Bruton's tyrosine kinase inhibitor-related cardiotoxicity: The quest for predictive biomarkers and improved risk stratification.

Ibrutinib was the first Bruton's tyrosine kinase (BTK) inhibitor approved for the treatment of patients with chronic lymphocytic leukemia (CLL). While producing durable responses and prolonging survival, roughly 20-25% of patients experience dose limiting side effects, mostly consisting of cardiovascular toxicities like severe hypertension and atrial fibrillation. While clinical predictors of BTK inhibitor-related cardiotoxicity have been proposed and may aid in risk stratification, there is no routine risk model used in clinical practice today to identify patients at highest risk. A recent study investigating genetic predictors of ibrutinib-related cardiotoxicity found that single nucleotide polymorphisms in KCNQ1 and GATA4 were significantly associated with cardiotoxic events. If replicated in larger studies, these biomarkers may improve risk stratification in combination with clinical factors. A clinicogenomic risk model may aid in identifying patients at highest risk of developing BTK inhibitor-related cardiotoxicity in which further risk mitigation strategies may be explored.

Polygenic Risk Score Assessment for Coronary Artery Disease in Asian Indians.

We evaluated the performance of various polygenic risk score (PRS) models derived from European (EU), South Asian (SA), and Punjabi Asian Indians (AI) studies on 13,974 subjects from AI ancestry. While all models successfully predicted Coronary artery disease (CAD) risk, the AI, SA, and EU + AI were superior predictors and more transportable than the EU model; the predictive performance in training and test sets was 18% and 22% higher in AI and EU + AI models, respectively than in EU. Comparing individuals with extreme PRS quartiles, the AI and EU + AI captured individuals with high CAD risk showed 2.6 to 4.6 times higher efficiency than the EU. Interestingly, including the clinical risk score did not significantly change the performance of any genetic model. The enrichment of diversity variants in EU PRS improves risk prediction and transportability. Establishing population-specific normative and risk factors and inclusion into genetic models would refine the risk stratification and improve the clinical utility of CAD PRS.

Nanoapatite-Loaded κ-Carrageenan/Poly(vinyl alcohol)-Based Injectable Cryogel for Hemostasis and Wound Healing.

Immediate control of excessive bleeding and prevention of infections are of utmost importance in the management of wounds. Cryogels have emerged as promising materials for the rapid release of medication and achieving hemostasis. However, their quick release properties pose the challenge of exposing patients to high concentrations of drugs. In this study, hybrid nanocomposites were developed to address this issue by combining poly(vinyl alcohol) and κ-carrageenan with whitlockite nanoapatite (WNA) particles and ciprofloxacin, aiming to achieve rapid hemostasis and sustained antibacterial effects. A physically cross-linked cryogel was obtained by subjecting a blend of poly(vinyl alcohol) and κ-carrageenan to successive freezing-thawing cycles, followed by the addition of WNA. Furthermore, ciprofloxacin was introduced into the cryogel matrix for subsequent evaluation of its wound healing properties. The resulting gel system exhibited a 3D microporous structure and demonstrated excellent swelling, low cytotoxicity, and outstanding mechanical properties. These characteristics were evaluated through analytical and rheological experiments. The nanocomposite cryogel with 4% whitlockite showed extended drug release of 71.21 ± 3.5% over 21 days and antibacterial activity with a considerable growth inhibition zone (4.19 ± 3.55 cm). Experiments on a rat model demonstrated a rapid hemostasis property of cryogels within an average of 83 ± 4 s and accelerated the process of wound healing with 96.34% contraction compared to the standard, which exhibited only ∼78% after 14 days. The histopathological analysis revealed that the process of epidermal re-epithelialization took around 14 days following the skin incision. The cryogel loaded with WNAs and ciprofloxacin holds great potential for strategic utilization in wound management applications as an effective material for hemostasis and anti-infection purposes.

Novel and known variants in GJA3 and LIM2 in congenital cataract families from North India.

BACKGROUND: To identify the underlying genetic defects in autosomal dominant (ADCC) and autosomal recessive (ARCC) congenital cataract families from North India. METHODS: Detailed family histories were collected, pedigrees drawn followed by slit-lamp examination and lens photography. Mutation screening was performed using Sanger sequencing in the known candidate genes for crystallins, connexins, and membrane proteins. The pathogenicity of identified variants was assessed bioinformatically. RESULTS: In two ADCC families (CC-281 and CC-3015) with posterior lenticonus cataract, a novel change c.263C > T (p.P88L) in GJA3 in CC-281 family and a previously reported substitution c.388C > T (p.R130C) in LIM2 in CC-3015 family was observed. In an ARCC family (CC-3005) having central pulverulent cataract, a novel frameshift deletion (c.764delT;p.L255R46fs) in GJA3 was detected. The observed variants segregated completely with phenotypes in the affected members and were neither present in unaffected family members nor in the ethnically matched 150 controls (tested for two novel variants), hence excluding these as polymorphisms. CONCLUSIONS: Present study identified two novel mutations i.e., c.263C > T;p.P88L and c.764delT;p.L255R46fs in GJA3 in an ADCC and an ARCC family having posterior lenticonus and central pulverulent cataract, respectively. In another ADCC family with posterior lenticonus cataract, a previously reported mutation c.388C > T;p.R130C in LIM2 was observed. R130 may be a mutation hotspot as previously ADCC families from different ethnicities (UK/Czechia, China, Spain, Japan) also harbored the same substitution, however, with different phenotypes i.e., nuclear pulverulent, membranous, nuclear, lamellar, and sutural/lamellar. Findings in present study thus expand the mutation spectrum and phenotypic heterogeneity linked with GJA3 and LIM2.

Protein tyrosine phosphatase 1B is a regulator of alpha-actinin4 in the glomerular podocyte.

Glomerular podocytes are instrumental for the barrier function of the kidney, and podocyte injury contributes to proteinuria and the deterioration of renal function. Protein tyrosine phosphatase 1B (PTP1B) is an established metabolic regulator, and the inactivation of this phosphatase mitigates podocyte injury. However, there is a paucity of data regarding the substrates that mediate PTP1B actions in podocytes. This study aims to uncover novel substrates of PTP1B in podocytes and validate a leading candidate. To this end, using substrate-trapping and mass spectroscopy, we identified putative substrates of this phosphatase and investigated the actin cross-linking cytoskeletal protein alpha-actinin4. PTP1B and alpha-actinin4 co-localized in murine and human glomeruli and transiently transfected E11 podocyte cells. Additionally, podocyte PTP1B deficiency in vivo and culture was associated with elevated tyrosine phosphorylation of alpha-actinin4. Conversely, reconstitution of the knockdown cells with PTP1B attenuated alpha-actinin4 tyrosine phosphorylation. We demonstrated co-association between alpha-actinin4 and the PTP1B substrate-trapping mutant, which was enhanced upon insulin stimulation and disrupted by vanadate, consistent with an enzyme-substrate interaction. Moreover, we identified alpha-actinin4 tandem tyrosine residues 486/487 as mediators of its interaction with PTP1B. Furthermore, knockdown studies in E11 cells suggest that PTP1B and alpha-actinin4 are modulators of podocyte motility. These observations indicate that PTP1B and alpha-actinin4 are likely interacting partners in a signaling node that modulates podocyte function. Targeting PTP1B and plausibly this one of its substrates may represent a new therapeutic approach for podocyte injury that warrants additional investigation.

Assessing the prediction of type 2 diabetes risk using polygenic and clinical risk scores in South Asian study populations.

Background: Genome-wide polygenic risk scores (PRS) have shown high specificity and sensitivity in predicting type 2 diabetes (T2D) risk in Europeans. However, the PRS-driven information and its clinical significance in non-Europeans are underrepresented. We examined the predictive efficacy and transferability of PRS models using variant information derived from genome-wide studies of Asian Indians (AIs) (PRSAI) and Europeans (PRSEU) using 13,974 AI individuals. Methods: Weighted PRS models were constructed and analyzed on 4602 individuals from the Asian Indian Diabetes Heart Study/Sikh Diabetes Study (AIDHS/SDS) as discovery/training and test/validation datasets. The results were further replicated in 9372 South Asian individuals from UK Biobank (UKBB). We also assessed the performance of each PRS model by combining data of the clinical risk score (CRS). Results: Both genetic models (PRSAI and PRSEU) successfully predicted the T2D risk. However, the PRSAI revealed 13.2% odds ratio (OR) 1.80 [95% confidence interval (CI) 1.63-1.97; p = 1.6 × 10-152] and 12.2% OR 1.38 (95% CI 1.30-1.46; p = 7.1 × 10-237) superior performance in AIDHS/SDS and UKBB validation sets, respectively. Comparing individuals of extreme PRS (ninth decile) with the average PRS (fifth decile), PRSAI showed about two-fold OR 20.73 (95% CI 10.27-41.83; p = 2.7 × 10-17) and 1.4-fold OR 3.19 (95% CI 2.51-4.06; p = 4.8 × 10-21) higher predictability to identify subgroups with higher genetic risk than the PRSEU. Combining PRS and CRS improved the area under the curve from 0.74 to 0.79 in PRSAI and 0.72 to 0.75 in PRSEU. Conclusion: Our data suggest the need for extending genetic and clinical studies in varied ethnic groups to exploit the full clinical potential of PRS as a risk prediction tool in diverse study populations.

Investigating the role of glycans in Omicron sub-lineages XBB.1.5 and XBB.1.16 binding to host receptor using molecular dynamics and binding free energy calculations.

Omicron derived lineages viz. BA.2, BA.3, BA.4 BA.5, BF.7 and XBBs show prominence with improved immune escape, transmissibility, infectivity, and pathogenicity in general. Sub-variants, XBB.1.5 and XBB.1.16 have shown rapid spread, with mutations embedded throughout the viral genome, including the spike protein. Changing atomic landscapes in spike contributes significantly to modulate host pathogen interactions and infections thereof. In the present work, we computationally analyzed the binding affinities of spike receptor binding domains (RBDs) of XBB.1.5 and XBB.1.16 towards human angiotensin-converting enzyme 2 (hACE2) compared to Omicron. We have employed simulations and binding energy estimation of molecular complexes of spike-hACE2 to assess the interplay of interaction pattern and effect of mutations if any in the binding mode of the RBDs of these novel mutants. We calculated the binding free energy (BFE) of the RBD of the Omicron, XBB.1.5 and XBB.1.16 spike protein to hACE2. We showed that XBB.1.5 and XBB.1.16 can bind to human cells more strongly than Omicron due to the increased charge of the RBD, which enhances the electrostatic interactions with negatively charged hACE2. The per-residue decompositions further show that the Asp339His, Asp405Asn and Asn460Lys mutations in the XBBs RBD play a crucial role in enhancing the electrostatic interactions, by acquiring positively charged residues, thereby influencing the formation/loss of interfacial bonds and thus strongly affecting the spike RBD-hACE2 binding affinity. Simulation results also indicate less interference of heterogeneous glycans of XBB.1.5 spike RBD towards binding to hACE2. Moreover, despite having less interaction at the three interfacial contacts between XBB S RBD and hACE2 compared to Omicron, variants XBB.1.5 and XBB.1.16 had higher total binding free energies (ΔGbind) than Omicron due to the contribution of non-interfacial residues to the free energy, providing insight into the increased binding affinity of XBB1.5 and XBB.1.16. Furthermore, the presence of large positively charged surface patches in the XBBs act as drivers of electrostatic interactions, thus support the possibility of a higher binding affinity to hACE2.

Mutation screening in autosomal dominant congenital cataract families from North India.

Congenital cataract an opacity of the eye lens is present at birth and results in visual impairment during early childhood. If left untreated, it can lead to permanent blindness. Its prevalence is ten times higher in developing countries like India. Thus, we aimed to investigate the underlying genetic defects in three autosomal dominant congenital cataract (ADCC) families from North India. Detailed family histories were collected, pedigrees drawn followed by slit-lamp examination and lens photography. Mutation screening was performed in the candidate genes for crystallins, connexins, and membrane proteins by Sanger sequencing. Pathogenicity of novel variant was assessed bioinformatically. In an ADCC (CC-3006) family with bilateral membranous cataract and microcornea, a novel change (c.1114C>T;p.P372S) in GJA3 has been detected. In other two ADCC families affected with subcapsular (CC-286) and shrunken membranous hypermature cataract (CC-3014), a nonsense mutation (c.463C>T;p.Q155X) in CRYßB2 and a frameshift deletion (c.590_591delAG;p.E197VfsX22) in CRYßA1/A3 respectively, are observed. These variants segregated completely with the phenotypes in respective families and were absent in their unaffected family members and unrelated controls (tested for novel variant in GJA3). Earlier p.Q155X (CRYßB2) and p.E197VfsX22 (CRYßA1/A3) are reported with entirely different phenotypes. Thus, findings in present study expand the mutation spectrum and phenotypic heterogeneity linked with GJA3, CRYßB2, and CRYßA1/A3 for congenital cataracts. Identifying underlying genetic defects is essential for disease management and appropriate genetic counseling.

Evaluation of changes in Mallampati class in patients undergoing lumbar spine surgeries in the prone position: A prospective observational study.

Background: Positioning of patients during surgery, whether prone or head down, can lead to airway edema which, in turn, may lead to a difficult airway, and enhanced chances for reintubation. We aimed to assess and evaluate modified Mallampati class (MMC) change in patients scheduled for lumbar spine surgery in the prone position. Materials and Methods: This prospective observational study included 80 patients scheduled for lumbar spine surgery. The MMC was assessed up to 48 h postoperatively. The time taken by the patients in the postoperative period for MMC class to revert to preoperative value and airway complications, if any, was noted. Other parameters observed were surgical duration, intraoperative fluids used, and blood loss to look for any significant correlation with changes in MMC. Results: MMC increase by one grade was observed in 73 patients (91%). MMC in 54 patients (74%) returned to baseline within 18 h, in 12 patients (16%) it took 24 h, and in the remaining 7 patients (10%) the time taken was 36 h. Conclusion: It was concluded and established by this study that the MMC declined by one grade and reverted to baseline value within 36 h. This change in MMC necessitates extra caution to be adopted during the postoperative period as surgery in a prone position may predispose to an increased risk of encountering difficult reintubation. The change in MMC was not significantly correlated to intraoperative variables like duration of surgery, amount of intraoperative fluid given, and blood loss.

Cardio-oncology and transplantation for acute myeloid leukemia.

Despite the rapidly evolving treatment landscape for acute myeloid leukemia (AML), allogeneic hematopoietic cell transplantation (allo-HCT) remains an important and potentially curative treatment option for many high-risk AML patients. Cardiovascular disease is an important competing risk throughout allo-HCT and a key driver of morbidity and mortality long after treatment. Cardio-oncology is a new discipline in cardiology which provides multidisciplinary care and expertise to complex cancer patients with the aims of optimizing cardiovascular health plus monitoring and treating potential cardiotoxicity related to cancer treatments. As allogeneic HCT techniques get more sophisticated there will be an increase in transplant eligible older patients with a rise in comorbidities including established cardiovascular disease highlighting the need for close collaboration with cardio-oncology specialists from the time of diagnosis through late survivorship.

Exploring the path to pathos "Lived experiences of parents of children with autism spectrum disorder": An interpretative phenomenological analysis.

Background: Children with autism spectrum disorder (ASD) require lifetime support by the family, thus posing a great amount of stress among parents. Understanding lived experiences of parents who provide lifelong support will guide in planning effective treatment for children with ASD. In view of this, the study was aimed to depict and understand the lived experiences of parents of children with ASD and making sense of it. Methods: This interpretative phenomenological analysis research design was carried out on 15 parents of children with ASD coming to the tertiary care referral hospital of eastern zone of India. In-depth interviews were conducted to understand the lived experiences of parents. Results: The current study identified six themes: major symptom recognition; myths, beliefs, and stigma related to children with ASD; help seeking behavior; coping with challenging experiences; support system; uncertainties, insecurities, and gleam of hope. Conclusion: Lived experiences were found to be predominantly difficult for most of the parents of children with ASD, and inadequate services pose a major challenge to them. The findings highlight the need for involving the parents in the treatment programs as early as possible or extending appropriate support to the family.

Application of hybrid biophysical-biochemical methods to unravel the molecular basis for auto-inhibition and activation of protein tyrosine phosphatase TCPTP/PTPN2.

Since the discovery of protein tyrosine phosphorylation as one of the critical post-translational modifications, it has been well known that the activity of protein tyrosine kinases (PTKs) is tightly regulated. On the other hand, protein tyrosine phosphatases (PTPs) are often regarded to act constitutively active, but recently we and others have shown that many PTPs are expressed in an inactive form due to allosteric inhibition by their unique structural features. Furthermore, their cellular activity is highly regulated in a spatiotemporal manner. In general, PTPs share a conserved catalytic domain comprising about 280 residues that is flanked by either an N-terminal or a C-terminal non-catalytic segment, which differs significantly in size and structure from each other and is known to regulate specific PTP's catalytic activity. The well-characterized non-catalytic segments can be globular or intrinsically disordered. In this work, we have focused on the T-Cell Protein Tyrosine Phosphatase (TCPTP/PTPN2) and demonstrated how the hybrid biophysical-biochemical methods can be applied to unravel the underlying mechanism through which TCPTP's catalytic activity is regulated by the non-catalytic C-terminal segment. Our analysis showed that TCPTP is auto-inhibited by its intrinsically disordered tail and trans-activated by Integrin alpha-1's cytosolic region.

SUMO1 hinders α-Synuclein fibrillation by inducing structural compaction.

Small Ubiquitin-like Modifier 1 (SUMO1) is an essential protein for many cellular functions, including regulation, signaling, etc., achieved by a process known as SUMOylation, which involves covalent attachment of SUMO1 to target proteins. SUMO1 also regulates the function of several proteins via non-covalent interactions involving the hydrophobic patch in the target protein identified as SUMO Binding or Interacting Motif (SBM/SIM). Here, we demonstrate a crucial functional potential of SUMO1 mediated by its non-covalent interactions with α-Synuclein, a protein responsible for many neurodegenerative diseases called α-Synucleinopathies. SUMO1 hinders the fibrillation of α-Synuclein, an intrinsically disordered protein (IDP) that undergoes a transition to ß-structures during the fibrillation process. Using a plethora of biophysical techniques, we show that SUMO1 transiently binds to the N-terminus region of α-Synuclein non-covalently and causes structural compaction, which hinders the self-association process and thereby delays the fibrillation process. On the one hand, this study demonstrates an essential functional role of SUMO1 protein concerning neurodegeneration; it also illustrates the commonly stated mechanism that IDPs carry out multiple functions by structural adaptation to suit specific target proteins, on the other. Residue-level details about the SUMO1-α-Synuclein interaction obtained here also serve as a reliable approach for investigating the detailed mechanisms of IDP functions.

Comparative analysis of biochemical, hormonal, and mineral compositions of preovulatory and cystic ovarian follicles in buffalo during the non-breeding season.

This study is a comparative analysis of the biochemical, hormonal, and mineral compositions of follicular fluid in preovulatory and cystic follicles of water buffalo (Bubalus bubalis). In total, reproductive tracts from 215 buffalo along with intact ovaries were collected randomly from an abattoir. The incidence of cystic conditions found in this study was 3.72% (8/215), involving the right ovary in 62.5% of instances and the left ovary in 37.5% of instances during the non-breeding season. Follicular fluid was aspirated from preovulatory follicles (12-15 mm diameter, oestrogen-active, follicular phase or stage IV corpus luteum on one of the two ovaries, n = 10) and cystic follicles (at least 20 mm diameter, no corpus luteum on any one of the two ovaries, n = 8). The follicular fluid samples were assayed for biochemical components (uric acid, creatinine, blood urea nitrogen, cholesterol, total protein, glucose, ascorbic acid, and alkaline phosphatase), hormones (progesterone, estradiol, and insulin), and minerals (calcium, magnesium, phosphorus, copper, zinc, and cobalt). Cystic follicles had greater (P < 0.05) concentrations of creatinine, blood urea nitrogen, cholesterol, progesterone, copper, zinc, and cobalt, and lesser (P < 0.05) concentrations of uric acid, glucose, ascorbic acid, estradiol, insulin, calcium, magnesium, and phosphorus compared with preovulatory follicles. These results indicated the marked differences in follicular fluid composition between preovulatory and cystic follicles in buffalo. Some of the changes were indicative of oxidative stress and disturbed steroidogenesis, two important mechanisms shown to be associated with cystic ovarian disease in various species. Further studies are warranted to investigate whether these differences are directly or indirectly involved in the formation of cystic follicles or are mere manifestations of the condition.

Quantifying environmental emissions of microplastics from urban rivers in Melbourne, Australia.

This study aims to understand the amount and type of microplastics flowing into Port Phillip Bay from urban rivers around Melbourne. Water samples were collected from the Patterson, Werribee, Maribyrnong, and Yarra Rivers, which contribute 97 % to the total flow into Port Phillip Bay. On average, the rivers contained a mean of 9 ± 15 microplastics/L and ranged from 4 ± 3 microplastics/L (Patterson) to 22 ± 11 microplastics/L (Werribee). Of the eight polymers investigated, polyamide and polypropylene were the most frequently detected polymers. Using the mean concentration of each river, the flow of microplastics into Port Philip Bay was estimated to be 7.5 × 106 microplastics per day and 3.7 × 1010 microplastics per year. To fully understand the fate and transport of microplastics into Port Phillip Bay, this study would be the foundation for a more in-depth investigation. Here, further samples will be collected at more points along the river and at the midpoint of each season.

Luminescence nanothermometry using a trivalent lanthanide co-doped perovskite.

This study investigates in detail the laser-mediated upconversion emission and temperature-sensing capability of (Ca0.99-a Yb0.01Er a )TiO3. Samples were prepared at different concentrations to observe the effect of erbium on upconversion while increasing its concentration and keeping all the other parameters constant. Doping is a widespread technological process which involves incorporating an element called a dopant in a lower ratio to the host lattice to derive hybrid materials with desired properties. The (Ca0.99-a Yb0.01Er a )TiO3 perovskite nanoparticles were synthesized via a sol-gel technique. The frequency upconversion was performed using a 980 nm laser diode excitation source. X-ray diffractometry (XRD) confirmed that the synthesized samples are crystalline in nature and have an orthorhombic structure. The temperature-sensing ability was examined using the fluorescence intensity ratio (FIR) algorithm of two emission bands (2H11/2 → 4I15/2 and 4S3/2 → 4I15/2) of the Er3+ ion. Temperature-dependent upconversion luminescence is observed over a broad temperature range of 298-623 K. The maximum sensor sensitivity obtained is 6.71 × 10-3 K-1 at 110°.

Non-invasive diagnosis of transthyretin cardiac amyloidosis utilizing typical late gadolinium enhancement pattern on cardiac magnetic resonance and light chains.

AIMS: While cardiac magnetic resonance (CMR) is often obtained early in the evaluation of suspected cardiac amyloidosis (CA), it currently cannot be utilized to differentiate immunoglobulin (AL) and transthyretin (ATTR) CA. We aimed to determine whether a novel CMR and light-chain biomarker-based algorithm could accurately diagnose ATTR-CA. METHODS AND RESULTS: Patients with confirmed AL or ATTR-CA with typical late gadolinium enhancement (LGE) and Look-Locker pattern for CA on CMR were retrospectively identified at three academic medical centres. Comprehensive light-chain analysis including free light chains, serum, and urine electrophoresis/immunofixation was performed. The diagnostic accuracy of the typical CMR pattern for CA in combination with negative light chains for the diagnosis of ATTR-CA was determined both in the entire cohort and in the subset of patients with invasive tissue biopsy as the gold standard. A total of 147 patients (age 70 ± 11, 76% male, 51% black) were identified: 89 ATTR-CA and 58 AL-CA. Light-chain biomarkers were abnormal in 81 (55%) patients. Within the entire cohort, the sensitivity and specificity of a typical LGE and Look-Locker CMR pattern and negative light chains for ATTR-CA was 73 and 98%, respectively. Within the subset with biopsy-confirmed subtype, the CMR and light-chain algorithm were 69% sensitive and 98% specific. CONCLUSION: The combination of a typical LGE and Look-Locker pattern on CMR with negative light chains is highly specific for ATTR-CA. The successful non-invasive diagnosis of ATTR-CA using CMR has the potential to reduce diagnostic and therapeutic delays and healthcare costs for many patients.

Active-site cysteine 215 sulfonation targets protein tyrosine phosphatase PTP1B for Cullin1 E3 ligase-mediated degradation.

Reactive oxygen species (ROS), released as byproducts of mitochondrial metabolism or as products of NADPH oxidases and other processes, can directly oxidize the active-site cysteine (Cys) residue of protein tyrosine phosphatases (PTPs) in a mammalian cell. Robust degradation of irreversibly oxidized PTPs is essential for preventing accumulation of these permanently inactive enzymes. However, the mechanism underlying the degradation of these proteins was unknown. In this study, we found that the active-site Cys215 of endogenous PTP1B is sulfonated in H9c2 cardiomyocytes under physiological conditions. The sulfonation of Cys215 led PTP1B to exhibit a conformational change, and drive the subsequent ubiquitination and degradation of this protein. We then discovered that Cullin1, an E3 ligase, interacts with the Cys215-sulfonated PTP1B. The functional impairment of Cullin1 prevented PTP1B from oxidation-dependent ubiquitination and degradation in H9c2 cells. Moreover, delivery of the terminally oxidized PTP1B resulted in proteotoxicity-caused injury in the affected cells. In conclusion, we elucidate how sulfonation of the active-site Cys215 can direct turnover of endogenous PTP1B through the engagement of ubiquitin-proteasome system. These data highlight a novel mechanism that maintains PTP homeostasis in cardiomyocytes with constitutive ROS production.

Using the Endsley Model to Evaluate Simulation-Based Situation Awareness Training for Medical and Nursing Students in India: A Qualitative Analysis.

INTRODUCTION: Situation awareness (SA) training is a vital part of healthcare training, and opportunities to provide SA training to healthcare workers are limited in low- and middle-income countries. We aimed to analyze undergraduate medical and nursing students' perception of their understanding of SA through an interprofessional obstetric neonatal emergency simulation workshop (ONE-Sim) and subsequently evaluate their perceived changes in SA understanding using the Endsley model ( Hum Factors 1995;37(1):32-64). METHODS: Feedback on SA before and after the workshop was collected through questionnaire-based surveys. Thematic analysis was performed, with themes emerging from an inductive analysis followed by a deductive analysis using the Endsley model. RESULTS: The themes emerging from the inductive analysis included environmental awareness, evolving knowledge, skill development, and applicability to practice. These aligned with the 3 levels of SA in the Endsley model in the deductive analysis suggesting that participants transformed their perception, comprehension, and projection of SA after the workshop. CONCLUSION: Simulation-based education enhanced SA perception in obstetric and neonatal emergencies for medical and nursing students in a low- and middle-income country, and the Endsley model is a feasible framework to measure learner perceived changes in SA understanding through simulation-based education.

Level of patient satisfaction with online psychiatric outdoor services.

BACKGROUND: The COVID-19 global pandemic exposed gaps in the treatment of common physical and mental disorders that had to do with things like lockdowns, poor convenience, fear of contracting COVID, and economic constraints. Hence, to address these treatment gaps while also limiting exposure to the COVID-19 infection, telemedicine in the form of telephone and internet consultations has increasingly become the recourse around the world. Our center adopted this trend and also launched a telepsychiatry initiative in order to better cater to the needs of patients with pre-existing mental health disorders and to ensure regular follow-ups and compliance with prescription regiments. AIM: The present study aimed to assess the level of patient satisfaction with the online psychiatric services/telepsychiatry. METHODS: The sample consisted of 100 patients with pre-existing mental health disorders. This was a cross-sectional study lasting 6 months. The DigiDoc app by Hospital Information Software (HIS) software, which is used to manage a patients appointment schedule, relevant clinical and lab details, along with follow-up prescriptions, was used to follow the selected patients for the purpose of this study. This software also provides a digital platform for video calls for online consultation. The Client Satisfaction Questionnaires-8 (CSQ-8) was employed to collect patient data for analysis. RESULTS: The mean total CSQ-8 score of the study sample was 21.015.80 (832), which corresponds to a low-to-moderate level of satisfaction with online psychiatric services/telepsychiatry. Most patients (45%) reported low satisfaction levels, followed by 37% who reported moderate levels of satisfaction. Only 18% of patients reported higher satisfaction with telepsychiatry. CONCLUSION: Despite the psychiatrists ability to provide adequate professional advice and psychoeducation through online psychiatric services, patients level of satisfaction proved moderate-to-low. This suggests a need to design standard protocols and guidelines in the search and provision of consultation services on online psychiatric service platforms that could help enhance patients levels of satisfaction.