Retinal drusen formation is not only a clinical hallmark for the development of age-related macular degeneration (AMD) but also for other disorders, such as Alzheimer's disease and renal diseases. ...The initiation and growth of drusen is poorly understood. Attention has focused on lipids and minerals, but relatively little is known about the origin of drusen-associated proteins and how they are retained in the space between the basal lamina of the retinal pigment epithelium and the inner collagenous layer space (sub-RPE-BL space). While some authors suggested that drusen proteins are mainly derived from cellular debris from processed photoreceptor outer segments and the RPE, others suggest a choroidal cell or blood origin.
Here, we reviewed and supplemented the existing literature on the molecular composition of the retina/choroid complex, to gain a more complete understanding of the sources of proteins in drusen. These “drusenomics” studies showed that a considerable proportion of currently identified drusen proteins is uniquely originating from the blood. A smaller, but still large fraction of drusen proteins comes from both blood and/or RPE. Only a small proportion of drusen proteins is uniquely derived from the photoreceptors or choroid. We next evaluated how drusen components may “meet, greet and stick” to each other and/or to structures like hydroxyapatite spherules to form macroscopic deposits in the sub-RPE-BL space. Finally, we discuss implications of our findings with respect to the previously proposed homology between drusenogenesis in AMD and plaque formation in atherosclerosis.
•A substantial amount of human drusen proteins is derived from blood.•The second-best source of drusen proteins is the RPE.•Only few drusen proteins come uniquely from photoreceptor, RPE, or choroid.•Drusen/blood protein identification may open up prevention for drusen formation.•BM structure, HAP spherules and blood (pressure) play a role in drusen formation.
Chronic granulomatous disease (CGD) is a primary immunodeficiency resulting in life-threatening infections and inflammatory complications. Allogeneic hematopoietic cell transplantation (allo-HCT) can ...cure the disease, but the indication to transplant remains controversial. We performed a retrospective multicenter study of 712 patients with CGD who underwent allo-HCT transplantation from March 1993 through December 2018. We studied 635 children (aged <18 years) and 77 adults. Median follow-up was 45 months. Median age at transplantation was 7 years (range, 0.1-48.6). Kaplan-Meier estimates of overall survival (OS) and event-free survival (EFS) at 3 years were 85.7% and 75.8%, respectively. In multivariate analysis, older age was associated with reduced survival and increased chronic graft-versus-host disease. Nevertheless, OS and EFS at 3 years for patients ≥18 years were 76% and 69%, respectively. Use of 1-antigen-mismatched donors was associated with reduced OS and EFS . No significant difference was found in OS, but a significantly reduced EFS was noted in the small group of patients who received a transplant from a donor with a >1 antigen mismatch. Choice of conditioning regimen did not influence OS or EFS. In summary, we report an excellent outcome after allo-HCT in CGD, with low incidence of graft failure and mortality in all ages. Older patients and recipients of 1-antigen-mismatched grafts had a less favorable outcome. Transplantation should be strongly considered at a younger age and particularly in the presence of a well-matched donor.
•An excellent outcome was obtained after allo-HCT in 712 patients with CGD, with a low incidence of graft failure and mortality.•HCT for CGD should be strongly considered in young patients, particularly in the presence of a well-matched donor.
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Disease transmission models are used in impact assessment and economic evaluations of infectious disease prevention and treatment strategies, prominently so in the COVID-19 response. These models ...rarely consider dimensions of equity relating to the differential health burden between individuals and groups. We describe concepts and approaches which are useful when considering equity in the priority setting process, and outline the technical choices concerning model structure, outputs, and data requirements needed to use transmission models in analyses of health equity.
We reviewed the literature on equity concepts and approaches to their application in economic evaluation and undertook a technical consultation on how equity can be incorporated in priority setting for infectious disease control. The technical consultation brought together health economists with an interest in equity-informative economic evaluation, ethicists specialising in public health, mathematical modellers from various disease backgrounds, and representatives of global health funding and technical assistance organisations, to formulate key areas of consensus and recommendations.
We provide a series of recommendations for applying the Reference Case for Economic Evaluation in Global Health to infectious disease interventions, comprising guidance on 1) the specification of equity concepts; 2) choice of evaluation framework; 3) model structure; and 4) data needs. We present available conceptual and analytical choices, for example how correlation between different equity- and disease-relevant strata should be considered dependent on available data, and outline how assumptions and data limitations can be reported transparently by noting key factors for consideration.
Current developments in economic evaluations in global health provide a wide range of methodologies to incorporate equity into economic evaluations. Those employing infectious disease models need to use these frameworks more in priority setting to accurately represent health inequities. We provide guidance on the technical approaches to support this goal and ultimately, to achieve more equitable health policies.
•Evidence from economic evaluations using transmission models is increasingly influential in priority setting decisions for infectious disease control, yet few such studies explicitly consider equity, despite the known heterogeneous impact of infectious disease interventions across population groups.•Including equity considerations in priority setting presents a number of conceptual and empirical challenges, including a) choices of equity frameworks and measures, b) the availability of disaggregated data in numerous health and equity dimensions, c) adjustments to standard model structures and analyses.•Transmission model-based analyses that include equity should consider and report explicitly on the following key points, in addition to the standard reporting of economic evaluations: 1) specification of equity concepts; 2) choice of evaluation framework; 3) decisions on model structure related to the inclusion of equity considerations; and 4) data sources and limitations.
In patients with COPD, it has not been comprehensively assessed whether the predictive value of comorbidities for mortality differs between men and women. We therefore aimed to examine sex ...differences of COPD comorbidities in regard with prognosis by classifying comorbidities into a comorbidome related to extrapulmonary disorders and a pulmorbidome, referring to pulmonary disorders. The study population comprised 1044 women and 1531 men with the diagnosis of COPD from COSYCONET, among them 2175 of GOLD grades 1-4 and 400 at risk. Associations of comorbidities with mortality were studied using Cox regression analysis for men and women separately. During the follow-up (median 3.7 years) 59 women and 159 men died. In men, obesity, hypertension, coronary artery disease, liver cirrhosis, osteoporosis, kidney disease, anaemia and increased heart rate (HR) predict mortality, in women heart failure, hyperuricemia, mental disorders, kidney disease and increased HR (p < 0.05 each). Regarding the pulmorbidome, significant predictors in men were impairment in diffusion capacity and hyperinflation, in women asthma and hyperinflation. Similar results were obtained when repeating the analyses in GOLD 1-4 patients only. Gender differences should be considered in COPD risk assessment for a tailored approach towards the treatment of COPD.Clinical Trial Registration: ClinicalTrials.gov NCT01245933.
A catalytic system for the mild amination of aryl chlorides is described. This system consists of a Pd(0) precursor and a dihydroimidazoline carbene ligand, which is generated in situ from its ...protonated tetrafluoroborate salt (2). Using this catalyst, aryl and heteroaryl chlorides react with secondary amines and anilines within hours at room temperature. Turnover numbers as high as 5000 are obtained at elevated temperatures for reaction of morpholine with an unactivated aryl chloride.
The reactions of aryl bromides with amines occurs at room temperature when using Pd(0) and P(t-Bu)3 in a 1:1 ratio, and the reactions of aryl chlorides occur at room temperature or 70 °C. The ...arylation of indoles and the new arylation of carbamates also occur when using P(t-Bu)3 as ligand.
The plasmalemmal norepinephrine transporter (NET) regulates cardiovascular sympathetic activity by clearing extracellular norepinephrine in the synaptic cleft. Here, we investigate the subunit ...stoichiometry and function of NET using single-molecule fluorescence microscopy and flux assays. In particular, we show the effect of phosphatidylinositol 4,5-bisphosphate (PIP
) on NET oligomerization and efflux. NET forms monomers (~60%) and dimers (~40%) at the plasma membrane. PIP
depletion results in a decrease in the average oligomeric state and decreases NET-mediated substrate efflux while not affecting substrate uptake. Mutation of the putative PIP
binding residues R121, K334, and R440 to alanines does not affect NET dimerization but results in decreased substrate efflux that is not altered upon PIP
depletion; this indicates that PIP
interactions with these residues affect NET-mediated efflux. A dysregulation of norepinephrine and PIP
signaling have both been implicated in neuropsychiatric and cardiovascular diseases. This study provides evidence that PIP
directly regulates NET organization and function.
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