Recent cadmium exposure among male partners may affect oocyte fertilization during in vitro fertilization (IVF)

We recently reported evidence suggesting associations between urine cadmium concentrations, reflecting long-term exposure, measured in 25 female patients (relative risk = 1.41, P = 0.412) and 15 of their male partners (relative risk = 0.19, P = 0.097) and oocyte fertilization in vitro. Blood cadmium concentrations reflect more recent exposure. We here incorporate those measures into our prior data set and employ multivariable log-binomial regression models to generate hypotheses concerning the relative effects of long-term and recent cadmium exposure on oocyte fertilization in vitro. No association is indicated for blood cadmium from women and oocyte fertilization, adjusted for urine cadmium and creatinine, blood lead and mercury, age, race/ethnicity and cigarette smoking (relative risk = 0.88, P = 0.828). However, we suggest an inverse adjusted association between blood cadmium from men and oocyte fertilization (relative risk = 0.66, P = 0.143). These results suggest that consideration of long-term and recent exposures are both important for assessing the effect of partner cadmium levels on oocyte fertilization in vitro

Central nervous system involvement in systemic lupus erythematosus: data from the Spanish Society of Rheumatology Lupus Register (RELESSER)

Objectives: To analyze the prevalence, incidence, survival and contribution on mortality of major central nervous system (CNS) involvement in systemic lupus erythematosus (SLE). Methods: Patients fulfilling the SLE 1997 ACR classification criteria from the multicentre, retrospective RELESSER-TRANS (Spanish Society of Rheumatology Lupus Register) were included. Prevalence, incidence and survival rates of major CNS neuropsychiatric (NP)-SLE as a group and the individual NP manifestations cere-brovascular disease (CVD), seizure, psychosis, organic brain syndrome and transverse myelitis were calculated. Furthermore, the contribution of these manifestations on mortality was analysed in Cox regression models adjusted for confounders. Results: A total of 3591 SLE patients were included. Of them, 412 (11.5%) developed a total of 522 major CNS NP-SLE manifestations. 61 patients (12%) with major CNS NP-SLE died. The annual mortality rate for patients with and without ever major CNS NP-SLE was 10.8% vs 3.8%, respectively. Individually, CVD (14%) and organic brain syndrome (15.5%) showed the highest mortality rates. The 10% mortality rate for patients with and without ever major CNS NP-SLE was reached after 12.3 vs 22.8 years, respectively. CVD (9.8 years) and organic brain syndrome (7.1 years) reached the 10% mortality rate earlier than other major CNS NP-SLE manifestations. Major CNS NP-SLE (HR 1.85, 1.29-2.67) and more specifically CVD (HR 2.17, 1.41-3.33) and organic brain syndrome (HR 2.11, 1.19-3.74) accounted as independent prognostic factors for poor survival. Conclusion: The presentation of major CNS NP-SLE during the disease course contributes to a higher mortality, which may differ depending on the individual NP manifestation. CVD and organic brain syndrome are associated with the highest mortality rates.Pathophysiology and treatment of rheumatic disease

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Wall shear stress distribution of 20 cerebral aneurysms during cardiac cycle

<p>Animation of the changing WSS fields during the cardiac cycle. To emphasize changes in distribution rather than magnitude, colormaps were normalized at each timestep by using the space-averaged WSS on the aneurysm as unit. View points were selected to best visualize the aneurysm, so images are not necessarily at the same scale.</p> <p> </p> <p>The animation was created as part of this study:</p> <p>Geers AJ, Larrabide I, Morales HG, Frangi AF. Approximating hemodynamics of cerebral aneurysms with steady flow simulations. Journal of Biomechanics, 47(1):178–185, 2014.</p> <p> </p> <p>Contact: [email protected]</p

Wall shear stress at the initiation site of cerebral aneurysms: Distribution on flattened branches

<p>Animation of the wall shear stress field during the cardiac cycle. Data was created as part of the following study:</p><p>Geers AJ, Morales HG, Larrabide I, Butakoff C, Bijlenga P, Frangi AF. Wall shear stress at the aneurysm initiation site. Biomechanics and Modeling in Mechanobiology, 2016. [In press]</p><p>Cases were anterior cerebral arteries (ACAs) harboring an aneurysm that had been virtually removed to approximate the pre-aneurysm geometry. Controls were ACAs that had never formed an aneurysm. ACA branches were flattened using the Vascular Modeling Toolkit (VMTK) to be able to view the whole branch surface at once.</p> <p>wss_normalized_ps.gif uses a fixed color range from 0 to 2 times the average WSS on the branch at peak systole.</p> <p>wss_normalized.gif uses a variable color range from 0 to 2 times the average WSS on the branch at the current timestep. This way of normalizing the color range emphasizes changes in distribution rather than magnitude.</p> <p>Contact: [email protected]</p

Wall shear stress at the initiation site of cerebral aneurysms: Vascular models

<p><strong>License</strong></p> <p>This data is licensed under a CC-BY-NC license (http://creativecommons.org/licenses/by-nc/3.0/)</p> <p>In addition to the CC-BY-NC license terms, this data is intended for exclusive use by bona fide researchers, according to the MRC Policy on Sharing of Research Data from Population and Patient Studies definition by the Medical Research Council of the United Kingdom (http://www.mrc.ac.uk/research/research-policy-ethics/data-sharing/population-patient-studies/). Any other use is expressly forbidden. If in doubt whether you are allowed to use the data, please contact Prof Alejandro F Frangi ([email protected]).</p> <p> </p> <p><strong>Description</strong></p> <p>Surface mesh representations of part of the cerebral vasculature. Data was created as part of the following study:</p><p>Geers AJ, Morales HG, Larrabide I, Butakoff C, Bijlenga P, Frangi AF. Wall shear stress at the aneurysm initiation site. Biomechanics and Modeling in Mechanobiology, 2016. [In press]</p> <p>Twenty patients, ten cases and ten controls, were drawn from a large multicenter database created within the @neurIST*. The cases were all the patients in the database with an aneurysm on the A1 segment of the anterior cerebral artery (ACA-A1). They were selected because of their remarkable consistency in location: all aneurysms were just distal to the internal carotid artery (ICA) bifurcation with nine cases directed posteriorly and one case directed anteriorly (case 10). Moreover, the location was neither a bifurcation apex nor the outer wall of a vascular bend, which -- attributed to being high WSS regions -- are the most common aneurysm locations. The controls were patients with an aneurysm at the middle cerebral artery (MCA) bifurcation, hence predisposed to having aneurysms, that did not form an aneurysm at the same location as the cases. They were selected to match cases by patient age (within 2 years) and aneurysm hemisphere (left or right). No other information was considered during the selection process.</p> <p>*@neurIST was a project funded by the European Commission (FP6-IST-027703), which ran from Jan 2006 till Mar 2010. Find more information on www.aneurist.org</p> <p> </p> <p><strong>Files</strong></p> <p>case1_aneurysm.vtp etc. are the 10 cases with aneurysm.</p> <p>case1.vtp etc. are the 10 cases with the aneurysm virtually removed. </p> <p>control1.vtp etc. are the 10 controls.</p> <p>  </p> <p><strong>Contact</strong>:</p> <p>[email protected] (Arjan Geers)</p> <p>[email protected] (Alejandro Frangi)</p

Genomic erosion in a demographically recovered bird species during conservation rescue

The pink pigeon (Nesoenas mayeri) is an endemic species of Mauritius that has made a remarkable recovery after a severe population bottleneck in the 1970s to early 1990s. Prior to this bottleneck, an ex situ population was established from which captive-bred individuals were released into free-living subpopulations to increase population size and genetic variation. This conservation rescue led to rapid population recovery to 400–480 individuals, and the species was twice down-listed on the International Union for the Conservation of Nature (IUCN) Red List. We analyzed the impacts of the bottleneck and genetic rescue on neutral genetic variation during and after population recovery (1993 to 2008) with RAD sequencing, microsatellite analyses, and quantitative genetic analysis of studbook data of 1112 birds from zoos in Europe and the United States. We used computer simulations to study the predicted changes in genetic variation and population viability from the past into the future. Genetic variation declined rapidly, despite the population rebound, and the effective population size was approximately an order of magnitude smaller than census size. The species carried a high genetic load of circa 15 lethal equivalents for longevity. Our computer simulations predicted continued inbreeding will likely result in increased expression of deleterious mutations (i.e., a high realized load) and severe inbreeding depression. Without continued conservation actions, it is likely that the pink pigeon will go extinct in the wild within 100 years. Conservation rescue of the pink pigeon has been instrumental in the recovery of the free-living population. However, further genetic rescue with captive-bred birds from zoos is required to recover lost variation, reduce expression of harmful deleterious variation, and prevent extinction. The use of genomics and modeling data can inform IUCN assessments about the viability and extinction risk of species, and it helps to assess the conservation dependency of populations