Increasing the reach: optimizing screening for atrial fibrillation-the STROKESTOP III study.

AIMS: Atrial fibrillation (AF) is the most common type of cardiac arrythmia and is an important risk factor for ischaemic stroke. Many cases of AF remain undiagnosed due to its paroxysmal, intermittent, and often asymptomatic nature. Early detection of AF through screening and initiation of treatment with oral anticoagulants can prevent stroke, increase life expectancy, and decrease the cost of healthcare for the society. However, participation has been low in previous AF screening studies employing population screening. The aim of this study is to determine whether opportunistic screening is a superior method to increase participation in comparison to population screening. We hypothesize that opportunistic screening will significantly increase participation. METHODS AND RESULTS: In our study, STROKESTOP III, a randomized prospective cohort study, we compare two different methods of AF screening in high-risk individuals: population screening vs. opportunistic screening. Sixteen different primary clinics in Värmland, Sweden, serving 75-76-year-old individuals (n = 2954), will be randomized to either population screening or opportunistic screening. The individuals will be instructed to record electrocardiogram (ECG) for 30 s, 3 times daily for 2 weeks, using a handheld one-lead ECG device. Patients with detected AF will be referred to their primary healthcare physician and offered treatment. The main objective of the study is to determine the rate of participation in opportunistic screening in comparison to population screening. CONCLUSIONS: The STROKESTOP III study will provide valuable information on which screening method to use for improved participation in atrial fibrillation screening.

Warfarin intake in relation to diagnosis reduces mortality in patients with colorectal cancer - a register-based study.

BACKGROUND: Several studies have analyzed the effect of anticoagulants on cancer survival, with varying results. This study aimed to assess the effect of warfarin on survival in patients with colorectal cancer (CRC) in relation to timing of warfarin initiation. METHODS: Data on 10,051 individuals aged ≥45 years in the Västra Götaland Region of Sweden, and diagnosed with CRC between 2000 and 2009, were obtained from the Swedish National Cancer Register. Those who received warfarin treatment (n= 1,216) during the study period were labeled cases and those who did not (n= 8,873) were labeled controls. For statistical analysis, National Cancer Register data were merged with mortality data from the Swedish National Cause of Death register and data from the regional warfarin treatment register. RESULTS: Hazard rates for CRC-specific mortality were lower in cases than in controls. When warfarin was used for any reason at any time, cases had a significantly lower CRC-specific mortality than controls among both women (hazard ratio [HR] 0.71; 95 % confidence interval [CI] 0.59-0.85; p= 0.0002) and men (HR 0.61; 95 % CI 0.52-0.72; p < 0001). Warfarin treatment after CRC diagnosis reduced CRC-specific mortality by 80 %; however, when warfarin was given before or ≥5 years after diagnosis, CRC-specific mortality did not significantly decrease. The number needed to treat to avoid one death was four. CONCLUSION: Use of warfarin early after diagnosis in patients with CRC was associated with improved survival.

Exploring the performance of automatic speaker recognition using twin speech and deep learning-based artificial neural networks.

This study assessed the influence of speaker similarity and sample length on the performance of an automatic speaker recognition (ASR) system utilizing the SpeechBrain toolkit. The dataset comprised recordings from 20 male identical twin speakers engaged in spontaneous dialogues and interviews. Performance evaluations involved comparing identical twins, all speakers in the dataset (including twin pairs), and all speakers excluding twin pairs. Speech samples, ranging from 5 to 30 s, underwent assessment based on equal error rates (EER) and Log cost-likelihood ratios (Cllr). Results highlight the substantial challenge posed by identical twins to the ASR system, leading to a decrease in overall speaker recognition accuracy. Furthermore, analyses based on longer speech samples outperformed those using shorter samples. As sample size increased, standard deviation values for both intra and inter-speaker similarity scores decreased, indicating reduced variability in estimating speaker similarity/dissimilarity levels in longer speech stretches compared to shorter ones. The study also uncovered varying degrees of likeness among identical twins, with certain pairs presenting a greater challenge for ASR systems. These outcomes align with prior research and are discussed within the context of relevant literature.

The genetic legacy of the expansion of Bantu-speaking peoples in Africa.

The expansion of people speaking Bantu languages is the most dramatic demographic event in Late Holocene Africa and fundamentally reshaped the linguistic, cultural and biological landscape of the continent1-7. With a comprehensive genomic dataset, including newly generated data of modern-day and ancient DNA from previously unsampled regions in Africa, we contribute insights into this expansion that started 6,000-4,000 years ago in western Africa. We genotyped 1,763 participants, including 1,526 Bantu speakers from 147 populations across 14 African countries, and generated whole-genome sequences from 12 Late Iron Age individuals8. We show that genetic diversity amongst Bantu-speaking populations declines with distance from western Africa, with current-day Zambia and the Democratic Republic of Congo as possible crossroads of interaction. Using spatially explicit methods9 and correlating genetic, linguistic and geographical data, we provide cross-disciplinary support for a serial-founder migration model. We further show that Bantu speakers received significant gene flow from local groups in regions they expanded into. Our genetic dataset provides an exhaustive modern-day African comparative dataset for ancient DNA studies10 and will be important to a wide range of disciplines from science and humanities, as well as to the medical sector studying human genetic variation and health in African and African-descendant populations.

H2O2(s) and H2O2·2H2O(s) crystals compared with ices: DFT functional assessment and D3 analysis.

The H2O and H2O2 molecules resemble each other in a multitude of ways as has been noted in the literature. Here, we present density functional theory (DFT) calculations for the H2O2(s) and H2O2·2H2O(s) crystals and make selected comparisons with ice polymorphs. The performance of a number of dispersion-corrected density functionals-both self-consistent and a posteriori ones-are assessed, and we give special attention to the D3 correction and its effects. The D3 correction to the lattice energies is large: for H2O2(s) the D3 correction constitutes about 25% of the lattice energy using PBE, much more for RPBE, much less for SCAN, and it primarily arises from non-H-bonded interactions out to about 5 Å.The large D3 corrections to the lattice energies are likely a consequence of several effects: correction for missing dispersion interaction, the ability of D3 to capture and correct various other kinds of limitations built into the underlying DFT functionals, and finally some degree of cell-contraction-induced polarization enhancement. We find that the overall best-performing functionals of the twelve examined are optPBEvdW and RPBE-D3. Comparisons with DFT assessments for ices in the literature show that where the same methods have been used, the assessments largely agree.

Cardiac Enlargement in a Medicolegal Autopsy Setting.

ABSTRACT: A key element for diagnosing cardiac enlargement in an autopsy setting is relevant heart weight references. However, most available references are to a large extent not representative of a medicolegal autopsy population, implying that reference weights are likely lower than those in the relevant population.To establish more applicable heart weight references in a medicolegal autopsy population, we designed a heart weight model that accounts for undiagnosed cardiac enlargement using data from 11,897 nontraumatic Swedish medicolegal autopsy cases autopsied between 2010 and 2019. The model was validated in 296 nonobese young adult suicidal hanging cases.For a decedent of average height (174 cm), the evidence that a heart weight was enlarged reached weak support at approximately 430 g, substantial support at approximately 480 g, and strong support at 520 g. The modeled prevalence of cardiac enlargement was very high among elderly and obese decedents.We believe that our model is more applicable in a medicolegal setting than those previously published. The presented quantification of the degree of uncertainty regarding diagnosis can help the pathologist in diagnosing cardiac enlargement. To facilitate the use of this model, we also made it available through a simple online tool ( https://formedum.shinyapps.io/HeartWeightCalc/ ).

On the speaker discriminatory power asymmetry regarding acoustic-phonetic parameters and the impact of speaking style.

This study aimed to assess what we refer to as the speaker discriminatory power asymmetry and its forensic implications in comparisons performed in different speaking styles: spontaneous dialogues vs. interviews. We also addressed the impact of data sampling on the speaker's discriminatory performance concerning different acoustic-phonetic estimates. The participants were 20 male speakers, Brazilian Portuguese speakers from the same dialectal area. The speech material consisted of spontaneous telephone conversations between familiar individuals, and interviews conducted between each individual participant and the researcher. Nine acoustic-phonetic parameters were chosen for the comparisons, spanning from temporal and melodic to spectral acoustic-phonetic estimates. Ultimately, an analysis based on the combination of different parameters was also conducted. Two speaker discriminatory metrics were examined: Cost Log-likelihood-ratio (Cllr) and Equal Error Rate (EER) values. A general speaker discriminatory trend was suggested when assessing the parameters individually. Parameters pertaining to the temporal acoustic-phonetic class depicted the weakest performance in terms of speaker contrasting power as evidenced by the relatively higher Cllr and EER values. Moreover, from the set of acoustic parameters assessed, spectral parameters, mainly high formant frequencies, i.e., F3 and F4, were the best performing in terms of speaker discrimination, depicting the lowest EER and Cllr scores. The results appear to suggest a speaker discriminatory power asymmetry concerning parameters from different acoustic-phonetic classes, in which temporal parameters tended to present a lower discriminatory power. The speaking style mismatch also seemed to considerably impact the speaker comparison task, by undermining the overall discriminatory performance. A statistical model based on the combination of different acoustic-phonetic estimates was found to perform best in this case. Finally, data sampling has proven to be of crucial relevance for the reliability of discriminatory power assessment.

From Prototype to Inference: A Pipeline to Apply Deep Learning in Sorghum Panicle Detection.

Head (panicle) density is a major component in understanding crop yield, especially in crops that produce variable numbers of tillers such as sorghum and wheat. Use of panicle density both in plant breeding and in the agronomy scouting of commercial crops typically relies on manual counts observation, which is an inefficient and tedious process. Because of the easy availability of red-green-blue images, machine learning approaches have been applied to replacing manual counting. However, much of this research focuses on detection per se in limited testing conditions and does not provide a general protocol to utilize deep-learning-based counting. In this paper, we provide a comprehensive pipeline from data collection to model deployment in deep-learning-assisted panicle yield estimation for sorghum. This pipeline provides a basis from data collection and model training, to model validation and model deployment in commercial fields. Accurate model training is the foundation of the pipeline. However, in natural environments, the deployment dataset is frequently different from the training data (domain shift) causing the model to fail, so a robust model is essential to build a reliable solution. Although we demonstrate our pipeline in a sorghum field, the pipeline can be generalized to other grain species. Our pipeline provides a high-resolution head density map that can be utilized for diagnosis of agronomic variability within a field, in a pipeline built without commercial software.

The utility of histology in assessing the cause of death in medico-legal autopsies in selected trauma deaths: Suspension-, immersion-, fire-, and traffic-related.

The goal of a medico-legal autopsy is primarily to determine the cause and manner of death. To this end, the pathologist often uses auxiliary analyses, including histology. However, the utility of routine histology in all medico-legal autopsies is unknown. Earlier studies on the utility of routine histology have shown inconsistent effects, with some studies recommending it and others rejecting it. To study the degree to which histology informs on the underlying cause of death, we sent autopsy reports from suspension-, immersion-, fire-, and traffic-related deaths to senior board-certified forensic pathologists and had them assess the cause of death, first without knowledge of the histological findings and then with knowledge thereof. Fifty cases were identified in each of four subgroups: fire-, immersion-, suspension-, and traffic-related deaths. The autopsy reports were anonymized, and the histological findings and conclusions were removed. Two board-certified forensic pathologists independently reviewed the reports in each subgroup and assessed the manner and underlying cause of death (including their certainty of this assessment on a five-level scale) with and without access to histological findings. The probability of changing the underlying cause of death posthistology was low in all study groups. There was a slight increase in the degree of certainty posthistology in cases where the underlying cause of death was not changed, but only when the antehistology certainty was low. Our results suggest that histology does not meaningfully inform on the underlying cause of death in suspension-, immersion-, fire-, and traffic-related deaths except when antehistology certainty is low.

Increased lung weight in fatal intoxications is not unique to opioid drugs.

Fatal intoxications with opioids are known to be associated with an increased lung weight, as well as with brain and pulmonary edema and urinary retention. However, there is evidence to suggest that fatal intoxications with non-opioid substances are also associated with increased lung weight; however, the latter aspect has not been comprehensively analyzed. To determine to what extent opioid and non-opioid substances are associated with increased lung and brain weight, we studied these organs in cases where the cause of death was attributed to intoxication with a single agent. Using data from cases autopsied at the National Board of Forensic Medicine (NBFM) in Sweden from 2009 through 2019 where the cause of death was attributed to a single substance, we created models of combined lung weight and brain weight. The models used age and sex as predictors as well as nested varying effects for the specific intoxicant and category of intoxicant. Suicidal hanging with negative toxicology cases served as controls. The population majority was male among both intoxications (68%) and controls (83%). The most common single substance group was opioids. All tested substances were associated with heavier lungs than controls, with the largest effect in the opioid group. Our findings show that several substances are associated with increased lung weight and that among intoxication deaths there is no difference in expected brain weight between substances. Hence, heavy lungs, without a reasonable explanation, should prompt a broad toxicological screening.

The Plasma Environment of Comet 67P/Churyumov-Gerasimenko.

The environment of a comet is a fascinating and unique laboratory to study plasma processes and the formation of structures such as shocks and discontinuities from electron scales to ion scales and above. The European Space Agency's Rosetta mission collected data for more than two years, from the rendezvous with comet 67P/Churyumov-Gerasimenko in August 2014 until the final touch-down of the spacecraft end of September 2016. This escort phase spanned a large arc of the comet's orbit around the Sun, including its perihelion and corresponding to heliocentric distances between 3.8 AU and 1.24 AU. The length of the active mission together with this span in heliocentric and cometocentric distances make the Rosetta data set unique and much richer than sets obtained with previous cometary probes. Here, we review the results from the Rosetta mission that pertain to the plasma environment. We detail all known sources and losses of the plasma and typical processes within it. The findings from in-situ plasma measurements are complemented by remote observations of emissions from the plasma. Overviews of the methods and instruments used in the study are given as well as a short review of the Rosetta mission. The long duration of the Rosetta mission provides the opportunity to better understand how the importance of these processes changes depending on parameters like the outgassing rate and the solar wind conditions. We discuss how the shape and existence of large scale structures depend on these parameters and how the plasma within different regions of the plasma environment can be characterised. We end with a non-exhaustive list of still open questions, as well as suggestions on how to answer them in the future.

The Statin Target Hmgcr Regulates Energy Metabolism and Food Intake through Central Mechanisms.

The statin drug target, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), is strongly linked to body mass index (BMI), yet how HMGCR influences BMI is not understood. In mammals, studies of peripheral HMGCR have not clearly identified a role in BMI maintenance and, despite considerable central nervous system expression, a function for central HMGCR has not been determined. Similar to mammals, Hmgcr is highly expressed in the Drosophila melanogaster brain. Therefore, genetic and pharmacological studies were performed to identify how central Hmgcr regulates Drosophila energy metabolism and feeding behavior. We found that inhibiting Hmgcr, in insulin-producing cells of the Drosophila pars intercerebralis (PI), the fly hypothalamic equivalent, significantly reduces the expression of insulin-like peptides, severely decreasing insulin signaling. In fact, reducing Hmgcr expression throughout development causes decreased body size, increased lipid storage, hyperglycemia, and hyperphagia. Furthermore, the Hmgcr induced hyperphagia phenotype requires a conserved insulin-regulated α-glucosidase, target of brain insulin (tobi). In rats and mice, acute inhibition of hypothalamic Hmgcr activity stimulates food intake. This study presents evidence of how central Hmgcr regulation of metabolism and food intake could influence BMI.

Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress.

The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors.

Ancestral genomic contributions to complex traits in contemporary Europeans.

The contemporary European genetic makeup formed in the last 8,000 years when local Western Hunter-Gatherers (WHGs) mixed with incoming Anatolian Neolithic farmers and Pontic Steppe pastoralists.1-3 This encounter combined genetic variants with distinct evolutionary histories and, together with new environmental challenges faced by the post-Neolithic Europeans, unlocked novel adaptations.4 Previous studies inferred phenotypes in these source populations, using either a few single loci5-7 or polygenic scores based on genome-wide association studies,8-10 and investigated the strength and timing of natural selection on lactase persistence or height, among others.6,11,12 However, how ancient populations contributed to present-day phenotypic variation is poorly understood. Here, we investigate how the unique tiling of genetic variants inherited from different ancestral components drives the complex traits landscape of contemporary Europeans and quantify selection patterns associated with these components. Using matching individual-level genotype and phenotype data for 27 traits in the Estonian biobank13 and genotype data directly from the ancient source populations, we quantify the contributions from each ancestry to present-day phenotypic variation in each complex trait. We find substantial differences in ancestry for eye and hair color, body mass index, waist/hip circumferences, and their ratio, height, cholesterol levels, caffeine intake, heart rate, and age at menarche. Furthermore, we find evidence for recent positive selection linked to four of these traits and, in addition, sleep patterns and blood pressure. Our results show that these ancient components were differentiated enough to contribute ancestry-specific signatures to the complex trait variability displayed by contemporary Europeans.