Design, Synthesis, and Evaluation of Antifungal Activity of Pyrazoleacetamide Derivatives.

BACKGROUND: Fungal infections have posed a big challenge in the management of their treatment. Due to the resistance and toxicity of existing drug molecules in the light of pandemic infections, like COVID-19, there is an urgent need to find newer derivatives of active molecules, which can be effective in fungal infections. OBJECTIVE: In the present study, we aimed to design pyrazole derivatives using molecular modeling studies against target 1EA1 and synthesize 10 molecules of pyrazole derivatives using a multi-step synthesis approach. METHODS: Designed pyrazole derivatives were synthesized by conventional organic methods. The newly synthesized pyrazole molecules were characterized by using FT-IR, 1HNMR, 13CNMR, and LC-MS techniques. Molecular docking studies were also performed. The antifungal activity of newly synthesized compounds was assessed in vitro against Candida albicans and Aspergillus niger using the well plate method. RESULTS: Two of the compounds, OK-7 and OK-8, have been found to show significant docking interaction with target protein 1EA1. These two compounds have also been found to show significant anti-fungal activity against Candida albicans and Aspergillus nigra when compared to the standard fluconazole. The Minimum Inhibitory Concentration (MIC) value of these two compounds has been found to be 50 µg/ml. CONCLUSION: Pyrazole derivatives with -CH3, CH3O-, and -CN groups have been found to be active against tested fungi and can be further explored for their potential as promising anti-fungal agents for applications in the field of medicinal chemistry.

Plasmonic Resonant Intercluster Coulombic Decay.

Light-induced energy confinement in nanoclusters via plasmon excitations influences applications in nanophotonics, photocatalysis, and the design of controlled slow electron sources. The resonant decay of these excitations through the cluster's ionization continuum provides a unique probe of the collective electronic behavior. However, the transfer of a part of this decay amplitude to the continuum of a second conjugated cluster may offer control and efficacy in sharing the energy nonlocally to instigate remote collective events. With the example of a spherically nested dimer Na_{20}@C_{240} of two plasmonic systems we find that such a transfer is possible through the resonant intercluster Coulombic decay (RICD) as a fundamental process. This plasmonic RICD signal can be experimentally detected by the photoelectron velocity map imaging technique.

Risk Factors for Common Kidney Stones Are Correlated with Kidney Function Independent of Stone Composition.

INTRODUCTION: Kidney stone type varies with age, sex, season, and medical conditions. Lower estimate glomerular filtration rate (eGFR) leads to changes in urine chemistry, and risk factors for kidney stones are thought to vary by stone type. We explore the association between eGFR, urine risk factors, and common stone compositions. METHODS: This was a retrospective cohort study of 811 kidney stone patients seen at Yale Medicine between 1994 and 2021 with serum chemistries and 24-h urine chemistries matched within 1 year of baseline stone analysis. Patients' eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 equation. Demographics and medical history were compared by χ2 tests. 24-h urine chemistries and stone analyses were analyzed by one-way ANOVA. Linear regressions were performed to control for demographics, comorbidities, and stone composition. RESULTS: With lower eGFR, the proportion of calcium stones declined while uric acid (UA) stones increased. On univariable analysis, lower eGFR was associated with lower urine pH, calcium, citrate, UA, magnesium, phosphorus, and ammonium. On multivariable analysis, controlling for age, sex, ethnicity, body mass index, comorbidities, and stone type, these factors remained significant. Stone formers with lower eGFR had elevated supersaturation for UA, but reduced supersaturations for calcium-containing stones. Though urine oxalate was significant on univariable analysis, it was not on multivariable analysis. CONCLUSION: Changes in urine parameters are strongly correlated with eGFR regardless of stone type. Renal function may play a key role in modulating kidney stone risk factors. Strategies to mitigate stone risk may need to vary with kidney function, especially when patient urine or stone composition data are unavailable.

Adverse Outcomes Associated With Atrial Arrhythmias After Veno-Venous Extracorporeal Membrane Oxygenation.

Veno-venous extracorporeal membrane oxygenation (VV ECMO) is used as a treatment modality in those who fail to respond to conventional care. Hypoxia and medications used in the intensive care unit may increase risk for atrial arrhythmias (AA). This study aims to evaluate the impact of AA on post-VV ECMO outcome. A retrospective review of patients who were placed on VV ECMO between October 2016 and October 2021. One hundred forty-five patients were divided into two groups, AA and no AA. Baseline characteristic and potential risk factors were assessed. Uni- and multivariate analysis using logistic regression models were constructed to evaluate the predictors of mortality between groups. Survival between groups was estimated by the Kaplan-Meier method using the log-rank test. Advanced age with history of coronary artery disease and hypertension were associated with increased risk to develop AA post-VV ECMO placement ( p value < 0.05). Length on ECMO, time intubated, hospital length of stay, and sepsis were significantly increased in patients in the AA group ( p value < 0.05). There was no difference in the overall mortality between the two groups. AAs were associated with worse hospital course and complications but no difference in overall mortality rate. Age and cardiovascular disease seem to be predisposing risk factors for this. Further studies are needed to investigate potential strategies to prevent AAs development in this population.

Bridging strategies and cardiac replacement outcomes in patients with acute decompensated heart failure-related cardiogenic shock.

AIMS: To describe outcomes associated with bridging strategies in patients with acute decompensated heart failure-related cardiogenic shock (ADHF-CS) bridged to durable left ventricular assist device (LVAD) or heart transplantation (HTx). METHODS AND RESULTS: Durable LVAD or HTx recipients from 2014 to 2019 with pre-operative ADHF-CS were identified in the Society of Thoracic Surgeons Adult Cardiac Surgery Database and stratified by bridging strategy. The primary outcome was operative or 30-day post-operative mortality. Secondary outcomes included post-operative major bleeding. Exploratory comparisons between bridging strategies and outcomes were performed using overlap weighting with and without covariate adjustment. Among 9783 patients with pre-operative CS, 8777 (89.7%) had ADHF-CS. Medical therapy (n = 5013) was the most common bridging strategy, followed by intra-aortic balloon pump (IABP; n = 2816), catheter-based temporary mechanical circulatory support (TMCS; n = 417), and veno-arterial extracorporeal membrane oxygenation (VA-ECMO; n = 465). Mortality was highest in patients bridged with VA-ECMO (22%), followed by catheter-based TMCS (10%), IABP (9%), and medical therapy (7%). Adverse post-operative outcomes were more frequent in LVAD recipients compared with HTx recipients. CONCLUSION: Among patients with ADHF-CS bridged to HTx or durable LVAD, the highest rates of death and adverse events during index hospitalization were observed in those bridged with VA-ECMO, followed by catheter-based TMCS, IABP, and medical therapy. Patients who received durable LVAD had higher rates of post-operative complications compared with HTx recipients. Prospective trials are needed to define optimal bridging strategies in patients with ADHF-CS.

The Cost-effectiveness of Transplanting Hearts From Hepatitis C-infected Donors Into Uninfected Recipients.

BACKGROUND: The DONATE HCV trial demonstrated the safety and efficacy of transplanting hearts from hepatitis C viremic (HCV+) donors. In this report, we examine the cost-effectiveness and impact of universal HCV+ heart donor eligibility in the United States on transplant waitlist time and life expectancy. METHODS: We developed a microsimulation model to compare 2 waitlist strategies for heart transplant candidates in 2018: (1) status quo (SQ) and (2) SQ plus HCV+ donors (SQ + HCV). From the DONATE HCV trial and published national datasets, we modeled mean age (53 years), male sex (75%), probabilities of waitlist mortality (0.01-0.10/month) and transplant (0.03-0.21/month) stratified by medical urgency, and posttransplant mortality (0.003-0.052/month). We assumed a 23% increase in transplant volume with SQ + HCV compared with SQ. Costs (2018 United States dollar) included waitlist care ($2200-190 000/month), transplant ($213 400), 4-wk HCV treatment ($26 000), and posttransplant care ($2500-11 300/month). We projected waitlist time, quality-adjusted life-years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs [$/QALY, discounted 3%/year]; threshold ≤$100 000/QALY). RESULTS: Compared with SQ, SQ + HCV decreased waitlist time from 8.7 to 6.7 months, increased undiscounted life expectancy from 8.9 to 9.2 QALYs, and increased discounted lifetime costs from $671 400/person to $690 000/person. Four-week HCV treatment comprised 0.5% of lifetime costs. The ICER of SQ + HCV compared with SQ was $74 100/QALY and remained ≤$100 000/QALY with up to 30% increases in transplant and posttransplant costs. CONCLUSIONS: Transplanting hearts from HCV-infected donors could decrease waitlist times, increase life expectancy, and be cost-effective. These findings were robust within the context of current high HCV treatment costs.

Relapsing Polychondritis in a Patient With Auricular Chondritis and Inflammatory Bowel Disease: A Case Report With Literature Review.

Relapsing polychondritis (RP) most commonly presents as inflammation and degeneration of cartilaginous tissue in the auricles, nasal septum, and lungs (in severe instances). RP is a rare autoimmune condition associated with other autoimmune diseases in 30% of cases. The prevalence of gastrointestinal involvement with RP is tenuous; however, there is a growing collection of case studies associating auricular chondritis with concomitant inflammatory bowel disease (IBD), including both ulcerative colitis and Crohn's disease. We report the case of a 35-year-old patient presenting with autoimmune pancreatitis, with a past medical history of Crohn's disease, primary sclerosing cholangitis (PSC), and suspected RP. Although RP is rare, the disease's multiple clinical presentations and recurrent episodic nature can cause significant diagnostic delays and are often overlooked by physicians. Thus, low disease prevalence may be due to under-recognition and under-reporting of disease symptoms. As RP is a clinical diagnosis, increased awareness of the disease presentation and clinical characteristics may increase disease recognition and improve treatment outcomes.

Zebras in the Era of COVID.

Malaria remains a significant global health concern. Non-malarial areas, including North America and Europe, largely report cases in association with recent travel to endemic regions. Though cyclic symptoms and chills are characteristic of the infection, thorough social histories including previous travels is the basic prerequisite for timely diagnosis, treatment initiation, and ultimate prognosis of this potentially life-threatening condition.

A Complex Case of Aspergillus Infection of the Brain and Its Future Medical Implications.

Aspergillus is a fungal genus found worldwide, which causes infection most commonly in the respiratory system and in other systems, including the central nervous system. Fungal species, such as Aspergillus fumigatus or flavus, are more common in immunocompromised patient populations, such as those taking immunosuppressants post-transplantation, those on long-term corticosteroids, or those with immunodeficiencies such as AIDS. In this paper, we describe a rare case of aspergillosis that occurred due to a history of taking corticosteroids to treat arthritis pain in a patient with type 2 diabetes. Given the rise in antifungal-resistant species and environmental changes, it is noteworthy for further research to be conducted on new treatment plans and the management of such fungal infections to prepare against opportunistic infections caused by Aspergillus in the future.

Effectiveness of introduction of JEV vaccination into routine immunization program in a tribal district of Odisha.

Background: A severe outbreak of Japanese encephalitis (JE) and acute encephalitis syndrome (AES) with high case fatality among tribal children was reported from Malkangiri district of Odisha, during September to November 2016 affecting 336 children with 103 deaths. Following the outbreak, a mass vaccination campaign was introduced in Malkangiri district in2017. In 2018, the JE vaccine was introduced into the routine immunization program as per National Immunization Schedule. Our study surveys the JE vaccination coverage among children of Malkangiri and the incidence of JE cases for a period of three years. Methodology: The current study was conducted by establishing prospective and retrospective AES surveillance system and household vaccine coverage surveys in Malkangiri district. In the target population, the vaccination coverage survey was undertaken and also additional immunization coverage data from sub-centers was collected. Results: After 2016 JE outbreak, a mass vaccination campaign was carried out in children up to 15 years of age, where 96% of children were covered in the district in 2017 and only four AES cases were detected. Under routine immunization program, the vaccine coverage for the year 2018 was 68% for JE-1 dose and 37% for JE-2 dose. There were 8 AES cases detected in 2018 out of which four children died. Vaccination coverage for 2019 was 97% for JE-1 dose and 84% for JE-2 dose. The AES cases detected in 2019 was nil. Conclusion: Vaccination against JEV and AES surveillance systems has an important role in prevention and control of AES outbreaks.

Single-Cell Multiomics Reveals Clonal T-Cell Expansions and Exhaustion in Blastic Plasmacytoid Dendritic Cell Neoplasm.

The immune system represents a major barrier to cancer progression, driving the evolution of immunoregulatory interactions between malignant cells and T-cells in the tumor environment. Blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare acute leukemia with plasmacytoid dendritic cell (pDC) differentiation, provides a unique opportunity to study these interactions. pDCs are key producers of interferon alpha (IFNA) that play an important role in T-cell activation at the interface between the innate and adaptive immune system. To assess how uncontrolled proliferation of malignant BPDCN cells affects the tumor environment, we catalog immune cell heterogeneity in the bone marrow (BM) of five healthy controls and five BPDCN patients by analyzing 52,803 single-cell transcriptomes, including 18,779 T-cells. We test computational techniques for robust cell type classification and find that T-cells in BPDCN patients consistently upregulate interferon alpha (IFNA) response and downregulate tumor necrosis factor alpha (TNFA) pathways. Integrating transcriptional data with T-cell receptor sequencing via shared barcodes reveals significant T-cell exhaustion in BPDCN that is positively correlated with T-cell clonotype expansion. By highlighting new mechanisms of T-cell exhaustion and immune evasion in BPDCN, our results demonstrate the value of single-cell multiomics to understand immune cell interactions in the tumor environment.

Generation of formaldehyde and formaldehyde-d2 for hydroxymethylations and hydroxydeuteromethylations of difluoroenolates and difluorobenzyl carbanions.

A method for the in situ production of formaldehyde from dimethylsulfoxide, bromine, and cesium carbonate is reported for reactions with difluoroenolates and difluorobenzyl carbanions. This process also generates formaldehyde-d2 for the production of 2,2-difluoro-1,1-deuteroethanols. Mechanistic and computational studies further characterize the production of hydroxymethylated and hydroxydeuteromethylated difluorinated organic molecules.

The impact of hospital size on national trends and outcomes in isolated open proximal aortic surgery.

OBJECTIVE: To determine the impact of hospital size on national trend estimates of isolated open proximal aortic surgery for benchmarking hospital performance. METHODS: Patients age >18 years who underwent isolated open proximal aortic surgery for aneurysm and dissection from 2002 to 2014 were identified using the National Inpatient Sample. Concomitant valvular, vessel revascularization, re-do procedures, endovascular, and surgery for descending and thoracoabdominal aorta were excluded. Discharges were stratified by hospital size and analyzed using trend, multivariable regression, propensity-score matching analysis. RESULTS: Over a 13-year period, 53,657 isolated open proximal aortic operations were performed nationally. Although the total number of operations/year increased (∼2.9%/year increase) and overall in-hospital mortality decreased (∼4%/year; both P < .001 for trend), these did not differ by hospital size (P > .05). Large hospitals treated more sicker and older patients but had shorter length of stay and lower hospital costs (both P < .001). Even after propensity-score matching, large hospital continued to demonstrate superior in-hospital outcomes, although only statistically for major in-hospital cardiac complications compared with non-large hospitals. In our subgroup analysis of dissection versus non-dissection cohort, in-hospital mortality trends decreased only in the non-dissection cohort (P < .01) versus dissection cohort (P = .39), driven primarily by the impact of large hospitals (P < .01). CONCLUSIONS: This study demonstrates increasing volume and improving outcomes of isolated open proximal aortic surgeries nationally over the last decade regardless of hospital bed size. Moreover, the resource allocation of sicker patients to larger hospital resulted shorter length of stay and hospital costs, while maintaining similar operative mortality to small- and medium-sized hospitals.

Breakthrough SARS-CoV-2 infections among BBV-152 (COVAXIN®) and AZD1222 (COVISHIELDTM ) recipients: Report from the eastern state of India.

In this study, we attempted to record the breakthrough cases reported through passive and voluntary reporting at various healthcare facilities from different districts of Odisha, their clinical presentation, requirement of hospitalization postinfection, and antibody titer against spike antigen. Nasopharyngeal swab and serum samples alongwith demographic, clinical presentation and requirement of hospitalization postinfection were collected from vaccinated individuals through passive and voluntary reporting to various healthcare facilities of Odisha state to detect the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus infection and quantitative estimation of antibody titers. A total of 274 samples were found to be positive after 14 days of receiving complete doses of the vaccines. More than 83.2% of the individuals were found to be symptomatic with 9.9% of those required hospitalization. The seropositivity in individuals receiving Covishield (96.7%) was significantly higher than in Covaxin (77.1%). Hospitalized patients were having less median antibody titers than individuals in home isolation. The median age for breakthrough infection among the referred cases was 47.0 years (interquartile range [IQR]: 28.0) with a significantly older age group among Covishield recipients. The median spike receptor binding domain IgG titer values for Covaxin and Covishield recipients were 213.5 AU/ml (IQR: 537.5) and 647.5 AU/ml (IQR: 1645.1), respectively. The results reported here highlight the need for systematic data capture for the breakthrough infections to monitor the emergence of any vaccine escape variants and to plan the next steps in the coronavirus disease-19 (COVID-19) vaccine development by understanding the link between clinical protection and measured immunity against SARS-CoV-2 infection.

1-year outcomes for lung transplantation recipients with non-alcoholic fatty liver disease.

Advanced hepatic fibrosis and cirrhosis are absolute contraindications to lung transplantation. [ 1] However, whether fatty liver disease with mild-moderate fibrosis contributes to increased adverse outcomes post-lung transplantation remains unknown. We present a retrospective analysis of patients transplanted at Brigham and Women's Hospital between 2015 and 2017 to identify whether patients with mild-moderate non-alcoholic fatty liver disease (NAFLD) experience increased short-term complications compared to patients with normal liver architecture. Patients with advanced (F3-F4) fibrosis and/or cirrhosis were considered non-suitable transplant candidates, a priori. This study was powered for a difference in index hospital-free days within the first 30 days of 25% (α=0.05, ß=0.8). Secondary outcomes included index intensive care unit (ICU)-free days within the first 10 days post-transplant, perioperative blood product transfusion, incidence of index hospitalisation arrhythmias and delirium, need for insulin on discharge post-transplant, tacrolimus dose required to maintain a trough of 8-12 ng·mL-1 at index hospital discharge, and 1-year post-transplant incidence of insulin-dependent diabetes, acute kidney injury, acute cellular rejection, unplanned hospital readmissions and infection. 150 patients underwent lung transplantation between 2015 and 2017 and were included in the analysis; of these patients 40 (27%) had evidence of NAFLD. Median index hospital-free days for patients with NAFLD were non-inferior to those without (16 days, IQR 10.5-19.5 versus 12 days, IQR 0-18.0, p=0.03). Regarding secondary outcomes, both index hospitalisation and 1-year outcomes were non-inferior between patients with NAFLD and those with normal liver architecture. This study demonstrates that mild-moderate severity NAFLD may not be a contraindication to lung transplantation.

N-myc-interactor mediates microbiome induced epithelial to mesenchymal transition and is associated with chronic lung allograft dysfunction.

BACKGROUND: Recent evidence suggests a role for lung microbiome in occurrence of chronic lung allograft dysfunction (CLAD). However, the mechanisms linking the microbiome to CLAD are poorly delineated. We investigated a possible mechanism involved in microbial modulation of mucosal response leading to CLAD with the hypothesis that a Proteobacteria dominant lung microbiome would inhibit N-myc-interactor (NMI) expression and induce epithelial to mesenchymal transition (EMT). METHODS: Explant CLAD, non-CLAD, and healthy nontransplant lung tissue were collected, as well as bronchoalveolar lavage from 14 CLAD and matched non-CLAD subjects, which were followed by 16S rRNA amplicon sequencing and quantitative polymerase chain reaction (PCR) analysis. Pseudomonas aeruginosa (PsA) or PsA-lipopolysaccharide was cocultured with primary human bronchial epithelial cells (PBEC). Western blot analysis and quantitative reverse transcription (qRT) PCR was performed to evaluate NMI expression and EMT in explants and in PsA-exposed PBECs. These experiments were repeated after siRNA silencing and upregulation (plasmid vector) of EMT regulator NMI. RESULTS: 16S rRNA amplicon analyses revealed that CLAD patients have a higher abundance of phyla Proteobacteria and reduced abundance of the phyla Bacteroidetes. At the genera level, CLAD subjects had an increased abundance of genera Pseudomonas and reduced Prevotella. Human CLAD airway cells showed a downregulation of the N-myc-interactor gene and presence of EMT. Furthermore, exposure of human primary bronchial epithelial cells to PsA resulted in downregulation of NMI and induction of an EMT phenotype while NMI upregulation resulted in attenuation of this PsA-induced EMT response. CONCLUSIONS: CLAD is associated with increased bacterial biomass and a Proteobacteria enriched airway microbiome and EMT. Proteobacteria such as PsA induces EMT in human bronchial epithelial cells via NMI, demonstrating a newly uncovered mechanism by which the microbiome induces cellular metaplasia.

Advanced Surgical and Percutaneous Approaches to Pulmonary Vascular Disease.

Despite progress in modern medical therapy, pulmonary hypertension remains an unremitting disease. Once severe or refractory to medical therapy, advanced percutaneous and surgical interventions can palliate right ventricular overload, bridge to transplantation, and overall extend a patient's course. These approaches include atrial septostomy, Potts shunt, and extracorporeal life support. Bilateral lung transplantation is the ultimate treatment for eligible patients, although the need for suitable lungs continues to outpace availability. Measures such as ex vivo lung perfusion are ongoing to expand donor lung availability, increase rates of transplant, and decrease waitlist mortality.

Long-term Outcomes of Aortic Valve Replacement With Aortic Homograft: 27 Years Experience.

BACKGROUND: Aortic homografts have been used in young patients requiring aortic valve replacement. Currently, these grafts are generally reserved for aortic valve endocarditis with or without root abscess; however, longitudinal data are lacking. Our aim was to assess the long-term safety and durability of homograft implantation. METHODS: All adult patients undergoing aortic homograft implantation at a single institution from 1992 to 2019 were included. Outcomes of interest included all-cause mortality and aortic valve reoperation, studied over a median follow-up duration of 19 years. RESULTS: In all, 252 patients with a mean age of 49 years were included. Infective endocarditis was the primary indication for surgery in 95 patients (38%). The endocarditis group, compared with the no-endocarditis group, had a higher prevalence of New York Heart Association class III-IV (56% vs 26%), chronic kidney disease (22% vs 1%), prior cardiac surgery (40% vs 10%), and emergency status (7% vs 0%; all P < .001). Operative mortality was higher among endocarditis patients (16% vs 0.6%, P < .001), which persisted after risk adjustment. Among patients who survived to discharge, however, there was no difference in long-term survival between the endocarditis group and no-endocarditis group. Overall survival and freedom from reoperation were 88.3% and 80% at 15 years and 87.2% and 78% at 25 years, respectively. Indications for reoperation included structural valve deterioration (83%), endocarditis (12%), and mitral valve disease (5%). Reoperative mortality occurred in 2 patients (4.9%). CONCLUSIONS: Aortic homografts are associated with good long-term survival and admissible freedom from reoperation. Operative mortality is high among patients with endocarditis; however, for those who survive to discharge, long-term survival and durability are the same as for patients without endocarditis.