Citations

Background Patients with single ventricle (SV) congenital heart disease (CHD) undergo several interventions in the first years of life. Advanced diagnostics are required for interstage assessment of anatomy, but are associated with significant diagnostic risk. We sought to evaluate image quality, risk, and accuracy of cardiac computed tomography (CCT) for evaluation of anatomy prior to superior cavopulmonary connection (SCPC) compared to surgical findings across 2 institutions. Methods A retrospective evaluation of image quality, risk, and accuracy of pre-SCPC CCT was performed at 2 institutions between January 1, 2010 and September 30, 2016. Results CCT was performed in 90 SV CHD patients with a median age of 4.03 months (interquartile range [IQR] 3.36, 5.33) prior to SCPC. Image quality was optimal (84%) or good (16%) in all patients, without significant discrepancy compared to surgical findings. 7 patients (8%) required interventional cardiac catheterization subsequent to CCT and before surgical intervention. 49% of scans were performed without sedation, 43% of scans were performed with mild to moderate sedation, and 8% of scans were performed with general anesthesia. The median total procedural dose-length product (DLP) was 18 (IQR 14, 26) mGy*cm, estimating an age adjusted radiation dose of 1.4 millisievert (mSv). One minor (1%) adverse event was reported within 24 h of the CCT. Surgical complications were unrelated to the presurgical findings. Conclusions CCT for pre-SCPC evaluation is safe, with excellent accuracy for anatomy at the time of surgical intervention across 2 institutions. In select patients, noninvasive evaluation with CCT may be indicated.

During the COVID-19 pandemic, efforts have been made worldwide to develop effective therapies to address the devastating immune-mediated effects of SARS-CoV-2. With the exception of monoclonal antibody-mediated therapeutics and preventive approaches such as mass immunization, most experimental or repurposed drugs have failed in large randomized clinical trials ( https://www.who.int/publications/i/item/therapeutics-and-covid-19-living-guideline ). The worldwide spread of SARS-CoV-2 virus revealed specific susceptibilities to the virus among the elderly and individuals with age-related syndromes. These populations were more likely to experience a hyperimmune response characterized by a treatment-resistant acute lung pathology accompanied by multiple organ failure. These observations underscore the interplay between the virus, the biology of aging, and outcomes observed in the most severe cases of SARS-CoV-2 infection. The ectoenzyme CD38 has been implicated in the process of “inflammaging” in aged tissues. In a current publication, Horenstein et al. present evidence to support the hypothesis that CD38 plays a central role in altered immunometabolism resulting from COVID-19 infection. The authors discuss a critical but underappreciated trifecta of CD38-mediated NAD + metabolism, aging, and COVID-19 immune response and speculate that the CD38/NAD + axis is a promising therapeutic target for this disease.

AbstractBackgroundThe SARS‐CoV‐2 pandemic disrupted hospital operations, affected the blood supply, and challenged the health care system to develop new therapeutic options, including convalescent plasma (CCP). The aim of this study is to describe and analyze blood supply fluctuations and the use of convalescent plasma in 2020.MethodsAABB distributed a weekly and biweekly questionnaire through email to hospital‐based members (HBM).ResultsThe survey was sent to 887 HBM with 479 unique respondents, most of the hospitals served pediatric and adult patients, and all states of the country participated, except Idaho and Vermont. Fifty four percent of HBM reported increased wastage in the early phase of the pandemic (May), which decreased to 4% by the end of June and throughout the rest of the year. The majority of HBM reported receiving alerts from their blood suppliers reporting blood shortages throughout the year. During March and April, only 12% of HBM were performing elective surgical procedures. The top reasons to delay procedures were: bed availability (28%); COVID‐19 caseload (23%; and blood availability (19%). By mid‐April, 42% HBM had transfused CCP and reported >24 h delay in getting the units; the vast majority obtained CCP using the Expanded Access Protocol, and later, the Emergency Use Authorization. HBM consistently prioritized the most severe patients to receive CCP, but the proportion of severely ill recipients fell from 52% to 37% between May and October, with an increase from 5% to 21% of HBM providing CCP transfusion early in the course of the disease.DiscussionBlood utilization and availability fluctuated during the pandemic. The fluctuations appeared to be related to the number of COVID‐19 in the community. The use and regulatory landscape of CCP rapidly evolved over the first 8 months of the pandemic.

Abstract Cellular senescence contributes to age-related disorders including physical dysfunction, disabilities, and mortality caused by tissue inflammation and damage. Senescent cells accumulate in multiple tissues with aging and at etiological sites of multiple chronic disorders. The senolytic drug combination, Dasatinib plus Quercetin (D+Q), is known to reduce senescent cell abundance in aged mice. However, the effects of long-term D+Q treatment on intestinal senescent cell and inflammatory burden and microbiome composition in aged mice remain unknown. Here, we examine the effect of D+Q on senescence (p16Ink4a and p21Cip1) and inflammation (Cxcl1, Il1β, Il6, Mcp1, and Tnfα) markers in small (ileum) and large (caecum and colon) intestine in aged mice (n = 10) compared to age-matched placebo-treated mice (n = 10). Additionally, we examine microbial composition along the intestinal tract in these mice. D+Q-treated mice show significantly lower senescent cell (p16 and p21 expression) and inflammatory (Cxcl1, Il1β, Il6, Mcp1, and Tnfα expression) burden in small and large intestine compared with control mice. Further, we find specific microbial signatures in ileal, cecal, colonic, and fecal regions that are distinctly modulated by D+Q, with modulation being most prominent in small intestine. Further analyses reveal specific correlation of senescence and inflammation markers with specific microbial signatures. Together, these data demonstrate that the senolytic treatment reduces intestinal senescence and inflammation while altering specific microbiota signatures and suggest that the optimized senolytic regimens might improve health via reducing intestinal senescence, inflammation, and microbial dysbiosis in older subjects.

Purpose of review Here we review recent literature on the emerging role of nicotinamide adenine dinucleotide (NAD + ) metabolism and its dysfunction via the enzyme CD38 in the pathogenesis of rheumatologic diseases. We evaluate the potential of targeting CD38 to ameliorate NAD + -related metabolic imbalance and tissue dysfunction in the treatment of systemic sclerosis (SSc), systemic lupus erythematous (SLE), and rheumatoid arthritis (RA). Recent findings In this review, we will discuss emerging basic, preclinical, and human data that point to the novel role of CD38 in dysregulated NAD + -homeostasis in SSc, SLE, and RA. In particular, recent studies implicate increased activity of CD38, one of the main enzymes in NAD + catabolism, in the pathogenesis of persistent systemic fibrosis in SSc, and increased susceptibility of SLE patients to infections. We will also discuss recent studies that demonstrate that a cytotoxic CD38 antibody can promote clearance of plasma cells involved in the generation of RA antibodies. Summary Recent studies identify potential therapeutic approaches for boosting NAD + to treat rheumatologic diseases including SSc, RA, and SLE, with particular attention to inhibition of CD38 enzymatic activity as a target. Key future directions in the field include the determination of the cell-type specificity and role of CD38 enzymatic activity versus CD38 structural roles in human diseases, as well as the indicators and potential side effects of CD38-targeted treatments.

Cellular senescence represents one of the major risk factors for chronic liver disease and contributes to morbidity, mortality, and increased healthcare spending. A relevant strategy for understanding the role of senescent cells in liver pathogenesis is to use genetic or pharmacological strategies to eliminate senescent cells. The combination of the senolytic drugs, Dasatinib and Quercetin (D+Q), effectively reduces senescent cell burden in multiple tissues, extending both healthspan and lifespan in mice, and alliviating obesity and age‐associated hepatic steatosis. The aim of this study was to investigate effects of D+Q treatment on livers of young and old female mice. A total of 40 mice, 20 young females (3‐months) and 20 old females (18‐months), was divided into 4 groups: Young (Y) mice treated with either D+Q or placebo and old (O) mice treated with D+Q or placebo. The treatment was performed for 3 consecutive days every 2 weeks over 10 weeks. Comparative analysis of hepatic miRNAs indicated that D+Q treatment significantly decreased levels of senescence‐specific miR‐126 expression in livers of old mice treated with D+Q compared to vehicle‐treated old mice (p=0.025), As expected, there was no effect of D+Q treatment in young animals. Analysis of miR‐126 target genes indicated that PI3K gene expression was significantly increased in response to D+Q treatment (p=0.003). Additionally, Akt1 and mTOR mRNA levels were increased in D+Q‐treated mice (p=0.008 and p=0.02, respectively). In summary, our data suggest that the mechanism of PI3K signaling pathway activation upon elimination of senescent cells by treatment with D+Q is mediated through downregulation of senescence‐specific miR‐126. Support or Funding Information This work is supported by National Institutes of Health (NIH) (R56AG061414, R15AG059190 and R03AG059846)

Objective This study aimed to develop and validate a patient-reported outcome measure (PROM) in acute pancreatitis (AP) as an endpoint centred on the patient. Design A PROM instrument (PAtieNt-rePoRted OutcoMe scale in acute pancreatItis, an international proSpEctive cohort study, PAN-PROMISE scale) was designed based on the opinion of patients, professionals and an expert panel. The scale was validated in an international multicentre prospective cohort study, describing the severity of AP and quality of life at 15 days after discharge as the main variables for validation. The COSMIN (COnsensus-based Standards for the selection of health status Measurement INstruments) methodology was applied. Both the design and validation stages considered the content and face validity of this new instrument; the metric properties of the different items, reliability (reproducibility and internal consistence), the construct, structural and criterion validity, responsiveness and interpretability of this scale. Results PAN-PROMISE consists of a seven-item scale based on the symptoms that cause the most discomfort and concern to patients with AP. The validation cohort involved 15 countries, 524 patients. The intensity of symptoms changed from higher values during the first 24 hours to lower values at discharge and 15 days thereafter. Items converged into a unidimensional ordinal scale with good fit indices. Internal consistency and split-half reliability at discharge were adequate. Reproducibility was confirmed using test–retest reliability and comparing the PAN-PROMISE score at discharge and 15 days after discharge. Evidence is also provided for the convergent-discriminant and empirical validity of the scale. Conclusion The PAN-PROMISE scale is a useful tool to be used as an endpoint in clinical trials, and to quantify patient well-being during the hospital admission and follow-up. Trial registration number NCT03650062