Differential lipid signaling from CD4+ and CD8+ T cells contributes to type 1 diabetes development.

Introduction: We reported that Ca2+-independent phospholipase A2ß (iPLA2ß)-derived lipids (iDLs) contribute to type 1 diabetes (T1D) onset. As CD4+ and CD8+ T cells are critical in promoting ß-cell death, we tested the hypothesis that iDL signaling from these cells participates in T1D development. Methods: CD4+ and CD8+ T cells from wild-type non-obese diabetic (NOD) and NOD.iPLA2ß+/- (NOD.HET) mice were administered in different combinations to immunodeficient NOD.scid. Results: In mice receiving only NOD T cells, T1D onset was rapid (5 weeks), incidence 100% by 20 weeks, and islets absent. In contrast, onset was delayed 1 week and incidence reduced 40%-50% in mice receiving combinations that included NOD.HET T cells. Consistently, islets from these non-diabetic mice were devoid of infiltrate and contained insulin-positive ß-cells. Reduced iPLA2ß led to decreased production of proinflammatory lipids from CD4+ T cells including prostaglandins and dihydroxyeicosatrienoic acids (DHETs), products of soluble epoxide hydrolase (sEH), and inhibition of their signaling decreased (by 82%) IFNγ+CD4+ cells abundance. However, only DHETs production was reduced from CD8+ T cells and was accompanied by decreases in sEH and granzyme B. Discussion: These findings suggest that differential select iDL signaling in CD4+ and CD8+ T cells contributes to T1D development, and that therapeutics targeting such signaling might be considered to counter T1D.

Stellabody: A novel hexamer-promoting mutation for improved IgG potency.

Advances in antibody engineering are being directed at the development of next generation immunotherapeutics with improved potency. Hexamerisation of IgG is a normal physiological aspect of IgG biology and recently described mutations that facilitate this process have a substantial impact upon monoclonal antibody behavior resulting in the elicitation of dramatically enhanced complement-dependent cytotoxicity, Fc receptor function, and enhanced antigen binding effects, such as targeted receptor agonism or microbe neutralization. Whereas the discovery of IgG hexamerisation enhancing mutations has largely focused on residues with exposure at the surface of the Fc-Fc and CH2-CH3 interfaces, our unique approach is the engineering of the mostly buried residue H429 in the CH3 domain. Selective substitution at position 429 forms the basis of Stellabody technology, where the choice of amino acid results in distinct hexamerisation outcomes. H429F results in monomeric IgG that hexamerises after target binding, so called "on-target" hexamerisation, while the H429Y mutant forms pH-sensitive hexamers in-solution prior to antigen binding. Moreover, Stellabody technologies are broadly applicable across the family of antibody-based biologic therapeutics, including conventional mAbs, bispecific mAbs, and Ig-like biologics such as Fc-fusions, with applications in diverse diseases.

Race and ethnicity expression in reproductive endocrinology and infertility research studies compared with other obstetrics and gynecology subspecialty studies.

Objective: To compare the percentage of patients per race and ethnicity group in the most cited reproductive endocrinology and infertility studies with the most cited studies in 3 other obstetrics and gynecology (OBGYN) subspecialties: gynecologic oncology, urogynecology (URO), and maternal-fetal medicine. Design: Retrospective cohort study. Setting: Not applicable. Patients: Patients previously recruited in research studies. Interventions: None. Main Outcome Measures: Expression of minorities in research studies. Results: Individual searches were conducted for the most cited articles in OBGYN subspecialties until 50 studies met the inclusion criteria for each OBGYN subspecialty. A total of 29,821,148 patients were included and compared between subspecialty and US Census data. Reproductive endocrinology and infertility studies had the highest percentage of White patients (80.5%), although URO studies had fewer Black patients (6.6%) compared with other subspecialties. Reproductive endocrinology and infertility studies had the lowest percentage of Hispanic patients (4.9%), yet more Asian patients were present in URO studies (3.3%) than in other subspecialties. Gynecologic oncology studies were most likely to have missing data in race expression (19.3%). Comparing study types, retrospective studies had the highest percentage of White patients (61.9%), although randomized controlled trials had the lowest expression of Hispanic patients (8.8%). Conclusions: Reproductive endocrinology and infertility studies featured the highest rates of White patients compared with other OBGYN subspecialty studies, although URO studies had the lowest rates of Black patients. Randomized controlled trials featured higher rates of White patients and lower levels of Hispanic patients compared with US Census data.

An altered natural killer cell immunophenotype characterizes clinically severe pediatric RSV infection.

Respiratory syncytial virus (RSV) infects nearly all children by 2 years of age and is a leading cause of pediatric hospitalizations. A subset of children with RSV infection (RSV+ children) develop respiratory failure requiring intensive care, but immune mechanisms distinguishing severe pediatric RSV infection are not fully elucidated. Natural killer (NK) cells are key innate immune effectors of viral host defense. In this study of 47 critically ill RSV+ children, we coupled NK cell immunophenotype and cytotoxic function with clinical parameters to identify an NK cell immune signature of severe pediatric RSV disease. Airway NK cells were increased in intubated RSV+ children with severe hypoxemia and prolonged duration of mechanical ventilation and were correlated with clinical severity scores. Peripheral blood NK cells were decreased in RSV+ patients and had altered activating receptor expression, with increased expression of CD69 and decreased expression of NKG2D. Ex vivo, circulating NK cells from RSV+ patients exhibited functional impairment characterized by decreased cytotoxicity as well as aberrant immune synapse assembly and lytic granule trafficking. NK cell frequency and phenotype correlated with clinical measures that defined disease severity. These findings implicate a role for NK cells in mediating RSV immunopathology and suggest that an altered NK cell immunophenotype is associated with severe RSV disease in young children.

MrgprA3 neurons drive cutaneous immunity against helminths through selective control of myeloid-derived IL-33.

Skin uses interdependent cellular networks for barrier integrity and host immunity, but most underlying mechanisms remain obscure. Herein, we demonstrate that the human parasitic helminth Schistosoma mansoni inhibited pruritus evoked by itch-sensing afferents bearing the Mas-related G-protein-coupled receptor A3 (MrgprA3) in mice. MrgprA3 neurons controlled interleukin (IL)-17+ γδ T cell expansion, epidermal hyperplasia and host resistance against S. mansoni through shaping cytokine expression in cutaneous antigen-presenting cells. MrgprA3 neuron activation downregulated IL-33 but induced IL-1ß and tumor necrosis factor in macrophages and type 2 conventional dendritic cells partially through the neuropeptide calcitonin gene-related peptide. Macrophages exposed to MrgprA3-derived secretions or bearing cell-intrinsic IL-33 deletion showed increased chromatin accessibility at multiple inflammatory cytokine loci, promoting IL-17/IL-23-dependent changes to the epidermis and anti-helminth resistance. This study reveals a previously unrecognized intercellular communication mechanism wherein itch-inducing MrgprA3 neurons initiate host immunity against skin-invasive parasites by directing cytokine expression patterns in myeloid antigen-presenting cell subsets.

Research protocol for bridging research, accurate information and dialogue (BRAID)-clinical trials: a mixed-methods study of a community-based intervention to improve trust and diversify participation in clinical trials.

Cultural beliefs, personal experiences, and historic abuses within the healthcare system-rooted in structural racism-all contribute to community distrust in science and medicine. This lack of trust, particularly within underserved communities, contributes to decreased participation in clinical trials and a lack of representation in the data. Open dialogue about community concerns and experiences related to research participation and medical care processes can help build trust and change attitudes and behaviors that affect community health. This protocol outlines an approach to increase trust in science and clinical trials among communities in the Bronx, New York that are typically underrepresented in research data. Bridging Research, Accurate Information and Dialogue (BRAID) is a two-phased, evidence-based community engagement model that creates safe spaces for bilateral dialogues between trusted community messengers, and clinicians and scientists. The team will conduct a series of BRAID Conversation Circles on the topic of clinical trials with local trusted community messengers. Participants will be members of the community who are perceived as "trusted messengers" and can represent the community's voice because they have insight into "what matters" locally. Conversation Circles will be audiotaped, transcribed, and analyzed to identify emergent challenges and opportunities surrounding clinical trial participation. These key themes will subsequently inform the codesign and co-creation of tailored messages and outreach efforts that community participants can disseminate downstream to their social networks. Surveys will be administered to all participants before and after each Conversation Circle to understand participants experience and evaluate changes in knowledge and attitudes about clinical trials, including protections for research participants the advantages of having diverse representation. Changes in motivation and readiness to share accurate clinical trial information downstream will also be assessed. Lastly, we will measure participants dissemination of codesigned science messages through their social networks by tracking participant specific resource URLs of materials and videos posted on a BRAID website. This protocol will assess the effectiveness and adoptability of an innovative CBPR model that can be applied to a wide range of public health issues and has the potential to navigate the ever-changing needs of the communities that surround health systems.

Sudden Death in Pediatric Patient With Dilated Cardiomyopathy Due to Founder Variant in NKX2-5: Case Report.

Background: The NKX2-5 gene encodes a transcription factor that plays a role in atrioventricular nodal and myocardial development. Pathogenic variants of NKX2-5 are associated with congenital heart disease and sudden cardiac death. The missense variant in this case is one of the more common ones in Northern Europe and has high penetrance in familial cases. To our knowledge, this is the youngest person who died due to this variant. Case summary: This was a healthy, asymptomatic 14-year-old male with well-managed mild congenital dilated cardiomyopathy who died unexpectedly in his home. Postmortem examination revealed the NKX2-5 pathogenic missense variant, p.Phe145Leu, as the only explicable cause of death. Discussion: We propose that immediate family members of those who die suddenly due to NKX2-5 disease undergo genetic counseling and longitudinal screening to include this gene, as pathogenic variants in the NKX2-5 gene may manifest in a time-dependent manner.

4-Phenyl-thiazole-based dual inhibitors of fatty acid amide hydrolase and soluble epoxide hydrolase do not alleviate orofacial inflammatory pain in female rats.

Pain arising from trigeminal systems such as headache is common, debilitating, and current treatments (e.g., sumatriptan) are limited. New treatments that target novel mechanisms of action may be required to innovate both short- and long-term pain therapy. Fatty acid amide hydrolase and soluble epoxide hydrolase are two pain-related enzymes that regulate pain and inflammation via independent pathways. We have previously demonstrated that simultaneous inhibition of these enzymes using a novel dual inhibitor alleviates acute inflammatory pain in the hindpaw and does not depress wheel running in rats. Here, we expanded on these findings and performed structure-activity relationships of our lead compound, the 4-phenyl-thiazole-based dual inhibitor SW-17, to generate 18 analogs and tested them for their inhibition at both enzymes. Conversion of the sulfonamide group to a tertiary amine led to a general decrease in the potency for the sEH enzyme, while this change was well-tolerated at the FAAH enzyme yielding several strong inhibitors. Six selected inhibitors were evaluated in mouse and rat sEH inhibition assays and results showed a species difference, i.e. 4-phenyl-thiazole-based analogs are significantly less or not active in mouse sEH compared to human and rat enzymes. The most potent inhibitor, SW-17, was evaluated in a plasma stability assay in human and rat plasma and showed moderate stability. However, SW-17 did not alleviate orofacial inflammatory pain in female rats compared to the traditional anti-migraine agent sumatriptan. Although modification of 4-phenyl-thiazole-based dual inhibitor SW-17 changes potencies at both FAAH and sEH, these approaches may not produce antinociception against trigeminal pain. Key Words: polypharmacology, formalin, inflammation, enzyme inhibition, structure-activity relationship studies.

Randomized, double-blind, phase 1a single-ascending dose and food effect studies assessing safety and pharmacokinetics of EC5026 in healthy volunteers.

Chronic pain represents a significant unmet medical need, affecting one-fifth of the U.S. population. EC5026 is a small molecule inhibitor of the enzyme soluble epoxide hydrolase (sEH) which is being developed as a novel non-opioid, non-NSAID analgesic. EC5026 prolongs the action of epoxy fatty acids, endogenous analgesic lipid mediators that are rapidly metabolized by sEH. We evaluated the safety and pharmacokinetic profile of EC5026 in two phase I trials, a single-ascending dose (SAD) study and a fed-fasted study. The SAD study evaluated EC5026 doses ranging from 0.5 to 24 mg in healthy volunteers. EC5026 was well tolerated. No treatment-emergent adverse events were considered related to EC5026. No apparent treatment- or dose-related trends in laboratory results, vital signs, physical examinations, or electrocardiograms were observed. A linear, near-dose-proportional increase in exposure was observed with progressive doses in the SAD study; plasma exposure was below or near the lower limit of quantification after 0.5-2 mg doses. Mean half-lives ranged from 41.8 to 59.1 h. for doses of 8-24 mg, supporting a once-daily dosing regimen. In the fed-fasted study using 8 mg EC5026 tablets, higher peak concentrations (66%) and total exposures (53%) were observed under the fed condition. Plasma concentrations declined in a monoexponential manner with mean half-lives of 59.5 h. in the fed state and 66.9 h. in the fasted state. Future clinical trials using EC5026 for the treatment of pain are justified based on the favorable outcomes from both clinical trials along with preclinical evidence of analgesic activity.

Mitochondrial DNA copy number variation in asthma risk, severity, and exacerbations.

BACKGROUND: Asthma pathophysiology is associated with mitochondrial dysfunction. Mitochondrial DNA copy number (mtDNA-CN) has been used as a proxy of mitochondrial function, with lower levels indicating mitochondrial dysfunction in population studies of cardiovascular diseases and cancers. OBJECTIVES: We investigated whether lower levels of mtDNA-CN are associated with asthma diagnosis, severity, and exacerbations. METHODS: mtDNA-CN is evaluated in blood from 2 cohorts: UK Biobank (UKB) (asthma, n = 39,147; no asthma, n = 302,302) and Severe Asthma Research Program (SARP) (asthma, n = 1283; nonsevere asthma, n = 703). RESULTS: Individuals with asthma have lower mtDNA-CN compared to individuals without asthma in UKB (beta, -0.006 [95% confidence interval, -0.008 to -0.003], P = 6.23 × 10-6). Lower mtDNA-CN is associated with asthma prevalence, but not severity in UKB or SARP. mtDNA-CN declines with age but is lower in individuals with asthma than in individuals without asthma at all ages. In a 1-year longitudinal study in SARP, mtDNA-CN was associated with risk of exacerbation; those with highest mtDNA-CN had the lowest risk of exacerbation (odds ratio 0.333 [95% confidence interval, 0.173 to 0.542], P = .001). Biomarkers of inflammation and oxidative stress are higher in individuals with asthma than without asthma, but the lower mtDNA-CN in asthma is independent of general inflammation or oxidative stress. Mendelian randomization studies suggest a potential causal relationship between asthma-associated genetic variants and mtDNA-CN. CONCLUSION: mtDNA-CN is lower in asthma than in no asthma and is associated with exacerbations. Low mtDNA-CN in asthma is not mediated through inflammation but is associated with a genetic predisposition to asthma.

Phase 1 Trial of Total Neoadjuvant Therapy With Short-Course Chemoradiotherapy Followed by Chemotherapy for Patients With Potentially Resectable Gastric Cancer.

PURPOSE: The purpose of this phase 1 trial was to evaluate the safety and toxicity of preoperative short-course chemoradiotherapy (CRT) as part of total neoadjuvant therapy (TNT) for patients with potentially resectable gastric or gastroesophageal adenocarcinoma. METHODS AND MATERIALS: Patients were enrolled between March 2021 and December 2022 and received CRT (30 Gy radiation in 10 fractions with concurrent capecitabine or 5-fluorouracil), then received systemic therapy for 2 months, and then underwent surgery. The primary endpoint was CRT safety; secondary endpoints were pathologic complete response, perioperative complications, and overall survival (OS). RESULTS: Of the 24 patients enrolled in the trial, 10 (42%) had bleeding, 3 (13%) had gastric outlet obstruction, and 2 (8%) had cirrhosis. Twelve patients (50%) had clinical nodal involvement. Twenty patients (83%) had poorly differentiated tumors, and 13 (54%) had signet ring cell histology. All patients completed CRT. CRT treatment-related toxic effects included grade 3 lymphopenia in 7 patients (29%), grade 4 lymphopenia in 1 (4%), and grade 3 anemia in 1 (4%). After CRT, 22 patients (92%) received chemotherapy, 1 patient (4%) with a microsatellite instability-high tumor received immunotherapy, and 1 patient (4%) underwent resection without systemic therapy. All patients underwent attempted resection, and gastrectomy was performed in 20 (83%). The R0 resection rate was 95%. Two patients had pathologic complete response, and an additional 5 had ≤1% viable tumor. Three patients had surgical complications [grade 1 in 1 patient (4%), grade 3b in 1 (4%), and grade 4a in 1 (4%)]; no patients died within 90 days. The median follow-up time was 28 months, and median OS was not reached. The 1- and 3-year OS rates were 96% and 85%, respectively. CONCLUSION: Short-course CRT may be safely used as part of planned TNT for patients with potentially resectable gastric or gastroesophageal adenocarcinoma. The promising rates of treatment completion, pathologic response, and OS support further research of TNT for gastric cancer.

Conformationally Constrained Isoquinolinones as Orally Efficacious Hepatitis B Capsid Assembly Modulators.

Isoquinolinone-based HBV capsid assembly modulators that bind at the dimer:dimer interface of HBV core protein have been shown to suppress viral replication in chronic hepatitis B patients. Analysis of their binding mode by protein X-ray crystallography has identified a region of the small molecule where the application of a constraint can lock the preferred binding conformation and has allowed for further optimization of this class of compounds. Key analogues demonstrated single digit nM EC50 values in reducing HBV DNA in a HepDE19 cellular assay in addition to favorable ADME and pharmacokinetic properties, leading to a high degree of oral efficacy in a relevant in vivo hydrodynamic injection mouse model of HBV infection, with 12e effecting a 3 log10 decline in serum HBV DNA levels at a once daily dose of 1 mg/kg. Additionally, maintenance of activity was observed in clinically relevant HBV core protein variants T33N and I105T.

Urinary metabolic profile and its predictive indexes after MSG consumption in rat.

Monosodium glutamate (MSG) is a widely used food additive with conflicting evidence regarding its potential effects on human health, with proposed relevance for obesity and metabolic syndrome (MetS) or chronic kidney disease. As being able to accurately quantify the MSG dietary intake would help clarify the open issues, we constructed a predictive formula to estimate the daily intake of MSG in a rat model based on the urinary metabolic profile. Adult male Wistar rats were divided into groups receiving different daily amounts of MSG in drinking water (0.5, 1.5, and 3.0 g%), no MSG, and MSG withdrawal after 3.0% MSG treatment for 4 weeks. We then analyzed 24-hour urine samples for chemistries and metabolites using 1H NMR spectrometry and observed a strong correlation between urine pH, sodium, bicarbonate, alpha-ketoglutarate, citrate, fumarate, glutamate, methylamine, N-methyl-4-pyridone-3-carboxamide, succinate, and taurine and the daily MSG intake. Following the multiple linear regression analysis a simple formula model based on urinary Na+, citrate, and glutamate was most accurate and could be validated for estimating daily MSG intake. In conclusion, we propose that the daily MSG intake correlates with urinary metabolites in a rat model and that this new tool for monitoring the impact of MSG on health measures.

Aortic Root Dilation and Genotype Associations in Phelan-McDermid Syndrome.

Phelan-McDermid syndrome (PMS) is a rare genetic neurodevelopmental disorder that results from the loss of one functional copy of the SHANK3 gene. While many clinical features of PMS are well-understood, there is currently limited literature on cardiovascular abnormalities in PMS. This report aims to evaluate the prevalence of aortic root dilation (ARD) among individuals with PMS and to understand if underlying genetic variation relates to risk for ARD. We present findings from 59 participants collected from a multisite observational study evaluating the phenotype and natural history of PMS. Individual echocardiographic and genetic reports were analyzed for aortic root measurements and genetic variant data, respectively. Our a priori hypothesis was that participants with chromosome 22 deletions with hg19 start coordinates on or before 49,900,000 (larger deletions) would have more instances of ARD than participants with deletion start coordinates after 49,900,000 (smaller deletions). Eight participants (14%) had ARD, and its presence was statistically significantly associated with large deletions (p = 0.047). Relatedly, participants with ARD had significantly more genes deleted on chromosome 22 than participants without ARD (p = 0.013). These results could aid in the identification of individuals with PMS who are at higher risk for ARD.

Inhibition of Soluble Epoxide Hydrolase Ameliorates Cerebral Blood Flow Autoregulation and Cognition in Alzheimer's Disease and Diabetes-Related Dementia Rat Models.

Alzheimer's Disease and Alzheimer's Disease-related dementias (AD/ADRD) pose major global healthcare challenges, with diabetes mellitus (DM) being a key risk factor. Both AD and DM-related ADRD are characterized by reduced cerebral blood flow, although the exact mechanisms remain unclear. We previously identified compromised cerebral hemodynamics as early signs in TgF344-AD and type 2 DM-ADRD (T2DN) rat models. Genome-wide studies have linked AD/ADRD to SNPs in soluble epoxide hydrolase (sEH). This study explored the effects of sEH inhibition with TPPU on cerebral vascular function and cognition in AD and DM-ADRD models. Chronic TPPU treatment improved cognition in both AD and DM-ADRD rats without affecting body weight. In DM-ADRD rats, TPPU reduced plasma glucose and HbA1C levels. Transcriptomic analysis of primary cerebral vascular smooth muscle cells from AD rats treated with TPPU revealed enhanced pathways related to cell contraction, alongside decreased oxidative stress and inflammation. Both AD and DM-ADRD rats exhibited impaired myogenic responses and autoregulation in the cerebral circulation, which were normalized with chronic sEH inhibition. Additionally, TPPU improved acetylcholine-induced vasodilation in the middle cerebral arteries (MCA) of DM-ADRD rats. Acute TPPU administration unexpectedly caused vasoconstriction in the MCA of DM-ADRD rats at lower doses. In contrast, higher doses or longer durations were required to induce effective vasodilation at physiological perfusion pressure in both control and ADRD rats. Additionally, TPPU decreased reactive oxygen species production in cerebral vessels of AD and DM-ADRD rats. These findings provide novel evidence that chronic sEH inhibition can reverse cerebrovascular dysfunction and cognitive impairments in AD/ADRD, offering a promising avenue for therapeutic development.

Safety implications of mask use: a systematic review and evidence map.

BACKGROUND: Widespread use of respiratory protection masks has become a critical component of public health response. OBJECTIVES: This systematic review synthesises the evidence on the acute physiological, cognitive and psychological impacts associated with different types of masks and provides an evidence map of research gaps. METHODS: A comprehensive search from 2000 to 2023 was conducted across multiple databases (MEDLINE, EMBASE, Cochrane databases, Scopus and PubMed). An umbrella systematic overview was conducted for physiological outcomes using existing systematic reviews. We conducted de novo systematic reviews for cognitive and psychological outcomes. Pairs of independent reviewers determined eligibility, extracted data and assessed risk of bias. Certainty at an outcome level was appraised using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: The search resulted in 13 370 potential citations, leading to the inclusion of nine systematic reviews for physiological outcomes (87 primary studies) and 10 primary studies for cognitive and psychological outcomes (3815 participants), with the majority of participants being healthy adults. Studies evaluating physiological outcomes demonstrated that various types of masks have little to no significant difference in heart rate (surgical mask (mean difference (MD): 0.96 (-1.01 to 2.93)), N95 mask (MD: 1.63 (-2.79 to 6.05)) and cloth mask (MD: -0.94 (-6.39 to 4.52))) or respiratory rate during rest or exercise (surgical mask (MD: -1.35 (-3.00 to 0.29)), N95 mask (MD: 0.10 (-3.10 to 3.29)) and cloth mask (MD: -2.57 (-6.44 to 1.29)) (low certainty for most outcomes)). Mask use may be associated with very small changes in minute ventilation (surgical mask (MD: -13.9 (-20.30 to -7.53)) and N95 mask (MD: -16.3 (-28.7 to -3.9))), tidal volume (surgical mask (MD: -0.14 (-0.23 to -0.05)) and N95 mask (MD: -0.10 (-0.33 to 0.13))), oxygen saturation (surgical mask (MD: -0.59% (-0.87 to -0.30)), N95 mask (MD: -0.35% (-0.75 to 0.05)) and cloth mask (MD: -0.50% (-1.23; 0.24))), carbon dioxide partial pressure (surgical mask (standardised MD (SMD): 1.17 (0.70 to 1.64)) and N95 mask (SMD: 0.43 (0.08 to 0.79))) and exercise performance (surgical mask (SMD: -0.12 (-0.39 to 0.15)), N95 mask (SMD: -0.42 (-0.76 to -0.08)) and cloth mask (SMD: -0.26 (-0.54 to 0.02)) (low certainty for most outcomes)). Studies evaluating cognitive outcomes showed mixed results. Some studies reported reduced mental workload, and others showed no significant effect or decreased performance. The impact on attention, errors and reaction time was variable. These studies were small and at moderate to high risk of bias. Evidence was insufficient to estimate the effect of mask use on psychological outcomes (claustrophobia, depression and anxiety) as these studies were small, non-longitudinal and at high risk of bias. CONCLUSION: This evidence map provides a comprehensive insight into the multifaceted impact of respiratory protection mask use, and highlights the limited certainty in the available body of evidence. This evidence map supports the development of future research agenda.

Soluble epoxide hydrolase inhibition impairs triggering receptor expressed on myeloid cells-1 in periodontal tissue.

AIMS: Periodontitis is a prevalent inflammatory disorder affecting the oral cavity, driven by dysbiotic oral biofilm and host immune response interactions. While the major clinical focus of periodontitis treatment is currently controlling oral biofilm, understanding the immune response is crucial to prevent disease progression. Soluble epoxide hydrolase (sEH) inhibition has shown promise in preventing alveolar bone resorption. Triggering receptors expressed on myeloid cells (TREMs) play pivotal roles in regulating inflammation and bone homeostasis, and dysregulation of TREM signaling is implicated in periodontitis. Here, we investigated the impact of sEH inhibition on TREM 1 and 2 expression, associated with inflammatory cytokines, and histologically assessed the inflammatory infiltrate in periodontal tissue. METHODS: The experimental periodontitis model was induced by placing a ligature around the upper second molar. For 14 days, animals were treated daily with a sEH inhibitor (TPPU) or vehicle. The alveolar bone loss was examined using a methylene blue stain. Gingival tissues were used to measure the mRNA expression of TREM-1, TREM-2, IKKß, NF-κB, IL-1ß, IL-6, IL-8, and TNF-α by RT-qPCR. Another set of experiments was performed to determine the histological inflammatory scores. RESULTS: In a ligature-induced periodontitis model, sEH inhibition prevented alveolar bone loss and reduced TREM1 expression, albeit with a slight elevation compared to the disease-free group. In contrast, TREM2 expression remained elevated, suggesting sustained immunomodulation favoring resolution. The inhibition of sEH reduced the expression of NF-κB, IL-1ß, and TNF-α, while no differences were found in the expression of IL-6, IL-8, and IKKß. In histological analysis, sEH inhibition reduced the inflammatory leukocyte infiltrate in periodontal tissues close to the ligature. CONCLUSION: These findings underscore the potential of sEH inhibition to modulate periodontal inflammation by regulating TREM-1 alongside decreased IL-1ß and TNF-α expression, highlighting a promising therapeutic approach for periodontitis management.

The BabySeq Project: A clinical trial of genome sequencing in a diverse cohort of infants.

Efforts to implement and evaluate genome sequencing (GS) as a screening tool for newborns and infants are expanding worldwide. The first iteration of the BabySeq Project (2015-2019), a randomized controlled trial of newborn sequencing, produced novel evidence on medical, behavioral, and economic outcomes. The second iteration of BabySeq, which began participant recruitment in January 2023, examines GS outcomes in a larger, more diverse cohort of more than 500 infants up to one year of age recruited from pediatric clinics at several sites across the United States. The trial aims for families who self-identify as Black/African American or Hispanic/Latino to make up more than 50% of final enrollment, and key aspects of the trial design were co-developed with a community advisory board. All enrolled families receive genetic counseling and a family history report. Half of enrolled infants are randomized to receive GS with comprehensive interpretation of pathogenic and likely pathogenic variants in more than 4,300 genes associated with childhood-onset and actionable adult-onset conditions, as well as larger-scale chromosomal copy number variants classified as pathogenic or likely pathogenic. GS result reports include variants associated with disease (Mendelian disease risks) and carrier status of autosomal-recessive and X-linked disorders. Investigators evaluate the utility and impacts of implementing a GS screening program in a diverse cohort of infants using medical record review and longitudinal parent surveys. In this perspective, we describe the rationale for the second iteration of the BabySeq Project, the outcomes being assessed, and the key decisions collaboratively made by the study team and community advisory board.

Measurable imaging-based changes in enhancement of intrahepatic cholangiocarcinoma after radiotherapy reflect physical mechanisms of response.

Background: Although escalated doses of radiation therapy (RT) for intrahepatic cholangiocarcinoma (iCCA) are associated with durable local control (LC) and prolonged survival, uncertainties persist regarding personalized RT based on biological factors. Compounding this knowledge gap, the assessment of RT response using traditional size-based criteria via computed tomography (CT) imaging correlates poorly with outcomes. We hypothesized that quantitative measures of enhancement would more accurately predict clinical outcomes than size-based assessment alone and developed a model to optimize RT. Methods: Pre-RT and post-RT CT scans of 154 patients with iCCA were analyzed retrospectively for measurements of tumor dimensions (for RECIST) and viable tumor volume using quantitative European Association for Study of Liver (qEASL) measurements. Binary classification and survival analyses were performed to evaluate the ability of qEASL to predict treatment outcomes, and mathematical modeling was performed to identify the mechanistic determinants of treatment outcomes and to predict optimal RT protocols. Results: Multivariable analysis accounting for traditional prognostic covariates revealed that percentage change in viable volume following RT was significantly associated with OS, outperforming stratification by RECIST. Binary classification identified ≥33% decrease in viable volume to optimally correspond to response to RT. The model-derived, patient-specific tumor enhancement growth rate emerged as the dominant mechanistic determinant of treatment outcome and yielded high accuracy of patient stratification (80.5%), strongly correlating with the qEASL-based classifier. Conclusion: Following RT for iCCA, changes in viable volume outperformed radiographic size-based assessment using RECIST for OS prediction. CT-derived tumor-specific mathematical parameters may help optimize RT for resistant tumors.