The International Classification of Diseases (ICD) has long been the main basis for comparability of statistics on causes of mortality and morbidity between places and over time. This paper provides ...an overview of the recently completed 11th revision of the ICD, focusing on the main innovations and their implications.
Changes in content reflect knowledge and perspectives on diseases and their causes that have emerged since ICD-10 was developed about 30 years ago. Changes in design and structure reflect the arrival of the networked digital era, for which ICD-11 has been prepared. ICD-11's information framework comprises a semantic knowledge base (the Foundation), a biomedical ontology linked to the Foundation and classifications derived from the Foundation. ICD-11 for Mortality and Morbidity Statistics (ICD-11-MMS) is the primary derived classification and the main successor to ICD-10. Innovations enabled by the new architecture include an online coding tool (replacing the index and providing additional functions), an application program interface to enable remote access to ICD-11 content and services, enhanced capability to capture and combine clinically relevant characteristics of cases and integrated support for multiple languages.
ICD-11 was adopted by the World Health Assembly in May 2019. Transition to implementation is in progress. ICD-11 can be accessed at icd.who.int.
Improved understanding of the quality of survival of patients is crucial in evaluating trauma care, understanding recovery patterns and timeframes, and informing healthcare, social, and disability ...service provision. We aimed to describe the longer-term health status of seriously injured patients, identify predictors of outcome, and establish recovery trajectories by population characteristics.
A population-based, prospective cohort study using the Victorian State Trauma Registry (VSTR) was undertaken. We followed up 2,757 adult patients, injured between July 2011 and June 2012, through deaths registry linkage and telephone interview at 6-, 12-, 24-, and 36-months postinjury. The 3-level EuroQol 5 dimensions questionnaire (EQ-5D-3L) was collected, and mixed-effects regression modelling was used to identify predictors of outcome, and recovery trajectories, for the EQ-5D-3L items and summary score. Mean (SD) age of participants was 50.8 (21.6) years, and 72% were male. Twelve percent (n = 333) died during their hospital stay, 8.1% (n = 222) of patients died postdischarge, and 155 (7.0%) were known to have survived to 36-months postinjury but were lost to follow-up at all time points. The prevalence of reporting problems at 36-months postinjury was 37% for mobility, 21% for self-care, 47% for usual activities, 50% for pain/discomfort, and 41% for anxiety/depression. Continued improvement to 36-months postinjury was only present for the usual activities item; the adjusted relative risk (ARR) of reporting problems decreased from 6 to 12 (ARR 0.87, 95% CI: 0.83-0.90), 12 to 24 (ARR 0.94, 95% CI: 0.90-0.98), and 24 to 36 months (ARR 0.95, 95% CI: 0.95-0.99). The risk of reporting problems with pain or discomfort increased from 24- to 36-months postinjury (ARR 1.06, 95% CI: 1.01, 1.12). While loss to follow-up was low, there was responder bias with patients injured in intentional events, younger, and less seriously injured patients less likely to participate; therefore, these patient subgroups were underrepresented in the study findings.
The prevalence of ongoing problems at 3-years postinjury is high, confirming that serious injury is frequently a chronic disorder. These findings have implications for trauma system design. Investment in interventions to reduce the longer-term impact of injuries is needed, and greater investment in primary prevention is needed.
Recurrent Glioblastoma Treated with Recombinant Poliovirus Desjardins, Annick; Gromeier, Matthias; Herndon, 2nd, James E ...
New England journal of medicine/The New England journal of medicine,
07/2018, Volume:
379, Issue:
2
Journal Article
Peer reviewed
Open access
The prognosis of patients with recurrent World Health Organization (WHO) grade IV malignant glioma is dismal, and there is currently no effective therapy. We conducted a dose-finding and toxicity ...study in this population of patients, evaluating convection-enhanced, intratumoral delivery of the recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO). PVSRIPO recognizes the poliovirus receptor CD155, which is widely expressed in neoplastic cells of solid tumors and in major components of the tumor microenvironment.
We enrolled consecutive adult patients who had recurrent supratentorial WHO grade IV malignant glioma, confirmed on histopathological testing, with measurable disease (contrast-enhancing tumor of ≥1 cm and ≤5.5 cm in the greatest dimension). The study evaluated seven doses, ranging between 10
and 10
50% tissue-culture infectious doses (TCID
), first in a dose-escalation phase and then in a dose-expansion phase.
From May 2012 through May 2017, a total of 61 patients were enrolled and received a dose of PVSRIPO. Dose level -1 (5.0×10
TCID
) was identified as the phase 2 dose. One dose-limiting toxic effect was observed; a patient in whom dose level 5 (10
TCID
) was administered had a grade 4 intracranial hemorrhage immediately after the catheter was removed. To mitigate locoregional inflammation of the infused tumor with prolonged glucocorticoid use, dose level 5 was deescalated to reach the phase 2 dose. In the dose-expansion phase, 19% of the patients had a PVSRIPO-related adverse event of grade 3 or higher. Overall survival among the patients who received PVSRIPO reached a plateau of 21% (95% confidence interval, 11 to 33) at 24 months that was sustained at 36 months.
Intratumoral infusion of PVSRIPO in patients with recurrent WHO grade IV malignant glioma confirmed the absence of neurovirulent potential. The survival rate among patients who received PVSRIPO immunotherapy was higher at 24 and 36 months than the rate among historical controls. (Funded by the Brain Tumor Research Charity and others; ClinicalTrials.gov number, NCT01491893 .).
The premise of research in human physiology is to explore a multifaceted system whilst identifying one or a few outcomes of interest. Therefore, the control of potentially confounding variables ...requires careful thought regarding the extent of control and complexity of standardisation. One common factor to control prior to testing is diet, as food and fluid provision may deviate from participants’ habitual diets, yet a self‐report and replication method can be flawed by under‐reporting. Researchers may also need to consider standardisation of physical activity, whether it be through familiarisation trials, wash‐out periods, or guidance on levels of physical activity to be achieved before trials. In terms of pharmacological agents, the ethical implications of standardisation require researchers to carefully consider how medications, caffeine consumption and oral contraceptive prescriptions may affect the study. For research in females, it should be considered whether standardisation between‐ or within‐participants in regards to menstrual cycle phase is most relevant. The timing of measurements relative to various other daily events is relevant to all physiological research and so it can be important to standardise when measurements are made. This review summarises the areas of standardisation which we hope will be considered useful to anyone involved in human physiology research, including when and how one can apply standardisation to various contexts.
T cell dysfunction contributes to tumor immune escape in patients with cancer and is particularly severe amidst glioblastoma (GBM). Among other defects, T cell lymphopenia is characteristic, yet ...often attributed to treatment. We reveal that even treatment-naïve subjects and mice with GBM can harbor AIDS-level CD4 counts, as well as contracted, T cell-deficient lymphoid organs. Missing naïve T cells are instead found sequestered in large numbers in the bone marrow. This phenomenon characterizes not only GBM but a variety of other cancers, although only when tumors are introduced into the intracranial compartment. T cell sequestration is accompanied by tumor-imposed loss of S1P1 from the T cell surface and is reversible upon precluding S1P1 internalization. In murine models of GBM, hindering S1P1 internalization and reversing sequestration licenses T cell-activating therapies that were previously ineffective. Sequestration of T cells in bone marrow is therefore a tumor-adaptive mode of T cell dysfunction, whose reversal may constitute a promising immunotherapeutic adjunct.
Venetoclax is a highly selective, potent, oral BCL-2 inhibitor, which induces apoptosis in multiple myeloma cells. Venetoclax plus bortezomib and dexamethasone has shown encouraging clinical efficacy ...with acceptable safety and tolerability in a phase 1 trial. The aim of this study was to evaluate venetoclax plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma.
In this randomised, double-blind, multicentre, phase 3 trial, patients aged 18 years or older with relapsed or refractory multiple myeloma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received one to three previous therapies were enrolled from 90 hospitals in 16 countries. Eligible patients were randomly assigned (2:1) centrally using an interactive response technology system and a block size of three to receive venetoclax (800 mg per day orally) or placebo with bortezomib (1·3 mg/m2 subcutaneously or intravenously and dexamethasone (20 mg orally). Treatment was given in 21-day cycles for the first eight cycles and 35-day cycles from the ninth cycle until disease progression, unacceptable toxicity, or patient withdrawal. Randomisation was stratified by previous exposure to a proteasome inhibitor and the number of previous therapies. Sponsors, investigators, study site personnel, and patients were masked to the treatment allocation throughout the study. The primary endpoint was independent review committee-assessed progression-free survival in the intention-to-treat population. Safety analyses were done in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02755597.
Between July 19, 2016, and Oct 31, 2017, 291 patients were randomly assigned to receive venetoclax (n=194) or placebo (n=97). With a median follow-up of 18·7 months (IQR 16·6–21·0), median progression-free survival according to independent review committee was 22·4 months (95% CI 15·3–not estimable) with venetoclax versus 11·5 months (9·6–15·0) with placebo (hazard ratio HR 0·63 95% CI 0·44–0·90; p=0·010). The most common grade 3 or worse treatment-emergent adverse events were neutropenia (35 18% of 193 patients in the venetoclax group vs seven 7% of 96 patients in the placebo group), pneumonia (30 16% vs nine 9%), thrombocytopenia (28 15% vs 29 30%), anaemia (28 15% vs 14 15%), and diarrhoea (28 15% vs 11 11%). Serious treatment-emergent adverse events occurred in 93 (48%) patients in the venetoclax group and 48 (50%) patients in the placebo group, with eight (4%) treatment-emergent fatal infections reported in the venetoclax group and none reported in the placebo group. Three deaths in the venetoclax group (two from pneumonia and one from septic shock) were considered treatment-related; no deaths in the placebo group were treatment-related.
The primary endpoint was met with a significant improvement in independent review committee-assessed progression-free survival with venetoclax versus placebo plus bortezomib and dexamethasone. However, increased mortality was seen in the venetoclax group, mostly because of an increased rate of infections, highlighting the importance of appropriate selection of patients for this treatment option.
AbbVie and Genentech.
In response to even a single chromosomal double-strand DNA break, cells enact the DNA damage checkpoint. This checkpoint triggers cell cycle arrest, providing time for the cell to repair damaged ...chromosomes before entering mitosis. This mechanism helps prevent the segregation of damaged or mutated chromosomes and thus promotes genomic stability. Recent work has elucidated the molecular mechanisms underlying several critical steps in checkpoint activation, notably the recruitment of the upstream checkpoint kinases of the ATM and ATR families to different damaged DNA structures and the molecular events through which these kinases activate their effectors. Chromatin modification has emerged as one important component of checkpoint activation and maintenance. Following DNA repair, the checkpoint pathway is inactivated in a process termed recovery. A related but genetically distinct process, adaptation, controls cell cycle re-entry in the face of unrepairable damage.
We describe a quantitative magnetic unmixing method based on principal component analysis (PCA) of first‐order reversal curve (FORC) diagrams. For PCA, we resample FORC distributions on grids that ...capture diagnostic signatures of single‐domain (SD), pseudosingle‐domain (PSD), and multidomain (MD) magnetite, as well as of minerals such as hematite. Individual FORC diagrams are recast as linear combinations of end‐member (EM) FORC diagrams, located at user‐defined positions in PCA space. The EM selection is guided by constraints derived from physical modeling and imposed by data scatter. We investigate temporal variations of two EMs in bulk North Atlantic sediment cores collected from the Rockall Trough and the Iberian Continental Margin. Sediments from each site contain a mixture of magnetosomes and granulometrically distinct detrital magnetite. We also quantify the spatial variation of three EM components (a coarse silt‐sized MD component, a fine silt‐sized PSD component, and a mixed clay‐sized component containing both SD magnetite and hematite) in surficial sediments along the flow path of the North Atlantic Deep Water (NADW). These samples were separated into granulometric fractions, which helped constrain EM definition. PCA‐based unmixing reveals systematic variations in EM relative abundance as a function of distance along NADW flow. Finally, we apply PCA to the combined data set of Rockall Trough and NADW sediments, which can be recast as a four‐EM mixture, providing enhanced discrimination between components. Our method forms the foundation of a general solution to the problem of unmixing multicomponent magnetic mixtures, a fundamental task of rock magnetic studies.
Key Points:
FORC diagrams are powerful for unmixing magnetic domain states
PCA represents FORC data according to natural variability in data sets
Samples are recast as linear combinations of end‐member FORCs in PCA space
We assessed the quality of Global Burden of Disease-2010 (GBD-2010) estimates of road injury deaths by comparing with government statistics for Organisation for Economic Co-operation and Development ...(OECD) countries that report to the International Road Traffic Accident Database (IRTAD).
We obtained tabulated data for 25 OECD countries that report to IRTAD and also report vital registration (VR) data to WHO. We collated VR deaths corresponding to the GBD-2010 road injury definition and estimated 'traffic', 'non-traffic' and 'unspecified whether traffic or non-traffic' components. We estimated national road injury deaths by redistributing partially specified causes of death, as was done by GBD until this was replaced by more complex methods in GBD-2010.
GBD-2010 estimates of road injury deaths exceeded IRTAD by 45% overall. IRTAD values fell below the GBD-2010 95% uncertainty interval in all but three countries. Mismatch of conceptual scope accounted for about 8% of this discrepancy, 5% was because GBD-2010 included cases other than road traffic and 3% because GBD-2010 (unlike IRTAD) includes deaths >30 days after injury. Pro rata distribution of partially specified causes in VR data gave estimates that were 18% higher than IRTAD but closer than GBD-2010 estimates for all but two countries. Cases in VR data specified as road injury gave estimates closer to IRTAD.
GBD-2010 road injury mortality estimates are substantially higher than the road death toll in OECD countries. The discrepancy is not explained by wider scope of the GBD road injury construct nor by undercounting by IRTAD. GBD-2010 likely attributed substantially more deaths with partially specified causes to road injuries than is appropriate.
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