Structural and functional insights into the delivery of a bacterial Rhs pore-forming toxin to the membrane.

Bacterial competition is a significant driver of toxin polymorphism, which allows continual compensatory evolution between toxins and the resistance developed to overcome their activity. Bacterial Rearrangement hot spot (Rhs) proteins represent a widespread example of toxin polymorphism. Here, we present the 2.45 Å cryo-electron microscopy structure of Tse5, an Rhs protein central to Pseudomonas aeruginosa type VI secretion system-mediated bacterial competition. This structural insight, coupled with an extensive array of biophysical and genetic investigations, unravels the multifaceted functional mechanisms of Tse5. The data suggest that interfacial Tse5-membrane binding delivers its encapsulated pore-forming toxin fragment to the target bacterial membrane, where it assembles pores that cause cell depolarisation and, ultimately, bacterial death.

The P. aeruginosa effector Tse5 forms membrane pores disrupting the membrane potential of intoxicated bacteria.

The type VI secretion system (T6SS) of Pseudomonas aeruginosa injects effector proteins into neighbouring competitors and host cells, providing a fitness advantage that allows this opportunistic nosocomial pathogen to persist and prevail during the onset of infections. However, despite the high clinical relevance of P. aeruginosa, the identity and mode of action of most P. aeruginosa T6SS-dependent effectors remain to be discovered. Here, we report the molecular mechanism of Tse5-CT, the toxic auto-proteolytic product of the P. aeruginosa T6SS exported effector Tse5. Our results demonstrate that Tse5-CT is a pore-forming toxin that can transport ions across the membrane, causing membrane depolarisation and bacterial death. The membrane potential regulates a wide range of essential cellular functions; therefore, membrane depolarisation is an efficient strategy to compete with other microorganisms in polymicrobial environments.

"Just Like Any Other Patient": Transgender Stigma among Physicians in Puerto Rico.

BACKGROUND: Transgender women (TW) in Puerto Rico (PR) face social stigmatization. Physicians' transgender stigma can have detrimental consequences for TW's health. PURPOSE: The objective of this study was to document physicians' knowledge, competencies, and attitudes towards TW in PR and study their associations with stigma towards TW. METHODS: We implemented an exploratory sequential mixed-methods study. We used in-depth interviews (n=30) and self-administered questionnaire (n=255). RESULTS: Qualitative results illustrated lack of recognition of the needs of TW; they also evidenced the impact of stigmatizing attitudes on clinical decisions. Quantitative results showed that more willingness and knowledge to provide health services to TW were negatively associated with stigma. Participants who reported history of training in working with TW presented significantly less stigma than participants who had not received such training. CONCLUSION: In order to provide stigma-free services for TW in PR, specialized training regarding the particular needs of this population is needed.

Arteriovenous fistula construction with the VasQ™ external support device: a pilot study.

BACKGROUND AND OBJECTIVE: Arteriovenous fistulas (AVF) are currently the gold standard for access, exhibiting the best combination of a low complication profile with a long patency period and attractive pricing. Despite a steady increase in the use of autogenous AVF in recent years, there is still a high rate of non-maturation of native fistulas. VasQ™ (Laminate Medical Technologies, Israel) is an external support device for AVFs designed to improve flow and reduce neointimal hyperplasia at the anastomotic site. Preliminary data are presented of its use, assessing its safety and efficacy for brachiocephalic AVFs in haemodialysis patients. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: A single institution study of VasQ™ use was conducted with placement of the device in patients undergoing a brachiocephalic fistula, followed for 6 months. The VasQ™ was available in three sizes and was deployed externally over the fistula. Patients were assessed for flow, maturation and patency at 1, 3 and 6 months by Doppler ultrasonography. RESULTS: Twenty patients were implanted. Mean venous flow at 1, 3 and 6 months was 1130, 1426 and 1304 mL/min, respectively. Primary patency rates for these time periods were 95%, 79% and 79%, respectively, with unassisted maturation rates of 80%, 79% and 74%, respectively. There were no device-related serious adverse events. At the end of the follow-up period, 14/15 patients requiring dialysis were able to use the AVF. CONCLUSIONS: VasQ™ is safe with high unassisted maturation and patency rates. The device may prevent perianastomotic stenosis, the leading cause of AVF failure.

Telaprevir or boceprevir based therapy for chronic hepatitis C infection: development of resistance-associated variants in treatment failure.

The use of triple-therapy, pegylated-interferon, ribavirin and either of the first generation hepatitis C virus (HCV) protease inhibitors telaprevir or boceprevir, is the new standard of care for treating genotype 1 chronic HCV. Clinical trials have shown response rates of around 70-80%, but there is limited data from the use of this combination outside this setting. Through an expanded access programme, we treated 59 patients, treatment naïve and experienced, with triple therapy. Baseline factors predicting treatment response or failure during triple therapy phase were identified in 58 patients. Thirty seven (63.8%) of 58 patients had undetectable HCV RNA 12weeks after the end of treatment. Genotype 1a (p=0.053), null-response to previous treatment (p=0.034), the rate of viral load decline after 12weeks of previous interferon-based treatment (p=0.033) were all associated with triple-therapy failure. The most common cause of on-treatment failure for telaprevir-based regimens was the development of resistance-associated variants (RAVs) at amino acids 36 and/or 155 of HCV protease (p=0.027) whereas in boceprevir-based regimens mutations at amino acid 54 were significant (p=0.015). SVR12 rates approaching 64% were achieved using triple therapy outside the clinical trial setting, in a patient cohort that included cirrhotics.

Hipema traumático. Experiencia con 11 casos / Traumatic hypaema : experience with 11 cases

En un período de 6 meses estudiamos 11 casos de hipema traumático y tratamos de establecer su causa. La mayoría de ellos fueron accidentes de trabajo en personas jovenes que no tenían protección adecuada para el trabajo que estaban realizando. Todos los pacientes recibieron tratamiento médico y en tres de ellos fue necesario tambien paracentesis y drenaje de la camara anterior