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Estimating causal effects from large experimental and observational data has become increasingly prevalent in both industry and research. The bootstrap is an intuitive and powerful technique used to construct standard errors and confidence intervals of estimators. Its application however can be prohibitively demanding in settings involving large data. In addition, modern causal inference estimators based on machine learning and optimization techniques exacerbate the computational burden of the bootstrap. The bag of little bootstraps has been proposed in non-causal settings for large data but has not yet been applied to evaluate the properties of estimators of causal effects. In this article, we introduce a new bootstrap algorithm called causal bag of little bootstraps for causal inference with large data. The new algorithm significantly improves the computational efficiency of the traditional bootstrap while providing consistent estimates and desirable confidence interval coverage. We describe its properties, provide practical considerations, and evaluate the performance of the proposed algorithm in terms of bias, coverage of the true 95% confidence intervals, and computational time in a simulation study. We apply it in the evaluation of the effect of hormone therapy on the average time to coronary heart disease using a large observational data set from the Women's Health Initiative., (© 2024 John Wiley & Sons Ltd.)

Saffron is a spice derived from the flower of Crocus sativus L., which has been used for centuries as a coloring and flavoring agent, as well as a source of medicinal compounds. Saffron contains various bioactive constituents, such as crocin, crocetin, safranal, picrocrocin, and kaempferol, that have shown potential benefits for human health. Among them, crocin is the most abundant and characteristic constituent of saffron, responsible for its bright red color and antioxidant properties. One of the most promising applications of saffron and its constituents is in the prevention and treatment of neurological disorders, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, and other brain disorders. Saffron and its constituents have been reported to exert neuroprotective effects through various mechanisms, such as modulating neurotransmitters, enhancing neurogenesis, reducing neuroinflammation, regulating oxidative stress, activating the Nrf2 signaling pathway, and modulating epigenetic factors. Several clinical and preclinical studies have demonstrated the efficacy and safety of saffron and its constituents in improving cognitive function, mood, and other neurological outcomes. In this review, we summarize the current evidence on the therapeutic potential of saffron and its constituents in neurological disorders, from bench to bedside. We also discuss the challenges and future directions for the development of saffron-based therapies for brain health., (© 2024 John Wiley & Sons Ltd.)

Objective: Due to the high mortality of patients with refractory status epilepticus (SE), new antiseizure medications (ASMs) are needed to improve long-term outcomes. In this study, we evaluated the efficacy and safety of eslicarbazepine acetate (ESL), a new sodium channel blocker, based on the data from a large epilepsy register., Methods: Data on the efficacy and safety of ESL for the treatment of refractory SE were gathered from the Mainz Epilepsy Registry (MAINZ-EPIREG). Logistic regression was applied to identify predictors of status interruption., Results: In total, 64 patients with remote symptomatic refractory SE were treated with ESL. No cases of idiopathic generalized epilepsy were included. The average age was 61.4 ± 11.0 years. The median number of administered ASMs before the start of ESL was three. On average, 2 days had elapsed since the onset of SE before the administration of ESL. The initial dose of 800 mg/day was increased up to a maximum daily dose of 1600 mg in case of nonresponse. In 29 of 64 patients (45.3%), the SE could be interrupted within 48 h of ESL therapy. In patients with poststroke epilepsy, the control of SE was achieved in 62% of patients (15/23). The earlier initiation of ESL therapy was an independent predictor of control of SE. Hyponatraemia occurred in five patients (7.8%). Other side effects were not observed., Significance: Based on these data, ESL may be used as an adjunct therapy for the treatment of refractory SE. The best response was found in patients with poststroke epilepsy. In addition, early initiation of ESL therapy appears to result in better control of SE. Besides a few cases of hyponatraemia, no other adverse events were detected., (© 2023 The Authors. Epileptic Disorders published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: There is a lack of consensus regarding the role of investigations among patients presenting to the emergency department (ED) with recurrent seizures. The aim of this systematic review was to determine the frequency and utility of commonly requested investigations for nontrauma patients presenting to the ED with recurrent seizures., Methods: The MEDLINE, EMBASE, and Cochrane Library databases were searched (March 2021) for articles on this topic using search terms related to recurrent seizures, investigations, and the ED. The inclusion criteria required that articles include adult nontrauma patients presenting to the ED. Studies exclusively investigating first-episode seizures, trauma patients, and status epilepticus were excluded. Eligible studies were assessed for bias using the Newcastle-Ottawa scale. Results of studies were presented using proportions., Results: There were six cohort studies included that contributed data from 36,595 patients. All six studies assessed at least one of our primary outcomes for computed tomography (CT) brain scans. The proportion of patients who underwent a head CT ranged from 13% to 42%. The rates of abnormal head CT findings ranged from 8% to 21%. One study reported on magnetic resonance imaging (MRI) and found it used infrequently in 0.79% of cases. The proportion and yield of nonneuroimaging investigations were not well evaluated in this patient population. Only one study reported on the utility of sodium levels or blood glucose results for this population and reported abnormalities in sodium levels for 19% of patients and abnormalities in glucose levels in 50% of patients., Conclusions: In this population, CT brain scans appeared to be performed uncommonly but with moderate rates of abnormal findings. In the absence of prolonged alteration of consciousness, a history of brain tumor, or positive neurologic findings, however, neuroimaging was of low yield. Given the heterogeneity and potential limitations of these studies, further research on this topic is required., (© 2021 Society for Academic Emergency Medicine.)

Traumatic brain injury (TBI) is a common disease worldwide with a high mortality and disability rate and is closely related to the inflammatory response. However, the molecular mechanisms during the pathophysiological responses are not completely understood. This study was conducted to investigate the protective effect of curcumin on TBI and the molecular mechanisms of the p38/MAPK signal pathway. We found that curcumin remarkably ameliorated secondary brain injury after TBI, including effects on the neurological severity score and inflammation. After injection of curcumin, the neurological function score of mice decreased significantly. Curcumin exhibited antiinflammatory pharmacological effects, as reflected by inhibition of inflammatory factors (e.g., interleukin [IL]-1β, IL-6, and tumor necrosis factor [TNF]-α). Additionally, curcumin notably reduced the expression of p-p38 according to western blotting and immunohistochemical analyses. In conclusion, curcumin remarkably alleviated posttraumatic inflammation and thus shows potential for treating inflammation associated with TBI., (© 2022 John Wiley & Sons Ltd.)

Tracheitis associated with the chronic respiratory disease in chickens caused by Mycoplasma gallisepticum is marked by infiltration of leukocytes into the mucosa. Although cytokines/chemokines are known to play a key role in the recruitment, differentiation, and proliferation of leukocytes, those that are produced and secreted into the trachea during the chronic stages of infection with M. gallisepticum have not been described previously. In this study, the levels of transcription in the trachea of genes encoding a panel of 13 cytokines/chemokines were quantified after experimental infection with the M. gallisepticum wild-type strain Ap3AS in unvaccinated chickens and chickens vaccinated 40-, 48- or 57-weeks previously with the novel attenuated strain ts-304. These transcriptional levels in unvaccinated/infected and vaccinated/infected chickens were compared with those of unvaccinated/uninfected and vaccinated/uninfected chickens. Pathological changes and subsets of leukocytes infiltrating the tracheal mucosa were concurrently assessed by histopathological examination and indirect immunofluorescent staining. After infection, unvaccinated birds had a significant increase in tracheal mucosal thickness and in transcription of genes for cytokines/chemokines, including those for IFN-γ, IL-17, RANTES (CCLi4), and CXCL-14, and significant downregulation of IL-2 gene transcription. B cells, CD3 + or CD4 + cells and macrophages (KUL01 + ) accumulated in the mucosa but CD8 + cells were not detected. In vaccinated birds, the levels of transcription of the genes for IL-6, IL-2, RANTES and CXCL-14 were significantly lower after infection than in the unvaccinated/infected and/or unvaccinated/uninfected birds, while the transcription of the IFN-γ gene was significantly upregulated, and there were aggregations of B cells in the tracheal mucosa. These observations indicated that M. gallisepticum may have suppressed Th2 responses by upregulating secretion of IFN-γ and IL-17 by CD4 + cells and induced immune dysregulation characterized by depletion of CD8 + cells and downregulation of IL-2 in the tracheas of unvaccinated birds. The ts-304 vaccine appeared to induce long-term protection against this immune dysregulation. TAKE AWAY: The ts-304 vaccine-induced long-term protection against immune dysregulation caused by M. gallisepticum Detection of B cells and plasma cells in the tracheal mucosa suggested that long-term protection is mediated by mucosal B cell memory Infection of unvaccinated birds with M. gallisepticum resulted in CD8 + cell depletion and downregulation of IL-2 in the tracheal mucosa, suggestive of immune dysregulation Infection of unvaccinated birds with M. gallisepticum resulted in upregulation of IFN-γ and infiltration of CD4 + cells and antigen presenting cells (B and KUL01 + cells) into the tracheal mucosa, suggesting enhanced antigen processing and presentation during chronic infection Th2 responses to infection with M. gallisepticum may be dampened by CD4 + cells through upregulation of IFN-γ and IL-17 during chronic infection., (© 2021 John Wiley & Sons Ltd.)

Purpose: Migraine is an exclusively human chronic disorder with ictal manifestations characterized by a multifaceted clinical complexity pointing to a cerebral cortical involvement. The present review is aimed to cover the clinical, neuroimaging, and neurophysiological literature on the role of the cerebral cortex in migraine pathophysiology., Overview: Converging clinical scenarios, advanced neuroimaging data, and experimental neurophysiological findings, indicate that fluctuating excitability, plasticity, and metabolism of cortical neurons represent the pathophysiological substrate of the migraine cycle. Abnormal cortical responsivity and sensory processing coupled to a mismatch between the brain's energy reserve and workload may ignite the trigeminovascular system, leading to the migraine attack through the activation of subcortical brain trigeminal and extra-trigeminal structures, and driving its propagation and maintenance., Discussion: The brain cortex emerges as the crucial player in migraine, a disorder lying at the intersection between neuroscience and daily life. Migraine disorder stems from an imbalance in inhibitory/excitatory cortical circuits, responsible for functional changes in the activity of different cortical brain regions encompassing the neurolimbic-pain network, and secondarily allowing a demodulation of subcortical areas, such as hypothalamus, amygdala, and brainstem nuclei, in a continuous mutual crosstalk., (© 2020 American Headache Society.)

Epidemiological studies have strongly associated lower levels of vitamin D and its metabolites with an increased risk of colorectal cancer (CRC). The action of calcitriol, the active metabolite of vitamin D, is mediated by the vitamin D receptor (VDR) that is present in most tissues. In advanced CRC, VDR expression is lowered. Calcitriol has several antineoplastic effects in CRC: it promotes the G1-phase cycle arrest, lowers vascular endothelial growth factor (VEGF) synthesis and acts on tumour stromal fibroblasts to limit cell migration and angiogenesis. Hyperinsulinemia and insulin-like growth factors (IGFs) have been implicated in the pathophysiology of CRC. IGF-1 and IGFBP-3 have been the most studied components of the IGF system. Only 1% of the total serum IGF-1 is free and bioactive, and 80% of it binds to IGFBP-3. IGF-1 and its receptor IGF-1R are known to induce cell proliferation. Both IGF-1 and IGFBP-3 can favour angiogenesis by increasing the transcription of the VEGF gene. A high serum IGF-1/IGFBP-3 ratio is associated with increased risk for CRC. VDR is a transcription factor for the IGFBP-3 gene, and IGF-1 can increase calcitriol synthesis. Studies examining the effect of vitamin D treatment on serum IGF-1 and IGFBP-3 have not been in agreement since different populations, dosages and intervention periods have been used. New vitamin D treatment studies that examine CRC should take in account confounding factors such as obesity or VDR genotypes., (© 2020 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Objectives: The HIV prevalence among Chinese men who have sex with men (MSM) is high, while the HIV testing rate is low. HIV self-testing (HIVST) is a promising means of scaling up HIV testing among MSM in China, as the ability to test in private is appealing to many individuals. We evaluated the feasibility of promoting oral HIVST via the internet in the MSM population., Methods: From April 2013 to April 2014, MSM in two major cities in China were recruited for an observational study with assessment at baseline and follow-up. Data were collected via questionnaire, oral HIVST, and clinic-based HIV confirmatory testing., Results: A total of 510 MSM were recruited at baseline and 279 (54.7%) returned for a clinic follow-up visit. Compared to MSM recruited via peer referral, those recruited via the internet were better educated, had a higher monthly income, sought and met male sex partners online more frequently, had less often tested or orally tested for HIV before, and being more likely to seek HIV knowledge or HIV intervention information online. The sensitivity of oral HIVST among MSM recruited via the internet was 92.9%, and the specificity was 96.8%. A total of 19.0% of MSM sought both male sex partners and HIV intervention programmes online. The associated factors were > 10 past male sex partners and ever testing for HIV using an oral self-test kit. All MSM who were followed up re-administered oral HIVST, yet fewer MSM recruited via the internet accepted blood retesting than other MSM., Conclusions: Promoting oral HIVST via the internet could be a feasible and promising approach to facilitate HIV testing among MSM in China., (© 2019 British HIV Association.)

Over the past decade, the insulin-like growth factor (IGF)-signaling pathway has gained substantial interest as potential therapeutic target in oncology. Xentuzumab, a humanized IgG1 monoclonal antibody, binds to IGF-I and IGF-II thereby inhibiting the downstream signaling essential for survival and tumor growth. This pathway is further regulated by circulating IGF binding proteins (IGFBPs). In this work, a mechanistic model characterizing the dynamics and interactions of IGFs, IGFBPs, and Xentuzumab has been developed to guide dose selection. Therefore, in vitro and in vivo literature information was combined with temporal IGF-I, IGF-II, and IGFBP-3 total plasma concentrations from two phase I studies. Based on the established quantitative framework, the time-course of free IGFs as ultimate drug targets not measured in clinics was predicted. Finally, a dose of 1000 mg/week-predicted to reduce free IGF-I and free IGF-II at steady-state by at least 90% and 64%, respectively-was suggested for phase II., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)