There is some evidence that statins may have a protective and symptomatic benefit in Alzheimer disease (AD). The LEADe study is a randomized controlled trial (RCT) evaluating the efficacy and safety ...of atorvastatin in patients with mild to moderate AD.
This was an international, multicenter, double-blind, randomized, parallel-group study. Subjects had mild to moderate probable AD (Mini-Mental State Examination score 13-25), were aged 50-90 years, and were taking donepezil 10 mg daily for > or 3 months prior to screening. Entry low-density lipoprotein cholesterol levels (LDL-C) were > 95 and < 195 mg/dL. Patients were randomized to atorvastatin 80 mg/day or placebo for 72 weeks followed by a double-blind, 8-week atorvastatin withdrawal phase. Coprimary endpoints were changes in cognition (Alzheimer's Disease Assessment Scale-Cognitive Subscale ADAS-Cog) and global function (Alzheimer's Disease Cooperative Study Clinical Global Impression of Change ADCS-CGIC) at 72 weeks.
A total of 640 patients were randomized in the study. There were no significant differences in the coprimary endpoints of ADAS-cog or ADCS-CGIC or the secondary endpoints. Atorvastatin was generally well-tolerated.
In this large-scale randomized controlled trial evaluating statin therapy as a treatment for mild to moderate Alzheimer disease, atorvastatin was not associated with significant clinical benefit over 72 weeks. This treatment was generally well-tolerated without unexpected adverse events.
This study provides Class II evidence that intensive lipid lowering with atorvastatin 80 mg/day in patients with mild to moderate probable Alzheimer disease (aged 50-90), taking donepezil, with low-density lipoprotein cholesterol levels between 95 and 195 mg/dL over 72 weeks does not benefit cognition (as measured by Alzheimer's Disease Assessment Scale-Cognitive Subscale) (p = 0.26) or global function (as measured by Alzheimer's Disease Cooperative Study Clinical Global Impression of Change) (p = 0.73) compared with placebo.
Estimating absolute and relative abundance of wildlife populations is critical to addressing ecological questions and conservation needs, yet obtaining reliable estimates can be challenging because ...surveys are often limited spatially or temporally. Community science (i.e., citizen science) provides opportunities for semi-structured data collected by the public (e.g., eBird) to improve capacity of relative abundance estimation by complementing structured survey data collected by trained observers (e.g., North American breeding bird survey BBS). We developed two state-space models to estimate relative abundance and population trends: one using BBS data and the other jointly analyzing BBS and eBird data. We applied these models to seven bird species with diverse life history characteristics. Joint analysis of eBird and BBS data improved precision of mean and year-specific relative abundance estimates for all species, but the BBS-only model produced more precise trend estimates compared to the joint model for most species. The relative abundance estimates of the joint model were particularly more precise than the BBS-only estimates in areas where species detectability was low resulting from either low BBS survey effort or low abundance. These results suggest that community science data can be a valuable resource for cost-effective improvement in wildlife abundance estimation.
The Popeye domain containing (POPDC) genes encode sarcolemma-localized cAMP effector proteins. Mutations in blood vessel epicardial substance (BVES) also known as POPDC1 and POPDC2 have been ...associated with limb-girdle muscular dystrophy and cardiac arrhythmia. Muscle biopsies of affected patients display impaired membrane trafficking of both POPDC isoforms. Biopsy material of patients carrying mutations in BVES were immunostained with POPDC antibodies. The interaction of POPDC proteins was investigated by co-precipitation, proximity ligation, bioluminescence resonance energy transfer and bimolecular fluorescence complementation. Site-directed mutagenesis was utilised to map the domains involved in protein-protein interaction. Patients carrying a novel homozygous variant, BVES (c.547G > T, p.V183F) displayed only a skeletal muscle pathology and a mild impairment of membrane trafficking of both POPDC isoforms. In contrast, variants such as BVES p.Q153X or POPDC2 p.W188X were associated with a greater impairment of membrane trafficking. Co-transfection analysis in HEK293 cells revealed that POPDC proteins interact with each other through a helix-helix interface located at the C-terminus of the Popeye domain. Site-directed mutagenesis of an array of ultra-conserved hydrophobic residues demonstrated that some of them are required for membrane trafficking of the POPDC1-POPDC2 complex. Mutations in POPDC proteins that cause an impairment in membrane localization affect POPDC complex formation while mutations which leave protein-protein interaction intact likely affect some other essential function of POPDC proteins.
Although southern Poland and western Ukraine are not often thought of in terms of decisive battles in World War I, the impulses that precipitated the battle for Galicia in August 1914-and the ...unprecedented carnage that resulted-effectively doomed the Austro-Hungarian Empire just six weeks into the war.
InFall of the Double Eagle, John R. Schindler explains how Austria-Hungary, despite military weakness and the foreseeable ill consequences, consciously chose war in that fateful summer of 1914. Through close examination of the Austro-Hungarian military, especially its elite general staff, Schindler shows how even a war that Vienna would likely lose appeared preferable to the "foul peace" the senior generals loathed. After Serbia outgunned the polyglot empire in a humiliating defeat, and the offensive into Russian Poland ended in the massacre of more than four hundred thousand Austro-Hungarians in just three weeks, the empire never recovered. While Austria-Hungary's ultimate defeat and dissolution were postponed until the autumn of 1918, the late summer of 1914 on the plains and hills of Galicia sealed its fate.
Lorentz and CPT violation in hadronic physics must be tied to symmetry violations at the underlying quark and gluon level. Chiral perturbation theory provides a method for translating novel operators ...that may appear in the Lagrange density for color-charged parton fields into equivalent forms for effective theories at the meson and baryon levels. We extend the application of this technique to the study of Lorentz-violating and potentially CPT-violating operators from the minimal standard model extension. For dimension-4 operators, there are nontrivial relations between the coefficients of baryon-level operators related to underlying quark and gluon operators with the same Lorentz structures. Moreover, in the mapping of the dimension-3 operators from the quark and gluon level to the hadron level (considered here for the first time), many of the hadronic observables contain no new low-energy coupling constants at all, which makes it possible to make direct translations of bounds derived using experiments on one kind of hadron into bounds in a completely different corner of the hadronic sector. A notable consequence of this is bounds (at 10−15 − 10−20 GeV levels) on differences aBμ − aB′μ of Lorentz and CPT violation coefficients for SU(3)f octet baryons that differ in their structure by the replacement of a single valance d quark by a s quark. Never before has there been any proposal for how these kinds of differences could be constrained.
Acute kidney injury (AKI) may be associated with short- and long-term patient morbidity and mortality. Therefore, the impact of AKI after cardiac arrest on survival and neurological outcome was ...evaluated.
An observational single center study was conducted and consecutively included all out and in hospital cardiac arrest (OHCA/IHCA) patients treated with therapeutic temperature management between 2006 and 2013. Patient morbidity, mortality and neurological outcome according to the widely used Pittsburgh Cerebral Performance Category (CPC) were assessed. A good neurological outcome was defined as a CPC of 1–2 versus a poor neurological outcome with a CPC of 3–5. AKI was defined by using the KDIGO Guidelines 2012.
503 patients were observed in total. 29.4% (n = 148) developed AKI during their intensive care unit (ICU) stay. 70.6% (n = 355) did not experience AKI. The mean age at admission was 62 years, of those 72.8% were male and 77% experienced an out-of-hospital cardiac arrest (OHCA). AKI occurred with 41.2% more often in the group with poor neurological outcome compared to 17.1% in the group with good neurological outcome. The median survival for patients after cardiac arrest with AKI was 0.07 years compared to 6.5 years for patients without AKI.
Our data suggest that AKI is a major risk factor for a poor neurological outcome and a higher mortality after cardiac arrest. Further important risk factors were age, time to ROSC and high NSE.
•AKI is a major risk factor for a poor neurological outcome after cardiac arrest.•AKI predisposes to a higher mortality among those who survived cardiac arrest.•AKI may reflect both, more severe chronic comorbid conditions and the extent of cardiac disease.
Delays in the diagnosis of Alzheimer's disease, and, therefore, delays in treatment, may have a detrimental effect on a patient's long-term well-being. This study assessed the effects of postponing ...donepezil treatment for 1 year by comparing patients treated continuously for 3 years with those who received placebo for 1 year followed by open-label donepezil for 2 years. Patients (n = 286) with possible or probable Alzheimer's disease (according to DSM-IV, NINCDS-ADRDA, and Mini-Mental State Examination criteria; see text) were randomized to receive donepezil (5 mg/day for 4 weeks, 10 mg/day thereafter) or placebo (delayed-start group) for 1 year. Of the 192 completers, 157 began a 2-year, open-label phase of donepezil treatment. Outcome measures were the Gottfries-Bråne-Steen scale, the Mini-Mental State Examination, the Global Deterioration Scale, the Progressive Deterioration Scale, the Neuropsychiatric Inventory, and safety (adverse events). Mixed regression analysis was used to compare changes between the groups over 3 years on the efficacy measures. There was a trend for patients receiving continuous therapy to have less global deterioration (Gottfries-Bråne-Steen scale) than those who had delayed treatment (p = 0.056). Small but statistically significant differences between the groups were observed for the secondary measures of cognitive function (Mini-Mental State Examination; p = 0.004) and cognitive and functional abilities (Global Deterioration Scale; p = 0.0231) in favor of continuous donepezil therapy. Over 90% of the patients in both cohorts experienced one treatment-emergent adverse event; most were considered mild or moderate. In conclusion, patients in whom the start of treatment is delayed may demonstrate slightly reduced benefits as compared with those seen in patients starting donepezil therapy early in the course of Alzheimer's disease. These data support the long-term efficacy and safety of donepezil.
Microinflammation in renal failure has been the subject of numerous studies, but the causes of the inflammatory response in these patients are not clear. There are several potential causes and ...possible therapies for microinflammation, and they are discussed in this review with regard to uraemia and acidosis, heart failure and volume overload, oxidative stress and iron therapy, and bioincompatibility, especially regarding dialysis membranes. In addition, issues regarding dialysate contamination and access site infection are examined, followed by a discussion of possible drug therapy for microinflammation with angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, statins, aspirin, and antioxidants, such as vitamin E.
Loss and degradation of grasslands in the Great Plains region have resulted in major declines in abundance of grassland bird species. To ensure future viability of grassland bird populations, it is ...crucial to evaluate specific effects of environmental factors among species to determine drivers of population decline and develop effective conservation strategies. We used threshold models to quantify the effects of land cover and weather changes in "lesser prairie‐chicken" and "greater prairie‐chicken" (Tympanuchus pallidicinctus and T. cupido, respectively), northern bobwhites (Colinus virginianus), and ring‐necked pheasants (Phasianus colchicus). We demonstrated a novel approach for estimating landscape conditions needed to optimize abundance across multiple species at a variety of spatial scales. Abundance of all four species was highest following wet summers and dry winters. Prairie chicken and ring‐necked pheasant abundance was highest following cool winters, while northern bobwhite abundance was highest following warm winters. Greater prairie chicken and northern bobwhite abundance was also highest following cooler summers. Optimal abundance of each species occurred in landscapes that represented a grassland and cropland mosaic, though prairie chicken abundance was optimized in landscapes with more grassland and less edge habitat than northern bobwhites and ring‐necked pheasants. Because these effects differed among species, managing for an optimal landscape for multiple species may not be the optimal scenario for any one species.
We quantified the effects of land cover and weather changes in Galliformes in Kansas. We found evidence of nonlinear, threshold effects of land cover change in abundance of all four focal species, suggesting that the presence of both grassland and cropland is important in the landscape to simultaneously maintain these populations.
SEE PDF The corrected affiliation assignment and Fig. 3 have been provided in this Correction article and the original article 1 has been updated Correction Open Access Published:11 July 2023 ...Correction: Differential effects of mutations of POPDC proteins on heteromeric interaction and membrane trafficking Alexander H. Swan ORCID: orcid.org/0000-0003-2177-87031,2, Roland F. R. Schindler ORCID: orcid.org/0000-0001-6823-96221,9, Marco Savarese ORCID: orcid.org/0000-0002-2591-244X3, Isabelle Mayer1, Susanne Rinné ORCID: orcid.org/0000-0003-2326-70694, Felix Bleser4, Anne Schänzer ORCID: orcid.org/0000-0002-2014-20285, Andreas Hahn ORCID: orcid.org/0000-0003-0235-52116, Mario Sabatelli ORCID: orcid.org/0000-0001-6635-49857, Francesco Perna ORCID: orcid.org/0000-0002-9019-94928, Kathryn Chapman9, Mark Pfuhl ORCID: orcid.org/0000-0001-9592-663910, Alan C. Spivey ORCID: orcid.org/0000-0001-5114-490X2, Niels Decher ORCID: orcid.org/0000-0002-9433-687X4, Bjarne Udd ORCID: orcid.org/0000-0002-1101-973011, Giorgio Tasca ORCID: orcid.org/0000-0003-0849-914412 nAff13 & … Fig. 3 figure 3 The expression of POPDC1 and POPDC2 is greatly reduced at the sarcolemma of skeletal muscle fibers expressing POPDC1 p.Q153X. a and b Transverse sections of skeletal muscle biopsies from a patient (PT) carrying the POPDC1 p.Q153X variant in homozygosity and a matched control (CT) were stained for a POPDC1 or b POPDC2, along with SGCA as a sarcolemma marker. Data were analyzed using Mann–Whitney test; ***p < 0.0001 Full size image The corrected affiliation assignment and Fig. 3 have been provided in this Correction article and the original article 1 has been updated
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