Validation of a deep neural network-based algorithm supporting clinical management of adnexal mass

BackgroundConservative management of adnexal mass is warranted when there is imaging-based and clinical evidence of benign characteristics. Malignancy risk is, however, a concern due to the mortality rate of ovarian cancer. Malignancy occurs in 10–15% of adnexal masses that go to surgery, whereas the rate of malignancy is much lower in masses clinically characterized as benign or indeterminate. Additional diagnostic tests could assist conservative management of these patients. Here we report the clinical validation of OvaWatch, a multivariate index assay, with real-world evidence of performance that supports conservative management of adnexal masses.MethodsOvaWatch utilizes a previously characterized neural network-based algorithm combining serum biomarkers and clinical covariates and was used to examine malignancy risk in prospective and retrospective samples of patients with an adnexal mass. Retrospective data sets were assembled from previous studies using patients who had adnexal mass and were scheduled for surgery. The prospective study was a multi-center trial of women with adnexal mass as identified on clinical examination and indeterminate or asymptomatic by imaging. The performance to detect ovarian malignancy was evaluated at a previously validated score threshold.ResultsIn retrospective, low prevalence (N = 1,453, 1.5% malignancy rate) data from patients that received an independent physician assessment of benign, OvaWatch has a sensitivity of 81.8% [95% confidence interval (CI) 65.1–92.7] for identifying a histologically confirmed malignancy, and a negative predictive value (NPV) of 99.7%. OvaWatch identified 18/22 malignancies missed by physician assessment. A prospective data set had 501 patients where 106 patients with adnexal mass went for surgery. The prevalence was 2% (10 malignancies). The sensitivity of OvaWatch for malignancy was 40% (95% CI: 16.8–68.7%), and the specificity was 87% (95% CI: 83.7–89.7) when patients were included in the analysis who did not go to surgery and were evaluated as benign. The NPV remained 98.6% (95% CI: 97.0–99.4%). An independent analysis set with a high prevalence (45.8%) the NPV value was 87.8% (95% CI: 95% CI: 75.8–94.3%).ConclusionOvaWatch demonstrated high NPV across diverse data sets and promises utility as an effective diagnostic test supporting management of suspected benign or indeterminate mass to safely decrease or delay unnecessary surgeries

Alzheimer's disease: Clinical practice guideline

El Grupo de Trabajo de Neurología de la Conducta y Neurociencias Cognitivas de la Sociedad Neurológica Argentina publicó en 2006 la primera Guía de práctica clínica sobre la enfermedad de Alzheimer para su aplicación en nuestro medio y, eventualmente, en el resto de los países hispanoparlantes del Cono Sur. La Guía que hoy publicamos, mediante la revisión y actualización del estado actual del conocimiento sobre la enfermedad de Alzheimer y su manejo clínico y neurológico, provee a los profesionales los estándares surgidos de la medicina basada en la evidencia para una adecuada implementación de las conductas diagnósticas y terapéuticas a su alcance en nuestro medio.In 2006, the Argentine Neurological Society Research Group on Behavioral Neurology and Cognitive Neurosciences published the first Clinical Practice Guideline on Alzheimer's Disease to be consulted in Argentina and eventually in other countries in Latin America. The present Guideline is a review of the state of the art concerning the 2010 knowledge on the management of this disease. It provides physicians with the usual standards provided by evidence based medicine in order to reach the most adequate diagnostic and therapeutic measures at hand in our countries.Fil: Allegri, Ricardo Francisco. Sociedad Neurológica Argentina; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Instituto de Neurociencias - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Neurociencias; ArgentinaFil: Arizaga, Raúl Luciano. Sociedad Neurológica Argentina; ArgentinaFil: Bavec, Claudia V.. Sociedad Neurológica Argentina; ArgentinaFil: Colli, Liliana P.. Sociedad Neurológica Argentina; ArgentinaFil: Demey, Ignacio. Sociedad Neurológica Argentina; ArgentinaFil: Fernández, María C.. Sociedad Neurológica Argentina; ArgentinaFil: Frontera, Silvina A.. Sociedad Neurológica Argentina; ArgentinaFil: Garau, María L.. Sociedad Neurológica Argentina; ArgentinaFil: Jiménez, Julio J.. Sociedad Neurológica Argentina; ArgentinaFil: Golimstok, Angel. Sociedad Neurológica Argentina; ArgentinaFil: Kremer, Janus. Sociedad Neurológica Argentina; ArgentinaFil: Labos, Edith. Sociedad Neurológica Argentina; ArgentinaFil: Mangone, Carlos Antonio. Sociedad Neurológica Argentina; ArgentinaFil: Ollari, Juan A.. Sociedad Neurológica Argentina; ArgentinaFil: Rojas, Zenón Galeno. Centro de Educación Médica e Investigaciones Clínicas "Norberto Quirno"; Argentina. Sociedad Neurológica Argentina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Salmini, Omar. Sociedad Neurológica Argentina; ArgentinaFil: Ure, Jorge A.. Sociedad Neurológica Argentina; ArgentinaFil: Zuin, Daniel R.. Sociedad Neurológica Argentina; Argentin

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

In Vitro Phase I Metabolism of CRV431, a Novel Oral Drug Candidate for Chronic Hepatitis B

The cytochrome P450-mediated Phase I in vitro metabolism of CRV431 was studied using selective chemical inhibition and recombinant human enzymes. Additionally, the metabolic profile of CRV431 in human, rat, and monkey liver microsomes was investigated. Liver microsomes were incubated for 0–80 min with CRV431, and the metabolite profile was assessed by electrospray ionization liquid chromatography mass spectrometry (ESI-LCMS). CRV431 was extensively metabolized through oxidation to produce various hydroxylated and demethylated species. Species identified included monohydroxylated CRV431 (two distinct products), dihydroxylated CRV431, demethylated CRV431 (two distinct products), demethylated and hydroxylated CRV431 (two distinct products), didemethylated and hydroxylated CRV431, and didemethylated and dihydroxylated CRV431. The magnitude of metabolism was greatest in monkey, followed by human, followed by rat. Importantly, all of the species identified in human microsomes were correspondingly identified in monkey and/or rat microsomes. Human liver microsome studies using selective chemical inhibition, as well as studies using recombinant human cytochrome P450 enzymes, revealed that the major enzymes involved are cytochromes P450 3A4 and 3A5. Enzymes 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6 are not involved in the in vitro metabolism of CRV431. This information will be useful for the further development of CRV431 both preclinically and clinically