Age-related macular degeneration (AMD) is a leading cause of blindness. Genetic variants at the chromosome 1q31.3 encompassing the complement factor H (CFH, FH) and CFH related genes (CFHR1-5) are ...major determinants of AMD susceptibility, but their molecular consequences remain unclear. Here we demonstrate that FHR-4 plays a prominent role in AMD pathogenesis. We show that systemic FHR-4 levels are elevated in AMD (P-value = 7.1 × 10
), whereas no difference is seen for FH. Furthermore, FHR-4 accumulates in the choriocapillaris, Bruch's membrane and drusen, and can compete with FH/FHL-1 for C3b binding, preventing FI-mediated C3b cleavage. Critically, the protective allele of the strongest AMD-associated CFH locus variant rs10922109 has the highest association with reduced FHR-4 levels (P-value = 2.2 × 10
), independently of the AMD-protective CFHR1-3 deletion, and even in those individuals that carry the high-risk allele of rs1061170 (Y402H). Our findings identify FHR-4 as a key molecular player contributing to complement dysregulation in AMD.
An abrupt transition from oxic to anoxic–sulfidic (euxinic) marine bottom waters occurred in the Cariaco Basin in response to increasing productivity resulting from the late Pleistocene post-glacial ...rise in sea level and corresponding increase in surface-water nutrient availability. The microlaminated sediments of the euxinic interval, which span the last ∼14.5 ky, suggest a predominance of water-column (syngenetic) pyrite formation based on (1) high pyrite sulfur (S
py) concentrations in the surficial sediment layers, (2) values for degree-of-pyritization (DOP) that generally do not increase appreciably with increasing burial, (3) ratios of total iron (Fe
T) to Al that are elevated above the continental baseline recorded in the underlying oxic sediments, and (4) S
py isotope trends that largely mimic the
δ
34S
HS
−
of the modern water column. Intermediate DOP values in the microlaminated deposits and Fe
T/Al ratios that are slightly above continental levels indicate an iron reservoir controlled by scavenging during syngenetic pyrite formation in combination with intermediate rates of Fe-bearing siliciclastic accumulation. As predicted from the relative rates of siliciclastic delivery, Fe
T/Al and DOP data lie between end-member values observed in the modern Black Sea. As viewed broadly, Fe
T/Al and DOP relationships in euxinic sediments reflect the balance between syngenetic Fe scavenging and temporal and spatial gradients in siliciclastic input.
Pyrite concentrations are generally low in the underlying oxic marine deposits because of limitations in the supply of organic carbon (C
org). However, the upper 80 cm of the Fe-rich, C
org-poor, bioturbated sediment show evidence for a strong diffusional HS
− overprint from the overlying, Fe-limited euxinic marine environment. This post-glacial transition manifests in pyrite overprints that are strongly
34S-depleted relative to those in restricted, presently euxinic marine settings elsewhere in the world, such as the Black Sea, where the sedimentary sequence spanning the last glacial–interglacial transition begins with a shift from freshwater to C
org-poor oxic marine deposition and thus dominantly sulfate diffusion.
Trends for Mo/Al ratios in the microlaminated sediments suggest that Mo is enriched by roughly two orders of magnitude above the continental levels recorded in the oxic deposits. Organic matter plays a role by enhancing HS
− production and/or by providing a substrate for Mo scavenging. Significant Mo enrichment via diffusion into the upper portion of the bioturbated zone was not observed despite HS
−-rich pore waters as recorded in the heavy iron sulfide overprint. We have not, however, proven that high sulfide concentrations within the water column are required for enhanced Mo sequestration in sediments.
To examine the role of complement factor D (CFD) in age-related macular degeneration (AMD) by analysis of genetic association, copy number variation, and plasma CFD concentrations.
Single nucleotide ...polymorphisms (SNPs) in the CFD gene were genotyped and the results analyzed by binary logistic regression. CFD gene copy number was analyzed by gene copy number assay. Plasma CFD was measured by an enzyme-linked immunosorbent assay.
Genetic association was found between CFD gene SNP rs3826945 and AMD (odds ratio 1.44; P = 0.028) in a small discovery case-control series (462 cases and 325 controls) and replicated in a combined cohorts meta-analysis of 4765 cases and 2693 controls, with an odds ratio of 1.11 (P = 0.032), with the association almost confined to females. Copy number variation in the CFD gene was identified in 13 out of 640 samples examined but there was no difference in frequency between AMD cases (1.3%) and controls (2.7%). Plasma CFD concentration was measured in 751 AMD cases and 474 controls and found to be elevated in AMD cases (P = 0.00025). The odds ratio for those in the highest versus lowest quartile for plasma CFD was 1.81. The difference in plasma CFD was again almost confined to females.
CFD regulates activation of the alternative complement pathway, which is implicated in AMD pathogenesis. The authors found evidence for genetic association between a CFD gene SNP and AMD and a significant increase in plasma CFD concentration in AMD cases compared with controls, consistent with a role for CFD in AMD pathogenesis.
Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality ...associated with this agent.
We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days.
Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval CI, -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11).
Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).
Agriculture in the Central Valley of California, one of the USA’s main sources of fruits, nuts, and vegetables, is highly vulnerable to climate change impacts in the next 50 years. This ...interdisciplinary case study in Yolo County shows the urgency for building adaptation strategies to climate change. Climate change and the effects of greenhouse gas emissions are complex, and several of the county’s current crops will be less viable in 2050. The study uses a variety of methods to assemble information relevant to Yolo County’s agriculture, including literature reviews, models, geographic information system analysis, interviews with agency personnel, and a survey of farmers. Potential adaptation and mitigation responses by growers include changes in crop taxa, irrigation methods, fertilization practices, tillage practices, and land use. On a regional basis, planning must consider the vulnerability of agricultural production and the tradeoffs associated with diversified farmlands, drought, flooding of cropland, loss of habitat for wild species of concern, and urbanization.
The lack of a standardized system for describing cell therapies acts as a barrier to advancement in clinical and basic research and practice. The aim of this study was to establish an international ...expert consensus on strategies to improve standardization and transparency when describing cell therapies. The secondary aim was to develop a consensus among experts on the contents of a standardized tool for describing cell therapies.
The need for expert consensus on strategies to improve cell therapy communication was confirmed at the American Academy of Orthopaedic Surgeons/National Institutes of Health Optimizing Clinical Use of Biologics Symposium in 2018. A working group of 6 experts convened an international consensus process involving clinicians and basic scientists using validated Delphi methodology. This iterative process was used to define statements on communication of cell therapies and develop a standardized tool for describing cell therapies.
Thirty-four experts completed 3 rounds survey with use of the Delphi process. After 3 rounds, 27 statements relating to existing nomenclature, solutions to improve communication, ideal characteristics of a framework, mandatory elements of a new framework, and future work to facilitate application reached consensus with >80% agreement and <5% disagreement. Consensus was reached on the contents of a tool for improving standardization and transparency when describing cell therapies. This tool, dubbed "DOSES," is based on the reporting of 5 core items: donor (i.e., autologous, allogeneic, xenogeneic), origin of tissue, separation from other cell types/preparation method, exhibited cell characteristics associated with behavior, and the site of delivery.
This study has established expert consensus on the communication of cell therapies. The DOSES tool has been developed to improve standardization and transparency in describing cell therapies.
The DOSES tool for describing cell therapies can be utilized by researchers, clinicians, regulators, and industry professionals to improve standardization and transparency when describing cell therapies. The use of this tool may allow clinicians and patients to better understand the characteristics of current and future cell preparations.
Major concerns of pregnancies complicated by diabetes mellitus are an increased risk of adverse perinatal outcome. The objective of this study was to analyse the rate of fetal distress during labor ...in women with type 1, type 2 and gestational diabetes compared to control women.
A retrospective case-cohort study was conducted at the VU University Medical Center, Amsterdam; a tertiary care hospital. 117 women with type 1 diabetes, 59 women with type 2 diabetes, 303 women with gestational diabetes and 15,260 control women were included, who delivered between March 2004 and February 2014. Linear and logistic regression analyses were used to compare maternal and pregnancy characteristics. Risk of fetal distress and perinatal asphyxia was assessed by multiple regression analyses, adjusted for confounding factors as age, smoking, parity, previous cesarean section, hypertensive disorder, pre-eclampsia, prematurity, induction of labor and macrosomia. Main outcome measure was fetal distress, defined either as clinical indication for instrumental or cesarean delivery; or low umbilical artery pH (UA pH), or admission to neonatal unit (NU).
The indication for instrumental or cesarean delivery in women with type 1 and type 2 diabetes mellitus was more frequently based on fetal distress as compared to controls (adjusted OR 2.76 CI 1.74-4.40 and adjusted OR 2.31 CI 1.19-4.51, respectively). In comparison with the control group, infants of women with type 1 diabetes had an increased risk of UA pH < 7.20 (adjusted OR 1.88 CI 1.23-2.87) or UA pH < 7.10 (adjusted OR 3.35 CI 1.79-6.27). Also, infants of women with type 1 diabetes were at increased risk for admission to NU as compared to infants of control women (OR 8.07 CI 4.75-13.70).
Women with type 1 and type 2 diabetes are at increased risk of fetal distress during labor as compared to controls.
We report on the first observation of time-reversal symmetry violation through a comparison of the probabilities of
K
0
transforming into K
0 and K
0 into
K
0
as a function of the neutral-kaon ...eigentime
t. The comparison is based on the analysis of the neutral-kaon semileptonic decays recorded in the CPLEAR experiment. There, the strangeness of the neutral kaon at time
t=0 was tagged by the kaon charge in the reaction
p
p
→
K
±π
∓
K
0
(
K
0
)
at rest, whereas the strangeness of the kaon at the decay time
t=
τ was tagged by the lepton charge in the final state. An average decay-rate asymmetry
〈
R(
K
0
t=0→
e
+
π
−
ν
t=τ)−R(
K
0
t=0→
e
−
π
+
ν
t=τ)
R(
K
0
t=0→
e
+
π
−
ν
t=τ)+R(
K
0
t=0→
e
−
π
+
ν
t=τ)
〉=(6.6±1.3
stat
±1.0
syst
)×10
−3
was measured over the interval
1
τ
S
<τ<20
τ
S
, thus leading to evidence for time-reversal non-invariance.
Summary
Objective Renal function is profoundly influenced by thyroid status; however, this has not been studied in detail in human subjects. The purpose of the present study was to determine the ...relationship between renal function and thyroid status before and after treatment for hypothyroidism and hyperthyroidism, respectively.
Design and patients In 37 consecutive hypothyroid and 14 hyperthyroid patients renal function as measured by plasma creatinine and glomerular filtration rate (GFR) based on the modification of diet in renal disease (MDRD) formula was determined before treatment and after regaining euthyroidism.
Results Renal function improved significantly during treatment of hypothyroidism and decreased during treatment of hyperthyroidism. There was a strong correlation between the change in thyroid status determined as the ratio log10(fT4 post‐treatment/fT4 pretreatment) and the change in renal function as a result of therapy expressed as serum creatinine (r2 = 0·81, P < 0·0001) and estimated GFR (0·69, P < 0·0001).
Conclusion The kidney is an important target of thyroid hormone action.
Limiting the spread and impacts of invasive alien species (IAS) on biodiversity and ecosystems has become a goal of global, regional and national biodiversity policies. Evidence based management of ...IAS requires support by risk assessments, which are often based on expert judgment. We developed a tool to prioritize potentially new IAS based on their ecological risks, socio-economic impact and feasibility of management using multidisciplinary expert panels. Nine expert panels reviewed scientific studies, grey literature and expert knowledge for 152 species. The quality assessment of available knowledge revealed a lack of peer-reviewed data and high dependency on best professional judgments, especially for impacts on ecosystem services and feasibility of management. Expert consultation is crucial for conducting and validating rapid assessments of alien species. There is still a lack of attention for systematic and methodologically sound assessment of impacts on ecosystem services and weighting negative and positive effects of alien species.
•A novel rapid assessment method prioritizes 152 alien species using expert panels.•In total, 66 and 40 species potentially have high and medium ecological risks respectively.•Rapid assessment of various impact criteria strongly relies on expert judgement for 36%–83% of the species.•Lack of documented scientific data in particular for feasibility of management measures.•Consensus-based expert panels limit inter-assessor variability.
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