Smartphone-Guided Self-prone Positioning vs Usual Care in Nonintubated Hospital Ward Patients With COVID-19: A Pragmatic Randomized Clinical Trial.

BACKGROUND: Safe, effective, and easily implementable treatments that reduce the progression of respiratory failure in COVID-19 are urgently needed. Despite the increased adoption of prone positioning during the pandemic, the effectiveness of this technique on progression of respiratory failure among nonintubated patients is unclear. RESEARCH QUESTION: What is the effectiveness of smartphone-guided self-prone positioning recommendations and instructions compared with usual care in reducing progression of respiratory failure among nonintubated patients with COVID-19? STUDY DESIGN AND METHODS: Awake Prone Position for Early Hypoxemia in COVID-19 (APPEX-19) is a multicenter randomized clinical trial that randomized nonintubated adults with COVID-19 on < 6 L/min of supplemental oxygen to receive a smartphone-guided self-prone positioning intervention or usual care. The primary outcome was the composite of respiratory deterioration (an increase in supplemental oxygen requirement) or ICU transfer. Using a Bayesian statistical approach, the posterior probability of superiority within each treatment arm (superiority threshold 95%) was calculated. RESULTS: The trial was stopped early for slow enrollment. A total of 293 participants were included in the modified intention-to-treat analysis (159 self-prone positioning intervention and 134 usual care). Among participants who self-reported body positioning (n = 139 [70 intervention, 69 usual care]), 71.4% in the intervention arm and 59.4% in the usual care arm attempted prone positioning. Thirty-one participants (posterior mean, 24.7%; 95% credible interval, 18.6-31.4) receiving usual care and 32 participants (posterior mean, 22.1%; 95% credible interval, 16.6-28.1) receiving the self-prone positioning intervention experienced the primary outcome; the posterior probability of superiority for the self-prone positioning intervention was 72.1%, less than the 95% threshold for superiority. Adverse events occurred in 26.9% of participants in the usual care arm and in 11.9% of participants in the intervention arm. INTERPRETATION: Among nonintubated patients with COVID-19, smartphone-guided self-prone positioning recommendations and instructions did not promote strong adherence to prone positioning. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04344587; URL: www. CLINICALTRIALS: gov.

ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder.

PURPOSE: To identify the molecular cause in five unrelated families with a distinct autosomal dominant ocular systemic disorder we called ROSAH syndrome due to clinical features of retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache. METHODS: Independent discovery exome and genome sequencing in families 1, 2, and 3, and confirmation in families 4 and 5. Expression of wild-type messenger RNA and protein in human and mouse tissues and cell lines. Ciliary assays in fibroblasts from affected and unaffected family members. RESULTS: We found the heterozygous missense variant in the ɑ-kinase gene, ALPK1, (c.710C>T, [p.Thr237Met]), segregated with disease in all five families. All patients shared the ROSAH phenotype with additional low-grade ocular inflammation, pancytopenia, recurrent infections, and mild renal impairment in some. ALPK1 was notably expressed in retina, retinal pigment epithelium, and optic nerve, with immunofluorescence indicating localization to the basal body of the connecting cilium of the photoreceptors, and presence in the sweat glands. Immunocytofluorescence revealed expression at the centrioles and spindle poles during metaphase, and at the base of the primary cilium. Affected family member fibroblasts demonstrated defective ciliogenesis. CONCLUSION: Heterozygosity for ALPK1, p.Thr237Met leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder.

Failure of immunosuppressive drug levels to predict T-cell reactivity in pediatric transplant patients.

PURPOSE: In children, therapeutic management of immunosuppression relies on allograft function, drug levels, and clinical insight. Using a Food and Drug Administration-approved test for T-cell response, T-cell activation in vitro can be measured to monitor the immune response. METHODS: In a retrospective study, 92 posttransplant children who received either a liver and/or kidney transplant and were followed by routine screening had their T-cell response tested by the Cylex ImmuKnow assay (Columbia, MD). After phytohemagglutinin-L stimulation of T-cells, adenosine triphosphate (ATP) concentrations were measured. In this assay, light emission at lambda = 562 nm is proportional to the ATP concentration (ng/mL). Immunosuppressive drug trough levels were also measured. Quantitative real-time polymerase chain reaction Epstein-Barr virus (EBV) viral titers were determined for 2 patients. RESULTS: Separating the results into younger than 12 years and 12-year or older populations, we found that for the younger than 12 years, 28% of patients were in the low immune function category, 47% in the moderate, and 25% in the high category. For the 12 years or older, 25% of patients were in the low immune function category, 47% in the moderate, and 28% in the high category. The immune function distribution was not different (P = not significant) between the younger than 12 years and 12-year or older groups. Tacrolimus trough levels were 6.3 +/- 2.4 ng/mL for younger than 12 years and 5.6 +/- 3.3 ng/mL for 12 years or older (P = not significant), and rapamycin was similar, but both showed no correlation to immune function. We observed increased ATP values with decreased EBV viral loads. CONCLUSIONS: These results suggest that tacrolimus and/or rapamycin levels do not adequately determine the biologic effect of immunosuppression. We expect that future T-cell activation monitoring will allow us to diminish rejection and infection events posttransplantation and lead to a healthier pediatric transplant population.