Several lines of geological and geochemical evidence indicate that the level of atmospheric oxygen was extremely low before 2.45 billion years (Gyr) ago, and that it had reached considerable levels ...by 2.22 Gyr ago. Here we present evidence that the rise of atmospheric oxygen had occurred by 2.32 Gyr ago. We found that syngenetic pyrite is present in organic-rich shales of the 2.32-Gyr-old Rooihoogte and Timeball Hill formations, South Africa. The range of the isotopic composition of sulphur in this pyrite is large and shows no evidence of mass-independent fractionation, indicating that atmospheric oxygen was present at significant levels (that is, greater than 10(-5) times that of the present atmospheric level) during the deposition of these units. The presence of rounded pebbles of sideritic iron formation at the base of the Rooihoogte Formation and an extensive and thick ironstone layer consisting of haematitic pisolites and oölites in the upper Timeball Hill Formation indicate that atmospheric oxygen rose significantly, perhaps for the first time, during the deposition of the Rooihoogte and Timeball Hill formations. These units were deposited between what are probably the second and third of the three Palaeoproterozoic glacial events.
Summary Background Disbursements of development assistance for health (DAH) have risen substantially during the past several decades. More recently, the international community's attention has turned ...to other international challenges, introducing uncertainty about the future of disbursements for DAH. Methods We collected audited budget statements, annual reports, and project-level records from the main international agencies that disbursed DAH from 1990 to the end of 2015. We standardised and combined records to provide a comprehensive set of annual disbursements. We tracked each dollar of DAH back to the source and forward to the recipient. We removed transfers between agencies to avoid double-counting and adjusted for inflation. We classified assistance into nine primary health focus areas: HIV/AIDS, tuberculosis, malaria, maternal health, newborn and child health, other infectious diseases, non-communicable diseases, Ebola, and sector-wide approaches and health system strengthening. For our statistical analysis, we grouped these health focus areas into two categories: MDG-related focus areas (HIV/AIDS, tuberculosis, malaria, child and newborn health, and maternal health) and non-MDG-related focus areas (other infectious diseases, non-communicable diseases, sector-wide approaches, and other). We used linear regression to test for structural shifts in disbursement patterns at the onset of the Millennium Development Goals (MDGs; ie, from 2000) and the global financial crisis (impact estimated to occur in 2010). We built on past trends and associations with an ensemble model to estimate DAH through the end of 2040. Findings In 2015, US$36·4 billion of DAH was disbursed, marking the fifth consecutive year of little change in the amount of resources provided by global health development partners. Between 2000 and 2009, DAH increased at 11·3% per year, whereas between 2010 and 2015, annual growth was just 1·2%. In 2015, 29·7% of DAH was for HIV/AIDS, 17·9% was for child and newborn health, and 9·8% was for maternal health. Linear regression identifies three distinct periods of growth in DAH. Between 2000 and 2009, MDG-related DAH increased by $290·4 million (95% uncertainty interval UI 174·3 million to 406·5 million) per year. These increases were significantly greater than were increases in non-MDG DAH during the same period (p=0·009), and were also significantly greater than increases in the previous period (p<0·0001). Between 2000 and 2009, growth in DAH was highest for HIV/AIDS, malaria, and tuberculosis. Since 2010, DAH for maternal health and newborn and child health has continued to climb, although DAH for HIV/AIDS and most other health focus areas has remained flat or decreased. Our estimates of future DAH based on past trends and associations present a wide range of potential futures, although our mean estimate of $64·1 billion (95% UI $30·4 billion to $161·8 billion) shows an increase between now and 2040, although with a large uncertainty interval. Interpretation Our results provide evidence of two substantial shifts in DAH growth during the past 26 years. DAH disbursements increased faster in the first decade of the 2000s than in the 1990s, but DAH associated with the MDGs increased the most out of all focus areas. Since 2010, limited growth has characterised DAH and we expect this pattern to persist. Despite the fact that DAH is still growing, albeit minimally, DAH is shifting among the major health focus areas, with relatively little growth for HIV/AIDS, malaria, and tuberculosis. These changes in the growth and focus of DAH will have critical effects on health services in some low-income countries. Coordination and collaboration between donors and domestic governments is more important than ever because they have a great opportunity and responsibility to ensure robust health systems and service provision for those most in need. Funding Bill & Melinda Gates Foundation.
In the EMBRACA phase III trial, talazoparib (1mg daily, orally) demonstrated a statistically significant improvement in PFS versus physician’s choice of chemotherapy (PCT; capecitabine, eribulin, ...gemcitabine, or vinorelbine) in patients with HER2-negative advanced breast cancer carrying a germline BRCA1/2 mutation; we evaluated patient-reported outcomes (PROs).
Patients were randomized 2 : 1 to receive talazoparib or PCT. PROs were assessed at day 1 (baseline), the start of each treatment cycle (every 3weeks), and at the end of treatment, using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-30) and its breast cancer module, QLQ-BR23. Prespecified exploratory analyses included a longitudinal mixed-effect model comparing treatment arms and a time to definitive clinically meaningful deterioration (TTD) analysis carried out in the global health status/quality of life (GHS/QoL), and all functional and symptom scales from the EORTC QLQ-C30 and -BR23 questionnaires. Between-arm TTD comparisons were made using a stratified log-rank test and a Cox proportional hazards model.
Baseline scores were similar between arms. Statistically significant estimated overall improvement from baseline in GHS/QoL was seen for talazoparib compared with statistically significant deterioration for PCT {3.0 95% confidence interval (CI) 1.2, 4.8 versus −5.4 95% CI −8.8, −2.0; between arms, P<0.0001}. A statistically significant greater delay was observed in TTD in GHS/QoL, favoring talazoparib over PCT hazard ratio, 0.38 (95% CI 0.26, 0.55; median, 24.3 versus 6.3months, respectively; P<0.0001). A statistically significant overall change and a statistically significant delay in TTD, all favoring talazoparib, were also observed in multiple functions and symptoms.
Patients who received talazoparib had significant overall improvements and significant delay in TTD in multiple cancer-related and breast cancer-specific symptoms, functions, and GHS/QoL.
NCT01945775.
Health care spending in the United States increased substantially from 1995 to 2015 and comprised 17.8% of the economy in 2015. Understanding the relationship between known factors and spending ...increases over time could inform policy efforts to contain future spending growth.
To quantify changes in spending associated with 5 fundamental factors related to health care spending in the United States: population size, population age structure, disease prevalence or incidence, service utilization, and service price and intensity.
Data on the 5 factors from 1996 through 2013 were extracted for 155 health conditions, 36 age and sex groups, and 6 types of care from the Global Burden of Disease 2015 study and the Institute for Health Metrics and Evaluation's US Disease Expenditure 2013 project. Decomposition analysis was performed to estimate the association between changes in these factors and changes in health care spending and to estimate the variability across health conditions and types of care.
Change in population size, population aging, disease prevalence or incidence, service utilization, or service price and intensity.
Change in health care spending from 1996 through 2013.
After adjustments for price inflation, annual health care spending on inpatient, ambulatory, retail pharmaceutical, nursing facility, emergency department, and dental care increased by $933.5 billion between 1996 and 2013, from $1.2 trillion to $2.1 trillion. Increases in US population size were associated with a 23.1% (uncertainty interval UI, 23.1%-23.1%), or $269.5 (UI, $269.0-$270.0) billion, spending increase; aging of the population was associated with an 11.6% (UI, 11.4%-11.8%), or $135.7 (UI, $133.3-$137.7) billion, spending increase. Changes in disease prevalence or incidence were associated with spending reductions of 2.4% (UI, 0.9%-3.8%), or $28.2 (UI, $10.5-$44.4) billion, whereas changes in service utilization were not associated with a statistically significant change in spending. Changes in service price and intensity were associated with a 50.0% (UI, 45.0%-55.0%), or $583.5 (UI, $525.2-$641.4) billion, spending increase. The influence of these 5 factors varied by health condition and type of care. For example, the increase in annual diabetes spending between 1996 and 2013 was $64.4 (UI, $57.9-$70.6) billion; $44.4 (UI, $38.7-$49.6) billion of this increase was pharmaceutical spending.
Increases in US health care spending from 1996 through 2013 were largely related to increases in health care service price and intensity but were also positively associated with population growth and aging and negatively associated with disease prevalence or incidence. Understanding these factors and their variability across health conditions and types of care may inform policy efforts to contain health care spending.
US health care spending has continued to increase, and now accounts for more than 17% of the US economy. Despite the size and growth of this spending, little is known about how spending on each ...condition varies by age and across time.
To systematically and comprehensively estimate US spending on personal health care and public health, according to condition, age and sex group, and type of care.
Government budgets, insurance claims, facility surveys, household surveys, and official US records from 1996 through 2013 were collected and combined. In total, 183 sources of data were used to estimate spending for 155 conditions (including cancer, which was disaggregated into 29 conditions). For each record, spending was extracted, along with the age and sex of the patient, and the type of care. Spending was adjusted to reflect the health condition treated, rather than the primary diagnosis.
Encounter with US health care system.
National spending estimates stratified by condition, age and sex group, and type of care.
From 1996 through 2013, $30.1 trillion of personal health care spending was disaggregated by 155 conditions, age and sex group, and type of care. Among these 155 conditions, diabetes had the highest health care spending in 2013, with an estimated $101.4 billion (uncertainty interval UI, $96.7 billion-$106.5 billion) in spending, including 57.6% (UI, 53.8%-62.1%) spent on pharmaceuticals and 23.5% (UI, 21.7%-25.7%) spent on ambulatory care. Ischemic heart disease accounted for the second-highest amount of health care spending in 2013, with estimated spending of $88.1 billion (UI, $82.7 billion-$92.9 billion), and low back and neck pain accounted for the third-highest amount, with estimated health care spending of $87.6 billion (UI, $67.5 billion-$94.1 billion). The conditions with the highest spending levels varied by age, sex, type of care, and year. Personal health care spending increased for 143 of the 155 conditions from 1996 through 2013. Spending on low back and neck pain and on diabetes increased the most over the 18 years, by an estimated $57.2 billion (UI, $47.4 billion-$64.4 billion) and $64.4 billion (UI, $57.8 billion-$70.7 billion), respectively. From 1996 through 2013, spending on emergency care and retail pharmaceuticals increased at the fastest rates (6.4% UI, 6.4%-6.4% and 5.6% UI, 5.6%-5.6% annual growth rate, respectively), which were higher than annual rates for spending on inpatient care (2.8% UI, 2.8%-2.8% and nursing facility care (2.5% UI, 2.5%-2.5%).
Modeled estimates of US spending on personal health care and public health showed substantial increases from 1996 through 2013; with spending on diabetes, ischemic heart disease, and low back and neck pain accounting for the highest amounts of spending by disease category. The rate of change in annual spending varied considerably among different conditions and types of care. This information may have implications for efforts to control US health care spending.
Prior studies have demonstrated that immunologic dysfunction underpins severe illness in COVID-19 patients, but have lacked an in-depth analysis of the immunologic drivers of death in the most ...critically ill patients. We performed immunophenotyping of viral antigen-specific and unconventional T cell responses, neutralizing antibodies, and serum proteins in critically ill patients with SARS-CoV-2 infection, using influenza infection, SARS-CoV-2-convalescent health care workers, and healthy adults as controls. We identify mucosal-associated invariant T (MAIT) cell activation as an independent and significant predictor of death in COVID-19 (HR = 5.92, 95% CI = 2.49-14.1). MAIT cell activation correlates with several other mortality-associated immunologic measures including broad activation of CD8+ T cells and non-Vδ2 γδT cells, and elevated levels of cytokines and chemokines, including GM-CSF, CXCL10, CCL2, and IL-6. MAIT cell activation is also a predictor of disease severity in influenza (ECMO/death HR = 4.43, 95% CI = 1.08-18.2). Single-cell RNA-sequencing reveals a shift from focused IFNα-driven signals in COVID-19 ICU patients who survive to broad pro-inflammatory responses in fatal COVID-19 -a feature not observed in severe influenza. We conclude that fatal COVID-19 infection is driven by uncoordinated inflammatory responses that drive a hierarchy of T cell activation, elements of which can serve as prognostic indicators and potential targets for immune intervention.
Proteolysis-targeting chimeras (PROTACs) that degrade disease-causing proteins by hijacking the endogenous ubiquitin-proteasome system have emerged as an exciting and transformative technology in ...both chemical biology and drug discovery. Currently, the majority of PROTACs use reversible non-covalent ligands for both the target protein of interest (POI) and E3 ligase. In this review, we explore the burgeoning role of reversible and irreversible covalent chemistry in targeted protein degradation. We highlight the key advantages of targeted covalent inhibitors, whether as the target POI or E3 ligase ligand, such as their ability to enhance the selectivity of PROTACs, enable access to more of the “undruggable” proteome and expand the repertoire of recruited E3 ligases.
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Kiely-Collins et al. explore the emergence of reversible covalent and irreversible covalent PROTACs. We discuss the relative kinetics of covalent bond formation and target degradation and advances in chemoproteomic methods that are accelerating the discovery of novel covalent ligands to expand the scope of amenable targets and ligandable E3 ligases.
Coordination of redox‐active ligands to metals is a compelling strategy for making reduced complexes more accessible. In this work, we explore the use of redox‐active formazanate ligands in ...low‐coordinate iron chemistry. Reduction of an iron(II) precursor occurs at milder potentials than analogous non‐redox‐active β‐diketiminate complexes, and the reduced three‐coordinate formazanate‐iron compound is characterized in detail. Structural, spectroscopic, and computational analysis show that the formazanate ligand undergoes reversible ligand‐centered reduction to form a formazanate radical dianion in the reduced species. The less negative reduction potential of the reduced low‐coordinate iron formazanate complex leads to distinctive reactivity with formation of a new N−I bond that is not seen with the β‐diketiminate analogue. Thus, the storage of an electron on the supporting ligand changes the redox potential and enhances certain reactivity.
In reduced circumstances: Low‐coordinate iron formazanate complexes undergo reversible ligand‐centered reduction, which is possible at milder potentials than related iron complexes with non‐redox‐active β‐diketiminate ligands.
Health care spending on children in the United States continues to rise, yet little is known about how this spending varies by condition, age and sex group, and type of care, nor how these patterns ...have changed over time.
To provide health care spending estimates for children and adolescents 19 years and younger in the United States from 1996 through 2013, disaggregated by condition, age and sex group, and type of care.
Health care spending estimates were extracted from the Institute for Health Metrics and Evaluation Disease Expenditure 2013 project database. This project, based on 183 sources of data and 2.9 billion patient records, disaggregated health care spending in the United States by condition, age and sex group, and type of care. Annual estimates were produced for each year from 1996 through 2013. Estimates were adjusted for the presence of comorbidities and are reported using inflation-adjusted 2015 US dollars.
From 1996 to 2013, health care spending on children increased from $149.6 (uncertainty interval UI, 144.1-155.5) billion to $233.5 (UI, 226.9-239.8) billion. In 2013, the largest health condition leading to health care spending for children was well-newborn care in the inpatient setting. Attention-deficit/hyperactivity disorder and well-dental care (including dental check-ups and orthodontia) were the second and third largest conditions, respectively. Spending per child was greatest for infants younger than 1 year, at $11 741 (UI, 10 799-12 765) in 2013. Across time, health care spending per child increased from $1915 (UI, 1845-1991) in 1996 to $2777 (UI, 2698-2851) in 2013. The greatest areas of growth in spending in absolute terms were ambulatory care among all types of care and inpatient well-newborn care, attention-deficit/hyperactivity disorder, and asthma among all conditions.
These findings provide health policy makers and health care professionals with evidence to help guide future spending. Some conditions, such as attention-deficit/hyperactivity disorder and inpatient well-newborn care, had larger health care spending growth rates than other conditions.
Endoscopic duodenal stenting is the current standard treatment for malignant gastric outlet obstruction (GOO) in patients with limited life expectancy. However, duodenal stenting is prone to stent ...dysfunction. Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) is a novel technique with potentially superior stent patency. We compared clinical success, safety, and stent dysfunction of EUS-GE and duodenal stenting in patients with malignant GOO using propensity score matching.
This international, multicenter, retrospective study analyzed consecutive patients undergoing EUS-GE or duodenal stenting for GOO between 2015 and 2021 in three European centers. Primary outcomes were clinical success (GOO scoring system GOOSS ≥ 2) and stent dysfunction (GOOSS ≤ 1 after initial clinical success). A propensity score matching (1:1) analysis was performed using age, sex, underlying disease, disease stage, ascites, and peritoneal carcinomatosis as variables.
214 patients underwent EUS-GE (n = 107) or duodenal stenting (n = 107). After propensity score matching, 176 patients were matched and compared. Technical success rates for EUS-GE and duodenal stenting were 94 % (95 %CI 89 %-99 %) vs. 98 % (95 %CI 95 %-100 %), respectively (
= 0.44). Clinical success rates were 91 % (95 %CI 85 %-97 %) vs. 75 % (95 %CI 66 %-84 %;
= 0.008). Stent dysfunction occurred in 1 % (95 %CI 0-4 %) vs. 26 % (95 %CI 15 %-37 %) of patients (
< 0.001). Adverse event rate was 10 % (95 %CI 4 %-17 %) vs. 21 % (95 %CI 12 %-29 %;
= 0.09).
EUS-GE had higher clinical success and lower stent dysfunction, with similar safety, compared with duodenal stenting, suggesting that EUS-GE may be preferred over duodenal stenting in patients with malignant GOO.
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