Evaluation of GPT Large Language Model Performance on RSNA 2023 Case of the Day Questions.

Background GPT-4V (GPT-4 with vision, ChatGPT; OpenAI) has shown impressive performance in several medical assessments. However, few studies have assessed its performance in interpreting radiologic images. Purpose To assess and compare the accuracy of GPT-4V in assessing radiologic cases with both images and textual context to that of radiologists and residents, to assess if GPT-4V assistance improves human accuracy, and to assess and compare the accuracy of GPT-4V with that of image-only or text-only inputs. Materials and Methods Seventy-two Case of the Day questions at the RSNA 2023 Annual Meeting were curated in this observer study. Answers from GPT-4V were obtained between November 26 and December 10, 2023, with the following inputs for each question: image only, text only, and both text and images. Five radiologists and three residents also answered the questions in an "open book" setting. For the artificial intelligence (AI)-assisted portion, the radiologists and residents were provided with the outputs of GPT-4V. The accuracy of radiologists and residents, both with and without AI assistance, was analyzed using a mixed-effects linear model. The accuracies of GPT-4V with different input combinations were compared by using the McNemar test. P < .05 was considered to indicate a significant difference. Results The accuracy of GPT-4V was 43% (31 of 72; 95% CI: 32, 55). Radiologists and residents did not significantly outperform GPT-4V in either imaging-dependent (59% and 56% vs 39%; P = .31 and .52, respectively) or imaging-independent (76% and 63% vs 70%; both P = .99) cases. With access to GPT-4V responses, there was no evidence of improvement in the average accuracy of the readers. The accuracy obtained by GPT-4V with text-only and image-only inputs was 50% (35 of 70; 95% CI: 39, 61) and 38% (26 of 69; 95% CI: 27, 49), respectively. Conclusion The radiologists and residents did not significantly outperform GPT-4V. Assistance from GPT-4V did not help human raters. GPT-4V relied on the textual context for its outputs. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Katz in this issue.

Expression of Plasmodium major facilitator superfamily protein in transporters - Δ Candida identifies a drug transporter.

Aim: To assess the functional relevance of a putative Major Facilitator Superfamily protein (PF3D7_0210300; 'PfMFSDT') as a drug transporter, using Candida glabrata for orthologous protein expression.Methods: Complementary Determining Sequence encoding PfMFSDT was integrated into the genome of genetically engineered C. glabrata strain MSY8 via homologous recombination, followed by assessing its functional relevance as a drug transporter.Results & conclusion: The modified C. glabrata strain exhibited plasma membrane localization of PfMFSDT and characteristics of an Major Facilitator Superfamily transporter, conferring resistance to antifungals, ketoconazole and itraconazole. The nanomolar inhibitory effects of the drugs on the intra-erythrocytic growth of Plasmodium falciparum highlight their antimalarial properties. This study proposes PfMFSDT as a drug transporter, expanding the repertoire of the currently known antimalarial 'resistome'.

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Prefoldins are novel regulators of the unfolded protein response in artemisinin resistant Plasmodium falciparum malaria.

Emerging Artemisinin (ART) resistance in Plasmodium falciparum (Pf) poses challenges for the discovery of novel drugs to tackle ART-resistant parasites. Concentrated efforts toward the ART resistance mechanism indicated a strong molecular link of ART resistance with upregulated expression of unfolded protein response pathways involving Prefoldins (PFDs). However, a complete characterization of PFDs as molecular players taking part in ART resistance mechanism, and discovery of small molecule inhibitors to block this process have not been identified to date. Here, we functionally characterized all Pf Prefoldin subunits (PFD1-6) and established a causative role played by PFDs in ART resistance by demonstrating their expression in intra-erythrocytic parasites along with their interactions with Kelch13 protein through immunoprecipitation coupled MS/MS analysis. Systematic biophysical interaction analysis between all subunits of PFDs revealed their potential to form a complex. The role of PFDs in ART resistance was confirmed in orthologous yeast PFD6 mutants, where PfPFD6 expression in yeast mutants reverted phenotype to ART resistance. We identified an FDA-approved drug "Biperiden" that restricts the formation of Prefoldin complex and inhibits its interaction with its key parasite protein substrates, MSP-1 and α-tubulin-I. Moreover, Biperiden treatment inhibits the parasite growth in ART-sensitive Pf3D7 and resistant Pf3D7k13R539T strains. Ring survival assays that are clinically relevant to analyze ART resistance in Pf3D7k13R539T parasites demonstrate the potency of BPD to inhibit the growth of survivor parasites. Overall, our study provides the first evidence of the role of PfPFDs in ART resistance mechanisms and opens new avenues for the management of resistant parasites.

Undiagnosed rheumatic carditis causing sudden death in a young adult: A case report and review.

Acute rheumatic fever-related acquired heart disease in children and young adults is a worldwide issue, but it poses a serious public health threat in developing nations like India. We present a case report of a young adult who collapsed suddenly during a routine walk and was declared dead in an emergency ward on arrival. There was no significant past medical history. On autopsy, massive cardiomegaly and a "butter and bread" appearance of the pericardium, along with findings suggestive of mitral stenosis and aortic regurgitation, raised suspicion about rheumatic heart disease. Rheumatic carditis was confirmed by a microscopic examination that showed Aschoff bodies in the left ventricle, mitral valve and interventricular septum, in addition to uncommon Anitschkow cells in the left ventricle. A sudden death due to undiagnosed rheumatic carditis causing such massive cardiomegaly is rare. This case highlights the need to keep rheumatic carditis as a cause of sudden death.

Dengue induced acute liver failure: A meta summary of case reports.

BACKGROUND: Dengue fever is the most common cause of viral hemorrhagic fever, with more than 400 million cases being reported annually, worldwide. Even though hepatic involvement is common, acute liver failure (ALF) is a rare complication of dengue fever. AIM: To analyze the demographic profile, symptomology, hospital course and outcomes of patients presenting with ALF secondary to dengue infection by reviewing the published case reports. METHODS: A systematic search was performed from multiple databases including PubMed, Reference Citation Analysis, Science Direct, and Google Scholar. The search terms used were "dengue" OR "severe dengue" OR "dengue shock syndrome" OR "dengue haemorrhagic syndrome" OR "dengue fever" AND "acute liver failure" OR "hepatic failure" OR "liver injury". The inclusion criteria were: (1) Case reports or case series with individual patient details; (2) Reported acute liver failure secondary to dengue infection; and (3) Published in English language and on adult humans. The data were extracted for patient demographics, clinical symptomatology, clinical interventions, hospital and intensive care unit course, need for organ support and clinical outcomes. RESULTS: Data from 19 case reports fulfilling the predefined inclusion criteria were included. The median age of patients was 38 years (inter quartile range: Q3-Q1 26.5 years) with a female preponderance (52.6%). The median days from diagnosis of dengue to development of ALF was 4.5 d. The increase in aspartate aminotransferase was higher than that in alanine aminotransferase (median 4625 U/L vs 3100 U/L). All the patients had one or more organ failure, with neurological failure present in 73.7% cases. 42.1% patients required vasopressor support and hepatic encephalopathy was the most reported complication in 13 (68.4%) cases. Most of the patients were managed conservatively and 2 patients were taken up for liver transplantation. Only 1 death was reported (5.3%). CONCLUSION: Dengue infection may rarely lead to ALF. These patients may frequently require intensive care and organ support. Even though most of these patients may improve with supportive care, liver transplantation may be a therapeutic option in refractory cases.

Correlation of oxygenation indices in invasive mechanical ventilated adult patients.

BACKGROUND: Mechanical ventilation is essential for managing acute respiratory failure, but traditional methods of assessing oxygenation, like the PaO2/FiO2 ratio, pose challenges due to invasiveness and cost. OBJECTIVE: This single-centre prospective observational study aimed to assess the potential of the non-invasive Oxygen Saturation Index (OSI), utilising SpO2 measurements, to diagnose hypoxemia in mechanically ventilated adults. The study sought to establish correlations between OSI, oxygenation index (OI), PaO2/FiO2 ratio and SpO2/FiO2 ratio. METHODS: From August 2022 to July 2023, data was collected from 1055 mechanically ventilated intensive care unit patients. Statistical analysis included correlation tests, receiver operating curve (ROC) analysis and cut-off value determination for hypoxemia diagnosis. RESULTS: We found that the P/F ratio had a statistically significant negative correlation with OI (correlation coefficient -0.832, P value: 0.000 in hypoxemic group and correlation coefficient -0.888, P value: 0.000 in the non-hypoxemic group), and OSI (correlation coefficient -0.746, P value: 0.000 in hypoxemic group and correlation coefficient -0.629, P value: 0.000 in non-hypoxemic group) and has a positive correlation with P/F ratio (correlation coefficient 0.92, P value: 0.000 in hypoxemic group and correlation coefficient -0.67, P value: 0.000 in non-hypoxemic group). OI and OSI had a statistically significant correlation (correlation coefficient 0.955, P value: 0.000 in hypoxemic group and correlation coefficient 0.815, P value: 0.000 in non-hypoxemic group). on ROC analysis P/F ratio was the most accurate in predicting hypoxia followed by OI and OSI. with a cut-off value, of OI being 7.07, and that for OSI being 3.90, at an 80% sensitivity level to diagnose hypoxemia. CONCLUSION: OSI can serve as a dependable surrogate for OI, simplifying ARDS severity assessment. The P/F ratio is the most accurate predictor of hypoxia. Further research, especially in larger multicentre studies, is needed to validate these findings and explore the long-term clinical implications of using OSI for oxygenation monitoring in mechanically ventilated patients.

An Unusual Presentation of Rhino-Orbital Mucormycosis with MDR-TB: an Unforeseen Challenge for Treatment Post COVID-19.

ROCM is an invasive fungal infection that has seen a substantial rise in the post covid-19 patients. Here we present an intriguing case of ROCM existing as a coinfection with MDR-TB. The purpose of this manuscript is to highlight the dilemma faced by the clinicians whether to take the risks associated with standard treatment protocols of mucormycosis contraindicated due to coexisting MDR-TB or to play safe and face the consequences of inadequate management.

Biological evaluation of novel side chain containing CQTrICh-analogs as antimalarials and their development as PfCDPK1 kinase inhibitors.

The rapid emergence of resistance to existing frontline antimalarial drugs emphasizes a need for the development of target-oriented molecules with novel modes of action. Given the importance of a plant-like Calcium-Dependent Protein Kinase 1 (PfCDPK1) as a stand-alone multistage signalling regulator of P. falciparum, we designed and synthesized 7-chloroquinoline-indole-chalcones tethered with a triazole (CQTrICh-analogs 7 (a-s) and 9) directed towards PfCDPK1. This was accomplished by reacting substituted 1-phenyl-3-(1-(prop-2-yn-1-yl)-1H-indol-3-yl) prop-2-en-1-one and 1-(prop-2-yn-1-yl)-1H-indole-3-carbaldehyde with 4-azido-7-chloroquinoline, respectively via a 'click' reaction. The selected CQTrICh-analogs: 7l and 7r inhibited the growth of chloroquine-sensitive 3D7 strain and -resistant RKL-9 isolate of Plasmodium falciparum, with IC50 values of 2.4 µM & 1.8 µM (7l), and 3.5 µM & 2.7 µM (7r), respectively, and showed no apparent hemolytic activity and cytotoxicity in mammalian cells. Intra-erythrocytic progression studies revealed that the active hybrids: 7l and 7r are effective against the mature stages of the parasite. 7l and 7r were found to stably interact with the catalytically active ATP-binding pocket of PfCDPK1 via energetically favourable H-bonds. The interaction was confirmed in vitro by microscale thermophoresis and kinase assays, which demonstrated that the active hybrids interact with PfCDPK1 and inhibit its kinase activity which is presumably responsible for the parasite growth inhibition. Interestingly, 7l and 7r showed no inhibitory effect on the human kinases, indicating their selectivity for the parasite kinase. We report the antiplasmodial potential of novel kinase-targeting bio-conjugates, a step towards developing pan-kinase inhibitors which is a prerequisite for multistage anti-malarial protection.

Nasogastric tube syndrome: A Meta-summary of case reports.

BACKGROUND: Since its description in 1790 by Hunter, the nasogastric tube (NGT) is commonly used in any healthcare setting for alleviating gastrointestinal symptoms or enteral feeding. However, the risks associated with its placement are often underestimated. Upper airway obstruction with a NGT is an uncommon but potentially life-threatening complication. NGT syndrome is characterized by the presence of an NGT, throat pain and vocal cord (VC) paralysis, usually bilateral. It is potentially life-threatening, and early diagnosis is the key to the prevention of fatal upper airway obstruction. However, fewer cases may have been reported than might have occurred, primarily due to the clinicians' unawareness. The lack of specific signs and symptoms and the inability to prove temporal relation with NGT insertion has made diagnosing the syndrome quite challenging. AIM: To review and collate the data from the published case reports and case series to understand the possible risk factors, early warning signs and symptoms for timely detection to prevent the manifestation of the complete syndrome with life-threatening airway obstruction. METHODS: We conducted a systematic search for this meta-summary from the database of PubMed, EMBASE, Reference Citation Analysis (https://www.referencecitationanalysis.com/) and Google scholar, from all the past studies till August 2023. The search terms included major MESH terms "Nasogastric tube", "Intubation, Gastrointestinal", "Vocal Cord Paralysis", and "Syndrome". All the case reports and case series were evaluated, and the data were extracted for patient demographics, clinical symptomatology, diagnostic and therapeutic interventions, clinical course and outcomes. A datasheet for evaluation was further prepared. RESULTS: Twenty-seven cases, from five case series and 13 case reports, of NGT syndrome were retrieved from our search. There was male predominance (17, 62.96%), and age at presentation ranged from 28 to 86 years. Ten patients had diabetes mellitus (37.04%), and nine were hypertensive (33.33%). Only three (11.11%) patients were reported to be immunocompromised. The median time for developing symptoms after NGT insertion was 14.5 d (interquartile range 6.25-33.75 d). The most commonly reported reason for NGT insertion was acute stroke (10, 37.01%) and the most commonly reported symptoms were stridor or wheezing 17 (62.96%). In 77.78% of cases, bilateral VC were affected. The only treatment instituted in most patients (77.78%) was removing the NG tube. Most patients (62.96%) required tracheostomy for airway protection. But 8 of the 23 survivors recovered within five weeks and could be decannulated. Three patients were reported to have died. CONCLUSION: NGT syndrome is an uncommon clinical complication of a very common clinical procedure. However, an under-reporting is possible because of misdiagnosis or lack of awareness among clinicians. Patients in early stages and with mild symptoms may be missed. Further, high variability in the presentation timing after NGT insertion makes diagnosis challenging. Early diagnosis and prompt removal of NGT may suffice in most patients, but a significant proportion of patients presenting with respiratory compromise may require tracheostomy for airway protection.

Screening of traditional medicinal plant extracts and compounds identifies a potent anti-leishmanial diarylheptanoid from Siphonochilus aethiopicus.

Available anti-leishmanial drugs are associated with toxic side effects, necessitating the search for safe and effective alternatives. This study is focused on identifying traditional medicinal plant natural products for anti-leishmanial potential and possible mechanism of action. Compounds S and T. cordifolia residual fraction (TC-5) presented the best anti-leishmanial activity (IC50: 0.446 and 1.028 mg/ml) against promastigotes at 48 h and less cytotoxicity to THP-1 macrophages. These test agents elicited increased expression of pro-inflammatory cytokines; TNFα and IL-12. In infected untreated macrophages, NO release was suppressed but was significantly (p < 0.05) increased in infected cells treated with compound S. Importantly, Compound S was found to interact with LdTopoIIdimer in silico, resulting in a likely reduced ability of nucleic acid (dsDNA)-remodelling and, as a result, parasite proliferation in vitro. Thereby, Compound S possesses anti-leishmanial activity and this effect occurs via a Th1-mediated pro-inflammatory response. An increase in NO release and its inhibitory effect on LdTopoII may also contribute to the anti-leishmanial effect of compound S. These results show the potential of this compound as a potential starting point for the discovery of novel anti-leishmanial leads.Communicated by Ramaswamy H. Sarma.

Finding the Optimal Resistance Training Intensity for Your Bones: Protocol for a Randomized Controlled Trial.

OBJECTIVE: The purpose of this trial is to evaluate the effect of twice-weekly, moderate-to-high intensity progressive resistance training (PRT) for 1 year on lumbar spine bone mineral density (BMD) in individuals with low BMD, compared to attention control. Secondary analyses will examine if resistance training improves other health outcomes; if high intensity is more effective than moderate intensity resistance training for all outcomes; the cost of intervention versus benefit; the willingness to pay; and harms. METHODS: For this study, 324 men or postmenopausal women aged ≥50 years with a femoral neck, total hip, or lumbar spine BMD T-score of ≤-1, or a Fracture Risk Assessment Tool probability of ≥20% for major osteoporotic fracture or ≥ 3% for hip fracture are being recruited to participate in a randomized controlled trial with 1:1:1 randomization. Participants will be stratified by site (3 centers) to twice-weekly, supervised PRT at moderate intensity (about 10 repetitions maximum), to high intensity PRT (≤6 repetitions maximum), or to a home posture and balance exercise program (attention control) for 1 year (resistance training to comparator allocation ratio of 2:1). The primary outcome is lumbar spine BMD via dual-energy X-ray absorptiometry. Secondary outcomes include trabecular bone score, proximal femur and total hip BMD and structure, bone-free and appendicular lean mass, physical functioning, falls, fractures, glucose metabolism, cost per life-year gained, adverse events, and quality of life. Between-group differences will be tested in intention-to-treat and per-protocol analyses using analysis of covariance, chi-square tests, or negative binomial or logistic regression, adjusting for site and baseline values. IMPACT: The Finding the Optimal Resistance Training Intensity For Your Bones trial will support decision making on resistance training for people at risk of fracture.

Sodium-glucose Cotransporter-2 Inhibitors induced euglycemic diabetic ketoacidosis: A meta summary of case reports.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are commonly prescribed to manage patients with diabetes mellitus. These agents may rarely lead to the development of euglycemic diabetic ketoacidosis (EDKA), which may complicate the disease course of these patients. AIM: To analyze the demographic profile, predisposing factors, symptomology, clinical interventions and outcomes of patients presenting with EDKA secondary to SGLT2i use by reviewing the published case reports and series. METHODS: We performed a systematic search of PubMed, Science Direct, Google Scholar and Reference Citation Analysis databases using the terms "canagliflozin" OR "empagliflozin" OR "dapagliflozin" OR "SGLT2 inhibitors" OR "Sodium-glucose cotransporter-2" AND "euglycemia" OR "euglycemic diabetic ketoacidosis" OR "metabolic acidosis". The inclusion criteria were: (1) Case reports or case series with individual patient details; and (2) Reported EDKA secondary to SGLT2i. Furthermore, the data were filtered from the literature published in the English language and on adults (> 18 years). We excluded: (1) Conference abstracts; and (2) Case reports or series which did not have individual biochemical data. All the case reports and case series were evaluated. The data extracted included patient demographics, clinical symptomatology, clinical interventions, intensive care unit course, need for organ support and outcomes. RESULTS: Overall, 108 case reports and 17 cases series with 169 unique patients that met all the inclusion criteria were included. The majority of patients were females (54.4%, n = 92), and the commonly reported symptoms were gastrointestinal (nausea/vomiting 65.1%, abdominal pain 37.3%) and respiratory (breathlessness 30.8%). One hundred and forty-nine (88.2%) patients had underlying type II diabetes, and the most commonly involved SGLT-2 inhibitor reported was empagliflozin (46.8%). A triggering factor was reported in most patients (78.7%), the commonest being acute severe infection (37.9%), which included patients with sepsis, coronavirus disease 2019, other viral illnesses, and acute pancreatitis. 61.5% were reported to require intensive unit care, but only a minority of patients required organ support in the form of invasive mechanical ventilation (13%), vasopressors (6.5%) or renal replacement therapy (5.9%). The overall mortality rate was only 2.4%. CONCLUSION: Patients on SGLT2i may rarely develop EDKA, especially in the presence of certain predisposing factors, including severe acute infections and following major surgery. The signs and symptoms of EDKA may be similar to that of DKA but with normal blood sugar levels, which may make the diagnosis challenging. Outcomes of EDKA are good if recognized early and corrective actions are taken. Hence, physicians managing such patients must be aware of this potential complication and must educate their patients accordingly to ensure early diagnosis and management.

Tackling the emerging Artemisinin-resistant malaria parasite by modulation of defensive oxido-reductive mechanism via nitrofurantoin repurposing.

Oxidative stress-mediated cell death has remained the prime parasiticidal mechanism of front line antimalarial, artemisinin (ART). The emergence of resistant Plasmodium parasites characterized by oxidative stress management due to impaired activation of ART and enhanced reactive oxygen species (ROS) detoxification has decreased its clinical efficacy. This gap can be filled by development of alternative chemotherapeutic agents to combat resistance defense mechanism. Interestingly, repositioning of clinically approved drugs presents an emerging approach for expediting antimalarial drug development and circumventing resistance. Herein, we evaluated the antimalarial potential of nitrofurantoin (NTF), a clinically used antibacterial drug, against intra-erythrocytic stages of ART-sensitive (Pf3D7) and resistant (PfKelch13R539T) strains of P. falciparum, alone and in combination with ART. NTF exhibited growth inhibitory effect at submicro-molar concentration by arresting parasite growth at trophozoite stage. It also inhibited the survival of resistant parasites as revealed by ring survival assay. Concomitantly, in vitro combination assay revealed synergistic association of NTF with ART. NTF was found to enhance the reactive oxygen and nitrogen species, and induced mitochondrial membrane depolarization in parasite. Furthermore, we found that exposure of parasites to NTF disrupted redox balance by impeding Glutathione Reductase activity, which manifests in enhanced oxidative stress, inducing parasite death. In vivo administration of NTF, alone and in combination with ART, in P. berghei ANKA-infected mice blocked parasite multiplication and enhanced mean survival time. Overall, our results indicate NTF as a promising repurposable drug with therapeutic potential against ART-sensitive as well as resistant parasites.

Oligometastatic carcinoma prostate - An overview of the last decade.

Introduction: Oligometastatic prostate cancer (OMPC) has gained profound interest lately due to its different tumor biology and our ability to use multimodality therapy for cure or prolonged survival. Selecting the appropriate patient for treatment has become the aim of treating urologists, medical oncologists, and radiation oncologists. Through this review, we try to highlight the management of OMPC in light of recent literature. Methods: Literature search was performed on Pubmed, Scopus and Embase using keywords "Oligometastatic", " Prostate Cancer" using operators such as "And" & "Or". Relevant articles were screened and all the latest articles on this emerging entity were included in this review. Results: All trials relevant to oligometastatic prostate cancer defining the role of surgery, radiotherapy and systemic therapy were included and appropriate inferences were drawn. Relevant studies were compiled in tabular form for this article. Conclusion: The current standard of care of management for OMPC remains systemic therapy on the lines of hormone-sensitive metastatic prostate cancer. The evolving role of surgery, and radiotherapy along with systemic therapy is highlighted in this article.

Non-pharmacological management of osteoporotic vertebral fractures: health-care professional perspectives and experiences.

PURPOSE: To understand experiences and perceptions on non-pharmacological treatment of vertebral fractures and virtual-care from the perspective of care professionals' (HCPs). DESIGN AND SETTING: We conducted semi-structured interviews with 13 HCPs within Canada (7 F, 6 M, aged 46 ± 12 years) and performed a thematic and content analysis from a post-positivism perspective. RESULTS: Two themes were identified: acuity matters when selecting appropriate interventions; and roadblocks to receiving non-pharmacological interventions. We found that treatment options were dependent on the acuity/stability of fracture and were individualized accordingly. Pain medication was perceived as important, but non-pharmacological strategies were also considered helpful in supporting recovery. Participants discussed barriers related to the timely identification of fracture, referral to physiotherapy, and lack of knowledge among HCPs on how to manage osteoporosis and vertebral fractures. HCPs reported positive use of virtual-care, but had concerns related to patient access, cost, and comprehensive assessments. CONCLUSION: HCPs used and perceived non-pharmacological interventions as helpful and selected specific treatments based on the recency of fracture and patient symptoms. HCPs' also believed that virtual-care that included an educational component, an assessment by a physiotherapist, and an exercise group was a feasible alternative, but concerns exist and may require further evaluation.Implications for RehabilitationNon-pharmacological strategies in combination with pain medication may be a more effective strategy to support recovery than pain medication alone but should be informed by fracture acuity and patient symptoms.To improve access to physiotherapy and other non-pharmacological treatment options during the acute or chronic management of vertebral fractures, it may be worthwhile to explore the effectiveness and feasibility of virtual-care.

Liver injury from direct oral anticoagulants.

BACKGROUND: Drug-induced liver injury (DILI) can be caused by any prescribed drug and is a significant reason for the withdrawal of newly launched drugs. Direct-acting oral anticoagulants (DOACs) are non-vitamin K-based antagonists recently introduced and increasingly used for various clinical conditions. A meta-analysis of 29 randomised controlled trials and 152116 patients reported no increased risk of DILI with DOACs. However, it is challenging to predict the risk factors for DILI in individual patients with exclusion of patients with pre-existing liver disease from these studies. AIM: To determine the risk factors and outcomes of patients who developed DILI secondary to DOACs by systematic review and meta-summary of recent case reports and series. METHODS: A systematic search was conducted on multiple databases including PubMed, Science Direct, Reference Citation Analysis, and Google Scholar. The search terms included "Acute Liver Failure" OR "Acute-On-Chronic Liver Failure" OR "Acute Chemical and Drug Induced Liver Injury" OR "Chronic Chemical and Drug Induced Liver Injury" AND "Factor Xa Inhibitors" OR "Dabigatran" OR "Rivaroxaban" OR "apixaban" OR "betrixaban" OR "edoxaban" OR "Otamixaban". The results were filtered for literature published in English and on adult patients. Only case reports and case studies reporting cases of DILI secondary to DOACs were included. Data on demographics, comorbidities, medication history, laboratory investigations, imaging, histology, management, and outcomes were extracted. RESULTS: A total of 15 studies (13 case reports and 2 case series) were included in the analysis, comprising 27 patients who developed DILI secondary to DOACs. Rivaroxaban was the most commonly implicated DOAC (n = 20, 74.1%). The mean time to onset of DILI was 40.6 d. The most common symptoms were jaundice (n = 15, 55.6%), malaise (n = 9, 33.3%), and vomiting (n = 9, 33.3%). Laboratory investigations showed elevated liver enzymes and bilirubin levels. Imaging studies and liver biopsies revealed features of acute hepatitis and cholestatic injury. Most patients had a favourable outcome, and only 1 patient (3.7%) died due to liver failure. CONCLUSION: DOACs are increasingly used for various clinical conditions, and DILI secondary to DOACs is a rare but potentially serious complication. Prompt identification and cessation of the offending drug are crucial for the management of DILI. Most patients with DILI secondary to DOACs have a favourable outcome, but a small proportion may progress to liver failure and death. Further research, including post-marketing population-based studies, is needed to better understand the incidence and risk factors for DILI secondary to DOACs.

Characterization of thiamine pyrophosphokinase of vitamin B1 biosynthetic pathway as a drug target of Leishmania donovani.

Vitamin B1 is an essential cofactor for enzymes involved in the metabolism of carbohydrates, particularly Transketolases. These enzymes are amenable to therapeutic interventions because of their specificity. In the final step of the Vitamin B1 biosynthesis pathway, Thiamine Pyrophosphokinase (TPK) converts thiamin into its active form, Thiamin Pyrophosphate (TPP), allowing researchers to investigate the functional importance of this enzyme and the pathway's dispensability in Leishmania donovani, a protozoan parasite that causes visceral leishmaniasis. In this study, various in silico, biochemical, biophysical, and cellular assays-based experiments have been conducted to identify and characterize LdTPK, and to provide a sound platform for the discovery of potential LdTPK inhibitors. LdTPK structural modelling ensured high protein quality. Oxythiamine and pyrithiamine were found to bind well with LdTPK with considerable binding energies, and MD simulation-based experiments indicated the stability of the complexation. Additionally, LdTPK1 was found to activate ROS defense in amastigotes, and its inhibition using oxythiamine and pyrithiamine led to the growth inhibition of L. donovani promastigotes and intracellular amastigotes. These findings highlight LdTPK as a promising target for the development of new anti-leishmanial agents. An in-depth analysis of the enzymes involved in TPP biosynthesis in L. donovani has the potential to yield novel therapeutic strategies for Leishmaniasis.Communicated by Ramaswamy H. Sarma.

Host-Erythrocytic Sphingosine-1-Phosphate Regulates Plasmodium Histone Deacetylase Activity and Exhibits Epigenetic Control over Cell Death and Differentiation.

The evolution of resistance to practically all antimalarial drugs poses a challenge to the current malaria elimination and eradication efforts. Given that the epigenome of Plasmodium falciparum governs several crucial parasite functions, pharmaceutical interventions with transmission-blocking potential that target epigenetic molecular markers and regulatory mechanisms are likely to encounter drug resistance. In the malaria parasite, histone deacetylases (HDACs) are essential epigenetic modulators that regulate cellular transcriptional rearrangements, notably the molecular mechanisms underlying parasite proliferation and differentiation. We establish "lipid sequestration" as a mechanism by which sphingolipids, specifically Sphingosine-1-Phosphate (S1P) (a metabolic product of Sphingosine Kinase 1 [SphK-1]), regulate epigenetic reprogramming in the parasite by interacting with, and modulating, the histone-deacetylation activity of PfHDAC-1, thereby regulating Plasmodium pathogenesis. Furthermore, we demonstrate that altering host S1P levels with PF-543, a potent and selective Sphk-1 inhibitor, dysregulates PfHDAC-1 activity, resulting in a significant increase in the global histone acetylation signals and, consequently, transcriptional modulation of genes associated with gametocytogenesis, virulence, and proliferation. Our findings point to a hitherto unrecognized functional role for host S1P-mediated sphingolipid signaling in modulating PfHDAC-1's enzymatic activity and, as a result, the parasite's dynamic genome-wide transcriptional patterns. The epigenetic regulation of parasite proliferation and sexual differentiation offers a novel approach for developing host-targeted therapeutics to combat malaria resistance to conventional regimens. IMPORTANCE Sphingolipid is an 18-carbon amino-alcohol-containing lipid with a sphingosine backbone, which when phosphorylated by sphingosine kinase 1 (SphK-1), generates sphingosine-1-phosphate (S1P), an essential lipid signaling molecule. Dysregulation of S1P function has been observed in a variety of pathologies, including severe malaria. The malaria parasite Plasmodium acquires a host S1P pool for its growth and survival. Here, we describe the molecular attuning of histone deacetylase-1 (PfHDAC-1), a crucial epigenetic modulator that contributes to the establishment of epigenetic chromatin states and parasite survival, in response to S1P binding. Our findings highlight the host lipid-mediated epigenetic regulation of malaria parasite key genes.

Developing a fall prevention intervention economic model.

PURPOSE: Model-based economic evaluations require conceptualization of the model structure. Our objectives were to identify important health states, events, and patient attributes to be included in a model-based cost-effectiveness analysis of fall prevention interventions, to develop a model structure to examine cost-effectiveness of fall prevention interventions, and to assess the face validity of the model structure. METHODS: An expert panel comprising clinicians, health service researchers, health economists, a patient partner, and policy makers completed two rounds of online surveys to gain consensus on health states, events, and patient attributes important for fall prevention interventions. The surveys were informed by a literature search on fall prevention interventions for older adults (≥65 years) including economic evaluations and clinical practice guidelines. The results of the Delphi surveys and subsequent discussions can support the face validity of a state-transition model for an economic evaluation of fall prevention interventions. RESULTS: In total, 11 experts rated 24 health states/events and 41 patient attributes. Consensus was achieved on 14 health states/events and 26 patient characteristics. The proposed model structure incorporated 12 of the 14 selected health states/events. Panelists confirmed the face validity of the model structure during teleconferences. CONCLUSIONS: There is a dearth of studies presenting the model conceptualization process; consequently, this study involving multiple end user partners with opportunities for input at several stages adds to the literature as another case study. This process is an example of how a fall prevention economic model was developed using a modified Delphi process and assessed for face validity.

Non-pharmacological management of osteoporotic vertebral fractures: Patient perspectives and experiences.

OBJECTIVE: To understand perceptions on rehabilitation after vertebral fracture, non-pharmacological strategies, and virtual care from the perspective of individuals living with vertebral fractures. DESIGN AND SETTING: We conducted semi-structured interviews online and performed a thematic and content analysis from a post-positivism perspective. PARTICIPANTS: Ten individuals living with osteoporotic vertebral fractures (9F, 1 M, aged 71 ± 8 years). RESULTS: Five themes emerged: pain is the defining limitation of vertebral fracture recovery; delayed diagnosis impacts recovery trajectory; living with fear; being dissatisfied with fracture management; and "getting back into the game of life" using non-pharmacological strategies. CONCLUSION: Participants reported back pain and an inability to perform activities of daily living, affecting psychological and social well-being. Physiotherapy, education, and exercise were considered helpful and important to patients; however, issues with fracture identification and referral limited the use of these options. Participants believed that virtual rehabilitation was a feasible and effective alternative to in-person care, but perceived experience with technology, cost, and individualization of programs as barriers.