Role of urinary concentrating ability in the generation of toxic papillary necrosis

Role of urinary concentrating ability in the generation of toxic papillary necrosis. We studied the pathogenesis of chemically induced papillary necrosis in six groups of rats. Papillary necrosis was produced by a single injection of 2-bromoethylamine hydrobromide (BEA), 50 mg, i.v.; the animals were followed for 7 to 10 days after the administration of the compound. Following BEA, heterozygous Brattleboro rats developed all the functional and morphologic lesions of papillary necrosis that we previously described in Sprague-Dawley rats. They were unable to maintain sodium balance when dietary sodium was withdrawn. Homozygous Brattleboro rats, on the other hand, developed none of the manifestations of papillary necrosis (that is, animals with central diabetes insipidus were protected completely from the nephrotoxic effects of BEA). They adapted normally to a zero sodium diet. Chronic administration of vasopressin to homozygous Brattleboro rats fully restored the toxic effects of BEA. Lowering urinary concentrating ability by inducing a water diuresis in Sprague-Dawley rats completely protected against BEA-induced papillary necrosis. Decreasing papillary solute concentration by furosemide or increasing urine flow after abrupt withdrawal of vasopressin to homozygous Brattleboro rats did not protect against BEA-induced papillary necrosis. We conclude that the combination, but not either alone, of increased urine flow and decreased papillary solute concentration protects against the development of BEA-induced papillary necrosis.Rôle du pouvoir de concentration urinaire sur l'apparition d'une nécrose papillaire toxique. Nous avons étudié la physiopathologie d'une nécrose papillaire induite chimiquement chez six groupes de rats. La nécrose papillaire était produite par une injection unique de 2-bromoéthylamine hydrobromide (BEA), 50 mg, i.v.; les animaux étaient suivis pendant 7 à 10 jours après administration du produit. Après le BEA, des rats Brattleboro hétérozygotes ont développé toutes les lésions fonctionnelles et morphologiques d'une nécrose papillaire telles que nous les avions déjà décrites chez des rats Sprague-Dawley. Ils n'étaient pas capables d'assurer l'équilibre de la balance sodée lorsque le sodium alimentaire était supprimé. Par ailleurs, des rats Brattleboro homozygotes n'ont développé aucune des manifestations de nécrose papillaire (c'est-à-dire que les animaux ayant un diabète insipide central étaient complètement protégés des effets néphrotoxiques du BEA). Ils s'adaptaient normalement à un régime sans sodium. L'administration chronique de vasopressine à des rats Brattleboro homozygotes a totalement restauré l'effet toxique du BEA. Le fait d'abaisser la capacité de concentration des urines en induisant une diurèse aqueuse dans les rats Sprague-Dawley a complètement protégé contre la nécrose papillaire induite par le BEA. La diminution de la concentration de solutés papillaires par le furosémide ou l'augmentation du débit urinaire après arrêt brutal de la vasopressine chez des rats Brattleboro homozygotes ne protégeait pas contre la nécrose papillaire induite par le BEA. Nous concluons que la combinaison, mais non chaque facteur séparément, d'une augmentation du débit urinaire et d'une diminution de la concentration de solutés papillaires protègent contre le développement d'une nécrose papillaire induite par le BEA

Clinical and pathophysiologic spectrum of acquired distal renal tubular acidosis

Clinical and pathophysiologic spectrum of acquired distal renal tubular acidosis. Urinary acidification was studied in nine patients with hyper-chloremic metabolic acidosis. The aim of this study was to investigate the mechanism(s) of impaired distal acidification by the systematic administration of sodium sulfate and neutral phosphate. No impairment of proximal acidification was apparent because all patients had a fractional bicarbonate excretion below 5% at plasma bicarbonate concentrations above 22 mEq/liter. All patients except two were unable to lower urine pH below 5.5 despite systemic metabolic acidosis. The two patients who lowered urine pH normally were hyperkalemic and had selective aldosterone deficiency. Six patients failed to lower the urine pH below 5.5 with sodium sulfate (6.04 ± 0.16) and were unable to achieve a normal urine minus blood (U-B) Pco2 gradient with neutral phosphate (2.8 ± 3.5mm Hg). Control subjects, the two patients with selective aldosterone deficiency, and the remaining patient lowered the urine pH below 5.5 and increased the U-B Pco2 gradient above 25mm Hg in response to sodium sulfate and neutral phosphate infusion, respectively. The abnormal response to these agents exhibited by six patients strongly suggests that the mechanism of impaired distal acidification was that of secretory failure of the proton pump. The normal response of the remaining three patients indicates that the proton pump was able to secrete hydrogen ions normally under maximal stimulation. This pattern is totally predictable in patients with isolated selective aldosterone deficiency who are also capable of lowering the urine pH normally in the presence of systemic metabolic acidosis. The distinctive acidification pattern of the remaining patient who was also hyperkalemic can be explained on the basis of a voltage-dependent type of distal renal tubular acidosis. This type may be disclosed by the findings of impairment of both hydrogen ion and potassium secretion.Aspects clinique et physiopathologique de l'acidose tubulaire distale acquise. L'acidification urinaire a été étudiée chez neuf malades ayant une acidose métabolique hyperchlorémique. Le but de ce travail était d'étudier le mécanisme de l'altération de l'acidification distale par l'administration de sulfate de sodium et de phosphate neutre. Il n'est pas apparu d'altération de l'acidication proximale puisque tous les malades avaient une excrétion fractionnelle de bicarbonate inférieure à 5% à des concentrations de bicarbonate plasmatique supérieures à 22 mEq/litre. Tous les malades sauf deux étaient incapables d'abaisser leur pH urinaire au dessous de 5,5 malgré l'acidose métabolique. Les deux malades qui abaissaient le pH de l'urine à des valeurs normales étaient hyperkaliémiques et avaient un déficit sélectif d'aldostérone. Six malades n'ont pu abaisser leur pH urinaire en dessous de 5,5 avec le sulfate de sodium (6,04 ± 0,16) et ont été incapables de réaliser un gradient de Pco2 normal urine-sang sous phosphate neutre (2,8 ± 3,5mm Hg). Les sujets contrôles, les deux malades ayant un déficit d'aldostérone et le dernier malade ont abaissé le pH de l'urine au dessous de 5,5 et augmenté le gradient de Pco2 à plus de 25mm Hg en réponse aux administrations de sulfate de sodium et de phosphate neutre, respectivement. La résponse anormale des six malades suggère fortement que le mécanisme de l'altération de l'acidification distale est un défaut de fonctionnement de la pompe à protons. La réponse normale des trois derniers malades indique que la pompe était capable de sécréter des ions hydrogène dans des conditions de stimulation maximales. Cette modalité est prévisible chez les malades qui ont un déficit sélectif et isolé d'aldostérone et qui sont aussi capables d'abaisser le pH de leur urine en présence d'une acidose métabolique systémique. La modalité d'acidification particulière du dernier malade qui était en même temps hyperkaliémique peut être expliquée par un mécanisme dépendant de la différence de potentiel. Cette situation peut être reconnue par la constatation d'un désordre portant à la fois sur la sécrétion de ions hydrogène et celle de potassium

Artificial intelligence for dementia drug discovery and trials optimization

Drug discovery and clinical trial design for dementia have historically been challenging. In part these challenges have arisen from patient heterogeneity, length of disease course, and the tractability of a target for the brain. Applying big data analytics and machine learning tools for drug discovery and utilizing them to inform successful clinical trial design has the potential to accelerate progress. Opportunities arise at multiple stages in the therapy pipeline and the growing availability of large medical data sets opens possibilities for big data analyses to answer key questions in clinical and therapeutic challenges. However, before this goal is reached, several challenges need to be overcome and only a multi‐disciplinary approach can promote data‐driven decision‐making to its full potential. Herein we review the current state of machine learning applications to clinical trial design and drug discovery, while presenting opportunities and recommendations that can break down the barriers to implementation

Associations of autozygosity with a broad range of human phenotypes

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F-ROH) for >1.4 million individuals, we show that F-ROH is significantly associated (p <0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F-ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F-ROH are confirmed within full-sibling pairs, where the variation in F-ROH is independent of all environmental confounding.Peer reviewe

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation

Erratum: "A Gravitational-wave Measurement of the Hubble Constant Following the Second Observing Run of Advanced LIGO and Virgo" (2021, ApJ, 909, 218)

[no abstract available

Search for Gravitational Waves Associated with Gamma-Ray Bursts Detected by Fermi and Swift during the LIGO-Virgo Run O3b

We search for gravitational-wave signals associated with gamma-ray bursts (GRBs) detected by the Fermi and Swift satellites during the second half of the third observing run of Advanced LIGO and Advanced Virgo (2019 November 1 15:00 UTC-2020 March 27 17:00 UTC). We conduct two independent searches: A generic gravitational-wave transients search to analyze 86 GRBs and an analysis to target binary mergers with at least one neutron star as short GRB progenitors for 17 events. We find no significant evidence for gravitational-wave signals associated with any of these GRBs. A weighted binomial test of the combined results finds no evidence for subthreshold gravitational-wave signals associated with this GRB ensemble either. We use several source types and signal morphologies during the searches, resulting in lower bounds on the estimated distance to each GRB. Finally, we constrain the population of low-luminosity short GRBs using results from the first to the third observing runs of Advanced LIGO and Advanced Virgo. The resulting population is in accordance with the local binary neutron star merger rate. © 2022. The Author(s). Published by the American Astronomical Society

Narrowband Searches for Continuous and Long-duration Transient Gravitational Waves from Known Pulsars in the LIGO-Virgo Third Observing Run

Isolated neutron stars that are asymmetric with respect to their spin axis are possible sources of detectable continuous gravitational waves. This paper presents a fully coherent search for such signals from eighteen pulsars in data from LIGO and Virgo's third observing run (O3). For known pulsars, efficient and sensitive matched-filter searches can be carried out if one assumes the gravitational radiation is phase-locked to the electromagnetic emission. In the search presented here, we relax this assumption and allow both the frequency and the time derivative of the frequency of the gravitational waves to vary in a small range around those inferred from electromagnetic observations. We find no evidence for continuous gravitational waves, and set upper limits on the strain amplitude for each target. These limits are more constraining for seven of the targets than the spin-down limit defined by ascribing all rotational energy loss to gravitational radiation. In an additional search, we look in O3 data for long-duration (hours-months) transient gravitational waves in the aftermath of pulsar glitches for six targets with a total of nine glitches. We report two marginal outliers from this search, but find no clear evidence for such emission either. The resulting duration-dependent strain upper limits do not surpass indirect energy constraints for any of these targets. © 2022. The Author(s). Published by the American Astronomical Society

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe