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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.

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).

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.

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.).

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.

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.

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...

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.

Background Loose anagen hair is a rare form of impaired hair anchorage in which anagen hairs that lack inner and outer root sheaths can be gently and painlessly plucked from the scalp. This condition usually occurs in children and is often self-limiting. A genetic basis for the disorder has been suggested but not proven. A better understanding the aetiology of loose anagen hair may improve prevention and treatment strategies. Objectives To identify a possible genetic basis of loose anagen hair using next-generation DNA sequencing and functional analysis of variants identified. Methods In this case study, whole-exome sequencing analysis of a pedigree with one affected individual with features of loose anagen hair was performed. Results The patient was found to be compound heterozygous for two single-nucleotide substitutions in TKFC resulting in the following missense mutations: c.574G> C (p.Gly192Arg) and c.682C> T (p.Arg228Trp). Structural analysis of human TKFC showed that both mutations are located near the active site cavity. Kinetic assays of recombinant proteins bearing either of these amino acid substitutions showed almost no dihydroxyacetone kinase or D-glyceraldehyde kinase activity, and FMN cyclase activity reduced to just 10% of wildtype catalytic activity. Conclusions TKFC missense mutations may predispose to the development of loose anagen hairs. Identification of this new biochemical pathobiology expands the metabolic and genetic basis of hypotrichosis.

CaCl2 has applications for electrochemical processing of nuclear materials. Thermal dehydration leads to formation of oxide ions, which are shown to react and cause precipitation of dissolved CeCl3 that was selected as a surrogate for actinide chlorides. Thus, measurement of residual water in CaCl2 is an essential capability. Thermogravimetric analysis (TGA) was shown to underestimate starting water concentration. Subsequent analysis of solid samples via acid–base titration and cyclic voltammetry (CV) of the molten salt yielded consistent values within 5% for residual water. Hydroxides were shown to be unstable, thus oxygen is retained as oxide ions. Thus, total water in a sample of CaCl2 can be quantified by combining TGA with with either CV of molten salt or titration of salt samples. The importance of quantifying residual water in the salt was demonstrated by showing that cerium chloride (surrogate for actinide chlorides) will react with oxide ions in CaCl2 to form insoluble oxides and oxychlorides.

Electrolytic uranium oxide reduction has the potential to be a key process for recycling spent fuel from commercial light water reactors to advanced nuclear reactors—including molten salt reactors and metal fueled reactors. However, several problems with the process have been identified that need to be addressed to support efficient, cost-effective commercial implementation. Process optimization requires attention to metal corrosion, anode stability, cell efficiency, and cathode product purity. Generation of oxygen bubbles at the anode combined with high temperature (650oC) and molten chloride salt (LiCl + 1 wt% Li2O) create a highly oxidizing environment for metals needed for salt containment and shrouding of the anode. The current standard choice for the inert anode is platinum metal, which has fairly good stability in the system. But given the high cost of platinum, alternative anode materials need to be discovered. Efficient removal of oxygen bubbles requires use of a shroud around the anode. The easy fabricability of metals makes them a reasonable choice for the shroud material, but corrosion due to interaction with the salt and oxygen needs to be minimized. Cell efficiency is affected by hydroxide impurity in the salt. Methods for removing water and hydroxides from the salt will be reported that improve cell efficiency. Cell efficiency can also be affected by controlling the reduction mechanism. Uranium oxide can either be reduced chemically by reaction with electrochemically generated lithium atoms or electrolytically with direct reduction of UO2. The reduction mechanism also affects the buildup of entrained lithium oxide in the cathode product. Entrained lithium oxide is problematic as it gets carried on to subsequent processing steps such as electrorefining and molten salt oxidation.

Signature-based safeguards (SBS) is being developed to assist tradition nuclear material accountancy methods in tracking material in pyroprocessing facilities. SBS involves identifying off-normal scenarios that would result in improper movement of material in a pyroprocessing facilities and determining associated sensor response signatures. SBS investigations are undertaken in the computational space utilizing an electrochemical transport code known as enhanced REFIN with anodic dissolution (ERAD) to calculate the affect of off-normal conditions in the electrorefiner (ER) on material movement. Work is undertaken to experimentally validate the predictions and assumptions made by ERAD for off-normal occurrences. These experiments were undertaken on a benchtop scale and involved operating an electrochemical cell at 10 separate current densities for constant current operations to deposit U and Gd at a W cathode. These experiments were then modeled using ERAD to compare calculated predictions versus analytical experimental results it was found. It was discovered both the experimental and calculated results reflect a trend of increased codeposition of U and Gd with increasing current density. ERAD was thus demonstrated to be useful for predicting trends from anomalous operation but will require further optimization to be utilized as a quantitative design tool.

A novel nuclear waste form was synthesized for the disposal of electrorefiner salt from pyrometallurgical reprocessing of used nuclear fuel. Its synthesis constitutes two steps: waste salt dehalogenation via ion exchange with H–Y zeolite, followed by thermal treatment for phase transition and consolidation. Salt cation-loaded zeolite exhibiting greater than 90% dehalogenation was sintered for 12 h at 925 °C and achieved 3 vol% open porosity (determined via Archimedes method). Microstructural imaging and structural characterization revealed a multiphase assemblage of alkali aluminosilicate and mixed oxide phases. Chemical durability experiments were performed using modified ASTM C1308 tests in demineralized water and different silica solutions. Si-containing species appear to exhibit congruent dissolution, while the release behaviors of alkali elements appear to include diffusion-limited contributions. The 4-day cumulative releases for the dehalogenated salt waste form (DSWF) are less than 33% of those measured for the baseline glass-bonded sodalite advanced ceramic waste form (GBS ACWF). Furthermore, the dehalogenation and consolidation processing steps provide a 35% decrease in required storage volume for a given waste salt mass relative to the GBS ACWF.

Patients awaiting lung transplantation face high wait-list mortality, as injury precludes the use of most donor lungs. Although ex vivo lung perfusion (EVLP) is able to recover marginal quality donor lungs, extension of normothermic support beyond 6 h has been challenging. Here we demonstrate that acutely injured human lungs declined for transplantation, including a lung that failed to recover on EVLP, can be recovered by cross-circulation of whole blood between explanted human lungs and a Yorkshire swine. This xenogeneic platform provided explanted human lungs a supportive, physiologic milieu and systemic regulation that resulted in functional and histological recovery after 24 h of normothermic support. Our findings suggest that cross-circulation can serve as a complementary approach to clinical EVLP to recover injured donor lungs that could not otherwise be utilized for transplantation, as well as a translational research platform for immunomodulation and advanced organ bioengineering. In a new strategy for increasing the availability of lungs for transplantation, human lungs declined for transplantation because of their poor quality can be recuperated by connecting them to the circulation of a pig.

Macromolecular crowding is known to modulate chemical equilibria, reaction rates, and molecular binding events, both in aqueous solutions and at lipid bilayer membranes, natural barriers that enclose the crowded environments of cells and their subcellular compartments. Previous studies on the effects of macromolecular crowding in aqueous compartments on conduction through membranes have focused on single-channel ionic conduction through previously formed pores at thermodynamic equilibrium. Here, the effects of macromolecular crowding on the mechanism of pore formation itself were studied using the droplet interface bilayer (DIB) technique with the voltage-dependent pore-forming peptide alamethicin (alm). Macromolecular crowding was varied using 8 kDa molecular weight polyethylene glycol (PEG8k) or 500 kDa dextran (DEX500k) in two aqueous droplets on both sides of the bilayer membrane. In general, voltage thresholds for pore formation in the presence of crowders in the droplets decreased compared to their values in the absence of crowders, due to excluded volume effects, water binding by PEG, and changes in the ordering of water molecules and hydrogen-bonding interactions involving the polar lipid headgroups. In addition, asymmetric crowder loading (e.g., PEG8k-DEX500k on either side of the membrane) resulted in transmembrane osmotic pressure gradients that either enhanced or degraded the ionic conduction through the pores.

Although seeking broad-based benefit from space activity has been an objective of international space policy and a principle of international space law since the first decade of the space age, the concept of benefit irrespective of the beneficiary’s degree of economic or scientific development may be emerging as a pathway to political support for the growing entrepreneurial interest in pursuing commercial activities beyond Earth’s atmosphere. After a brief review of the concept’s history in policy and law, this article will explore the role it might play in building broad political support for off-Earth commerce.

Molten salt solutions consisting of eutectic LiCl-KCl and concentrations of samarium chloride (0.5 to 3.0 wt%) at 500℃ were analyzed using both cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The CV technique gave the average diffusion coefficient for Sm3+ over the concentration range. Equipped with Sm3+ diffusion coefficient, the Randles-Sevcik equation predicted Sm3+ concentration values that agree with the given experimental values. From CV measurements; the anodic, cathodic, and half-peak potentials were identified and subsequently used as a parameter to acquire EIS spectra. A six-element Voigt model was used to model the EIS data in terms of resistance-time constant pairs. The lowest resistances were observed at the half-peak potential with the associated resistance-time constant pairs characterizing the reversible reaction between Sm3+ and Sm2+. By extrapolation, the Voigt model estimated the polarization resistance and established a polarization resistance-concentration relationship.

Sterol-C4-methyl oxidase (SC4MOL) deficiency was recently described as an autosomal recessive cholesterol biosynthesis disorder caused by mutations in the MSMO1 (sometimes also referred to as SC4MOL) gene. To date, 5 patients from 4 unrelated families with SC4MOL deficiency have been reported. Diagnosis can be challenging as the biochemical accumulation of methylsterols can affect global development and cause skin and ocular pathology. Herein, we describe 2 siblings from a consanguineous Turkish family with SC4MOL deficiency presenting with psoriasiform dermatitis, ocular abnormalities (nystagmus, optic hypoplasia, myopia, and strabismus), severe intellectual disability, and growth and motor delay. We undertook whole-exome sequencing and identified a new homozygous missense mutation c.81A>C; p.Asn27Thr in MSMO1. Segregation analysis in all available family members confirmed recessive inheritance of the mutation. The siblings were treated with a combination of oral and topical statin and cholesterol which resulted in clinical improvement. This study demonstrates how genomics-based diagnosis and therapy can be helpful in clinical practice.

Based on a previous molecular phylogenetic analysis, Cryptantha, an herbaceous plant genus of the family Boraginaceae, subtribe Amsinckiinae, was split into five genera: Eremocarya, Greeneocharis, Johnstonella, Oreocarya, and a reduced Cryptantha, the last in two separate clades. As a result of this study, Johnstonella was expanded to 13 species and 15 minimum-rank taxa, these formerly classified in Cryptantha s.l. More recent analyses of this complex, with an increased sample size and high-throughput sequence data, indicate that four additional Cryptantha species not previously sampled—C. albida, C. mexicana, C. texana—plus what was originally identified as C. hispida nest within Johnstonella with strong support. However, the identity of C. hispida used in this analysis is now in doubt. The material used likely represents a new species, in the process of being investigated. Two additional species not sequenced to date—C. geohintonii and C. gypsites—are clearly close relatives of C. albida and C. mexicana, based on morphological similarity. In order to maintain monophyly of genera, we here make new combinations in transferring four of these species from Cryptantha to Johnstonella, with the new combinations Johnstonella albida, J. geohintonii, J. gypsites, and J. mexicana. We delay the transfer of Cryptantha texana to Johnstonella because of its morphological similarity to other species that clearly nest within Cryptantha s.s. These same molecular phylogenetic studies may also support the transfer of two previously recognized Johnstonella species—J. echinosepala and J. micromeres—to Cryptantha, one to each of two separate clades. Additional phylogenetic studies focusing on some of these taxa are needed to confirm the position of these latter three species and the possible recognition of a new genus in the complex.

ObjectiveTo establish whether clinical patient characteristics routinely measured in primary care can identify people with differing short-term benefits and risks for SGLT2-inhibitor and DPP4-inhibitor therapies, and to derive and validate a treatment selection algorithm to identify the likely optimal therapy for individual patients.DesignProspective cohort study.SettingRoutine clinical data from United Kingdom general practice (Clinical Practice Research Datalink [CPRD]), and individual-level clinical trial data from 14 multi-country trials of SGLT2-inhibitor and DPP4-inhibitor therapies.Participants26,877 new users of SGLT2-inhibitor and DPP4-inhibitor therapy in CPRD over 2013-2019, and 10,414 participants randomised to SGLT2-inhibitor or DPP4-inhibitor therapy in 14 clinical trials, including 3 head-to-head trials of the two therapies (n=2,499).Main outcome measuresThe primary outcome was achieved HbA1c 6 months after initiating therapy. Clinical features associated with differential HbA1c outcomes with SGLT2-inhibitor and DPP4-inhibitor therapies were identified in routine clinical data, with associations then tested in trial data. A multivariable treatment selection algorithm to predict differential HbA1c outcomes was developed in a CPRD derivation cohort (n=14,069), with validation in a CPRD validation cohort (n=9,376) and the head-to-head trials. In CPRD, we further explored the relationship between model predictions and secondary outcomes of weight loss and treatment discontinuation.ResultsThe final treatment selection algorithm included HbA1c, eGFR, ALT, age, and BMI, which were identified as predictors of differential HbA1c outcomes with SGLT2-inhibitor and DPP4-inhibitor therapies using both routine and trial data. In validation cohorts, patient strata predicted to have a ≥5 mmol/mol HbA1c reduction with SGLT2-inhibitor therapy compared with DPP4-inhibitor therapy (38.8% of CPRD validation sample) had an observed greater reduction of 8.8 mmol/mol [95%CI 7.8-9.8] in the CPRD validation sample, a 5.8 mmol/mol (95%CI 3.9-7.7) greater reduction in the Cantata D/D2 trials, and a 6.6 mmol/mol [95%CI 2.2-11.0]) greater reduction in the BI1245.20 trial. In CPRD, there was a greater weight reduction with SGLT2-inhibitor therapy regardless of predicted glycaemic benefit. Strata predicted to have greater reduction in HbA1c on SGLT2-inhibitor therapy had a similar risk of discontinuation as on DPP4-inhibitor therapy. In contrast, strata predicted to have greater reduction in HbA1c with DPP4-inhibitor therapy were half as likely to discontinue DPP4-inhibitor therapy than SGLT2-inhibitor therapy.ConclusionsRoutinely measured clinical features are robustly associated with differential glycaemic responses to SGLT2-inhibitor and DPP4-inhibitor therapies. Combining features into a treatment selection algorithm can inform clinical decisions concerning optimal type 2 diabetes treatment choices.Key messagesWhat is already known on this subjectDespite there being multiple glucose-lowering treatment options available for people with type 2 diabetes, current guidelines do not provide clear advice on selecting the optimal treatment for most patients.It is unknown whether routinely measured clinical features modify the risks and benefits of two common treatment options, DPP4-inhibitor or SGLT2-inhibitor therapy, and which could be used to target these treatments to those patients most likely to benefit.What this study addsUsing data from 10,414 participants in 14 randomised trials, and 26,877 patients in UK primary care, we show several routinely available clinical features, notably glycated haemoglobin (HbA1c) and kidney function, are robustly associated with differential HbA1c responses to initiating SGLT2-inhibitor and DPP4-inhibitor therapies.Combining clinical features into a multivariable treatment selection model identifies validated patient strata with 1) a >5 mmol/mol HbA1c benefit for SGLT2-i therapy compared with DPP4-inhibitor therapy ; 2) a 50% reduced risk of early treatment discontinuation with DPP4-inhibitor therapy compared with SGLT2-inhibitor therapy.Our findings demonstrate a precision medicine approach based on routine clinical features can inform clinical decisions concerning optimal type 2 diabetes treatment choices.

Cryptantha arenophila Rebman & M.G.Simpson (Boraginaceae) is described as new. This species is restricted to sandy dunes near San Quintin, Baja California, Mexico and adjacent coastal regions. It is similar to the more common Cryptantha patula Greene in stem vestiture, calyx morphology, and inflorescence morphology. Cryptantha arenophila differs from that species in having significantly larger corolla limbs and narrowly oblong to narrowly elliptic leaves with obtuse-rounded leaf apices, as opposed to linear to narrowly lanceolate leaves with acute to obtuse leaf apices in C. patula. In addition, nutlets of C. arenophila tend to have more numerous and shorter tubercles, while those of C. patula have tubercles that are less dense and larger, although variation in this species needs further investigation. The dune habitats where the type locality of C. arenophila occurs are currently under severe impacts from animal grazing and off-road traffic, necessitating the conservation of these regions.

Calculating the intraocular lens power for a particular patient requires an empirical “lens constant” to estimate the final axial location after surgery. This is normally calculated from clinical results for each new lens style, but it can also be estimated without clinical data by comparing a new style to an existing style. The lenses are axially positioned in a model eye at comparable locations, and image distances are used to estimate the change in lens constant. The A-constant used by the SRK/T calculation method is evaluated here, but this can be easily converted for other calculations using an average eye. Raytrace calculations demonstrate the method, and also illustrate the effects that refractive index, shape factor, and asphericity have on the refractive error. Actual lens measurements at 35°C in saline are preferable if details of the reference lens are uncertain.

A review of the species Cryptantha maritima (Boraginaceae) supports the continued recognition of the three varieties, these differing in corolla size, ovule and nutlet number, and calyx vestiture. Mapping of these taxa from verified specimens demonstrates some geographic trends, but also some overlap in ranges. In the process of our study, we discovered a new taxonomic entity. Cryptantha maritima var. vizcainensis is described as new. This variety is restricted to the Vizcaíno Desert of Baja California Sur, Mexico and should be considered rare, as it is known to date from only eleven collections. It differs from the other three varieties of the species in having a canescent, appressed-strigose stem vestiture lacking spreading trichomes, in having a relatively large corolla, and in having a fruit derived from two 1-ovuled ovary lobes, developing into two heteromorphic nutlets. We also discovered that the species Cryptantha pondii, previously treated as a synonym of C. patula, should be resurrected as a distinct taxon. Cryptantha pondii is restricted to the western Vizcaíno Desert and to Natividad Island of Baja California Sur. It is morphologically distinctive in having bracteate flowers, relatively large corollas, and four smooth nutlets heteromorphic by size. It is to date known from only three collections and should be considered extremely rare. We also reviewed the morphological and phylogenetic status of Johnstonella echinosepala. This taxon shows similarities to Cryptantha maritima and also exhibits some morphological discontinuity between Pacific and Gulf populations in Baja California Sur. Evidence from both morphological and phylogenetic studies supports the transfer of this species from the genus Johnstonella back to the genus Cryptantha. Finally, we propose that both C. pondii and C. echinosepala are likely close relatives of C. maritima, all of the “Maritimae clade,” a group distantly related to the main core of the genus Cryptantha. This study confirms the great importance of studying herbarium specimens in taxonomic research.

Social media platforms provide valuable and powerful means with which users can share content, comment, and communicate. They also suffer from abuse through the dissemination of fake news and misinformation. While a fair amount of work has been done on detecting fake news, on the complementary problem of limiting its propagation, progress has been modest. Once an item is detected as fake, a social media company can intervene on the item and take an appropriate action, including hard intervention (e.g., removing an account) and soft intervention (e.g., labeling the item as "suspicious"). Given that fake news detectors are not 100% reliable, we study the problem of developing a cost aware intervention policy which decides whether to intervene based on the truthiness and popularity of the item. Our solution, Solomon, consists of three modular components - truthiness estimation, popularity estimation (with and without intervention), and intervention policy. Our extensive experiments on real and fake news from multiple domains show that Solomon can perform effective intervention.

During the preparation of the treatment of the genus Cryptantha Lehmann ex G. Don for South America, numerous names were identified as needing typification to stabilize their nomenclature. As a result, lectotypes are designated for 11 names and second-step lectotypes for 20 names. Furthermore, supporting information about the type material of the basionyms of four Cryptantha names already typified by Johnston (Eritrichium talquinum Phil., Eritrichium dimorphum Phil., Eritrichium carrizalense Phil., and Eritrichium subamplexicaule Phil.) is provided Fil: Moroni, Pablo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Botánica Darwinion. Academia Nacional de Ciencias Exactas, Físicas y Naturales. Instituto de Botánica Darwinion; Argentina Fil: Martinez, Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Botánica Darwinion. Academia Nacional de Ciencias Exactas, Físicas y Naturales. Instituto de Botánica Darwinion; Argentina Fil: Simpson, Michael G.. San Diego State University; Estados Unidos

Fake news is a major threat to global democracy resulting in diminished trust in government, journalism and civil society. The public popularity of social media and social networks has caused a contagion of fake news where conspiracy theories, disinformation and extreme views flourish. Detection and mitigation of fake news is one of the fundamental problems of our times and has attracted widespread attention. While fact checking websites such as snopes, politifact and major companies such as Google, Facebook, and Twitter have taken preliminary steps towards addressing fake news, much more remains to be done. As an interdisciplinary topic, various facets of fake news have been studied by communities as diverse as machine learning, databases, journalism, political science and many more. The objective of this tutorial is two-fold. First, we wish to familiarize the database community with the efforts by other communities on combating fake news. We provide a panoramic view of the state-of-the-art of research on various aspects including detection, propagation, mitigation, and intervention of fake news. Next, we provide a concise and intuitive summary of prior research by the database community and discuss how it could be used to counteract fake news. The tutorial covers research from areas such as data integration, truth discovery and fusion, probabilistic databases, knowledge graphs and crowdsourcing from the lens of fake news. Effective tools for addressing fake news could only be built by leveraging the synergistic relationship between database and other research communities. We hope that our tutorial provides an impetus towards such synthesis of ideas and the creation of new ones.

Investigation of the kinetics of the ion exchange between protonated ultrastable Y-type (USHY) and surrogate electrorefiner (ER) waste salt was performed to optimize the dechlorination process. The...

Background: Invasive lobular breast cancer (ILC) accounts for approximately 15% of invasive breast carcinomas and is commonly associated with lobular carcinoma in situ (LCIS). Both have been shown to have higher familial risks than the more common ductal cancers. However, there are little data on the prevalence of the known high and moderate penetrance breast cancer predisposition genes in ILC. The aim of this study was to assess the frequency of germline variants in CDH1, BRCA2, BRCA1, CHEK2, PALB2, and TP53 in sporadic ILC and LCIS diagnosed in women ages ≤60 years. Methods: Access Array technology (Fluidigm) was used to amplify all exons of CDH1, BRCA2, BRCA1, TP53, CHEK2, and PALB2 using a custom-made targeted sequencing panel in 1,434 cases of ILC and 368 cases of pure LCIS together with 1,611 controls. Results: Case–control analysis revealed an excess of pathogenic variants in BRCA2, CHEK2, PALB2, and CDH1 in women with ILC. CHEK2 was the only gene that showed an association with pure LCIS [OR = 9.90; 95% confidence interval (CI), 3.42–28.66, P = 1.4 × 10−5] with a larger effect size seen in LCIS compared with ILC (OR = 4.31; 95% CI, 1.61–11.58, P = 1.7 × 10−3). Conclusions: Eleven percent of patients with ILC ages ≤40 years carried germline variants in known breast cancer susceptibility genes. Impact: Women with ILC ages ≤40 years should be offered genetic screening using a panel of genes that includes BRCA2, CHEK2, PALB2, and CDH1.

Parkinson’s disease (PD) reduces independence and quality of life through deterioration of upper limb motor function. Transcranial direct current stimulation (tDCS) may offer an alternative, adjunctive therapy for PD. However, the efficacy of tDCS for upper limb motor rehabilitation in PD is unknown. In this systematic review, evidence is compiled regarding the effects of tDCS on upper limb motor function in PD. Studies of tDCS applied to PD patients that assessed upper limb motor function, conducted between January 2000 and November 2018, were screened for inclusion via a systematic search of Medline, Cochrane, PsycINFO, EMBASE, CINAHL, and Web of Science. Ten out of 606 studies were included and their findings synthesized into five categories regarding the effects of tDCS on: (1) Unified Parkinson’s Disease Rating Scale motor section (UPDRS III), (2) upper limb motor tasks, (3) manual dexterity, (4) reaction time, and (5) neurophysiology. When applied to the primary motor cortex, tDCS may improve UPDRS III and the speed and force of movement. Considerable variation was found in tDCS parameters and further study is needed to clarify the long-term effects of tDCS on both simple and complex motor tasks and to compile relevant neurophysiological evidence.