Treatment of Primary Aldosteronism with mTORC1 Inhibitors

mTORC1 activity is often increased in the adrenal cortex of patients with primary aldosteronism and mTORC1 inhibition decreases aldosterone production in adrenocortical cells, suggesting the mTORC1 pathway as a possible target for treatment of primary aldosteronism.; To investigate the effect of mTORC1 inhibition on adrenal steroid hormones and hemodynamic parameters in mice and in patients with primary aldosteronism.; (i) Plasma aldosterone, corticosterone and angiotensin II were measured in mice treated for 24 hours with vehicle or rapamycin. (ii) Plasma aldosterone levels after a saline infusion test, plasma renin, 24-hour urine steroid hormone metabolome and hemodynamic parameters were measured during an open-label study in 12 patients with primary aldosteronism before and after two-weeks of treatment with everolimus and after a two-week washout period.; (i) Change in plasma aldosterone levels. (ii) Change in other steroid hormones, renin, angiotensin II and hemodynamic parameters.; Treatment of mice with rapamycin significantly decreased plasma aldosterone levels (P = 0.007). Overall, treatment of primary aldosteronism patients with everolimus significantly decreased blood pressure (P < 0.05) and increased renin levels (P = 0.001) but did not lead to a significant reduction in aldosterone levels. However, prominent reduction of aldosterone levels upon everolimus treatment was observed in 4 out of 12 patients.; In mice, mTORC1 inhibition was associated with reduced plasma aldosterone levels. In patients with primary aldosteronism, mTORC1 inhibition was associated with improved blood pressure and renin suppression. In addition, mTORC1 inhibition appeared to reduce plasma aldosterone in a subset of patients

DNA storage in thermoresponsive microcapsules for repeated random multiplexed data access

In support of the publication "DNA storage in thermoresponsive microcapsules for repeated random multiplexed data access" we share the following datasets and code: AutoCAD drawing of the microfluidic trapping device. Sequences of the DNA used to encode the 25 files used in the current study. FASTQ-files of the sequencing experiments of Figures 5b and d. Python scripts that allow for the reproduction of our sequencing data analysis. The code has been tested on MacOS 13.0.1, Python 3.7.13, samtools 1.16.1 and BWA 0.7.17

Transmission of Chronic Wasting Disease Identifies a Prion Strain Causing Cachexia and Heart Infection in Hamsters

Chronic wasting disease (CWD) is an emerging prion disease of free-ranging and captive cervids in North America. In this study we established a rodent model for CWD in Syrian golden hamsters that resemble key features of the disease in cervids including cachexia and infection of cardiac muscle. Following one to three serial passages of CWD from white-tailed deer into transgenic mice expressing the hamster prion protein gene, CWD was subsequently passaged into Syrian golden hamsters. In one passage line there were preclinical changes in locomotor activity and a loss of body mass prior to onset of subtle neurological symptoms around 340 days. The clinical symptoms included a prominent wasting disease, similar to cachexia, with a prolonged duration. Other features of CWD in hamsters that were similar to cervid CWD included the brain distribution of the disease-specific isoform of the prion protein, PrPSc, prion infection of the central and peripheral neuroendocrine system, and PrPSc deposition in cardiac muscle. There was also prominent PrPSc deposition in the nasal mucosa on the edge of the olfactory sensory epithelium with the lumen of the nasal airway that could have implications for CWD shedding into nasal secretions and disease transmission. Since the mechanism of wasting disease in prion diseases is unknown this hamster CWD model could provide a means to investigate the physiological basis of cachexia, which we propose is due to a prion-induced endocrinopathy. This prion disease phenotype has not been described in hamsters and we designate it as the ‘wasting’ or WST strain of hamster CWD

Diffusion of excellence: evaluating a system to identify, replicate, and spread promising innovative practices across the Veterans health administration

IntroductionThe Veterans Health Administration (VHA) Diffusion of Excellence (DoE) program provides a system to identify, replicate, and spread promising practices across the largest integrated healthcare system in the United States. DoE identifies innovations that have been successfully implemented in the VHA through a Shark Tank style competition. VHA facility and regional directors bid resources needed to replicate promising practices. Winning facilities/regions receive external facilitation to aid in replication/implementation over the course of a year. DoE staff then support diffusion of successful practices across the nationwide VHA.MethodsOrganized around the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) Framework, we summarize results of an ongoing long-term mixed-methods implementation evaluation of DoE. Data sources include: Shark Tank application and bid details, tracking practice adoptions through a Diffusion Marketplace, characteristics of VHA facilities, focus groups with Shark Tank bidders, structured observations of DoE events, surveys of DoE program participants, and semi-structured interviews of national VHA program office leaders, VHA healthcare system/facility executives, practice developers, implementation teams and facilitators.ResultsIn the first eight Shark Tanks (2016–2022), 3,280 Shark Tank applications were submitted; 88 were designated DoE Promising Practices (i.e., practices receive facilitated replication). DoE has effectively spread practices across the VHA, with 1,440 documented instances of adoption/replication of practices across the VHA. This includes 180 adoptions/replications in facilities located in rural areas. Leadership decisions to adopt innovations are often based on big picture considerations such as constituency support and linkage to organizational goals. DoE Promising Practices that have the greatest national spread have been successfully replicated at new sites during the facilitated replication process, have close partnerships with VHA national program offices, and tend to be less expensive to implement. Two indicators of sustainment indicate that 56 of the 88 Promising Practices are still being diffused across the VHA; 56% of facilities originally replicating the practices have sustained them, even up to 6 years after the first Shark Tank.ConclusionDoE has developed a sustainable process for the identification, replication, and spread of promising practices as part of a learning health system committed to providing equitable access to high quality care

De novo design of protein homo-oligomers with modular hydrogen-bond network-mediated specificity.

In nature, structural specificity in DNA and proteins is encoded differently: In DNA, specificity arises from modular hydrogen bonds in the core of the double helix, whereas in proteins, specificity arises largely from buried hydrophobic packing complemented by irregular peripheral polar interactions. Here, we describe a general approach for designing a wide range of protein homo-oligomers with specificity determined by modular arrays of central hydrogen-bond networks. We use the approach to design dimers, trimers, and tetramers consisting of two concentric rings of helices, including previously not seen triangular, square, and supercoiled topologies. X-ray crystallography confirms that the structures overall, and the hydrogen-bond networks in particular, are nearly identical to the design models, and the networks confer interaction specificity in vivo. The ability to design extensive hydrogen-bond networks with atomic accuracy enables the programming of protein interaction specificity for a broad range of synthetic biology applications; more generally, our results demonstrate that, even with the tremendous diversity observed in nature, there are fundamentally new modes of interaction to be discovered in proteins

Impact of different anticoagulation management strategies on outcomes in atrial fibrillation: Dutch and Belgian results from the GARFIELD-AF registry.

The uptake rate of non-vitamin K oral anticoagulants (NOAC) for the treatment of non-valvular atrial fibrillation (AF) was far lower in the Netherlands (NL) compared to Belgium (BE). Also, patients on VKA in NL were treated with a higher target international normalized ratio (INR) range of 2.5 to 3.5. To explore the effect of these differences on thromboembolism (TE) and bleeding. Data from the GARFIELD-AF registry was used. Patients with new-onset AF and ≥1 investigator-determined risk factor for stroke were included between 2010 and 2016. Event rates from 2 years of follow-up were used. In NL and BE, 1186 and 1705 patients were included, respectively. Female sex (42.3% vs 42.2%), mean age (70.7 vs 71.3 years), CHA DS -VASc (3.1 vs 3.1), and HAS-BLED score (1.4 vs 1.5) were comparable between NL and BE. At diagnosis in NL vs BE, 72.1% vs 14.6% received vitamin K antagonists (VKA) and 17.8% vs 65.5% NOACs, varying greatly across cohorts. Mean INR was 2.9 (±1.0) and 2.4 (±1.0) in NL and BE, respectively. Event rates per 100 patient-years in NL and BE, respectively, of all-cause mortality (3.38 vs 3.90; hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.65-1.15), ischemic stroke/TE (0.82 vs 0.72; HR 1.14, 95% CI 0.62-2.11), and major bleeding (2.06 vs 1.54; HR 1.33, 95% CI 0.89-1.99) did not differ significantly. In GARFIELD-AF, despite similar characteristics, patients on anticoagulants were treated differently in NL and BE. Although the rate of major bleeding was 33% higher in NL, variations in bleeding, mortality, and TE rates were not statistically significant