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Current treatment guidelines do not provide recommendations to support the selection of treatment for most people with type 2 diabetes. We aimed to develop and validate an algorithm to allow selection of optimal treatment based on glycaemic response, weight change, and tolerability outcomes when choosing between SGLT2 inhibitor or DPP-4 inhibitor therapies.In this retrospective cohort study, we identified patients initiating SGLT2 and DPP-4 inhibitor therapies after Jan 1, 2013, from the UK Clinical Practice Research Datalink (CPRD). We excluded those who received SGLT2 or DPP-4 inhibitors as first-line treatment or insulin at the same time, had estimated glomerular filtration rate (eGFR) of less than 45 mL/min per 1·73 mAmong 10 253 patients initiating SGLT2 inhibitors and 16 624 patients initiating DPP-4 inhibitors in CPRD, baseline HbAA validated treatment selection algorithm for SGLT2 inhibitor and DPP-4 inhibitor therapies can support decisions on optimal treatment for people with type 2 diabetes.BHF-Turing Cardiovascular Data Science Award and the UK Medical Research Council.

Cell-free protein synthesis is an important tool for studying gene expression and harnessing it for applications. In cells, gene expression is regulated in part by the spatial organization of transcription and translation. Unfortunately, current cell-free approaches are unable to control the organization of molecular components needed for gene expression, which limits the ability to probe and utilize its effects. Here, we show, using complementary computational and experimental approaches, that macromolecular crowding can be used to control the spatial organization and translational efficiency of gene expression in cell-sized vesicles. Computer simulations and imaging experiments reveal that, as crowding is increased, DNA plasmids become localized at the inner surface of vesicles. Ribosomes, in contrast, remain uniformly distributed, demonstrating that crowding can be used to differentially organize components of gene expression. We further carried out cell-free protein synthesis reactions in cell-sized vesicles and quantified mRNA and protein abundance. At sufficiently high levels of crowding, we observed localization of mRNA near vesicle surfaces, a decrease in translational efficiency and protein abundance, and anomalous scaling of protein abundance as a function of vesicle size. These results are consistent with high levels of crowding causing altered spatial organization and slower diffusion. Our work demonstrates a straightforward way to control the organization of gene expression in cell-sized vesicles and provides insight into the spatial regulation of gene expression in cells.

Warfarin induces coagulopathy. Guidelines protocolize reversal of supratherapeutic international normalized ratio (INR) in patients dependent on anticoagulation, but practices vary for reversing warfarin-induced coagulopathy after overdose in non-warfarin-dependent patients.This is the report of a 15-year-old female who ingested her father's warfarin (100-200 mg) in a self-harm attempt. At hour 24 post-ingestion, her INR was 2.00 and she was admitted for monitoring. Reversal of coagulopathy was initially deferred pending the INR trend. The INR was 5.10 at hour 60 and 2.5 mg oral vitamin KA restrictive approach to coagulopathy reversal in non-warfarin-dependent patients with intentional warfarin overdose may result in worsening coagulopathy, bleeding, and lengthy hospital stay. Given the risk for significant, prolonged coagulopathy, these patients should be treated early with VK1, with subsequent serial INR monitoring and probable additional VK1 dosing. Delayed peak warfarin concentrations support consideration of gastrointestinal decontamination in late presenters.

OBJECTIVES The Commando technique for reconstruction of the aortomitral intervalvular fibrous body is effective to facilitate double valve surgery in cases of endocarditis or infiltrative calcification. The length of patch utilized in reconstruction of the intervalvular fibrous body has an important relationship to the geometry of the mitral and aortic valves and may impact on potential future valve-in-valve therapy. Here we report anatomic measurements after Commando reconstruction in a small group of patients and analyze the impact of reconstruction techniques on transcatheter valve-in-valve therapies. METHODS Seven patients from January 2018 to April 2022 who underwent double valve surgery with the Commando technique with postoperative computed tomography scans were identified. Computed tomographic reconstruction of the aortic and mitral valves was performed using 3mensio software and virtual transcatheter valve replacement was performed. Two of these patients who had preoperative imaging was analyzed to assess the change in aortomitral geometry resulting from reconstruction. RESULTS Measurements for each patient post-reconstruction are given in Table 1. Aortomitral length was grossly inversely proportional to aortomitral angle. Aortomitral angle and aortomitral curtain length were significantly altered post-Commando in two analyzed patients with pre- and post-operative computed tomography scan. Transcatheter aortic and mitral valve replacements were feasible in all patients post-Commando. The aortomitral angle was larger and more favorable for mitral valve-in-valve in patients in which the aortomitral curtain was short. CONCLUSIONS Aortomitral curtain length, as determined by location of aortic valve annular sutures, may be an important consideration in surgical decision-making for valve-in-valve after the Commando procedure.

Veno-arterial membrane oxygenation (VA-ECMO) can be used as a rescue therapy for patients in refractory cardiogenic shock. While there is experience as a bridge-to-transplant and bridge-to-ventricular assist device in the heart failure population, there are not reports of its use as a bridge to definitive valvular intervention. Here we present a case of VA-ECMO as a bridge to transcatheter mitral valve-in-valve (TMVIV) with a Sapien aortic prosthesis (Edwards Life Sciences, Irvine, CA).

Degenerative mitral valve (MV) regurgitation (MR) is a highly prevalent heart disease that requires surgery in severe cases. Here, we show that a decrease in the activity of the serotonin transporter (SERT) accelerates MV remodeling and progression to MR. Through studies of a population of patients with MR, we show that selective serotonin reuptake inhibitor (SSRI) use and SERT promoter polymorphism 5-HTTLPR LL genotype were associated with MV surgery at younger age. Functional characterization of 122 human MV samples, in conjunction with in vivo studies in SERT −/− mice and wild-type mice treated with the SSRI fluoxetine, showed that diminished SERT activity in MV interstitial cells (MVICs) contributed to the pathophysiology of MR through enhanced serotonin receptor (HTR) signaling. SERT activity was decreased in LL MVICs partially because of diminished membrane localization of SERT. In mice, fluoxetine treatment or SERT knockdown resulted in thickened MV leaflets. Similarly, silencing of SERT in normal human MVICs led to up-regulation of transforming growth factor β1 ( TGF β 1 ) and collagen ( COL1A1 ) in the presence of serotonin. In addition, treatment of MVICs with fluoxetine not only directly inhibited SERT activity but also decreased SERT expression and increased HTR2B expression. Fluoxetine treatment and LL genotype were also associated with increased COL1A1 expression in the presence of serotonin in MVICs, and these effects were attenuated by HTR2B inhibition. These results suggest that assessment of both 5-HTTLPR genotype and SERT-inhibiting treatments may be useful tools to risk-stratify patients with MV disease to estimate the likelihood of rapid disease progression.

To use optical modeling to compare a 6.0 mm and 7.0 mm intraocular lens (IOL) optic diameters on peripheral retinal illumination with implications for negative dysphotopsia.Mayo Clinic, Rochester, Minnesota, and Simpson Optics LLC, Arlington, Texas.Model eye.Ray-tracing software was used to simulate retinal illumination from an extended light source for a pseudophakic eye with in-the-bag biconvex IOLs (refractive index [n] = 1.46 and 1.55) and a 2.5 mm pupil. Ray-tracing diagrams and simulated retina illumination profiles were compared using the 6.0 mm and 7.0 mm optic diameter IOLs. Retinal locations were scaled to relative visual angles from 70 to 110 degrees horizontally.A 7.0 mm optic (n = 1.46) expands the image field by 2.8 degrees compared with a 6.0 mm optic. High-angle input light misses a 7.0 mm optic at a larger visual angle than a 6.0 mm optic, shifting illumination of the peripheral retina by this light anteriorly by 5.6 degrees. Consequently, a region of nonilluminated peripheral nasal retina is enlarged and shifted peripherally using a 7.0 mm optic (visual angle, 86.3 to 96.3 degrees) compared with a 6.0 mm optic (visual angle, 83.5 to 90.7 degrees). Similar illumination changes were seen modeling a 1.55 n IOL.A narrow dark region in the nasal retina when using a 6.0 mm optic is changed to a broader, more peripheral dark region when using a 7.0 mm optic. An extended, more peripheral dark nasal region may make a temporal shadow less bothersome and explain lower negative dysphotopsia rates using a 7.0 mm optic.

BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection.METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis.RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives.CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.).

Funding: Social Sciences and Humanities Research Council of Canada (752-2019-0520), Rothermere Foundation, Canadian Centennial Scholarship Fund, University of St Andrews. Community ownership of wind energy has been found to increase acceptance, but the reasons for this are poorly understood. Here, we compare different communities’ attitudes towards local onshore wind energy projects in order to gain a deeper understanding of the characteristics of ownership which are conducive to community acceptance. Using a postal survey in Scotland (n = 318), we compared three communities with varying degrees of ownership regarding their (1) support for the local wind project; (2) perceptions of energy justice; (3) perceived impacts; and (4) ownership and benefit preferences. One-way ANOVAs and the Potential for Conflict Index2 identified that residents in the two communities with a degree of ownership were more associated with greater acceptance, processes, and outcomes (i.e. more just and inclusive development processes and more fairly distributed benefits and impacts), than residents living near the privately-owned development. Additionally, we provide evidence that a co-operative can achieve similar acceptance and energy justice as a fully community-owned project. Overall, the results indicate that policymakers should take seriously the connection between the tenets of energy justice and ownership models in their policy and planning efforts. Publisher PDF

PURPOSE To specify a keratoprosthesis (KPro) power value for use with an intraocular lens (IOL). METHODS Raytracing software was used to determine the imaging properties of both the natural cornea and conceptual KPro designs, and IOL power calculation methods were reviewed. Traditional calculations use 'thick lens' models for the overall eye, while also using 'thin lens' approximations for the cornea and IOL. The power of the natural cornea acts approximately at the apex, although this is unlikely to be the case for a KPro. The IOL location is determined using an empirical adjustment that is calculated from clinical results for natural eyes. RESULTS The use of a KPro has a similar optical effect to corneal refractive surgery, where the cornea no longer matches the original eye. A modification of the 'double-K' calculation method can be used by specifying the KPro effective power at the original corneal apex, but still estimating the postoperative IOL location using the original corneal power. The KPro power is measured by assembling the KPro with fluid and a window to simulate the way it is used, recording the best focus power at room temperature with a 3 mm diameter aperture, rescaling to the in situ power at 35°C using refractive index changes, and then rescaling again to the power expected relative to the original corneal apex. When expressed as a K value, a keratometer refractive index of 1.332 is proposed. If necessary, clinical results may be used later to make empirical adjustments to the calculation method. CONCLUSIONS A KPro power can be specified relative to the expected location of the original corneal apex using a keratometer index of 1.332. A double-K calculation can then be used to determine the correct KPro and IOL power values for a pseudophakic eye.

A method of ranking the rate of corrosion of metals in molten fluoride or chloride salts is proposed based on a zero-resistance ammeter (ZRA). The metal of interest for the corrosion study is shorted to a relatively noble metal counter electrode. Stainless steel 316 was tested in FLiNaK (LiF-NaF-KF). Haynes 230, stainless steel 316L, and Hastelloy C-22 were tested in MgCl2-NaCl-KCl. The ZRA oxidation current from SS-316L was reduced by 89% in FLiNaK after the addition of Li metal, which is known to reduce the redox potential. Post-test examination of metal surfaces and salt samples were also consistent with the relative ZRA current response in fluoride salt. Consistency was also observed between the relative ZRA response for the different metal alloys in the chloride salt and post-test analysis of metal and salt samples.

Objectives: Psoriatic arthritis (PsA) has a strong genetic component, and the identification of genetic risk factors could help identify the ~30% of psoriasis patients at high risk of developing PsA. Our objectives were to identify genetic risk factors and pathways that differentiate PsA from cutaneous-only psoriasis (PsC) and to evaluate the performance of PsA risk prediction models. Methods: Genome-wide meta-analyses were conducted separately for 5,065 patients with PsA and 21,286 healthy controls and separately for 4,340 patients with PsA and 6,431 patients with PsC. The heritability of PsA was calculated as a single-nucleotide polymorphism (SNP)–based heritability estimate (h2SNP) and biologic pathways that differentiate PsA from PsC were identified using Priority Index software. The generalizability of previously published PsA risk prediction pipelines was explored, and a risk prediction model was developed with external validation. Results: We identified a novel genome-wide significant susceptibility locus for the development of PsA on chromosome 22q11 (rs5754467; P = 1.61 × 10−9), and key pathways that differentiate PsA from PsC, including NF-κB signaling (adjusted P = 1.4 × 10−45) and Wnt signaling (adjusted P = 9.5 × 10−58). The heritability of PsA in this cohort was found to be moderate (h2SNP = 0.63), which was similar to the heritability of PsC (h2SNP = 0.61). We observed modest performance of published classification pipelines (maximum area under the curve 0.61), with similar performance of a risk model derived using the current data. Conclusion: Key biologic pathways associated with the development of PsA were identified, but the investigation of risk classification revealed modest utility in the available data sets, possibly because many of the PsC patients included in the present study were receiving treatments that are also effective in PsA. Future predictive models of PsA should be tested in PsC patients recruited from primary care.

Among left ventricular assist device patients, the most commonly infected component is the drive line, which can be managed with antibiotics and local debridement. Infection of intrathoracic device components is less common but more difficult to manage. Herein we describe the incidence of deep device infection (DDI) at our center as well as management and outcomes.We retrospectively reviewed 658 patients who underwent implantable left ventricular assist device insertion with HeartMate 2 (Abbott) or HeartMate 3 (Abbott) devices between January 2004 and June 2021. DDI was defined according to radiographic and clinical criteria. Cumulative incidence was calculated using a Fine-Gray subdistribution model; survival analysis was performed using the method of Kaplan and Meier.There were 32 (4.8%) DDIs during this study period. Drive line infection and re-exploration for bleeding were associated with development of DDI. Cumulative incidence of DDI increased over time, affecting 11% (7%-18%) at 5 years. The dominant microbes involved in DDI were Pseudomonas aeruginosa (19%) and methicillin-resistant Staphylococcus aureus (13%). Nineteen patients (59%) with device infection underwent device exchange, 6 (19%) underwent initial transplant, and 7 (22%) were treated solely with debridement and antibiotics. Of those who underwent device exchange, 12 (63%) developed reinfection of their new device and 6 underwent subsequent heart transplant. Patients who underwent transplantation for management of device infection had improved 5-year survival (80% vs 11%; P = .01) but 3 patients (25%) developed deep sternal wound infection after transplant.DDI is a rare but challenging complication in this destination era. Heart transplantation is the preferred management strategy for eligible patients but infectious complication is common.

BackgroundDespite advances in next generation sequencing technologies, the identification of variants of uncertain significance (VUS) can often hinder definitive diagnosis in patients with complex neurodevelopmental disorders.ObjectiveThe objective of this study was to identify and characterize the underlying cause of disease in a family with two children with severe developmental delay associated with generalized dystonia and episodic status dystonicus, chorea, epilepsy, and cataracts.MethodsCandidate genes identified by autozygosity mapping and whole-exome sequencing were characterized using cellular and vertebrate model systems.ResultsHomozygous variants were found in three candidate genes: MED27, SLC6A7, and MPPE1. Although the patients had features of MED27-related disorder, the SLC6A7 and MPPE1 variants were functionally investigated. SLC6A7 variant in vitro overexpression caused decreased proline transport as a result of reduced cell-surface expression, and zebrafish knockdown of slc6a7 exhibited developmental delay and fragile motor neuron morphology that could not be rescued by L-proline transporter–G396S RNA. Lastly, patient fibroblasts displayed reduced cell-surface expression of glycophosphatidylinositol-anchored proteins linked to MPPE1 dysfunction.ConclusionsWe report a family harboring a homozygous MED27 variant with additional loss-of-function SLC6A7 and MPPE1 gene variants, which potentially contribute to a blended phenotype caused by multilocus pathogenic variants. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

In this study, the stability of Ag|Ag+ molten chloride reference electrodes was studied using mullite and magnesia tubes as reference electrode membrane materials in molten MgCl2-KCl-NaCl for continuous immersion up to 31 d. Two electrochemical methods were used to characterize the long-term performance of the reference electrodes at 500 °C in an inert atmosphere using a Mg rod as the working electrode: open circuit potential (OCP) and onset of Mg(II) reduction as measured by cyclic voltammetry (CV). There was only a 3% difference between the average OCP measured versus the mullite and MgO reference electrodes. Potential drift was higher for mullite (−1.34 mV d−1) than MgO (0.22 mV d−1). But both drift rates were very low compared to the OCP data standard deviation, indicating that no significant drift was measured for us to 31 d.

This study addressed the problem of measuring the total mass of molten salt in a nuclear system such as a nuclear fuel electrorefiner or a molten salt reactor. In theory, soluble tracers can be add...

Molten eutectic LiCl-KCl salt is a widely used electrolyte for electrorefining uranium from spent nuclear fuel. Due to the hygroscopic nature of this salt, such operations must be performed under c...