Effect of Smoking on Pharmacokinetics of Clopidogrel, an Antiplatelet Drug

Purpose: To assess the influence of smoking cigarettes on the pharmacokinetics of the antiplatelet drug, clopidogrel.Methods: Thirty four male patients, mean age and weight of 59.3 years and 81.1 kg, respectively, who underwent percutaneous coronary intervention (PCI), took part in the study. Each subject received an oral loading dose of 600 mg clopidogrel eight tablets, each 75 mg). Clopidogrel carboxylate plasma level was measured and non-compartmental analysis was used to determine peak plasma concentration (Cmax), time to achieve peak plasma concentration (Tmax), elimination half-life (t1/2e), and area under the curve (AUC0-∞). Other parameters measured include gamma-glutamyltransferase enzyme (GGT), low density lipoprotein cholesterol (LDL-cholesterol), blood urea nitrogen (BUN) and platelet count.Results: Nineteen patients were smokers (55.9 %). Smokers had higher levels of GGT compared to non-smokers (31.73 ± 14.42 vs. 21.63 ± 11.41 IU/L, p = 0.08) as well as higher levels of LDL-cholesterol (116.79 ± 42.08 vs. 87.07 ± 27.34 mg/dl, p = 0.041, respectively). Smokers had shorter half-life (smokers: 3.47 ± 1.9 h vs. non-smokers: 5.83 ± 4.09 h, p = 0.012). Smoking behavior had no influence on Cmax (p = 0.16), AUC0-∞ (p = 0.65) or Tmax (p = 0.91). In general, the pharmacokinetic parameters were characterized by considerable inter-individual variation (Cmax = 23.2 ± 8.79 μg/ml, coefficient of variation (CV) = 37.9 %), (Tmax = 1.71 ± 1.15 h, CV = 67.2 %), (AUC0-∞ = 120.97 ± 44.4 μg.h/ml, CV = 36.7 %) and (t1/2e = 4.57 ± 3.15 h, CV = 68.9 %).Conclusion: Smoking behavior may not be a significant determinant of the pharmacokinetics of clopidogrel following oral administration of 600 mg dose in patients undergoing PCI.Keywords: Antiplatelet, Clopidogrel, Pharmacokinetics, Smoking, Cigarett

Ensemble-Instruct: Generating Instruction-Tuning Data with a Heterogeneous Mixture of LMs

Using in-context learning (ICL) for data generation, techniques such as Self-Instruct (Wang et al., 2023) or the follow-up Alpaca (Taori et al., 2023) can train strong conversational agents with only a small amount of human supervision. One limitation of these approaches is that they resort to very large language models (around 175B parameters) that are also proprietary and non-public. Here we explore the application of such techniques to language models that are much smaller (around 10B--40B parameters) and have permissive licenses. We find the Self-Instruct approach to be less effective at these sizes and propose new ICL methods that draw on two main ideas: (a) Categorization and simplification of the ICL templates to make prompt learning easier for the LM, and (b) Ensembling over multiple LM outputs to help select high-quality synthetic examples. Our algorithm leverages the 175 Self-Instruct seed tasks and employs separate pipelines for instructions that require an input and instructions that do not. Empirical investigations with different LMs show that: (1) Our proposed method yields higher-quality instruction tuning data than Self-Instruct, (2) It improves performances of both vanilla and instruction-tuned LMs by significant margins, and (3) Smaller instruction-tuned LMs generate more useful outputs than their larger un-tuned counterparts. Our codebase is available at https://github.com/IBM/ensemble-instruct

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Rapid Melanoma Death of an Adult Male with Congenital Bathing Trunk Nevus despite Initiation of Combination Immunotherapy

Dear Editors: Giant congenital melanocytic naevus (GCMN)-associated melanoma in adults is very rare [...

First Onset of Pityriasis Rubra Pilaris following SARS-CoV-2 Booster Vaccination: Case Report and Review of the Literature

There is increasing evidence of adverse events associated with the use of COVID-19 vaccines. Here, we report a case of the SARS-CoV-2-vaccination-related onset of pityriasis rubra pilaris (PRP) and provide an analysis of previously reported cases in the medical literature. A 67-year-old male presented with a 1-year history of histopathologically proven PRP that first developed 14 days after receiving a COVID-19 booster vaccination. Skin symptoms improved under ustekinumab medication after unsuccessful previous treatment approaches using systemic corticosteroids, brodalumab, and risankizumab. Among the published cases of post-COVID vaccination PRP, 12 (75%) males and 4 (25%) females were reported. The median age of the reported patients was 59 years. In 10 out of 16 patients (62.5%), PRP was diagnosed after the first vaccine dose, in 4 (25%) after the second dose, and in 2 of 15 patients (12.5%) after the third dose. The median time between COVID-19 vaccination and the onset of PRP was 9.5 days (range: 3&ndash;60 days). The majority of patients required systemic treatment, including systemic retinoids and methotrexate. PRP might be a rare adverse event after COVID-19 vaccination, particularly affecting older males. Even though most reported patients with COVID-19-vaccination-related PRP could be successfully treated with PRP standard medications, therapy refractory cases may also occur. Thus, clinicians must be aware of this rare but potentially severe complication

Using SPOT data and leaf area index for rice yield estimation in Egyptian Nile delta

The objective of the current work is to generate statistical empirical rice yield estimation models under the local conditions of the Egyptian Nile delta. The methodology is based on regressing measured yield with satellite derived spectral information or leaf area index (LAI). LAI field measurements and spectral information from SPOT data collected during two crop seasons are examined against measured yield to generate the yield models. Near-infrared and red bands, six vegetation indices and LAI of 100 points are used as the main inputs for the modeling process while 20 points of the same are used for validation process. Nine models are generated and tested against the observed yield. Comparing the generated models show relatively higher superiority of (LAI-yield) and (infrared-yield) models over the rest of the models with (0.061) and (0.090) as a standard error of estimate and (0.945) and (0.883) as coefficient of determinations between modeled and observed yield. The models are applicable a month before harvest for similar regions with same conditions

Fetal ECG extraction from maternal ECG using deeply supervised LinkNet++ model

Fetal heart monitoring and early disease detection using non-invasive fetal electrocardiograms (fECG) can help substantially to reduce infant death through improved diagnosis of Coronary Heart Disease (CHD) in the fetus. Despite the potential benefits, non-invasive fECG extraction from maternal abdominal ECG (mECG) is a challenging problem due to multiple factors such as the overlap of maternal and fetal R-peaks, low amplitude of fECG, and various systematic and environmental noises. Conventional fECG extraction techniques, such as adaptive filters, independent component analysis (ICA), empirical mode decomposition (EMD), etc., face various performance issues due to the fECG extraction challenges. In this paper, we proposed a novel deep learning architecture, LinkNet++ (motivated by the original LinkNet) to extract fECG from abdominal mECG automatically and efficiently using two different publicly available datasets. LinkNet++ is equipped with a feature-addition method to combine deep and shallow levels with residual blocks to overcome the limitations of U-Net and UNet++ models. It also has deep supervised and densely connected convolution blocks to overcome the limitations of the original LinkNet. The proposed LinkNet++ model was evaluated using fECG signal reconstruction and fetal QRS (fQRS) detection. As a signal-to-signal synthesis model, LinkNet++ performed very well in two real-life datasets and achieved 85.58% and 87.60% Pearson correlation coefficients (PCC) between the ground truth and predicted fECG on two datasets, respectively. In terms of fQRS detection, it also outperformed most of the previous works and showed excellent performance with more than 99% of F1 scores on both datasets. Our results indicate that the proposed model can potentially extract fECG non-invasively with excellent signal quality, thereby providing an excellent diagnostic tool for various fetal heart diseases.This study was funded by Qatar National Research Fund (QNRF), National Priorities Research Program (NPRP 10-0123-170222)

Quality of Life of Palestinian Patients on Hemodialysis: Cross-Sectional Observational Study

Background. Hemodialysis is life-saving and life-altering, affecting patients’ quality of life. The management of dialysis patients often focuses on renal replacement therapy to improve clinical outcomes and remove excess fluid; however, the patient’s quality of life is often not factored in. Objective. This study aimed to explore the factors affecting the quality of life of patients on dialysis in Palestine using the Kidney Disease Quality of Life (KDQOL-SFTM) questionnaire. Methods. A multicenter cross-sectional observational study was conducted at multiple dialysis centers in Palestine, including 271 participants receiving renal replacement therapy. Demographics, socioeconomic, and disease status data were collected. The Arabic version of KDQOL-SFTM was used to assess dialysis patient quality of life. Statistical analysis was performed using SPSS to find correlations among patient factors and the questionnaire’s three main domains, the kidney disease component summaries (KDCS), mental component summaries (MCS), and physical component summaries (PCS). Results. Mean KDCS, MCS, and PCS scores were 59.86, 47.10, and 41.15, respectively. KDC scores were lower among participants aged 40 years or older, with lower incomes, and with diabetes. PCS and MCS scores were lower among patients aged >40, less educated, and lower-income participants. There was a positive correlation between MCS and KDCS (r = 0.634, P-value <0.001), PCS and KDCS (r = 0.569, P-value <0.001), as well as MCS and PCS (r = 0.680, P-value <0.001). Conclusion. In this study, the KDQOL-SFTM questionnaire revealed lower PCS scores among hemodialysis patients in Palestine. Furthermore, the three domains of the questionnaire were adversely affected by patient income and education status. In addition, physical role, work status, and emotional role showed the lowest scores among the three main domains. Therefore, continuous assessment of patients’ quality of life during their journey of hemodialysis using the KDQOL-SFTM along with the clinical assessment will allow the healthcare professionals to provide interventions to optimize their care