Construction of recombinant vector harboring gene encoding scFv against EpEX and Pichia pastoris transformant isolation

Introduction As a transmembrane glycoprotein, the epithelial cell adhesion molecule (EpCAM) has been shown to be strongly overexpressed on the majority of tumor cells of epithelial origin and its overexpression has been supposed to support tumor progression and metastasis. Hence EpCAM has been made as a suitable antigen for targeted cancer therapy. In this case different types of antibodies including antibody fragments such as single chain fragment variable (ScFv) antibodies have been produced for drug delivery to this specific antigen. Pichia pastoris is a highly efficient and cost-effective system for expression of recombinant proteins. In this study, we used the Pichia expression system to express a ScFv against EpCAM extracellular domain (EpEX). Materials and Methods: A codon optimized gene encoding anti-EpEX protein was cloned into the XhoI and XbaI sites of the pPICZαB vector. Transformation of CS115 strain was performed via electroporation method. The recombinant protein was linearized by using SacI restriction endonuclease prior to gene integration into the genome. Results: Successfully cloned anti- EpEX gene into the pPICZαB vector was confirmed by restriction analysis and sequencing. The transforming agents with genome containing inserted pPICZαB- anti- EpEX were confirmed via PCR amplification of genomic DNA using AOX1 primers. Conclusion: These findings imply that the engineered strain is able to express the recombinant anti- EpEX which may be used as a potential candidate in cancer immunotherapy. &nbsp

Adherence to facility management and safety standards in Shiraz hospitals, Iran

Abstract   Background: Evaluate the adherence to facility management and safety standards among governmental and non-governmental hospitals in Shiraz, Iran.  Methods: In this cross sectional study, 22 hospitals of the 33 hospitals in Shiraz, Iran including 13 governmental and 9 non-governmental facilities were surveyed. A 74-item self-administered questionnaire was used. Collected data were entered to SPSS Version 15.0 software. The level for statistical significance was set at 0.05.  Results: Adherence to facility management and safety standards was 65.17% in governmental and 72.79% in non-governmental hospitals. Compliance by governmental hospital in the areas of leadership and planning, safety and security, emergency management, medical equipment, utility system and staff education ranged from 60% to 86%. However, hazardous materials and fire safety adherence was below 50%. For non-governmental hospitals standard compliance for all areas ranged from 60% to 86%. Compliance rates between governmental and non-governmental hospitals in the areas of hazardous materials and staff education standards were statistically significantly different (p=0.02 and p=0.05 respectively).  Conclusions: To achieve more effective functional health care services, additional studies must be undertaken to assess the nature and extent of problem areas that exist in planning, implementing and monitoring of facility management and safety programs

Optical coherence tomography angiography in intermediate uveitis-related cystoid macular edema

Background: Cystoid macular edema (CME) is the leading cause of permanent visual impairment in patients with uveitis, particularly in patients with intermediate uveitis (IU). This study was aimed at comparing the changes in the macular microvasculature in patients with IU with uveitic non-responsive CME and without macular edema. Methods: In this case-control study, 55 eyes of patients with IU were assessed for macular microvascular structures, including vascular density, foveal avascular zone (FAZ) measurement, and vascular morphological changes, using spectral-domain optical coherence tomography angiography (OCT-A) with the AngioVue OCT-A system. We divided patients into the following two groups: the case group, including 30 eyes with IU-related non-responsive CME, and the control group, including 25 eyes with IU without macular edema. Results: Participants in the case and control groups had comparable age (P = 0.753) and sex (P = 0.124) distributions. Superficial capillary plexus vessel density in the case group was significantly decreased in the whole image (P = 0.027) and the parafoveal area (P  = 0.001) compared to the control group. However, there were no statistically significant differences between the two groups in terms of foveal superficial vessel density, deep capillary plexus vessel density, FAZ area, FAZ perimeter, FAZ acircularity index, or foveal vessel density in a 300-µm-wide annulus around the FAZ (all P > 0.05). Vascular morphological changes, such as the capillary tuft, telangiectatic vessels, or micro-aneurism, were not different in the overview images of the OCT-A printout between the two groups. Conclusions: The mean superficial capillary plexus vessel density was lower in eyes with IU-related nonresponsive CME than in those without macular edema. We observed more cystoid spaces in SCP than in DCP. Microcystic changes in the inner retina and ischemia may be the underlying cause in eyes with nonresponsive CME. Future prospective longitudinal studies with healthy, matched controls are warranted to confirm our findings

Effects of Cultivation Conditions on the Expression Level of Recombinant scFv Antibody against EpEX in Escherichia coli

The EpCAM (epithelial cell adhesion molecule) is a cell surface antigen over expressed in many types of epithelial cell cancers including colon, stomach, pancreas, lung, ovarian, and breast. So, it can be an attractive target for active and passive immunotherapy of cancers. ScFv (single chain fragment variable) fragment is a class of engineered antibodies in which the genes coding for the heavy (VH) and light chains (VL) of an immunoglobulin have been linked with a short flexible peptide linker. Inexpensive media, rapid growth rates, and relatively minimal laboratory set up make Escherichia coli (E. coli) a suitable host for expression of a large variety of recombinant proteins. Here, we assessed the effect of cultivation conditions on the level of expressed scFv against extracellular domain of EpCAM (EpEX) in E. coli. pET22b-antiEpEX-scFv was transformed into prepared E. coli Rosetta™(DE3) competent cells. To evaluate the effect of cultivation conditions on protein expression level, three factors of incubation temperature (25, 30, 37°C), the IPTG (isopropyl-β-D-thiogalactoside) concentration (0.1, 0.25, 0.5, 1 mM), and induction duration (3, 5, 7, 18 h) were considered. SDS-PAGE and western blot analysis demonstrated an estimated 30 kDa-size protein band which was related to the recombinant scFv expressed in E. coli Rosetta™(DE3) strain. At optimal condition (5 h after induction with 0.5 mM IPTG at 25 °C), the final production yield of the antiEpEX-scFv was 403.29 ± 87.50 μg/mL. Our results provide a foundation for the development of scFv-based drugs’ production as effective therapeutic agents in cancers with epithelial origin.   HIGHLIGHTS The antiEpEX-scFv was successfully expressed in E. coli Rosetta™(DE3) strain. The highest concentration of protein was obtained with 0.5 mM IPTG at 30°C. The final yield of recombinant antiEpEX-scFv was approximately 403.29 ± 87.50 mg/L

The effectiveness of cognitive behavioral therapy and schema therapy on happiness and mental health of nursing students

Background and aims: Cognitive behavioral therapy and schema therapy are known as two common methods to promote happiness and mental health. This research aimed to investigate the effectiveness cognitive behavioral therapy and schema therapy in improving happiness and mental health of nursing students who referred to counseling center in Islamic Azad university of Mashhad Branch. Methods: This research was a quasi-experimental study with a pre-test and post-test design. The statistical population included all nursing girl students who referred to counseling center in Islamic Azad university of Mashhad Branch in 2014 year. 45 girl students were selected by convenience sampling and randomly assigned to three groups (each group 15 students) included experimental and control groups. The experimental groups educated by cognitive behavioral therapy and schema therapy in 10 sessions (each session for 70 minutes). All of groups completed the questionnaires of happiness (Argyle and Lu) and mental health (Goldberg and Hillier) as the pre-test and post-test. Data were analyzed using SPSS software and multivariate analysis and covariance methods. Results: The findings showed the happiness post-test mean of cognitive behavioral, schema therapy and control groups was (3.78±1.19), (3.67±1.12), and (1.96±0.65) respectivly. Also, the post-test mean of mental health in cognitive behavioral, schema therapy and control groups was (3.23±0.91), (3.12±0.87), and (1.68±0.70) respectivly. Moreover, there was a significant difference among experimental groups, cognitive behavioral therapy and schema therapy with control groups (P<0.005). Conclusion: The results of this study showed that both cognitive behavioral therapy and schema therapy methods can increase happiness and mental health in nursing students. So, it suggests that therapists use these methods to improve happiness and mental health in students

Pattern and Visual Prognostic Factors of Behcet’s Uveitis in Northwest Iran

Purpose: To investigate the pattern of ocular involvement in Behcet’s disease (BD) with predictors of patients’ final state of vision. Methods: This historical cohort encompassed the clinical records of 200 patients diagnosed according to the International Criteria for BD (ICBD), over a period of 17 years between 2004 and 2021. Results: The prevalence of Behcet’s uveitis (BU) was more common in females and patients in the fourth decade of life. Ninety-five patients (47.5%) had evidence of ocular involvement in the initial ophthalmologic evaluation, and 171 patients (85.5%) manifested evidence of BU during the follow-up visits of which bilateral non-granulomatous panuveitis was the most common anatomical pattern of involvement (32.9%) followed by posterior (27.6%), anterior (26.5%), and intermediate (13.8%) uveitis. The prevalent accompanying signs were oral aphthous (67%), skin lesions (29%), and genital ulcers (19.5%). Cystoid macular edema (CME) was the most frequent ocular complication (62%), followed by cataract (57.5%) and epiretinal membranes (ERM) (36.5%). Univariate analysis showed the following determinants: male gender, younger age at onset, panuveitis, posterior uveitis, retinal vasculitis, and longer duration of uveitis as poorer visual prognostic factors of the disease. Multivariate analysis demonstrated a higher chance of poor visual prognosis of BD in patients with panuveitis, posterior uveitis, retinal vasculitis, and longer duration of uveitis. Conclusion: This cohort study demonstrated an overview on epidemiological patterns of BU along with the visual prognostic factors in Iranian patients

Major and minor criteria for gastric dystemperaments in Persian Medicine: Sari gastric dystemperament criteria-I (SGDC-I)

&#60;div class="msocomtxt" id="com1" language="JavaScript" onmouseout="msoCommentHide('com1')" onmouseover="msoCommentShow('anchor1','com1')"&#62;Background: Gastric disorders are one of the most common human ailments, which impose a huge economic burden on countries. In Persian Medicine (PM), it is possible to predict the susceptibility to gastric diseases with diagnosis of gastric Mizajes (temperaments) and dystemperaments. The semiology of gastric dystemperaments has been investigated in PM textbooks, although the value of each sign and symptom is not mentioned. Consequently, this research is designed to determine the major and minor criteria for classifying gastric dystemperaments on the basis of valid manuscripts and with the help of PM specialists in the present era. Methods: This was a consensus-based study consisting of four phases. In the first phase, reference PM textbooks were studied. Symptoms and signs of gastric dystemperaments were collected and listed in four groups. In the second phase, semi-structured interviews with a sample of PM experts were carried out. Phase three included a focused group discussion with experts. Eventually, findings were integrated from the three study phases in a two-day meeting in Sari City. Results: Selected criteria included eight major and eight minor criteria for hot-cold dystemperament, as well as six major and eight minor criteria for wet-dry gastric dystemperament. Conclusion: Modern lifestyles and the interfering factors are responsible for some changes in diagnostic signs and symptoms according to PM. This was the first step to coordinate PM diagnostic criteria for gastric dystemperaments. Further studies are recommended to reach a unique protocol in the field of PM diagnostics. The next step includes design and validation of national diagnostic tools. &#160

Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

Background: Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period. Methods: 22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution. Findings: Global all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5–65·1] decline), and increased during the COVID-19 pandemic period (2020–21; 5·1% [0·9–9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98–5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50–6·01) in 2019. An estimated 131 million (126–137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7–17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8–24·8), from 49·0 years (46·7–51·3) to 71·7 years (70·9–72·5). Global life expectancy at birth declined by 1·6 years (1·0–2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67–8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4–52·7]) and south Asia (26·3% [9·0–44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations. Interpretation: Global adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic

Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

BACKGROUND: Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period. METHODS: 22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution. FINDINGS: Global all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5–65·1] decline), and increased during the COVID-19 pandemic period (2020–21; 5·1% [0·9–9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98–5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50–6·01) in 2019. An estimated 131 million (126–137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7–17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8–24·8), from 49·0 years (46·7–51·3) to 71·7 years (70·9–72·5). Global life expectancy at birth declined by 1·6 years (1·0–2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67–8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4–52·7]) and south Asia (26·3% [9·0–44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations. INTERPRETATION: Global adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic. FUNDING: Bill & Melinda Gates Foundation

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation