Global, regional, and national under-5 mortality, adult mortality, age-specific mortality, and life expectancy, 1970–2016: a systematic analysis for the Global Burden of Disease Study 2016

BACKGROUND: Detailed assessments of mortality patterns, particularly age-specific mortality, represent a crucial input that enables health systems to target interventions to specific populations. Understanding how all-cause mortality has changed with respect to development status can identify exemplars for best practice. To accomplish this, the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) estimated age-specific and sex-specific all-cause mortality between 1970 and 2016 for 195 countries and territories and at the subnational level for the five countries with a population greater than 200 million in 2016. METHODS: We have evaluated how well civil registration systems captured deaths using a set of demographic methods called death distribution methods for adults and from consideration of survey and census data for children younger than 5 years. We generated an overall assessment of completeness of registration of deaths by dividing registered deaths in each location-year by our estimate of all-age deaths generated from our overall estimation process. For 163 locations, including subnational units in countries with a population greater than 200 million with complete vital registration (VR) systems, our estimates were largely driven by the observed data, with corrections for small fluctuations in numbers and estimation for recent years where there were lags in data reporting (lags were variable by location, generally between 1 year and 6 years). For other locations, we took advantage of different data sources available to measure under-5 mortality rates (U5MR) using complete birth histories, summary birth histories, and incomplete VR with adjustments; we measured adult mortality rate (the probability of death in individuals aged 15-60 years) using adjusted incomplete VR, sibling histories, and household death recall. We used the U5MR and adult mortality rate, together with crude death rate due to HIV in the GBD model life table system, to estimate age-specific and sex-specific death rates for each location-year. Using various international databases, we identified fatal discontinuities, which we defined as increases in the death rate of more than one death per million, resulting from conflict and terrorism, natural disasters, major transport or technological accidents, and a subset of epidemic infectious diseases; these were added to estimates in the relevant years. In 47 countries with an identified peak adult prevalence for HIV/AIDS of more than 0·5% and where VR systems were less than 65% complete, we informed our estimates of age-sex-specific mortality using the Estimation and Projection Package (EPP)-Spectrum model fitted to national HIV/AIDS prevalence surveys and antenatal clinic serosurveillance systems. We estimated stillbirths, early neonatal, late neonatal, and childhood mortality using both survey and VR data in spatiotemporal Gaussian process regression models. We estimated abridged life tables for all location-years using age-specific death rates. We grouped locations into development quintiles based on the Socio-demographic Index (SDI) and analysed mortality trends by quintile. Using spline regression, we estimated the expected mortality rate for each age-sex group as a function of SDI. We identified countries with higher life expectancy than expected by comparing observed life expectancy to anticipated life expectancy on the basis of development status alone. FINDINGS: Completeness in the registration of deaths increased from 28% in 1970 to a peak of 45% in 2013; completeness was lower after 2013 because of lags in reporting. Total deaths in children younger than 5 years decreased from 1970 to 2016, and slower decreases occurred at ages 5-24 years. By contrast, numbers of adult deaths increased in each 5-year age bracket above the age of 25 years. The distribution of annualised rates of change in age-specific mortality rate differed over the period 2000 to 2016 compared with earlier decades: increasing annualised rates of change were less frequent, although rising annualised rates of change still occurred in some locations, particularly for adolescent and younger adult age groups. Rates of stillbirths and under-5 mortality both decreased globally from 1970. Evidence for global convergence of death rates was mixed; although the absolute difference between age-standardised death rates narrowed between countries at the lowest and highest levels of SDI, the ratio of these death rates-a measure of relative inequality-increased slightly. There was a strong shift between 1970 and 2016 toward higher life expectancy, most noticeably at higher levels of SDI. Among countries with populations greater than 1 million in 2016, life expectancy at birth was highest for women in Japan, at 86·9 years (95% UI 86·7-87·2), and for men in Singapore, at 81·3 years (78·8-83·7) in 2016. Male life expectancy was generally lower than female life expectancy between 1970 and 2016, an

SARS-CoV-2 infection of human pluripotent stem cell-derived liver organoids reveals potential mechanisms of liver pathology

Although respiratory symptoms are the most prevalent disease manifestation of infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), infection can also damage other organs, including the brain, gut, and liver. Symptoms of liver damage are observed in nearly half of patients that succumb to severe SARS-CoV-2 infection. Here we use human-induced pluripotent stem cell-derived liver organoids (HLOs) to recapitulate and characterize liver pathology following virus exposure. Utilizing single-cell sequencing technology, we identified robust transcriptomic changes that occur in SARS-CoV-2 infected liver cells as well as uninfected bystander cells. Our results show a significant induction of many inflammatory pathways, including IFN-α, INF-γ, and IL-6 signaling. Our results further identify IL-6 signaling as a potential mechanism for liver-mediated activation of circulating macrophages

Use of a Negative-Pressure Wound Dressing to Prevent Surgical Site Complications after Revision Knee Arthroplasty—A Randomized Controlled Trial

The aim of this study was to determine if a negative pressure wound therapy (NPWT) system can facilitate wound healing and withstand mechanical stress owing to the high range of motion of the knee joint in total knee arthroplasty. The benefits of NPWT include aiding wound granulation and a reduction in wound edema and secretion; our goal is to investigate its benefits in primary wound closure. Within an eight-day duration of treatment, we compared standard wound dressing (gauze and compression) with the disposable NPWT system (PICO)TM. A total of 79 patients were recruited in a controlled, randomized, prospective, single-institution clinical trial. A total of 40 patients were allocated to the study group and 39 to the control group. In terms of blood loss and infection parameters, there was no significant difference between both groups. In the NPWT group, we determined a significant reduction in wound edema but none in wound secretion. While the NPWT dressings survived the mechanical effects of movement during postoperative physiotherapy, conventional compressive dressings were often renewed. Even though the risk factors that could lead to delayed wound healing were reduced in the test group, we could not identify any significant difference pertaining to delayed wound healing that required surgical treatment

APP-guided assessment of acetabular defects in hip revision arthroplasty: a structured approach to a complex situation

Introduction!#!Acetabular defect recognition and classification remains a challenging field of practice for orthopedic surgeons. Recently, the Acetabular Defect Classification (ADC) has been introduced to provide a reliable, reproducible and intuitive classification system. In order to improve ease of use and efficiency of the ADC, a browser-based application has been created. We hypothesized that the ADC application can improve rating performance of non-specialists (medical students) to achieve good inter- and intra-rater agreement and will compare favorable to the results of specialists (experienced surgeons) without the help of the application.!##!Materials and methods!#!The ADC is based on the integrity of the acetabular rim and the supporting structures. It consists of four main types of defects ascending in severity. These defects are further subdivided in A-C, narrowing down defect location. 80 randomized radiographs were graded according to ADC by three non-specialists (medical students) with help of the ADC application and by three specialists (orthopedic surgeons) without help of the application to evaluate the difference in inter-rater agreement between groups. To account for intra-rater agreement, the rating process was repeated after a reasonable wash-out period.!##!Results!#!Inter-rater and intra-rater agreement within the non-specialist group rated lower when compared to the specialist group while still falling into the good agreement range. The student group presented with k values of 0.61 for inter-rater agreement and 0.68 for intra-rater agreement, while the surgeon group displayed k values of 0.72 for inter-rater agreement and 0.83 for intra-rater agreement.!##!Conclusion!#!The app-guided assessment of acetabular defects offers a promising innovative approach to simplify complex situations. It makes the challenging field of acetabular revision arthroplasty more approachable especially for less experienced surgeons and offers insight and guidance in the planning stage as well as intra-operative setting

Development of a physiological insulin resistance model in human stem cell–derived adipocytes

Adipocytes are key regulators of human metabolism, and their dysfunction in insulin signaling is central to metabolic diseases including type II diabetes mellitus (T2D). However, the progression of insulin resistance into T2D is still poorly understood. This limited understanding is due, in part, to the dearth of suitable models of insulin signaling in human adipocytes. Traditionally, adipocyte models fail to recapitulate in vivo insulin signaling, possibly due to exposure to supraphysiological nutrient and hormone conditions. We developed a protocol for human pluripotent stem cell–derived adipocytes that uses physiological nutrient conditions to produce a potent insulin response comparable to in vivo adipocytes. After systematic optimization, this protocol allows robust insulin-stimulated glucose uptake and transcriptional insulin response. Furthermore, exposure of sensitized adipocytes to physiological hyperinsulinemia dampens insulin-stimulated glucose uptake and dysregulates insulin-responsive transcription. Overall, our methodology provides a novel platform for the mechanistic study of insulin signaling and resistance using human pluripotent stem cell–derived adipocytes.</jats:p

LINE1-Mediated Reverse Transcription and Genomic Integration of SARS-CoV-2 mRNA Detected in Virus-Infected but Not in Viral mRNA-Transfected Cells

SARS-CoV-2 sequences can be reverse-transcribed and integrated into the genomes of virus-infected cells by a LINE1-mediated retrotransposition mechanism. Whole-genome sequencing (WGS) methods detected retrotransposed SARS-CoV-2 subgenomic sequences in virus-infected cells overexpressing LINE1, while an enrichment method (TagMap) identified retrotranspositions in cells that did not overexpress LINE1. LINE1 overexpression increased retrotranspositions about 1000-fold as compared to non-overexpressing cells. Nanopore WGS can directly recover retrotransposed viral and flanking host sequences, but its sensitivity depends on the depth of sequencing (a typical 20-fold sequencing depth would only examine 10 diploid cell equivalents). In contrast, TagMap enriches the host&ndash;virus junctions and can interrogate up to 20,000 cells and is able to detect rare viral retrotranspositions in LINE1 non-overexpressing cells. Although Nanopore WGS is 10&ndash;20-fold more sensitive per tested cell, TagMap can interrogate 1000&ndash;2000-fold more cells and, therefore, can identify infrequent retrotranspositions. When comparing SARS-CoV-2 infection and viral nucleocapsid mRNA transfection by TagMap, retrotransposed SARS-CoV-2 sequences were only detected in infected but not in transfected cells. Retrotransposition in virus-infected cells, in contrast to transfected cells, may be facilitated because virus infection, in contrast to viral RNA transfection, results in significantly higher viral RNA levels and stimulates LINE1 expression by causing cellular stress

Breast cancer stem cells, cytokine networks, and the tumor microenvironment

Many tumors, including breast cancer, are maintained by a subpopulation of cells that display stem cell properties, mediate metastasis, and contribute to treatment resistance. These cancer stem cells (CSCs) are regulated by complex interactions with the components of the tumor microenvironment — including mesenchymal stem cells, adipocytes, tumor associated fibroblasts, endothelial cells, and immune cells — through networks of cytokines and growth factors. Since these components have a direct influence on CSC properties, they represent attractive targets for therapeutic development

Acetabular defects in revision hip arthroplasty: a therapy-oriented classification

Introduction!#!The treatment of severe acetabular bone loss remains a difficult challenge. No classification system is available that combines intuitive use, structured design and offers a therapeutic recommendation according to the current literature and modern state of the art treatment options. The goal of this study is to introduce an intuitive, reproducible and reliable guideline for the evaluation and treatment of acetabular defects.!##!Methods!#!The proposed Acetabular Defect Classification (ADC) is based on the integrity of the acetabular rim and supporting structures. It consists of 4 main types of defects ascending in severity and subdivisions narrowing down-defect location. Type 1 presents an intact acetabular rim, type 2 includes a noncontained defect of the acetabular rim ≤ 10 mm, in type 3 the rim defect exceeds 10 mm and type 4 includes different kinds of pelvic discontinuity. A collective of 207 preoperative radiographs were graded according to ADC and correlated with intraoperative findings. Additionally, a randomized sample of 80 patients was graded according to ADC by 5 observers to account for inter- and intra-rater reliability.!##!Results!#!We evaluated the agreement of preoperative, radiographic grading and intraoperative findings presenting with a k value of 0.74. Interobserver agreement presented with a k value of 0.62 and intraobserver at a k value of 0.78.!##!Conclusion!#!The ADC offers an intuitive, reliable and reproducible classification system. It guides the surgeon pre- and intraoperatively through a complex field of practice

Femoral defects in revision hip arthroplasty: a therapy-oriented classification

Introduction!#!The complex field of femoral defects in revision hip arthroplasty displays a lack of standardized, intuitive pre- and intraoperative assessment. To address this issue, the femoral defect classification (FDC) is introduced to offer a reliable, reproducible and an intuitive classification system with a clear therapeutic guideline.!##!Materials and methods!#!The FDC is based on the integrity of the main femoral segments which determine function and structural support. It focuses on the femoral neck, the metaphysis consisting of the greater and lesser trochanter, and the femoral diaphysis. The four main categories determine the location of the defect while subcategories a, b and c are being used to classify the extent of damage in each location. In total, 218 preoperative radiographs were retrospectively graded according to FDC and compared to intraoperatively encountered bone defects. To account for inter-rater and intra-rater agreement, 5 different observers evaluated 80 randomized cases at different points in time.!##!Results!#!A Cohens kappa of 0.832 ± 0.028 could be evaluated, accounting for excellent agreement between preoperative radiographs and intraoperative findings. To account for inter-rater reliability, 80 patients have been evaluated by 5 different observers. Testing for inter-rater reliability, a Fleiss Kappa of 0.688 could be evaluated falling into the good agreement range. When testing for intra-rater reliability, Cohens Kappa of each of the 5 raters has been analyzed and the mean was evaluated at 0.856 accounting for excellent agreement.!##!Conclusion!#!The FDC is a reliable and reproducible classification system. It combines intuitive use and structured design and allows for consistent preoperative planning and intraoperative guidance. A therapeutic algorithm has been created according to current literature and expert opinion. Due to the combination of the FDC with the recently introduced Acetabular Defect Classification (ADC) a structured approach to the entire field of hip revision arthroplasty is now available

Accuracy of Positioning and Risk Factors for Malpositioning Custom-Made Femoral Stems in Total Hip Arthroplasty—A Retrospective Multicenter Analysis

Total hip arthroplasty (THA) is commonly performed using off-the-shelf implants. In the case of a severe mismatch between the anatomy of the proximal femur and the geometry of the stem, the use of custom-made stems might become necessary. The goal of this study was to investigate the precision of the implantation of custom-made stems of one manufacturer (CTX stem, AQ Implants) and to determine risk factors for malpositioning. All patients receiving a custom-made CTX stem between 2014 and 2020 at six high-volume academic centers were retrospectively recruited. The achieved position of the stem, as determined by stem version, stem coronal angle, and implantation depth on radiographs, was compared to the plan. The influence of radiographic and demographic parameters on the position was investigated. The results revealed a high variability of the achieved implant position in relation to the preoperative plan. While the stem coronal angle only differed slightly from the intended position, the stem version and the implantation depth showed a high frequency and amount of deviation. Right stems showed significantly higher positions than planned. Surgeons must be aware of this potential problem when implanting custom-made stems