Rituximab responsive immune thrombocytopenic purpura in an adult with underlying autoimmune lymphoproliferative syndrome due to a splice-site mutation (IVS7+2 T>C) affecting the Fas gene

A 36 yr-old man of Israeli descent with a history of childhood splenectomy for severe thrombocytopenia and a family history of autoimmune lymphoproliferative syndrome (ALPS), presented with severe immune thrombocytopenic purpura refractory to standard therapy. He was found to possess a heterozygous mutation in the Fas gene (also termed TNFRSF6, CD95, Apo-1) affecting the donor splice site of intron 7 (IVS7+2 T>C). This frameshift mutation truncates the cytoplasmic domain of the Fas death receptor, resulting in circulating CD4/8 double negative T lymphocytes, lymphadenopathy and autoimmune complications typical of ALPS. Administration of Rituximab in this patient was associated with a durable hematologic response (currently more than 12 months). This report highlights the need to consider rare inherited causes of thrombocytopenia in adults with a family history of immune cytopenia(s) and the effective use of anti-CD20 monoclonal antibody in patients unresponsive to immunosuppression and splenectomy

The type-B moral error theory

I introduce a new version of Moral Error Theory, which I call Type-B Moral Error Theory. According to a Type-B theorist there are no facts of the kind required for there to be morality in stricto sensu, but there can be irreducible ‘normative’ properties which she deems, strictly speaking, to be morally irrelevant. She accepts that there are instrumental all things considered oughts, and categorical pro tanto oughts (both of which she deems morally irrelevant), but denies that there are categorical all things considered oughts on pain of requiring ‘queer’ facts to obtain. I detail the most central motivation of this version of the theory against its more traditional rival, according to which there are no irreducible normative properties at all. The motivation is that it, unlike its rival, can successfully be defended against the notorious charge of self-defeat

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950-2019 : a comprehensive demographic analysis for the Global Burden of Disease Study 2019

Background: Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. Methods: 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10–14 and 50–54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. Findings: The global TFR decreased from 2·72 (95% uncertainty interval [UI] 2·66–2·79) in 2000 to 2·31 (2·17–2·46) in 2019. Global annual livebirths increased from 134·5 million (131·5–137·8) in 2000 to a peak of 139·6 million (133·0–146·9) in 2016. Global livebirths then declined to 135·3 million (127·2–144·1) in 2019. Of the 204 countries and territories included in this study, in 2019, 102 had a TFR lower than 2·1, which is considered a good approximation of replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted for 27·1% (95% UI 26·4–27·8) of global livebirths. Global life expectancy at birth increased from 67·2 years (95% UI 66·8–67·6) in 2000 to 73·5 years (72·8–74·3) in 2019. The total number of deaths increased from 50·7 million (49·5–51·9) in 2000 to 56·5 million (53·7–59·2) in 2019. Under-5 deaths declined from 9·6 million (9·1–10·3) in 2000 to 5·0 million (4·3–6·0) in 2019. Global population increased by 25·7%, from 6·2 billion (6·0–6·3) in 2000 to 7·7 billion (7·5–8·0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased from 58·6 years (56·1–60·8) in 2000 to 63·5 years (60·8–66·1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019

Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017.

BACKGROUND: Global development goals increasingly rely on country-specific estimates for benchmarking a nation's progress. To meet this need, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 estimated global, regional, national, and, for selected locations, subnational cause-specific mortality beginning in the year 1980. Here we report an update to that study, making use of newly available data and improved methods. GBD 2017 provides a comprehensive assessment of cause-specific mortality for 282 causes in 195 countries and territories from 1980 to 2017. METHODS: The causes of death database is composed of vital registration (VR), verbal autopsy (VA), registry, survey, police, and surveillance data. GBD 2017 added ten VA studies, 127 country-years of VR data, 502 cancer-registry country-years, and an additional surveillance country-year. Expansions of the GBD cause of death hierarchy resulted in 18 additional causes estimated for GBD 2017. Newly available data led to subnational estimates for five additional countries-Ethiopia, Iran, New Zealand, Norway, and Russia. Deaths assigned International Classification of Diseases (ICD) codes for non-specific, implausible, or intermediate causes of death were reassigned to underlying causes by redistribution algorithms that were incorporated into uncertainty estimation. We used statistical modelling tools developed for GBD, including the Cause of Death Ensemble model (CODEm), to generate cause fractions and cause-specific death rates for each location, year, age, and sex. Instead of using UN estimates as in previous versions, GBD 2017 independently estimated population size and fertility rate for all locations. Years of life lost (YLLs) were then calculated as the sum of each death multiplied by the standard life expectancy at each age. All rates reported here are age-standardised

Diverse Coordination Modes and Transformations of Allenes at Adjacent Iridium/Osmium Centers

The methylene-bridged complex, [IrOs­(CO)₃(μ-CH₂)­(dppm)₂]­[BF₄] (dppm = μ-Ph₂PCH₂PPh₂) (<b>2</b>), reacts with allene, resulting in C–C bond formation, to yield an equilibrium mix of two isomers of [IrOs­(CO)₃(μ-η³:κ¹-C­(CH₂)₃)­(dppm)₂]­[BF₄] (<b>3</b>/<b>3a</b>), in which the hapticity of the trimethylenemethane ligand with respect to the two metals, as well as the carbonyl ligand arrangement, is different in each isomer. Reaction of <b>2</b>, as the triflate salt (<b>2-CF</b>_<b>3</b><b>SO</b>_<b>3</b>), with methylallene also yields two isomers, [IrOs­(CO)₃(μ-η³:κ¹-C­(CHCH₃)­(CH₂)₂)­(dppm)₂]­[CF₃SO₃] (<b>4</b>/<b>4a</b>); however, in this case, the binding mode of the substituted trimethylenemethane moiety is the same in each isomer and differs only in the position of the methyl group on the allylic moiety. The addition of 1,1-dimethylallene to <b>2-CF</b>_<b>3</b><b>SO</b>_<b>3</b> results in loss of 4-methyl-1,3-pentadiene and subsequent reaction of the remaining “[IrOs­(CO)₃(dppm)₂]⁺” species with excess 1,1-dimethylallene to give [IrOs­(CO)₃(μ-η³:κ¹-CH₂CCMe₂)­(dppm)₂]­[CF₃SO₃] (<b>5</b>), in which the dimethylallene moiety is κ¹-bound to Os through the central carbon and η³-bound to Ir. Both allene and methylallene react with the tetracarbonyl complex, [IrOs­(CO)₄(dppm)₂]­[BF₄] (<b>6</b>), to generate analogous products, [IrOs­(CO)₃(μ-η³:κ¹-CH₂CCHR)­(dppm)₂]­[BF₄] (R = H (<b>7</b>), CH₃ (<b>8</b>), respectively). Reaction of <b>6-CF</b>_<b>3</b><b>SO</b>_<b>3</b> with 1,1-dimethylallene yields [IrOs­(CO)₄(μ-CC­(H)­C­(CH₃)CH₂)­(dppm)₂]­[CF₃SO₃] (<b>9</b>), the result of activation of the geminal C–H bonds of the unsubstituted end of the allene, and additional activation of a methyl C–H bond. The addition of 1,1-difluoroallene to <b>6-CF</b>_<b>3</b><b>SO</b>_<b>3</b> yields [IrOs­(CO)₄(μ-κ¹:κ¹-F₂C<i>C</i><i>C</i>H₂)­(dppm)₂][CF₃SO₃] (<b>10</b>), in which this cumulene bridges both metal centers through the central carbon and the CH₂ end of the substrate. These reactivities are compared to those of related Ir₂, Rh/Ru, Rh/Os, and Ir/Ru complexes

Diverse Coordination Modes and Transformations of Allenes at Adjacent Iridium/Osmium Centers

The methylene-bridged complex, [IrOs­(CO)₃(μ-CH₂)­(dppm)₂]­[BF₄] (dppm = μ-Ph₂PCH₂PPh₂) (<b>2</b>), reacts with allene, resulting in C–C bond formation, to yield an equilibrium mix of two isomers of [IrOs­(CO)₃(μ-η³:κ¹-C­(CH₂)₃)­(dppm)₂]­[BF₄] (<b>3</b>/<b>3a</b>), in which the hapticity of the trimethylenemethane ligand with respect to the two metals, as well as the carbonyl ligand arrangement, is different in each isomer. Reaction of <b>2</b>, as the triflate salt (<b>2-CF</b>_<b>3</b><b>SO</b>_<b>3</b>), with methylallene also yields two isomers, [IrOs­(CO)₃(μ-η³:κ¹-C­(CHCH₃)­(CH₂)₂)­(dppm)₂]­[CF₃SO₃] (<b>4</b>/<b>4a</b>); however, in this case, the binding mode of the substituted trimethylenemethane moiety is the same in each isomer and differs only in the position of the methyl group on the allylic moiety. The addition of 1,1-dimethylallene to <b>2-CF</b>_<b>3</b><b>SO</b>_<b>3</b> results in loss of 4-methyl-1,3-pentadiene and subsequent reaction of the remaining “[IrOs­(CO)₃(dppm)₂]⁺” species with excess 1,1-dimethylallene to give [IrOs­(CO)₃(μ-η³:κ¹-CH₂CCMe₂)­(dppm)₂]­[CF₃SO₃] (<b>5</b>), in which the dimethylallene moiety is κ¹-bound to Os through the central carbon and η³-bound to Ir. Both allene and methylallene react with the tetracarbonyl complex, [IrOs­(CO)₄(dppm)₂]­[BF₄] (<b>6</b>), to generate analogous products, [IrOs­(CO)₃(μ-η³:κ¹-CH₂CCHR)­(dppm)₂]­[BF₄] (R = H (<b>7</b>), CH₃ (<b>8</b>), respectively). Reaction of <b>6-CF</b>_<b>3</b><b>SO</b>_<b>3</b> with 1,1-dimethylallene yields [IrOs­(CO)₄(μ-CC­(H)­C­(CH₃)CH₂)­(dppm)₂]­[CF₃SO₃] (<b>9</b>), the result of activation of the geminal C–H bonds of the unsubstituted end of the allene, and additional activation of a methyl C–H bond. The addition of 1,1-difluoroallene to <b>6-CF</b>_<b>3</b><b>SO</b>_<b>3</b> yields [IrOs­(CO)₄(μ-κ¹:κ¹-F₂C<i>C</i><i>C</i>H₂)­(dppm)₂][CF₃SO₃] (<b>10</b>), in which this cumulene bridges both metal centers through the central carbon and the CH₂ end of the substrate. These reactivities are compared to those of related Ir₂, Rh/Ru, Rh/Os, and Ir/Ru complexes

Diverse Coordination Modes and Transformations of Allenes at Adjacent Iridium/Osmium Centers

The methylene-bridged complex, [IrOs­(CO)₃(μ-CH₂)­(dppm)₂]­[BF₄] (dppm = μ-Ph₂PCH₂PPh₂) (<b>2</b>), reacts with allene, resulting in C–C bond formation, to yield an equilibrium mix of two isomers of [IrOs­(CO)₃(μ-η³:κ¹-C­(CH₂)₃)­(dppm)₂]­[BF₄] (<b>3</b>/<b>3a</b>), in which the hapticity of the trimethylenemethane ligand with respect to the two metals, as well as the carbonyl ligand arrangement, is different in each isomer. Reaction of <b>2</b>, as the triflate salt (<b>2-CF</b>_<b>3</b><b>SO</b>_<b>3</b>), with methylallene also yields two isomers, [IrOs­(CO)₃(μ-η³:κ¹-C­(CHCH₃)­(CH₂)₂)­(dppm)₂]­[CF₃SO₃] (<b>4</b>/<b>4a</b>); however, in this case, the binding mode of the substituted trimethylenemethane moiety is the same in each isomer and differs only in the position of the methyl group on the allylic moiety. The addition of 1,1-dimethylallene to <b>2-CF</b>_<b>3</b><b>SO</b>_<b>3</b> results in loss of 4-methyl-1,3-pentadiene and subsequent reaction of the remaining “[IrOs­(CO)₃(dppm)₂]⁺” species with excess 1,1-dimethylallene to give [IrOs­(CO)₃(μ-η³:κ¹-CH₂CCMe₂)­(dppm)₂]­[CF₃SO₃] (<b>5</b>), in which the dimethylallene moiety is κ¹-bound to Os through the central carbon and η³-bound to Ir. Both allene and methylallene react with the tetracarbonyl complex, [IrOs­(CO)₄(dppm)₂]­[BF₄] (<b>6</b>), to generate analogous products, [IrOs­(CO)₃(μ-η³:κ¹-CH₂CCHR)­(dppm)₂]­[BF₄] (R = H (<b>7</b>), CH₃ (<b>8</b>), respectively). Reaction of <b>6-CF</b>_<b>3</b><b>SO</b>_<b>3</b> with 1,1-dimethylallene yields [IrOs­(CO)₄(μ-CC­(H)­C­(CH₃)CH₂)­(dppm)₂]­[CF₃SO₃] (<b>9</b>), the result of activation of the geminal C–H bonds of the unsubstituted end of the allene, and additional activation of a methyl C–H bond. The addition of 1,1-difluoroallene to <b>6-CF</b>_<b>3</b><b>SO</b>_<b>3</b> yields [IrOs­(CO)₄(μ-κ¹:κ¹-F₂C<i>C</i><i>C</i>H₂)­(dppm)₂][CF₃SO₃] (<b>10</b>), in which this cumulene bridges both metal centers through the central carbon and the CH₂ end of the substrate. These reactivities are compared to those of related Ir₂, Rh/Ru, Rh/Os, and Ir/Ru complexes

Amyloid burden in ageing subjects with and without cognitive decline

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