Effectiveness of Entrustable Professional Activity-Based Clinical Psychiatry Training for Indian Medical Interns: A Preliminary Study.

ObjectiveEntrustable Professional Activities (EPA) are discretely measurable specific professional tasks that integrate multiple competencies to define and provide varying levels of faculty support per trainee needs. Methods: We developed an EPA-based psychiatry curriculum for medical interns. Fifty-four interns completed the OSCE stations, Multiple Choice Questions, and Attitude questionnaires to assess EPAs, knowledge and attitudes towards the relevance and utility of clinical psychiatry in general practice. Results: Two weeks of EPA-based psychiatry training resulted in improvement in median scores on attitude questions (p < 0.05), clinical skills measured using EPA levels. Conclusions: EPA-based curriculum can improve clinical skills, knowledge, and attitudes towards clinical psychiatry in interns.

Full Mass Range ΦSDM Orbitrap Mass Spectrometry for DIA Proteome Analysis.

Optimizing data-independent acquisition methods for proteomics applications often requires balancing spectral resolution and acquisition speed. Here, we describe a real-time full mass range implementation of the phase-constrained spectrum deconvolution method (ΦSDM) for Orbitrap mass spectrometry that increases mass resolving power without increasing scan time. Comparing its performance to the standard enhanced Fourier transformation signal processing revealed that the increased resolving power of ΦSDM is beneficial in areas of high peptide density and comes with a greater ability to resolve low-abundance signals. In a standard 2 h analysis of a 200 ng HeLa digest, this resulted in an increase of 16% in the number of quantified peptides. As the acquisition speed becomes even more important when using fast chromatographic gradients, we further applied ΦSDM methods to a range of shorter gradient lengths (21, 12, and 5 min). While ΦSDM improved identification rates and spectral quality in all tested gradients, it proved particularly advantageous for the 5 min gradient. Here, the number of identified protein groups and peptides increased by >15% in comparison to enhanced Fourier transformation processing. In conclusion, ΦSDM is an alternative signal processing algorithm for processing Orbitrap data that can improve spectral quality and benefit quantitative accuracy in typical proteomics experiments, especially when using short gradients.

Cell-selective proteomics segregates pancreatic cancer subtypes by extracellular proteins in tumors and circulation.

Cell-selective proteomics is a powerful emerging concept to study heterocellular processes in tissues. However, its high potential to identify non-cell-autonomous disease mechanisms and biomarkers has been hindered by low proteome coverage. Here, we address this limitation and devise a comprehensive azidonorleucine labeling, click chemistry enrichment, and mass spectrometry-based proteomics and secretomics strategy to dissect aberrant signals in pancreatic ductal adenocarcinoma (PDAC). Our in-depth co-culture and in vivo analyses cover more than 10,000 cancer cell-derived proteins and reveal systematic differences between molecular PDAC subtypes. Secreted proteins, such as chemokines and EMT-promoting matrisome proteins, associated with distinct macrophage polarization and tumor stromal composition, differentiate classical and mesenchymal PDAC. Intriguingly, more than 1,600 cancer cell-derived proteins including cytokines and pre-metastatic niche formation-associated factors in mouse serum reflect tumor activity in circulation. Our findings highlight how cell-selective proteomics can accelerate the discovery of diagnostic markers and therapeutic targets in cancer.

Current practises and the future of robotic surgical training.

INTRODUCTION: This study reviews the current state of robotic surgery training for surgeons, including the various curricula, training methods, and tools available, as well as the challenges and limitations of these. METHODS: The authors carried out a literature search across PubMed, MEDLINE, and Google Scholar using keywords related to 'robotic surgery', 'computer-assisted surgery', 'simulation', 'virtual reality', 'surgical training', and 'surgical education'. Full text analysis was performed on 112 articles. TRAINING PROGRAMMES: The training program for robotic surgery should focus on proficiency, deliberation, and distribution principles. The curricula can be broadly split up into pre-console and console-side training. Pre-Console and Console-Side Training: Simulation training is an important aspect of robotic surgery training to improve technical skill acquisition and reduce mental workload, which helps prepare trainees for live procedures. OPERATIVE PERFORMANCE ASSESSMENT: The study also discusses the various validated assessment tools used for operative performance assessments. FUTURE ADVANCES: Finally, the authors propose potential future directions for robotic surgery training, including the use of emerging technologies such as AI and machine learning for real-time feedback, remote mentoring, and augmented reality platforms like Proximie to reduce costs and overcome geographic limitations. CONCLUSION: Standardisation in trainee performance assessment is needed. Each of the robotic curricula and platforms has strengths and weaknesses. The ERUS Robotic Curriculum represents an evidence-based example of how to implement training from novice to expert. Remote mentoring and augmented reality platforms can overcome the challenges of high equipment costs and limited access to experts. Emerging technologies offer promising advancements for real-time feedback and immersive training environments, improving patient outcomes.

Laparoscopic cholecystectomy in children: A systematic review and meta-analysis.

BACKGROUND: Laparoscopic cholecystectomy (LC) has become the procedure of choice for the removal of gallbladder within the paediatric population. The aim of this study was to perform a systematic review and meta-analysis of the literature spanning the last 20 years to understand the indications for and safety of LCs in children. METHODS: A comprehensive search of the published English language literature from January 2000 to June 2020 was done on PubMed, MEDLINE, and Google Scholar. RESULTS: In total, 76,524 LC cases were identified from 114 studies. 78.9% of the patients were female and average age was 12 years old. Associated haematological disorders were identified in 16% of cases. The commonest indication for LC was cholelithiasis (68.4% in 66 studies), followed by cholecystitis (59.2% in 53 studies). Median operating time was 77 min. Median hospital stay was 2 days. The overall postoperative complication rate was 3.4% Major complications included bile duct injury (0.4%) and intra- or post-operative bleeding (0.9%). The conversion rate to open procedure was 2%. When comparing post-operative outcomes between emergency and elective admissions, three papers lent themselves to meta-analysis demonstrating no significant difference (p = 0.42). There was no statistically significant difference in postoperative complication rate between "hot" and "cold" laparoscopic cholecystectomies (p = 0.6). CONCLUSION: This systematic review and meta-analysis is the largest collection of subjects on laparoscopic cholecystectomies in children. Laparoscopic cholecystectomy is a safe operation in children, with complication rates similar or comparable to the adult literature. Cholelithiasis, cholecystitis and biliary dyskinesia were the commonest indications for LC.

The Combination of Thought-Stopping And Exposure and Response Prevention in the Treatment of Predominant Obsessions: A Case Report.

The behavioral technique of thought-stopping is no longer used to treat obsessive-compulsive disorder (OCD) because of its ineffectiveness and concerns about the detrimental effects of thought suppression. However, it can be effective when used as a part of exposure and response prevention (ERP) treatment in those with predominant obsessions without overt compulsions. We present the case of a female with long-standing medication-resistant obsessions without compulsions. The combination of thought-stopping, ERP, and simple techniques to address neutralization and dysfunctional cognitions was effective in reducing her symptoms. Treatment gains were maintained for two years. The successful treatment of this patient with a combination of thought-stopping with ERP suggests that it might be worthwhile to examine the effectiveness of this integrated treatment in properly controlled trials of patients with predominant obsessions.

Efficacy of screening and brief intervention for hazardous alcohol use in patients with mood disorders: A randomized clinical trial from a psychiatric out-patient clinic in India.

AIM: To determine the efficacy of individual-based, face-to-face screening and brief intervention (SBI) for hazardous alcohol use among treatment-seeking outpatients with mood disorders. METHODS: It was a parallel-group, single-blind, randomized controlled trial of 84 participants who met the selection criteria for hazardous alcohol use, defined by alcohol use disorder identification test (AUDIT) score 8-19. Participants were randomly allocated to either SBI or general advice group. Both groups had received a standard care for mood disorders. The outcome was assessed after 3 months. The primary outcome was a change in the mean AUDIT score and the secondary outcomes were a change in frequency of heavy episodic drinking and stages of motivation. RESULTS: Majority (60%) had major depressive episodes. There was no significant difference in baseline demography and clinical variables between the groups. Both intention to treat and per-protocol analyses showed a small but significant effect of SBI on mean AUDIT score. Age, baseline AUDIT, and motivation did not moderate the effect. SBI was associated with a significant decrease in the frequency of heavy drinking and improvement in stages of motivation. CONCLUSION: SBI among patients with mood disorders had a small but significant effect on alcohol use.

Methods of Sentinel Lymph Node Detection and Management in Urinary Bladder Cancer-A Narrative Review.

INTRODUCTION: Detection of lymph node status in bladder cancer significantly impacts clinical decisions regarding its management. There is a wide range of detection modalities for this task, including lymphoscintigraphy, computed tomography, magnetic resonance imaging, single-photon emission computed tomography, positron emission tomography, and fluoroscopy. We aimed to study the pre- and intraoperative detection modalities of sentinel lymph nodes in urinary bladder cancer. METHOD: This narrative review was performed by searching the PubMed and EMBASE libraries using the following search terms: ("Transitional cell carcinoma of the bladder" OR "urothelial cancer" OR "urinary bladder cancer" OR "bladder cancer") AND (("sentinel lymph node") OR ("lymphatic mapping") OR ("lymphoscintigraphy") OR ("lymphangiography") OR ("lymph node metastases")). Studies analysing the effectiveness and outcomes of sentinel lymph node detection in bladder cancer were included, while non-English language, duplicates, and non-article studies were excluded. After analysing the libraries and a further manual search of bibliographies, 31 studies were included in this paper. We followed the RAMESES publication standard for narrative reviews to produce this paper. RESULTS: Of the 31 studies included, 7 studies included multiple detection methods; 5 studies included lymphoscintigraphy; 5 studies included computed tomography and/or single-photon emission computed tomography; 5 studies included fluoroscopy; 4 studies included magnetic resonance imaging; and 5 studies included positron emission tomography. DISCUSSION: Anatomical, radioactive, and functional detection modalities have been studied independently and in combination. The consensus is that preoperative detection with imaging helps guide surgical management and intraoperative detection methods help capture any lymph nodes that may have been missed. Each of these types of detection represent their own set of benefits and drawbacks, but there is currently limited evidence to support any change in overall practice to replace conventional staging.

Identification of covalent modifications regulating immune signaling complex composition and phenotype.

Cells signal through rearrangements of protein communities governed by covalent modifications and reversible interactions of distinct sets of proteins. A method that identifies those post-transcriptional modifications regulating signaling complex composition and functional phenotypes in one experimental setup would facilitate an efficient identification of novel molecular signaling checkpoints. Here, we devised modifications, interactions and phenotypes by affinity purification mass spectrometry (MIP-APMS), comprising the streamlined cloning and transduction of tagged proteins into functionalized reporter cells as well as affinity chromatography, followed by MS-based quantification. We report the time-resolved interplay of more than 50 previously undescribed modification and hundreds of protein-protein interactions of 19 immune protein complexes in monocytes. Validation of interdependencies between covalent, reversible, and functional protein complex regulations by knockout or site-specific mutation revealed ISGylation and phosphorylation of TRAF2 as well as ARHGEF18 interaction in Toll-like receptor 2 signaling. Moreover, we identify distinct mechanisms of action for small molecule inhibitors of p38 (MAPK14). Our method provides a fast and cost-effective pipeline for the molecular interrogation of protein communities in diverse biological systems and primary cells.

Mammary epithelial cells have lineage-rooted metabolic identities.

Cancer metabolism adapts the metabolic network of its tissue of origin. However, breast cancer is not a disease of a single origin. Multiple epithelial populations serve as the culprit cell of origin for specific breast cancer subtypes, yet our knowledge of the metabolic network of normal mammary epithelial cells is limited. Using a multi-omic approach, here we identify the diverse metabolic programmes operating in normal mammary populations. The proteomes of basal, luminal progenitor and mature luminal cell populations revealed enrichment of glycolysis in basal cells and of oxidative phosphorylation in luminal progenitors. Single-cell transcriptomes corroborated lineage-specific metabolic identities and additional intra-lineage heterogeneity. Mitochondrial form and function differed across lineages, with clonogenicity correlating with mitochondrial activity. Targeting oxidative phosphorylation and glycolysis with inhibitors exposed lineage-rooted metabolic vulnerabilities of mammary progenitors. Bioinformatics indicated breast cancer subtypes retain metabolic features of their putative cell of origin. Thus, lineage-rooted metabolic identities of normal mammary cells may underlie breast cancer metabolic heterogeneity and targeting these vulnerabilities could advance breast cancer therapy.

NASH limits anti-tumour surveillance in immunotherapy-treated HCC.

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.

Magnetic resonance imaging reveals specific anatomical changes in the brain of Agat- and Gamt-mice attributed to creatine depletion and guanidinoacetate alteration.

Arginine:glycine amidinotransferase- and guanidinoacetate methyltransferase deficiency are severe neurodevelopmental disorders. It is not known whether mouse models of disease express a neuroanatomical phenotype. High-resolution magnetic resonance imaging (MRI) with advanced image analysis was performed in perfused, fixed mouse brains encapsulated with the skull from male, 10-12 week old Agat -exc and B6J.Cg-Gamt tm1Isb mice (n = 48; n = 8 per genotype, strain). T2-weighted MRI scans were nonlinearly aligned to a 3D atlas of the mouse brain with 62 structures identified. Local differences in brain shape related to genotype were assessed by analysis of deformation fields. Creatine (Cr) and guanidinoacetate (GAA) were measured with high-performance liquid chromatography (HPLC) in brain homogenates (n = 24; n = 4 per genotype, strain) after whole-body perfusion. Cr was decreased in the brain of Agat- and Gamt mutant mice. GAA was decreased in Agat-/- and increased in Gamt-/- . Body weight and brain volume were lower in Agat-/- than in Gamt-/- . The analysis of entire brain structures revealed corpus callosum, internal capsule, fimbria and hypothalamus being different between the genotypes in both strains. Eighteen and fourteen significant peaks (local areas of difference in relative size) were found in Agat- and Gamt mutants, respectively. Comparing Agat-/- with Gamt-/- , we found changes in three brain regions, lateral septum, amygdala, and medulla. Intra-strain differences in four brain structures can be associated with Cr deficiency, while the inter-strain differences in three brain structures of the mutant mice may relate to GAA. Correlating these neuroanatomical findings with gene expression data implies the role of Cr metabolism in the developing brain and the importance of early intervention in patients with Cr deficiency syndromes.

Dissecting intercellular signaling with mass spectrometry-based proteomics.

Physiological functions depend on a coordinated interplay of numerous different cell types. Proteins serve as major signaling molecules between cells; however, their comprehensive investigation in physiologically relevant settings has remained challenging. Mass spectrometry (MS)-based shotgun proteomics is emerging as a powerful technology for the systematic analysis of protein-mediated intercellular signaling and regulated post-translational modifications. Here, we discuss recent advancements in cell biological, chemical, and biochemical MS-based approaches for the profiling of cellular messengers released by sending cells, receptors expressed on the cell surface, and their interactions. We highlight methods tailored toward the mapping of dynamic signal transduction mechanisms at cellular interfaces and approaches to dissect communication cell specifically in heterocellular systems. Thereby, MS-based proteomics contributes a unique systems biology perspective for the identification of intercellular signaling pathways deregulated in disease.

Neuroleptic malignant syndrome associated with the use of injection zuclopenthixol acetate.

Zuclopenthixol is usually used in parental form to manage acute agitation and psychosis.[1] It has high affinity for dopamine D1 and D2 receptors. There are very few reports of Neuroleptic Malignant Syndrome (NMS) with use of zuclopenthixol monotherapy. In this case report, we present a 35 year old male with alcohol dependence, presented to the emergency with altered sensorium, fever and stiffness of limbs. He had history of receiving Injection Zuclopenthixol acetate 200 mg thrice over 24 hours. Within 12-14 hours of the last injection, patient developed features suggestive of NMS. On investigations he was found to have raised serum creatinine phosphokinase levels (839.9U/L; reference laboratory value: 26 to 308 U/L) and leukocytosis. In view of these features, he was diagnosed with NMS and was started on supportive management to address the dehydration and was given Thiamine 500 mg thrice daily. Additionally he was started on Tab. Bromocriptine 5 mg thrice daily and lorazepam 2 mg/day. With this intervention, his symptoms improved over the period of 1 week and tablet bromocriptine was tapered off, after 1 week of being asymptomatic.

Neuroleptic malignant syndrome associated with the use of injection zuclopenthixol acetate.

Zuclopenthixol is available in two parenteral formulation,i.e., in the form of acetate and decanoate. It has high affinity for dopamine D1 and D2 receptors. There is limited literature of association of neuroleptic malignant syndrome with the use of zuclopenthixol monotherapy. These case reports have mostly implicated zuclopenthixol decanoate, and also zuclopenthixol acetate. In this report, we present a case of neuroleptic malignant syndrome associated with use of zuclopenthixol acetate.

Genome-wide germline correlates of the epigenetic landscape of prostate cancer.

Oncogenesis is driven by germline, environmental and stochastic factors. It is unknown how these interact to produce the molecular phenotypes of tumors. We therefore quantified the influence of germline polymorphisms on the somatic epigenome of 589 localized prostate tumors. Predisposition risk loci influence a tumor's epigenome, uncovering a mechanism for cancer susceptibility. We identified and validated 1,178 loci associated with altered methylation in tumoral but not nonmalignant tissue. These tumor methylation quantitative trait loci influence chromatin structure, as well as RNA and protein abundance. One prominent tumor methylation quantitative trait locus is associated with AKT1 expression and is predictive of relapse after definitive local therapy in both discovery and validation cohorts. These data reveal intricate crosstalk between the germ line and the epigenome of primary tumors, which may help identify germline biomarkers of aggressive disease to aid patient triage and optimize the use of more invasive or expensive diagnostic assays.