Comparison of Three Deep Learning Models in Accurate Classification of 770 Dermoscopy Skin Lesion Images.

Accurately determining and classifying different types of skin cancers is critical for early diagnosis. In this work, we propose a novel use of deep learning for classification of benign and malignant skin lesions using dermoscopy images. We obtained 770 de-identified dermoscopy images from the University of Missouri (MU) Healthcare. We created three unique image datasets that contained the original images and images obtained after applying a hair removal algorithm. We trained three popular deep learning models, namely, ResNet50, DenseNet121, and Inception-V3. We evaluated the accuracy and the area under the curve (AUC) receiver operating characteristic (ROC) for each model and dataset. DenseNet121 achieved the best accuracy (80.52%) and AUC ROC score (0.81) on the third dataset. For this dataset, the sensitivity and specificity were 0.80 and 0.81, respectively. We also present the SHAP (SHapley Additive exPlanations) values for the predictions made by different models to understand their interpretability.

Clinical profile of adult and pediatric patients with hepatic Wilson's disease.

BACKGROUND: The clinical profile varies in patients with Wilson's disease (WD). There is paucity of data regarding adult and pediatric patients with hepatic WD. METHODS: As many as 140 consecutive patients diagnosed with hepatic WD between December 2006 and January 2021 were included in the study. Data was collected regarding the demographic parameters, clinical presentation, extrahepatic organ involvement, liver histology and laboratory investigations. Adult and children (0-14 years) with hepatic WD were compared regarding these features. RESULT: Eighty-eight adults and 52 children were included in the study. The median age of presentation was 17 years (range: 1.1-42 years). Male preponderance was seen (adult 68/88, 69%; children 40/52, 77%). Adults as compared to children presented more commonly as cirrhosis (52/88 vs. 15/52, p = 0.0005) and with hepatic decompensation (35/88 vs. 9/52, p = 0.005). Presentation with acute-on-chronic liver failure (ACLF) was more common in children (10/52 vs. 2/88, p = 0.0005). Twenty-eight-day mortality was 50% (5/10) in children and none in adults presenting with ACLF. Nazer's Prognostic Index (≥ 7) and New Wilson Index were more accurate in predicting mortality among children with ACLF with AUROC 1, while AARC (APASL ACLF Research Consortium) was less accurate with AUROC 0.45. Liver histology findings were similar in adults and children. Extrahepatic involvement was also similar. (8/88 in adults vs. 3/52 children, p value 0.48). CONCLUSION: Most patients with WD present as cirrhosis in adulthood. ACLF is more common in children. Nazer's prognostic index and new Wilson Index score are accurate in predicting mortality in children with ACLF.

Claims data analysis of provider-to-provider tele-mentoring program impact on opioid prescribing in Missouri.

OBJECTIVE: The objective of this study was to assess opioid prescribing patterns of primary care providers (PCPs) participating in a virtual tele-mentoring program for patients with chronic pain as compared to nonparticipants. DESIGN: We utilized Missouri Medicaid claims from 2013 to 2021 to compare opioid prescription dosages and daily supply of opioids prescribed by PCPs. Participants and nonparticipants were matched using propensity score matching. SETTING: Missouri Medicaid data were received through partnership with the Center for Health Policy's MO HealthNet Data Project, the state's leading provider of Medicaid data. PARTICIPANTS: Missouri-based prescribers. INTERVENTION: Show-Me Project Extension for Community Healthcare Outcomes (ECHO), an evidence-based provider-to-provider telehealth intervention that connects PCPs with a team of specialists. MAIN OUTCOME MEASURES: We compared the rate of prescription opioid >50 morphine milligram equivalents (MMEs), mean MMEs/day, and mean number of daily supply to understand the impact of the ECHO model on providers' opioid prescribing. RESULTS: Patients treated by ECHO providers have 33 percent lower odds of being prescribed opioid dose >50 MME/day (p < 0.001) compared to non-ECHO providers. There is also a 14 percent reduction in the average opioid dose prescribed to patients of ECHO providers (p < 0.001). We observed a 3 percent (p < 0.001) reduction in average daily supply of opioids among patients of ECHO providers compared to the comparison group. CONCLUSIONS: Pain Management ECHO supports PCPs with needed education and skills to provide specialty care in the management of pain conditions and safe prescribing of opioid medications.

Post-Translational Modifications in Tau and Their Roles in Alzheimer's Pathology.

Microtubule-Associated Protein Tau (also known as tau) has been shown to accumulate into paired helical filaments and neurofibrillary tangles, which are known hallmarks of Alzheimer's disease (AD) pathology. Decades of research have shown that tau protein undergoes extensive post-translational modifications (PTMs), which can alter the protein's structure, function, and dynamics and impact the various properties such as solubility, aggregation, localization, and homeostasis. There is a vast amount of information describing the impact and role of different PTMs in AD pathology and neuroprotection. However, the complex interplay between these PTMs remains elusive. Therefore, in this review, we aim to comprehend the key post-translational modifications occurring in tau and summarize potential connections to clarify their impact on the physiology and pathophysiology of tau. Further, we describe how different computational modeling methods have helped in understanding the impact of PTMs on the structure and functions of the tau protein. Finally, we highlight the tau PTM-related therapeutics strategies that are explored for the development of AD therapy.

Safety of bubble nasal intermittent positive pressure ventilation (NIPPV) versus bubble nasal continuous positive airway pressure (NCPAP) in preterm infants with respiratory distress.

OBJECTIVE: Nasal Intermittent Positive Pressure Ventilation (NIPPV) is an effective therapy for infants in respiratory distress. We here report the safety of a novel, low-cost, non-electric bubble NIPPV device in comparison with bubble NCPAP. STUDY DESIGN: At Paramitha Children's Hospital (Hyderabad, India), preterm (n = 60) neonates with moderate respiratory distress were pragmatically allocated to bubble NCPAP (5-8 cm H2O) or bubble NIPPV (Phigh 8-12 cm H2O/Plow 5-8 cm H2O) based on staff and equipment availability. Primary outcomes to assess safety included clinically relevant pneumothorax, nasal septal necrosis, or abdominal distention. RESULTS: One patient in each arm developed minor nasal septal injury (grade 3 on NCPAP, grade 2 on NIPPV); no patients in either arm developed a clinically significant pneumothorax or abdominal distention. CONCLUSION: The similar rates of nasal septal injury, pneumothorax and abdominal distention suggest that bubble NIPPV has a similar safety profile as bubble NCPAP for preterm infants in respiratory distress.

Safety, immunogenicity and efficacy of Relcovax®, a dual receptor binding domain (RBD) and nucleocapsid (N) subunit protein vaccine candidate against SARS-CoV-2 virus.

SARS-CoV-2, severe acute respiratory syndrome coronavirus-2, causes coronavirus disease- 2019 (COVID-19). Mostly, COVID-19 causes respiratory symptoms that can resemble those of a cold, the flu, or pneumonia. COVID-19 may harm more than just lungs and respiratory systems. It may also have an impact on other parts of the body and debilitating effects on humans, necessitating the development of vaccines at an unprecedented rate in order to protect humans from infections. In response to SARS-CoV-2 infection, mRNA, viral vector-based carrier and inactivated virus-based vaccines, as well as subunit vaccines, have recently been developed. We developed Relcovax®, a dual antigen (Receptor binding domain (RBD) and Nucleocapsid (N) proteins) subunit protein vaccine candidate. Preliminary mouse preclinical studies revealed that Relcovax® stimulates cell-mediated immunity and provides broader protection against two SARS-CoV-2 variants, including the delta strain. Before conducting human studies, detailed preclinical safety assessments are required, so Relcovax® was tested for safety, and immunogenicity in 28-day repeated dose toxicity studies in rats and rabbits. In the toxicity studies, there were no mortality or morbidity, abnormal clinical signs, abnormalities in a battery of neurobehavioral observations, abnormalities in detailed clinical and ophthalmological examinations, or changes in body weights or feed consumption. In any of the studies, no abnormal changes in organ weights, haematology, clinical chemistry, urinalysis parameters, or pathological findings were observed. Immunogenicity tests on rats and rabbits revealed 100 % seroconversion. Relcovax® was therefore found to be safe in animals, with a No Observed Adverse Effect Level (NOAEL) of 20 µg/protein in rats and rabbits. In efficacy studies, Relcovax® immunised hamsters demonstrated dose-dependent protection against SARS-CoV-2 infection, with a high dose (20 µg/protein) being the most protective, while in cynomolgus macaque monkey study, lowest dose 5 µg/protein had the highest efficacy. In conclusion, Relcovax® was found to be safe, immunogenic, and efficacious in in vivo studies.

Small Molecules N-Phenylbenzofuran-2-carboxamide and N-Phenylbenzo[b]thiophene-2-carboxamide Promote Beta-Amyloid (Aß42) Aggregation and Mitigate Neurotoxicity.

This study reports the unusual ability of small molecules N-phenylbenzofuran-2-carboxamide (7a) and N-phenylbenzo[b]thiophene-2-carboxamide (7b) to promote and accelerate Aß42 aggregation. In the in vitro aggregation kinetic assays, 7a was able to demonstrate rapid increases in Aß42 fibrillogenesis ranging from 1.5- to 4.7-fold when tested at 1, 5, 10, and 25 µM compared to Aß42-alone control. Similarly, compound 7b also exhibited 2.9- to 4.3-fold increases in Aß42 fibrillogenesis at the concentration range tested. Electron microscopy studies at 1, 5, 10, and 25 µM also demonstrate the ability of compounds 7a and 7b to promote and accelerate Aß42 aggregation with the formation of long, elongated fibril structures. Both 7a and 7b were not toxic to HT22 hippocampal neuronal cells and strikingly were able to prevent Aß42-induced cytotoxicity in HT22 hippocampal neuronal cells (cell viability ∼74%) compared to the Aß42-treated group (cell viability ∼20%). Fluorescence imaging studies using BioTracker 490 green, Hoeschst 33342, and the amyloid binding dye ProteoStat further demonstrate the ability of 7a and 7b to promote Aß42 fibrillogenesis and prevent Aß42-induced cytotoxicity to HT22 hippocampal neuronal cells. Computational modeling studies suggest that both 7a and 7b can interact with the Aß42 oligomer and pentamers and have the potential to modulate the self-assembly pathways. The 8-anilino-1-naphthalenesulfonic acid (ANS) dye binding assay also demonstrates the ability of 7a and 7b to expose the hydrophobic surface of Aß42 to the solvent surface that promotes self-assembly and rapid fibrillogenesis. These studies demonstrate the unique ability of small molecules 7a and 7b to alter the self-assembly and misfolding pathways of Aß42 by promoting the formation of nontoxic aggregates. These findings have direct implications in the discovery and development of novel small-molecule-based chemical and pharmacological tools to study the Aß42 aggregation mechanisms, and in the design of novel antiamyloid therapies to treat Alzheimer's disease.

The effects of amyloid beta aggregation on neuronal transcription.

Alzheimer's disease (AD) is a debilitating condition that impairs cognition and episodic memory. AD is well known for its behavioural phenotype however, knowing its cellular pathology, which is primarily based on the presence of amyloid beta (Aß) in various aggregation states, is crucial for the development of research efforts against the disorder. The most notable of these aggregation states are the oligomeric and fibril forms of Aß. This paper aims to describe the transcriptomic profile of neuronal cells exposed to these aggregation states in order to better understand the disorder and identify potential therapeutic genetic targets. The primary findings of this paper illustrate the significant effects of Aß on genes associated with metabolism as well as the dramatically increased effects of oligomeric Aß relative to fibril Aß with respect to the overall changes in gene expression. The presented results also support the further examination of the role of GTPases in the deleterious effects of Aß.

Worldwide survey on implantation of and outcomes for conduction system pacing with His bundle and left bundle branch area pacing leads.

BACKGROUND: Adoption and outcomes for conduction system pacing (CSP), which includes His bundle pacing (HBP) or left bundle branch area pacing (LBBAP), in real-world settings are incompletely understood. We sought to describe real-world adoption of CSP lead implantation and subsequent outcomes. METHODS: We performed an online cross-sectional survey on the implantation and outcomes associated with CSP, between November 15, 2020, and February 15, 2021. We described survey responses and reported HBP and LBBAP outcomes for bradycardia pacing and cardiac resynchronization CRT indications, separately. RESULTS: The analysis cohort included 140 institutions, located on 5 continents, who contributed data to the worldwide survey on CSP. Of these, 127 institutions (90.7%) reported experience implanting CSP leads. CSP and overall device implantation volumes were reported by 84 institutions. In 2019, the median proportion of device implants with CSP, HBP, and/or LBBAP leads attempted were 4.4% (interquartile range [IQR], 1.9-12.5%; range, 0.4-100%), 3.3% (IQR, 1.3-7.1%; range, 0.2-87.0%), and 2.5% (IQR, 0.5-24.0%; range, 0.1-55.6%), respectively. For bradycardia pacing indications, HBP leads, as compared to LBBAP leads, had higher reported implant threshold (median [IQR]: 1.5 V [1.3-2.0 V] vs 0.8 V [0.6-1.0 V], p = 0.0008) and lower ventricular sensing (median [IQR]: 4.0 mV [3.0-5.0 mV] vs. 10.0 mV [7.0-12.0 mV], p < 0.0001). CONCLUSION: In conclusion, CSP lead implantation has been broadly adopted but has yet to become the default approach at most surveyed institutions. As the indications and data for CSP continue to evolve, strategies to educate and promote CSP lead implantation at institutions without CSP lead implantation experience would be necessary.

Differential Effects of Endocannabinoids on Amyloid-Beta Aggregation and Toxicity.

The regulation and metabolism of the endocannabinoid system has received extensive attention for their potential neuroprotective effect in neurodegenerative diseases such as Alzheimer's disease (AD), which is characterized by amyloid ß (Aß) -induced cell toxicity, inflammation, and oxidative stress. Using in vitro techniques and two cell lines, the mouse hippocampus-derived HT22 cells and Chinese hamster ovary (CHO) cells expressing human cannabinoid receptor type 1 (CB1), we investigated the ability of endocannabinoids to inhibit Aß aggregation and protect cells against Aß toxicity. The present study provides evidence that endocannabinoids N-arachidonoyl ethanol amide (AEA), noladin and O-arachidonoyl ethanolamine (OAE) inhibit Aß42 aggregation. They were able to provide protection against Aß42 induced cytotoxicity via receptor-mediated and non-receptor-mediated mechanisms in CB1-CHO and HT22 cells, respectively. The aggregation kinetic experiments demonstrate the anti-Aß aggregation activity of some endocannabinoids (AEA, noladin). These data demonstrate the potential role and application of endocannabinoids in AD pathology and treatment.

Mapping Clinical Documents to the Logical Observation Identifiers, Names and Codes (LOINC) Document Ontology using Electronic Health Record Systems Structured Metadata.

As Electronic Health Record (EHR) systems increase in usage, organizations struggle to maintain and categorize clinical documentation so it can be used for clinical care and research. While prior research has often employed natural language processing techniques to categorize free text documents, there are shortcomings relative to computational scalability and the lack of key metadata within notes' text. This study presents a framework that can allow institutions to map their notes to the LOINC document ontology using a Bag of Words approach. After preliminary manual value- set mapping, an automated pipeline that leverages key dimensions of metadata from structured EHR fields aligns the notes with the dimensions of the document ontology. This framework resulted in 73.4% coverage of EHR documents, while also mapping 132 million notes in less than 2 hours; an order of magnitude more efficient than NLP based methods.

Constructing custom-made radiotranscriptomic signatures of vascular inflammation from routine CT angiograms: a prospective outcomes validation study in COVID-19.

BACKGROUND: Direct evaluation of vascular inflammation in patients with COVID-19 would facilitate more efficient trials of new treatments and identify patients at risk of long-term complications who might respond to treatment. We aimed to develop a novel artificial intelligence (AI)-assisted image analysis platform that quantifies cytokine-driven vascular inflammation from routine CT angiograms, and sought to validate its prognostic value in COVID-19. METHODS: For this prospective outcomes validation study, we developed a radiotranscriptomic platform that uses RNA sequencing data from human internal mammary artery biopsies to develop novel radiomic signatures of vascular inflammation from CT angiography images. We then used this platform to train a radiotranscriptomic signature (C19-RS), derived from the perivascular space around the aorta and the internal mammary artery, to best describe cytokine-driven vascular inflammation. The prognostic value of C19-RS was validated externally in 435 patients (331 from study arm 3 and 104 from study arm 4) admitted to hospital with or without COVID-19, undergoing clinically indicated pulmonary CT angiography, in three UK National Health Service (NHS) trusts (Oxford, Leicester, and Bath). We evaluated the diagnostic and prognostic value of C19-RS for death in hospital due to COVID-19, did sensitivity analyses based on dexamethasone treatment, and investigated the correlation of C19-RS with systemic transcriptomic changes. FINDINGS: Patients with COVID-19 had higher C19-RS than those without (adjusted odds ratio [OR] 2·97 [95% CI 1·43-6·27], p=0·0038), and those infected with the B.1.1.7 (alpha) SARS-CoV-2 variant had higher C19-RS values than those infected with the wild-type SARS-CoV-2 variant (adjusted OR 1·89 [95% CI 1·17-3·20] per SD, p=0·012). C19-RS had prognostic value for in-hospital mortality in COVID-19 in two testing cohorts (high [≥6·99] vs low [<6·99] C19-RS; hazard ratio [HR] 3·31 [95% CI 1·49-7·33], p=0·0033; and 2·58 [1·10-6·05], p=0·028), adjusted for clinical factors, biochemical biomarkers of inflammation and myocardial injury, and technical parameters. The adjusted HR for in-hospital mortality was 8·24 (95% CI 2·16-31·36, p=0·0019) in patients who received no dexamethasone treatment, but 2·27 (0·69-7·55, p=0·18) in those who received dexamethasone after the scan, suggesting that vascular inflammation might have been a therapeutic target of dexamethasone in COVID-19. Finally, C19-RS was strongly associated (r=0·61, p=0·00031) with a whole blood transcriptional module representing dysregulation of coagulation and platelet aggregation pathways. INTERPRETATION: Radiotranscriptomic analysis of CT angiography scans introduces a potentially powerful new platform for the development of non-invasive imaging biomarkers. Application of this platform in routine CT pulmonary angiography scans done in patients with COVID-19 produced the radiotranscriptomic signature C19-RS, a marker of cytokine-driven inflammation driving systemic activation of coagulation and responsible for adverse clinical outcomes, which predicts in-hospital mortality and might allow targeted therapy. FUNDING: Engineering and Physical Sciences Research Council, British Heart Foundation, Oxford BHF Centre of Research Excellence, Innovate UK, NIHR Oxford Biomedical Research Centre, Wellcome Trust, Onassis Foundation.

Glutamine Metabolism Mediates Sensitivity to Respiratory Complex II Inhibition in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a hematologic malignancy metabolically dependent on oxidative phosphorylation and mitochondrial electron transport chain (ETC) activity. AML cells are distinct from their normal hematopoietic counterparts by this metabolic reprogramming, which presents targets for new selective therapies. Here, metabolic changes in AML cells after ETC impairment are investigated. Genetic knockdown of the ETC complex II (CII) chaperone protein SDHAF1 (succinate dehydrogenase assembly factor 1) suppressed CII activity and delayed AML cell growth in vitro and in vivo. As a result, a novel small molecule that directly binds to the ubiquinone binding site of CII and inhibits its activity was identified. Pharmacologic inhibition of CII induced selective death of AML cells while sparing normal hematopoietic progenitors. Through stable isotope tracing, results show that genetic or pharmacologic inhibition of CII truncates the tricarboxylic acid cycle (TCA) and leads to anaplerotic glutamine metabolism to reestablish the truncated cycle. The inhibition of CII showed divergent fates, as AML cells lacked the metabolic plasticity to adequately utilize glutamine metabolism, resulting in preferential depletion of key TCA metabolites and death; normal cells were unaffected. These findings provide insight into the metabolic mechanisms that underlie AML's selective inhibition of CII. IMPLICATIONS: This work highlights the effects of direct CII inhibition in mediating selective AML cell death and provides insights into glutamine anaplerosis as a metabolic adaptation that can be therapeutically targeted.

Peptide-Modified Gemini Surfactants as Delivery System Building Blocks with Dual Functionalities for Glaucoma Treatment: Gene Carriers and Amyloid-Beta (Aß) Self-Aggregation Inhibitors.

Retinal ganglion cell (RGC) neurodegeneration in glaucoma has potential links with amyloid-ß (Aß) deposition. Targeting the Aß pathway was shown to reduce RGC apoptosis and protect RGCs from degeneration. We report exploratory studies on the amyloid Aß40 aggregation inhibition properties of four cell adhesion peptide (CAP)-gemini surfactants that are intended as building blocks for gene carrier nanoparticles for glaucoma treatment. The CAP-gemini surfactants (18-7N(p1-4)-18) were evaluated as potential Aß40 peptide aggregation inhibitors by a fluorescence kinetic assay and for their binding interactions with Aß40 dimers by molecular docking studies. In vitro Aß40 peptide aggregation inhibition studies showed that the 18-7N(p3)-18 and 18-7N(p1)-18 ligands inhibit Aß40 peptide aggregation and prevent the formation of higher order structures. CDOCKER energies and CDOCKER interaction energies demonstrated that the CAP-gemini surfactants formed more stable complexes in the Aß40 dimer assembly and underwent both polar and nonpolar interactions compared to CAP peptides alone. Also, 18-7N(p3)-18 showed a significantly lower CDOCKER energy compared to that of the unmodified gemini surfactant 18-7NH-18 (p < 0.0001) and 18-7N(p4)-18 (p < 0.001), 18-7N(p1)-18, and 18-7N(p2)-18. Similarly, 18-7N(p3)-18 showed a significantly lower CDOCKER interaction energy compared to that of 18-7NH-18, 18-7N(p4)-18 (p < 0.0001), and 18-7N(p2)-18 (p < 0.001), while 18-7N(p3)-18 and 18-7N(p1)-18 showed similar CDOCKER interaction energies. These studies suggest that a combination of both hydrophobic and electrostatic interactions contributes to the anti-Aß40 aggregation activity of CAP-gemini surfactants. CAP-gemini surfactants showed 10-fold better Aß40 peptide aggregation inhibition compared to previously reported values and could provide a new opportunity for glaucoma treatment as dual-functional gene carriers.

RelCoVax®, a two antigen subunit protein vaccine candidate against SARS-CoV-2 induces strong immune responses in mice.

The COVID-19 pandemic has spurred an unprecedented movement to develop safe and effective vaccines against the SARS-CoV-2 virus to immunize the global population. The first set of vaccine candidates that received emergency use authorization targeted the spike (S) glycoprotein of the SARS-CoV-2 virus that enables virus entry into cells via the receptor binding domain (RBD). Recently, multiple variants of SARS-CoV-2 have emerged with mutations in S protein and the ability to evade neutralizing antibodies in vaccinated individuals. We have developed a dual RBD and nucleocapsid (N) subunit protein vaccine candidate named RelCoVax® through heterologous expression in mammalian cells (RBD) and E. coli (N). The RelCoVax® formulation containing a combination of aluminum hydroxide (alum) and a synthetic CpG oligonucleotide as adjuvants elicited high antibody titers against RBD and N proteins in mice after a prime and boost dose regimen administered 2 weeks apart. The vaccine also stimulated cellular immune responses with a potential Th1 bias as evidenced by increased IFN-γ release by splenocytes from immunized mice upon antigen exposure particularly N protein. Finally, the serum of mice immunized with RelCoVax® demonstrated the ability to neutralize two different SARS-CoV-2 viral strains in vitro including the Delta strain that has become dominant in many regions of the world and can evade vaccine induced neutralizing antibodies. These results warrant further evaluation of RelCoVax® through advanced studies and contribute towards enhancing our understanding of multicomponent subunit vaccine candidates against SARS-CoV-2.

Delta Variant with P681R Critical Mutation Revealed by Ultra-Large Atomic-Scale Ab Initio Simulation: Implications for the Fundamentals of Biomolecular Interactions.

The SARS-CoV-2 Delta variant is emerging as a globally dominant strain. Its rapid spread and high infection rate are attributed to a mutation in the spike protein of SARS-CoV-2 allowing for the virus to invade human cells much faster and with an increased efficiency. In particular, an especially dangerous mutation P681R close to the furin cleavage site has been identified as responsible for increasing the infection rate. Together with the earlier reported mutation D614G in the same domain, it offers an excellent instance to investigate the nature of mutations and how they affect the interatomic interactions in the spike protein. Here, using ultra large-scale ab initio computational modeling, we study the P681R and D614G mutations in the SD2-FP domain, including the effect of double mutation, and compare the results with the wild type. We have recently developed a method of calculating the amino-acid-amino-acid bond pairs (AABP) to quantitatively characterize the details of the interatomic interactions, enabling us to explain the nature of mutation at the atomic resolution. Our most significant finding is that the mutations reduce the AABP value, implying a reduced bonding cohesion between interacting residues and increasing the flexibility of these amino acids to cause the damage. The possibility of using this unique mutation quantifiers in a machine learning protocol could lead to the prediction of emerging mutations.

Adverse Events with D-penicillamine Therapy in Hepatic Wilson's Disease: A Single-Center Retrospective Audit.

BACKGROUND AND OBJECTIVE: There are limited data on the adverse events of D-penicillamine in Wilson's disease (WD) that can result in dose modification or treatment discontinuation. The objective of this study was to observe the adverse events related to D-penicillamine in patients with hepatic WD. METHODS: A retrospective audit of prospectively registered hepatic WD patients at a tertiary care center between December 2006 and January 2020 was carried out. Demographic variables, laboratory parameters, and details of treatment were noted. Adverse events (AEs) related to D-penicillamine treatment, the timing and management of these AEs were analysed. RESULTS: The study included 112 patients with hepatic WD on D-penicillamine. D-penicillamine intolerance was seen in 28/112 (25%) over 179 person-years. Of the 28 AEs, severe AEs leading to permanent D-penicillamine discontinuation occurred in 16 (57%) [never reintroduced 12 (43%), discontinued after intolerant to rechallenge, 4 (14%)], temporary cessation followed by reintroduction to initial dose 13 (46%) and continuation with reduced dose in 3 (11%) patients. Overall, most common AEs were hematological [16, 57% (pancytopenia n = 8, bicytopenia n = 5 and hemolytic anemia n = 3)] while renal adverse events (n = 7, 25%) constituted the most common indication for permanent discontinuation. Cytopenias developed beyond 12 months of D-penicillamine initiation whereas hemolytic anemia developed within first 3 months. Following D-penicillamine discontinuation in 25 patients, it was reintroduced to initial dose in 13/25 (52%), switched to trientine due to neurological worsening in 2/25 (8%) and switched to zinc in 10/25 (40%). In patients with reintroduction, gradual dose escalation was tolerated in 9/13 (69%) with a recurrence of AEs leading to permanent discontinuation in 4/13 (31%). CONCLUSION: D-penicillamine treatment is associated with significant AEs mainly related to blood, kidney, and skin. Temporary cessation of drug with reintroduction at a lower dose is an effective and safe option.

COVID-19 pandemic and inflammatory bowel disease from patients' perspective: A survey from COVID epicenter in India.

BACKGROUND AND AIM: The COVID pandemic and countrywide lockdown has had significant impact on patients with inflammatory bowel disease (IBD), with delay in diagnosis, difficulty in access to healthcare and unavailability of drugs. We conducted a telephonic survey to assess this impact. METHODS: Out of 350, 302 participated in the survey. Demographic data, disease severity at the time of survey, extent of disease, details of therapy, and adherence were noted. A validated questionnaire addressing information source, perception of COVID-19 situation, contact with healthcare, and adherence to standard precautions was administered telephonically. RESULTS: Out of 350 contacted patients, 302 (86.28%) patients participated in the survey. Median age of cohort was 39 years. Ulcerative colitis (UC) constituted 79%, 16% Crohn's disease (CD), and 5% IBD-unclassified. At the time of survey, 86.98% patients with UC were in clinical remission and 75.75% of CD patients were generally well. A total of 115 (38%) cases were nonadherent to therapy due to unavailability of medicines (66.38%), financial constraints (25.21%) and inability to reach healthcare facility (3.6%). Disease flare was seen in 14.2% and correlated well with nonadherence. Existing drug therapy was switched to alternative drug in 70 (23.17%) cases due to unavailability (74%). Social media (52.3%) and television (40.4%) were the common sources of information about the pandemic. Telemedicine platforms (WhatsApp and telephone) were used by 180 (59.6%) patients for consultation with good acceptance (81.6%). 87 (28.8%) patients failed to contact healthcare. Apprehension regarding severe COVID infection was noted in 80% while 29% thought that IBD therapy could increase infection risk. Adherence to wearing mask, hand washing, and social distancing was 100%. CONCLUSION: Pandemic resulted in disruption of healthcare visits and medication supply. Majority were concerned about increased risk of COVID-19 infection and adhered to standard precautions. Mobile phone-based formats for patient care may be an alternative due to patient acceptance and convenience.