Tapping into non-English-language science for the conservation of global biodiversity.

The widely held assumption that any important scientific information would be available in English underlies the underuse of non-English-language science across disciplines. However, non-English-language science is expected to bring unique and valuable scientific information, especially in disciplines where the evidence is patchy, and for emergent issues where synthesising available evidence is an urgent challenge. Yet such contribution of non-English-language science to scientific communities and the application of science is rarely quantified. Here, we show that non-English-language studies provide crucial evidence for informing global biodiversity conservation. By screening 419,679 peer-reviewed papers in 16 languages, we identified 1,234 non-English-language studies providing evidence on the effectiveness of biodiversity conservation interventions, compared to 4,412 English-language studies identified with the same criteria. Relevant non-English-language studies are being published at an increasing rate in 6 out of the 12 languages where there were a sufficient number of relevant studies. Incorporating non-English-language studies can expand the geographical coverage (i.e., the number of 2° × 2° grid cells with relevant studies) of English-language evidence by 12% to 25%, especially in biodiverse regions, and taxonomic coverage (i.e., the number of species covered by the relevant studies) by 5% to 32%, although they do tend to be based on less robust study designs. Our results show that synthesising non-English-language studies is key to overcoming the widespread lack of local, context-dependent evidence and facilitating evidence-based conservation globally. We urge wider disciplines to rigorously reassess the untapped potential of non-English-language science in informing decisions to address other global challenges. Please see the Supporting information files for Alternative Language Abstracts.

In-Hospital Management and Long-term Clinical Outcomes and Adherence in Patients With Acute Decompensated Heart Failure: Primary Results of the First Brazilian Registry of Heart Failure (BREATHE).

BACKGROUND: Heart failure (HF), a common cause of hospitalization, is associated with poor short-term clinical outcomes. Little is known about the long-term prognoses of patients with HF in Latin America. METHODS: BREATHE was the first nationwide prospective observational study in Brazil that included patients hospitalized due to acute heart failure (HF). Patients were included during 2 time periods: February 2011-December 2012 and June 2016-July 2018 SUGGESTION FOR REPHRASING: In-hospital management, 12-month clinical outcomes and adherence to evidence-based therapies were evaluated. RESULTS: A total of 3013 patients were enrolled at 71 centers in Brazil. At hospital admission, 83.8% had clear signs of pulmonary congestion. The main cause of decompensation was poor adherence to HF medications (27.8%). Among patients with reduced ejection fraction, concomitant use of beta-blockers, renin-angiotensin-aldosterone inhibitors and spironolactone decreased from 44.5% at hospital discharge to 35.2% at 3 months. The cumulative incidence of mortality at 12 months was 27.7%, with 24.3% readmission at 90 days and 44.4% at 12 months. CONCLUSIONS: In this large national prospective registry of patients hospitalized with acute HF, rates of mortality and readmission were higher than those reported globally. Poor adherence to evidence-based therapies was common at hospital discharge and at 12 months of follow-up.

Phylogenomics of Scorpions Reveal Contemporaneous Diversification of Scorpion Mammalian Predators and Mammal-Active Sodium Channel Toxins.

Scorpions constitute a charismatic lineage of arthropods and comprise more than 2500 described species. Found throughout various tropical and temperate habitats, these predatory arachnids have a long evolutionary history, with a fossil record that began in the Silurian. While all scorpions are venomous, the asymmetrically diverse family Buthidae harbors nearly half the diversity of extant scorpions, and all but one of the 58 species that are medically significant to humans. However, the lack of a densely sampled scorpion phylogeny has hindered broader inferences of the diversification dynamics of scorpion toxins. To redress this gap, we assembled a phylogenomic data set of 100 scorpion venom gland transcriptomes and genomes, emphasizing the sampling of highly toxic buthid genera. To infer divergence times of venom gene families, we applied a phylogenomic node dating approach for the species tree in tandem with phylostratigraphic bracketing to estimate the minimum ages of mammal-specific toxins. Our analyses establish a robustly supported phylogeny of scorpions, particularly with regard to relationships between medically significant taxa. Analysis of venom gene families shows that mammal-active sodium channel toxins (NaTx) have independently evolved in five lineages within Buthidae. Temporal windows of mammal-targeting toxin origins are correlated with the basal diversification of major scorpion mammal predators such as shrews, bats, and rodents. These results suggest an evolutionary model of relatively recent diversification of buthid NaTx homologs in response to the diversification of scorpion predators. [Adaptation; arachnids; phylogenomic dating; phylostratigraphy; venom.].

The Clinical Impact of Thoracic Endovascular Aortic Repair in the Management of Thoracic Aortic Diseases.

PURPOSE: Thoracic endovascular aortic repair (TEVAR) has been described to be superior to an open surgical approach, and previous studies have found superiority in TEVAR by reducing overall morbidity and mortality rates. This study aimed to describe the outcomes of TEVAR for patients with thoracic aortic disease at a high complexity. MATERIALS AND METHODS: Descriptive study, developed by a retrospective review of a prospectively collected database. Patients aged above 18 years who underwent TEVAR between 2012 and 2022 were included. Patient demographics, perioperative data, surgical outcomes, morbidity, and mortality were described. Statistical and multivariate analyses were made. Statistical significance was reached when p values were <0.05. RESULTS: A total of 66 patients were included. Male patients were 60.61% and the mean age was 69.24 years. Associated aortic diseases were aneurysms (68.18%), ulcer-related (4.55%), intramural-related hematoma (7.58%), trauma-related pathology (1.52%), and aortic dissection (30.30%). The mean hospital stay was 18.10 days, and intensive care unit was required for 98.48%. At 30 days, the mortality rate was 10.61% and the reintervention rate was 21.21%. Increased intraoperative blood loss (p=0.001) and male sex (p=0.04) showed statistical relationship with mortality. Underweight patients have 6.7 and 11.4 times more risk of complications and endoleak compared with higher body mass index values (p=0.04, 95% confidence interval [CI]=0.82-7.21) and (p=0.02, 95% CI=1.31-12.57), respectively. CONCLUSION: Thoracic endovascular aortic repair seems to be a feasible option for patients with thoracic aortic pathologies, with adequate rates of mortality and morbidity. Underweight patients seem to have an increased risk of overall morbidity and increased risk for endoleak. Further prospective studies are needed to prove our results. CLINICAL IMPACT: Obesity and BMI are widely studied in the surgical literature. According to our study, there is a paradox regarding the outcomes of patients treated with TEVAR in terms of postoperative complications and mortality related to the body mass index. And shouldn't be considered as a high-risk feature in terms of postoperative morbidity and mortality in this procedure.

Incidence of appendiceal neoplasms in appendectomy patients.

BACKGROUND: Non-operative management has been suggested as a therapy for uncomplicated appendicitis. Notwithstanding, the risk of missing an appendiceal tumor must be considered, being the surgical piece crucial to rule out neoplasms. Therefore, we aim to determine the incidence of appendiceal neoplasms in patients with acute appendicitis, tumor types and the importance of the anatomopathological study of the surgical piece. STUDY DESIGN: Retrospective study in which we described patients who underwent emergent appendectomy with histopathological findings of appendiceal neoplasms from January 2012 to September 2018. Descriptive analysis included demographic variables, diagnostic methods, and surgical techniques. RESULTS: 2993 patients diagnosed with acute appendicitis who underwent an emergency appendectomy. 64 neoplasms of the appendix were found with an incidence of 2,14%. 67.2% were women, the mean age was 46,4 years (± 19.5). The most frequent appendiceal neoplasms were neuroendocrine tumors (42,2%), followed by appendiceal mucinous neoplasms (35,9%), sessile serrated adenomas (18,8%), and adenocarcinomas (3,1%). In 89,1% of the cases, acute appendicitis was determined by imaging, and 14% of cases were suspected intraoperatively. Appendectomy was performed in 78,1% without additional procedures. CONCLUSIONS: Appendiceal tumors are rare and must be ruled out in patients with suspected acute appendicitis. The incidence of incidental neoplasms is higher in this study than in the previously reported series. This information must be included in decision-making when considering treatment options for acute appendicitis.

Variations in clinical course and surgical outcomes of acute appendicitis during COVID-19 Pandemic: a multicenter cohort study.

BACKGROUND: COVID-19 pandemic has led to changes in the presentation and treatment of surgical pathologies. Therefore, we aim to describe the influence of the COVID-19 pandemic on the clinical presentation and management of acute appendicitis (AAp) and its surgical outcomes. STUDY DESIGN: A multicenter cohort study with prospectively collected databases. Three high-volume centers were included and all patients over 18 years of age who underwent appendectomy for AAp were included. Multiple logistic regression and multinomial logistic regression were performed, and odds ratio, relative risk, and B-coefficient were reported when appropriate, statistical significance was reached with p-values < 0.05. RESULTS: 1.468 patients were included (709 in the pre-pandemic group and 759 in the COVID-19 group). Female patients constituted 51.84%. Mean age was 38.13 ± 16.96 years. Mean Alvarado's score was 7.01 ± 1.59 points. Open surgical approach was preferred in 90.12%. Conversion rate of 1.29%. Mortality rate was 0.75%. There was an increase of perforated and localized peritonitis (p 0.01) in the COVID-19 group. Presence of any postoperative complication (p 0.00), requirement of right colectomy and ileostomy (p 0.00), and mortality (p 0.04) were higher in the COVID-19 group. Patients in the pre-pandemic group have a lesser risk of mortality (OR 0.14, p 0.02, 95% CI 0.02-0.81) and a lesser relative risk of having complicated appendicitis (RR 0.68, p 0.00, 95% CI 0.54-0.86). CONCLUSION: Complicated appendicitis was an unexpected consequence of the COVID-19 pandemic, due to surgical consultation delay, increased rates of morbidity, associated procedures, and mortality, influencing the clinical course and surgical outcomes of patients with AAp.

Allelic and genotypic frequencies of SNP related to beef and carcass quality in Romosinuano cattle in Mexico.

Romosinuano is a tropically adapted Bos taurus breed, and some Mexican breeders aim to improve it genetically. The aim was to estimate allelic and genotypic frequencies for SNPs associated with meat quality in a Mexican Romosinuano population. Four hundred ninety-six animals were genotyped using the Axiom©BovMDv3 array. Only SNPs related to meat quality in this array were studied in this analysis. The Calpain, Calpastatin, and Melanocortin-4 receptor alleles were considered. Allelic and genotypic frequencies and Hardy-Weinberg equilibrium were estimated with the PLINK software. Alleles associated with meat tenderness and higher marbling scores were found in the Romosinuano cattle population. CAPN1_4751 was not found in Hardy-Weinberg equilibrium. The rest of the markers could not be affected by selection and inbreeding. Romosinuano cattle in Mexico have similar genotypic frequencies in markers related to meat quality to Bos taurus breeds known for their meat tenderness. Breeders can choose a marker-assisted selection to improve meat quality characteristics.

Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure.

BACKGROUND: Acute decompensated heart failure accounts for more than 1 million hospitalizations in the United States annually. Whether the initiation of sacubitril-valsartan therapy is safe and effective among patients who are hospitalized for acute decompensated heart failure is unknown. METHODS: We enrolled patients with heart failure with reduced ejection fraction who were hospitalized for acute decompensated heart failure at 129 sites in the United States. After hemodynamic stabilization, patients were randomly assigned to receive sacubitril-valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or enalapril (target dose, 10 mg twice daily). The primary efficacy outcome was the time-averaged proportional change in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration from baseline through weeks 4 and 8. Key safety outcomes were the rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema. RESULTS: Of the 881 patients who underwent randomization, 440 were assigned to receive sacubitril-valsartan and 441 to receive enalapril. The time-averaged reduction in the NT-proBNP concentration was significantly greater in the sacubitril-valsartan group than in the enalapril group; the ratio of the geometric mean of values obtained at weeks 4 and 8 to the baseline value was 0.53 in the sacubitril-valsartan group as compared with 0.75 in the enalapril group (percent change, -46.7% vs. -25.3%; ratio of change with sacubitril-valsartan vs. enalapril, 0.71; 95% confidence interval [CI], 0.63 to 0.81; P<0.001). The greater reduction in the NT-proBNP concentration with sacubitril-valsartan than with enalapril was evident as early as week 1 (ratio of change, 0.76; 95% CI, 0.69 to 0.85). The rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema did not differ significantly between the two groups. CONCLUSIONS: Among patients with heart failure with reduced ejection fraction who were hospitalized for acute decompensated heart failure, the initiation of sacubitril-valsartan therapy led to a greater reduction in the NT-proBNP concentration than enalapril therapy. Rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema did not differ significantly between the two groups. (Funded by Novartis; PIONEER-HF ClinicalTrials.gov number, NCT02554890 .).

The Phylogeny and Evolution of the Flashiest of the Armored Harvestmen (Arachnida: Opiliones).

Gonyleptoidea, largely restricted to the Neotropics, constitutes the most diverse superfamily of Opiliones and includes the largest and flashiest representatives of this arachnid order. However, the relationships among its main lineages (families and subfamilies) and the timing of their origin are not sufficiently understood to explain how this tropical clade has been able to colonize the temperate zone. Here, we used transcriptomics and divergence time dating to investigate the phylogeny of Gonyleptoidea. Our results support the monophyly of Gonyleptoidea and all of its families with more than one species represented. Resolution within Gonyleptidae s.s. is achieved for many clades, but some subfamilies are not monophyletic (Gonyleptinae, Mitobatinae, and Pachylinae), requiring taxonomic revision. Our data show evidence for one colonization of today's temperate zone early in the history of Gonyleptidae, during the Paleogene, at a time when the Neotropical area extended poleward into regions now considered temperate. This provides a possible mechanism for the colonization of the extratropics by a tropical group following the Paleocene-Eocene Thermal Maximum, explaining how latitudinal diversity gradients can be established. Taxonomic acts: Ampycidae Kury 2003 is newly ranked as family; Neosadocus Mello-Leitão is transferred to Progonyleptoidellinae (new subfamilial assignment). [Arachnids; biogeography; phylogenomics; transcriptomics.].

Postoperative outcomes of minimally invasive adrenalectomy: do body mass index and tumor size matter? A single-center experience.

BACKGROUND: Since Gagner performed the first laparoscopic adrenalectomy in 1992, laparoscopy has become the gold-standard procedure in the treatment of adrenal surgical diseases. A review of the literature indicates that the rate of intra- and postoperative complications are not negligible. This study aims to describe the single-center experience of adrenalectomies; and explore the associations between body mass index (BMI) and tumor volume in main postoperative outcomes. METHODS: Retrospective observational study with a prospective database in which we described patients who underwent adrenalectomy between January 2015 and December 2020. Operative time, intraoperative blood loss, conversion rate, complications, length of hospital stay, and comparison of the number of antihypertensive drugs used before and after surgery were analyzed. Analysis of BMI and tumor volume with postoperative outcomes such as anti-hypertensive change (AHC) in drug usage and pre-operative conditions were performed. RESULTS: Forty-five adrenalectomies were performed, and all of them were carried out laparoscopically. Four were performed as a robot-assisted laparoscopy approach. Nineteen were women and 26 were men. Mean age was 54.9 ± 13.8 years. Mean tumor volume was 95.698 mm3 (3.75-1010.87). Mean operative time was shorter in right tumors (2.64 ± 0.75 h) than in left tumors (3.33 ± 2.73 h). Pearson correlation was performed to assess the relationship between BMI and AHC showing a direct relationship between increased BMI and higher change in anti-hypertensive drug usage at postoperative period r(45) = 0.92, p > 0.05 CI 95%. Higher tumor volume showed a longer operative time, r(45) = 0.6 (p = 0.000 CI 95%). CONCLUSIONS: Obese patients could have an increased impact with surgery with an increased change in postoperative anti-hypertensive management. Tumor volume is associated with increased operative time and blood loss, our data suggest that it could be associated with increased rates of morbidity. However, further prospective studies with larger sample sizes are needed to validate our results.

Optimizing bat bioacoustic surveys in human-modified Neotropical landscapes.

During the last decades, the use of bioacoustics as a non-invasive and cost-effective sampling method has greatly increased worldwide. For bats, acoustic surveys have long been known to complement traditional mist-netting, however, appropriate protocol guidelines are still lacking for tropical regions. Establishing the minimum sampling effort needed to detect ecological changes in bat assemblages (e.g., activity, composition, and richness) is crucial in view of workload and project cost constraints, and because detecting such changes must be reliable enough to support effective conservation management. Using one of the most comprehensive tropical bat acoustic data sets, collected in the Amazon, we assessed the minimum survey effort required to accurately assess the completeness of assemblage inventories and habitat selection in fragmented forest landscapes for aerial insectivorous bats. We evaluated a combination of 20 different temporal sampling schemes, which differed regarding number of hours per night, number of nights per site, and sampling only during the wet or dry season, or both. This was assessed under two different landscape scenarios: in primary forest fragments embedded in a matrix of secondary forest and in the same forest fragments, but after they had been re-isolated through clearing of the secondary forest. We found that the sampling effort required to achieve 90% inventory completeness varied considerably depending on the research aim and the landscape scenario evaluated, averaging ~80 and 10 nights before and after fragment re-isolation, respectively. Recording for more than 4 h per night did not result in a substantial reduction in the required number of sampling nights. Regarding the effects of habitat selection, except for assemblage composition, bat responses in terms of richness, diversity, and activity were similar across all sampling schemes after fragment re-isolation. However, before re-isolation, a minimum of four to six sampling hours per night after dusk and three to five nights of sampling per site were needed to detect significant effects that could otherwise go unnoticed. Based on our results, we propose guidelines that will aid to optimize sampling protocols for bat acoustic surveys in the Neotropics.

A new cure rate model with flexible competing causes with applications to melanoma and transplantation data.

In this article, we introduce a long-term survival model in which the number of competing causes of the event of interest follows the zero-modified geometric (ZMG) distribution. Such distribution accommodates equidispersion, underdispersion, and overdispersion and captures deflation or inflation of zeros in the number of lesions or initiated cells after the treatment. The ZMG distribution is also an appropriate alternative for modeling clustered samples when the number of competing causes of the event of interest consists of two subpopulations, one containing only zeros (cure proportion), while in the other (noncure proportion) the number of competing causes of the event of interest follows a geometric distribution. The advantage of this assumption is that we can measure the cure proportion in the initiated cells. Furthermore, the proposed model can yield greater or lower cure proportion than that of the geometric distribution when modeling the number of competing causes. In this article, we present some statistical properties of the proposed model and use the maximum likelihood method to estimate the model parameters. We also conduct a Monte Carlo simulation study to evaluate the performance of the estimators. We present and discuss two applications using real-world medical data to assess the practical usefulness of the proposed model.

Guidelines for communicating about bats to prevent persecution in the time of COVID-19.

While the current COVID-19 pandemic continues to wreak havoc on human health and national economies, conservationists are struggling to prevent misguided persecution of bats, which are misleadingly being blamed for spreading the disease. Although at a global level, such persecution is relatively uncommon, even a few misguided actions have the potential to cause irrevocable damage to already vulnerable species. Here, we draw on the latest findings from psychology, to explain why some conservation messaging may be reinforcing misleading negative associations. We provide guidelines to help ensure that conservation messaging is working to neutralize dangerous and unwarranted negative-associations between bats and disease-risk. We provide recommendations around three key areas of psychological science: (i) debunking misinformation; (ii) counteracting negative associations; and (iii) changing harmful social norms. We argue that only by carefully framing accurate, honest, and duly contextualized information, will we be able to best serve society and present an unbiased perspective of bats. We hope this guidance will help conservation practitioners and researchers to develop effective message framing strategies that minimize zoonotic health risks and support biodiversity and its associated ecosystem services.

Cardiovascular biomarkers in patients with acute decompensated heart failure randomized to sacubitril-valsartan or enalapril in the PIONEER-HF trial.

AIMS: Circulating high-sensitivity cardiac troponin (hsTn) and soluble ST2 (sST2) reflect myocardial stress in patients with heart failure (HF). Production of cyclic guanosine 3'5' monophosphate (cGMP) in response to activation of natriuretic peptide receptors reduces cardiac afterload and preload. We assessed the effects of sacubitril/valsartan on these biomarkers in patients with reduced ejection fraction and acute decompensated HF (ADHF). METHODS AND RESULTS: PIONEER-HF was a randomized, double-blind trial of sacubitril/valsartan vs. enalapril in hospitalized patients with ADHF following haemodynamic stabilization. We measured circulating hsTnT, sST2, and urinary cGMP at baseline, 1, 2 (sST2, cGMP), 4, and 8 weeks (n = 694 with all baseline biomarkers). Ratios of geometric means (timepoint/baseline) were determined and compared as a ratio for sacubitril/valsartan vs. enalapril. Compared with enalapril, sacubitril/valsartan led to a significantly greater decline in hsTnT and sST2. This effect emerged as early as 1 week for sST2 and was significant for both at 4 weeks with a 16% greater reduction in hsTnT (P < 0.001) and 9% greater reduction in sST2 (P = 0.0033). Serial urinary cGMP increased with sacubitril/valsartan compared with enalapril (P < 0.001, 1 week). The significant differences between treatment groups for each biomarker were sustained at 8 weeks. In an exploratory multivariable-adjusted analysis of cardiovascular death or HF-rehospitalization, the concentrations of hsTnT, sST2 at week 1 were significantly associated with subsequent outcome. CONCLUSION: Biomarkers of myocardial stress are elevated in patients with ADHF and associated with outcome. Compared with enalapril, sacubitril/valsartan reduces myocardial injury and haemodynamic stress as reflected by biomarkers, with an onset that is apparent within 1-4 weeks. CLINICAL TRIALS REGISTRATION: NCT02554890 clinical.trials.gov.

Phylogeography of Sodreaninae harvestmen (Arachnida: Opiliones: Gonyleptidae): Insights into the biogeography of the southern Brazilian Atlantic Forest.

The Brazilian Atlantic Forest has long been considered a global biodiversity hotspot. In the last decade, the phylogeographic patterns of endemic taxa have been unraveling the biogeographic history of the biome. However, highly diverse invertebrate species have still been poorly studied. Sodreana harvestmen (Gonyleptidae) are distributed in most of the humid coastal forests in the southern portion of the Atlantic Forest, a region that has experienced complex topographic evolution and differing climatic conditions since the Early Cretaceous, which likely affected the geographic distribution and diversification of the group. In this study, we investigated the molecular phylogeny and phylogeography of Sodreana to clarify the species relationships and to make inferences about the historical biogeography of the southern Atlantic Forest. We applied coalescent-based phylogenetic analyses using one mitochondrial and three nuclear markers coupled with an ecological niche modeling approach to verify relationships among species, date the main divergence events in the genus, and make inferences concerning possible changes in the geographical distribution and population dynamics from the past. Our results supported the validity of most Sodreana species and suggested that Paleogene-Neogene geomorphologic processes such as the formation of rivers systems, uplift of mountain ranges and related environmental changes have profoundly affected the evolutionary history of Sodreana. The ecological niche models showed that the areas potentially occupied by the species were greatly reduced during Quaternary glacial periods but no recent lineage divergences or genetic bottlenecks were detected, suggesting that climatically stable micro-habitats could have helped maintain populations during drier periods. Our study highlights the importance of humidity-dependent and poor-dispersal taxa in understanding the effects of ancient geological and climate processes on the Atlantic Forest biota.

Effect of Sacubitril-Valsartan vs Enalapril on Aortic Stiffness in Patients With Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial.

IMPORTANCE: Compared with enalapril, sacubitril-valsartan reduces cardiovascular mortality and heart failure hospitalization in patients with heart failure and reduced ejection fraction (HFrEF). These benefits may be related to effects on hemodynamics and cardiac remodeling. OBJECTIVE: To determine whether treatment of HFrEF with sacubitril-valsartan improves central aortic stiffness and cardiac remodeling compared with enalapril. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind clinical trial of 464 participants with heart failure and ejection fraction of 40% or less enrolled across 85 US sites between August 17, 2016, and June 28, 2018. Follow-up was completed on January 26, 2019. INTERVENTIONS: Randomization (1:1) to sacubitril-valsartan (n = 231; target dosage, 97/103 mg twice daily) vs enalapril (n = 233; target dosage, 10 mg twice daily) for 12 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was change from baseline to week 12 in aortic characteristic impedance (Zc), a measure of central aortic stiffness. Prespecified secondary outcomes included change from baseline to week 12 in N-terminal pro-B-type natriuretic peptide, ejection fraction, global longitudinal strain, mitral annular relaxation velocity, mitral E/e' ratio, left ventricular end-systolic and end-diastolic volume indexes (LVESVI and LVEDVI), left atrial volume index, and ventricular-vascular coupling ratio. RESULTS: Of 464 validly randomized participants (mean age, 67.3 [SD, 9.1] years; 23.5% women), 427 completed the study. At 12 weeks, Zc decreased from 223.8 to 218.9 dyne × s/cm5 in the sacubitril-valsartan group and increased from 213.2 to 214.4 dyne × s/cm5 in the enalapril group (treatment difference, -2.2 [95% CI, -17.6 to 13.2] dyne × s/cm5; P = .78). Of 9 prespecified secondary end points, no significant between-group difference in change from baseline was seen in 4, including left ventricular ejection fraction (34%-36% with sacubitril-valsartan vs 33 to 35% with enalapril; treatment difference, 0.6% [95% CI, -0.4% to 1.7%]; P = .24). However, greater reductions from baseline were seen with sacubitril-valsartan than with enalapril in all others, including left atrial volume (from 30.4 mL/m2 to 28.2 mL/m2 vs from 29.8 mL/m2 to 30.5 mL/m2; treatment difference, -2.8 mL/m2 [95% CI, -4.0 to -1.6 mL/m2]; P < .001), LVEDVI (from 75.1 mL/m2 to 70.3 mL/m2 vs from 79.1 mL/m2 to 75.6 mL/m2; treatment difference, -2.0 mL/m2 [95% CI, -3.7 to 0.3 mL/m2]; P = .02), LVESVI (from 50.8 mL/m2 to 46.3 mL/m2 vs from 54.1 to 50.6 mL/m2; treatment difference, -1.6 mL/m2 [95% CI, -3.1 to -0.03 mL/m2]; P = .045), and mitral E/e' ratio (from 13.8 to 12.3 vs from 13.4 to 13.8; treatment difference, -1.8 [95% CI, -2.8 to -0.8]; P = .001). Rates of adverse events including hypotension (1.7% vs 3.9%) were similar in both groups. CONCLUSIONS AND RELEVANCE: Treatment of HFrEF with sacubitril-valsartan, compared with enalapril, did not significantly reduce central aortic stiffness. The study findings may provide insight into mechanisms underlying the effects of sacubitril-valsartan in HFrEF. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02874794.

Association of Change in N-Terminal Pro-B-Type Natriuretic Peptide Following Initiation of Sacubitril-Valsartan Treatment With Cardiac Structure and Function in Patients With Heart Failure With Reduced Ejection Fraction.

IMPORTANCE: In patients with heart failure and reduced ejection fraction (HFrEF), treatment with sacubitril-valsartan reduces N-terminal pro-b-type natriuretic peptide (NT-proBNP) concentrations. The effect of sacubitril-valsartan on cardiac remodeling is uncertain. OBJECTIVE: To determine whether NT-proBNP changes in patients with HFrEF treated with sacubitril-valsartan correlate with changes in measures of cardiac volume and function. DESIGN, SETTING, AND PARTICIPANTS: Prospective, 12-month, single-group, open-label study of patients with HFrEF enrolled in 78 outpatient sites in the United States. Sacubitril-valsartan was initiated and the dose adjusted. Enrollment commenced on October 25, 2016, and follow-up was completed on October 22, 2018. EXPOSURES: NT-proBNP concentrations among patients treated with sacubitril-valsartan. MAIN OUTCOMES AND MEASURES: The primary outcome was the correlation between changes in log2-NT-proBNP concentrations and left ventricular (LV) EF, LV end-diastolic volume index (LVEDVI), LV end-systolic volume index (LVESVI), left atrial volume index (LAVI), and ratio of early transmitral Doppler velocity/early diastolic annular velocity (E/e') at 12 months. RESULTS: Among 794 patients (mean age, 65.1 years; 226 women [28.5%]; mean LVEF = 28.2%), 654 (82.4%) completed the study. The median NT-proBNP concentration at baseline was 816 pg/mL (interquartile range [IQR], 332-1822) and 455 pg/mL (IQR, 153-1090) at 12 months (difference, P < .001). At 12 months, the change in log2-NT-proBNP concentration was correlated with changes in LVEF (r = -0.381 [IQR, -0.448 to -0.310]; P < .001), LVEDVI (r = 0.320 [IQR, 0.246 to 0.391]; P < .001), LVESVI (r = 0.405 [IQR, 0.335 to 0.470]; P < .001), LAVI (r = 0.263 [IQR, 0.186 to 0.338]; P < .001), and E/e' (r = 0.269 [IQR, 0.182 to 0.353]; P < .001). At 12 months, LVEF increased from 28.2% to 37.8% (difference, 9.4% [95% CI, 8.8% to 9.9%]; P < .001), while LVEDVI decreased from 86.93 to 74.15 mL/m2 (difference, -12.25 mL/m2 [IQR, -12.92 to -11.58]; P < .001) and LVESVI decreased from 61.68 to 45.46 mL/m2 (difference, -15.29 mL/m2 [95% CI, -16.03 to -14.55]; P < .001). LAVI and E/e' ratio also decreased significantly. The most frequent adverse events were hypotension (17.6%), dizziness (16.8%), hyperkalemia (13.2%), and worsening kidney function (12.3%). CONCLUSIONS AND RELEVANCE: In this exploratory study of patients with HFrEF treated with sacubitril-valsartan, reduction in NT-proBNP concentration was weakly yet significantly correlated with improvements in markers of cardiac volume and function at 12 months. The observed reverse cardiac remodeling may provide a mechanistic explanation for the effects of sacubitril-valsartan in patients with HFrEF. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02887183.

Defective regression models for cure rate modeling with interval-censored data.

Regression models in survival analysis are most commonly applied for right-censored survival data. In some situations, the time to the event is not exactly observed, although it is known that the event occurred between two observed times. In practice, the moment of observation is frequently taken as the event occurrence time, and the interval-censored mechanism is ignored. We present a cure rate defective model for interval-censored event-time data. The defective distribution is characterized by a density function whose integration assumes a value less than one when the parameter domain differs from the usual domain. We use the Gompertz and inverse Gaussian defective distributions to model data containing cured elements and estimate parameters using the maximum likelihood estimation procedure. We evaluate the performance of the proposed models using Monte Carlo simulation studies. Practical relevance of the models is illustrated by applying datasets on ovarian cancer recurrence and oral lesions in children after liver transplantation, both of which were derived from studies performed at A.C. Camargo Cancer Center in São Paulo, Brazil.

Efficacy of the re-utilization of an ear implant impregnated with progestogen in estrus synchronization response and pregnancy in sheep.

The goal of this study was to assess the efficacy of the re-utilization of an ear implant impregnated with norgestomet on estrus synchronization response and pregnancy rates in sheep. Fifty-five Texel ewes were classified according to body condition (3.5) and live weight (65 kg), and randomly assigned to two experimental groups: NORN-new (n = 30) and NORU-used (n = 25). The dose of norgestomet used in the treatments was half of that recommended for bovine (1.5 mg). The synchronization protocol consisted of an ear implant inserted on day 0 (beginning of the experiment) and kept for 6 days. The removal of the implant on day 6 was followed by an injection of a prostaglandin analogue (0.263 mg) and eCG (250 IU). Rams with paint applied to their chest were used to facilitate estrus detection for 5 days following implant withdrawal. Estrus behavior was observed in 93.3% (28/30) and 90% for NORN and NORU, respectively. Pregnancy rates for NORN were 73.3% and for NORU were 68%. Estrus behavior and pregnancy rates between treatment groups did not differ statistically. Therefore, the re-utilization of ear implants impregnated with norgestomet, in addition to eCG and a prostaglandin analogue in short-term estrus synchronization protocols, allow acceptable estrus response and pregnancy rates in sheep.

Simplified ethanol wet-bonding technique: an alternative strategy for resin-dentin bonding in root canals.

The objective of this study was to evaluate the effect of the simplified ethanol wet-bonding technique on luting of posts to intraradicular dentin. The effect was assessed by push-out bond strength testing and confocal laser scanning microscopic analysis. Thirty endodontically treated roots were distributed into 3 groups (n = 10): water wet-bonding; stepwise ethanol wet-bonding; and simplified ethanol wet-bonding. After cementation of the posts, the roots were sectioned. Specimens were stored for 24 hours or 1 year before they were stressed to failure. Specimens from each group were processed for microscopic analysis. Data were analyzed using a 2-way analysis of variance and the Tukey test (α = 0.05). Statistically significant differences in push-out bond strength values were observed between the technique groups (P < 0.001) and between the storage periods (P = 0.009). The bond strength results in the group bonded using the simplified ethanol wet-dehydration approach did not differ from those in the group bonded using the stepwise ethanol technique at either storage time interval (P > 0.05). From 24 hours to 1 year, there was a similar decrease in bond strength for specimens prepared with the simplified and stepwise techniques. The microscopic results confirmed that ethanol wet-bonding technique improved the quality of the interface. The simplified ethanol wet-dehydration protocol achieved bond strengths and stability over time that were similar to those obtained with the stepwise ethanol technique and may be considered an alternative strategy to accomplish resin cement-root dentin bonding.