Hop, The Heat Shock Link between Hsp90 and the Piwi-piRNA Pathway

The Piwi-piRNA pathway is an RNA interference pathway that is conserved across eukaryotes; it is involved with the maintenance of genomic stability through its actions on the germline. We have studied the relationship between a protein complex involving factors in the Piwi-piRNA pathway, Piwi and Aubergine, and the Hsp90-Hop-Hsp70 molecular chaperone machinery. Through a series of in vitro experiments and previous data, we have shown that an interaction between Piwi, Hop, and Hsp90 occurs, when all three proteins are present. Shedding light on this interaction could give us insight on how the PiwipiRNA pathway functions. Through in vivo experiments performed, we have shown that germline knockdowns of Hop, Hsc70-4, and Hsp83 have impacts on the Piwi-piRNA pathway’s ability to perform its function suppressing transposable elements. Through deep sequencing of the total small RNA population present under a Hop germline knockdown, as well as analysis of the population of piRNAs bound to Piwi when Hop is knocked down, we have shown the first evidence of molecular chaperone involvement in both the biogenesis and the loading of piRNAs onto Piwi. This work will help to elucidate the function of the Piwi-piRNA pathway in Drosophila melanogaster. We aim to continue this work by performing deep sequencing experiments on the Hsc70-4 and Hsp83 germline knockdown samples to fully assess their impacts on the loading and biogenesis of piRNAs

(iv) Managing bone loss of the femur and tibia in revision total knee arthroplasty

The number of primary and revision knee arthroplasty procedures performed yearly is steadily increasing. The management of bone loss at the time of revision surgery will play an integral role in the longevity and function of these knees into the future. There are a variety of options for addressing these defects varying from the use of polymethylmethacrylate bone cement, metal augments, sleeves, cones and large allograft replacements. This manuscript discusses the evaluation, classification and management of bone loss of the distal femur and proximal tibia

Aquacel Surgical Dressing Reduces the Rate of Acute PJI Following Total Joint Arthroplasty: A Case-Control Study.

An effort to prevent PJI has led to the development of antimicrobial dressings that support wound healing. We sought to determine whether Aquacel Surgical dressing independently reduces the rate of acute PJI following TJA. A single institution retrospective chart review of 903 consecutive cases who received the Aquacel Surgical dressing and 875 consecutive cases who received standard gauze dressing was conducted to determine the incidence of acute PJI (within 3months). The incidence of acute PJI is 0.44% in the Aquacel dressing group compared to 1.7% in the standard gauze dressing group (P=0.005). Multivariate analysis revealed that use of Aquacel dressing was an independent risk factor for reduction of PJI (odds ratio of 0.165, 95% confidence interval: 0.051-0.533). Aquacel Surgical dressing significantly reduces the incidence of acute PJI

Periprosthetic joint infection increases the risk of one-year mortality.

BACKGROUND: Periprosthetic joint infection continues to potentially complicate an otherwise successful joint replacement. The treatment of this infection often requires multiple surgical procedures associated with increased complications and morbidity. This study examined the relationship between periprosthetic joint infection and mortality and aimed to determine the effect of periprosthetic joint infection on mortality and any predictors of mortality in patients with periprosthetic joint infection. METHODS: Four hundred and thirty-six patients with at least one surgical intervention secondary to confirmed periprosthetic joint infection were compared with 2342 patients undergoing revision arthroplasty for aseptic failure. The incidence of mortality at thirty days, ninety days, one year, two years, and five years after surgery was assessed. Multivariate analysis was used to assess periprosthetic joint infection as an independent predictor of mortality. In the periprosthetic joint infection population, variables investigated as potential risk factors for mortality were evaluated. RESULTS: Mortality was significantly greater (p \u3c 0.001) in patients with periprosthetic joint infection compared with those undergoing aseptic revision arthroplasty at ninety days (3.7% versus 0.8%), one year (10.6% versus 2.0%), two years (13.6% versus 3.9%), and five years (25.9% versus 12.9%). After controlling for age, sex, ethnicity, number of procedures, involved joint, body mass index, and Charlson Comorbidity Index, revision arthroplasty for periprosthetic joint infection was associated with a fivefold increase in mortality compared with revision arthroplasty for aseptic failures. In the periprosthetic joint infection population, independent predictors of mortality included increasing age, higher Charlson Comorbidity Index, history of stroke, polymicrobial infections, and cardiac disease. CONCLUSIONS: Although it is well known that periprosthetic joint infection is a devastating complication that severely limits joint function and is consistently difficult to eradicate, surgeons must also be cognizant of the systemic impact of periprosthetic joint infection and its major influence on fatal outcome in patients

Natural History of Very Early Onset Inflammatory Bowel Disease in North America: A Retrospective Cohort Study

Background: The incidence of very early onset inflammatory bowel disease (VEOIBD) is increasing, yet the phenotype and natural history of VEOIBD are not well described. Methods: We performed a retrospective cohort study of patients diagnosed with VEOIBD (6 years of age and younger) between 2008 and 2013 at 25 North American centers. Eligible patients at each center were randomly selected for chart review. We abstracted data at diagnosis and at 1, 3, and 5 years after diagnosis. We compared the clinical features and outcomes with VEOIBD diagnosed younger than 3 years of age with children diagnosed with VEOIBD at age 3 to 6 years. Results: The study population included 269 children (105 [39%] Crohn\u27s disease, 106 [39%] ulcerative colitis, and 58 [22%] IBD unclassified). The median age of diagnosis was 4.2 years (interquartile range 2.9-5.2). Most (94%) Crohn\u27s disease patients had inflammatory disease behavior (B1). Isolated colitis (L2) was the most common disease location (70% of children diagnosed younger than 3 years vs 43% of children diagnosed 3 years and older; P = 0.10). By the end of follow-up, stricturing/penetrating occurred in 7 (6.6%) children. The risk of any bowel surgery in Crohn\u27s disease was 3% by 1 year, 12% by 3 years, and 15% by 5 years and did not differ by age at diagnosis. Most ulcerative colitis patients had pancolitis (57% of children diagnosed younger than 3 years vs 45% of children diagnosed 3 years and older; P = 0.18). The risk of colectomy in ulcerative colitis/IBD unclassified was 0% by 1 year, 3% by 3 years, and 14% by 5 years and did not differ by age of diagnosis. Conclusions: Very early onset inflammatory bowel disease has a distinct phenotype with predominantly colonic involvement and infrequent stricturing/penetrating disease. The cumulative risk of bowel surgery in children with VEOIBD was approximately 14%-15% by 5 years. These data can be used to provide anticipatory guidance in this emerging patient population

Genomic amplifications identified by circulating tumor DNA analysis guide prognosis in metastatic castration-resistant prostate cancer

PurposeAnalysis of circulating tumor DNA (ctDNA) in patients with metastatic prostate cancer (mPC) provides an opportunity to identify and monitor genomic alterations during a patient’s treatment course. We evaluated whether the presence of specific gene amplifications (GAs) and plasma copy number (PCN) alterations are associated with disease features.MethodsThis is a single-institution retrospective study of patients with mPC who underwent ctDNA profiling using Guardant360® (Guardant Health Inc.). This test identifies single nucleotide variants (SNVs) and GAs of select genes by next-generation sequencing. A total of 155 men with mPC were studied. Patients were stratified by GA status. The Kaplan-Meier method and multivariate cox regression models were used to estimate overall survival (OS) or failure-free survival (FFS) from either the date of GA detection or the initiation of systemic therapy. The chi-square test was used to evaluate associations between clinical factors and GAs. ResultsThe presence of liver and/or lung metastases was associated with GAs of BRAF, CDK6, PI3KCA, and FGFR1. Survival analyses were completed on a subset of 83 patients with metastatic castration-resistant prostate cancer (mCRPC). Median OS was improved in patients with 1 GA compared to patients with ≥2 GAs, whether determined from the date of initial GA(s) detection (14.9 mo vs. 8.9 mo) or date of therapy initiation nearest to GA detection (16.7 mo vs. 9.0 mo). Patients without GAs had not reached median OS. Patients with androgen receptor (AR) GA only were also found to have better median OS compared to patients with AR GA plus at least one other additional GA (19.3 mo vs. 8.9 mo). Patients with PIK3CA GA had significantly lower median OS compared to patients with GAs that did not have a PIK3CA GA (5.9 mo vs. 16.0 mo). In patients with AR and/or MYC GA(s), median OS improved in those with reduced AR or MYC PCN during therapy compared to those without such a reduction (25.1 mo vs. 15.9 mo). ConclusionsThe association of select GAs with survival provides an additional tool for assessing mCRPC prognosis and informing management. Serial monitoring of ctDNA GAs is also useful to guide prognosis and therapeutic response

Safety, Tolerability, and Efficacy of Raltegravir in a Diverse Cohort of HIV-Infected Patients: 48-Week Results from the REALMRK Study

The racial diversity and gender distribution of HIV-infected patients make it essential to confirm the safety and efficacy of raltegravir in these populations. A multicenter, open-label, single-arm observational study was conducted in a diverse cohort of HIV-infected patients (goals: ≥25% women; ≥50% blacks in the United States), enrolling treatment-experienced patients failing or intolerant to current antiretroviral therapy (ART) and treatment-naive patients (limited to ≤20%). All patients received raltegravir 400 mg b.i.d. in a combination antiretroviral regimen for up to 48 weeks. A total of 206 patients received study treatment at 34 sites in the United States, Brazil, Dominican Republic, Jamaica, and South Africa: 97 (47%) were female and 153 (74%) were black [116 (56%) in the United States]. Of these, 185 patients were treatment experienced: 97 (47%) were failing and 88 (43%) were intolerant to current therapy; 21 patients (10%) were treatment naive. Among treatment-intolerant patients, 55 (63%) had HIV-1 RNA<50 copies/ml at baseline. Overall, 15% of patients discontinued: 13% of men, 18% of women, 14% of blacks, and 17% of nonblacks. At week 48, HIV RNA was <50 copies/ml in 60/94 (64%) patients failing prior therapy, 61/80 (76%) patients intolerant to prior therapy, and 16/21 (76%) treatment-naive patients. Response rates were similar for men vs. women and black vs. nonblack patients. Drug-related clinical adverse events were reported by 8% of men, 18% of women, 14% of blacks, and 9% of nonblacks. After 48 weeks of treatment in a diverse cohort of HIV-infected patients, raltegravir was generally safe and well tolerated with potent efficacy regardless of gender or race