The potent HIV-1 capsid inhibitor GS-6207 is an investigational principal component of long-acting antiretroviral therapy. We found that GS-6207 inhibits HIV-1 by stabilizing and thereby preventing ...functional disassembly of the capsid shell in infected cells. X-ray crystallography, cryo-electron microscopy, and hydrogen-deuterium exchange experiments revealed that GS-6207 tightly binds two adjoining capsid subunits and promotes distal intra- and inter-hexamer interactions that stabilize the curved capsid lattice. In addition, GS-6207 interferes with capsid binding to the cellular HIV-1 cofactors Nup153 and CPSF6 that mediate viral nuclear import and direct integration into gene-rich regions of chromatin. These findings elucidate structural insights into the multimodal, potent antiviral activity of GS-6207 and provide a means for rationally developing second-generation therapies.
OBJECTIVE:The objective of this study was to document trends in the performance of open arterial vascular surgery procedures (OAVP) by general surgery residents (GSR).
BACKGROUND:The ACGME Review ...Committee for Surgery considers vascular surgery (VS) to be an “essential content area.” However, the operative experience in VS for GSRs is threatened by 1) increasing numbers of GSRs, 2) increasing numbers of VS trainees, and 3) the proliferation of endovascular surgery.
METHODS:The last 16 years of ACGME national reports of case logs for completing GSRs were reviewed. Total vascular operations and OAVPs performed as “surgeon” were recorded and analyzed. The number of individuals completing ACGME programs in general and vascular surgery annually over that period were also recorded and analyzed. To better understand long-term and more recent trends, trends were analyzed for the 15-year period spanned by the 16 years of data as well as the most recent 10- and 5-year periods.
RESULTS:The number of individuals completing both general and vascular surgery programs increased significantly. Over 15 years, the total vascular operations performed by GSRs significantly declined as did the total OAVPs and the OAVPs in 7 of 9 categories. In just the last 5 years, significant declines occurred in 5 OAVP categories.
CONCLUSIONS:Operative experience in OAVPs for GSRs has significantly declined. Because fundamental VS skills are necessary for operative general surgery, VS should remain an essential content area. However, programs cannot solely depend on operative experience to teach fundamental VS skills.
In the developing retina, multipotent neural progenitors undergo unidirectional differentiation in a precise spatiotemporal order. Here we profile the epigenetic and transcriptional changes that ...occur during retinogenesis in mice and humans. Although some progenitor genes and cell cycle genes were epigenetically silenced during retinogenesis, the most dramatic change was derepression of cell-type-specific differentiation programs. We identified developmental-stage-specific super-enhancers and showed that most epigenetic changes are conserved in humans and mice. To determine how the epigenome changes during tumorigenesis and reprogramming, we performed integrated epigenetic analysis of murine and human retinoblastomas and induced pluripotent stem cells (iPSCs) derived from murine rod photoreceptors. The retinoblastoma epigenome mapped to the developmental stage when retinal progenitors switch from neurogenic to terminal patterns of cell division. The epigenome of retinoblastomas was more similar to that of the normal retina than that of retina-derived iPSCs, and we identified retina-specific epigenetic memory.
•Changes in histone modifications were more prominent than those in DNA methylation•Epigenetic changes were more prevalent at differentiation genes than progenitors•The retinoblastoma epigenome resembles the retina at a developmental transition•Histone modifications are important for neuronal epigenetic memory in iPSCs
Aldiri, Xu, and colleagues show in this article how the epigenome of the mouse and human retina changes during development in coordination with transcriptional programs. They also relate those developmental changes to retinoblastoma and epigenetic memory in retina-derived iPSCs.
The Hidden Cost of Medicine Valentine, R James, MD, FACS
Journal of the American College of Surgeons,
07/2017, Letnik:
225, Številka:
1
Journal Article
Background Aorto-enteric fistulas (AEF) represent a lethal subset of aortic graft infections. The optimal management of AEF remains unclear. We aimed to identify predictors of morbidity and ...mortality. Study Design We performed a single-center retrospective review of consecutive AEF repairs. Demographics, comorbidities, and perioperative variables were obtained. Descriptive statistics, chi-square, Kruskall-Wallis, and Cox proportional-hazards modeling were used where appropriate. Results Between June 1995 and October 2014, 50 patients (30 male; 60%) presented with AEF, with a median age of 70 years (interquartile range IQR 61 to 75 years). Median follow-up for the entire cohort was 14 months (IQR 5 to 27 months). Thirty-four (68%) subjects underwent aortic reconstruction with femoral vein; 12 (24%) with extra-anatomic bypass and aortic ligation; 3 (6%) with rifampin-soaked Dacron graft; and 1 (2%) with cryopreserved aortic allograft. The duodenum was the most common location of the enteric defect (n = 40, 80%). Duodenal leak complicated 6 (12%) of the primary enteric repairs, but none of the complex enteric repairs performed with resection and/or bypass. Twenty-three patients (46%) died by 60 days. Advanced age, chronic renal insufficiency, any complications, and gastrointestinal (GI) complications (n = 13, 26%) were all associated with an increase in overall mortality on univariate analysis (p < 0.05). Gastrointestinal complications (hazard ratio HR 3.23; 95% CI 1.27 to 8.25; p = 0.015) and advanced age (HR 1.07; 95% CI 1.01 to 1.13; p = 0.01) were the only independent predictors of mortality on multivariable regression models. Conclusions Over 20 years, approximately 50% of patients with AEF repairs died within 60 days. Gastrointestinal complications increase the risk of mortality more than 3-fold, representing an attractive surgically modifiable risk factor. Future multicenter studies are required to clarify optimal methods of arterial and GI reconstruction in AEF.
Huntington’s disease (HD) is a genetic neurodegenerative disorder caused by an expanded polyglutamine (polyQ) domain near the N-terminus of the huntingtin (htt) protein. Expanded polyQ leads to htt ...aggregation. The first 17 amino acids (Nt17) in htt comprise a lipid-binding domain that undergoes a number of posttranslational modifications that can modulate htt toxicity and subcellular localization. As there are three lysines within Nt17, we evaluated the impact of lysine acetylation on htt aggregation in solution and on model lipid bilayers. Acetylation of htt-exon1(51Q) and synthetic truncated htt-exon 1 mimicking peptides (Nt17-Q35-P10-KK) was achieved using a selective covalent label, sulfo-N-hydroxysuccinimide (NHSA). With this treatment, all three lysine residues (K6, K9, and K15) in Nt17 were significantly acetylated. N-terminal htt acetylation retarded fibril formation in solution and promoted the formation of larger globular aggregates. Acetylated htt also bound lipid membranes and disrupted the lipid bilayer morphology less aggressively compared with the wild-type. Computational studies provided mechanistic insights into how acetylation alters the interaction of Nt17 with lipid membranes. Our results highlight that N-terminal acetylation influences the aggregation of htt and its interaction with lipid bilayers.
Rhabdomyosarcoma is a soft-tissue sarcoma with molecular and cellular features of developing skeletal muscle. Rhabdomyosarcoma has two major histologic subtypes, embryonal and alveolar, each with ...distinct clinical, molecular, and genetic features. Genomic analysis shows that embryonal tumors have more structural and copy number variations than alveolar tumors. Mutations in the RAS/NF1 pathway are significantly associated with intermediate- and high-risk embryonal rhabdomyosarcomas (ERMS). In contrast, alveolar rhabdomyosarcomas (ARMS) have fewer genetic lesions overall and no known recurrently mutated cancer consensus genes. To identify therapeutics for ERMS, we developed and characterized orthotopic xenografts of tumors that were sequenced in our study. High-throughput screening of primary cultures derived from those xenografts identified oxidative stress as a pathway of therapeutic relevance for ERMS.
•There are higher rates of mutation in ERMS than in ARMS tumors•RAS pathway mutations are associated with intermediate- and high-risk ERMS•ERMS tumor cells have elevated oxidative stress•ERMS tumors are sensitive to drugs that target oxidative stress
Non-randomised studies of the effects of interventions are critical to many areas of healthcare evaluation, but their results may be biased. It is therefore important to understand and appraise their ...strengths and weaknesses. We developed ROBINS-I (“Risk Of Bias In Non-randomised Studies - of Interventions”), a new tool for evaluating risk of bias in estimates of the comparative effectiveness (harm or benefit) of interventions from studies that did not use randomisation to allocate units (individuals or clusters of individuals) to comparison groups. The tool will be particularly useful to those undertaking systematic reviews that include non-randomised studies.
Background This study was conducted to quantify the effect of multidisciplinary care (MDC) on amputation-free survival (AFS) and wound healing within a chronic critical limb ischemia (CLI) ...population. Methods We performed a retrospective, single-center cohort study of consecutive CLI patients presenting to the Vascular Surgery Service. Patients who received initial and follow-up wound care from the MDC were compared with patients who received standard wound care (SWC). The MDC team consisted of vascular, plastic, and podiatric surgeons who jointly managed wound care and directed any other consults or services as deemed necessary. SWC consisted of an inconsistent mix of providers without a defined manager, including nurses, wound care midlevel providers, general surgeons, internists, or the patients themselves. The referring physician determined the allocation of patients. The primary outcome variable was AFS, with a secondary evaluation of wound healing. The effects of baseline demographics, comorbid medical conditions, laboratory values, ischemic lesion severity and location, Rutherford classification, and participation in MDC were assessed. Significant univariate predictors ( P < .10) of AFS were entered into a multivariate Cox regression model and assessed at an α = .05. Results Between August 2010 and June 2012, 146 CLI patients (91 male 63%) were evaluated by the Vascular Surgery Service and were followed up for a median of 539 days (interquartile range 314-679 days). Ischemic tissue loss was present in 85 patients (38 at Rutherford category 5, and 47 at Rutherford category 6). Within this cohort, 51 (60%) had MDC, and 34 (40%) had SWC. Fifty-eight patients (68%) underwent revascularization (open in 17, endovascular in 35, and hybrid in 6), 14 (8%) were managed with primary major amputation, and 13 (15%) declined revascularization. AFS was superior for patients in the MDC arm vs the SWC arm (593.3 ± 53.5 days vs 281.0 ± 38.2 days; log-rank, P = .02). Wound-healing times favored the MDC arm over the SWC arm (444.5 ± 33.2 days vs 625.2 ± 126.5 days), although this was not statistically significant (log-rank, P = .74). Multivariate modelling revealed that independent predictors of major amputation or death, or both, were nonrevascularized patients (hazard ratio HR, 3.76; 95% confidence interval CI, 1.78-8.02; χ2 , P < .01), treatment by SWC (HR, 2.664; 95% CI, 1.23-5.77; χ2 , P = .012), and baseline nonambulatory status (HR, 1.89; 95% CI, 1.17-2.85; χ2 , P < .01). Conclusions MDC pathways for the management of a population of CLI patients improved AFS by greater than twofold and should be the standard of care for the CLI population. Baseline nonambulatory status and unrevascularized patients also predict worse AFS. Wound healing remains prolonged regardless of preoperative or postoperative wound care. Future study is required to evaluate the costs and functional outcomes for MDC in the management of CLI.
The General Surgery Milestones Project Cogbill, Thomas H., MD, FACS; Malangoni, Mark A., MD, FACS; Potts, John R., MD, FACS ...
Journal of the American College of Surgeons,
05/2014, Letnik:
218, Številka:
5
Journal Article
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