Naturally occurring cancer-associated mutations disrupt oligomerization and activity of protein arginine methyltransferase 1 (PRMT1).

Protein arginine methylation is a posttranslational modification catalyzed by the protein arginine methyltransferase (PRMT) enzyme family. Dysregulated protein arginine methylation is linked to cancer and a variety of other human diseases. PRMT1 is the predominant PRMT isoform in mammalian cells and acts in pathways regulating transcription, DNA repair, apoptosis, and cell proliferation. PRMT1 dimer formation, which is required for methyltransferase activity, is mediated by interactions between a structure called the dimerization arm on one monomer and a surface of the Rossman Fold of the other monomer. Given the link between PRMT1 dysregulation and disease and the link between PRMT1 dimerization and activity, we searched the Catalogue of Somatic Mutations in Cancer (COSMIC) database to identify potential inactivating mutations occurring in the PRMT1 dimerization arm. We identified three mutations that correspond to W215L, Y220N, and M224V substitutions in human PRMT1V2 (isoform 1) (W197L, Y202N, M206V in rat PRMT1V1). Using a combination of site-directed mutagenesis, analytical ultracentrifugation, native PAGE, and activity assays, we found that these conservative substitutions surprisingly disrupt oligomer formation and substantially impair both S-adenosyl-L-methionine (AdoMet) binding and methyltransferase activity. Molecular dynamics simulations suggest that these substitutions introduce novel interactions within the dimerization arm that lock it in a conformation not conducive to dimer formation. These findings provide a clear, if putative, rationale for the contribution of these mutations to impaired arginine methylation in cells and corresponding health consequences.

Statin and aspirin as adjuvant therapy in hospitalised patients with SARS-CoV-2 infection: a randomised clinical trial (RESIST trial).

BACKGROUND: Statins and aspirin have been proposed for treatment of COVID-19 because of their anti-inflammatory and anti-thrombotic properties. Several observational studies have shown favourable results. There is a need for a randomised controlled trial. METHODS: In this single-center, open-label, randomised controlled trial, 900 RT-PCR positive COVID-19 patients requiring hospitalisation, were randomly assigned to receive either atorvastatin 40 mg (Group A, n = 224), aspirin 75 mg (Group B, n = 225), or both (Group C, n = 225) in addition to standard of care for 10 days or until discharge whichever was earlier or only standard of care (Group D, n = 226). The primary outcome variable was clinical deterioration to WHO Ordinal Scale for Clinical Improvement ≥ 6. The secondary outcome was change in serum C-reactive protein, interleukin-6, and troponin I. RESULTS: The primary outcome occurred in 25 (2.8%) patients: 7 (3.2%) in Group A, 3 (1.4%) in Group B, 8 (3.6%) in Group C, and 7 (3.2%) in Group D. There was no difference in primary outcome across the study groups (P = 0.463). Comparison of all patients who received atorvastatin or aspirin with the control group (Group D) also did not show any benefit [Atorvastatin: HR 1.0 (95% CI 0.41-2.46) P = 0.99; Aspirin: HR 0.7 (95% CI 0.27-1.81) P = 0.46]. The secondary outcomes revealed lower serum interleukin-6 levels among patients in Groups B and C. There was no excess of adverse events. CONCLUSIONS: Among patients admitted with mild to moderate COVID-19 infection, additional treatment with aspirin, atorvastatin, or a combination of the two does not prevent clinical deterioration. Trial Registry Number CTRI/2020/07/026791 ( http://ctri.nic.in ; registered on 25/07/2020).

A nanometric window on fullerene formation in the interstellar medium: Insights from molecular dynamics studies.

Understanding the fundamental mechanisms that underlie the synthesis of fullerene molecules in the interstellar medium (ISM) and in the environments of astrophysical objects is an open question. In this regard, using classical molecular dynamics, we demonstrate the possibility of in situ formation of fullerene molecules, such as C60 from graphite, which is known to occur in the ISM, in particular, circumstellar environments. Specifically, when graphite is subjected to thermal and mechanical stimuli that are typical of circumstellar shells, we find that the graphite sheet edges undergo significant restructuring and curling, leading to edge-induced interlayer-interactions and formation of mechanically strained five-membered-ring structural units. These units serve as precursors for the formation of fullerene structures, such as pristine and metastable C60 molecules. The pathways leading to molecular C60 formation consist of a series of steps that involve bond-breakage and subsequent local rearrangement of atoms, with the activation energy barriers of the rate-limiting step(s) being comparable to the energetics of Stone-Wales rearrangement reactions. The identified chemical pathways provide fundamental insights into the mechanisms that underlie C60 formation. Moreover, they clearly demonstrate that top-down synthesis of C60 from graphitic sources is a viable synthesis route at conditions pertaining to circumstellar matter.

Molecular Conformation in Charge Tunneling across Large-Area Junctions.

Self-assembled monolayers are predicated on thermodynamic equilibrium; hence, their properties project accessible relaxation pathways. Herein, we demonstrate that charge tunneling correlates with conformational degrees of freedom(s). Results from open chain and cyclic head groups show that, as expected, distribution in tunneling data correlates with the orientation of the head group, akin to the odd-even effect and more importantly the degree of conformational freedom, but fluctuates with applied bias. Trends in nature of distributions in current density illuminate the need for higher statistical moments in understanding these rather dynamic systems. We employ skewness, kurtosis, and estimation plots to show that the conformational degree of freedom in the head group significantly amplifies the odd-even effect and may lead to enhanced or perturbed tunneling based on whether the head group is on an odd- or even-parity spacer.

Substrate-Dependent Mobile Loop Conformational Changes in Alkanesulfonate Monooxygenase from Accelerated Molecular Dynamics.

Substrate-induced conformational changes present in alkanesulfonate monooxygenase (SsuD) are crucial to catalysis and lead to distinct interactions between a dynamic loop region and the active site. Accelerated molecular dynamics (aMD) simulations have been carried out to examine this potential correlation by studying wild-type SsuD and variant enzymes bound with different combinations of reduced flavin (FMNH2), C4a-peroxyflavin intermediate (FMNOO-), and octanesulfonate (OCS). Three distinct mobile loop conformations were identified: "open", "closed", and "semiclosed". The substrate-free SsuD system possessed a wide opening capable of providing full access for substrates to enter the active site. Upon binding FMNH2, SsuD adopts a closed conformation that would prevent unproductive oxidation reactions in the absence of OCS. Two salt bridges, Asp111-Arg263 and Glu205-Arg271, were identified as particularly important in maintaining the closed conformation. Experimental substitution of Arg271 to Ala did not alter the catalytic activity, but the variant in the presence of reduced flavin was more susceptible to proteolytic digestion compared to wild-type. With both FMNH2 and OCS bound in SsuD, a second conformation was formed dependent upon a favorable π-π interaction between His124 and Phe261. Accordingly, there was no observed activity with the F261W SsuD variant in steady-state kinetic assays. This semiclosed conformation may be more appropriate for accepting O2 into the binding pocket and/or may properly orient the active site for the ensuing oxygenolytic cleavage. Finally, simulations of SsuD simultaneously bound with FMNOO- and OCS found an open mobile loop region that suggests alternative flavin intermediates may participate in the reaction mechanism.

Examining Product Specificity in Protein Arginine Methyltransferase 7 (PRMT7) Using Quantum and Molecular Mechanical Simulations.

Protein arginine methyltransferase 7 (PRMT7) catalyzes the formation of monomethylarginine (MMA) but is incapable of performing a dimethylation. Given that PRMT7 performs vital functions in mammalian cells and has been implicated in a variety of diseases, including breast cancer and age-related obesity, elucidating the origin of its strict monomethylation activity is of considerable interest. Three active site residues, Glu172, Phe71, and Gln329, have been reported as particularly important for product specificity and enzymatic activity. To better understand their roles, mixed quantum and molecular mechanical (QM/MM) calculations coupled to molecular dynamics and free energy perturbation theory were carried out for the WT, F71I, and Q329S trypanosomal PRMT7 (TbPRMT7) enzymes bound with S-adenosyl- L-methionine (AdoMet) and an arginine substrate in an unmethylated or methylated form. The Q329S mutation, which experimentally abolished enzymatic activity, was appropriately computed to give an outsized Δ G‡ of 30.1 kcal/mol for MMA formation compared to 16.9 kcal/mol for WT. The F71I mutation, which has been experimentally shown to convert the enzyme from a type III PRMT into a mixed type I/II capable of forming dimethylated arginine products, yielded a reasonable Δ G‡ of 21.9 kcal/mol for the second turnover compared to 28.8 kcal/mol in the WT enzyme. Similar active site orientations for both WT and F71I TbPRMT7 allowed Glu172 and Gln329 to better orient the substrate for SN2 methylation, enhanced the nucleophilicity of the attacking guanidino group by reducing positive charge, and facilitated the binding of the subsequent methylated products.

Alkaline-encrusting pyelitis - A rare disastrous complication postPCNL leading to chronic renal failure.

Alkaline-encrusting pyelitis (AEP) is a severe form of infectious disease characterized by encrustation along the lining of the urinary tract leading to loss of renal function. Common predisposing factors are chronic infection, immunosuppression, and endourology procedures. Urea-producing organisms arefrequently associated, and urine alkalization leads to calcific deposition in the pelvicalyceal system. We present a 23-year male with AEP in a solitary kidney leading to chronic renal failure postpercutaneous nephrolithotomy for renal stones.

Phe71 in Type III Trypanosomal Protein Arginine Methyltransferase 7 (TbPRMT7) Restricts the Enzyme to Monomethylation.

Protein arginine methyltransferase 7 (PRMT7) is unique within the PRMT family as it is the only isoform known to exclusively make monomethylarginine (MMA). Given its role in epigenetics, the mechanistic basis for the strict monomethylation activity is under investigation. It is thought that PRMT7 enzymes are unable to add a second methyl group because of steric hindrance in the active site that restricts them to monomethylation. To test this, we probed the active site of trypanosomal PRMT7 (TbPRMT7) using accelerated molecular dynamics, site-directed mutagenesis, kinetic, binding, and product analyses. Both the dynamics simulations and experimental results show that the mutation of Phe71 to Ile converts the enzyme from a type III methyltransferase into a mixed type I/II, that is, an enzyme that can now perform dimethylation. In contrast, the serine and alanine mutants of Phe71 preserve the type III behavior of the native enzyme. These results are inconsistent with a sterics-only model to explain product specificity. Instead, molecular dynamics simulations of these variants bound to peptides show hydrogen bonding between would-be substrates and Glu172 of TbPRMT7. Only in the case of the Phe71 to Ile mutation is this interaction between MMA and the enzyme maintained, and the geometry for optimal SN2 methyl transfer is obtained. The results of these studies highlight the benefit of combined computational and experimental methods in providing a better understanding for how product specificity is dictated by PRMTs.

Cyclic vomiting syndrome: epidemiology, diagnosis, and treatment.

Cyclic-vomiting syndrome (CVS) is a chronic functional gastrointestinal disorder characterized by recurrent episodes of nausea and vomiting. Although once thought to be a pediatric disorder, there has been a considerable increase in recognition of CVS in adults. The exact pathogenesis is unknown and several theories have been proposed. Migraine and CVS share a similar pathophysiology as suggested by several studies. Since there are no specific biomarkers available for this disorder, physicians should rely on Rome criteria for the diagnosis. Due to the lack of randomized control trials, the treatment of CVS is primarily empirical.

Comparison of effectiveness and safety of excimer lamp vs topical calcipotriol-clobetasol propionate combination in the treatment of palmoplantar psoriasis.

BACKGROUND: Very few studies have assessed the efficacy of excimer in the treatment of palmoplantar psoriasis (PPP), and none has compared the excimer with calcipotriol-clobetasol propionate combination. PURPOSE: To compare the effectiveness and safety of excimer lamp vs topical ointment containing calcipotriol (0.005% w/w) and clobetasol propionate (0.05% w/w) combination in PPP. METHODS: This right-left randomization trial included 36 patients with PPP, who received treatment with excimer lamp (twice weekly) on one side and calcipotriol-clobetasol combination (once daily) on another side for 12 weeks, followed by 8 weeks of follow-up. Recruitment and response assessment was done by 2 experienced dermatologists (SD and TN) using modified palmoplantar pustular psoriasis area and severity index score (mPPPASI, originally devised for palmoplantar pustulosis, suitably modified to assess response in PPP). Primary outcome measure was percentage improvement in mPPPASI at 12 weeks, which was classified as minimal (≤25%), mild (>25%-50%), moderate (>50%-75%), and marked (>75%). Secondary outcome measures were the proportion of patients achieving >75% reduction in mPPPASI and the time taken to achieve it. RESULTS: Of 36 recruited patients, 33 completed treatment and 21 adhered to 8-weeks follow-up. The mean mPPPASI on the excimer-treated sides reduced significantly from 7.75 ± 4.62 to 4.01 ± 4.07 (P < .001) at 12th week (end of the treatment) and 2.66 ± 3.97 at 20th week (at 8 weeks follow-up). The mean mPPPASI on the calcipotriol-clobetasol combination treated sides reduced significantly from 7.36 ± 4.46 to 3.55 ± 3.77 (P < .001) and 2.70 ± 3.97 at 12th week and 20th week, respectively. The reduction was significant for both treatment and the difference between the two was not statistically significant. Minimal, mild, moderate, and marked improvement was seen in 5/33 (15.2%) and 1/33 (3.0%), 6/33 (18.2%) and 8/33 (24.2%), 12/33 (36.4%) and 13/33 (39.4%), and 8/33 (24.2%) and 8/33 (24.2%) sides in the excimer and calcipotriol-clobetasol combination, respectively. A total of 8 patients in each group achieved mPPPASI 75 at 12 weeks. The mPPPASI 75 was achieved at 2, 4, and 8 weeks in 1, 2, and 8 patients, respectively, using either modalities. The adverse effects (most commonly hyperpigmentation) were noted more frequently on the excimer-treated sides; however, they were well tolerated. CONCLUSION: Both excimer lamp and calcipotriol-clobetasol propionate combination are equally effective in the treatment of PPP.

A Case of Optic Neuritis Secondary to Lyme Disease.

INTRODUCTION: Optic neuritis is a condition associated with various systemic diseases, such as multiple sclerosis, and is also considered a rare complication of Lyme disease. CASE: A 46-year-old white woman presented with sudden onset of bilateral vision loss. After extensive workup, she was diagnosed with Lyme optic neuritis based on the clinical presentation and positive serology. She was treated with doxycycline for 2 weeks. DISCUSSION: Lyme disease is caused by infection with the spirochete Borrelia burgdorferi. The most commonly affected areas include the skin, joints, heart, and nervous system. Lyme optic neuritis is a challenging diagnosis and therefore often underreported. Doxycycline or ceftriaxone for 2 weeks are recommended for treatment. CONCLUSION: We report this case to increase awareness among clinicians to include Lyme disease in the differential diagnosis of optic neuritis for unexplained cases of vision loss, particularly in Lyme endemic areas.

Evolutionary sequence and structural basis for the distinct conformational landscapes of Tyr and Ser/Thr kinases.

Protein kinases are molecular machines with rich sequence variation that distinguishes the two main evolutionary branches - tyrosine kinases (TKs) from serine/threonine kinases (STKs). Using a sequence co-variation Potts statistical energy model we previously concluded that TK catalytic domains are more likely than STKs to adopt an inactive conformation with the activation loop in an autoinhibitory "folded" conformation, due to intrinsic sequence effects. Here we investigated the structural basis for this phenomenon by integrating the sequence-based model with structure-based molecular dynamics (MD) to determine the effects of mutations on the free energy difference between active and inactive conformations, using a novel thermodynamic cycle involving many (n=108) protein-mutation free energy perturbation (FEP) simulations in the active and inactive conformations. The sequence and structure-based results are consistent and support the hypothesis that the inactive conformation "DFG-out Activation Loop Folded", is a functional regulatory state that has been stabilized in TKs relative to STKs over the course of their evolution via the accumulation of residue substitutions in the activation loop and catalytic loop that facilitate distinct substrate binding modes in trans and additional modes of regulation in cis for TKs.

Potts Hamiltonian Models and Molecular Dynamics Free Energy Simulations for Predicting the Impact of Mutations on Protein Kinase Stability.

Single-point mutations in kinase proteins can affect their stability and fitness, and computational analysis of these effects can provide insights into the relationships among protein sequence, structure, and function for this enzyme family. To assess the impact of mutations on protein stability, we used a sequence-based Potts Hamiltonian model trained on a kinase family multiple-sequence alignment (MSA) to calculate the statistical energy (fitness) effects of mutations and compared these against relative folding free energies (ΔΔGs) calculated from all-atom molecular dynamics free energy perturbation (FEP) simulations in explicit solvent. The fitness effects of mutations in the Potts model (ΔEs) showed good agreement with experimental thermostability data (Pearson r = 0.68), similar to the correlation we observed with ΔΔGs predicted from structure-based relative FEP simulations. Recognizing the possible advantages of using Potts models to rapidly estimate protein stability effects of kinase mutations seen in cancer genomics data, we used the Potts statistical energy model to estimate the stability effects of 65 conservative and nonconservative mutations across three distinct kinases (Wee1, Abl1, and Cdc7) with somatic mutations reported in the Genomic Data Commons (GDC) database. The ΔEs of these mutations calculated from the Potts model are consistent with the corresponding ΔΔGs from FEP simulations (Pearson ratio of 0.72). The agreement between these methods suggests that the Potts model may be used as a sequence-based tool for high-throughput screening of mutational effects as part of a computational pipeline for predicting the stability effects of mutations. We also demonstrate how the scalability of the fitness-based Potts model calculations permits analyses that are not easily accessed using FEP simulations. To this end, we employed site-saturation mutagenesis in the Potts model in order to investigate the relative stability effects of mutations seen in different cancer evolutionary scenarios. We used this approach to analyze the effects of drug pressure in Abl kinase by contrasting the relative fitness penalties of somatic mutations seen in miscellaneous cancer types with those calculated for mutations associated with cancer drug resistance. We observed that, in contrast to somatic mutations of Abl seen in various tumors that appear to have evolved neutrally, cancer mutations that evolved under drug pressure in Abl-targeted therapies tend to preserve enzyme stability.

Deep Learning Approaches for Medical Image Analysis and Diagnosis.

In addition to enhancing diagnostic accuracy, deep learning techniques offer the potential to streamline workflows, reduce interpretation time, and ultimately improve patient outcomes. The scalability and adaptability of deep learning algorithms enable their deployment across diverse clinical settings, ranging from radiology departments to point-of-care facilities. Furthermore, ongoing research efforts focus on addressing the challenges of data heterogeneity, model interpretability, and regulatory compliance, paving the way for seamless integration of deep learning solutions into routine clinical practice. As the field continues to evolve, collaborations between clinicians, data scientists, and industry stakeholders will be paramount in harnessing the full potential of deep learning for advancing medical image analysis and diagnosis. Furthermore, the integration of deep learning algorithms with other technologies, including natural language processing and computer vision, may foster multimodal medical data analysis and clinical decision support systems to improve patient care. The future of deep learning in medical image analysis and diagnosis is promising. With each success and advancement, this technology is getting closer to being leveraged for medical purposes. Beyond medical image analysis, patient care pathways like multimodal imaging, imaging genomics, and intelligent operating rooms or intensive care units can benefit from deep learning models.

Evolutionary sequence and structural basis for the distinct conformational landscapes of Tyr and Ser/Thr kinases.

Protein kinases are molecular machines with rich sequence variation that distinguishes the two main evolutionary branches - tyrosine kinases (TKs) from serine/threonine kinases (STKs). Using a sequence co-variation Potts statistical energy model we previously concluded that TK catalytic domains are more likely than STKs to adopt an inactive conformation with the activation loop in an autoinhibitory "folded" conformation, due to intrinsic sequence effects. Here we investigated the structural basis for this phenomenon by integrating the sequence-based model with structure-based molecular dynamics (MD) to determine the effects of mutations on the free energy difference between active and inactive conformations, using a novel thermodynamic cycle involving many (n=108) protein-mutation free energy perturbation (FEP) simulations in the active and inactive conformations. The sequence and structure-based results are consistent and support the hypothesis that the inactive conformation "DFG-out Activation Loop Folded", is a functional regulatory state that has been stabilized in TKs relative to STKs over the course of their evolution via the accumulation of residue substitutions in the activation loop and catalytic loop that facilitate distinct substrate binding modes in trans and additional modes of regulation in cis for TKs.

Tuning Caco-2 permeability by cocrystallization: Insights from molecular dynamics simulation.

Emerging evidence suggests that intestinal permeability can be potentially enhanced through cocrystallization. However, a mechanism for this effect remains to be established. In this study, we first demonstrate the enhancement in intestinal permeability, evaluated by the Caco-2 cell permeability assay, of acetazolamide (ACZ) in the presence of a conformer, p-aminobenzoic acid (PABA), delivered in the form of a 1:1 cocrystal. The binding strength of ACZ and PABA with the Pgp efflux transporter, either alone or as a mixture, was calculated using molecular dynamics simulation. Results show that PABA weakens the binding of ACZ with Pgp, which leads to a lower efflux ratio and elevated permeability of ACZ. This work provides molecular-level insights into a potentially effective strategy to improve the intestinal permeability of drugs. If the same cocrystal also exhibits higher solubility, oral bioavailability of BCS IV drugs can likely be improved by forming a cocrystal with a Pgp inhibitor.

Septic arthritis by Nocardia farcinica: Case report and literature review.

Nocardiosis is a bacterial infection caused by organisms of the Nocardia genus. The disease typically involves the skin, central nervous system or pulmonary system. Very rarely nocardiosis can cause disease of other organs including bone and joints. Nocardiosis is typically a chronic, somewhat indolent infection, occurring in patients with defective cell mediated immunity. We describe a 78-year-old female with right shoulder septic arthritis resulting from Nocardia farcinica with associated involvement of her skin and lungs as well. She was treated with surgical debridement and combination antibiotic therapy. We also share a literature review of bone and joint infection caused by the N. farcinica species, highlighting its rarity. Understanding uncommon manifestations of nocardiosis allows for early recognition and treatment of the condition and optimal patient care.

Allogenic adipose derived mesenchymal stem cells are effective than antibiotics in treating endometritis.

Endometritis is a uterine inflammatory disease that causes reduced livestock fertility, milk production and lifespan leading to significant economic losses to the dairy industry. Mesenchymal stem cells (MSC) may act as an alternative for inefficacy of antibiotics and rising antibiotic resistance in endometritis. The present study aimed to cure the chronic endometritic buffaloes using allogenic adipose-derived MSCs (AD-MSC). AD-MSCs were isolated from buffalo adipose tissue and characterized by multilineage differentiation as well as MSC-specific markers. The in vivo safety and efficacy were assessed after infusion of AD-MSCs. In safety trial, cells were administered in healthy buffaloes via different routes (IV and IC) followed by examination of clinical and hematological parameters. In efficacy study, AD-MSCs treatments (IV and IC) and antibiotic therapy (ABT) in endometritic buffaloes were comparatively evaluated. AD-MSCs did not induced any immunological reaction in treated buffaloes. PMN count, CRP levels and VDS were significantly (p ≤ 0.05) reduced after AD-MSCs infusions in IV and IC groups and no significant difference was observed in antibiotic group. The IV group was marked with 50% absolute risk reduction in endometritis and 50% live calf births after artificial insemination in comparison with ABT group. Anti-inflammatory cytokines (IL4 and IL10) and anti-microbial peptides (PI3, CATHL4, LCN2 and CST3) expressions were significantly (p ≤ 0.05) upregulated in IV group. The calf delivery rate after the treatments in IV group was higher (50%, 3 calves) than the other groups (IC: 33.3%, 2 calves; ABT: 16.6%, 1 calf). In conclusion, the administration of AD-MSCs through IV route was found to be safe and efficacious for alleviating chronic endometritis in dairy buffaloes.

Coronary Stent Infections - A Systematic Review and Meta-Analysis.

BACKGROUND: Coronary stent infection (CSI) represents a rare but potentially fatal complication of percutaneous coronary interventions (PCI). A systematic review and meta-analysis of published reports was performed to profile CSI and its management strategies. METHODS: Online database searches were performed using MeSH and keywords. The primary outcome of the study was in-hospital mortality. A unique Artificial Intelligence-based predictive model was developed for need for delayed surgery and probability of survival on medical therapy alone. RESULTS: A total of 79 subjects were included in the study. Twenty eight (35.0 %) patients had type 2 diabetes mellitus. Subjects most commonly reported symptoms within the first week of the procedure (43 %). Fever was the most common initial symptom (72 %). Thirty eight percent of patients presented with acute coronary syndrome. The presence of mycotic aneurysms was described in 62 % of patients. Staphylococcus species were the most common (65 %) isolated organism. The primary outcome of in-hospital mortality was seen in a total of 24 patients out of 79 (30.3 %). A comparative univariate analysis comparing those encountering in-hospital mortality versus otherwise revealed the presence of structural heart disease (83 % mortality vs 17 % survival, p = 0.009), and the presence of non ST elevation acute coronary syndrome (11 % mortality vs 88 % survival, p = 0.03), to be a statistically significant factor predicting in-hospital mortality. In an analysis between patients with successful versus failed initial medical therapy, patients from private teaching hospitals (80.0 % vs 20.0 %; p = 0.01, n = 10) had a higher survival with medical therapy alone. CONCLUSION: CSI is a highly under-studied disease entity with largely unknown risk factors and clinical outcomes. Larger studies are needed to further define the characteristics of CSI. (PROSPERO ID CRD42021216031).