The origins and spread of domestic horses from the Western Eurasian steppes

This is the final version. Available on open access from Nature Research via the DOI in this recordData availability: All collapsed and paired-end sequence data for samples sequenced in this study are available in compressed fastq format through the European Nucleotide Archive under accession number PRJEB44430, together with rescaled and trimmed bam sequence alignments against both the nuclear and mitochondrial horse reference genomes. Previously published ancient data used in this study are available under accession numbers PRJEB7537, PRJEB10098, PRJEB10854, PRJEB22390 and PRJEB31613, and detailed in Supplementary Table 1. The genomes of ten modern horses, publicly available, were also accessed as indicated in their corresponding original publications57,61,85-87.NOTE: see the published version available via the DOI in this record for the full list of authorsDomestication of horses fundamentally transformed long-range mobility and warfare. However, modern domesticated breeds do not descend from the earliest domestic horse lineage associated with archaeological evidence of bridling, milking and corralling at Botai, Central Asia around 3500 BC. Other longstanding candidate regions for horse domestication, such as Iberia and Anatolia, have also recently been challenged. Thus, the genetic, geographic and temporal origins of modern domestic horses have remained unknown. Here we pinpoint the Western Eurasian steppes, especially the lower Volga-Don region, as the homeland of modern domestic horses. Furthermore, we map the population changes accompanying domestication from 273 ancient horse genomes. This reveals that modern domestic horses ultimately replaced almost all other local populations as they expanded rapidly across Eurasia from about 2000 BC, synchronously with equestrian material culture, including Sintashta spoke-wheeled chariots. We find that equestrianism involved strong selection for critical locomotor and behavioural adaptations at the GSDMC and ZFPM1 genes. Our results reject the commonly held association between horseback riding and the massive expansion of Yamnaya steppe pastoralists into Europe around 3000 BC driving the spread of Indo-European languages. This contrasts with the scenario in Asia where Indo-Iranian languages, chariots and horses spread together, following the early second millennium BC Sintashta culture

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

A COVID–19-halandóság életkor-specifikus regionális jellemzői 2021-ben = Age-specific regional characteristics of COVID–19 mortality in 2021

Bevezetés: A legtöbb országban a COVID–19-mortalitás az életkor előrehaladtával exponenciálisan nő, de a növekedési ráta országonként jelentősen eltér. A halálozás eltérő progressziója utalhat a népesség egészségi állapotának, az egészségügyi-kórházi ellátás színvonalának, valamint a kódolási gyakorlatnak a különbségére. Célkitűzés: Tanulmányunkban azt vizsgáltuk, hogy a pandémia második évében a COVID–19-halandóság életkor-specifikus megyei jellemzői között milyen természetű különbségek fedezhetők fel. Módszer: A COVID–19-mortalitás felnőtt életkori mintázatát megyénként, nemek szerint külön-külön Gompertz-függvénnyel, többszintű modellek segítségével becsültük. Eredmények: Eredményeink azt mutatták, hogy a Gompertz-függvény alkalmas a COVID–19-halandóság megyei mintázatainak leírására. A mortalitás életkori progressziójában nem, a szintjében azonban jelentős területi különbségeket találtunk. A mortalitás szintje a várakozásnak megfelelő előjelű, de eltérő erősségű kapcsolatot mutatott a társadalmi-gazdasági tényezők és az egészségügyi ellátás indikátoraival. Megbeszélés és következtetés: A COVID–19-pandémia 2021-ben a várható élettartamnak a második világháború óta nem tapasztalt drámai visszaesését idézte elő Magyarországon. A tanulmány a társadalmi sérülékenység mellett az egészségügyi ellátás fontosságára hívja fel a figyelmet, továbbá rámutat arra, hogy az életkori mintázat megértése segít a járvány következményeinek mérséklésében. Orv Hetil. 2023; 164(17): 643–650. | Introduction: In most countries, COVID–19 mortality increases exponentially with age, but the growth rate varies considerably between countries. The different progression of mortality may reflect differences in population health, the quality of health care or coding practices. Objective: In this study, we investigated differences in age-specific county characteristics of COVID–19 mortality in the second year of the pandemic. Method: Age-specific patterns of COVID–19 adult mortality were estimated according to county level and sex using a Gompertz function with multilevel models. Results: The Gompertz function is suitable for describing age patterns of COVID–19 adult mortality at county level. We did not find significant differences in the age progression of mortality between counties, but there were significant spatial differences in the level of mortality. The mortality level showed a relationship with socioeconomic and health care indicators with the expected sign, but with different strengths. Discussion and conclusion: The COVID–19 pandemic in 2021 resulted in a decline in life expectancy in Hungary not seen since World War II. The study highlights the importance of healthcare in addition to social vulnerability. It also points out that understanding age patterns will help to mitigate the consequences of the epidemic

The Race for Sponsored Links: Bidding Patterns for Search Advertising

Paid placements on search engines reached sales of nearly $11 billion in the United States last year and represent the most rapidly growing form of online advertising today. In its classic form, a search engine sets up an auction for each search word in which competing websites bid for their sponsored links to be displayed next to the search results. We model this advertising market, focusing on two of its key characteristics: (1) the interaction between the list of search results and the list of sponsored links on the search page and (2) the inherent differences in attractiveness between sites. We find that both of these special aspects of search advertising have a significant effect on sites' bidding behavior and the equilibrium prices of sponsored links. Often, sites that are not among the most popular ones obtain the sponsored links, especially if the marginal return of sites on clicks is quickly decreasing and if consumers do not trust sponsored links. In three extensions, we also explore (1) heterogeneous valuations across bidding sites, (2) the endogenous choice of the number of sponsored links that the search engine sells, and (3) a dynamic model where websites' bidding behavior is a function of their previous positions on the sponsored list. Our results shed light on the seemingly random order of sites on search engines' list of sponsored links and their variation over time. They also provide normative insights for both buyers and sellers of search advertising.Internet marketing, position auctions, game theory

Incidence and Clinical Characteristics of Anaerobic Bacteremia at a University Hospital in Hungary: A 5-Year Retrospective Observational Study

Strict anaerobes have been reported to account for 0.5&ndash;13% of episodes of bacteremia in the adult population, with a growing awareness among clinicians regarding anaerobic bacteremia, especially in patients with specific predisposing factors. The aim of our present study was to assess the incidence and clinical characteristics of anaerobic bacteremia during a 5-year period (2016&ndash;2020) at a tertiary care teaching hospital, and to compare our findings with other studies in Hungary. Overall, n = 160 strict anaerobes were detected, out of which, 44.4% (n = 71; 0.1% of positive blood cultures, 0.1/1000 hospitalizations, 3.3/100,000 patient days) were clinically significant, while Cutibacterium spp. accounted for 55.6% (n = 89) of isolates. Among relevant pathogens, the Bacteroides/Parabacteroides spp. group (32.4%; n = 23), Clostridium spp. (22.5%; n = 16) and Gram-positive anaerobic cocci (15.5%; n = 11) were the most common. The mean age of patients was 67.1 &plusmn; 14.1 years, with a male majority (59.2%; n = 42). A total of 38.0% of patients were affected by a malignancy or immunosuppression, while an abscess was identified in 15.5% of cases. A total of 74.7% (n = 53) of patients received antibiotics prior to blood culture sampling; in instances where antimicrobials were reported, anaerobic coverage of the drugs was appropriate in 52.1% (n = 37) of cases. The 30-day crude mortality rate was 39.4% (n = 28); age &ge; 75 years was a significant predictor of 30-day mortality (OR: 5.0; CI: 1.8&ndash;14.4; p = 0.003), while malignancy and immunosuppression, lack of anti-anaerobic coverage or female sex did not show a significant relationship with the mortality of these patients. Early recognition of the role played by anaerobes in sepsis and timely initiation of adequate, effective antimicrobial treatment have proven efficient in reducing the mortality of patients affected by anaerobic bacteremia