, molecular characteristics contributed to the high clearance. Clinically selected doses were within twofold of predicted for 58% of projects. With 42% and 25% of projects selecting clinical doses higher than two- or threefold the predicted value, respectively, the importance of better understanding not only the pharmacokinetic (PK) but also the predictivity of pharmacodynamic models is highlighted. CONCLUSIONS: We provide a clinical pharmacology perspective on the commonly accepted twofold range of human clearance predictions as well as the implications of higher than predicted targeted efficacious plasma concentration on clinical development. Finally, an analysis of key success factors for biologics at BI was conducted, which may be relevant for the entire pharmaceutical industry. This is one of the largest retrospective analyses for biologics and provides further evidence that successful predictions of human PK and efficacious dose will be further facilitated by gathering key translational data early in research.