Deep Machine Learning Might Aid in Combating Intensive Care Unit-Acquired Weakness.

Secondary muscle weakness in critically ill patients like intensive care unit (ICU)-associated weakness is frequently noted in patients with prolonged mechanical ventilation and ICU stay. It can be a result of critical illness, myopathy, or neuropathy. Although ICU-acquired weakness (ICU-AW) has been known for a while, there is still no effective treatment for it. Therefore, prevention of ICU-AW becomes the utmost priority, and knowing the risk factors is crucial. Nevertheless, the pathophysiology and the attributing causes are complex for ICU-AW, and proper delineation and formulation of a preventive strategy from such vast, multifaceted data are challenging. Artificial intelligence has recently helped healthcare professionals understand and analyze such intricate data through deep machine learning. Hence, using such a strategy also helps in knowing the risk factors and their weight as contributors, applying them in formulating a preventive path for ICU-AW worth trials.

Soundless Trouble: Syringe Pump Malfunction and the Hypotension Threat.

Drug infusion devices have become indispensable tools in ICU patient care, drug delivery, and operation rooms (OR) and for controlled fluid delivery. Syringe pump safety is paramount in healthcare and laboratory settings to ensure accurate medication delivery and prevent adverse events. Healthcare professionals must receive thorough training on syringe pump operation, including loading syringes, programming infusion rates, and responding to alarms. Using the correct syringe size and type is essential to prevent inaccuracies in drug/fluid delivery. Regular calibration and maintenance checks are necessary to ensure the accuracy and reliability of the syringe pumps. Two cases of refractory hypotension are reported here, which were resolved by careful inspection of the infusion pumps.

The diagnostic accuracy of preoperative perfusion index as a predictor of postspinal anesthesia hypotension in parturients undergoing cesarean delivery: A prospective non-blinded observational study.

Background and Objectives: Spinal anesthesia is the technique of choice for elective cesarean section with a prominent side effect of postspinal anesthesia hypotension (PSH). This needs an early prediction to avoid feto-maternal complication. This study aimed to assess the diagnostic accuracy of perfusion index (PI) and inferior vena cava collapsibility index (IVCCI) in the prediction of PSH. Material and Methods: Thirty parturients of American Society of Anesthesiologists Physical Status (ASA-PS) 1 and two undergoing cesarean delivery participated in the study. IVCCI, PI, baseline systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), and heart rate (HR) were noted in the preoperative period. The fall of MBP by 20% from baseline or below 65 mm Hg was considered PSH. After spinal anesthesia, SBP, DBP, MBP, and HR were noted again for diagnosing PSH. Results: It did not show any statistical difference when comparing the PI between the PSH and non-PSH groups in both the PSH definition groups. IVCCI was significantly higher when PSH was considered MBP <65 mm Hg (P = 0.01). However, IVCCI was found to be statistically insignificant if PSH was considered a 20% reduction in baseline MBP. The correlation matrix between IVCCI and PI showed Pearson's r-value of 0.525, indicating a substantial relationship between the two (P = 0.003). Multivariate logistic regression analysis had shown that neither IVCCI nor PI was a good predictor of PSH in parturients for both definition groups for PSH. Conclusion: Although there is a modest correlation between PI and IVCCI, both cannot be used to predict postspinal hypotension in parturients undergoing elective lower-segment cesarean section (LSCS).

Experimental procedures to investigate fibrillation of proteins.

The unwanted phenomenon of protein fibrillation is observed in vivo and during therapeutic protein development in the industry. Protein aggregation is associated with various degenerative disorders and might induce immune-related challenges post-administration of biopharmaceutics. A pipeline for early detection, identification, and removal of pre-formed fibrils is needed to improve the quality, efficacy, and effectiveness of the formulation. Protein fibril formation is accompanied by unfolding, secondary structural changes and the formation of larger aggregates. However, most detection processes come with extensive sample preparation steps and inefficient repeatability, incurring a financial burden on research. The current article summarizes and critically discusses six simple yet powerful methods to detect aggregation phenomena in the line of detecting fibrillar aggregates in heat-induced bovine serum albumin protein. Comparing the native and heat-induced protein samples would provide insights about aggregates. Easy, inexpensive and optimized protocols for detecting the fibrillation of proteins are explained. The procedures mentioned here detected the appearance of ß-sheet-rich fibrils in the heat-induced protein sample. The aggregation is characterized by enhanced thioflavin-T fluorescence, alteration in the intrinsic fluorescence, decrease in helicity and subsequent increase in ß-sheet and appearance of particles with larger hydrodynamic diameters. •This article summarizes various analytical techniques to easily characterize the fibrillation of proteins.•Various techniques to detect the formation of ß-sheet rich structures, changes in the secondary structures and size of aggregates have been discussed.•The stated methodologies are validated on a model protein, albumin.

Preintubation Machine-Delivered Pressure Support Ventilation With Positive End-Expiratory Pressure Versus Manual Bag-Mask Ventilation for Oxygenation in Overweight and Obese Patients: A Randomized, Pilot Study.

BACKGROUND: Noninvasive positive pressure ventilation (NIPPV) maintains mean airway pressures well, and its usability for preoxygenation is well described. Anesthesia machine-delivered NIPPV-based preoxygenation has recently been evaluated against the traditional manual bag-mask ventilation (BMV). The efficiency of such a technique over the traditional one is yet to be established well. The present study evaluated the feasibility of machine-delivered preoxygenation using pressure support ventilation (PSV) with positive end-expiratory pressure (PEEP) and compared the effectiveness with BMV. METHODS: Thirty overweight and obese adults belonging to the American Society of Anesthesiologist's physical status I-II were randomized to receive PSV+PEEP or BMV for preintubation preoxygenation targeted to a fraction of expired oxygen (FeO2) of 85% and 90% or for a maximum period of five minutes, whichever came first. Postintubation, the patient was observed for the time taken until 1% desaturation without ventilation. Arterial blood gases, respiratory variables, FeO2 achieved, and different times were collected and compared. RESULTS: The baseline characteristics and arterial blood gases were similar between the two groups. The PSV+PEEP group had consistent and favorable tidal volume and airway pressure delivery. The difference in time to reach a FeO2 of 85% between the two groups was not statistically different. Only two patients achieved a FeO2 of 90% in the PSV+PEEP group versus none in the BMV group. However, partial pressure of oxygen at 1% desaturation (217.42±109.47 versus 138.073±71.319 mmHg, p 0.0259) was higher in the PSV+PEEP group. Similarly, the time until 1% desaturation was significantly prolonged in the PSV+PEEP group (206.6±76.952 versus 140.466±54.245 seconds, p 0.0111). CONCLUSION: The present pilot study findings indicate that preintubation machine-delivered PSV+PEEP-based preoxygenation is feasible and might be more effective than traditional BMV in overweight and obese patients.

Structural, kinetic, and thermodynamic aspects of insulin aggregation.

Given the significance of protein aggregation in proteinopathies and the development of therapeutic protein pharmaceuticals, revamped interest in assessing and modelling the aggregation kinetics has been observed. Quantitative analysis of aggregation includes data of gradual monomeric depletion followed by the formation of subvisible particles. Kinetic and thermodynamic studies are essential to gain key insights into the aggregation process. Despite being the medical marvel in the world of diabetes, insulin suffers from the challenge of aggregation. Physicochemical stresses are experienced by insulin during industrial formulation, storage, delivery, and transport, considerably impacting product quality, efficacy, and effectiveness. The present review briefly describes the pathways, mathematical kinetic models, and thermodynamics of protein misfolding and aggregation. With a specific focus on insulin, further discussions include the structural heterogeneity and modifications of the intermediates incurred during insulin fibrillation. Finally, different model equations to fit the kinetic data of insulin fibrillation are discussed. We believe that this review will shed light on the conditions that induce structural changes in insulin during the lag phase of fibrillation and will motivate scientists to devise strategies to block the initialization of the aggregation cascade. Subsequent abrogation of insulin fibrillation during bioprocessing will ensure stable and globally accessible insulin for efficient management of diabetes.

Ischemic Stroke as the Presenting Feature for Non-acute Promyelocytic Leukemia Variant of Acute Myeloid Leukemia: A Case Report.

Acute myeloid leukemia (AML) patients encounter complications mainly due to their underlying disease or chemotherapy. Although they are at high risk for both hemorrhagic and thrombotic complications, thrombotic vascular complication as an initial manifestation is less common and rarely reported, especially in non-acute promyelocytic leukemia (non-APML). A 58-year-old female with no co-morbidity presented with fever, decreased appetite, headache, and weakness in her left upper and lower limbs. Laboratory findings showed hyperleukocytosis with 90% blast cells and thrombocytopenia (50,000/dl). While investigated and conservatively managed, she developed a seizure and loss of consciousness on the same day and was admitted to the intensive care unit. Computed tomography showed a massive right infarct in the middle cerebral artery territory with a significant midline shift. Flow cytometry indicated the diagnosis of non-APML; chemotherapy, platelet transfusion, unfractionated heparin, mechanical ventilation, and other supportive treatments were started. While managing this case, we faced challenges in decision-making on thrombolysis, craniotomy, and chemotherapy. The case highlights the salient points and dilemmas in managing such an acutely ill patient in critical care.

Perioperative Management of Emergency Craniotomes in Children With Cyanotic Congenital Heart Disease: A Case Series.

While congenital heart disease is not uncommon, cyanotic congenital heart disease (CCHD) accounts for a minor fraction of them. However, when cyanosis is present, it usually indicates a severe or critical illness. Tetralogy of Fallot (TOF) is one of the common CCHDs, representing 7-10% of all congenital cardiac malformations. Double-outlet right ventricle (DORV) is another CCHD similar to the TOF and associated with decreased pulmonary flow, ventricular septal defect (VSD), and aorta receiving blood from both ventricles. Reduced oxygen arterial saturation and increased viscosity by polycythemia induce focal cerebral ischemia, often in the area supplied by the middle cerebral artery leading to brain abscess. Brain abscesses require craniotomy, which is a major surgery. These patients also often show features of sepsis and increased intracranial pressure. The presence of CCHD further complicates the situation, making perioperative management even more challenging. There are studies in the literature on the management of similar cases, and they report successful management in most of them. However, not all such cases need intensive postoperative management. We present four pediatric cases who had either TOF or DORV and had to undergo craniotomy for brain abscess or ventriculoperitoneal shunt placement. We describe case management and highlight the critical features and cases that require prolonged postoperative critical care management.

Transillumination and Point-of-Care Ultrasonography to Delineate Tracheal Deviation for Challenging Tracheostomy: A Case Report.

Tracheostomy is indicated for varied reasons and is a relatively safe procedure that can be done with both open and percutaneous methods. However, the procedure is often challenging in cases of distorted neck anatomy. Neck swellings often push the trachea laterally or shield it. Even some gross intrathoracic pathology may shift the trachea from the typical trajectory making it challenging to delineate the course of the trachea. A bedside point-of-care technique having a visual aid that can guide the performer thus appears beneficiary. Fiber-optic assistance for correct puncture and confirmation is known, and light-based techniques have been used for tracheostomies. As fiberscopes are not infrequent in tertiary and even secondary care hospitals, transillumination from a flexible bronchoscope can identify the altered course of the trachea, much like a navigation system, and systematically aid the performer in steering away from the obstacles. We present two cases in two scenarios with tracheal deviation who underwent either open or percutaneous tracheostomy with point-of-care ultrasound and transillumination to delineate the course of the trachea and facilitate difficult tracheostomies safely.

Practices During Intubation in COVID-19 Intensive Care Units in India: A Cross-Sectional Questionnaire-Based Survey.

Background Healthcare workers are committed to learning from each other's experience to safely optimize patient management of COVID-19. Acute hypoxemic failure is common in COVID-19 patients, and nearly 3.2% may require intubation. Intubation is an aerosol-generating procedure (AGP) that might predispose the performer to COVID-19 infection. This survey was intended to evaluate the practices during tracheal intubation in COVID-19 intensive care units (ICUs) and analyze them against the recommendations of the All India Difficult Airway Association (AIDAA) for safe practice. Methodology It was a web-based, multicentric cross-sectional survey. The choices in the questions were based on guidelines for airway management in COVID-19. Survey questions were divided into two parts - the first part consisted of demographics and general information, and the second part focused on safe intubation practices. Results A total of 230 responses were obtained from physicians all over India, presuming their active involvement in COVID-19 cases, of which 226 responses were taken into account. Two-thirds of responders did not receive any training before ICU posting. The Indian Council of Medical Research (ICMR) guideline was followed by 89% of responders for personal protective equipment use. Intubation in COVID-19 patients was predominantly conducted by a senior anesthesiologist/intensivist in the team and a senior resident (37.2%). Rapid sequence intubation (RSI) and modified RSI were preferable among the responder's hospitals (46.5% vs. 33.6%). In most centers, responders used direct laryngoscope for intubation (62.8%), whereas video laryngoscope was used by 34%. Most responders confirmed the endotracheal tube (ETT) position by visual inspection (66.3%) over end-tidal carbon dioxide (EtCO2) concentration tracing (53.9%). Conclusions Safe intubation practices were followed in most of the centers across India. However, teaching and training, preoxygenation methods, alternative ventilation strategies, and confirmation of intubation pertinent to COVID-19 airway management need more attention.

Atypical Presentations of Myocardial Infarction: A Systematic Review of Case Reports.

There is a rising incidence of coronary artery diseases and myocardial infarction (MI). Mortality associated with acute MI (AMI) is directly linked to the time to receive treatment and missed diagnoses. Although health professionals are aware of typical AMI presentation, atypical MI is difficult to diagnose, which on the other hand, is likely to have an impact on morbidity and mortality. Therefore, it is prudent to know such atypical presentations, especially for emergency and primary care physicians. We aimed to systematically evaluate the clinical presentations of atypical MI and analyze them to characterize the common clinical presentations of atypical MI. We researched the PubMed database, did citation tracking, and performed Google Scholar advanced search to find the cases reported on the atypical presentation of MI published from January 2000 to September 2022. Articles of all languages were included; Google Translate was used to translate articles published in languages other than English. A total of 496 (56 PubMed articles, 340 citations from included PubMed articles, and 100 articles from Google Scholar advanced search) were screened; 52 case reports were evaluated, and their data were analyzed. Atypical presentations of myocardial infarction are vast; patients may have chest pain without typical characteristics of angina pain or may not have chest pain. No typical characterization could be done. Most patients were in their fifth decade or above of their life and commonly presented with pain and discomfort in the abdomen, head, and neck regions. Prodromal symptoms were consistent findings, and many patients had two to three comorbidities out of four common comorbidities, i.e., diabetes, hypertension, dyslipidemia, and substance abuse. A patient who is 50 years old or more, having comorbidities such as diabetes, hypertension, dyslipidemia, history of tobacco or marijuana usage, presenting with prodromal symptoms like shortness of breath, dizziness, fatigue, syncope, gastrointestinal discomfort or head/neck pain should be suspected for atypical MI.

Potential of siRNA in COVID-19 therapy: Emphasis on in silico design and nanoparticles based delivery.

Small interfering RNA (siRNA)-mediated mRNA degradation approach have imparted its eminence against several difficult-to-treat genetic disorders and other allied diseases. Viral outbreaks and resulting pandemics have repeatedly threatened public health and questioned human preparedness at the forefront of drug design and biomedical readiness. During the recent pandemic caused by the SARS-CoV-2, mRNA-based vaccination strategies have paved the way for a new era of RNA therapeutics. RNA Interference (RNAi) based approach using small interfering RNA may complement clinical management of the COVID-19. RNA Interference approach will primarily work by restricting the synthesis of the proteins required for viral replication, thereby hampering viral cellular entry and trafficking by targeting host as well as protein factors. Despite promising benefits, the stability of small interfering RNA in the physiological environment is of grave concern as well as site-directed targeted delivery and evasion of the immune system require immediate attention. In this regard, nanotechnology offers viable solutions for these challenges. The review highlights the potential of small interfering RNAs targeted toward specific regions of the viral genome and the features of nanoformulations necessary for the entrapment and delivery of small interfering RNAs. In silico design of small interfering RNA for different variants of SARS-CoV-2 has been discussed. Various nanoparticles as promising carriers of small interfering RNAs along with their salient properties, including surface functionalization, are summarized. This review will help tackle the real-world challenges encountered by the in vivo delivery of small interfering RNAs, ensuring a safe, stable, and readily available drug candidate for efficient management of SARS-CoV-2 in the future.

Bi-Directional Relationship Between Autophagy and Inflammasomes in Neurodegenerative Disorders.

The innate immune system, as the first line of cellular defense, triggers a protective response called inflammation when encountered with invading pathogens. Inflammasome is a multi-protein cytosolic signaling complex that induces inflammation and is critical for inflammation-induced pyroptotic cell death. Inflammasome activation has been found associated with neurodegenerative disorders (NDs), inflammatory diseases, and cancer. Autophagy is a crucial intracellular quality control and homeostasis process which removes the dysfunctional organelles, damaged proteins, and pathogens by sequestering the cytosolic components in a double-membrane vesicle, which eventually fuses with lysosome resulting in cargo degradation. Autophagy disruption has been observed in many NDs presented with persistent neuroinflammation and excessive inflammasome activation. An interplay between inflammation activation and the autophagy process has been realized over the last decade. In the case of NDs, autophagy regulates neuroinflammation load and cellular damage either by engulfing the misfolded protein deposits, dysfunctional mitochondria, or the inflammasome complex itself. A healthy two-way regulation between both cellular processes has been realized for cell survival and cell defense during inflammatory conditions. Therefore, clinical interest in the modulation of inflammasome activation by autophagy inducers is rapidly growing. In this review, we discuss the structural basis of inflammasome activation and the mechanistic ideas of the autophagy process in NDs. Along with comments on multiple ways of neuroinflammation regulation by microglial autophagy, we also present a perspective on pharmacological opportunities in this molecular interplay pertaining to NDs.

An update on Cryptosporidium biology and therapeutic avenues.

Cryptosporidium species has been identified as an important pediatric diarrheal pathogen in resource-limited countries, particularly in very young children (0-24 months). However, the only available drug (nitazoxanide) has limited efficacy and can only be prescribed in a medical setting to children older than one year. Many drug development projects have started to investigate new therapeutic avenues. Cryptosporidium's unique biology is challenging for the traditional drug discovery pipeline and requires novel drug screening approaches. Notably, in recent years, new methods of oocyst generation, in vitro processing, and continuous three-dimensional cultivation capacities have been developed. This has enabled more physiologically pertinent research assays for inhibitor discovery. In a short time, many great strides have been made in the development of anti-Cryptosporidium drugs. These are expected to eventually turn into clinical candidates for cryptosporidiosis treatment in the future. This review describes the latest development in Cryptosporidium biology, genomics, transcriptomics of the parasite, assay development, and new drug discovery.

An update on cerebral malaria for therapeutic intervention.

BACKGROUND: Cerebral malaria is often pronounced as a major life-threatening neurological complication of Plasmodium falciparum infection. The complex pathogenic landscape of the parasite and the associated neurological complications are still not elucidated properly. The growing concerns of drugresistant parasite strains along with the failure of anti-malarial drugs to subdue post-recovery neuro-cognitive dysfunctions in cerebral malaria patients have called for a demand to explore novel biomarkers and therapeutic avenues. Due course of the brain infection journey of the parasite, events such as sequestration of infected RBCs, cytoadherence, inflammation, endothelial activation, and blood-brain barrier disruption are considered critical. METHODS: In this review, we briefly summarize the diverse pathogenesis of the brain-invading parasite associated with loss of the blood-brain barrier integrity. In addition, we also discuss proteomics, transcriptomics, and bioinformatics strategies to identify an array of new biomarkers and drug candidates. CONCLUSION: A proper understanding of the parasite biology and mechanism of barrier disruption coupled with emerging state-of-art therapeutic approaches could be helpful to tackle cerebral malaria.

The Relationship of Respiratory Rate-Oxygenation (ROX) and Modified ROX Index With High-Flow Nasal Cannula Oxygen Therapy in COVID-19 Patients: An Observational Pilot Study.

Background and aim Respiratory Rate-Oxygenation (ROX) and modified ROX (mROX) indexes have been proposed to detect early high-flow nasal cannula (HFNC) therapy failure. We evaluated the utility and relationship of ROX and mROX indexes in COVID-19 patients started on HFNC oxygen therapy. Methods This pilot study collected data from adult COVID-19 patients requiring HFNC oxygenation from 29 Jan - 29 Jun 2021. The patients were divided into two cohorts based on HFNC therapy success. ROX and mROX were compared using statistical diagnostic testing, including receiver operating characteristics and area under the curve (AUC) using online Epitools (https://epitools.ausvet.com.au/) and MedCalc software (MedCalc Software Ltd, Ostend, Belgium, https://www.medcalc.org/); p<0.05 was considered significant. Results Twenty-seven patients fulfilled the inclusion criteria; 48.15% of therapy failed. The cohort's mean ± standard deviation age was 53.93 ± 10.67 years; 74.1% were male. The accuracy of predicting failure for mean ROX versus mROX at baseline and six-hour values was 59.81 versus 70.68 and 67.42 versus 74.88, respectively (all p>0.05). The AUC for ROX and mROX at baseline and at six hours were statistically indifferent. Only an mROX of 4.05 (mean value) and 3.34 (Youden's J cut-off) had a sensitivity plus specificity at 156% and 163%, respectively. Conclusion Both ROX and mROX at baseline and six hours had fair-to-good accuracies and AUC; the differences were insignificant. Both ROX and mROX had better accuracies at six hours. However, only mROX < 4.05 at six hours fulfilled the sensitivity plus specificity criteria to be a clinically valuable screener.

Aggregated Tau-PHF6 (VQIVYK) Potentiates NLRP3 Inflammasome Expression and Autophagy in Human Microglial Cells.

Intra-neuronal misfolding of monomeric tau protein to toxic ß-sheet rich neurofibrillary tangles is a hallmark of Alzheimer's disease (AD). Tau pathology correlates not only with progressive dementia but also with microglia-mediated inflammation in AD. Amyloid-beta (Aß), another pathogenic peptide involved in AD, has been shown to activate NLRP3 inflammasome (NOD-like receptor family, pyrin domain containing 3), triggering the secretion of proinflammatory interleukin-1ß (IL1ß) and interleukin-18 (IL18). However, the effect of tau protein on microglia concerning inflammasome activation, microglial polarization, and autophagy is poorly understood. In this study, human microglial cells (HMC3) were stimulated with the unaggregated and aggregated forms of the tau-derived PHF6 peptide (VQIVYK). Modulation of NLRP3 inflammasome was examined by qRT-PCR, immunocytochemistry, and Western blot. We demonstrate that fibrillar aggregates of VQIVYK upregulated the NLRP3 expression at both mRNA and protein levels in a dose- and time-dependent manner, leading to increased expression of IL1ß and IL18 in HMC3 cells. Aggregated PHF6-peptide also activated other related inflammation and microglial polarization markers. Furthermore, we also report a time-dependent effect of the aggregated PHF6 on BECN1 (Beclin-1) expression and autophagy. Overall, the PHF6 model system-based study may help to better understand the complex interconnections between Alzheimer's PHF6 peptide aggregation and microglial inflammation, polarization, and autophagy.