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Christina Mueller,1 Ayushe A Sharma,2 Jerzy P Szaflarski3 1Department of Neurology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; 2Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA; 3Departments of Neurology, Neurobiology, and Neurosurgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USACorrespondence: Christina Mueller, Department of Neurology, Heersink School of Medicine, University of Alabama at Birmingham, 1719 6th Ave S, Birmingham, AL, 35222, USA, Tel +1 205-975-4219, Fax +1 205-996-4802, Email cm1@uab.eduPurpose: Inflammation may link trauma to clinical symptoms in functional seizures (FS). We compared brain temperature and metabolites in FS, psychiatric (PCs) and healthy controls (HCs) and quantified their associations with serum biomarkers of inflammation and clinical symptoms.Patients and Methods: Brain temperature and metabolites were measured with whole-brain magnetic resonance spectroscopic imaging (MRSI) and compared between groups in regions of interest and the whole brain. Relationships with inflammatory biomarkers and symptoms were assessed with Pearson correlations.Results: Brain temperature was higher in FS than HCs in the orbitofrontal cortex (OFC) and anterior cingulate gyrus (ACG) and lower in the occipital cortex and frontal lobe. PCs showed lower temperatures than HCs in the frontal lobe including precentral gyrus and in the cerebellum. Myo-inositol (MINO) was higher in FS than HCs in the precentral gyrus, posterior temporal gyrus, ACG and OFC, and choline (CHO) was higher in the occipital lobe. CHO was higher in PCs than HCs in the ACG and OFC, and N-acetylaspartate (NAA) was higher in the ACG. There were no significant correlations with the serum inflammatory biomarkers. In FS, brain temperature correlated with depression, quality of life, psychological symptoms, and disability, CHO correlated with disability, and MINO correlated with hostility, disability, and quality of life.Conclusion: Some of the previously identified neuroimaging abnormalities in FS may be related to comorbid psychiatric symptoms, while others, such as abnormalities in sensorimotor cortex, occipital regions, and the temporo-parietal junction may be specific to FS. Overlapping MINO and temperature increases in the ACG and OFC in FS suggest neuroinflammation.Keywords: brain temperature, magnetic resonance spectroscopy, functional seizures, inflammatory biomarkers, metabolites

Purpose: The association of obesity with hypertension has been recognized for the decades which are the important risk factors for the cardiovascular disease. So the purpose of the present study was to determine association of obesity with hypertension in school going children of Surat. Methodology: School going children aged between 12-18 years, of five schools in Surat were selected for the study. Height and weight were measured and BMI was calculated. Blood pressure measurements were taken as per recommendation of American heart society and family history of hypertension has also been assessed. Hypertension was considered if blood pressure is more than 95th percentile according to the update of task force report and Obesity was diagnosed by BMI for age. Results: Of 682 children, 8.94% were obese and 20.09% were hypertensive. Conclusion: Obesity is strongly associated with hypertension in children and both together may risk factors for later coronary disease.

Since their discovery in 1991, carbon nanotubes (CNTs) have found widespread use in various industries, from aerospace to energy, due to their excellent mechanical, thermal, electrical, and tribological properties. Their lightweight nature, small size, incredible tensile strength, and conductivity have made them very popular as reinforcements in metals, polymers, and even finding employment in additive manufacturing. In this review, we provide a rundown of these structures and discuss in detail the numerous methods used to process CNT-reinforced materials, such as chemical vapor deposition (CVD), ball milling, hot pressing, and selective laser melting. The limitations of manufacturing and processing these composites are also discussed, strengthened by the support of different published works. To understand the changes in the properties of these composites in terms of varying parameters such as temperature, CNT length, diameter, etc., an extensive summary is provided, describing several techniques to perform experimental analysis and giving plausible reasons for attributing these changes. Consequently, we explore the specific areas of applications for these CNT-reinforced composites in fields such as aerospace, energy, biomedical, and automobile, and how they can be further processed and changed to allow for more affordable and efficient solutions in the future.

The research suggests an approach that prioritizes customer needs and aims to reduce energy expenses while safeguarding customer privacy. Furthermore, it is recommended that smart homes incorporate a home energy management system to optimize appliance energy consumption. Conversely, the introduction of demand-side management addresses the energy management challenges faced by smart households. The main goal of this approach is to decrease energy usage and electricity costs for customers. Moreover, it enhances user satisfaction while waiting at common intervals. The primary emphasis of this study is on a smart residence furnished with energy management technology and smart home gadgets capable of supplying electricity to the grid. These objectives are considered distinct aspects in the multi-objective optimization issue stemming from this approach. The study utilizes the grasshopper optimization algorithm (GOA) to optimize battery and home appliance scheduling in smart homes with flexible devices. The goal is to reduce the overall cost of microgrid systems through demand-side management implementation. This comparison highlights the superiority of the proposed method in optimizing energy consumption and reducing carbon emissions in a variety of scenarios. By achieving lower energy costs and carbon emissions while maintaining a comfortable indoor environment, the proposed method proves to be a highly effective and sustainable solution for energy management in buildings. These simulation results provide strong evidence of the method’s potential to significantly impact energy efficiency and environmental sustainability in real-world applications. Furthermore, the consistent minimization of the discomfort index showcases the method’s ability to prioritize occupant comfort while still achieving significant energy savings and emissions reductions. Overall, the comparison with other algorithms solidifies the effectiveness and practicality of the proposed method in addressing the complex challenges of energy management and sustainability in smart homes.

Helicoverpa armigera is a global agricultural pest of serious concern. Continued use of chemical insecticides as control measures has raised grave health and environment concerns, necessitating a search for botanicals as safe alternatives. The current study investigates the effects of β-sitosterol, a bioactive phytocomponent in Thevetia neriifolia, on the growth and development, as well as on midgut enzymes of H. armigera. Dietary β-sitosterol produced dose-dependent systemic toxicity and growth inhibitory effects in H. armigera; the most significant effects were obtained with 10 μg/mL dietary β-sitosterol. Higher prepupal and pupal mortality in comparison to larval mortality and a comparatively greater reduction in average weight gained by later instars point to cumulative effects of β-sitosterol. The delayed effects were ascertained by the 82.05%-57.89% reduction in adult emergence in comparison to 95.02% emergence in controls. Dose-dependent effects of β-sitosterol were observed as significantly decreased enzyme activities of alanine aminotransaminase (ALT), aspartate aminotransaminase (AST) and alkaline phosphatase (ALP) in the larval midgut. Suppression of enzyme activity was obtained in the order ALT>AST>ALP. Impaired activity of gut enzymes possibly lowered the energy reserves and affected nutrient transport through the gut epithelium, affecting the growth and development of H. armigera. Our study points to a promising use of β-sitosterol against H. armigera, although further examination and field studies are needed to ascertain its possible use in control programs.

Abstract Background There are well-established socio-economic differences in the prevalence of smoking in the UK, but conventional socio-economic measures may not capture the range and degree of these associations. We have used a commercial geodemographic profiling system, Mosaic, to explore associations with smoking prevalence in a large primary care dataset and to establish whether this tool provides new insights into socio-economic determinants of smoking. Methods We analysed anonymised data on over 2 million patients from The Health Improvement Network (THIN) database, linked via patients' postcodes to Mosaic classifications (11 groups and 61 types) and quintiles of Townsend Index of Multiple Deprivation. Patients' current smoking status was identified using Read Codes, and logistic regression was used to explore the associations between the available measures of socioeconomic status and smoking prevalence. Results As anticipated, smoking prevalence increased with increasing deprivation according to the Townsend Index (age and sex adjusted OR for highest vs lowest quintile 2.96, 95% CI 2.92-2.99). There were more marked differences in prevalence across Mosaic groups (OR for group G vs group A 4.41, 95% CI 4.33-4.49). Across the 61 Mosaic types, smoking prevalence varied from 8.6% to 42.7%. Mosaic types with high smoking prevalence were characterised by relative deprivation, but also more specifically by single-parent households living in public rented accommodation in areas with little community support, having no access to a car, few qualifications and high TV viewing behaviour. Conclusion Conventional socio-economic measures may underplay social disparities in smoking prevalence. Newer classification systems, such as Mosaic, encompass a wider range of demographic, lifestyle and behaviour data, and are valuable in identifying characteristics of groups of heavy smokers which might be used to tailor cessation interventions.

Abstract Background Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide that is particularly refractory to chemotherapy. Several studies have proposed combination chemotherapy regimen for HCC treatment. However, these therapies are not effective in regressing tumor and prolonging survival of patient's suffering from HCC. Therefore, the development of more effective therapeutic tools and new strategies for the treatment of HCC are urgently needed. Over the last decade much attention has been focused on "bystander effect" as a possible therapeutic strategy for the treatment of certain human tumors. Interest in this therapeutic approach originated from numerous reports describing the radiation induced bystander effect. However, the knowledge about chemotherapy induced bystander effect is still limited. Hence, chemotherapy induced bystander phenomenon in hepatoma cells was explored by utilizing Mitomycin C (MMC). Results MMC induced bystander killing was observed only in hepatoma cells and it did not occur in cervical cancer cells. MMC induced bystander killing was transferable via medium. It occurred in co-cultured cells indicating the involvement of secreted as well as membrane bound factors. FasL and TRAIL were detected in the conditioned medium from treated cells. In medium transfer experiment, pre-treatment with EDTA (a broad range protease inhibitor) diminished MMC induced bystander killing. Following drug exposure, expression of Fas and TRAIL receptors increased and treatment with neutralizing antibodies against FasL and TRAIL inhibited bystander killing. Conclusion Our results highlight the therapeutic importance of MMC in the treatment of HCC and implicate role of membrane bound and secreted forms of FasL and TRAIL in MMC induced bystander killing.

Objective: Epileptogenesis is linked to neuroinflammation. We hypothesized that local heat production caused by neuroinflammation can be visualized non-invasively in vivo via brain magnetic resonance spectroscopic imaging (MRSI) and MRSI-thermometry (MRSI-t) and that there is a relationship in patients with temporal lobe epilepsy (TLE) between MRSI-t and brain metabolites choline and myo-inositol and between neuroimaging and cellular and serum biomarkers of inflammation., Methods: Thirty-six (36) participants, 18 with temporal lobe epilepsy (13 females) and 18 age-matched healthy controls (nine females), were enrolled prospectively and underwent MRSI/MRSI-t; TLE participants also provided blood samples. Temperature was measured using creatine as a reference metabolite. Analysis of Functional NeuroImages 3dttest++ tool was used to analyze voxel-level group differences in temperature, choline, and myo-inositol. Associations with immune cell subsets, cytokines, and chemokines related to inflammation were quantified using correlation coefficients with significant relationships as noted., Results: Patients with TLE showed elevated temperature, choline, and myo-inositol in the temporal lobes. Higher brain temperature was associated with higher levels of cytokines and chemokines, including GM-CSF, TNF, IL-1β, and IL - 12p70, and lower frequency of immune cells including CD3 + T-cells, CD4 + T-cells, CD8 + T-cells, and classical monocytes. Higher choline was associated with higher levels of the cytokines including LT-α, IL-13, and IL-4, and higher myo-inositol was associated with a higher frequency of CD4 + T-cell and CD19 + B-cell subsets and higher levels of cytokines and chemokines including LT-α, IL-13, and CCL3., Significance: This study, for the first time, showed that in temporal lobes of patients with TLE temperature and metabolite changes correlate with cellular and serum biomarkers of inflammation. Our results provide support for further development of MRSI-t as a measure of neuroinflammation in epilepsy and potentially other neurological disorders and as an investigative and clinical tool., Plain Language Summary: Neuroinflammation is associated with excessive heat production which can be visualized with magnetic resonance spectroscopic imaging and thermometry (MRSI-t). We prospectively investigated the relationship between MRSI-t and cellular and serum measures of peripheral inflammation in patients with temporal lobe epilepsy (TLE); we compared the results of MRSI-t in patients with TLE to healthy controls. We showed a relationship between the temperature elevations in TLE and elevations of various measures of peripheral inflammation. Our results support further development of MRSI-t as a measure of neuroinflammation in epilepsy and potentially other neurological disorders and as an investigative and clinical tool., (© 2024 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Mechanotherapy has emerged as a promising treatment for tissue injury. However, existing robots for mechanotherapy are often designed on intuition, lack remote and wireless control, and have limited motion modes. Herein, through topology optimization and hybrid fabrication, wireless magneto-active soft robots are created that can achieve various modes of programmatic deformations under remote magnetic actuation and apply mechanical forces to tissues in a precise and predictable manner. These soft robots can quickly and wirelessly deform under magnetic actuation and are able to deliver compressing, stretching, shearing, and multimodal forces to the surrounding tissues. The design framework considers the hierarchical tissue-robot interaction and, therefore, can design customized soft robots for different types of tissues with varied mechanical properties. It is shown that these customized robots with different programmable motions can induce precise deformations of porcine muscle, liver, and heart tissues with excellent durability. The soft robots, the underlying design principles, and the fabrication approach provide a new avenue for developing next-generation mechanotherapy., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

A subset of people living with HIV (PLWH) can produce broadly neutralizing antibodies (bNAbs) against HIV, but the lymph node (LN) dynamics that promote the generation of these antibodies are poorly understood. Here, we explored LN-associated histological, immunological, and virological mechanisms of bNAb generation in a cohort of anti-retroviral therapy (ART)-naïve PLWH. We found that participants who produce bNAbs, termed neutralizers, have a superior LN-associated B cell follicle architecture compared with PLWH who do not. The latter was associated with a significantly higher in situ prevalence of Bcl-6 hi follicular helper CD4 T cells (TFH), expressing a molecular program that favors their differentiation and stemness, and significantly reduced IL-10 follicular suppressor CD4 T cells. Furthermore, our data reveal possible molecular targets mediating TFH- B cell interactions in neutralizers. Together, we identify cellular and molecular mechanisms that contribute to the development of bNAbs in PLWH., Competing Interests: Disclosure of Conflicts of Interest The authors declare no competing conflicts of interest.

Introduction: With medical science advancing in leaps and bounds, average lifespan is now trending upward, and we are now facing an increasing prevalence of diseases of the elderly, sarcopenia being one of them. Unfortunately, sarcopenia, especially in India, remains to be frequently overlooked, underdiagnosed, and largely understudied. One of the greatest hindrances to the diagnosis of sarcopenia is high costs and limited availability of diagnostic modalities such as magnetic resonance imaging (MRI) and dual energy X-ray absorptiometry (DEXA) scan. Accessible, feasible, and affordable means to diagnose sarcopenia is thus the need of the hour., Materials and Methods: We performed a cross-sectional observational study among 300 patients aged 65 years or above (including both outpatient and inpatient departments) at MM Institute of Medical Sciences, Mullana between June 2021 and June 2022. Patients were evaluated as per the European Working Group for Sarcopenia in Older People (EWGSOP) algorithm using bioelectrical impedance analysis (BIA) and the results were compared with results of the SARC-F questionnaire. Statistical analyses were then carried out using IBM Statistical Package for the Social Sciences (SPSS) Statistics version 26., Results: Out of 300 patients, 56 (18.7%) were sarcopenic. Sarcopenia showed no significant association with sex ( p = 0.74). SARC-F showed a sensitivity of 73.2% and a specificity of 37.3% with a positive predictive value of 86.51% and a negative predictive value of 32.84% in diagnosing sarcopenia. SARC-F showed good internal reliability with a Cronbach's α > 0.7., Conclusion: The SARC-F questionnaire can be used as a bedside screening tool for sarcopenia, especially in a developing country like India where diagnostic resources are frequently scarce., (© Journal of the Association of Physicians of India 2024.)

Background: Avelumab, a programmed death ligand-1 inhibitor, has shown success in providing durable responses for difficult-to-treat Merkel cell carcinomas (MCCs)., Objective: Evaluate the efficacy and safety of avelumab in the treatment of advanced MCC., Methods: Studies reporting the use of avelumab as a monotherapy or in combination with other agents in the treatment of stage III or IV (advanced) MCC were included. The primary outcomes were overall response rate, overall survival (OS), and treatment-related adverse events., Results: A total of 48 studies were included, involving 1,565 patients with advanced MCC. Most patients were male (1,051, 67.3%) with stage IV MCC (517, 97.0%). The overall response rate was 46.1% (partial response-25.4% and complete response-20.7%) after a mean follow-up period of 9.5 months. Kaplan-Meier survival curves for the pooled stage III and IV group demonstrated OS rates of 58% at 1 year, 47% at 2 years, and 28% at 5 years after completion of treatment with avelumab (median OS: 23.1 months). The most common treatment-related adverse events consisted of constitutional (44%), gastrointestinal (19%), and dermatologic (12%) symptoms., Conclusion: Avelumab monotherapy and combination therapy have shown success in the overall response rate and survival for patients with advanced MCC., (Copyright © 2024 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

The pathophysiology underlying the post-acute sequelae of COVID-19 remains understudied and poorly understood, particularly in healthy adults with a history of mild infection. Chronic neuroinflammation may underlie these enduring symptoms, but studying neuroinflammatory phenomena in vivo is challenging, especially without a comparable pre-COVID-19 dataset. In this study, we present a unique dataset of 10 otherwise healthy individuals scanned before and after experiencing mild COVID-19. Two emerging MR-based methods were used to map pre- to post-COVID-19 brain temperature and free water changes. Post-COVID-19 brain temperature and free water increases, which are indirect biomarkers of neuroinflammation, were found in structures functionally associated with olfactory, cognitive, and memory processing. The largest pre- to post-COVID brain temperature increase was observed in the left olfactory tubercle (p = 0.007, 95% CI [0.48, 3.01]), with a mean increase of 1.75 °C. Notably, the olfactory tubercle is also the region of the primary olfactory cortex where participants with chronic olfactory dysfunction showed the most pronounced increases as compared to those without lingering olfactory dysfunction (adjusted p FDR  = 0.0189, 95% CI [1.42, 5.27]). These preliminary insights suggest a potential link between neuroinflammation and chronic cognitive and olfactory dysfunction following mild COVID-19, although further investigations are needed to improve our understanding of what underlies these phenomena., (© 2024. The Author(s).)

Pattern recognition receptor responses are profoundly attenuated before the third trimester of gestation in the relatively low-oxygen human fetal environment. However, the mechanisms regulating these responses are uncharacterized. Herein, genome-wide transcription and functional metabolic experiments in primary neonatal monocytes linked the negative mTOR regulator DDIT4L to metabolic stress, cellular bioenergetics, and innate immune activity. Using genetically engineered monocytic U937 cells, we confirmed that DDIT4L overexpression altered mitochondrial dynamics, suppressing their activity, and blunted LPS-induced cytokine responses. We also showed that monocyte mitochondrial function is more restrictive in earlier gestation, resembling the phenotype of DDIT4L-overexpressing U937 cells. Gene expression analyses in neonatal granulocytes and lung macrophages in preterm infants confirmed upregulation of the DDIT4L gene in the early postnatal period and also suggested a potential protective role against inflammation-associated chronic neonatal lung disease. Taken together, these data show that DDIT4L regulates mitochondrial activity and provide what we believe to be the first direct evidence for its potential role supressing innate immune activity in myeloid cells during development.

Neuroinflammation (NI) is a key pathophysiological contributor to treatment-resistant epilepsy (TRE) that remains challenging to observe in vivo. Magnetic resonance spectroscopic imaging and thermometry (MRSI-t) is an emerging technique that can be used to non-invasively map brain temperature, whereby brain temperature elevations serve as a surrogate for the cellular and biochemical processes associated with NI. In a previous multimodal imaging study of focal epilepsy patients, we observed MRSI-t-based brain temperature elevations ipsilateral to the seizure onset zone (SOZ) that were concordant with evidence of edema (Sharma et al., 2023). Despite its potential as tool, it is unclear if MRSI-t can monitor changes in brain temperature in response to treatment. We imaged 25 participants approximately 12-weeks apart. Eight patients with TRE were imaged before receiving highly-purified pharmaceutical grade cannabidiol (CBD; pre-CBD) and after 12-weeks of CBD (on-CBD) therapy. Seventeen healthy controls (HCs) were also imaged twice. Repeated measures t-tests computed changes in TRE patients' seizure symptoms, mood, and brain temperature within their respective SOZs. Repeated measures ANOVAs tested Group*Time changes in imaging data. Participants with TRE had abnormally high peak brain temperatures within their SOZs that decreased after CBD initiation (p < 0.0001). Seizure severity scores also improved after CBD initiation (p < 0.001). These findings provide insights into the possible neural effects of CBD, and further demonstrate MRSI-t's potential as a tool for delineating SOZ. Further investigations into MRSI-t as a longitudinal measure of therapy-induced changes in NI are warranted., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Materials with long afterglow (LAG) became very renowned in the field of luminescence due to their high ability to store energy. However, the development of LAG phosphors is mostly dependent on rare-earth activators, which are commercially expensive due to their limited availability across the world. On the other hand, LAG phosphors that are not based on rare-earth and are developed as an alternative cannot compete with existing rare-earth LAG phosphors. Copper-doped zinc sulfide (ZnS:Cu) phosphor developed long ago has considerable afterglow, but its development has been too tedious, and expensive, and contains usage of toxic gasses such as H 2 S, CS 2 , etc. and most of the literature refers to the cubic phase of ZnS. To overcome these issues and simplify the process, we have developed a cost-effective approach to synthesize the hexagonal phase of ZnS, without the involvement of hazardous gases. This is one of the very few reports that highlights the appearance of LAG phenomenon from the hexagonal ZnS:Cu phosphor system. Structural, morphological, and optical studies of the developed ZnS:Cu LAG phosphor have been carried out. The phosphor showed a strong green photoluminescence at 515 nm and an afterglow duration of ~ 1 h useful for specific applications of visual markings in dark conditions. The thermoluminescence spectrum shows a broad and intense glow peak at 377.15 K that indicates the electron trap depth to be at 0.75 eV, supporting our afterglow results., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Alzheimer's disease (AD) is a neurodegenerative disease leading to dementia because of complex phathomechanisms like amyloid β (Aβ) aggregation, tau aggregates, and neurofibrillary tangles. Peroxisome proliferator-activated receptor (PPAR) agonists have been reported recently with neuroprotective and anti-inflammatory properties. PPARs belong to the superfamily of nuclear hormone receptors and function as ligand-activated transcription factors. These have emerged as crucial players in the pathogenesis of AD. This review presented the potential of PPARs and their agonists in treating neurodegenerative diseases like AD. PPARs regulate the expression of specific genes vital for synaptic function and neurotransmitter release. PPAR agonists play a critical role in increasing the clearance of Aβ peptides by lowdensity lipoprotein receptor-related protein 1 (LRP1) in the microvascular endothelial cells of the human brain. Studies have shown that PPAR agonists reduce the level of APoE-mRNA, contributing to the accumulation of Aβ plaques and up-regulation of PPAR. A knockout of miR-128 has been found to inhibit AD-like cognitive decline, amyloid precursor protein (APP) amyloidogenic processing, and inflammatory responses in AD. PPARs are involved in the pathomechanism of AD, and therefore, PPAR agonists could be viable options for controlling the neurodegenerative symptoms and may be useful in treating AD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Regular physical activity may promote beneficial neuroplasticity, e.g., increased hippocampus volume. However, it is unclear whether self-reported physical exercise in leisure (PEL) levels are associated with the brain structure features demonstrated by exercise interventions. This pilot study investigated the relationship between PEL, mood, cognition, and neuromorphometry in patients with idiopathic generalized epilepsy (IGEs) compared to healthy controls (HCs). Seventeen IGEs and 19 age- and sex-matched HCs underwent magnetic resonance imaging (MRI) at 3T. The Baecke Questionnaire of Habitual Physical Activity, Profile of Mood States, and Montreal Cognitive Assessment (MoCA) assessed PEL, mood, and cognition, respectively. Structural MRI data were analyzed by voxel- and surface-based morphometry. IGEs had significantly lower PEL ( p  < 0.001), poorer mood ( p  = 0.029), and lower MoCA scores ( p  = 0.027) than HCs. These group differences were associated with reduced volume, decreased gyrification, and altered surface topology (IGEs < HCs) in frontal, temporal and cerebellar regions involved in executive function, memory retrieval, and emotional regulation, respectively. These preliminary results support the notion that increased PEL may promote neuroplasticity in IGEs, thus emphasizing the role of physical activity in promoting brain health in people with epilepsy., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Inc.)

Objective: Mastalgia is the most common breast-related complaint. A multitude of hormonal changes and lifestyle associated factors have been implicated in its causation. A long list of treatment modalities have been tried with varying success rates. To identify the most common risk factors and the most effective management strategies for mastalgia in our clinic population., Materials and Methods: A total of 100 women between 18-65 years of age presenting to the breast clinic with mastalgia were followed throughout their course of diagnosis and management. Stepwise treatment was provided, starting with reassurance and breast support and progressing to include pharmacological measures, when necessary. The risk factors and outcomes of treatment were analysed., Results: The majority (66%) were aged 25-47 years and the left breast was found to be most frequently involved. Involvement of the upper outer quadrant was significantly more common. Lump/nodularity was the most prevalent risk factor. Most patients showed a positive response to non-steroid anti-inflammatories (NSAIDs) in addition to reassurance, breast support and dietary changes., Conclusion: A detailed history and clinical examination helps to identify the risk factors and the best approach for the management of mastalgia. Educating women regarding breast self-examination at regular intervals helps in early presentation and diagnosis of the underlying condition. Reassurance, breast support and lifestyle changes are the first line treatment and have good results in a significant number of patients. In our practice topical and oral NSAIDs, evening primrose oil and vitamin E were frequently used as additional treatments to non-pharmacological methods., Competing Interests: Conflict of Interest: The authors have no conflicts of interest to declare., (©Copyright 2024 by the Turkish Federation of Breast Diseases Societies / European Journal of Breast Health published by Galenos Publishing House.)

Poor penetration of many anti-tuberculosis (TB) antibiotics into the central nervous system (CNS) is thought to be a major driver of morbidity and mortality in TB meningitis (TBM). While the amount of a particular drug that crosses into the cerebrospinal fluid (CSF) varies from person to person, little is known about the host factors associated with interindividual differences in CSF concentrations of anti-TB drugs. In patients diagnosed with TBM from the country of Georgia (n=17), we investigate the association between CSF concentrations of anti-TB antibiotics and multiple host factors including serum drug concentrations and CSF concentrations of metabolites and cytokines. We found >2-fold differences in CSF concentrations of anti-TB antibiotics from person to person for all drugs tested including cycloserine, ethambutol, imipenem, isoniazid, levofloxacin, linezolid, moxifloxacin pyrazinamide, and rifampin. While serum drug concentrations explained over 40% of the variation in CSF drug concentrations for cycloserine, isoniazid, linezolid, and pyrazinamide (adjusted R 2 >0.4, p<0.001 for all), there was no evidence of an association between serum concentrations of imipenem and ethambutol and their respective CSF concentrations. CSF concentrations of carnitines were significantly associated with concentrations of ethambutol and imipenem (q<0.05), and imipenem was the only antibiotic significantly associated with CSF cytokine concentrations. These results indicate that there is high interindividual variability in CSF drug concentrations in patients treated for TBM, which is only partially explained by differences in serum drug concentrations and not associated with concentrations of cytokines and chemokines in the CSF.

Objective: Epilepsy and depression share neurobiological origins, and evidence suggests a possible bidirectional relationship that remains poorly understood. This exploratory, cross-sectional study aimed to investigate this relationship by employing magnetic resonance spectroscopic imaging (MRSI) and thermometry (MRSI-t) in patients with temporal lobe epilepsy (TLE) with comorbid depressive symptoms and control participants. This is the first study to combine MRSI and MRSI-t to examine brain temperature and choline abnormalities in regions implicated in seizure onset and depression., Methods: Twenty-six patients with TLE and 26 controls completed questionnaires and underwent imaging at 3T. Volumetric echo-planar MRSI/MRSI-t data were processed within the Metabolite Imaging and Data Analysis System (MIDAS). Choline (CHO) was quantified as a ratio over creatine (CRE; CHO/CRE). Brain temperature (T CRE ) was calculated based on the chemical shift difference of H 2 O relative to CRE's stable location on the ppm spectrum. The Hospital Anxiety and Depression Scale measured anxiety and depressive symptoms. The Chalfont Seizure Severity Scale measured seizure severity in patients with TLE. Two sets of voxelwise independent sample t tests examined group differences in CHO/CRE and T CRE maps. Voxel-based multimodal canonical correlation analysis (mCCA) linked both datasets to investigate if, how, and where CHO/CRE and T CRE abnormalities were correlated in TLE participants and controls., Results: Compared to controls, patients with TLE reported more depressive symptoms (P = 0.04) and showed CHO/CRE and T CRE elevations in left temporal and bilateral frontal regions implicated in seizure onset and depressive disorders (p FWE  < 0.05). For the TLE group, CHO/CRE levels in temporal and frontal cortices were associated with elevated T CRE in bilateral frontal and temporal gyri (r = 0.96), and decreased T CRE in bilateral fronto-parietal regions (r = -0.95)., Significance: Abnormalities in T CRE and CHO/CRE were observed in seizure-producing areas and in regions implicated in depression. These preliminary findings suggest that common metabolic changes may underlie TLE and depression. Our results suggest further investigations into the proposed bidirectional mechanisms underlying this relationship are warranted., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Despite antiretroviral therapy (ART), people living with human immunodeficiency virus (HIV) (PLWH) continue to experience chronic inflammation and immune dysfunction, which drives the persistence of latent HIV and prevalence of clinical comorbidities. Elucidating the mechanisms that lead to suboptimal immunity is necessary for developing therapeutics that improve the quality of life of PLWH. Although previous studies have found associations between gut dysbiosis and immune dysfunction, the cellular/molecular cascades implicated in the manifestation of aberrant immune responses downstream of microbial perturbations in PLWH are incompletely understood. Recent literature has highlighted that two abundant metabolite families, short-chain fatty acids (SCFAs) and bile acids (BAs), play a crucial role in shaping immunity. These metabolites can be produced and/or modified by bacterial species that make up the gut microbiota and may serve as the causal link between changes to the gut microbiome, chronic inflammation, and immune dysfunction in PLWH. In this review, we discuss our current understanding of the role of the microbiome on HIV acquisition and latent HIV persistence despite ART. Further, we describe cellular/molecular cascades downstream of SCFAs and BAs that drive innate or adaptive immune responses responsible for promoting latent HIV persistence in PLWH. This knowledge can be used to advance HIV cure efforts.

Psoriasis is a noncontagious, long-lasting skin infection that affects many people around the world. Numerous therapeutic artificial treatments are available for the treatment of psoriasis, such as photodynamic therapy using broadband ultraviolet (UV) lamps, which have harmful effects on human skin. Similarly, the natural healing systems such as sunlight have a higher risk of sunburn and can cause dangerous forms of skin cancer. Significant light emission of a specific wavelength (in the UV range), and phosphor-based devices demonstrate the effectiveness of treating psoriasis without damaging the skin. Gd 3+ -doped calcium magnesium silicate [Ca 2 MgSi 2 O 7 :Gd 3+ ,(CMS:Gd 3+ )] phosphor is one of the ideal phosphors that emit specific narrow UV wavelengths for curing psoriasis and is in great demand in the field of dermatology. Photoluminescence analysis at room temperature (~25°C) shows that the synthesized CMS:Gd 3+ phosphor emits narrowband UV-B light with a peak intensity at 314 nm. Comparative studies of the standard action spectrum of psoriasis with the emission spectrum of the CMS:Gd 3+ phosphor show that the synthesized phosphor was the most suitable material for treating a variety of diseases, including psoriasis, vitiligo, type-1 diabetes, dental disease, sleep and mood disorders, and other skin diseases., (© 2023 John Wiley & Sons Ltd.)

HIV infection persists during antiretroviral therapy (ART) due to a reservoir of latently infected cells that harbor replication-competent virus and evade immunity. Previous ex vivo studies suggested that CD8 + T cells from people with HIV may suppress HIV expression via non-cytolytic mechanisms, but the mechanisms responsible for this effect remain unclear. Here, we used a primary cell-based in vitro latency model and demonstrated that co-culture of autologous activated CD8 + T cells with HIV-infected memory CD4 + T cells promoted specific changes in metabolic and/or signaling pathways resulting in increased CD4 + T cell survival, quiescence, and stemness. Collectively, these pathways negatively regulated HIV expression and ultimately promoted the establishment of latency. As shown previously, we observed that macrophages, but not B cells, promoted latency in CD4 + T cells. The identification of CD8-specific mechanisms of pro-latency activity may favor the development of approaches to eliminate the viral reservoir in people with HIV., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Neuroinflammation (NI) is a pathophysiological factor in many neurological disorders, including epilepsy. Because NI causes microstructural tissue damage that worsens with increasing brain temperature, abnormally elevated brain temperatures may be a surrogate measure of the biochemical consequences of NI. This study investigated whether patients with temporal lobe epilepsy (TLE) have abnormal brain temperature elevations (T CRE ) in seizure-producing regions that show evidence of edema and/or microstructural damage., Methods: Twenty adults with TLE and 20 healthy controls (HCs) were scanned at 3-Tesla. T CRE in each voxel was calculated (T CRE  = -102.61(Δ H20-CRE)  + 206.1°C) by non-invasive volumetric magnetic resonance spectroscopic imaging and thermometry (MRSI-t). Multi-shell diffusion images were processed by neurite orientation and density imaging (NODDI). Voxel wise two-sample t tests computed group differences in imaging data. Multimodal data fusion (joint independent component analysis [ICA]) determined the spatial coupling of T CRE with NODDI., Results: T CRE analyses showed that, compared to HCs, TLEs had higher T CRE (p < .001). NODDI analyses showed increased extracellular free water (p FWE  < 0.05) in the medial temporal lobes, with the most pronounced increases ipsilateral to seizure onset. TLEs also had increased angular dispersion of neurites (p < .001) and decreased neurite density (p FWE  <0.05) in the ictal-onset medial temporal lobe, as well as more widespread, bilateral patterns of abnormalities. Focal increases in T CRE were spatially concordant with increased free water in the left inferior and middle temporal gyri and the associated cortex. In TLE, ICA loadings extracted from this region of overlap were associated with greater mood disturbance (r = .34, p = .02) and higher depression scores (r = .37, p = .009)., Significance: The spatial concordance between focal T CRE elevations and edema in TLE supports the notion that brain thermometry visualizes the correlates of focal NI. MRSI-t-based T CRE elevations may, therefore, be a useful biomarker for identifying seizure-producing tissue in patients with focal epilepsy caused by brain damage., (© 2023 International League Against Epilepsy.)

STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder., (© 2023 Sharma et al.)

The discovery of humans with monogenic disorders has a rich history of generating new insights into biology. Here we report the first human identified with complete deficiency of nuclear factor of activated T cells 1 (NFAT1). NFAT1, encoded by NFATC2, mediates calcium-calcineurin signals that drive cell activation, proliferation, and survival. The patient is homozygous for a damaging germline NFATC2 variant (c.2023&#95;2026delTACC; p.Tyr675Thrfs∗18) and presented with joint contractures, osteochondromas, and recurrent B-cell lymphoma. Absence of NFAT1 protein in chondrocytes caused enrichment in prosurvival and inflammatory genes. Systematic single-cell-omic analyses in PBMCs revealed an environment that promotes lymphomagenesis with accumulation of naïve B cells (enriched for oncogenic signatures MYC and JAK1), exhausted CD4+ T cells, impaired T follicular helper cells, and aberrant CD8+ T cells. This work highlights the pleiotropic role of human NFAT1, will empower the diagnosis of additional patients with NFAT1 deficiency, and further defines the detrimental effects associated with long-term use of calcineurin inhibitors., (© 2022 by The American Society of Hematology.)

Introduction: The present study was deliberated to assess the pre-emptive analgesic efficacy of diclofenac sodium and ketoprofen transdermal patches following open treatment of mandibular fractures., Methods: The present prospective, triple-blind, randomized controlled clinical study was carried out on 50 male patients with a mean age of 30-31 years having bifocal mandibular fractures. The subjects were assigned 1:1 to two groups; group K - ketoprofen group and group D - diclofenac sodium group. Patches were applied according to the group allocation one hour before induction. In the immediate post-operative (PO) phase, pain intensity was recorded using a 10-point Visual analog Scale at 2, 4, 8, 12, and 24 hourly. Statistical analysis was performed using descriptive and inferential statistics using SPSS 27.0 version (IBM SPSS, Armonk, NY) and GraphPad Prism 7.0 version (GraphPad Software, Inc., La Jolla, CA) and p<0.05 is considered a level of significance., Results: The present study demonstrated a statistical difference in mean pain intensity among both groups, with lower pain scores at all time intervals and fewer rescue analgesic consumption in the ketoprofen group., Conclusion: The ketoprofen transdermal patch was found to be superior in comparison to the diclofenac patch in terms of providing optimal post-operative analgesia with a reduced requirement for post-operative rescue analgesics and minimal adverse events., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Sharma et al.)

Recreational nitrous oxide (N 2 O) use is widespread, and complications associated with its use are increasingly common. We sought to identify risk factors, clinical features and outcomes in individuals presenting with effects of chronic N 2 O abuse to develop an approach to clinical assessment and management. A systemic literature review was completed with searches conducted across EMBASE, MEDLINE, PSYCINFO and Cochrane databases. Our search strategy identified 612 studies, 105 met inclusion criteria, and 10 were added via hand search. Subjects from 24 case series and 91 case reports were typically in their 20s, using over 100 bulbs daily for several months. Neurological presentations, including sensory change, gait disturbance or weakness, were characteristic. Serum Vitamin B12 was normal or raised in 133 out of 243 case series subjects and 37 out of 84 reports. Serum homocysteine and methylmalonic acid were usually raised. Macrocytosis and anaemia were not commonly seen. MRI findings were abnormal with dorsal column change where specified, typically involving the cervical spine. Nerve conduction studies mostly reported a sensorimotor polyneuropathy. B12 replacement was the treatment of choice and partial recovery was most reported. This review highlights the dose-dependent nature of chronic N 2 O toxicity and recognises functional B12 deficiency as the cause. As B12 is often normal, homocysteine and methylmalonic acid are important biomarkers of disease. An approach to diagnosis is offered but requires validation in prospective studies. Research exploring B12 and methionine therapy is required to refine management., (© 2022 Australasian College for Emergency Medicine.)

Patient-centered and physician-led innovations are key to promoting physicians as visionary leaders in the healthcare system especially during times of crises. COVID-19 has inspired some promising recent advancements within medicine worth noting, including improvements in telemedicine, 3-D printed personal protective equipment (PPE) and ventilators, drug and vaccine development, sterilization of PPE allowing for reuse, and point of care testing; they highlight a broader lesson for how we might innovate better within medicine, even after the crisis has passed. As such, with the complexities of modern-day medicine, to continue to foster this culture of innovation, it is paramount that going forward, medical education adapt and embrace an innovation curriculum that prepares physicians and healthcare workers to work with their communities and researchers to confidently tackle any challenges that may present. Integrating innovation into our careers and medical training is important for advancement of the field and to be able to handle challenges that may present to the healthcare system., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Reduced-intensity conditioning (RIC) regimens frequently provide insufficient disease control in patients with high-risk hematologic malignancies undergoing allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated intensification of fludarabine/busulfan (Flu/Bu) RIC with targeted marrow irradiation (TMI) in a dose escalation with expansion phase I clinical trial. TMI doses were delivered at 1.5 Gy in twice daily fractions on days -10 through -7 (dose levels: 3 Gy, 4.5 Gy, and 6 Gy), Flu (30 mg/m 2 for 5 days) and Bu (area under the curve, 4800 µM*minute for 2 days). Eligible patients were age ≥18 years with high-risk hematologic malignancy and compromised organ function ineligible for myeloablative transplantation (n = 26). The median patient age was 64 years (range, 25 to 76 years). Nineteen patients (73%) had active or measurable residual disease at transplantation. One-year disease-free survival and overall survival were 55% (95% confidence interval [CI], 34% to 76%) and 65% (95% CI, 46% to 85%), respectively. Day +100 and 1 year transplantation-related mortality were 4% (95% CI, 0.6% to 27%) and 8.5% (95% CI, 2% to 32%), respectively. The 1-year cumulative incidence of relapse was 43% (95% CI, 27% to 69%). Rates of grade II-IV and III-IV acute GVHD rates were 57% (95% CI, 39% to 84%) and 22% (95% CI, 9% to 53%), respectively. Whole blood immune profiling demonstrated enrichment of central/transitional memory-like T cells with higher TMI doses, which correlated with improved survival compared with control samples from patients undergoing allogeneic HSCT. Intensification of a Flu/Bu RIC regimen with TMI is feasible with a low incidence of transplantation-related mortality in medically frail patients with advanced malignancies. The recommended phase 2 TMI dose is 6 Gy., Competing Interests: Conflict of interest statement The authors did not have any conflicts of interest in the conduct of this study., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Plasmablastic lymphoma (PBL) is a rare type of non-Hodgkin lymphoma frequently found in the context of immunosuppression and infection with human immunodeficiency virus (HIV) and/or Epstein-Barr virus (EBV). A 33-year-old immunocompetent male presented with recurrent episodes of epistaxis and a growing intranasal mass. Excisional biopsy of the mass revealed an immunohistochemical profile diagnostic of PBL. Upon completion of chemoradiation, he underwent a transnasal endoscopic mucosal flap tissue rearrangement to restore patency for both functional and surveillance purposes. There was no endoscopic evidence of residual or recurrent disease. However, 8 months later, he was found to have a relapse involving the skin. The nasal cavity is one of the most common sites affected by PBL. Involvement of the nasal cavity may present with symptoms of persistent epistaxis accompanied by an enlarging mass. A plasmablastic immunophenotype in combination with HIV or EBV positivity can aid diagnosis.

People living with HIV (PLWH) who are immune nonresponders (INRs) are at greater risk of comorbidity and mortality than are immune responders (IRs) who restore their CD4+ T cell count after antiretroviral therapy (ART). INRs have low CD4+ T cell counts (<350 c/μL), heightened systemic inflammation, and increased CD4+ T cell cycling (Ki67+). Here, we report the findings that memory CD4+ T cells and plasma samples of INRs from several cohorts are enriched in gut-derived bacterial solutes p-cresol sulfate (PCS) and indoxyl sulfate (IS) that both negatively correlated with CD4+ T cell counts. In vitro PCS or IS blocked CD4+ T cell proliferation, induced apoptosis, and diminished the expression of mitochondrial proteins. Electron microscopy imaging revealed perturbations of mitochondrial networks similar to those found in INRs following incubation of healthy memory CD4+ T cells with PCS. Using bacterial 16S rDNA, INR stool samples were found enriched in proteolytic bacterial genera that metabolize tyrosine and phenylalanine to produce PCS. We propose that toxic solutes from the gut bacterial flora may impair CD4+ T cell recovery during ART and may contribute to CD4+ T cell lymphopenia characteristic of INRs.

The persistence of virally infected cells as reservoirs despite effective antiretroviral therapy is a major barrier to an HIV/SIV cure. These reservoirs are predominately contained within cells present in the B cell follicles (BCFs) of secondary lymphoid tissues, a site that is characteristically difficult for most cytolytic antiviral effector cells to penetrate. Here, we identified a population of NK cells in macaque lymph nodes that expressed BCF-homing receptor CXCR5 and accumulated within BCFs during chronic SHIV infection. These CXCR5+ follicular NK cells exhibited an activated phenotype coupled with heightened effector functions and a unique transcriptome characterized by elevated expression of cytolytic mediators (e.g., perforin and granzymes, LAMP-1). CXCR5+ NK cells exhibited high expression of FcγRIIa and FcγRIIIa, suggesting a potential for elevated antibody-dependent effector functionality. Consistently, accumulation of CXCR5+ NK cells showed a strong inverse association with plasma viral load and the frequency of germinal center follicular Th cells that comprise a significant fraction of the viral reservoir. Moreover, CXCR5+ NK cells showed increased expression of transcripts associated with IL-12 and IL-15 signaling compared with the CXCR5- subset. Indeed, in vitro treatment with IL-12 and IL-15 enhanced the proliferation of CXCR5+ granzyme B+ NK cells. Our findings suggest that follicular homing NK cells might be important in immune control of chronic SHIV infection, and this may have important implications for HIV cure strategies.

Type I IFNs (TI-IFNs) drive immune effector functions during acute viral infections and regulate cell cycling and systemic metabolism. That said, chronic TI-IFN signaling in the context of HIV infection treated with antiretroviral therapy (ART) also facilitates viral persistence, in part by promoting immunosuppressive responses and CD8+ T cell exhaustion. To determine whether inhibition of IFN-α might provide benefit in the setting of chronic, ART-treated SIV infection of rhesus macaques, we administered an anti-IFN-α antibody followed by an analytical treatment interruption (ATI). IFN-α blockade was well-tolerated and associated with lower expression of TI-IFN-inducible genes (including those that are antiviral) and reduced tissue viral DNA (vDNA). The reduction in vDNA was further accompanied by higher innate proinflammatory plasma cytokines, expression of monocyte activation genes, IL-12-induced effector CD8+ T cell genes, increased heme/metabolic activity, and lower plasma TGF-β levels. Upon ATI, SIV-infected, ART-suppressed nonhuman primates treated with anti-IFN-α displayed lower levels of weight loss and improved erythroid function relative to untreated controls. Overall, these data demonstrated that IFN-α blockade during ART-treated SIV infection was safe and associated with the induction of immune/erythroid pathways that reduced viral persistence during ART while mitigating the weight loss and anemia that typically ensue after ART interruption.

Patients with cancers have been severely affected by the COVID-19 pandemic. This is highlighted by the adverse outcomes in cancer patients with COVID-19 as well as by the impact of the COVID-19 pandemic on cancer care. Patients with cancer constitute a heterogeneous population that exhibits distinct mechanisms of immune dysfunction, associated with distinct systemic features of hot (T-cell-inflamed/infiltrated) and cold (Non-T-cell-inflamed and/or infiltrated) tumors. The former show hyper immune activated cells and a highly inflammatory environment while, contrastingly, the latter show the profile of a senescent and/or quiescent immune system. Thus, the evolution of SARS-CoV-2 infection in different types of cancers can show distinct trajectories which could lead to a variety of clinical and pathophysiological outcomes. The altered immunological environment including cytokines that characterizes hot and cold tumors will lead to different mechanisms of immune dysfunction, which will result in downstream effects on the course of SARS-CoV-2 infection. This review will focus on defining the known contributions of soluble pro- and anti-inflammatory mediators on immune function including altered T-cells and B-cells responses and as well on how these factors modulate the expression of SARS-CoV-2 receptor ACE2, TMPRSS2 expression, and lymph node fibrosis in cancer patients. We will propose immune mechanisms that underlie the distinct courses of SARS-CoV-2 infection in cancer patients and impact on the success of immune based therapies that have significantly improved cancer outcomes. Better understanding of the immune mechanisms prevalent in cancer patients that are associated to the outcomes of SARS-CoV-2 infection will help to identify the high-risk cancer patients and develop immune-based approaches to prevent significant adverse outcomes by targeting these pathways., (Copyright © 2021. Published by Elsevier Inc.)

Objective: Psychogenic nonepileptic seizures (PNES) are characterized by multifocal and global abnormalities in brain function and connectivity. Only a few studies have examined neuroanatomic correlates of PNES. Traumatic brain injury (TBI) is reported in 83% of patients with PNES and may be a key component of PNES pathophysiology. In this study, we included patients with TBI preceding the onset of PNES (TBI-PNES) and TBI without PNES (TBI-only) to identify neuromorphometric abnormalities associated with PNES., Methods: Adults diagnosed with TBI-PNES (n = 62) or TBI-only (n = 59) completed psychological questionnaires and underwent 3-T magnetic resonance imaging. Imaging data were analyzed by voxel- and surface-based morphometry. Voxelwise general linear models computed group differences in gray matter volume, cortical thickness, sulcal depth, fractal dimension (FDf), and gyrification. Statistical models were assessed with permutation-based testing at 5000 iterations with the Threshold-Free Cluster Enhancement toolbox. Logarithmically scaled p-values corrected for multiple comparisons using familywise error were considered significant at p < .05. Post hoc analyses determined the association between structural and psychological measures (p < .05)., Results: TBI-PNES participants demonstrated atrophy of the left inferior frontal gyrus and the right cerebellum VIII. Relative to TBI-only, TBI-PNES participants had decreased FDf in the right superior parietal gyrus and decreased sulcal depth in the left insular cortex. Significant clusters were positively correlated with global assessment of functioning scores, and demonstrated varying negative associations with measures of anxiety, depression, somatization, and global severity of symptoms., Significance: The diagnosis of PNES was associated with brain atrophy and reduced cortical folding in regions implicated in emotion processing, regulation, and response inhibition. Cortical folds primarily develop during the third trimester of pregnancy and remain relatively constant throughout the remainder of one's life. Thus, the observed aberrations in FDf and sulcal depth could originate early in development. The convergence of environmental, developmental, and neurobiological factors may coalesce to reflect the neuropathophysiological substrate of PNES., (© 2021 International League Against Epilepsy.)

Chimeric antigen receptor (CAR) T cells targeting the CD19 antigen are effective in treating adults and children with B-cell malignancies. Place-of-care manufacturing may improve performance and accessibility by obviating the need to cryopreserve and transport cells to centralized facilities. Here we develop an anti-CD19 CAR (CAR19) comprised of the 4-1BB co-stimulatory and TNFRSF19 transmembrane domains, showing anti-tumor efficacy in an in vivo xenograft lymphoma model. CAR19 T cells are manufactured under current good manufacturing practices (cGMP) at two disparate clinical sites, Moscow (Russia) and Cleveland (USA). The CAR19 T-cells is used to treat patients with relapsed/refractory pediatric B-cell Acute Lymphocytic Leukemia (ALL; n = 31) or adult B-cell Lymphoma (NHL; n = 23) in two independently conducted phase I clinical trials with safety as the primary outcome (NCT03467256 and NCT03434769, respectively). Probability of measurable residual disease-negative remission was also a primary outcome in the ALL study. Secondary outcomes include complete remission (CR) rates, overall survival and median duration of response. CR rates are 89% (ALL) and 73% (NHL). After a median follow-up of 17 months, one-year survival rate of ALL complete responders is 79.2% (95%CI 64.5‒97.2%) and median duration of response is 10.2 months. For NHL complete responders one-year survival is 92.9%, and median duration of response has not been reached. Place-of-care manufacturing produces consistent CAR-T cell products at multiple sites that are effective for the treatment of patients with B-cell malignancies., (© 2021. The Author(s).)

Introduction: Healthcare workers are at an increased risk of infectious disease transmission through occupational exposure. Despite this, rates of personal protective equipment (PPE) use vary among healthcare personnel. This cross-sectional study surveyed healthcare workers at a single academic center to determine how the coronavirus disease 2019 (COVID-19) pandemic affected the perceptions and behaviors of PPE usage., Methods: An anonymous online survey through the SurveyMonkey® tool (Zendesk Inc., San Francisco, California) was sent to the University of California, Irvine, Medical Center department listserv of nurses on March 20, 2021, and was closed on June 20, 2021., Results: Of 311 respondents, 23% admitted to suffering a splash injury to the face during a procedure. When compared to one year ago prior to the COVID-19 pandemic, PPE was more important (93% vs. 80%) and more frequently used (80% vs. 54%) by respondents. The recent COVID-19 pandemic had the strongest impact on increasing respondents' perception of the importance of PPE (44%)., Conclusion: The COVID-19 pandemic positively impacted rates of PPE usage and perceptions of the importance of PPE among healthcare workers at a single academic institution. Implementing clear and effective education and training programs, ensuring adequate access to protective gear, and promoting a positive safety climate can help improve adherence to safety protocols and appropriate use of PPE., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Shwe et al.)

Background: Germline pathogenic variants impairing the caspase recruitment domain family member 11 (CARD11)-B cell chronic lymphocytic leukemia/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) (CBM) complex are associated with diverse human diseases including combined immunodeficiency (CID), atopy, and lymphoproliferation. However, the impact of CARD11 deficiency on human B-cell development, signaling, and function is incompletely understood., Objectives: This study sought to determine the cellular, immunological, and biochemical basis of disease for 2 unrelated patients who presented with profound CID associated with viral and fungal respiratory infections, interstitial lung disease, and severe colitis., Methods: Patients underwent next-generation sequencing, immunophenotyping by flow cytometry, signaling assays by immunoblot, and transcriptome profiling by RNA-sequencing., Results: Both patients carried identical novel pathogenic biallelic loss-of-function variants in CARD11 (c.2509C>T; p.Arg837∗) leading to undetectable protein expression. This variant prevented CBM complex formation, severely impairing the activation of nuclear factor-κB, c-Jun N-terminal kinase, and MALT1 paracaspase activity in B and T cells. This functional defect resulted in a developmental block in B cells at the naive and type 1 transitional B-cell stage and impaired circulating T follicular helper cell (cT FH ) development, which was associated with impaired antibody responses and absent germinal center structures on lymph node histology. Transcriptomics indicated that CARD11-dependent signaling is essential for immune signaling pathways involved in the development of these cells. Both patients underwent hematopoietic stem cell transplantations, which led to functional normalization., Conclusions: Complete human CARD11 deficiency causes profound CID by impairing naive/type 1 B-cell and cT FH cell development and abolishing activation of MALT1 paracaspase, NF-κB, and JNK activity. Hematopoietic stem cell transplantation functionally restores impaired signaling pathways., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The neurobiological underpinnings of functional seizure (FS) development and maintenance represent an active research area. Recent work has focused on hardware (brain structure) and software (brain function and connectivity). However, understanding whether FS are an adaptive consequence of changes in brain structure, function, and/or connectivity is important for identifying a causative mechanism and for FS treatment and prevention. Further, investigation must also uncover what causes these structural and functional phenomena. Pioneering work in the field of psychoneuroimmunology has established a strong, consistent link between psychopathology, immune dysfunction, and brain structure/function. Based on this and recent FS biomarker findings, we propose a new etiologic model of FS pathophysiology. We hypothesize that early-life stressors cause neuroinflammatory and neuroendocrine changes that prime the brain for later FS development following secondary trauma (e.g., traumatic brain injury or psychological trauma). This framework coalesces existing knowledge regarding brain aberrations underlying FS and established neurobiological theories on the pathophysiology of underlying psychiatric disorders. We also propose brain temperature mapping as a way of indirectly visualizing neuroinflammation in patients with FS, particularly in emotion regulation, fear processing, and sensory-motor integration circuits. We offer a foundation on which future research can be built, with clear recommendations for future studies., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Nuclear factor kappa B (NF-κB) is a critical transcription factor involved in regulating cell activation, inflammation, and survival. The linear ubiquitin chain assembly complex (LUBAC) which consists of HOIL1, HOIP, and SHARPIN, catalyzes the linear ubiquitination of target proteins-a post-translational modification that is essential for NF-κB activation. Human germline pathogenic variants that dysregulate linear ubiquitination and NF-κB signaling are associated with immunodeficiency and/or autoinflammation including dermatitis, recurrent fevers, systemic inflammation and enteropathy. We previously identified MALT1 paracaspase as a novel negative regulator of LUBAC by proteolytic cleavage of HOIL1. To directly investigate the impact of HOIL1 cleavage activity on the inflammatory response, we employed a stable transduction system to express and directly compare non-cleavable HOIL1 with wild-type HOIL1 in primary HOIL1-deficient patient skin fibroblasts. We discovered that non-cleavable HOIL1 resulted in enhanced NF-κB signaling in response to innate stimuli. Transcriptomics revealed enrichment of inflammation and proinflammatory cytokine-related pathways after stimulation. Multiplexed cytokine assays confirmed a 'hyperinflammatory' phenotype in these cells. This work highlights the physiological importance of MALT1-dependent cleavage and modulation of HOIL1 on NF-κB signaling and inflammation, provides a mechanism for the autoinflammation observed in MALT1-deficient patients, and will inform the development of therapeutics that target MALT1 paracaspase and LUBAC function in treating autoinflammatory skin diseases., Competing Interests: TK was employed by Ducares/Triskelion BV. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fung, Lu, Sharma, Sharma, Saferali, Jia, Abraham, Klein, Gold, Noterangelo, Overall and Turvey.)