Human NK cell deficiency (NKD) is a primary immunodeficiency in which the main clinically relevant immunological defect involves missing or dysfunctional NK cells. Here, we describe a familial NKD case in which 2 siblings had a substantive NKD and neutropenia in the absence of other immune system abnormalities. Exome sequencing identified compound heterozygous variants in Go-Ichi-Ni-San (GINS) complex subunit 4 ( GINS4 , also known as SLD5 ), an essential component of the human replicative helicase, which we demonstrate to have a damaging impact upon the expression and assembly of the GINS complex. Cells derived from affected individuals and a GINS4 -knockdown cell line demonstrate delayed cell cycle progression, without signs of improper DNA synthesis or increased replication stress. By modeling partial GINS4 depletion in differentiating NK cells in vitro, we demonstrate the causal relationship between the genotype and the NK cell phenotype, as well as a cell-intrinsic defect in NK cell development. Thus, biallelic partial loss-of-function mutations in GINS4 define a potentially novel disease-causing gene underlying NKD with neutropenia. Together with the previously described mutations in other helicase genes causing NKD, and with the mild defects observed in other human cells, these variants underscore the importance of this pathway in NK cell biology.

We found very low quality evidence showing that people with stable angina who received ranolazine as monotherapy had increased risk of presenting non-serious adverse events compared to those given placebo. We found low quality evidence indicating that people with stable angina who received ranolazine showed uncertain effect on the risk of cardiovascular death (for ranolazine given as monotherapy), all-cause death and non-fatal AMI, and the frequency of angina episodes (for ranolazine given as monotherapy) compared to those given placebo. Moderate quality evidence indicated that people with stable angina who received ranolazine showed uncertain effect on quality of life compared with people who received placebo. Moderate quality evidence also indicated that people with stable angina who received ranolazine as add-on therapy had fewer angina episodes but increased risk of presenting non-serious adverse events compared to those given placebo.

Objetivos. Determinar los factores asociados a mortalidad de los pacientes adultos hospitalizados con COVID-19 en un hospital de referencia de la seguridad social. Materiales y métodos. Se realizó un estudio de cohorte prospectivo. Se incluyó a pacientes mayores de 18 años hospitalizados con el diagnostico de infección por SARS-CoV-2 y se excluyó a quienes ingresaron asintomáticos respiratorios, con prueba rápida serológica positiva al ingreso y sin imágenes compatibles. Los datos se recolectaron a partir de la historia clínica. Resultados. Se incluyó un total de 813 adultos, 544 (66.9%) tuvieron COVID-19 confirmado. La media de la edad fue de 61.2 años (DE: 15.0) y 575 (70.5%) fueron de sexo masculino. Las comorbilidades más frecuentes fueron hipertensión arterial (34.1%) y obesidad (25.9%). Los síntomas más frecuentes al ingreso fueron disnea (82.2%) y tos (53.9%). Un total de 114 (14.0%) pacientes recibieron ventilación mecánica, 38 (4.7%) ingresaron a UCI y 377 (46.4%) fallecieron. El requerimiento de soporte ventilatorio, el mayor compromiso pulmonar, las comorbilidades y los marcadores inflamatorios se asociaron a la mortalidad. Se halló que por cada 10 años que aumenta la edad, el riesgo de morir se incrementa en 32% (RR: 1.32 IC95%: 1.25 a 1.38). Aquellos que requirieron ingreso a UCI y ventilación mecánica tuvieron 1.39 (IC95%: 1.13 a 1.69) y 1.97 (IC95%: 1.69 a 2.29) veces el riesgo de morir, respectivamente. Conclusión. La mortalidad encontrada en nuestro estudio fue alta y estuvo asociada a la edad,  marcadores inflamatorios y compromiso respiratorio.

Objectives To describe and assess clinical characteristics and factors associated with mortality in adult patients with COVID-19 admitted to a national referral hospital in Peru. Methods We conducted a prospective cohort study that included hospitalized patients older than 18 years with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection diagnosis. Patients with a positive rapid serological test on admission but no respiratory symptoms nor compatible images were excluded. We collected the data from clinical records. Results A total of 813 adults were included, 544 (66.9%) with confirmed COVID-19. The mean age was 61.2 years (standard deviation: 15.0), and 575 (70.5%) were male. The most frequent comorbidities were hypertension (34.1%) and obesity (25.9%). On admission, the most frequent symptoms were dyspnea (82.2%) and cough (53.9%). A total of 114 (14.0%) patients received mechanical ventilation, 38 (4.7%) were admitted to the intensive care unit, and 377 (46.4%) died. The requirement for ventilatory support, greater lung involvement, and inflammatory markers were associated with higher mortality. It was found that for every 10-year age increase, the risk of dying increased 32% (relative risk: 1.32; 95% confidence interval: 1.25 to 1.38). Those who were admitted to the intensive care unit and and were placed on mechanical ventilation had 1.39 (95% confidence interval: 1.13 to 1.69) and 1.97 (95% confidence interval: 1.69 to 2.29) times the risk of dying compared to those who did not, respectively. Conclusion We found a high mortality rate among hospitalized patients associated with older age, higher inflammatory markers, and greater lung involvement.

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