A Three-Tier Model for Intertextuality in the Holy Qurᾱn

In previous literature, intertextuality has been applied to the interpretation of the Holy Qurᾱn, but it lacks a coherent and systematic approach. So far, little or no attempt has been made to propose or design a systematic model of intertextuality for the interpretation of the Holy Qurᾱn. This paper reviews both the modern Western and Islamic theoretical literature on intertextuality. Besides, it exhaustively reviews the intertextual approaches to the interpretation of the Holy Qurᾱn both in classical exegetical tradition and in modern research studies. The findings reveal that the existing approaches are either sketchy and sporadic, or generic or rigid, and cannot account for a comprehensive interpretation of the Holy Qurᾱn. They do not suggest any systematic model for search and selection of intertextual links in the Holy Qurᾱn. The review also shows that the modern theoretical literature on intertextuality in Western tradition misses the theoretical literature on the tool of intertextuality in Islamic discourse. On the basis of its findings, this paper, keeping in view the sensitivity of the religious discourse, suggests a 3-tier model of intertextuality for interpretation of the Holy Qurᾱn, consisting of lexical, topical and grammatical/stylistic intertextual links. This paper also suggests that future research may focus on its application to Qurᾱnic interpretation or/and to frame more vibrant models of intertextuality, drawing on the modern trends in linguistics, to serve the aim of comprehensive interpretation of the Holy Qurᾱn

Forensic investigation of small-scale digital devices: a futuristic view

Small-scale digital devices like smartphones, smart toys, drones, gaming consoles, tablets, and other personal data assistants have now become ingrained constituents in our daily lives. These devices store massive amounts of data related to individual traits of users, their routine operations, medical histories, and financial information. At the same time, with continuously evolving technology, the diversity in operating systems, client storage localities, remote/cloud storages and backups, and encryption practices renders the forensic analysis task multi-faceted. This makes forensic investigators having to deal with an array of novel challenges. This study reviews the forensic frameworks and procedures used in investigating small-scale digital devices. While highlighting the challenges faced by digital forensics, we explore how cutting-edge technologies like Blockchain, Artificial Intelligence, Machine Learning, and Data Science may play a role in remedying concerns. The review aims to accumulate state-of-the-art and identify a futuristic approach for investigating SSDDs

The Concise Health Risk Tracking-self Report: Psychometrics Within A Placebo-controlled Antidepressant Trial Among Depressed Outpatients

Background/aims: While substantial prior research has evaluated the psychometric properties of the 12-item Concise Health Risk Tracking-Self Report (CHRT-SR12), a measure of suicide propensity and suicidal thoughts, no prior research has investigated its factor structure, sensitivity to change over time, and other psychometric properties in a placebo-controlled trial of antidepressant medication, nor determined whether symptoms change throughout treatment. Methods: Participants in the multi-site Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study (n=278) provided data to evaluate the factor structure and sensitivity to change over time of the CHRT-SR12 through eight weeks of a clinical trial in which participants received either placebo or antidepressant medication (sertraline). Results/Outcomes: Factor analysis confirmed two factors: propensity (comprised of first-order factors including pessimism, helplessness, social support, and despair) and suicidal thoughts. Internal consistency (α’s ranged from 0.69–0.92) and external validity were both acceptable, with the total score and propensity factor scores significantly correlated with total scores and single-item suicidal-thoughts scores on the self-report Quick Inventory of Depressive Symptoms and the clinician-rated 17-item Hamilton Rating Scale for Depression. Through analyzing CHRT-SR12 changes over eight treatment weeks, the total score and both the factors decreased regardless of baseline suicidal thoughts. Change in clinician-rated suicidal thoughts was reflected by change in both the total score and propensity factor score. Conclusions/interpretation: These results confirm the reliability, validity, and applicability of the CHRT-SR12 to a placebo-controlled clinical trial of depressed outpatients receiving antidepressant medication

Cerebral Blood Perfusion Predicts Response To Sertraline Versus Placebo For Major Depressive Disorder In The Embarc Trial

Background: Major Depressive Disorder (MDD) has been associated with brain-related changes. However, biomarkers have yet to be defined that could “accurately” identify antidepressant-responsive patterns and reduce the trial-and-error process in treatment selection. Cerebral blood perfusion, as measured by Arterial Spin Labeling (ASL), has been used to understand resting-state brain function, detect abnormalities in MDD, and could serve as a marker for treatment selection. As part of a larger trial to identify predictors of treatment outcome, the current investigation aimed to identify perfusion predictors of treatment response in MDD. Methods: For this secondary analysis, participants include 231 individuals with MDD from the EMBARC study, a randomized, placebo-controlled trial investigating clincal, behavioral, and biological predictors of antidepressant response. Participants received sertraline (n=114) or placebo (n=117) and response was monitored for 8 weeks. Pre-treatment neuroimaging was completed, including ASL. A whole-brain, voxel-wise linear mixed-effects model was conducted to identify brain regions in which perfusion levels differentially predict (moderate) treatment response. Clinical effectiveness of perfusion moderators was investigated by composite moderator analysis and remission rates. Composite moderator analysis combined the effect of individual perfusion moderators and identified which contribute to sertraline or placebo as the “preferred” treatment. Remission rates were calculated for participants “accurately” treated based on the composite moderator (lucky) versus “inaccurately” treated (unlucky). Findings: Perfusion levels in multiple brain regions differentially predicted improvement with sertraline over placebo. Of these regions, perfusion in the putamen and anterior insula, inferior temporal gyrus, fusiform, parahippocampus, inferior parietal lobule, and orbital frontal gyrus contributed to sertraline response. Remission rates increased from 37% for all those who received sertraline to 53% for those who were lucky to have received it and sertraline was their perfusion-preferred treatment. Interpretation: This large study showed that perfusion patterns in brain regions involved with reward, salience, affective, and default mode processing moderate treatment response favoring sertraline over placebo. Accurately matching patients with defined perfusion patterns could significantly increase remission rates. Funding: National Institute of Mental Health, the Hersh Foundation, and the Center for Depression Research and Clinical Care, Peter O’Donnell Brain Institute at UT Southwestern Medical Cente

Maternal anaemia and the risk of postpartum haemorrhage: a cohort analysis of data from the WOMAN-2 trial

Background: Worldwide, more than half a billion women of reproductive age are anaemic. Each year, about 70 000 women who give birth die from postpartum haemorrhage. Almost all deaths are in low-income or middle-income countries. We examined the association between anaemia and the risk of postpartum haemorrhage. Methods: We did a prospective cohort analysis of data from the World Maternal Antifibrinolytic-2 (WOMAN-2) trial. This trial enrols women with moderate or severe anaemia giving birth vaginally in hospitals in Pakistan, Nigeria, Tanzania, and Zambia. Hospitals in each country where anaemia in pregnancy is common were identified from a network established during previous obstetric trials. Women who were younger than 18 years without permission provided by a guardian, had a known tranexamic acid allergy, or developed postpartum haemorrhage before the umbilical cord was cut or clamped were excluded from the study. Prebirth haemoglobin, the exposure, was measured after hospital arrival and just before giving birth. Postpartum haemorrhage, the outcome, was defined in three ways: (1) clinical postpartum haemorrhage (estimated blood loss ≥500 mL or any blood loss sufficient to compromise haemodynamic stability); (2) WHO-defined postpartum haemorrhage (estimated blood loss of at least 500 mL); and (3) calculated postpartum haemorrhage (calculated estimated blood loss of ≥1000 mL). Calculated postpartum haemorrhage was estimated from the peripartum change in haemoglobin concentration and bodyweight. We used multivariable logistic regression to examine the association between haemoglobin and postpartum haemorrhage, adjusting for confounding factors. Findings: Of the 10 620 women recruited to the WOMAN-2 trial between Aug 24, 2019, and Nov 1, 2022, 10 561 (99·4%) had complete outcome data. 8751 (82·9%) of 10 561 women were recruited from hospitals in Pakistan, 837 (7·9%) from hospitals in Nigeria, 525 (5·0%) from hospitals in Tanzania, and 448 (4·2%) from hospitals in Zambia. The mean age was 27·1 years (SD 5·5) and mean prebirth haemoglobin was 80·7 g/L (11·8). Mean estimated blood loss was 301 mL (SD 183) for the 8791 (83·2%) women with moderate anaemia and 340 mL (288) for the 1770 (16·8%) women with severe anaemia. 742 (7·0%) women had clinical postpartum haemorrhage. The risk of clinical postpartum haemorrhage was 6·2% in women with moderate anaemia and 11·2% in women with severe anaemia. A 10 g/L reduction in prebirth haemoglobin increased the odds of clinical postpartum haemorrhage (adjusted odds ratio [aOR] 1·29 [95% CI 1·21–1·38]), WHO-defined postpartum haemorrhage (aOR 1·25 [1·16–1·36]), and calculated postpartum haemorrhage (aOR 1·23 [1·14–1·32]). 14 women died and 68 either died or had a near miss. Severe anaemia was associated with seven times higher odds of death or near miss (OR 7·25 [95% CI 4·45–11·80]) than was moderate anaemia. Interpretation: Anaemia is strongly associated with postpartum haemorrhage and the risk of death or near miss. Attention should be given to the prevention and treatment of anaemia in women of reproductive age. Funding: The WOMAN-2 trial is funded by Wellcome and the Bill & Melinda Gates Foundation

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial

Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial

Background Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage. Methods In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15 000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15 000 to 20 000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283. Findings Between March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88–1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group. Interpretation Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset. Funding London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir

Artificial Neural Network based Classification of Lungs Nodule using Hybrid Features from Computerized Tomographic Images

An automated pulmonary nodule detection system is necessary to help radiologist to identify and detect the nodules at early stage. In this paper, a novel pulmonary nodule detection system is proposed using Artificial Neural Networks (ANN) based on hybrid features consist of 2D and 3D Geometric and Intensity based statistical features. The lung volume is segmented using thresholding, 3D connected component labeling, contour correction and morphological operators. The candidate nodules are extracted and pruned based on the rules that are built using characteristics of nodules. The 2D and 3D Geometric features and Intensity Based Statistical features are extracted and used to train a Neural Network. The proposed Computer-Aided Diagnostic (CAD) system is tested and validated using standard dataset of Lung Image Consortium Database (LIDC). The results obtained from proposed CAD system are good as compared to existing CAD systems. The sensitivity of 96.95% is achieved with accuracy of 96.68%