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Tetroxane derivatives are interesting drugs for antileishmaniasis and antimalaric treatments. The gas-phase thermal decomposition of 3,6,-dimethyl-1,2,4,5-tetroxane (DMT) and 3,3,6,6,-tetramethyl-1,2,4,5-tetroxane (acetone diperoxide (ACDP)) was studied at 493-543 K by direct gas chromatography by means of a flow reactor. The reaction is produced in the injector chamber at different temperatures. The resulting kinetics Arrhenius equations were calculated for both tetroxanes. Including the parent compound of the series 1,2,4,5-tetroxane (formaldehyde diperoxide (FDP)), the activation energy and frequency factors decrease linearly with the number of methyl groups. The reaction mechanisms of ACDP and 3,6,6-trimethyl-1,2,4,5-tetroxane (TMT) decomposition have been studied by means of the DFT method with the BHANDHLYP functional. Our calculations confirm that the concerted mechanism should be discarded and that only the stepwise mechanism occurs. The critical points of the singlet and triplet state potential energy surfaces (S- and T-PES) of the thermolysis reaction of both compounds have been determined. The calculated activation energies of the different steps vary linearly with the number of methyl groups of the methyl-tetroxanes series. The mechanism for the S-PES leads to a diradical O···O open structure, which leads to a C···O dissociation in the second step and the production of the first acetaldehyde/acetone molecule. This last one yields a second C···O dissociation, producing O2 and another acetone/acetaldehyde molecule. The O2 molecule is in the singlet state. A quasi-parallel mechanism for the T-PES from the open diradical to products is also found. Most of the critical points of both PES are linear with the number of methyl groups. Reaction in the triplet state is much more exothermic than the singlet state mechanism. Transitions from the singlet ground state, S0 and low-lying singlet states S1-3, to the low-lying triplet excited states, T1-4, (chemical excitation) in the family of methyl tetroxanes are also studied at the CASSCF/CASPT2 level. Two possible mechanisms are possible here: (i) from S0 to T3 by strong spin orbit coupling (SOC) and subsequent fast internal conversion to the excited T1 state and (ii) from S0 to S2 from internal conversion and subsequent S2 to T1 by SOC. From these experimental and theoretical results, the additivity effect of the methyl groups in the thermolysis reaction of the methyl tetroxane derivatives is clearly highlighted. This information will have a great impact for controlling these processes in the laboratory and chemical industries.

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Development of ventricular failure and pulmonary edema is associated with a worse prognosis in ST-elevation myocardial infarction (STEMI). We aimed to evaluate the prognostic ability of a novel classification combining lung ultrasound (LUS) and left ventricular outflow tract (LVOT) velocity time integral (VTI) in patients with STEMI. LUS and LVOT-VTI were performed within 24 h of admission in STEMI patients. A LUS combined with LVOT-VTI (LUV) classification was developed based on LUS with < or ≥ 3 positive zone scans, combined with LVOT-VTI > or ≤ 14. Patients were classified as A (< 3zones/ > 14 cm VTI), B (≥ 3zones/ > 14 cm VTI), C (< 3zones/ ≤ 14 cm VTI) and D (≥ 3zones/ ≤ 14 cm VTI). Primary outcome was occurrence of in-hospital mortality. Development of cardiogenic shock (CS) within 24 h was also assessed. A total of 308 patients were included. Overall in-hospital mortality was 8.8%, while mortality for LUV A, B, C, and D was 0%, 3%, 12%, and 45%, respectively. The area under the curve (AUC) for predicting in-hospital mortality was 0.915. Moreover, after exclusion of patients admitted in Killip IV, at each increasing degree of LUV, a higher proportion of patients developed CS within 24 h: LUV A = 0.0%, LUV B 5%, LUV C = 12.5% and LUV D = 30.8% (p < 0.0001). The AUC for predicting CS was 0.908 (p < 0.001). In a cohort of STEMI patients, LUV provided to be an excellent method for prediction of in-hospital mortality and development of CS. LUV classification is a fast, non-invasive and very user-friendly ultrasonographic evaluation method to stratify the risk of mortality and CS.

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PURPOSE: Arterial spin labeling (ASL) is a widely used contrast-free MRI method for assessing cerebral blood flow (CBF). Despite the generally adopted ASL acquisition guidelines, there is still wide variability in ASL analysis. We explored this variability through the ISMRM-OSIPI ASL-MRI Challenge, aiming to establish best practices for more reproducible ASL analysis. METHODS: Eight teams analyzed the challenge data, which included a high-resolution T1-weighted anatomical image and 10 pseudo-continuous ASL datasets simulated using a digital reference object to generate ground-truth CBF values in normal and pathological states. We compared the accuracy of CBF quantification from each team's analysis to the ground truth across all voxels and within predefined brain regions. Reproducibility of CBF across analysis pipelines was assessed using the intra-class correlation coefficient (ICC), limits of agreement (LOA), and replicability of generating similar CBF estimates from different processing approaches. RESULTS: Absolute errors in CBF estimates compared to ground-truth synthetic data ranged from 18.36 to 48.12 mL/100 g/min. Realistic motion incorporated into three datasets produced the largest absolute error and variability between teams, with the least agreement (ICC and LOA) with ground-truth results. Fifty percent of the submissions were replicated, and one produced three times larger CBF errors (46.59 mL/100 g/min) compared to submitted results. CONCLUSIONS: Variability in CBF measurements, influenced by differences in image processing, especially to compensate for motion, highlights the significance of standardizing ASL analysis workflows. We provide a recommendation for ASL processing based on top-performing approaches as a step toward ASL standardization.

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BACKGROUND: In patients with heart failure and reduced ejection fraction, sleep-disordered breathing, comprising obstructive sleep apnoea (OSA) and central sleep apnoea (CSA), is associated with increased morbidity, mortality, and sleep disruption. We hypothesised that treating sleep-disordered breathing with a peak-flow triggered adaptive servo-ventilation (ASV) device would improve cardiovascular outcomes in patients with heart failure and reduced ejection fraction. METHODS: We conducted a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial of peak-flow triggered ASV in patients aged 18 years or older with heart failure and reduced ejection fraction (left ventricular ejection fraction ≤45%) who were stabilised on optimal medical therapy with co-existing sleep-disordered breathing (apnoea-hypopnoea index [AHI] ≥15 events/h of sleep), with concealed allocation and blinded outcome assessments. The trial was carried out at 49 hospitals in nine countries. Sleep-disordered breathing was stratified into predominantly OSA with an Epworth Sleepiness Scale score of 10 or lower or predominantly CSA. Participants were randomly assigned to standard optimal treatment alone or standard optimal treatment with the addition of ASV (1:1), stratified by study site and sleep apnoea type (ie, CSA or OSA), with permuted blocks of sizes 4 and 6 in random order. Clinical evaluations were performed and Minnesota Living with Heart Failure Questionnaire, Epworth Sleepiness Scale, and New York Heart Association class were assessed at months 1, 3, and 6 following randomisation and every 6 months thereafter to a maximum of 5 years. The primary endpoint was the cumulative incidence of the composite of all-cause mortality, first admission to hospital for a cardiovascular reason, new onset atrial fibrillation or flutter, and delivery of an appropriate cardioverter-defibrillator shock. All-cause mortality was a secondary endpoint. Analysis for the primary outcome was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT01128816) and the International Standard Randomised Controlled Trial Number Register (ISRCTN67500535), and the trial is complete. FINDINGS: The first and last enrolments were Sept 22, 2010, and March 20, 2021. Enrolments terminated prematurely due to COVID-19-related restrictions. 1127 patients were screened, of whom 731 (65%) patients were randomly assigned to receive standard care (n=375; mean AHI 42·8 events per h of sleep [SD 20·9]) or standard care plus ASV (n=356; 43·3 events per h of sleep [20·5]). Follow-up of all patients ended at the latest on June 15, 2021, when the trial was terminated prematurely due to a recall of the ASV device due to potential disintegration of the motor sound-abatement material. Over the course of the trial, 41 (6%) of participants withdrew consent and 34 (5%) were lost to follow-up. In the ASV group, the mean AHI decreased to 2·8-3·7 events per h over the course of the trial, with associated improvements in sleep quality assessed 1 month following randomisation. Over a mean follow-up period of 3·6 years (SD 1·6), ASV had no effect on the primary composite outcome (180 events in the control group vs 166 in the ASV group; hazard ratio [HR] 0·95, 95% CI 0·77-1·18; p=0·67) or the secondary endpoint of all-cause mortality (88 deaths in the control group vs. 76 in the ASV group; 0·89, 0·66-1·21; p=0·47). For patients with OSA, the HR for all-cause mortality was 1·00 (0·68-1·46; p=0·98) and for CSA was 0·74 (0·44-1·23; p=0·25). No safety issue related to ASV use was identified. INTERPRETATION: In patients with heart failure and reduced ejection fraction and sleep-disordered breathing, ASV had no effect on the primary composite outcome or mortality but eliminated sleep-disordered breathing safely.

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Latin America continues to be severely underrepresented in genomics research, and fine-scale genetic histories and complex trait architectures remain hidden owing to insufficient data1. To fill this gap, the Mexican Biobank project genotyped 6,057 individuals from 898 rural and urban localities across all 32 states in Mexico at a resolution of 1.8 million genome-wide markers with linked complex trait and disease information creating a valuable nationwide genotype-phenotype database. Here, using ancestry deconvolution and inference of identity-by-descent segments, we inferred ancestral population sizes across Mesoamerican regions over time, unravelling Indigenous, colonial and postcolonial demographic dynamics2-6. We observed variation in runs of homozygosity among genomic regions with different ancestries reflecting distinct demographic histories and, in turn, different distributions of rare deleterious variants. We conducted genome-wide association studies (GWAS) for 22 complex traits and found that several traits are better predicted using the Mexican Biobank GWAS compared to the UK Biobank GWAS7,8. We identified genetic and environmental factors associating with trait variation, such as the length of the genome in runs of homozygosity as a predictor for body mass index, triglycerides, glucose and height. This study provides insights into the genetic histories of individuals in Mexico and dissects their complex trait architectures, both crucial for making precision and preventive medicine initiatives accessible worldwide.

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Aridoamerica and Mesoamerica are two distinct cultural areas in northern and central Mexico, respectively, that hosted numerous pre-Hispanic civilizations between 2500 BCE and 1521 CE. The division between these regions shifted southward because of severe droughts ~1100 years ago, which allegedly drove a population replacement in central Mexico by Aridoamerican peoples. In this study, we present shotgun genome-wide data from 12 individuals and 27 mitochondrial genomes from eight pre-Hispanic archaeological sites across Mexico, including two at the shifting border of Aridoamerica and Mesoamerica. We find population continuity that spans the climate change episode and a broad preservation of the genetic structure across present-day Mexico for the past 2300 years. Lastly, we identify a contribution to pre-Hispanic populations of northern and central Mexico from two ancient unsampled "ghost" populations.

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OBJECTIVE: The American Academy of Pediatrics recommends routine sleep problem screenings during child well-visits. However, studies suggest a discrepancy between caregiver- and clinician-reported child sleep problems. The present study examines whether caregiver-reported child sleep problems (ie, habitual snoring, insomnia symptoms, poor sleep health) and clinician-documented child sleep problems and management are congruent. METHODS: The sample included 170 caregiver-child dyads (child Mage = 3.3 years, range = 2-5 years; 56.5% girls; 64.1% Black, 20.0% non-Latinx White, and 4.1% Latinx; 86.5% maternal caregiver reporter). Caregivers' questionnaire-based reports of habitual snoring, insomnia symptoms, and sleep health behaviors (nighttime electronics, caffeine intake, insufficient sleep) were compared with clinician documentation in the electronic health record. RESULTS: About 92.3% of children had at least 1 caregiver-reported sleep problem (66% insomnia symptoms, 64% electronics, 38% insufficient sleep, 21% caffeine, 17% snoring). In contrast, a substantially lower percent of children had a clinician documented sleep problem (20% overall; 10% insomnia symptoms, 7% electronics, 0% insufficient sleep, 3% caffeine, 4% snoring), sleep-related referral (1% overall; 0.6% Otolaryngology, 0.6% polysomnogram, 0% sleep clinic), or recommendation (12% overall; 8% insomnia symptoms, 4% electronics, 0% insufficient sleep, 1% caffeine). CONCLUSIONS: There is a vast discrepancy between caregiver-reported child sleep problems and clinician-documented sleep problems and management, with a higher proportion of caregiver reports. To benefit overall child health and well-being, future research and quality improvement initiatives should focus on enhancing screening tools and educational opportunities to improve clinician documentation and enhance family conversations about early childhood sleep problems.

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OBJECTIVE: Adolescent mental health concerns increased during COVID-19, but it is unknown whether early increases in depression and suicide risk have been sustained. We examined changes in positive screens for depression and suicide risk in a large pediatric primary care network through May 2022. METHODS: Using an observational repeated cross-sectional design, we examined changes in depression and suicide risk during the pandemic using electronic health record data from adolescents. Segmented logistic regression was used to estimate risk differences (RD) for positive depression and suicide risk screens during the early pandemic (June 2020-May 2021) and late pandemic (June 2021-May 2022) relative to before the pandemic (March 2018-February 2020). Models adjusted for seasonality and standard errors accounted for clustering by practice. RESULTS: Among 222,668 visits for 115,627 adolescents (mean age 15.7, 50% female), the risk of positive depression and suicide risk screens increased during the early pandemic period relative to the prepandemic period (RD, 3.8%; 95% CI, 2.9, 4.8; RD, 2.8%; 95% CI, 1.7, 3.8). Risk of depression returned to baseline during the late pandemic period, while suicide risk remained slightly elevated (RD, 0.7%; 95% CI, -0.4, 1.7; RD, 1.8%; 95% CI, 0.9%, 2.7%). CONCLUSIONS: During the early months of the pandemic, there was an increase in positive depression and suicide risk screens, which later returned to prepandemic levels for depression but not suicide risk. Results suggest that pediatricians should continue to prioritize screening adolescents for depressive symptoms and suicide risk and connect them to treatment.

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