Introduction: This study aimed to assess the frequency of dosing inconsistencies in prescription data and the effect of four dosing assumption strategies on adherence estimates for antipsychotic treatment. Methods: A retrospective cohort, which linked prescription and dispensing data of adult patients with ≥ 1 antipsychotic prescription between 2015-2016 and followed up until 2019, in Catalonia (Spain). Four strategies were proposed for selecting the recommended dosing in overlapping prescription periods for the same patient and antipsychotic drug: 1) the minimum dosing prescribed; 2) the dose corresponding to the latest prescription issued, 3) the highest dosing prescribed, and 4) all doses included in the overlapped period. For each strategy, one treatment episode per patient was selected and the Continuous Medication Availability measure was used to assess adherence. Descriptive statistics were used to describe results by strategy. Results: Of 277,324 prescriptions included, 76% overlapped with other prescriptions (40% with different recommended dosing instructions). The number and characteristics of patients and treatment episodes (18,292, 18,303, 18,339, and 18,536, respectively per strategy) were similar across strategies. Mean adherence was similar between strategies, ranging from 57-60%. However, the proportion of patients with adherence ≥ 90% was lower when selecting all doses (28%) compared to the other strategies (35%). Conclusions: Despite the high prevalence of overlapping prescriptions, the strategies proposed did not show a major effect on the adherence estimates for antipsychotic treatment. Taking into consideration the particularities of antipsychotic prescription practices, selecting the highest dose in the overlapped period provided a more accurate adherence estimate.

Background and purpose Chymotrypsin is a serine protease produced by the pancreas and secreted into the lumen of the small intestine, where it digests food proteins. Due to its presence in the gut lumen, we hypothesized that chymotrypsin activity may be found close to epithelial cells and signals to them via Protease-activated receptors (PARs). We deciphered molecular pharmacology mechanisms for chymotrypsin signaling in intestinal epithelial cells. Experimental approaches The presence and activity of chymotrypsin were evaluated by western blot (WB) and enzymatic activity tests in luminal and mucosal compartments of murine and human gut samples. The ability of chymotrypsin to cleave the extracellular domain of PAR1 or PAR2 was assessed using cell lines expressing N-terminally-tagged receptors. The cleavage site of chymotrypsin on PAR1 and PAR2 was determined by HPLC-MS analysis. To study the pharmacology of chymotrypsin signals, we investigated calcium signaling and ERK1/2 activation using calcium mobilization assays and WB in CMT93 intestinal epithelial cells. Key results We found that chymotrypsin was present and active in the vicinity of the murine and human colonic epithelium. Molecular pharmacology studies evidenced that chymotrypsin cleaved both PARs receptors. While chymotrypsin activated calcium and ERK1/2 signaling pathways through PAR2, it disarmed PAR1, preventing further activation by its canonical agonist thrombin. CONCLUSION Our work suggests that the function of chymotrypsin in the gut lumen goes well beyond a simple digestive role. Our results highlight the ability of chymotrypsin to signal to intestinal epithelial cells via PARs, which may have important physiological consequences in gut homeostasis.

The rapid growth in the number of electric vehicles, driven by the ‘double carbon’ target, and the impact of uncontrolled charging and discharging behavior and discharged battery losses severely limit electric vehicles’ low carbon characteristics. Existing research on systemic low carbon emissions and electric vehicle charging and discharging issues is usually determined by considering only carbon trading markets or charging and discharging management on the source side. In this regard, a coordinated and optimized operation model that considers the participation of electric vehicle clusters in deep peaking and the source network load and storage adjustable resources is proposed. The upper layer establishes a real-time price-based demand response model for the load side with the minimum net load fluctuation as the objective function; the middle layer establishes a comprehensive operation mechanism for the source and storage side that includes an orderly charging and discharging peaking compensation mechanism for electric vehicles and a deep peaking mechanism that takes into account clean emissions, and constructs an optimal operation model with the minimum comprehensive operating cost as the objective function; the lower layer establishes a distribution network loss minimization model for the network side that takes into account the orderly charging and discharging of electric vehicle as the objective function. The optimal tidal model with the objective function of minimizing the distribution network loss is established at the lower level. Finally, the original problem is transformed into a mixed integer linear programming problem, and the model’s effectiveness is verified by setting different scenarios.

A document by Victor Gonzalez-Uribe. Click on the document to view its contents.

Environmental arsenic contamination adversely affects human health, and its accumulation diminishes food quality. Glutathione (GSH) is known to bind and detoxify arsenic and other toxic metals. GSH homeostasis in living cells is maintained via γ-glutamyl cycle. Previously, γ-glutamyl cyclotransferases ( GGCTs) have been shown to be involved in GSH degradation in plants and increasing tolerance to toxic metals. Here we characterized the GGCT2;1 homolog from Camelina sativa for its role in arsenic tolerance and accumulation. Overexpressing CsGGCT2;1 in Camelina resulted in strong tolerance to arsenite (AsIII). Compared to wild-type, overexpression (OE) lines had significantly higher shoot (2.6-3.5-fold) and root (7-10-fold) biomass on AsIII containing media and accumulated 40-60% less arsenic in root and shoot tissues. Further, OE lines had higher chlorophyll content, lower lipid peroxidation and oxidative stress. There was a small but nonsignificant increase in 5-oxoproline (5-OP) in OE lines and the upregulation of Oxoprolinase 1 ( OXP1) suggested accelerated conversion of 5-OP to glutamate, which is then utilized for GSH resynthesis for maintaining homeostasis. Overall, overexpression of GGCT2;1 and it homologs in Camelina and other crops will enable their cultivation on contaminated marginal lands to reduce As accumulation, addressing food safety issues as well as future food and biofuel needs.

Hemophagocytic lymphohistiocytosis in a patient of paroxysmal cold hemoglobinuria triggered by malaria: A case reportKEY CLINICAL MESSAGEWith Plasmodium falciparum and HLH, malaria is an uncommon but potentially deadly disease. Although HLH can be lethal if left untreated. It also offers a proposed method for identifying and treating malaria-related HLH.

Mismatch Negativity (MMN) is an event-related potential component automatically elicited by events that violate predictions based on prior events. To elicit this component, researchers use stimulus repetition to induce predictions, and the MMN is obtained by subtracting the brain response to rare or unpredicted stimuli from that of frequent stimuli. Under the predictive processing framework, one increasingly popular interpretation of the mismatch response postulates that MMN represents a prediction error. In this context, the reduced MMN amplitude to auditory stimuli has been considered a potential biomarker of Schizophrenia, representing a reduced prediction error and the inability to update the mental model of the world based on the sensory signals. It is unclear, however, whether this amplitude reduction is specific for auditory events or if the visual MMN reveals a similar pattern in Schizophrenia Spectrum Disorder. This review and meta-analysis aimed to summarise the available literature on the vMMN in Schizophrenia. A systematic literature search resulted in 11 eligible studies that resulted in a combined effect size of g = - 0.63, CI [-0.86, -0.41], reflecting lower vMMN amplitudes in patients. These results are in line with the findings in the auditory domain. This component offers certain advantages, such as less susceptibility to attentional influences. Future studies should use vMMN to explore abnormalities in the PPF in different stages and groups of the SSD and increase the knowledge in the search for biomarkers in Schizophrenia.

A document by Michael D’Netto. Click on the document to view its contents.

Background: The emergence of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in early 2020 and subsequent implementation of public health and social measures (PHSM) disrupted the epidemiology of respiratory viruses. This work describes the epidemiology of RSV observed during two winter seasons (weeks 40 to 20) and inter-seasonal periods (weeks 21 to 39) during the pandemic between October 2020 and September 2022. Methods: Using data submitted to The European Surveillance System (TESSy) by countries or territories in the World health Organization (WHO) European Region between weeks 40/2020 and 39/2022, we aggregated country-specific weekly RSV counts of sentinel, non-sentinel and Severe Acute Respiratory Infection (SARI) surveillance specimens and calculated percentage positivity. Results for both 2020/21 and 2021/22 seasons and inter-seasons were compared to pre-pandemic 2016/17 to 2019/20 seasons and inter-seasons. Results: Although more specimens were tested than in pre-COVID-19 pandemic seasons, very few RSV detections were reported during the 2020/21 season in all surveillance systems. During the 2021 inter-season, a gradual increase in detections was observed in all systems. In 2021/22, all systems saw early peaks of RSV infection, and during the 2022 inter-seasonal period, patterns of detections were closer to those seen before the COVID-19 pandemic. Conclusion: RSV surveillance continued throughout the COVID-19 pandemic, with an initial reduction in transmission, followed by very high and out-of-season RSV circulation (summer 2021) and then an early start of the 2021/22 season. RSV circulation during the 2022/23 season had not yet normalised.

Functional connectivity (FC) indicates the interdependencies between brain signals recorded from spatially distinct locations in different frequency bands, which is modulated by cognitive tasks and is known to change with aging and cognitive disorders. Recently, the power of narrow-band gamma oscillations induced by visual gratings has been shown to reduce with both healthy aging and in subjects with mild cognitive impairment (MCI). However, the impact of aging/MCI on stimulus-induced gamma FC has not been well studied. We recorded electroencephalogram (EEG) from a large cohort (N=229) of elderly subjects (>49 years) while they viewed large cartesian gratings to induce gamma oscillations and studied changes in alpha and gamma FC with healthy aging (N=218) and MCI (N=11). Surprisingly, we found that aging and disease changed power and FC in different ways. With healthy aging, alpha power did not change but FC decreased significantly. MCI reduced gamma but not alpha FC significantly compared with age and gender matched controls, even when power was matched between the two groups. Overall, our results show distinct effects of aging and disease on EEG power and FC, suggesting different mechanisms underlying aging and cognitive disorders.

This paper proposes a varying coefficient Susceptible-Exposed-Infected-Removed (vSEIR) model to dynamically simulate the early mpox epidemic that sparked panic in 2022, considering the time-varying infection rate and the group protected by the smallpox vaccination. We apply the recursive least squares algorithm with a forgetting factor for real-time identification of time-varying infection rates and the efficacy of non-pharmacological interventions. The sparse Hodrick-Prescott (HP) filter, tuned with leave-one-out cross-validation, captures mpox epidemic kinks via the effective reproduction number R t obtained from the discrete vSEIR model. We experiment with this approach in Brazil, Spain, UK and US, comparing COVID-19 and mpox outbreaks based on those kinks and transmission cycles, identifying that except for Spain, mpox epidemic reached its decline period earlier than COVID-19 without strong interventions. Additionally, the result regarding sensitivity analyses shows that the total number of mpox outbreak infections would have increased by 12% without smallpox vaccination and the data uncertainty can bring great variations in R t .

Introduction The human papillomavirus (HPV) is the most prevalent viral sexually transmitted infection globally, with cervical cancer being primarily caused by persistent HPV infection. Early diagnosis and monitoring of women with HPV infection can significantly improve treatment outcomes and lower mortality rates. This study aimed to determine the prevalence of HPV in cervical specimens sent to Aga Khan University Hospital Clinical Laboratories for diagnostic testing. Methods A retrospective review of 1062 test records from 2017-2022 was conducted, with high-risk HPV DNA testing performed by DNA Hybrid Capture 2 method. Results Out of 1062 patients, 764 underwent a Pap smear test, with 14.9% having abnormal epithelial lesions. High-risk HPV DNA was detected in 180(16.9%) cases, and biopsy findings were available in 118 specimens (11.1%). Squamous intraepithelial lesions were the most common biopsy finding, followed by non-specific cervicitis (36, 30.5%), squamous cell carcinoma (16, 13.6%), and adenocarcinoma in (6 ,5.1%) women. HPV positivity was correlated with cervical cytology and biopsy findings. Conclusions The data shows a strong correlation between hrHPV positivity and neoplasia in women tested in Pakistan, suggesting a delay in HPV detection. Routine HPV testing is strongly advised for women to screen for cervical cancer. Early diagnosis of high-risk HPV strains can improve triage, treatment, and follow-up of infected patients. Raising public awareness of the value of routine testing, early detection, and treatment of cervical cancer and HPV can significantly lower morbidity and mortality rates.

Kaposi sarcoma (KS) is a neoplasm of vascular origin that promotes angiogenesis and the growth of endothelial cells triggered by the Kaposi Sarcoma-associated Herpes Virus (KSHV). When associated with HIV, KSHV becomes more aggressive and rapidly evolves. The HIV-1 Tat protein can be essential in developing AIDS-associated KS by promoting angiogenesis and increasing KSHV replication. Therefore, we evaluated the genetic profile of the first exon of tat gene among groups of people living with HIV with (case group, n=36) or without Kaposi’s sarcoma, this later with (positive control group, n=46) and without KSHV infection (negative control group, n=24); all individuals under antiretroviral therapy. The genetic diversity, the DN/DS ratio, and the genetic entropy of the first exon of tat were higher in the case group, followed by the positive control group, which was higher than the negative control group. The number of tat codons under positive selection was seven in the case group, six in the positive control group, and one in the negative control group. The prevalence of HIV viral loads below the detection limit was equal in the Case and positive control groups, which were lower than in the negative control group. The mean CD4+ T cell counts were higher in the negative control group, followed by the positive control group, and followed by the case group. These results emphasize the negative influence of KSHV in antiretroviral treatment, as well as the HIV specific Tat profile among people living with HIV who developed KS.

Inflammation is a physiological response composed by well-defined and overlapping events that can eliminate pathogens and reestablish homeostasis of tissues. Physiological systems have an elastic capacity to deal with numerous perturbations. Infection may lead to inflammation, tissue damage and disease as consequence of breakdown of tissue resilience. The resolutive phase is a sine qua non condition to achieve homeostasis after acute inflammation. Exuberant or chronic inflammation occurs in diverse infectious diseases. Pro-resolving molecules may be useful for the treatment of certain infections, as these molecules modulate the immune response and avoid the exacerbated/misplaced inflammation unleashed by microbes. Some pro-resolving molecules may also favour pathogen clearance, in addition to decreasing tissue damage. In this review, we discuss the endogenous role and the therapeutic potential of the most relevant pro-resolving molecules in the context of bacterial and viral infections.

Widely graded loose soils (WGLS), a loose mixture comprising coarse and fine particles, are widely distributed in the western mountainous areas of China. Owing to rainfall infiltration, fine particles are eroded and migrated through the skeleton formed by coarse particles, thus altering the hydraulic and mechanical characteristics of WGLS. This paper intends to uncover the internal erosion process and its influencing factors in WGLS due to rainfall infiltration. To this end, a novel fixed-wall permeameter is developed, capable of applying an inflow rate-controlled condition and collecting effluent flowing out of the specimen. A simplified and cost-effective testing protocol is proposed for separating eroded silty clay particles, sandy gravel particles, and seepage water from the collected effluent. Several seepage tests are conducted on remolded specimens with different inflow rates and initial porosity utilizing the newly developed experimental setup and testing protocol. The results indicate four successive erosion stages in the internal erosion process: the suffusion stage, the suffosion stage, the piping stage, and the stabilization stage. Six critical hydraulic gradients correspond to the onset of the various stages. The inflow rate does not affect the critical hydraulic gradient for suffusion. However, it significantly impacts the critical hydraulic gradient for suffosion and subsequent internal erosion behavior. Increasing initial porosity does not necessarily result in higher erosion potential. These results are conducive to further understanding the formation mechanism of internal erosion-induced geologic hazards.

As survival rates for childhood cancer have improved, there has been increasing focus on identifying and addressing adverse impacts of cancer and its treatment on children and their families during treatment and into survivorship. The Behavioral Science Committee (BSC) of the Children’s Oncology Group (COG), comprised of psychologists, neuropsychologists, social workers, nurses, physicians, and clinical research associates, aims to improve the lives of children with cancer and their families through research and dissemination of empirically supported knowledge. Key achievements of the BSC include enhanced interprofessional collaboration through integration of liaisons into other key committees within COG, successful measurement of critical neurocognitive outcomes through standardized neurocognitive assessment strategies, contributions to evidence-based guidelines, and optimization of patient-reported outcome measurement. The collection of neurocognitive and behavioral data continues to be an essential function of the BSC, in the context of therapeutic trials that are modifying treatments to maximize event-free survival, minimize adverse outcomes, and optimize quality of life. In addition, through hypothesis-driven research and multi-disciplinary collaborations, the BSC will also begin to prioritize initiatives to expand the systematic collection of predictive factors (e.g., social determinants of health) and psychosocial outcomes, with overarching goals of addressing health inequities in cancer care and outcomes, and promoting evidence-based interventions to improve outcomes for all children, adolescents, and young adults with cancer.

IntroductionHypercalcemia is one of the most frequent electrolyte disorders in patients with malignant diseases [1], presenting in about one quarter of these patients [2]. Hypercalcemia could result from osteolytic lesions or from production of humoral substances like parathyroid hormone-related protein (PTHrP) or uncontrolled synthesis and secretion of 1-25(OH)2D3 by the tumoral cell or macrophages. Within tumor-related etiologies, multiple myeloma, breast, lung, and kidney cancers are the most frequent [3,4]. In these diseases, hypercalcemia has been reported in 30% and 60% of patients with multiple myeloma and T-cell non-Hodgkin lymphoma [1].However, hypercalcemia has only been reported in 7-8% of patients with B-cell non-Hodgkin lymphoma (NHL) and its prevalence and its prognostic value is unclear [2].

The fatigue analysis of structural components is a relevant research topic in both scientific and industrial communities. Despite major advances in understanding, fatigue damage remains a significant issue for both metallic and non-metallic components, sometimes leading to unexpected failures of in-service parts. Among the different assessment methodologies, critical plane methods have gained significance as they enable identification of a component’s critical location and direction of early crack propagation. However, the standard plane scanning method for calculating critical plane factors is computationally intensive and, for that, it is only applied when the component critical regions are already known. When critical areas are not easily identifiable due to complex geometries, loads or constraints, a more efficient method for evaluating critical plane factors would be required. This work presents a closed form solution for efficiently evaluating the Fatemi-Socie critical plane factor, in case of linear-elastic material behaviour and proportional loading conditions, based on tensor invariants and coordinates transformation laws. The proposed algorithm was tested on different test cases (i.e. hourglass, notched and welded joint geometries) under different loading conditions (i.e. tensile, bending and torsion) and showed a significant reduction in computation time compared to the standard plane scanning method.

Background: The purpose of our research was to discover the adverse events (AEs) not mentioned in the previous y drug instructions after using gemcitabine, so as to guide clinical medication. Methods: The Food and Drug Administration Adverse Event Reporting System (FAERS) database was utilized to retrieve AEs associated with the use of gemcitabine up to 2023. Four methods were used to detect new signals of adverse drug reactions（Reporting Odds Ratio, Proportional Reporting Ratio, Bayesian Confidence Propagation Neural Network, and Empirical Bayesian Geometric Mean）. AEs were considered positive signals only if they were detected by all four algorithms. Results: Between 2014 and 2023, 14,905 individuals experienced 42,360 AEs following the use of gemcitabine. totaling 437 preferred terms (PTs) distributed across 20 system organ classes (SOCs). We focused on AEs that were either not mentioned or mentioned less frequently in SOCs related to eye diseases, the nervous system, and the ear and labyrinth. After the administration of gemcitabine, patients exhibited retinopathy (Case number: 28), Purtscher retinopathy (Case number: 10), choroidal effusion (Case number: 9), amaurosis (Case number: 9), cystoid macular edema (Case number: 8), and other ocular organ system-related AEs. In terms of the nervous system, peripheral neuropathy (Case number: 363), neurotoxicity (Case number: 117), polyneuropathy (Case number: 92), and other neurologic AEs were observed. Furthermore, in the ear and labyrinth, ototoxicity (Case number: 9) was reported. Conclusion: Our study identified previously undetected AEs following treatment with gemcitabine, which may provide new insights for future medication guidance.

Background: The current study investigates how sensory processing and attention management mediate the associations between misophonia and the degree of disability, emotional characteristics, and disgust propensity. Methods: The structural equation modeling approach was applied on the data gathered from 495 students from public colleges through convenience sampling in order to carry out this study. Results: The findings demonstrated that misophonia significantly affects both attention control and sensory processing. It was also discovered that attention control has a mediating role in the relationships between misophonia and disgust propensity as well as in the relationship between misophonia, depression, and anxiety. Keywords: Misophonia, Sensory Processing, Attention Control, Severity of Disability, Emotional Characteristics, and Disgust Propensity

Coronary artery fistula is a rare cardiac disease which could be diagnosed by multiple imaging modalities and could be effectively treated by surgical or percutaneous closure. The patient is a 21 years old man initially presented with palpitation and paroxysmal atrial fibrillation. For further evaluation he underwent transthoracic echocardiography on which a mass like structure was found in right atrium. On transesophageal echocardiography this cystic structure was in continuation with dilated left circumflex coronary artery and based on data from both CT angiography and coronary angiography , coronary artery fistula with abnormal drainage right atrium was defined and percutaneous closure was proposed. Learning objective: As coronary artery fistula is a rare condition, making the acquaintance of its clinical presentation, the role of imaging modalities in diagnosis and therapeutic options is our concern. In this patient paroxysmal atrial fibrillation and then a cystic mass like structure in right atrium led us to the diagnosis in stepwise approach.

Aims: There is no clinical evidence of differences in drugs associated with long-term survival in patients with pulmonary arterial hypertension (PAH) due to a small population and the lack of information on death in the Japanese medical database systems. This study evaluated whether patient data from a spontaneous reporting database could be used for comparing the effects of pulmonary vasodilators on long-term survival in PAH patients. Methods: PAH patient data reported in the Japanese Adverse Drug Event Report (JADER) database from April 2004 to July 2022 were extracted. Kaplan-Meier curves were used to compare survival times. Adjusted hazard ratios (aHRs) for all-cause mortality were determined using Cox proportional hazards models. Results: Of 1969 PAH patients reported in the JADER database, 1208 patients were included in the survival analyses. The patient demographics were similar to those of the PAH population reported in the Japan Pulmonary Hypertension Registry. Among drugs targeting the prostacyclin pathway, epoprostenol was most associated with long-term survival (aHR: 0.38; 95% confidence interval [CI], 0.23–0.64). The PAH patients treated with endothelin receptor antagonists had improved survival, especially in the macitentan users (aHR: 0.30; 95% CI, 0.22–0.42). Sildenafil was associated with a poor prognosis in the PAH patients (aHR: 1.56; 95% CI, 1.19–2.04). Conclusion: Although our results must be interpreted with caution due to several limitations inherent to spontaneous reporting databases, our approach using the JADER database for survival analysis may provide useful information in limited situations such as the treatment of rare diseases including PAH.

Limited knowledge of bird microbiome in the all-body niche hinders our understanding of host–microbial relationships and animal health. Here, we characterized the microbial composition of the crested ibis from 13 body sites, representing the cloaca, oral, feather, and skin habitats, and explored assembly mechanism structuring the bacterial community of the four habitats, respectively. The bacterial community characteristics were distinct among the four habitats. The skin harbored the highest alpha diversity, most diverse functions, and more complex network, followed by feather, oral, and cloaca. Individual-specific features were observed when the skin and feathers were concentrated independently. Skin and feather samples of multiple body sites from the same individual were more similar than those from different individuals. Although a significant proportion of the microbiota in the host (3.5% to 14.5%) was not derived from the environmental microbiome, as body sites became more exposed to the environment, the relative importance of neutral processes increased. Neutral processes were the most important contributor in shaping the feather microbiome communities (R2=0.859). A higher percentage of taxa (29.3%) on the skin were selected by hosts compared to taxa on other body habitats. This study demonstrated that niche speciation and partial neutral processes, rather than environmental sources, contribute to microbiome variation in the crested ibis. These results enhance our knowledge of baseline microbial diversity in birds and will aid health management in crested ibises in the future.

The tree of heaven Ailanthus altissima is one of the most invasive plant species in Europe and Italy and poses a threat especially in urban environments, where it damages man-made structures. A deeper comprehension of how germination traits respond to environmental factors could help elucidate the process of invasion. Germination tests on A. altissima seeds collected at different altitudes were carried out at different light conditions (12-hr light/12-hr darkness and continuous darkness) and temperature regimes (15-6 °C, 20-10 °C and 25-15 °C). A further test was also performed to assess the germinative response of seeds retained on the plant during winter. Seeds have been demonstrated not to have clear preferences for temperature and light, nor to show an effect of the altitude at which they develop on their germination capacity. This characteristic makes A. altissima highly adaptable to different types of environments and not restrained to specifical conditions. Moreover, the continuous release of seeds throughout the year may maximize the chances of a successful germination. The nature of pioneer species of A. altissima emerges already during its reproduction and germination, both in its tolerance to different environmental conditions and in the adoption of a reproduction strategy oriented towards the extreme of r-strategist species, contributing to the invasiveness of the species.