IKAROS-Associated Diseases in 2020: Genotypes, Phenotypes, and Outcomes in Primary Immune Deficiency/Inborn Errors of Immunity.

IKAROS, encoded by IKZF1, is a zinc finger transcription factor and a critical regulator of hematopoiesis. Mutations in IKZF1 have been implicated in immune deficiency, autoimmunity, and malignancy in humans. Somatic IKZF1 loss-of-function mutations and deletions have been shown to increase predisposition to the development of B cell acute lymphoblastic leukemia (B-ALL) and associated with poor prognosis.

N-Glycan Modification in Covid-19 Pathophysiology: In vitro Structural Changes with Limited Functional Effects.

In 2014, we reported two siblings with a rare congenital disorder of glycosylation due to mutations in mannosyl-oligosaccharide glucosidase (MOGS). The glycan alteration derived from this disease resulted in an in vitro infection resistance to particular enveloped, N-glycosylation-dependent viruses as influenza and HIV. As part of the global effort to find safe and effective antiviral therapies for Covid-19, we assessed the in vitro activity of the FDA-approved α-glucosidase inhibitor miglustat against SARS-CoV-2.

Factors influencing loneliness in cancer caregivers: A longitudinal study.

Objective: To describe levels of loneliness in cancer caregivers over a 6 month time period, and to examine factors that influence changes in loneliness in caregivers over time.

Methods: Prospective, repeated measures design was utilized to examine levels of loneliness and factors that influence loneliness in 129 family caregivers of individuals undergoing cancer treatment at three time points over a 6 month period. Measures included: PROMIS global health and sleep disturbance; NIH Toolbox loneliness, self-efficacy and perceived stress; Family Care Inventory mutuality scale; and Caregiver Reaction Assessment.

IKAROS Family Zinc Finger 1-Associated Diseases in Primary Immunodeficiency Patients.

Ikaros zinc finger 1 (IKZF1 or Ikaros) is a hematopoietic zinc finger DNA-binding transcription factor that acts as a critical regulator of lymphocyte and myeloid differentiation. Loss-of-function germline heterozygous mutations in IKZF1 affecting DNA-binding were described as causative of 2 distinct primary immunodeficiency (PID)/inborn error of immunity diseases. Mutations acting by haploinsufficiency present with a common variable immune deficiency-like phenotype mainly characterized by increased susceptibility to infections.

Advantages of Using Lotteries to Select Participants for High-Demand Covid-19 Treatment Trials.

As hospitals have experienced a surge of Covid-19 patients, investigators of Covid-19 treatment trials face a difficult problem: when an institution has more eligible and interested patients than trial slots, who should be enrolled? Defining a clear strategy for selecting participants for "high-demand" Covid-19 treatment trials is important to avoid ad hoc and potentially biased decision-making by local investigators, which could inadvertently compromise a trial's social value, participants' interests, or fairness. In this article, we propose a set of ethical criteria for evaluating participant-selection strategies for such trials. We argue that the pandemic context-in particular, great urgency to develop safe and effective treatments, uncertainty surrounding Covid-19, and strain on the health care system that limits the time and effort available for trial enrollment-favors participant-selection strategies that optimize the ease of enrollment and, ideally, social value.

Androgen excess and diagnostic steroid biomarkers for nonclassic 21-hydroxylase deficiency without cosyntropin stimulation.

Objectives: The clinical presentation of patients with nonclassic 21-hydroxylase deficiency (N21OHD) is similar with that for other disorders of androgen excess. The diagnosis of N21OHD typically requires cosyntropin stimulation. Additionally, the management of such patients is limited by the lack of reliable biomarkers of androgen excess.

The Permissibility of Deception in Riskier Research.

The use of deception is typically prohibited in studies that pose greater than minimal risk overall. This approach prevents researchers from using deception to conceal significant risks or to deceive participants about the purpose, potential benefits, or other aspects of a study that are relevant to deciding whether to accept such risks. Yet this approach also mistakenly blocks appropriate research.

Disaster Preparedness for Clinics - Further Study from Haiti.

Objective: This team created a manual to train clinics in low- and middle-income countries (LMICs) to effectively respond to disasters. This study is a follow-up to a prior study evaluating disaster response. The team returned to previously trained clinics to evaluate retention and performance in a disaster simulation.

Treatment of Posaconazole-Induced Peripheral Neuropathy With Methylprednisolone and Magnesium Infusions: A Case Report.

The tolerability of long-term posaconazole use remains poorly defined. We present a patient who developed peripheral neuropathy following long-term exposure to the tablet formulation of posaconazole, which was treated with methylprednisolone and magnesium infusions. The potential role of methylprednisolone and magnesium infusions in managing this potentially irreversible triazole-associated complication requires further study.

PI3K pathway defects leading to immunodeficiency and immune dysregulation.

The phosphatidylinositol 3-kinase (PI3K) signaling pathway is involved in a broad range of cellular processes, including growth, metabolism, differentiation, proliferation, motility, and survival. The PI3Kδ enzyme complex is primarily present in the immune system and comprises a catalytic (p110δ) and regulatory (p85α) subunit. Dynamic regulation of PI3Kδ activity is required to ensure normal function and differentiation of immune cells.

Inhibition of blood group antibodies by soluble substances.

The presence of multiple alloantibodies or an antibody to a highprevalance antigen in a patient sample can pose challenges in antibody identification. The pattern of reactivity seen on an antibody panel may show various strengths of reactivity by different methods of testing or same strength of reactivity at one or more phases of testing. To ensure proper identification, multiple investigative tools may be used.

Distinct Clinical and Pathological Features of Melorheostosis Associated With Somatic MAP2K1 Mutations.

Melorheostosis is a rare hyperostotic disease of the long bones classically characterized by a "dripping candle-wax" radiographic appearance. We recently described somatic activating mutations in MAP2K1 as a cause of melorheostosis. Here, we report distinguishing characteristics of patients with MAP2K1-positive melorheostosis.

The Major Surface Glycoprotein of Pneumocystis murina Does Not Activate Dendritic Cells.

The major surface glycoprotein (Msg) is the most abundant surface protein among Pneumocystis species. Given that Msg is present on both the cyst and trophic forms of Pneumocystis and that dendritic cells play a critical role in initiating host immune responses, we undertook studies to examine activation of bone marrow-derived myeloid dendritic cells by Msg purified from Pneumocystis murina. Incubation of dendritic cells with Msg did not lead to increased expression of CD40, CD80, CD86, or major histocompatibility complex class II or to increased secretion of any of 10 cytokines.

Characterization of p57, a Stage-Specific Antigen of Pneumocystis murina.

Pneumocystis has a large multicopy gene family encoding proteins related to the major surface glycoprotein (Msg), whose functions are largely unknown. We expressed one such protein of Pneumocystis murina, p57, which is encoded by 3 highly conserved genes, and demonstrated by immunoblot that immunocompetent mice that were immunized with crude Pneumocystis antigens or that had cleared Pneumocystis infection developed antibodies to p57. Using hyperimmune anti-p57 serum combined with immunolabeling, we found that p57 was expressed by small trophic forms and intracystic bodies, whereas it was not expressed on larger trophic forms or externally by cysts.

Effect of Antiretroviral Therapy on Bone and Renal Health in Young Adults Infected With HIV in Early Life.

Context: HIV antiretroviral (ARV) therapy is associated with renal and bone toxicity, but little is known about the potential cumulative effects in adults exposed to ARVs from birth.

Objective: To prospectively evaluate renal and bone health in young adults with lifelong HIV and extensive ARV exposure.

Design: Cross-sectional comparison of bone mineral density (BMD) by dual-energy X-ray absorptiometry, bone turnover, and renal function in young adults infected with HIV in early life (n = 65) to matched healthy controls (n = 23) and longitudinal evaluation (mean follow-up = 4.

T-cell Activation and E-selectin Are Associated With Coronary Plaque in HIV-infected Young Adults.

We evaluated immune activation and coronary artery plaque in young adults with human immunodeficiency virus acquired in early life (n = 31). Coronary plaque was positively associated with lipids, immune activation marker %CD8+CD38+DR+ and E-selectin, a marker of endothelial inflammation. Immune activation and endothelial inflammation may drive coronary plaque formation during the early stages of atherosclerosis in the context of chronic human immunodeficiency virus.

Outcomes From the NIH Clinical Research Training Program: A Mentored Research Experience to Enhance Career Development of Clinician-Scientists.

Purpose: Clinician-scientists are considered an endangered species for many reasons, including challenges with establishing and maintaining a career pipeline. Career outcomes from yearlong medical and dental students' research enrichment programs have not been well determined. Therefore, the authors assessed career and research outcome data from a cohort of participants in the National Institutes of Health (NIH) Clinical Research Training Program (CRTP).

Midlife Cardiovascular Risk Factors and Late-Life Unrecognized and Recognized Myocardial Infarction Detect by Cardiac Magnetic Resonance: ICELAND-MI, the AGES-Reykjavik Study.

Background: Associations of atherosclerosis risk factors with unrecognized myocardial infarction (UMI) are unclear. We investigated associations of midlife risk factors with UMI and recognized MI (RMI) detected 31 years later by cardiac magnetic resonance.

Methods And Results: The Reykjavik Study (1967-1991) collected serial risk factors in subjects, mean (SD) age 48 (7) years.

Efavirenz but Not Atazanavir/Ritonavir Significantly Reduces Atovaquone Concentrations in HIV-Infected Subjects.

Background: The current study was conducted to determine if efavirenz (EFV) or atazanavir/ritonavir (ATV/r)-based combination antiretroviral therapy (cART) impacted steady-state atovaquone plasma concentrations in human immunodeficiency virus (HIV)-infected patients receiving treatment doses of atovaquone.

Methods: Thirty HIV-infected volunteers were recruited, 10 taking no cART and 10 each taking cART that included EFV or ATV/r. Subjects were randomly assigned to atovaquone 750 mg twice daily (BID) for 14 days followed by atovaquone 1500 mg BID for 14 days, or vice-versa, with a washout period in between.

Granulocyte transfusions in children and adults with hematological malignancies: benefits and controversies.

Bacterial and fungal infections continue to pose a major clinical challenge in patients with prolonged severe neutropenia after chemotherapy or hematopoietic stem cell transplantation (HSCT). With the advent of granulocyte colony-stimulating factor (G-CSF) to mobilize neutrophils in healthy donors, granulocyte transfusions have been broadly used to prevent and/or treat life-threatening infections in patients with severe febrile neutropenia and/or neutrophil dysfunction. Although the results of randomized controlled trials are inconclusive, there are suggestions from pilot and retrospective studies that granulocyte transfusions may benefit selected categories of patients.

Late systolic central hypertension as a predictor of incident heart failure: the Multi-ethnic Study of Atherosclerosis.

Background: Experimental studies demonstrate that high aortic pressure in late systole relative to early systole causes greater myocardial remodeling and dysfunction, for any given absolute peak systolic pressure.

Methods And Results: We tested the hypothesis that late systolic hypertension, defined as the ratio of late (last one third of systole) to early (first two thirds of systole) pressure-time integrals (PTI) of the aortic pressure waveform, independently predicts incident heart failure (HF) in the general population. Aortic pressure waveforms were derived from a generalized transfer function applied to the radial pressure waveform recorded noninvasively from 6124 adults.