Autopsy as an outcome and performance measure: three years of hospital autopsy as an instrument of clinical audit

An extensive literature documents a high prevalence of errors in clinical diagnosis discovered at autopsy. Multiple studies have suggested no significant decrease in these errors over time. Despite these findings, autopsies have dramatically decreased in frequency in the United States and many other countries. In 1994, the last year for which national U.S. data exist, the autopsy rate for all non-forensic deaths fell below 6%. The marked decline in autopsy rates from previous rates of 40\u201350% undoubtedly reflects various factors, including reimbursement issues, the attitudes of clinicians regarding the utility of autopsies in the setting of other diagnostic advances, and general unfamiliarity with the autopsy and techniques for requesting it, especially among physicians-in-training. The autopsy is valuable for its role in undergraduate and graduate medical education, the identification and characterization of new diseases, and contributions to the understanding of disease pathogenesis. Although extensive, these benefits are difficult to quantify. This review of the last three years of hospital autopsy in Lucca studied the more easily quantifiable benefits of the autopsy as a tool in performance measurement and improvement. Such benefits largely relate to the role of the autopsy in detecting errors in clinical diagnosis and unsuspected complications of treatment. It is hoped that characterizing the extent to which the autopsy provides data relevant to clinical performance measurement and improvement will help inform strategies for preserving the benefits of routinely obtained autopsies and for considering its wider use as an instrument for quality improvement

Examen médical des personnes victimes de violence : fréquence des facteurs aggravants au sens du Code pénal, hétérogénéité des pratiques

Objectifs En cas de violences volontaires, le Code pénal reconnaît l’existence de facteurs aggravants. Aucune donnée n’est disponible sur la fréquence des facteurs aggravants lors des situations de violence. L’objectif principal était de déterminer cette fréquence. L’objectif secondaire était de préciser les résultats de la détermination d’incapacité totale de travail (ITT) dans plusieurs consultations médico-judiciaires en France. Méthodes Le recueil de données prospectif porte sur six centres et 300 situations de violence. Les éléments recueillis concernaient l’existence de facteurs aggravants, les caractéristiques de la victime et des violences, les résultats de l’examen médical et les facteurs intervenus dans la détermination de l’ITT. Résultats Il existait un facteur aggravant dans 232 cas sur 300, 77 %. La durée médiane d’ITT était de deux jours (extrêmes : 0–60). La fréquence des cas sans ITT était comprise entre 0 et 56 % selon les centres (Chi2, p < 0,0001). Les médecins examinateurs considéraient ne pas avoir évalué l’état psychique dans 63 cas (21 %), d’importantes différences étant observées selon les centres (p < 0,0001). L’ITT était surtout fondée sur des éléments lésionnels dans 45 % des cas et sur des éléments fonctionnels dans 55 % des cas, cette répartition variant selon les centres (p = 0,01). L’état psychique était prépondérant dans la détermination de l’ITT dans 0 à 23 % des cas selon les centres (p = 0,009)

NF-κB, stem cells and breast cancer: the links get stronger

Self-renewing breast cancer stem cells are key actors in perpetuating tumour existence and in treatment resistance and relapse. The molecular pathways required for their maintenance are starting to be elucidated. Among them is the transcription factor NF-κB, which is known to play critical roles in cell survival, inflammation and immunity. Recent studies indicate that mammary epithelial NF-κB regulates the self-renewal of breast cancer stem cells in a model of Her2-dependent tumourigenesis. We will describe here the NF-κB-activating pathways that are involved in this process and in which progenitor cells this transcription factor is actually activated

A pilot feasibility trial of alcohol screening and brief intervention in the police custody setting (ACCEPT): study protocol for a cluster randomised controlled trial

BACKGROUND: There is evidence of an association between alcohol use and offending behaviour and around a quarter of police time is spent on alcohol-related incidents. Police custody, therefore, provides an important opportunity to intervene. This pilot trial aims to investigate whether a definitive evaluation of screening and brief interventions aimed at reducing risky drinking in arrestees is acceptable and feasible in the custody suite setting. METHODS: Screening will be carried out by trained detention officers or drug and alcohol workers in four police forces across two geographical areas (North East and South West England). Detention officers (or drug and alcohol workers) will be cluster randomised to one of three conditions: screening only (control group), screening followed immediately by 10 min of manualised brief structured advice delivered by the individual responsible for screening (intervention 1) or screening followed by 10 min of manualised brief structured advice delivered by the individual responsible for screening plus the offer of a subsequent 20-min session of behaviour change counselling delivered by a trained alcohol health worker (intervention 2). Participants will be arrestees aged 18+ who screen positive on the Alcohol Use Disorders Identification Test. Participants will be followed up at 6 and 12 months post-intervention. An embedded qualitative process evaluation will explore acceptability of alcohol screening and brief intervention to staff and arrestees as well as facilitators and barriers to the delivery of such approaches in this setting. RESULTS: Recruitment is currently underway and due to end May 2015. CONCLUSION: Results from this pilot trial will determine if a definitive evaluation is possible in the future and will provide stakeholder input to its design. TRIAL REGISTRATION: Reference number: ISRCTN89291046

The MACHO Project 2nd Year LMC Microlensing Results and Dark Matter Implications

The MACHO Project is searching for galactic dark matter in the form of massive compact halo objects (Machos). Millions of stars in the Large Magellanic Cloud (LMC), Small Magellanic Cloud (SMC), and Galactic bulge are photometrically monitored in an attempt to detect rare gravitational microlensing events caused by otherwise invisible Machos. Analysis of two years of photometry on 8.5 million stars in the LMC reveals 8 candidate microlensing events, far more than the $\sim1$ event expected from lensing by low-mass stars in known galactic populations. From these eight events we estimate the optical depth towards the LMC from events with 2 < \that < 200 days to be \tau_2^{200} \approx 2.9 ^{+1.4}_{-0.9} \ten{-7}. This exceeds the optical depth of 0.5\ten{-7} expected from known stars and is to be compared with an optical depth of 4.7\ten{-7} predicted for a ``standard'' halo composed entirely of Machos. The total mass in this lensing population is \approx 2^{+1.2}_{-0.7} \ten{11} \msun (within 50 kpc from the Galactic center). Event timescales yield a most probable Macho mass of 0.5^{+0.3}_{-0.2}\msun, although this value is quite model dependent.Comment: 10 pages, 6 epsf figures and style file included, 451k, also at http://wwwmacho.mcmaster.ca/Pubs/Pubs.html; To appear in the Proceedings of "Sources and Detection of Dark Matter in the Universe", Santa Monica, CA, Feb., 199

IKKβ Regulates the Repair of DNA Double-Strand Breaks Induced by Ionizing Radiation in MCF-7 Breast Cancer Cells

Activation of the IKK-NFκB pathway increases the resistance of cancer cells to ionizing radiation (IR). This effect has been largely attributed to the induction of anti-apoptotic proteins by NFκB. Since efficient repair of DNA double strand breaks (DSBs) is required for the clonogenic survival of irradiated cells, we investigated if activation of the IKK-NFκB pathway also regulates DSB repair to promote cell survival after IR. We found that inhibition of the IKK-NFκB pathway with a specific IKKβ inhibitor significantly reduced the repair of IR-induced DSBs in MCF-7 cells. The repair of DSBs was also significantly inhibited by silencing IKKβ expression with IKKβ shRNA. However, down-regulation of IKKα expression with IKKα shRNA had no significant effect on the repair of IR-induced DSBs. Similar findings were also observed in IKKα and/or IKKβ knockout mouse embryonic fibroblasts (MEFs). More importantly, inhibition of IKKβ with an inhibitor or down-regulation of IKKβ with IKKβ shRNA sensitized MCF-7 cells to IR-induced clonogenic cell death. DSB repair function and resistance to IR were completely restored by IKKβ reconstitution in IKKβ-knockdown MCF-7 cells. These findings demonstrate that IKKβ can regulate the repair of DSBs, a previously undescribed and important IKKβ kinase function; and inhibition of DSB repair may contribute to cance cell radiosensitization induced by IKKβ inhibition. As such, specific inhibition of IKKβ may represents a more effective approach to sensitize cancer cells to radiotherapy

Understanding the importance of selenium and selenoproteins in muscle function

Selenium is an essential trace element. In cattle, selenium deficiency causes dysfunction of various organs, including skeletal and cardiac muscles. In humans as well, lack of selenium is associated with many disorders, but despite accumulation of clinical reports, muscle diseases are not generally considered on the list. The goal of this review is to establish the connection between clinical observations and the most recent advances obtained in selenium biology. Recent results about a possible role of selenium-containing proteins in muscle formation and repair have been collected. Selenoprotein N is the first selenoprotein linked to genetic disorders consisting of different forms of congenital muscular dystrophies. Understanding the muscle disorders associated with selenium deficiency or selenoprotein N dysfunction is an essential step in defining the causes of the disease and obtaining a better comprehension of the mechanisms involved in muscle formation and maintenance

Polymorphisms in the Mitochondrial Ribosome Recycling Factor EF-G2mt/MEF2 Compromise Cell Respiratory Function and Increase Atorvastatin Toxicity

Mitochondrial translation, essential for synthesis of the electron transport chain complexes in the mitochondria, is governed by nuclear encoded genes. Polymorphisms within these genes are increasingly being implicated in disease and may also trigger adverse drug reactions. Statins, a class of HMG-CoA reductase inhibitors used to treat hypercholesterolemia, are among the most widely prescribed drugs in the world. However, a significant proportion of users suffer side effects of varying severity that commonly affect skeletal muscle. The mitochondria are one of the molecular targets of statins, and these drugs have been known to uncover otherwise silent mitochondrial mutations. Based on yeast genetic studies, we identify the mitochondrial translation factor MEF2 as a mediator of atorvastatin toxicity. The human ortholog of MEF2 is the Elongation Factor Gene (EF-G) 2, which has previously been shown to play a specific role in mitochondrial ribosome recycling. Using small interfering RNA (siRNA) silencing of expression in human cell lines, we demonstrate that the EF-G2mt gene is required for cell growth on galactose medium, signifying an essential role for this gene in aerobic respiration. Furthermore, EF-G2mt silenced cell lines have increased susceptibility to cell death in the presence of atorvastatin. Using yeast as a model, conserved amino acid variants, which arise from non-synonymous single nucleotide polymorphisms (SNPs) in the EF-G2mt gene, were generated in the yeast MEF2 gene. Although these mutations do not produce an obvious growth phenotype, three mutations reveal an atorvastatin-sensitive phenotype and further analysis uncovers a decreased respiratory capacity. These findings constitute the first reported phenotype associated with SNPs in the EF-G2mt gene and implicate the human EF-G2mt gene as a pharmacogenetic candidate gene for statin toxicity in humans

Can we use atmospheric CO₂ measurements to verify emission trends reported by cities? Lessons from a 6-year atmospheric inversion over Paris

Existing CO2 emissions reported by city inventories usually lag in real-time by a year or more and are prone to large uncertainties. This study responds to the growing need for timely and precise estimation of urban CO2 emissions to support present and future mitigation measures and policies. We focus on the Paris metropolitan area, the largest urban region in the European Union and the city with the densest atmospheric CO2 observation network in Europe. We performed long-term atmospheric inversions to quantify the citywide CO2 emissions, i.e., fossil fuel as well as biogenic sources and sinks, over 6 years (2016–2021) using a Bayesian inverse modeling system. Our inversion framework benefits from a novel near-real-time hourly fossil fuel CO2 emission inventory (Origins.earth) at 1 km spatial resolution. In addition to the mid-afternoon observations, we attempt to assimilate morning CO2 concentrations based on the ability of the Weather Research and Forecasting model with Chemistry (WRF-Chem) transport model to simulate atmospheric boundary layer dynamics constrained by observed layer heights. Our results show a long-term decreasing trend of around 2 % ± 0.6 % per year in annual CO2 emissions over the Paris region. The impact of the COVID-19 pandemic led to a 13 % ± 1 % reduction in annual fossil fuel CO2 emissions in 2020 with respect to 2019. Subsequently, annual emissions increased by 5.2 % ± 14.2 % from 32.6 ± 2.2 Mt CO2 in 2020 to 34.3 ± 2.3 Mt CO2 in 2021. Based on a combination of up-to-date inventories, high-resolution atmospheric modeling and high-precision observations, our current capacity can deliver near-real-time CO2 emission estimates at the city scale in less than a month, and the results agree within 10 % with independent estimates from multiple city-scale inventories.</p