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Am J Cardiol. 2022 Nov 4;186:30-35. doi: 10.1016/j.amjcard.2022.10.017. Online ahead of print.

ABSTRACT

Cachexia is often seen in patients with heart failure (HF). This study aimed to examine the association between cachexia and clinical outcomes in patients hospitalized for HF. We extracted all adult cases with a primary diagnosis of HF that were discharged between January and November, identified in the Nationwide Readmissions Database for 2016 through 2019. Exclusion criteria included cases with missing data or a diagnosis of acquired immunodeficiency syndrome, advanced liver disease, end-stage renal disease, chronic lung disease, or malignancy. Appropriate weighting was used to obtain national estimates. Primary outcomes were inpatient mortality, length of stay, and 30-day readmission in patients with HF with cachexia compared with patients with no cachexia. Multivariable logistic regression was used to estimate the association between cachexia and clinical outcomes. Survey procedures were applied using Statistical Analysis Software 9.4. The final analysis included 2,360,307 HF-related hospitalizations. Cachexia was present in about 7% of the study population. A greater percentage of patients with cachexia were female and older than patients without cachexia (52% vs 47% female, the mean age of 77 vs 72 years, respectively). However, after adjusting for demographics and co-morbidities, including coronary artery disease and atrial fibrillation, patients with cardiac cachexia had higher inpatient mortality (odds ratio 3.01, 95% confidence interval 2.88 to 3.15, p <0.001), prolonged hospital stays (9 vs 5 days, p <0.0001), and greater all-cause 30-day readmissions (23% vs 21%, p <0.0001). HF-related cachexia is associated with increased inpatient mortality, greater resource use, and additional healthcare costs.

PMID:36343443 | DOI:10.1016/j.amjcard.2022.10.017

Iran J Allergy Asthma Immunol. 2022 Oct 26;21(5):594-599. doi: 10.18502/ijaai.v21i5.11046.

ABSTRACT

Coronavirus disease 2019 (COVID-19) affects millions of people worldwide. Clinical manifestations range from asymptomatic to severe viral pneumonia. CVID patients with COVID-19 infection are not adequately studied. In some studies, CVID patients had higher mortality rates, although other studies showed that CVID patients might have an uncomplicated COVID-19 infection. We describe 14 cases of COVID-19 infection in Iranian CVID patients in this study, including clinical manifestations, laboratory findings, and treatment strategies. There were 29% of patients with mild disease, 43% with moderate disease, and 29% with severe disease in this study. A critical case and a death occurred in none of our patients. There were six cases of infection more than two weeks after receiving the second dose of Sinopharm BIBP COVID-19 vaccine; all had mild to moderate disease. Among these patients, Remdesivir was the most frequently prescribed medication. According to this study, most of our patients presented with an uncomplicated disease course.

PMID:36341567 | DOI:10.18502/ijaai.v21i5.11046

Front Immunol. 2022 Oct 19;13:1033338. doi: 10.3389/fimmu.2022.1033338. eCollection 2022.

ABSTRACT

DNA ligase I deficiency is an extremely rare primary immunodeficiency with only 6 patients reported in the literature. Most common manifestations include radiosensitivity, macrocytic anemia, lymphopenia with an increased percentage of gamma-delta T cells, and hypogammaglobulinemia requiring replacement therapy. Two-month-old girl with delayed development, T-B-NK+ SCID, and macrocytic anemia presented features of Omenn syndrome. Whole exome sequencing revealed two novel, heterozygous variants (c.2312 G>A, p.Arg771Gly and c.776+5G>T, p.Pro260*) in the LIG1 gene (NM_000234.1). Hematopoietic stem cell transplantation from a fully matched unrelated donor was performed at the age of 4 months using GEFA03 protocol. Mixed donor-recipient chimerism was observed, with 60-70% chimerism in the mononucleated cell compartment and over 90% in T-lymphocyte compartment, but autologous myeloid recovery. Stable CD4+ and CD8+ T-cell counts above 200/µL were achieved after 2 months, but the patient remained transfusion-dependent. Despite satisfactory immunological reconstitution, the second transplantation due to constitutional hemolytic defect has been considered. In light of possible re-transplantation, an issue of optimal conditioning protocol with sufficient myeloid engraftment is important. For the first time Omenn syndrome is described in a compound heterozygote carrying two the novel variants p.Arg771Gly and p.Pro260* in the LIG1 gene. Patients diagnosed with SCID and Omenn syndrome showing macrocytic anemia, should be screened for DNA ligase I deficiency.

PMID:36341401 | PMC:PMC9626757 | DOI:10.3389/fimmu.2022.1033338

Front Immunol. 2022 Oct 20;13:933463. doi: 10.3389/fimmu.2022.933463. eCollection 2022.

ABSTRACT

Common variable immunodeficiency (CVID) is one of the inborn errors of immunity that have the greatest clinical impact. Rates of morbidity and mortality are higher in patients with CVID who develop liver disease than in those who do not. The main liver disorder in CVID is nodular regenerative hyperplasia (NRH), the cause of which remains unclear and for which there is as yet no treatment. The etiology of liver disease in CVID is determined by analyzing the liver injury and the associated conditions. The objective of this study was to compare CVID patients with and without liver-spleen axis abnormalities in terms of clinical characteristics, as well as to analyze liver and duodenal biopsies from those with portal hypertension (PH), to elucidate the pathophysiology of liver injury. Patients were divided into three groups: Those with liver disease/PH, those with isolated splenomegaly, and those without liver-spleen axis abnormalities. Clinical and biochemical data were collected. Among 141 CVID patients, 46 (32.6%) had liver disease/PH; 27 (19.1%) had isolated splenomegaly; and 68 (48.2%) had no liver-spleen axis abnormalities. Among the liver disease/PH group, patients, even those with mild or no biochemical changes, had clinical manifestations of PH, mainly splenomegaly, thrombocytopenia, and esophageal varices. Duodenal celiac pattern was found to correlate with PH (p < 0.001). We identified NRH in the livers of all patients with PH (n = 11). Lymphocytic infiltration into the duodenal mucosa also correlated with PH. Electron microscopy of liver biopsy specimens showed varying degrees of lymphocytic infiltration and hepatocyte degeneration, which is a probable mechanism of lymphocyte-mediated cytotoxicity against hepatocytes and enterocytes. In comparison with the CVID patients without PH, those with PH were more likely to have lymphadenopathy (p < 0.001), elevated β₂-microglobulin (p < 0.001), low B-lymphocyte counts (p < 0.05), and low natural killer-lymphocyte counts (p < 0.05). In CVID patients, liver disease/PH is common and regular imaging follow-up is necessary. These patients have a distinct immunological phenotype that may predispose to liver and duodenal injury from lymphocyte-mediated cytotoxicity. Further studies could elucidate the cause of this immune-mediated mechanism and its treatment options.

PMID:36341360 | PMC:PMC9632424 | DOI:10.3389/fimmu.2022.933463

Front Genet. 2022 Oct 20;13:969895. doi: 10.3389/fgene.2022.969895. eCollection 2022.

ABSTRACT

Inborn errors of immunity are known to influence susceptibility to mycobacterial infections. The aim of this study was to characterize the genetic profile of nine patients with mycobacterial infections (eight with BCGitis and one with disseminated tuberculosis) from the Republic of Moldova using whole-exome sequencing. In total, 12 variants in eight genes known to be associated with Mendelian Susceptibility to Mycobacterial Disease (MSMD) were detected in six out of nine patients examined. In particular, a novel splice site mutation c.373-2A>C in STAT1 gene was found and functionally confirmed in a patient with disseminated tuberculosis. Trio analysis was possible for seven out of nine patients, and resulted in 23 candidate variants in 15 novel genes. Four of these genes – GBP2, HEATR3, PPP1R9B and KDM6A were further prioritized, considering their elevated expression in immune-related tissues. Compound heterozygosity was found in GBP2 in a single patient, comprising a maternally inherited missense variant c.412G>A/p.(Ala138Thr) predicted to be deleterious and a paternally inherited intronic mutation c.1149+14T>C. Functional studies demonstrated that the intronic mutation affects splicing and the level of transcript. Finally, we analyzed pathogenicity of variant combinations in gene pairs and identified five patients with putative oligogenic inheritance. In summary, our study expands the spectrum of genetic variation contributing to susceptibility to mycobacterial infections in children and provides insight into the complex/oligogenic disease-causing mode.

PMID:36338958 | PMC:PMC9632272 | DOI:10.3389/fgene.2022.969895

Front Oncol. 2022 Oct 19;12:1036511. doi: 10.3389/fonc.2022.1036511. eCollection 2022.

ABSTRACT

Fanconi anemia (FA) genes play critical roles in the repair of DNA lesions. Non-FA (or underlying FA) patients harboring heterozygous germline FA gene mutations may also face an increased risk of developing bone marrow failure, primary immunodeficiency disease, and hereditary cancer predisposition syndromes. We report a female patient who suffered from ovarian cancer at 50 years of age. During the initial treatment, six cycles of docetaxel and carboplatin (DC) combination chemotherapy were administered followed by two cycles of docetaxel maintenance therapy. Then, she received a routine follow-up every 3 months for the next 3 years, and all the results of the examination and laboratory tests were normal. Unfortunately, at 54 years of age, she developed a secondary cancer of therapy-related (t-) chronic myelomonocytic leukemia (t-CMML). After two courses of a highly intensive induction chemotherapy regimen with DAC (decitabine) and HAA (homoharringtonine, cytarabine), the patient suffered from severe and persistent bone marrow failure (BMF). Targeted next-generation sequencing (NGS) of a panel of 80 genes was performed on her initial bone marrow aspirate sample and identified PTPN11, NRAS, and DNMT3A somatic mutations. In addition, RNA sequencing (RNA-seq) revealed a rare NUP98-HOXC11 fusion. Whole-exome sequencing (WES) verified RAD51C, BRIP1, PALB2, and FANCG heterozygous germline mutations of the FA pathway, which were further confirmed in buccal swab samples by Sanger sequencing. For this patient, we hypothesized that an altered FA pathway resulted in genomic instability, hypersensitivity to DNA-crosslinking agents or cytotoxic chemotherapeutics, and unsuccessful DNA damage repair. Consequently, she developed ovarian cancer and secondary t-CMML and then suffered from BMF and delayed post-chemotherapy bone marrow recovery after several chemotherapy courses. This case highlights the importance of genetic counseling in patients with hematopoietic neoplasms with high clinical suspicion for carrying cancer susceptibility gene mutations, which require timely diagnosis and personalized management.

PMID:36338706 | PMC:PMC9626966 | DOI:10.3389/fonc.2022.1036511

Front Microbiol. 2022 Oct 20;13:968304. doi: 10.3389/fmicb.2022.968304. eCollection 2022.

ABSTRACT

The intersection between the human oral microbiome and oral health is an emerging area of study which has gained momentum over the last decade. This momentum has motivated a search for associations between the oral microbiome and oral cancer, in hopes of identifying possible biomarkers that facilitate earlier diagnosis and improved prognosis for patients with that disease. The present study examined the relationship between the microbiome in the human oral cavity and oral squamous cell carcinoma (OSCC). We searched the literature for case-control studies which focused on the relationship between the human oral microbiome and OSCC. We aggregated three types of data from these studies: bacteriome data at the genus level, predicted functional pathway data, and gene abundance data. From these data, we noted several microbial genera which may be associated with oral cancer status, including Fusobacterium. We also identified functional pathways which merit further investigation, including RNA degradation (ko03018) and primary immunodeficiency (ko05340). In addition, our analysis of gene abundance data identified the gene K06147 (ATP-binding cassette, subfamily B, bacterial) as being over abundant in OSCC samples. Our results are generalizations which identified some currents that we believe could guide further research. Our work faced several limitations related to the heterogeneity of the available data. Wide variation in methods for sample collection, methods for controlling for known behavioral risk factors, computing platform choice, and methods for case-control design all posed confounding factors in this work. We examined the current methods of data collection, data processing, and data reporting in order to offer suggestions toward the establishment of best practices within this field. We propose that these limitations should be addressed through the implementation of standardized data analytic practices that will conform to the rigor and reproducibility standards required of publicly funded research.

PMID:36338051 | PMC:PMC9632422 | DOI:10.3389/fmicb.2022.968304

Blood. 2022 Nov 4:blood.2022016074. doi: 10.1182/blood.2022016074. Online ahead of print.

ABSTRACT

X-Linked Chronic Granulomatous Disease (X-CGD) is a primary immunodeficiency caused by mutations in the CYBB gene resulting in the inability of phagocytic cells to eliminate infections. In order to design a lentiviral vector capable of recapitulating the endogenous regulation and expression of CYBB, a bioinformatics-guided approach was utilized to elucidate the cognate enhancer elements regulating the native CYBB gene. Using this approach, we analyzed a 600 kb topologically associated domain of the CYBB gene and identified endogenous enhancer elements to supplement the CYBB promoter to develop MyeloVec, a physiologically regulated lentiviral vector (LV) for the treatment of X-CGD. When compared to a LV currently in clinical trials for X-CGD, MyeloVec showed improved expression, superior gene transfer to hematopoietic stem and progenitor cells (HSPCs), corrected an X-CGD mouse model leading to complete protection against B. cepacia infection, and restored healthy donor levels of anti-microbial oxidase activity in neutrophils derived from X-CGD patient HSPCs. Our findings validate the bioinformatics-guided design approach and have yielded a novel lentiviral vector with clinical promise for the treatment of X-CGD.

PMID:36332160 | DOI:10.1182/blood.2022016074

Immunol Med. 2022 Nov 4:1-13. doi: 10.1080/25785826.2022.2137966. Online ahead of print.

ABSTRACT

Primary immunodeficiencies (PIDs)/Inborn errors of immunity (IEI) consist of a complex genetic group of disorders that cause susceptibility to infections, inflammation, immune dysregulation, autoimmunity, and malignancy. One of the key steps to reach an early diagnosis is improving knowledge of PID among the medical community. In this study, a web-based survey was conducted among 355 Japanese physicians, consisting of 121 pediatricians, 116 hematologists, and 118 general internal medicine physicians, to assess their awareness and knowledge about the diagnostic flow of PID. One of the major problems this study identified was the unawareness of optimal IgG trough levels among the physicians, while around half the physicians knew about the symptoms of PID. Results from the hypothetical case study revealed that over 70% of physicians considered PID after obtaining the past medical history of patients and 75.2% of physicians showed interest in gaining more knowledge about PID. The survey findings revealed that proper questioning to understand the exact medical history of patients may lead to basic immunological examination. There is a need to improve knowledge about PID, e.g., the ’10 warning signs of PID’ and ‘4 stages of testing for PID’, and to motivate physicians to ensure earlier diagnosis of PID.

PMID:36330855 | DOI:10.1080/25785826.2022.2137966

Arch Toxicol. 2022 Nov 3. doi: 10.1007/s00204-022-03405-z. Online ahead of print.

ABSTRACT

Per- and polyfluoroalkyl substances (PFASs) are omnipresent and have been shown to induce a wide range of adverse effects, including hepatotoxicity, developmental toxicity and immunotoxicity. So far, little information is available about the mechanisms underlying the toxicity of PFASs, including those related to their immunotoxicity. Reported immunotoxic effects of PFASs include decreased antibody responses in experimental animals and humans, indicating that PFASs may, among others, affect B cell function. In the present study, we first assessed the effects of PFOA on the transcriptome of the human Namalwa B cell line using RNA seq analysis. Gene expression changes, analyzed using Ingenuity Pathway Analysis, pointed to various cellular processes affected by PFOA, including ‘B cell development’ and ‘Primary immunodeficiency signaling’. Interestingly, PFOA decreased the expression of RAG1 and RAG2, genes involved in immunoglobulin and T cell receptor V(D)J recombination. As a next step, time- and concentration-dependent changes in the expression of RAG1 and RAG2 upon exposure to PFOA, PFNA, PFHxS and PFOS were studied through RT-qPCR analysis. Analysis with the concentration-response modeling software PROAST resulted in the following potency ranking: PFNA > PFOA > PFOS > PFHxS. Altogether, the present in vitro study provides insights into the effects of selected PFASs on B cells, identifying RAG1 and RAG2 expression as possible relevant targets that may play a role in the immunotoxicity of PFASs.

PMID:36326898 | DOI:10.1007/s00204-022-03405-z