SOX2 is a gene located on chromosome 3q26.33 that encodes a transcription factor important to maintenance of embryonic neural crest stem cell pluripotency. We have identified rare SOX2-immunoreactive cells in normal human skin at or near the established stem cell niches. Three subsets of SOX2-positive cells were defined in these regions: those expressing only SOX2 and those that co-expressed SOX2 and either CK20 or microphthalmia-associated transcription factor , which are consistent with dichotomous differentiation of SOX2-expressing precursors along neuroendocrine (Merkel cell) or melanocytic lines , respectively. Examination of Merkel cell carcinomas confirmed nuclear SOX2 expression in this tumor type. In human patient melanoma , strong nuclear expression of SOX2 was noted in a subset of tumors , and the ability to detect SOX2 in lesional cells significantly correlated with primary tumor thickness in a survey cohort. To assess the potential role of SOX2 in melanoma growth , an in vivo tumorigenesis assay was used. Whereas SOX2 knockdown failed to influence proliferation of cultured melanoma cells in vitro , tumor xenografts generated with the SOX2-knockdown cell line showed significant decrease in mean tumor volume as compared with controls. In aggregate , these findings suggest that SOX2 is a novel biomarker for subpopulations of normal skin cells that reside in established stem cell niches and that might relate to Merkel cell and melanocyte ontogeny and tumorigenesis.

Background and Aims: Roussel Uclaf Causality Assessment Method (RUCAM) for DILI has been hindered by subjectivity and poor reliability. We sought to improve the RUCAM using data from the Drug-Induced Liver Injury Network (DILIN) and the Spanish DILI Registry, published literature, and iterative computer modeling.Approach and Results: RUCAM criteria were updated, clarified, and computerized. We removed criteria 3 (risk factors) for lack of added value and criteria 4 because we felt it more useful to assess each drug separately. Criteria 6 (drug-specific risk) was anchored to LiverTox likelihood scores. Iterative testing in subsets of 50-100 single-agent, nonherbal cases from both registries was done to optimize performance. We used classification tree analysis to establish diagnostic cutoffs for this revised electronic causality assessment method (RECAM) and compared RECAM with RUCAM for correlation with expert opinion diagnostic categories in 194 DILI cases (98 DILIN, 96 Spanish DILI). Area under receiver operator curves for identifying at least probable DILI were the same at 0.89 for RECAM and RUCAM. However, RECAM

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IMPORTANCE Alteration in lung microbes is associated with disease progression in idiopathic pulmonary fibrosis. OBJECTIVE To assess the effect of antimicrobial therapy on clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS Pragmatic, randomized, unblinded clinical trial conducted across 35 US sites. A total of 513 patients older than 40 years were randomized from August 2017 to June 2019 (final follow-up was January 2020).INTERVENTIONS Patients were randomized in a 1:1 allocation ratio to receive antimicrobials (n = 254) or usual care alone (n = 259). Antimicrobials included co-trimoxazole (trimethoprim 160 mg/sulfamethoxazole 800 mg twice daily plus folic acid 5 mg daily, n = 128) or doxycycline (100 mg once daily if body weight <50 kg or 100 mg twice daily if Ն50 kg, n = 126). No placebo was administered in the usual care alone group. MAIN OUTCOMES AND MEASURESThe primary end point was time to first nonelective respiratory hospitalization or all-cause mortality. RESULTS Among the 513 patients who were randomized (mean age, 71 years; 23.6% women), all (100%) were included in the analysis. The study was terminated for futility on December 18, 2019. After a mean follow-up time of 13.1 months (median, 12.7 months), a total of 108 primary end point events occurred: 52 events (20.4 events per 100 patient-years [95% CI, 14.8-25.9]) in the usual care plus antimicrobial therapy group and 56 events (18.4 events per 100 patient-years [95% CI, 13.2-23.6]) in the usual care group, with no significant difference between groups (adjusted HR, 1.04 [95% CI, 0.71-1.53; P = .83]. There was no statistically significant interaction between the effect of the prespecified antimicrobial agent (co-trimoxazole vs doxycycline) on the primary end point (adjusted HR, 1.15 [95% CI 0.68-1.95] in the co-trimoxazole group vs 0.82 [95% CI, 0.46-1.47] in the doxycycline group; P = .66). Serious adverse events occurring at 5% or greater among those treated with usual care plus antimicrobials vs usual care alone included respiratory events (16.5% vs 10.0%) and infections (2.8% vs 6.6%); adverse events of special interest included diarrhea (10.2% vs 3.1%) and rash (6.7% vs 0%).CONCLUSIONS AND RELEVANCE Among adults with idiopathic pulmonary fibrosis, the addition of co-trimoxazole or doxycycline to usual care, compared with usual care alone, did not significantly improve time to nonelective respiratory hospitalization or death. These findings do not support treatment with these antibiotics for the underlying disease.

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Comparing outcomes related to dialysis modality is complicated by selection bias introduced by patients and physicians. To address the impact of selection bias, this study compared mortality by initial dialysis modality among patients who had ESRD and were placed on the transplant waiting list. This study was a historical prospective cohort of 12,568 patients in the United States who initiated dialysis between May 1, 1995, and October 31, 1998, and were placed on the transplant waiting list before dialysis initiation. Two-year mortality was compared using Kaplan-Meier curves and Cox proportional hazards models that analyzed patients primarily using an intention-to-treat approach and separately censored patients on a modality switch. At 2 yr, the unadjusted mortality rate was 6.6% among peritoneal dialysis (PD) patients compared with 6.9% among hemodialysis (HD) patients (hazard ratio [HR] 1.01; 95% confidence interval [CI] 0.82 to 1.23). After controlling for differences in baseline characteristics, comorbidities, and laboratory variables, the selection of PD versus HD remained associated with a similar 2-yr mortality risk (HR 1.03; 95% CI 0.83 to 1.28). In separate models, 2-yr mortality associated with PD versus HD was significant among patients with body mass index (BMI) >26 kg/m 2 (HR 1.37; 95% CI 1.01 to 1.83) but not among patients with BMI <26 kg/m 2 (HR 0.81; 95% CI 0.61 to 1.07). Results were similar after censoring on a modality switch. In conclusion, although choice of initial dialysis modality seems to be associated with equivalent outcomes among patients who have ESRD and are placed on the transplant waiting list, patients with BMI >26 kg/m 2 have increased 2-yr mortality associated with the selection of PD versus HD. Because the interpretation of observational data is highly affected by residual confounding and selection bias, further efforts should focus on the formation and testing of hypotheses to improve dialysis delivery.

Background Octreotide is used off-label in infants for treatment of chylothorax, congenital hyperinsulinism, and gastrointestinal bleeding. The safety profile octreotide in hospitalized infants has not been described; we sought to fill this information gap. Methods We identified all infants exposed to at least 1 dose of octreotide from a cohort of 887,855 infants discharged from 333 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012. We collected laboratory and clinical information while infants were exposed to octreotide and described the frequency of baseline diagnoses, laboratory abnormalities, and adverse events (AEs). Results A total of 428 infants received 490 courses of octreotide. The diagnoses most commonly associated with octreotide use were chylothorax (50%), pleural effusion (32%), and hypoglycemia (22%). The most common laboratory AEs that occurred during exposure to octreotide were thrombocytopenia (47/1000 infant-days), hyperkalemia (21/1000 infant-days), and leukocytosis (20/1000 infant-days). Hyperglycemia occurred in 1/1000 infant-days and hypoglycemia in 3/1000 infant-days. Hypotension requiring pressors (12%) was the most common clinical AE that occurred during exposure to octreotide. Necrotizing enterocolitis was observed in 9/490 (2%) courses, and death occurred in 11 (3%) infants during octreotide administration. Conclusion Relatively few AEs occurred during off-label use of octreotide in this cohort of infants. Additional studies are needed to further evaluate the safety, dosing, and efficacy of this medication in infants.

Refractive change and incidence of myopia among a group of highly selected senior high school students in China: a prospective study in an aviation cadet prerecruitment class.