Approximately 1 in 6 US patients undergoing integrase GRT for clinical decision making harbors significant resistance, with Q148 and N155 pathways equally common. Dolutegravir is likely to have full or partial activity against most variants observed.

The signaling pathways associated with estrogen-induced proliferation of epithelial cells in the reproductive tract have not been defined. To identify receptor tyrosine kinases that are activated in vivo by 17g3-estradiol (E2), uteri from ovariectomized mice were examined for enhanced tyrosine phosphorylation of various receptors and a receptor substrate following treatment with this hormone. Within 4 hr after hormone exposure, extracts showed increased phosphotyrosine (P-Tyr) immunoreactivity at several bands, including 170-and 180-kDa; these bands were still apparent at 24 hr after E2. Analysis of immunoprecipitates from uterine extracts revealed that E2 enhanced tyrosine phosphorylation of the insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor substrate-1 (IRS-1) by 6 hr. Comparison of supernatants from IRS-1 and control rabbit IgG immunoprecipitates indicated that the 170-kDa P-Tyr band in extracts was equivalent to IRS-1. The receptors for epidermal growth factor, platelet-derived growth factor, and basic fibroblast growth factor did not exhibit an E2-induced increase in P-Tyr content. The nonestrogenic steroid hormones examined did not stimulate the P-Tyr content of IGF-1R or IRS-1. Immunolocalization of P-Tyr and IRS-1 revealed strong reactivity in the epithelial layer of the uterus from E2-treated mice, suggesting that the majority of P-Tyr bands observed in immunoblots originate in the epithelium. Since hormonal activation of IRS-1 is epithelial, estrogenspecific, and initiated before maximal DNA synthesis occurs following treatment with hormone, this protein, as part of the IGF-1R pathway, may be important in mediating estrogenstimulated proliferation in the uterus.

The prevalence of CAN in diabetes mellitus is high. Higher age, longer duration of diabetes and peripheral neuropathy are significant risk factors. QTc interval in the ECG can be used to diagnose CAN with reasonable sensitivity, specificity and positive predictive value.

The PHR1 gene of Saccharomyces cerevisiae encodes a photolyase which repairs specifically and exclusively pyrimidine dimers, the most frequent lesions induced in DNA by far-UV radiation. We have asked whether expression of PHR1 is modulated in response to UV-induced DNA damage and to DNA-damaging agents that induce lesions structurally dissimilar to pyrimidine dimers. Using a PHR1-lacZ fusion gene in which expression of beta-galactosidase is regulated by PHR1 5' regulatory elements, we found that exposure of cells to 254-nm light, 4-nitroquinoline-N-oxide, methyl methanesulfonate, and N-methyl-N'-nitro-N-nitrosoguanidine induced synthesis of increased amounts of fusion protein. In contrast to these DNA-damaging agents, neither heat shock nor exposure to photoreactivating light elicited a response. Induction by far-UV radiation was evident both when the fusion gene was carried on a multicopy plasmid and when it replaced the endogenous chromosomal copy of PHR1, and it was accompanied by an increase in the steady-state concentration of PHR1-lacZ mRNA. Northern (RNA) blot analysis of PHR1 mRNA encoded by the chromosomal locus was consistent with either enhanced transcription of PHR1 after DNA damage or stabilization of the transcripts. Neither the intact PHR1 or RAD2 gene was required for induction. Comparison of the region of PHR1 implicated in regulation of its expression with other damage-inducible genes from yeast cells revealed a common conserved sequence that is present in the PHR1, RAD2, and RNR2 genes and is required for damage inducibility of the latter two genes. These sequences may constitute elements of a damage-responsive regulon in S. cerevisiae.

Dexmedetomidine provides a unique quality of conscious sedation which resembles natural sleep. • Its administration does not result in respiratory depression.

Objectives Despite prevention efforts new HIV diagnoses continue in the Southern US, where the epidemic is characterized by significant racial/ethnic disparities. We integrated phylogenetic analyses with clinical data to reveal trends in local HIV transmission. Design Cross-sectional analysis of 1671 HIV-infected individuals each with one B-subtype pol sequence obtained during chronic (82%; UNC Center for AIDS Research Clinical Cohort) or acute/recent (18%; Duke/UNC Acute HIV Consortium) infection. Methods Phylogenies were inferred using neighbor joining to select related sequences then confirmed with Bayesian methods. We characterized transmission clusters (clades n≥3 sequences supported by posterior probabilities=1) by factors including race/ethnicity and transmission risk. Factors associated with cluster membership were evaluated for newly diagnosed patients. Results Overall, 72% were male, 59% black and 39% MSM. A total of 557 (33%) sequences grouped in either 108 pairs (n=216) or 67 clusters (n=341). Clusters ranged from 3–36 (median 4) members. Composition was delineated primarily by race, with 28% exclusively black, and to a lesser extent by risk group. Both MSM and heterosexuals formed discrete clusters though substantial mixing was observed. In multivariable analysis, patients with age ≤30 years (P=0.009), acute infection (P=0.02), local residence (P=0.002), and transmitted drug resistance (P=0.02) were more likely to be cluster members while Latinos were less likely (P<0.001). Conclusions Integration of molecular, clinical and demographic data offers a unique view into the structure of local transmission networks. Clustering by black race, youth and TDR and inability to identify Latino clusters will inform prevention, testing and linkage to care strategies.

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Background:Oral lichen planus (OLP) is an immune-mediated potentially malignant disorder of the oral cavity. Dysplastic OLP has an altered cytogenic profile and can progress into oral squamous cell carcinoma. The epidemiology of OLP is well-described in several relatively large series from various geographic locations, whereas such series from southern India is rare. The aim of the present study was to determine the epidemiology of OLP in a cohort of South Indian population.Methods:All the case data records of 29,606 patients who visited Mar Baselios Dental College and Hospital, Kerala, India from 2014 to 2015 were retrospectively reviewed. For data review, 122 patients of OLP were selected Estimated were type, number, and location of lesions, clinical manifestation, age of the patient, gender, onset and duration of lesion, stressful life style, habits, skin involvement and associated systemic illness, and presence/absence of dysplasia.Results:When the distribution of OLP among the gender was considered, we found more prevalence in females than males. Fifty-seven percent of patients were associated with stressful lifestyle. Reticular lichen planus was the most common clinical subtype found. Bilateral buccal mucosal was the common site, when the distribution of sites of OLP were compared (P < 0.05). Hypersensitivity reaction was frequently associated with systemic illness with OLP (P < 0.05). Anaplasia was found among 5% of lichen planus lesions.Conclusions:OLP patients had high incidence of hypersensitivity reactions and 5% of OLP lesions showed anaplasia. Long term follow-up is necessary to monitor the recurrence, prognosis, and malignant transformation of OLP.