Prophylaxis reduces cytomegalovirus (CMV) disease, but is associated with increased costs and risks for side effects, viral resistance and late onset CMV disease. Preemptive therapy avoids drug costs but requires frequent monitoring and may not prevent complications of asymptomatic CMV replication. Kidney transplant recipients at risk for CMV (D+/R−, D+/R+, D−/R+) were randomized to prophylaxis (valganciclovir 900 mg q.d. for 100 days, n = 49) or preemptive therapy (900 mg b.i.d. for 21 days, n = 49) for CMV DNAemia (CMV DNA level >2000 copies/mL in ≥ 1 whole blood specimens by quantitative PCR) assessed weekly for 16 weeks and at 5, 6, 9 and 12 months. More patients in the preemptive group, 29 (59%) than in the prophylaxis group, 14 (29%) developed CMV DNAemia, p = 0.004. Late onset of CMV DNAemia (>100 days after transplant) occurred in 11 (24%) randomized to prophylaxis, and none randomized to preemptive therapy. Symptomatic infection occurred in five patients, four (3 D+/R− and 1 D+/R+) in the prophylactic group and one (D+/R−) in the preemptive group. Peak CMV levels were highest in the D+/R− patients. Both strategies were effective in preventing symptomatic CMV. Overall costs were similar and insensitive to wide fluctuations in costs of either monitoring or drug.

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Little is known about survival and hospitalization among alternative-regimen hemodialysis (HD) users compared to thrice-weekly conventional HD patients who have similar characteristics and medical histories. We conducted a cohort study of alternative-regimen HD users and propensity score (PS)-matched controls. Collaborating clinicians identified 101 patients in their programs who used nocturnal HD (NHD) and 44 patients who used short daily HD (SDHD) for 60 days or more. Ten PS-matched control patients for each NHD and SDHD patient were identified from the United States Renal Data System database. Primary outcomes were risk for all-cause mortality and risk for the composite outcome of mortality or major morbid event (AMI or stroke), investigated in Cox proportional hazards models. Risks for all-cause, cardiovascular-related, infection-related, and vascular access-related hospital admissions were also explored. NHD was associated with reduced mortality risk (HR 0.34; 95% CI, 0.21-0.58; P < 0.0001) and with reduced risk for mortality or major morbid event (HR 0.49; 95% CI, 0.31-0.78; P = 0.003) compared to controls. There was a reduced but non-significant risk of death for patients using SDHD compared to controls (HR 0.61; 95% CI, 0.30-1.24; P = 0.17). All-cause and specific hospitalizations did not differ significantly between NHD and SDHD patients and their matched control cohorts. This study provides additional evidence that NHD may improve patient survival.

Polycystic ovary syndrome (PCOS), characterized by increased ovarian androgen biosynthesis, anovulation, and infertility, affects 5-7% of reproductive-age women. Genome-wide association studies identified PCOS candidate loci that were replicated in subsequent reports, including DENND1A, which encodes a protein associated with clathrin-coated pits where cell-surface receptors reside. However, these studies provided no information about functional roles for DENND1A in the pathogenesis of PCOS. DENND1A protein was located in the cytoplasm as well as nuclei of theca cells, suggesting a possible role in gene regulation. DENND1A immunostaining was more intense in the theca of PCOS ovaries. Using theca cells isolated and propagated from normal cycling and PCOS women, we found that DENND1A variant 2 (DENND1A.V2) protein and mRNA levels are increased in PCOS theca cells. Exosomal DENND1A.V2 RNA was significantly elevated in urine from PCOS women compared with normal cycling women. Forced overexpression of DENND1A.V2 in normal theca cells resulted in a PCOS phenotype of augmented CYP17A1 and CYP11A1 gene transcription, mRNA abundance, and androgen biosynthesis. Knock-down of DENND1A.V2 in PCOS theca cells reduced androgen biosynthesis and CYP17A1 and CYP11A1 gene transcription. An IgG specific to DENND1A.V2 also reduced androgen biosynthesis and CYP17 and CYP11A1 mRNA when added to the medium of cultured PCOS theca cells. We conclude that the PCOS candidate gene, DENND1A, plays a key role in the hyperandrogenemia associated with PCOS. These observations have both diagnostic and therapeutic implications for this common disorder. P olycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting 5-7% of reproductive age women world-wide (1). PCOS is associated with hyperandrogenemia/ hyperandrogenism, anovulation, infertility, and a characteristic ovarian morphology consisting of multiple small subcortical follicular "cysts" embedded in bilaterally enlarged ovaries (2-5). The presence of elevated circulating concentrations of testosterone results primarily from increased production of androgens by the ovaries, and is a classic endocrine phenotype of women with PCOS. Although there has been debate about the diagnostic criteria for PCOS, hyperandrogenemia/hyperandrogenism and anovulation, not explained by other causes, is a hallmark of the disorder, and is included as a key element in all "consensus" diagnosis schemes (6-10).There is consensus that the ovarian theca cells are the primary source of excess androgen biosynthesis in women with PCOS (11-13). Studies on freshly isolated thecal tissue or cultures of theca cells derived from normal and PCOS women have demonstrated that PCOS theca secretes greater amounts of androgen than theca tissue or cells from regularly ovulating women (12,(14)(15)(16)(17)(18)(19). Increased androgen biosynthesis in PCOS theca cells results from increased expression of the key enzymes involved in androgen biosynthesis, steroid-17-α-hydroxylase/17,20 lyase (encoded by the CYP17...

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