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.

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.

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.

Candida Score: a Predictor of Mortality in Patients with Candidemia.

BACKGROUND: Candida score has been developed and used for identifying patients at risk for developing Candida infections. However, its usefulness in predicting outcome of patients with candidemia has not been evaluated. We aimed to determine the risk factors for mortality in patients with candidemia admitted to an Indian medical intensive care unit (ICU). METHODS: We conducted a retrospective cohort analysis of 56 patients with candidemia presented in 18 months duration. Baseline patient characteristics, ICU course and outcome were noted and Candida score was calculated. We conducted analysis based on the primary outcome measure of ICU mortality. RESULTS: Out of 3,142 ICU admissions, the incidence of candidemia was 17.8/1,000 admissions. The mean interval between ICU admission and candidemia was 12.9 ± 14.4 days. C. tropicalis was the commonest species isolated from 28.6% isolates, followed by Candida albicans (21.4%) and C. glabrata (12.5%). The mean length of ICU stay was 22.9 ± 28 days and hospital stay was 30.1 ± 30.2 days. Crude ICU mortality was 33.93%. There was no statistically significant difference between mortality of patients with albicans and non-albicans candidemia (p=0.732). On multivariate analysis, only two factors, previous antifungal therapy (p=0.004, OR=101.4, 95% CI=4.52-227.7) and Candida score >3 (p=0.028, OR=13.2, 95% CI=1.3-125) were found to be independently predicting mortality. CONCLUSION: Candida infection is generally late-onset and is associated with a prolonged ICU and hospital stay, and a high mortality. Candida non-albicans infection was more common but there was no difference in mortality among patients with C. albicans and non-albicans infection. Previous antifungal therapy and Candida score were found to be independently predicting mortality.

Vitamin C-induced Hemolysis: Meta-summary and Review of Literature.

Vitamin C is increasingly being used, and even high doses are considered safe. However, complications including hemolysis have been reported. We performed a systematic search from PubMed, Science Direct, and Google Scholar databases from January 1975 till July 31, 2021. Search terms used were "Vitamin C" OR "ascorbic acid" AND "haemolysis" OR "haemolytic anaemia." Data regarding patient's demographics, outcomes and dose, duration, and form of vitamin C were extracted. Fourteen case reports matched the selected criteria, with age ranging from 3 weeks to 75 years with 78.6% being males. About 71.4% were diagnosed to have glucose-6-phosphate dehydrogenase (G6PD) deficiency but previous hemolysis was reported in only two patients, and 57.1% were prescribed vitamin C for nutritional supplementation. The dose ranged from 1 to 200 g/day with 57.1% receiving intravenous formulations. Half of these patients developed other complications including acute kidney injury (AKI), disseminated intravascular coagulation, oxalosis, and methemoglobinemia. About 78.6% developed complications within 3 days of starting vitamin C and only one death was reported. Vitamin C is generally a safe drug but it should be prescribed with caution and only when benefits outweigh the risks. Physicians should be aware of potential complications like severe hemolysis and AKI, especially when using high doses and in G6PD deficiency. How to cite this article: Juneja D, Jain R, Nasa P. Vitamin C-induced Hemolysis: Meta-summary and Review of Literature. Indian J Crit Care Med 2022;26(2):224-227.

Effect of Urinary Trypsin Inhibitor (Ulinastatin) Therapy in COVID-19.

Purpose: End-organ damage in coronavirus disease-2019 (COVID-19) is linked to "cytokine storm" and excessive release of inflammatory mediators. Various novel therapies have been used in COVID-19 including urinary trypsin inhibitor therapy. This study explores the efficacy of ulinastatin in COVID-19. Materials and methods: We retrieved the medical records of patients admitted during one month and did a propensity score analysis to create matched treatment and control groups. We analyzed these groups and the outcomes were presented with appropriate statistics. Survival curve was prepared to compare the survival effect of ulinastatin therapy at the end of hospitalization, among both the groups. Results: A total of 736 patients were admitted, and after adjusting the data with propensity score matching, 55 cases were selected by the system. On the final outcome analysis, we found that intensive care unit (ICU) length of stay [median (interquartile range) days 3 (3.5-7.8) vs 2 (0-4); p-value 0.28] in control vs intervention groups, and in hospital mortality (odds ratio: 0.491, CI 95%: 0.099-2.44, p-value 0.435) were not statistically different among the groups. In survival plot analysis also, there was no statistical difference (p-value 0.414) among both the groups.Conclusion: In this retrospective study, we conclude that the final outcome of the ICU length of stay, and overall, in hospital mortality were not different among both the groups. Hence, adequately powered randomized control trials are urgently required to confirm any benefit of ulinastatin therapy in COVID-19 treatment. How to cite this article: Jain A, Kasliwal R, Jain SS, Jain R, Gupta D, Gupta P, et al. Effect of Urinary Trypsin Inhibitor (Ulinastatin) Therapy in COVID-19. Indian J Crit Care Med 2022;26(6):696-703.

Expert consensus statements for the management of COVID-19-related acute respiratory failure using a Delphi method.

BACKGROUND: Coronavirus disease 2019 (COVID-19) pandemic has caused unprecedented pressure on healthcare system globally. Lack of high-quality evidence on the respiratory management of COVID-19-related acute respiratory failure (C-ARF) has resulted in wide variation in clinical practice. METHODS: Using a Delphi process, an international panel of 39 experts developed clinical practice statements on the respiratory management of C-ARF in areas where evidence is absent or limited. Agreement was defined as achieved when > 70% experts voted for a given option on the Likert scale statement or > 80% voted for a particular option in multiple-choice questions. Stability was assessed between the two concluding rounds for each statement, using the non-parametric Chi-square (χ2) test (p < 0·05 was considered as unstable). RESULTS: Agreement was achieved for 27 (73%) management strategies which were then used to develop expert clinical practice statements. Experts agreed that COVID-19-related acute respiratory distress syndrome (ARDS) is clinically similar to other forms of ARDS. The Delphi process yielded strong suggestions for use of systemic corticosteroids for critical COVID-19; awake self-proning to improve oxygenation and high flow nasal oxygen to potentially reduce tracheal intubation; non-invasive ventilation for patients with mixed hypoxemic-hypercapnic respiratory failure; tracheal intubation for poor mentation, hemodynamic instability or severe hypoxemia; closed suction systems; lung protective ventilation; prone ventilation (for 16-24 h per day) to improve oxygenation; neuromuscular blocking agents for patient-ventilator dyssynchrony; avoiding delay in extubation for the risk of reintubation; and similar timing of tracheostomy as in non-COVID-19 patients. There was no agreement on positive end expiratory pressure titration or the choice of personal protective equipment. CONCLUSION: Using a Delphi method, an agreement among experts was reached for 27 statements from which 20 expert clinical practice statements were derived on the respiratory management of C-ARF, addressing important decisions for patient management in areas where evidence is either absent or limited. TRIAL REGISTRATION: The study was registered with Clinical trials.gov Identifier: NCT04534569.

Development of novel anti-malarial from structurally diverse library of molecules, targeting plant-like CDPK1, a multistage growth regulator of P. falciparum.

Upon Plasmodium falciparum merozoites exposure to low [K+] environment in blood plasma, there is escalation of cytosolic [Ca2+] which activates Ca2+-Dependent Protein Kinase 1 (CDPK1), a signaling hub of intra-erythrocytic proliferative stages of parasite. Given its high abundance and multidimensional attributes in parasite life-cycle, this is a lucrative target for designing antimalarials. Towards this, we have virtually screened MyriaScreenII diversity collection of 10,000 drug-like molecules, which resulted in 18 compounds complementing ATP-binding pocket of CDPK1. In vitro screening for toxicity in mammalian cells revealed that these compounds are non-toxic in nature. Furthermore, SPR analysis demonstrated differential binding affinity of these compounds towards recombinantly purified CDPK1 protein. Selection of lead compound 1 was performed by evaluating their inhibitory effects on phosphorylation and ATP binding activities of CDPK1. Furthermore, in vitro biophysical evaluations by ITC and FS revealed that binding of compound 1 is driven by formation of energetically favorable non-covalent interactions, with different binding constants in presence and absence of Ca2+, and TSA authenticated stability of compound 1 bound CDPK1 complex. Finally, compound 1 strongly inhibited intra-erythrocytic growth of P. falciparum in vitro. Conceivably, we propose a novel CDPK1-selective inhibitor, step towards developing pan-CDPK kinase inhibitors, prerequisite for cross-stage anti-malarial protection.

Molecular dynamics simulations and biochemical characterization of Pf14-3-3 and PfCDPK1 interaction towards its role in growth of human malaria parasite.

Scaffold proteins play pivotal role as modulators of cellular processes by operating as multipurpose conformation clamps. 14-3-3 proteins are gold-standard scaffold modules that recognize phosphoSer/Thr (pS/pT) containing conserved motifs, and confer conformational changes leading to modulation of functional parameters of their target proteins. Modulation in functional activity of kinases has been attributed to their interaction with 14-3-3 proteins. Herein, we have annotated and characterized PF3D7_0818200 as 14-3-3 isoform I in Plasmodium falciparum 3D7, and its interaction with one of the key kinases of the parasite, Calcium-Dependent Protein Kinase 1 (CDPK1) by performing various analytical biochemistry and biophysical assays. Molecular dynamics simulation studies indicated that CDPK1 polypeptide sequence (61KLGpS64) behaves as canonical Mode I-type (RXXpS/pT) consensus 14-3-3 binding motif, mediating the interaction. The 14-3-3I/CDPK1 interaction was validated in vitro with ELISA and SPR, which confirmed that the interaction is phosphorylation dependent, with binding affinity constant of 670 ± 3.6 nM. The interaction of 14-3-3I with CDPK1 was validated with well characterized optimal 14-3-3 recognition motifs: Mode I-type ARSHpSYPA and Mode II-type RLYHpSLPA, by simulation studies and ITC. This interaction was found to marginally enhance CDPK1 functional activity. Furthermore, interaction antagonizing peptidomimetics showed growth inhibitory impact on the parasite indicating crucial physiological role of 14-3-3/CDPK1 interaction. Overall, this study characterizes 14-3-3I as a scaffold protein in the malaria parasite and unveils CDPK1 as its previously unidentified target. This sets a precedent for the rational design of 14-3-3 based PPI inhibitors by utilizing 14-3-3 recognition motif peptides, as a potential antimalarial strategy.

Practice Pattern of Critical Care Physicians in India for Use of Corticosteroids in COVID-19.

Introduction: Steroids are recommended as the standard of care in managing severe COVID-19. However, several questions remain unanswered regarding the prescription of steroids which led to differing opinions and practice. We surveyed practice patterns of critical care physicians in India for the use of corticosteroids in COVID-19. Methods: This was a nationwide, cross-sectional, online, knowledge attitude practice-based survey, among intensivists for corticosteroid use in COVID-19. The survey questionnaire had seven questions for demographic data and 14 questions in the core survey. Results: 384 responses were analyzed from different parts of the country. A majority (81.2%) agreed that steroids improved oxygenation and survival chances. 88.3% agreed that steroids are indicated because of their anti-inflammatory properties, and should be prescribed in patients with moderate (75.8%), severe (59.9%), or critical (41.1%) COVID-19. 68.8% of physicians start steroids on the basis of "need for oxygen therapy" and hyperglycemia (85.2%) was the most commonly reported complication. 59.1% prefer prescribing methylprednisolone followed by Dexamethasone (38.8%). 51.8% preferred to use low dose steroids, and 59.1% have used "pulse steroids''. Rather than a fixed duration of therapy, 66.9% of the respondents rely on "clinical improvement" before stopping steroids, even if it meant continuing steroids for prolonged periods beyond 14 days (34.1%). 57.8% always taper steroids before stopping. Conclusions: We found wide variation in the practice patterns of critical care physicians in India for use of Corticosteroids in COVID-19. The dilemma regarding when to initiate, type of steroid, dose, and duration of therapy still persist emphasizing the need for further research.

Comparison of Predictive Ability of Epidemiological Factors, Inflammatory Biomarkers, and CT Severity Score for Mortality in COVID-19.

INTRODUCTION: COVID-19 patients are categorized as per their clinical severity and their level of care is decided based on the clinical severity. Apart from clinical severity of patients, a need for robust predictors was also felt for early categorization and accurate prediction of final fatal outcome in hospitalized patients. MATERIAL AND METHOD: In this retrospective observational cohort study all the adult patients admitted during November month were included. Available data for epidemiological factors, inflammatory biomarkers and CT severity score were collected and analyzed by univariate and multivariate logistic regression analysis to know predictive ability of each variable. A Receiver operating characteristic analysis was done to compare the predictive ability of each factor for final outcome of death. RESULTS: We analyzed records of 735 total patients. Most of them were male (72.38%), have a median (IQR) age of 60 years (50-69). Diabetes (42.85%), and hypertension (39.86%) were the most common co-morbidities. After univariate and multivariate regression analysis we could find that CRP, D-Dimer and CT severity score levels only can predict final outcome of death. During multivariate regression and receiver operative characteristic (ROC) analysis also, age and Charlson's co-morbidity index failed to predict in hospital mortality. CRP and D-Dimer on admission positively predicts final outcome of in hospital mortality with AUROC of 0.749(p=0.007, CI 0.61-0.88), and 0.864(p= 0.000, CI 0.74-0.99) respectively. Whereas, CT severity score had AUROC 0.73 (p= 0.014, CI 0.575-0.83). Cut off for CRP was 45 mg/L (Sn 0.8, Sp 0.56), D-dimer was 1000 µg/L (Sn:0.8, Sp: 0.9), and CT severity score was 15 (Sn 0.8, Sp 0.58). CONCLUSION: CRP level of 45 mg/l, D-dimer level of 1000 µg/L and CT severity level of >15 at the time of admission can be added to conventional clinical severity algorithm to more accurately predicting final outcome and stratifying the level of care offered at the time of admission, and hence may improve odds off survival.

Expert Consensus Statements on the Use of Corticosteroids in Non-severe COVID-19.

INTRODUCTION: There is strong evidence for the use of corticosteroid in the management of severe coronavirus disease-2019 (COVID-19). However, there is still uncertainty about the timing of corticosteroids. We undertook a modified Delphi study to develop expert consensus statements on the early identification of a subset of patients from non-severe COVID-19 who may benefit from using corticosteroids. METHODS: A modified Delphi was conducted with two anonymous surveys between April 30, 2021, and May 3, 2021. An expert panel of 35 experts was selected and invited to participate through e-mail. The consensus was defined as >70% votes in multiple-choice questions (MCQ) on Likert-scale type statements, while strong consensus as >90% votes in MCQ or >50% votes for "very important" on Likert-scale questions in the final round. RESULTS: Twenty experts completed two rounds of the survey. There was strong consensus for the increased work of breathing (95%), a positive six-minute walk test (90%), thorax computed tomography severity score of >14/25 (85%), new-onset organ dysfunction (using clinical or biochemical criteria) (80%), and C-reactive protein >5 times the upper limit of normal (70%) as the criteria for patients' selection. The experts recommended using oral or intravenous (IV) low-dose corticosteroids (the equivalent of 6 mg/day dexamethasone) for 5-10 days and monitoring of oxygen saturation, body temperature, clinical scoring system, blood sugar, and inflammatory markers for any "red-flag" signs. CONCLUSION: The experts recommended against indiscriminate use of corticosteroids in mild to moderate COVID-19 without the signs of clinical worsening. Oral or IV low-dose corticosteroids (the equivalent of 6 mg/day dexamethasone) for 5-10 days are recommended for patients with features of disease progression based on clinical, biochemical, or radiological criteria after 5 days from symptom onset under close monitoring. HOW TO CITE THIS ARTICLE: How to cite this article: Nasa P, Chaudhry D, Govil D, Daga MK, Jain R, Chhallani AA, et al. Expert Consensus Statements on the Use of Corticosteroids in Non-severe COVID-19. Indian J Crit Care Med 2021;25(11):1280-1285.

Factors associated with screening positive for high falls risk in fragility fracture patients: a cross-sectional study.

BACKGROUND: We sought to report the prevalence of fragility fracture patients who were screened at high falls risk using a large provincial database, and to determine the characteristics associated with being screened at high falls risk. METHODS: The study population included fragility fracture patients 50+ years of age who were screened at 35 hospital fracture clinics in Ontario over a 3.5 year period. The outcome was based on two screening questions measuring the risk of falling, both adapted from the STEADI (Stopping Elderly Accidents, Deaths & Injuries) tool. Multivariable associations of sociodemographic, fracture-related, and health-related characteristics were evaluated using logistic regression. RESULTS: Of the sample, 9735 (44.5%) patients were classified as being at high falls risk, and 12,089 (55.3%) were not. In the multivariable logistic regression, being 80+ years of age (vs. 50-64 years of age), non-community dwelling (vs. living with spouse, family member, roommate), having a mental/physical impairment (vs. none), and taking multiple medications, were all strongly associated with being screened at high falls risk. CONCLUSIONS: Living in a non-community dwelling and taking 4+ medications were the variables most strongly associated with being screened at high falls risk. These are potentially modifiable characteristics that should be considered when assessing falls risk in fragility fracture patients, and particularly when designing interventions for preventing subsequent falls. Ongoing work to address the higher risk of falls in the fragility fracture population is warranted.

Indian Society of Critical Care Medicine Position Statement for Central Venous Catheterization and Management 2020.

BACKGROUND AND PURPOSE: Short-term central venous catheterization (CVC) is one of the commonly used invasive interventions in ICU and other patient-care areas. Practice and management of CVC is not standardized, varies widely, and need appropriate guidance. Purpose of this document is to provide a comprehensive, evidence-based and up-to-date, one document source for practice and management of central venous catheterization. These recommendations are intended to be used by critical care physicians and allied professionals involved in care of patients with central venous lines. METHODS: This position statement for central venous catheterization is framed by expert committee members under the aegis of Indian Society of Critical Care Medicine (ISCCM). Experts group exchanged and reviewed the relevant literature. During the final meeting of the experts held at the ISCCM Head Office, a consensus on all the topics was made and the recommendations for final document draft were prepared. The final document was reviewed and accepted by all expert committee members and after a process of peer-review this document is finally accepted as an official ISCCM position paper.Modified grade system was utilized to classify the quality of evidence and the strength of recommendations. The draft document thus formulated was reviewed by all committee members; further comments and suggestions were incorporated after discussion, and a final document was prepared. RESULTS: This document makes recommendations about various aspects of resource preparation, infection control, prevention of mechanical complication and surveillance related to short-term central venous catheterization. This document also provides four appendices for ready reference and use at institutional level. CONCLUSION: In this document, committee is able to make 54 different recommendations for various aspects of care, out of which 40 are strong and 14 weak recommendations. Among all of them, 42 recommendations are backed by any level of evidence, however due to paucity of data on 12 clinical questions, a consensus was reached by working committee and practice recommendations given on these topics are based on vast clinical experience of the members of this committee, which makes a useful practice point. Committee recognizes the fact that in event of new emerging evidences this document will require update, and that shall be provided in due time. ABBREVIATIONS LIST: ABHR: Alcohol-based hand rub; AICD: Automated implantable cardioverter defibrillator; BSI: Blood stream infection; C/SS: CHG/silver sulfadiazine; Cath Lab: Catheterization laboratory (Cardiac Cath Lab); CDC: Centers for Disease Control and Prevention; CFU: Colony forming unit; CHG: Chlorhexidine gluconate; CL: Central line; COMBUX: Comparison of Bedside Ultrasound with Chest X-ray (COMBUX study); CQI: Continuous quality improvement; CRBSI: Catheter-related blood stream infection; CUS: Chest ultrasonography; CVC: Central Venous Catheter; CXR: Chest X-ray; DTTP: Differential time to positivity; DVT: Deep venous thrombosis; ECG: Electrocardiography; ELVIS: Ethanol lock and risk of hemodialysis catheter infection in critically ill patients; ER: Emergency room; FDA: Food and Drug Administration; FV: Femoral vein; GWE: Guidewire exchange; HD catheter: Hemodialysis catheter; HTS: Hypertonic saline; ICP: Intracranial pressure; ICU: Intensive Care Unit; IDSA: Infectious Disease Society of America; IJV: Internal jugular vein; IPC: Indian penal code; IRR: Incidence rate ratio; ISCCM: Indian Society of Critical Care Medicine; IV: Intravenous; LCBI: Laboratory confirmed blood stream infection; M/R: Minocycline/rifampicin; MBI-LCBI: Mucosal barrier injury laboratory-confirmed bloodstream infection; MRSA: Methicillin-resistant Staphylococcus aureus; NHS: National Health Service (UK); NHSN: National Healthcare Safety Network (USA); OT: Operation Theater; PICC: Peripherally-inserted central catheter; PIV: Peripheral intravenous line; PL: Peripheral line; PVI: Povidone-iodine; RA: Right atrium; RCT: Randomized controlled trial; RR: Relative risk; SCV/SV: Subclavian vein; ScVO2: Central venous oxygen saturation; Sn: Sensitivity; SOP: Standard operating procedure; SVC: Superior vena cava; TEE: Transesophageal echocardiography; UPP: Useful Practice Points; USG: Ultrasonography; WHO: World Health Organization. HOW TO CITE THIS ARTICLE: Javeri Y, Jagathkar G, Dixit S, Chaudhary D, Zirpe KG, Mehta Y, et al. Indian Society of Critical Care Medicine Position Statement for Central Venous Catheterization and Management 2020. Indian J Crit Care Med 2020;24(Suppl 1):S6-S30.

Design and synthesis of imidazolidinone derivatives as potent anti-leishmanial agents by bioisosterism.

Bioisosterism is a useful strategy in rational drug design to improve pharmacodynamic and pharmacokinetic properties of lead compounds. Imidazolidinones have been reported as potent kinase inhibitors and antileishmanial agents. In this study, bioisosteres of imidazolidinones (compounds 1-3) were evaluated for their antileishmanial properties. The modified imidazolidinones exhibited potent antileishmanial activity against extracellular as well as intracellular Leishmania donovani parasites in nanomolar concentrations. The selectivity index of these compounds on host cells was found to be more than 1000, emphasizing their specificity toward the parasite. Using SwissTargetPrediction software, we assessed the potential targets of these compounds and found MAPK as the most probable target. To in vitro validate, we developed a novel in vitro kinase assay that mimics the in vivo nature of the functional kinome. Compounds 1-3 displayed specific inhibition of parasite kinase activity accompanied by an increase in intracellular sodium levels in the parasites. This might be the effect of kinase inhibition that regulates sodium homeostasis through Na-ATPases. Finally, the compound-treated parasites underwent apoptosis-like death. This study represents bioisoterism as a novel approach for drug design to establish the structure-activity relationship, which in turn helps to improve the therapeutic activity of lead compounds.

Chronic Rhinosinusitis and the Evolving Understanding of Microbial Ecology in Chronic Inflammatory Mucosal Disease.

Chronic rhinosinusitis (CRS) encompasses a heterogeneous group of debilitating chronic inflammatory sinonasal diseases. Despite considerable research, the etiology of CRS remains poorly understood, and debate on potential roles of microbial communities is unresolved. Modern culture-independent (molecular) techniques have vastly improved our understanding of the microbiology of the human body. Recent studies that better capture the full complexity of the microbial communities associated with CRS reintroduce the possible importance of the microbiota either as a direct driver of disease or as being potentially involved in its exacerbation. This review presents a comprehensive discussion of the current understanding of bacterial, fungal, and viral associations with CRS, with a specific focus on the transition to the new perspective offered in recent years by modern technology in microbiological research. Clinical implications of this new perspective, including the role of antimicrobials, are discussed in depth. While principally framed within the context of CRS, this discussion also provides an analogue for reframing our understanding of many similarly complex and poorly understood chronic inflammatory diseases for which roles of microbes have been suggested but specific mechanisms of disease remain unclear. Finally, further technological advancements on the horizon, and current pressing questions for CRS microbiological research, are considered.

A study of attributable variables impacting orthopedic trauma surgical training.

PURPOSE: In medical colleges, resident training programs must provide adequate surgical experiences, making them qualified at the end of residency program. It is generally believed that it would take more time for a surgical resident to perform surgical procedures than a board-certified surgeon. There is no current benchmark with regards to operative time and surgical cases involving orthopedic surgery residents. In this study, we focused on two key aspects of surgical training variables, namely, surgical duration & C-arm shoots when the procedure is done by a faculty surgeon in comparison to done by an orthopedic resident under supervision of faculty surgeon. METHODS: It is an observational prospective study, we observed patients undergoing 1 of 5 common orthopedic trauma operations in a community teaching hospital. We recorded two variables, 'skin to skin' surgical duration & number of image intensifier television/C-arm shoots of faculty surgeons and orthopedic resident (postgraduate-3yr) under supervision of faculty surgeon. We calculated mean difference of two variables with or without resident & determined statistical significance, we also compared functional outcome at final follow-up. RESULTS: The total number of procedure observed was 402. On observing summarized results of all surgical procedures, faculty surgeons took on an average 33 min lesser (p < 0.05) & on an average 37 lesser number of shoots (p < 0.05) than resident surgeons. The difference in surgical duration tended to increase with the greater complexity of the surgical dissection. The difference in number of C-arm shoots tended to increase with the increase in surgical duration in closed procedures. In all the five procedures there was no significant difference (p > 0.05) in functional outcome of cases performed by faulty surgeon and resident. CONCLUSION: Little data has been previously published regarding the impact of teaching orthopedic resident in operating room. We demonstrate that resident participation increases the procedure time for commonly performed orthopedic procedures and also the number of C-arm shoots, hence there is a need for technical training facilities outside the operating room such as in cadaveric labs, saw bone labs & virtual surgery simulation. Also the preoperative plan should be thoroughly discussed by faculty surgeon with residents.

The Use of a Self-Occluding Topical Anasthetic in Daily Practice: A Non-Interventional Study.

INTRODUCTION: A variety of topical anesthetic creams are available to reduce pain associated with dermatological procedures. Pliaglis is a self-occluding eutectic mixture of lidocaine and tetracaine. STUDY OBJECTIVES: To evaluate the post-marketing safety profile of Pliaglis and efficacy in terms of pain reduction, product satisfaction, and daily practice use prior to pre-defined dermatological procedures. METHODS: A prospective, non-interventional study conducted at 44 sites in four European countries; 581 patients were treated prior to dermatological procedures such as pulsed-dye laser therapy, laser-assisted hair removal, non-ablative laser resurfacing, dermal filler injections, and vascular access. Efficacy was assessed by patients and investigators and included pain intensity (visual analogue scale [VAS]), satisfaction, and adequacy of pain relief. Safety was evaluated by adverse event (AE) reporting. RESULTS: In 75% of the performed procedures, patients scored the pain experienced during the procedure as ≤30 mm on the VAS and most were very satisfied or satisfied with the pain reduction. The investigators assessed the product as providing adequate anesthesia in 97% of the performed procedures and were mostly very satisfied or satisfied with the convenience of use (79%) and tolerability (95%). Twenty-four AEs were reported in 18 (3%) patients. DISCUSSION: Most patients experienced mild pain only as evident by the ≤ 30 mm VAS scores. Patients and investigators were aligned with regards to both product satisfaction and their opinion on adequacy of pain reduction. The AE frequency was low compared to previous studies, possibly relating to different ways of collecting AEs. CONCLUSION: Pliaglis was well-tolerated and provided adequate pain reduction prior to dermatological procedures. www.clinicaltrials.gov (NCT01800474).

J Drugs Dermatol. 2018;17(4):413-418.

Partial study data have been presented at the Anti-Aging Medicine European Congress (AMEC), Paris; October, 24-25, 2014, and the European Academy of Dermatology and Venereology (EADV), Istanbul; October 2-6, 2013.

Comprehensive Genome Scale Phylogenetic Study Provides New Insights on the Global Expansion of Chikungunya Virus.

Since the India and Indian Ocean outbreaks of 2005 and 2006, the global distribution of chikungunya virus (CHIKV) and the locations of epidemics have dramatically shifted. First, the Indian Ocean lineage (IOL) caused sustained epidemics in India and has radiated to many other countries. Second, the Asian lineage has caused frequent outbreaks in the Pacific islands and in 2013 was introduced into the Caribbean, followed by rapid spread to nearly all of the neotropics. Further, CHIKV epidemics, as well as exported cases, have been reported in central Africa after a long period of perceived silence. To understand these changes and to anticipate the future of the virus, the exact distribution, genetic diversity, transmission routes, and future epidemic potential of CHIKV require further assessment. To do so, we conducted the most comprehensive phylogenetic analysis to date, examined CHIKV evolution and transmission, and explored distinct genetic factors associated with the emergence of the East/Central/South African (ECSA) lineage, the IOL, and the Asian lineage. Our results reveal contrasting evolutionary patterns among the lineages, with growing genetic diversities observed in each, and suggest that CHIKV will continue to be a major public health threat with the potential for further emergence and spread. IMPORTANCE: Chikungunya fever is a reemerging infectious disease that is transmitted by Aedes mosquitoes and causes severe health and economic burdens in affected populations. Since the unprecedented Indian Ocean and Indian subcontinent outbreaks of 2005 and 2006, CHIKV has further expanded its geographic range, including to the Americas in 2013. Its evolution and transmission during and following these epidemics, as well as the recent evolution and spread of other lineages, require optimal assessment. Using newly obtained genome sequences, we provide a comprehensive update of the global distribution of CHIKV genetic diversity and analyze factors associated with recent outbreaks. These results provide a solid foundation for future evolutionary studies of CHIKV that can elucidate emergence mechanisms and also may help to predict future epidemics.

In-silico Hierarchical Approach for the Identification of Potential Universal Vaccine Candidates (PUVCs) from Neisseria gonorrhoeae.

OBJECTIVES: Resistance to the currently recommended extended-spectrum cephalosporins, which is used to treat Gonorrhea, is increasing continuously and leading to a threat of untreatable infection. It is, therefore, becoming extremely essential to search for new therapeutic strategies to control Gonorrhea. Vaccination may be considered as an effective control measure to control this disease, which is caused by Neisseria gonorrhoeae. METHODS: In-silico hierarchical approach was used to help identify candidate proteins of N. gonorrhoeae that might contribute significantly in vaccine research. In contrast to the conventional vaccine research which requires at least 10-12 years, the present approach would reduce the time period drastically and help to identify Potential Universal Vaccine Candidates (PUVCs). These proteins were further analyzed for the presence of T-cell and linear B-cell epitopes, by using HLAPred and ABCpred servers respectively, in order to facilitate the identification of Multi Epitope Peptide Vaccine Constructs. RESULTS: We have identified 23 non-host candidate proteins, using the proteomic information of four sequenced strains of N. gonorrhoeae namely FA 1090, TCDC_NG08107, NCCP11945 and MS11 and labeled them as PUVCs. Since all these identified 23 PUVCs contained both T cell and B cell epitopes, these have been further reiterated as PUVCs which could be used as promising leads for vaccine development. CONCLUSIONS: This hierarchical approach is the first comprehensive study to identify potential vaccine candidates which once utilized for vaccine development would surely serve as promising tools for effective control of Gonorrhea.