Case Report: Profound newborn leukopenia related to a novel RAC2 variant.

We report the case of a 1-week-old male born full-term, who had two inconclusive severe combined immunodeficiency (SCID) newborn screens and developed scalp cellulitis and Escherichia coli bacteremia. He did not pass early confirmatory hearing screens. Initial blood counts and lymphocyte flow cytometry revealed profound neutropenia and lymphopenia with a T-/B-/NK- phenotype. Red blood cell adenosine deaminase 1 activity was within normal limits. A presumptive diagnosis of reticular dysgenesis was considered. Granulocyte colony-stimulating factor was started, but there was no improvement in neutrophil counts. Subsequent lymphocyte flow cytometry at around 4 weeks of age demonstrated an increase in T-, B- and NK-cell numbers, eliminating suspicion for SCID and raising concern for congenital neutropenia and bone marrow failure syndromes. Genetic testing revealed a novel variant in RAC2 [c.181C>A (p.Gln61Lys)] (Q61K). RAC2, a Ras-related GTPase, is the dominant RAC protein expressed in hematopoietic cells and is involved with various downstream immune-mediated responses. Pathogenic RAC2 variants show significant phenotypic heterogeneity (spanning from neutrophil defects to combined immunodeficiency) across dominant, constitutively activating, dominant activating, dominant negative, and autosomal recessive subtypes. Given the identification of a novel variant, functional testing was pursued to evaluate aberrant pathways described in other RAC2 pathogenic variants. In comparison to wild-type RAC2, the Q61K variant supported elevated superoxide production under both basal and PMA-stimulated conditions, increased PAK1 binding, and enhanced plasma membrane ruffling, consistent with other dominant, constitutively active mutations. This case highlights the diagnostic challenge associated with genetic variants identified via next-generation sequencing panels and the importance of functional assays to confirm variant pathogenicity.

Mastocytosis and Mast Cell Activation Disorders: Clearing the Air.

Mast cells are derived from hematopoietic stem cell precursors and are essential to the genesis and manifestations of the allergic response. Activation of these cells by allergens leads to degranulation and elaboration of inflammatory mediators, responsible for regulating the acute dramatic inflammatory response seen. Mast cells have also been incriminated in such diverse disorders as malignancy, arthritis, coronary artery disease, and osteoporosis. There has been a recent explosion in our understanding of the mast cell and the associated clinical conditions that affect this cell type. Some mast cell disorders are associated with specific genetic mutations (such as the D816V gain-of-function mutation) with resultant clonal disease. Such disorders include cutaneous mastocytosis, systemic mastocytosis (SM), its variants (indolent/ISM, smoldering/SSM, aggressive systemic mastocytosis/ASM) and clonal (or monoclonal) mast cell activation disorders or syndromes (CMCAS/MMAS). Besides clonal mast cell activations disorders/CMCAS (also referred to as monoclonal mast cell activation syndromes/MMAS), mast cell activation can also occur secondary to allergic, inflammatory, or paraneoplastic disease. Some disorders are idiopathic as their molecular pathogenesis and evolution are unclear. A genetic disorder, referred to as hereditary alpha-tryptasemia (HαT) has also been described recently. This condition has been shown to be associated with increased severity of allergic and anaphylactic reactions and may interact variably with primary and secondary mast cell disease, resulting in complex combined disorders. The role of this review is to clarify the classification of mast cell disorders, point to molecular aspects of mast cell signaling, elucidate underlying genetic defects, and provide approaches to targeted therapies that may benefit such patients.

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors and Ezetimibe on Risk of New-Onset Diabetes: A Systematic Review and Meta-Analysis of Large, Double-Blinded Randomized Controlled Trials.

BACKGROUND: Previous meta-analyses have shown that statins may cause incident diabetes. This article reviews randomized controlled trials using proprotein convertase subtilisin/kexin 9 inhibitors (PCSK9i) or ezetimibe on the risk of new-onset diabetes. METHODS: Eight trials involving PCSK9i and 3 trials of ezetimibe were selected for review. PubMed, Cochrane Central Register of Controlled Trials, and Clinicaltrials.gov were thoroughly searched for relevant trials. Inclusion criteria included at least 100 patients per treatment arm, follow-up of at least 52 weeks, and at least double-blinded study design. Exclusion criteria included patients with previously diagnosed diabetes, nonrandomized, placebo-controlled, open-label, and crossover trials. The primary outcome was the number of incident diabetes cases. A random effects model was used. Heterogeneity in effect sizes was measured with I2 parameter and the Q statistic was used to test for excessive between-study heterogeneity. RESULTS: A total of 52 214 participants for the PCSK9i and a total of 20 084 for the ezetimibe meta-analyses were included. Participants randomized to PCSK9i did not differ from the control patients in diabetes incidence (risk ratio [RR] = 0.99, P = .87, 95% CI = 0.92-1.07). Participants randomized to ezetimibe did not differ from the control patients in diabetes incidence (RR = 1.05, P = .37, 95% CI = 0.95-1.15). DISCUSSION: The use of PCSK9i and ezetimibe does not appear to impact the risk of incident diabetes mellitus when added to guideline-directed medical therapy.

Psychological Distress Among Adolescent Students Following the April 25, 2015 Massive Earthquake in Nepal.

Introduction A massive earthquake on April 25, 2015, resulted in physical and emotional devastation in Nepal. This study aims to determine the prevalence of psychological distress among adolescents in Kathmandu and Sindhupalchowk districts within Nepal one year after the earthquake. Methods The Brief Symptoms Inventory tool was used to measure the level of psychological distress. The participants were students of four randomly selected schools from both districts. Surveys were conducted involving 200 students aged 13 to 17 years. Participants had diverse socioeconomic and cultural backgrounds. Results The prevalence of clinical threshold varied from 10% to 50% depending on each of the nine symptoms scales. Between the two districts, there was a statically significant difference in the prevalence of major psychological distresses. Sindhupalchowk had a higher percentage of students meeting the clinical threshold in each of the nine symptom scales than Kathmandu. Female students tended to have higher symptoms levels than male students. Conclusion The prevalence of psychological distress among adolescents living in areas of large impact is greater compared to the prevalence of psychological distress in adolescents living in less impacted areas. Given the current literature with respect to adolescent psychology in Nepal, more studies must be done to assess the level of distress in other regions of the country.

Data availability and feasibility of various techniques to predict response to volume expansion in critically ill patients.

OBJECTIVE: The accuracy of various techniques to predict response to volume expansion in shock has been studied, but less well known is how feasible these techniques are in the ICU. METHODS: This is a prospective observation single-center study of inpatients from a mixed profile ICU who received volume expansion. At time of volume expansion, we determined whether a particular technique to predict response was feasible, according to rules developed from available literature and nurse assessment. RESULTS: We studied 214 volume expansions in 97 patients. The most feasible technique was central venous pressure (50%), followed by vena cava collapsibility, (47%) passive leg raise (42%), and stroke volume variation (22%). Aortic velocity variation, and pulse pressure variation, and were rarely feasible (1% each). In 37% of volume expansions, no technique that we assessed was feasible. CONCLUSIONS: Techniques to predict response to volume expansion are infeasible in many patients in shock.

Long-term outcomes after severe shock.

Severe shock is a life-threatening condition with very high short-term mortality. Whether the long-term outcomes among survivors of severe shock are similar to long-term outcomes of other critical illness survivors is unknown. We therefore sought to assess long-term survival and functional outcomes among 90-day survivors of severe shock and determine whether clinical predictors were associated with outcomes. Seventy-six patients who were alive 90 days after severe shock (received ≥1 µg/kg per minute of norepinephrine equivalent) were eligible for the study. We measured 3-year survival and long-term functional outcomes using the Medical Outcomes Study 36-Item Short-Form Health Survey, the EuroQOL 5-D-3L, the Hospital Anxiety and Depression Scale, the Impact of Event Scale-Revised, and an employment instrument. We also assessed the relationship between in-hospital predictors and long-term outcomes. The mean long-term survival was 5.1 years; 82% (62 of 76) of patients survived, of whom 49 were eligible for follow-up. Patients who died were older than patients who survived. Thirty-six patients completed a telephone interview a mean of 5 years after hospital admission. The patients' Physical Functioning scores were below U.S. population norms (P < 0.001), whereas mental health scores were similar to population norms. Nineteen percent of the patients had symptoms of depression, 39% had symptoms of anxiety, and 8% had symptoms of posttraumatic stress disorder. Thirty-six percent were disabled, and 17% were working full-time. Early survivors of severe shock had a high 3-year survival rate. Patients' long-term physical and psychological outcomes were similar to those reported for cohorts of less severely ill intensive care unit survivors. Anxiety and depression were relatively common, but only a few patients had symptoms of posttraumatic stress disorder. This study supports the observation that acute illness severity does not determine long-term outcomes. Even extremely critically ill patients have similar outcomes to general intensive care unit survivor populations.

Glasgow Coma Scale score dominates the association between admission Sequential Organ Failure Assessment score and 30-day mortality in a mixed intensive care unit population.

OBJECTIVE: The Sequential Organ Failure Assessment (SOFA) score, a measure of multiple-organ dysfunction syndrome, is used to predict mortality in critically ill patients by assigning equally weighted scores across 6 different organ systems. We hypothesized that specific organ systems would have a greater association with mortality than others. DESIGN: We retrospectively studied patients admitted over a period of 4.2 years to a mixed-profile intensive care unit (ICU). We recorded age and comorbidities, and calculated SOFA organ scores. The primary outcome was 30-day all-cause mortality. We determined which organ subscores of the SOFA score were most associated with mortality using multiple analytic methods: random forests, conditional inference trees, distanced-based clustering techniques, and logistic regression. SETTING: A 24-bed mixed-profile adult ICU that cares for medical, surgical, and trauma (level 1) patients at an academic referral center. PATIENTS: All patients' first admission to the study ICU during the study period. MEASUREMENTS AND MAIN RESULTS: We identified 9120 first admissions during the study period. Overall 30-day mortality was 12%. Multiple analytical methods all demonstrated that the best initial prediction variables were age and the central nervous system SOFA subscore, which is determined solely by Glasgow Coma Scale score. CONCLUSIONS: In a mixed population of critically ill patients, the Glasgow Coma Scale score dominates the association between admission SOFA score and 30-day mortality. Future research into outcomes from multiple-organ dysfunction may benefit from new models for measuring organ dysfunction with special attention to neurologic dysfunction.