A recent prospective meta-analysis demonstrated that interleukin-6 antagonists are associated with lower all-cause mortality in hospitalised patients with COVID-19, compared with usual care or ...placebo. However, emerging evidence suggests that clinicians are favouring the use of tocilizumab over sarilumab. A new randomised comparison of these agents from the REMAP-CAP trial shows similar effects on in-hospital mortality. Therefore, we initiated a network meta-analysis, to estimate pairwise associations between tocilizumab, sarilumab and usual care or placebo with 28-day mortality, in COVID-19 patients receiving concomitant corticosteroids and ventilation, based on all available direct and indirect evidence. Eligible trials randomised hospitalised patients with COVID-19 that compared tocilizumab or sarilumab with usual care or placebo in the prospective meta-analysis or that directly compared tocilizumab with sarilumab. Data were restricted to patients receiving corticosteroids and either non-invasive or invasive ventilation at randomisation. One trial (REMAP-CAP) was identified that directly compared tocilizumab with sarilumab and supplied results on all-cause mortality at 28-days. This network meta-analysis was based on 898 eligible patients (278 deaths) from REMAP-CAP and 3710 eligible patients from 18 trials (1278 deaths) from the prospective meta-analysis. Summary ORs were similar for tocilizumab 0·82 0·71-0·95, p = 0·008 and sarilumab 0·80 0·61-1·04, p = 0·09 compared with usual care or placebo. The summary OR for 28-day mortality comparing tocilizumab with sarilumab was 1·03 95%CI 0·81-1·32, p = 0·80. The p-value for the global test of inconsistency was 0·28. Administration of either tocilizumab or sarilumab was associated with lower 28-day all-cause mortality compared with usual care or placebo. The association is not dependent on the choice of interleukin-6 receptor antagonist.
Cerebral autoregulation may become impaired after stroke. To provide a review of the nature and extent of any autoregulation impairment after stroke and its course over time, a technique allowing ...repeated bedside measurements with good temporal resolution is required. Transcranial Doppler (TCD) in combination with continuous blood pressure measurements allows noninvasive continuous bedside investigation with high temporal resolution of the dynamic and the steady-state components of cerebral autoregulation. Therefore, this review focuses on all TCD studies on cerebral autoregulation in the setting of documented ischemic stroke.
PubMed and EMBASE were searched for studies of stroke, autoregulation, and TCD. Studies were either acute phase (<96 hours after index stroke) or chronic phase (>96 hours after index stroke) autoregulation studies. Quality of studies was studied in a standardized fashion.
Twenty-three studies met the inclusion criteria. General agreement existed on cerebral autoregulation being impaired, even after minor stroke. Bilateral impairment of autoregulation was documented, particularly after lacunar stroke. Studies showed progressive deterioration of cerebral autoregulation in the first 5 days after stroke and recovery over the next 3 months. Impaired cerebral autoregulation as assessed by TCD was related to neurological deterioration, the necessity for decompressive surgery, and poor outcome. Synthesis of the data of various studies was, however, limited by studies not meeting key methodological criteria for observational studies.
TCD in combination with continuous blood pressure measurement offers a method with a high temporal resolution feasible for bedside evaluation of cerebral autoregulation in the stroke unit. TCD studies have shown impairment of cerebral autoregulation in various subtypes of ischemic stroke. To improve the synthesis of data from various research groups, there is urgent need for standardization of methodology of TCD studies in cerebral autoregulation.
The total number of ovarian follicles ≥ 3mm in diameter (antral follicle count, AFC) during follicular waves varies among cattle of similar age, but AFC is highly repeatable within individuals. We ...hypothesized that lower AFC could be associated with reduced fertility in cattle. The AFC was assessed by ultrasonography for 2 d consecutively during the first wave of follicular growth of the estrous cycle, 4.6±1.43 d (mean ± SD) after estrus, in 306 Holstein-Friesian dairy cows approximately 70 d postpartum. Cows were classified into 3 groups based on AFC: low (AFC ≤15), intermediate (AFC=16 to 24), and high (AFC ≥25). During the cycle in which AFC was assessed and in subsequent cycles, cows were artificially inseminated (AI) following detection of estrus, and pregnancy status was assessed using ultrasonography. Cows with high AFC had 3.34 times greater odds of being pregnant at the end of the breeding season compared with cows with low AFC; the odds of a successful pregnancy at first service were 1.75 times greater in the intermediate compared with the low group. The predicted probability of a successful pregnancy by the end of the breeding period (length of breeding season was 86±16.3 d) was 94, 88, and 84% for the high, intermediate, and low AFC groups, respectively. No difference was evident among groups in 21-d submission rate (proportion of all cows detected in estrus and submitted for AI in the first 21 d of the breeding season), but the interval from calving to conception was shorter in the high (109.5±5.1 d) versus low (117.1±4 d) group, and animals with intermediate AFC received fewer services during the breeding season (2.3±0.1) compared with animals with low AFC (2.7±0.1). Lactating cows with ≤15 ovarian follicles have lower reproductive performance compared with cows with higher numbers of follicles, but the existence of a positive association between high numbers of ovarian follicles and fertility is yet to be established.
Tremendous advancements in syndromic surveillance strategies over the last two decades, and specifically from prior mass gatherings, have been incorporated into day-to-day healthcare analysis ...worldwide and have left a lasting indirect impact since their inception. Mass gatherings are a daily occurrence worldwide and provide a scenario ripe for public health aims and objectives utilising syndromic surveillance. Europe is less than a decade away from hosting a colossal worldwide gathering (2024 Summer Olympics) in likely a time when the global agreement is in flux. A call to arms is needed for additional surveillance strategies incorporating mobile application symptom checker data, telemedicine, social media and social data sensing. There remains a need for an optimal combination of real-time data sensing that captures the whole population, but to reach that goal we must incorporate new advancements into baseline epidemiologic data monitoring, otherwise we will be tracking real-time mass gathering events on top of inaccurate baseline epidemiologic data.
The objective of the present study was to characterize the phenotypic performance of cows with similar proportions of Holstein genetics, similar genetic merit for milk production traits, but with ...good (Fert+) or poor (Fert−) genetic merit for fertility traits. Specifically, we tested the hypothesis that cows with a negative estimated breeding value for calving interval would have superior fertility performance and would have detectable differences in body reserve mobilization and circulating concentrations of metabolic hormones and metabolites compared with cows that had a positive estimated breeding value for calving interval. For the duration of the study, cows were managed identically as a single herd in a typical grass-based, spring-calving production system. A total of 80 lactation records were available from 26 Fert+ and 26 Fert− cows over 2 consecutive years (2008 and 2009). During yr 1, cows were monitored during a 20-wk breeding season to evaluate reproductive performance. Milk production, body condition score (scale 1 to 5), body weight, grass dry matter intake, energy balance, and metabolic hormone and metabolite data were collected during both years. The Fert+ cows had greater daily milk yield (19.5 vs. 18.7kg/d), shorter interval from calving to conception (85.6 vs. 113.8 d), and fewer services per cow (1.78 vs. 2.83). No difference between groups in grass dry matter intake, energy balance, or body weight was observed. The Fert+ cows maintained greater BCS during mid (2.84 vs. 2.74 units) and late lactation (2.82 vs. 2.73 units). Circulating concentrations of insulin-like growth factor-I were greater throughout the gestation-lactation cycle in Fert+ cows (148.3 vs. 128.2ng/mL). The Fert+ cows also had greater circulating concentrations of insulin during the first 4 wk of lactation (1.71 vs. 1.24μIU/mL). Analysis of records from national herd data verified the association between genetic merit for fertility traits and phenotypic reproductive performance; Fert+ cows (n=2,436) required 11.1 d less to recalve than did Fert− cows (n=1,388), and the percentage of cows that successfully calved for the second time within 365 and 400 d of the first calving was 8 and 13% greater for Fert+ compared with Fert− cows, respectively. These results demonstrate that genetic merit for fertility traits had a pronounced effect on reproductive efficiency, BCS profiles, and circulating concentrations of insulin-like growth factor-I.
It is widely accepted that climate change poses severe threats to freshwater ecosystems. Here we examine the scientific basis for adaptively managing vulnerable habitats and species. Our views are ...shaped by a literature survey of adaptation in practice, and by expert opinion. We assert that adaptation planning is constrained by uncertainty about evolving climatic and non-climatic pressures, by difficulties in predicting species- and ecosystem-level responses to these forces, and by the plasticity of management goals. This implies that adaptation measures will have greatest acceptance when they deliver multiple benefits, including, but not limited to, the amelioration of climate impacts. We suggest that many principles for biodiversity management under climate change are intuitively correct but hard to apply in practice. This view is tested using two commonly assumed doctrines: “increase shading of vulnerable reaches through tree planting” (to reduce water temperatures); and “set hands off flows” (to halt potentially harmful abstractions during low flow episodes). We show that the value of riparian trees for shading, water cooling and other functions is partially understood, but extension of this knowledge to water temperature management is so far lacking. Likewise, there is a long history of environmental flow assessment for allocating water to competing uses, but more research is needed into the effectiveness of ecological objectives based on target flows. We therefore advocate more multi-disciplinary field and model experimentation to test the cost-effectiveness and efficacy of adaptation measures applied at different scales. In particular, there is a need for a major collaborative programme to: examine natural adaptation to climatic variation in freshwater species; identify where existing environmental practice may be insufficient; review the fitness of monitoring networks to detect change; translate existing knowledge into guidance; and implement best practice within existing regulatory frameworks.
The ability to accurately predict breed composition using genomic information has many potential uses including increasing the accuracy of genetic evaluations, optimising mating plans and as a ...parameter for genotype quality control. The objective of the present study was to use a database of genotyped purebred and crossbred cattle to compare breed composition predictions using a freely available software, Admixture, with those from a single nucleotide polymorphism Best Linear Unbiased Prediction (SNP-BLUP) approach; a supplementary objective was to determine the accuracy and general robustness of low-density genotype panels for predicting breed composition.
All animals had genotype information on 49,213 autosomal single nucleotide polymorphism (SNPs). Thirteen breeds were included in the analysis and 500 purebred animals per breed were used to establish the breed training populations. Accuracy of breed composition prediction was determined using a separate validation population of 3,146 verified purebred and 4,330 two and three-way crossbred cattle.
When all 49,213 autosomal SNPs were used for breed prediction, a minimal absolute mean difference of 0.04 between Admixture vs. SNP-BLUP breed predictions was evident. For crossbreds, the average absolute difference in breed prediction estimates generated using SNP-BLUP and Admixture was 0.068 with a root mean square error of 0.08. Breed predictions from low-density SNP panels were generated using both SNP-BLUP and Admixture and compared to breed prediction estimates using all 49,213 SNPs (representing the gold standard). Breed composition estimates of crossbreds required more SNPs than predicting the breed composition of purebreds. SNP-BLUP required ≥3,000 SNPs to predict crossbred breed composition, but only 2,000 SNPs were required to predict purebred breed status. The absolute mean (standard deviation) difference across all panels <2,000 SNPs was 0.091 (0.054) and 0.315 (0.316) when predicting the breed composition of all animals using Admixture and SNP-BLUP, respectively compared to the gold standard prediction.
Nevertheless, a negligible absolute mean (standard deviation) difference of 0.009 (0.123) in breed prediction existed between SNP-BLUP and Admixture once ≥3,000 SNPs were considered, indicating that the prediction of breed composition could be readily integrated into SNP-BLUP pipelines used for genomic evaluations thereby avoiding the necessity for a stand-alone software.
Abstract One of the primary lines of defense against oxidative stress is the selenoprotein family, a class of proteins that contain selenium in the form of the 21st amino acid, selenocysteine. Within ...this class of proteins, selenoprotein P (Sepp1) is unique, as it contains multiple selenocysteine residues and is postulated to act in selenium transport. Recent findings have demonstrated that neuronal selenoprotein synthesis is required for the development of parvalbumin (PV)-interneurons, a class of GABAergic neurons involved in the synchronization of neural activity. To investigate the potential influence of Sepp1 on PV-interneurons, we first mapped the distribution of the Sepp1 receptor, ApoER2, and parvalbumin in the mouse brain. Our results indicate that ApoER2 is highly expressed on PV-interneurons in multiple brain regions. Next, to determine whether PV-interneuron populations are affected by Sepp1 deletion, we performed stereology on several brain regions in which we observed ApoER2 expression on PV-interneurons, comparing wild-type and Sepp1 −/− mice. We observed reduced numbers of PV-interneurons in the inferior colliculus of Sepp1 −/− mice, which corresponded with a regional increase in oxidative stress. Finally, as impaired PV-interneuron function has been implicated in several neuropsychiatric conditions, we performed multiple behavioral tests on Sepp1 −/− mice. Our behavioral results indicate that Sepp1 −/− mice have impairments in contextual fear extinction, latent inhibition, and sensorimotor gating. In sum, these findings demonstrate the important supporting role of Sepp1 on ApoER2-expressing PV-interneurons.
Anthropogenic pressures are restructuring coral reefs globally. Sound predictions of the expected changes in key reef functions require adequate knowledge of their drivers. Here we investigate the ...determinants of a poorly-studied yet relevant biogeochemical function sustained by marine bony fishes: the excretion of intestinal carbonates. Compiling carbonate excretion rates and mineralogical composition from 382 individual coral reef fishes (85 species and 35 families), we identify the environmental factors and fish traits that predict them. We find that body mass and relative intestinal length (RIL) are the strongest predictors of carbonate excretion. Larger fishes and those with longer intestines excrete disproportionately less carbonate per unit mass than smaller fishes and those with shorter intestines. The mineralogical composition of excreted carbonates is highly conserved within families, but also controlled by RIL and temperature. These results fundamentally advance our understanding of the role of fishes in inorganic carbon cycling and how this contribution will change as community composition shifts under increasing anthropogenic pressures.
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