Low-density PD-1 expression on resting human natural killer cells is functional and upregulated after transplantation.

Expression of programmed cell death protein 1 (PD-1) on natural killer (NK) cells has been difficult to analyze on human NK cells. By testing commercial clones and novel anti-PD-1 reagents, we found expression of functional PD-1 on resting human NK cells in healthy individuals and reconstituting NK cells early after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Peripheral blood samples from healthy individuals and transplant recipients were stained for PD-1 expression using the commercial anti-PD-1 clone PD1.3.1.3, fluorescein isothiocyanate (FITC)-labeled pembrolizumab, or an FITC-labeled single-chain variable fragment (scFv) reagent made from pembrolizumab. These reagents identified low yet consistent basal PD-1 expression on resting NK cells, a finding verified by finding lower PD-1 transcripts in sorted NK cells compared with those in resting or activated T cells. An increase in PD-1 expression was identified on paired resting NK cells after allo-HSCT. Blockade of PD-1 on resting NK cells from healthy donors with pembrolizumab did not enhance NK function against programmed death-ligand 1 (PD-L1)-expressing tumor lines, but blocking with its scFv derivative resulted in a twofold increase in NK cell degranulation and up to a fourfold increase in cytokine production. In support of this mechanism, PD-L1 overexpression of K562 targets suppressed NK cell function. Interleukin-15 (IL-15) activity was potent and could not be further enhanced by PD-1 blockade. A similar increase in function was observed with scFv PD-1 blockade on resting blood NK cells after allo-HSCT. We identify the functional importance of the PD-1/PD-L1 axis on human NK cells in which blockade or activation to overcome inhibition will enhance NK cell-mediated antitumor control.

Prevalence of comorbidities among individuals with COVID-19: A rapid review of current literature.

INTRODUCTION: On February 11, 2020 WHO designated the name "COVID-19" for the disease caused by "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2), a novel virus that quickly turned into a global pandemic. Risks associated with acquiring the virus have been found to most significantly vary by age and presence of underlying comorbidity. In this rapid literature review we explore the prevalence of comorbidities and associated adverse outcomes among individuals with COVID-19 and summarize our findings based on information available as of May 15, 2020. METHODS: A comprehensive systematic search was performed on PubMed, Medline, Scopus, Embase, and Google Scholar to find articles published until May 15, 2020. All relevant articles providing information on PCR tested COVID-19 positive patient population with clinical characteristics and epidemiological information were selected for review and analysis. RESULTS: A total of 27 articles consisting of 22,753 patient cases from major epicenters worldwide were included in the study. Major comorbidities seen in overall population were CVD (8.9%), HTN (27.4%), Diabetes (17.4%), COPD (7.5%), Cancer (3.5%), CKD (2.6%), and other (15.5%). Major comorbidity specific to countries included in the study were China (HTN 39.5%), South Korea (CVD 25.6%), Italy (HTN 35.9%), USA (HTN 38.9%), Mexico, (Other 42.3%), UK (HTN 27.8%), Iran (Diabetes 35.0%). Within fatal cases, an estimated 84.1% had presence of one or more comorbidity. Subgroup analysis of fatality association with having comorbidity had an estimated OR 0.83, CI [0.60-0.99], p<0.05. CONCLUSIONS: Based on our findings, hypertension followed by diabetes and cardiovascular diseases were the most common comorbidity seen in COVID-19 positive patients across major epicenters world-wide. Although having one or more comorbidity is linked to increased disease severity, no clear association was found between having these risk factors and increased risk of fatality.

Prevalence, clinical characteristics, and outcomes of pediatric COVID-19: A systematic review and meta-analysis.

INTRODUCTION: The novel coronavirus pandemic is an ongoing challenge faced by the public and health care systems around the globe. Majority of information and evidence gathered so far regarding COVID-19 has been derived from data and studies in adult populations. Crucial information regarding the characterization, clinical symptomatology, sequelae, and overall outcomes in the pediatric population is lacking. As such, we aimed to conduct a comprehensive meta-analysis and systematic review to collect and analyze current evidence about COVID-19 in the pediatric population. METHOD: A systematic search and review of scientific literatures was conducted following the PRISMA guidelines using PubMed, Embase, Scopus, Medline, and Google Scholar databases. All relevant studies until June 16, 2020 were included. Studies were reviewed for methodological quality, and random-effects model was used to conduct the primary meta-analysis. I2 value and Egger's test was used to estimate heterogeneity and publication bias respectively. RESULTS: We reviewed 20 eligible studies that included 1810 pediatric patient population (<21 yo) with PCR tested COVID-19 positivity. In pooled data, majority (25 % [CI 18-32], I2 59 %) of overall COVID-19 positive patients fell in the 6-10 yr age group. 13 % ([CI 11-14], I2 78 %) of the patients were asymptomatic, with headache (67 % [CI 60-74], I2 46 %), fever (55 % [CI 52-58], I2 61 %), and cough (45 % [CI 42-49], I2 79 %) accounting for the most prevalent physical signs seen in symptomatic patients. Leukopenia (12 % [CI 9-15], I250 %) and lymphopenia (15 % [CI 13-19], I2 85 %) was common. Elevated Ferritin (26 % [CI 16-40], I2 73 %), Procal (25 % [CI 21-29 %], I2 83 %), and CRP (19 % [CI 16-22 %], I2 74 %) were other laboratory abnormalities commonly observed. Common radiological features were ground-glass opacities (36 % [CI 32-39 %], I2 92 %), normal finding (33 % [CI 30-36 %], I2 81 %), and consolidation. 29 % ([CI 26-33], I2 85 %) of the patient cases was non-severe, whereas only 5 % ([CI 1-8], I2 87 %) was severe. Mortality was observed in 0.3 % ([CI 0.1-0.4], I2 0%) of the overall cases. CONCLUSION: COVID-19 is prevalent across all pediatric age-groups and presents with varying degree of symptomology. However, children have a milder course of the disease with extremely favorable prognosis. Laboratory and radiological features are inconsistent and require further investigations. Additional studies are needed on this topic to corroborate findings and establish evidence-based and consistent characterization of COVID-19 in the pediatric population.

Patient-Reported Experiences in Accessing Primary Healthcare among Immigrant Population in Canada: A Rapid Literature Review.

(1) Background: Immigrants represent around 21.9% of the total population in Canada and encounter multifaceted obstacles in accessing and receiving primary healthcare. This literature review explores patient experiences in primary care from the perspective of immigrants and identifies areas for further research and improvement. (2) Methods: A comprehensive search was performed on PubMed, MEDLINE, Embase, SCOPUS, and Google scholar to identify studies published from 2010 to July 2020. Relevant articles were peer-reviewed, in English language, and reported patient experiences in primary healthcare in Canada. (3) Results: Of the 1566 searched articles, 19 articles were included in this review. Overall, the finding from articles were summarized into four major themes: cultural and linguistic differences; socioeconomic challenges; health system factors; patient-provider relationship. (4) Conclusion: Understanding the gaps to accessing and receiving appropriate healthcare is important to shape policies, enhance the quality of services, and deliver more equitable healthcare services. It is therefore pertinent that primary healthcare providers play an active role in bridging these gaps with strong support from policymakers. Understanding and respecting diversity in culture, language, experiences, and systems is crucial in reducing health inequalities and improving access to quality care in a respectful and responsive manner.

Nonantibiotic Effects of Fluoroquinolones in Mammalian Cells.

Fluoroquinolones (FQ) are powerful broad-spectrum antibiotics whose side effects include renal damage and, strangely, tendinopathies. The pathological mechanisms underlying these toxicities are poorly understood. Here, we show that the FQ drugs norfloxacin, ciprofloxacin, and enrofloxacin are powerful iron chelators comparable with deferoxamine, a clinically useful iron-chelating agent. We show that iron chelation by FQ leads to epigenetic effects through inhibition of α-ketoglutarate-dependent dioxygenases that require iron as a co-factor. Three dioxygenases were examined in HEK293 cells treated with FQ. At sub-millimolar concentrations, these antibiotics inhibited jumonji domain histone demethylases, TET DNA demethylases, and collagen prolyl 4-hydroxylases, leading to accumulation of methylated histones and DNA and inhibition of proline hydroxylation in collagen, respectively. These effects may explain FQ-induced nephrotoxicity and tendinopathy. By the same reasoning, dioxygenase inhibition by FQ was predicted to stabilize transcription factor HIF-1α by inhibition of the oxygen-dependent hypoxia-inducible transcription factor prolyl hydroxylation. In dramatic contrast to this prediction, HIF-1α protein was eliminated by FQ treatment. We explored possible mechanisms for this unexpected effect and show that FQ inhibit HIF-1α mRNA translation. Thus, FQ antibiotics induce global epigenetic changes, inhibit collagen maturation, and block HIF-1α accumulation. We suggest that these mechanisms explain the classic renal toxicities and peculiar tendinopathies associated with FQ antibiotics.