Cytomegalovirus-induced peroxynitrite promotes virus entry and contributes to pathogenesis in a murine model of infection.

There are no licensed vaccines for human cytomegalovirus (HCMV), and current antiviral drugs that target viral proteins are toxic and prone to resistance. Targeting host pathways essential for virus replication provides an alternate strategy that may reduce opportunities for drug resistance to occur. Oxidative stress is triggered by numerous viruses including HCMV. Peroxynitrite is a reactive nitrogen species that is formed during oxidative stress. Herein, we identified that HCMV rapidly induces the generation of intracellular peroxynitrite upon infection in a manner partially dependent upon xanthine oxidase generation. Peroxynitrite promoted HCMV infection in both cell-free and cell-associated infection systems in multiple cell types. Inhibiting peroxynitrite within the first 24 hours of infection prevented HCMV replication and peroxynitrite promoted cell entry and pp65 translocation into the host cell nuclei. Furthermore, using the murine cytomegalovirus model, we demonstrated that antagonizing peroxynitrite significantly reduces cytomegalovirus replication and pathogenesis in vivo. Overall, our study highlights a proviral role for peroxynitrite in CMV infection and implies that RNS and/or the mechanisms that induce their production could be targeted as a novel strategy to inhibit HCMV infection. IMPORTANCE: Human cytomegalovirus (HCMV) causes significant disease in individuals with impaired or immature immune systems, such as transplant patients and after congenital infection. Antiviral drugs that target the virus directly are toxic and are susceptible to antiviral drug resistance due to virus mutations. An alternate strategy is to target processes within host cells that are required by the virus for replication. Herein, we show that HCMV infection triggers a highly reactive molecule, peroxynitrite, during the initial stages of infection. Peroxynitrite was required for the initial entry of the virus into the cell and promotes virus replication in multiple cell types, suggesting a broad pro-viral function. Importantly, targeting peroxynitrite dramatically inhibited cytomegalovirus replication in cells in the laboratory and in mice, suggesting that therapeutic targeting of this molecule and/or the cellular functions it regulates could represent a novel strategy to inhibit HCMV infection.

HER-2 directed therapies across gastrointestinal tract cancers - A new frontier.

Gastrointestinal (GI) cancers are common and in the metastatic setting they have a poor prognosis. The current mainstay of treatment of GI cancers is chemotherapy; however, the biomarker-directed treatment landscape is evolving. HER-2 is overexpressed in a portion of GI cancers and is an emerging target for therapy, with recent FDA tumor agnostic approval for trastuzumab deruxtecan. Testing for HER-2 expression is not standardized across GI cancers, methodology requires further optimization and standardization as HER-2 targeted therapy emerges into the treatment landscape. There is established rationale for use of HER-2 targeted therapy in first line treatment of metastatic gastric cancer, and emerging evidence with variable benefit in bile duct, pancreatic and colorectal cancers.

Improving academic performance through a school-based intervention targeting academic executive functions - a pilot study.

Background: Academic challenges such as losing/not turning in assignments, misplacing materials, and inefficient studying are common in middle-school students with autism spectrum disorder (ASD) without intellectual disability. Deficits in organization, planning, prioritizing, memory/materials management, and studying skills [i.e. academic executive functioning (EF) deficits] contribute to these challenges. Objectives: To assess the feasibility, satisfaction, and initial efficacy of the school-based version of the Achieving Independence and Mastery in School (AIMS) intervention in a proof-of-concept trial with 6 students with ASD. Methods: 6 middle-schoolers with ASD without ID participated in AIMS. Parents and teachers rated academic EFs and functioning. Results: Results suggest high feasibility, youth satisfaction, and improved EF skills and academic behaviors by parent and teacher report. Conclusion: These promising results support further intervention development and suggest that academic EF skills are malleable in students with ASD.

Treating Obsessive Compulsive Disorder in Adolescents and Adults with Down Syndrome: Results from a Scoping Rapid Review.

PURPOSE: Adolescents and adults with Down syndrome are noted to display symptoms and behaviors consistent with a diagnosis of Obsessive Compulsive Disorder. While evidenced-based interventions, including psychopharmacology and therapeutic interventions including exposure and response prevention, exist and effectively treat obsessive-compulsive symptoms in neurotypical populations, less is known about effective treatments for similar presentations in persons with Down syndrome. METHODS: A scoping rapid review was conducted in April 2023 to determine what treatments are being used to target obsessive-compulsive symptoms and related behaviors in adolescents and adults with Down syndrome, the quality of those treatments, and their alignment with current evidenced-based interventions. RESULTS: A total of eleven articles, all single case or case series, published between 1992 and 2017 were identified describing the treatment of 32 adolescents and adults with Down syndrome and obsessive-compulsive traits and behaviors including: hoarding, cleaning, gross motor compulsions, and food, hygiene, dressing, and checking rituals. Interventions used most often aligned with evidenced-based guidelines for treating obsessive compulsive disorder and included psychopharmacology, psychotherapy, and complementary and alternative medicine. CONCLUSIONS: While the outcomes of most interventions yielded partial or significant reduction in symptoms, poor research quality and limited generalizability noted across all studies make it difficult to inform guidelines for caring for this high-needs population. In the future, we believe it is necessary to perform more rigorous research focused on treating obsessive compulsive symptoms in individuals with Down syndrome with sufficient follow-up to fully assess treatment effectiveness.

A randomized, controlled, prehabilitation intervention to maximize early recovery (PRIMER) in liver transplantation.

Frailty and impaired functional status are associated with adverse outcomes on the liver transplant (LT) waitlist and after transplantation. Prehabilitation prior to LT has rarely been tested. We conducted a 2-arm patient-randomized pilot trial to evaluate the feasibility and efficacy of a 14-week behavioral intervention to promote physical activity prior to LT. Thirty patients were randomized 2:1 to intervention (n = 20) versus control (n = 10). The intervention arm received financial incentives and text-based reminders linked to wearable fitness trackers. Daily step goals were increased by 15% in 2-week intervals. Weekly check-ins with study staff assessed barriers to physical activity. The primary outcomes were feasibility and acceptability. Secondary outcomes included mean end-of-study step counts, short physical performance battery, grip strength, and body composition by phase angle. We fit regression models for secondary outcomes with the arm as the exposure adjusting for baseline performance. The mean age was 61, 47% were female, and the median Model for End-stage Liver Disease sodium (MELD-Na) was 13. One-third were frail or prefrail by the liver frailty index, 40% had impaired mobility by short physical performance battery, nearly 40% had sarcopenia by bioimpedance phase angle, 23% had prior falls, and 53% had diabetes. Study retention was 27/30 (90%; 2 unenrolled from intervention, 1 lost to follow-up in control arm). Self-reported adherence to exercise during weekly check-ins was about 50%; the most common barriers were fatigue, weather, and liver-related symptoms. End-of-study step counts were nearly 1000 steps higher for intervention versus control: adjusted difference 997, 95% CI, 147-1847; p = 0.02. On average, the intervention group achieved daily step targets 51% of the time. A home-based intervention with financial incentives and text-based nudges was feasible, highly accepted, and increased daily steps in LT candidates with functional impairment and malnutrition.

Alterations in GLP-1 and PYY release with aging and body mass in the human gut.

The lining of our intestinal surface contains an array of hormone-producing cells that are collectively our bodies' largest endocrine cell reservoir. These "enteroendocrine" (EE) cells reside amongst the billions of absorptive epithelial and other cell types that line our gastrointestinal tract and can sense and respond to the ever-changing internal environment in our gut. EE cells release an array of important signalling molecules that can act as hormones, including glucagon-like peptide (GLP-1) and peptide YY (PYY) which are co-secreted from L cells. While much is known about the effects of these hormones on metabolism, insulin secretion and food intake, less is understood about their secretion from human intestinal tissue. In this study we assess whether GLP-1 and PYY release differs across human small and large intestinal tissue locations within the gastrointestinal tract, and/or by sex, body weight and the age of an individual. We identify that the release of both hormones is greater in more distal regions of the human colon, but is not different between sexes. We observe a negative correlation of GLP-1 and BMI in the small, but not large, intestine. Increased aging correlates with declining secretion of both GLP-1 and PYY in human large, but not small, intestine. When the data for large intestine is isolated by region, this relationship with age remains significant for GLP-1 in the ascending and descending colon and in the descending colon for PYY. This is the first demonstration that site-specific differences in GLP-1 and PYY release occur in human gut, as do site-specific relationships of L cell secretion with aging and body mass.

COVID-19 in Western Australia: 'The last straw' and hopes for a 'new normal' for parents of children with long-term conditions.

BACKGROUND: Children with long-term conditions are vulnerable due to the treatments required for their conditions. Since the start of the coronavirus disease 2019 (COVID-19) pandemic, Western Australians experienced restrictions that changed daily life activities but were able to return to some of their previous routines due to the restrictions. AIM: The study explored the stress experiences of parents caring for children with long-term conditions during COVID-19 in Western Australia. DESIGN AND PARTICIPANTS: The study was codesigned with a parent representative caring for children with long-term conditions to ensure essential questions were targeted. Twelve parents of children with various long-term conditions were recruited. Ten parents completed the qualitative proforma, and two parents were interviewed in November 2020. Interviews were audio-recorded and transcribed verbatim. Data were anonymised and analysed using reflexive thematic analysis. FINDINGS: Two themes were produced: (1) 'Keep my child safe' describes the children's vulnerabilities due to their long-term conditions, the adjustments parents' made to keep their children safe and the various consequences faced. (2) 'COVID-19's silver lining' covers the positives of the COVID-19 pandemic, including their children having fewer infections, the availability of telehealth appointments, relationship improvements and the parent's hopes for a new normal where behaviours prevent transmission of infectious (e.g., hand sanitising). CONCLUSION: Western Australia provided a unique context for the COVID-19 pandemic due to no transmission of the virus severe acute respiratory syndrome coronavirus 2 at the time of the study. The tend and befriend theory aids in explaining the parents' stress experiences, and the application highlights a unique aspect of this theory. Parents tended to their children during COVID-19, but many could no longer rely on others for connection, support and respite, and became further isolated in attempting to protect their children due to COVID-19 consequences. The findings highlight that some parents of children with long-term conditions need specific attention during times of pandemics. Further review is recommended to support parents through the impact of COVID-19 and similar crises. PATIENT OR PUBLIC CONTRIBUTION: This study was codesigned with an experienced parent representative who was part of the research team and involved throughout the research process to ensure meaningful end-user engagement and ensure essential questions and priorities were addressed.

Nonlinear dynamics of EEG responses to unmanned vehicle visual detection with different levels of task difficulty.

The main objective of this study was to examine the presence of chaos in the EEG recordings of brain activity under simulated unmanned ground vehicle visual detection scenarios with different levels of task difficulty. One hundred and fifty people participated in the experiment and completed four visual detection task scenarios: (1) change detection, (2) a threat detection task, (3) a dual-task with different change detection task rates, and (4) a dual-task with different threat detection task rates. We used the largest Lyapunov exponent and correlation dimension of the EEG data and performed 0-1 tests on the EEG data. The results revealed a change in the level of nonlinearity in the EEG data corresponding to different levels of cognitive task difficulty. The differences in EEG nonlinearity measures among the studied levels of task difficulty, as well as between a single task scenario and a dual-task scenario, have also been assessed. The results increase our understanding of the nature of unmanned systems' operational requirements.

Noncovalent Host-Guest Complexes of Artemisinin with α-, ß-, and γ- Cyclodextrin Examined by Structural Mass Spectrometry Strategies.

Cyclodextrins (CDs) are a family of macrocyclic oligosaccharides with amphiphilic properties, which can improve the stability, solubility, and bioavailability of therapeutic compounds. There has been growing interest in the advancement of efficient and reliable analytical methods that assist with elucidating CD host-guest drug complexation. In this study, we investigate the noncovalent ion complexes formed between naturally occurring dextrins (αCD, ßCD, γCD, and maltohexaose) with the poorly water-soluble antimalarial drug, artemisinin, using a combination of ion mobility-mass spectrometry (IM-MS), tandem MS/MS, and theoretical modeling approaches. This study aims to determine if the drug can complex within the core dextrin cavity forming an inclusion complex or nonspecifically bind to the periphery of the dextrins. We explore the use of group I alkali earth metal additives to promote the formation of various noncovalent gas-phase ion complexes with different drug/dextrin stoichiometries (1:1, 1:2, 1:3, 1:4, and 2:1). Broad IM-MS collision cross section (CCS) mapping (n > 300) and power-law regression analysis were used to confirm the stoichiometric assignments. The 1:1 drug:αCD and drug:ßCD complexes exhibited strong preferences for Li+ and Na+ charge carriers, whereas drug:γCD complexes preferred forming adducts with the larger alkali metals, K+, Rb+, and Cs+. Although the ion-measured CCS increased with cation size for the unbound artemisinin and CDs, the 1:1 drug:dextrin complexes exhibit near-identical CCS values regardless of the cation, suggesting these are inclusion complexes. Tandem MS/MS survival yield curves of the [artemisinin:ßCD + X]+ ion (X = H, Li, Na, K) showed a decreased stability of the ion complex with increasing cation size. Empirical CCS measurements of the [artemisinin:ßCD + Li]+ ion correlated with predicted CCS values from the low-energy theoretical structures of the drug incorporated within the ßCD cavity, providing further evidence that gas-phase inclusion complexes are formed in these experiments. Taken together, this work demonstrates the utility of combining analytical information from IM-MS, MS/MS, and computational approaches in interpreting the presence of gas-phase inclusion phenomena.

Axons will not be silenced! A balancing act of attractive receptors.

Axons crossing the CNS midline regulate their responsiveness to both attractive and repulsive cues. In this issue, Dailey-Krempel et al. find different modes of action for DCC isoforms and uncover evidence against the silencing model of axon guidance.

Elevated Maternal Folate Status and Changes in Maternal Prolactin, Placental Lactogen and Placental Growth Hormone Following Folic Acid Food Fortification: Evidence from Two Prospective Pregnancy Cohorts.

Folic acid (FA) food fortification in Australia has resulted in a higher-than-expected intake of FA during pregnancy. High FA intake is associated with increased insulin resistance and gestational diabetes. We aimed to establish whether maternal one-carbon metabolism and hormones that regulate glucose homeostasis change in healthy pregnancies post-FA food fortification. Circulating folate, B12, homocysteine, prolactin (PRL), human placental lactogen (hPL) and placental growth hormone (GH2) were measured in early pregnancy maternal blood in women with uncomplicated pregnancies prior to (SCOPE: N = 604) and post (STOP: N = 711)-FA food fortification. FA food fortification resulted in 63% higher maternal folate. STOP women had lower hPL (33%) and GH2 (43%) after 10 weeks of gestation, but they had higher PRL (29%) and hPL (28%) after 16 weeks. FA supplementation during pregnancy increased maternal folate and reduced homocysteine but only in the SCOPE group, and it was associated with 54% higher PRL in SCOPE but 28% lower PRL in STOP. FA food fortification increased maternal folate status, but supplements no longer had an effect, thereby calling into question their utility. An altered secretion of hormones that regulate glucose homeostasis in pregnancy could place women post-fortification at an increased risk of insulin resistance and gestational diabetes, particularly for older women and those with obesity.

Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease.

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.

Digitally mediated service provision for children's social, emotional and mental health: key indicators for evaluation.

INTRODUCTION: Remote delivery of assessment, consultation and therapy via digital communication technologies in mental health services is important in rural locations, and has rapidly increased due to the COVID-19 pandemic. METHODS: This UK-based research investigated what factors should be considered in the development and evaluation of digitally mediated service provision for children and young people with social, emotional and mental health (SEMH) needs using two approaches: (1) a focus group with five young people (aged 16-19 years) and (2) an online survey with 18 parents/carers of primary-age children with SEMH difficulties. RESULTS: Getting help quickly was most important to both young people and parents/carers when accessing services, with having a say in their care of equal importance to young people but not parents/carers. Analysis identified participants' preferences and perceived positives and negatives of digitally mediated service provision. CONCLUSION: Digitally mediated service provision should be timely and patient-centred to be considered acceptable by young people with SEMH needs and their parents/carers. Evaluations should include comprehensive measures of service efficiency and service user experience to better understand the benefits of digital mediation.

An older adult advantage in autobiographical recall.

This pre-registered online study aimed to measure the effect of environmental support on age-differences in autobiographical memory alongside memory for images. Young and older adults reported autobiographical memories about which they regularly thought (high environmental support through practice) or that were experimentally cued to be mundane (low environmental support). The support manipulation was also applied to descriptions of images that were produced whilst images remained on screen (high support) or produced from memory (low support). In line with existing theory, support disproportionately benefitted older adults in the quantity of information produced. However, analysis of the autobiographical descriptions showed no age deficit in reporting episodic detail, in contrast to much of the existing literature. A second group of young and older adults also evaluated the descriptions produced, and older adults' descriptions were consistently rated as higher quality than young adults' descriptions across several dimensions, such as vividness and clarity. An unplanned meta-analysis was conducted to assess if a publication bias existed in the literature favoring the reporting of age-deficits in producing episodic detail in autobiographical memory: there was no evidence for a bias and the modal result of age deficits was generally supported. A key distinction is that the current study was conducted online - evidence is presented to argue that older adults may perform better at autobiographical memory tasks outside the lab.

Mothers' borderline personality disorder symptom severity and accuracy in predicting infant distress.

Maternal borderline personality disorder (BPD) symptoms have been found to relate to parenting difficulties that subsequently predict children's maladjustment. One specific area of difficulty for mothers with BPD symptoms surrounds responses to infant distress. Based in mentalization theories of BPD, the current study tested the relation between BPD symptom severity and maternal accuracy in predicting infant distress. Infant biological sex was also tested as a moderator. Participants included 101 mothers, varying in self-reported BPD symptom severity, and their 12- to 23-month-old infants. At a laboratory visit, mothers responded to structured questions about their predictions for infant distress behaviors in fear- and anger-eliciting tasks, which were then observed. Maternal accuracy represented the statistical association between maternal predictions and infant distress behaviors. Maternal accuracy did not differ between infant fear and anger. For male infants, mothers' higher BPD symptom severity related to lower accuracy across fear and anger contexts. For female infants, BPD symptom severity did not influence maternal accuracy. Results are discussed in relation to existing theories of emotional disruption in the relationships between mothers with BPD symptoms and their infants. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Marginal Engagement: The Adverse Experiences of White Women and People of Color Alumni at a PWI School of Public Health.

The University of Minnesota (UMN) School of Public Health (SPH) asked graduates about their experiences as students and as alumni. Of 1186 respondents indicating gender, 140 were women who self-identified as members of a marginalized group. Fifty-one percent of these respondents were White women. Compared with White women, Black, Indigenous, and people of color (BIPOC) women were more likely to report that they felt they did not belong, were uncomfortable, or experienced bias and/or discrimination in their program, although the results were not statistically significantly different at P < .05. Survey results show a clear difference in experience between White and BIPOC alumni. The results indicate a need to improve cultural competence/humility, along with a need to move away from what may be construed as White-centered events, pedagogy, and leadership. With this evidence, the UMN SPH has an opportunity to improve our outreach strategies and initiatives.

Gene editing to improve legume-rhizobia symbiosis in a changing climate.

In the last three years, several gene editing techniques have been developed for both model and crop legumes. CRISPR-Cas9-based tools, in particular, are outpacing other comparable gene editing technologies used in legume hosts and their microbial symbionts to understand the molecular basis of symbiotic nitrogen-fixation. Gene editing has helped identify new gene functions, validate genetic screens, resolve gene redundancy, examine the role of tandemly duplicated genes, and investigate symbiotic signaling networks in non-model plants. In this review, we discuss the advances made in understanding the legume-rhizobia symbiosis through the use of gene editing and highlight studies conducted under varying environmental conditions. We reason that future climate-hardy legumes must be able to better integrate environmental signals with nitrogen fixation by fine-tuning long distance signaling, continuing to select efficient rhizobial partners, and adjusting their molecular circuitry to function optimally under variable light and nutrient availability and rising atmospheric carbon dioxide.

Suspected adverse drug reactions of the type 2 antidiabetic drug class dipeptidyl-peptidase IV inhibitors (DPP4i): Can polypharmacology help explain?

To interpret the relationship between the polypharmacology of dipeptidyl-peptidase IV inhibitors (DPP4i) and their suspected adverse drug reaction (ADR) profiles using a national registry. A retrospective investigation into the suspected ADR profile of four licensed DPP4i in the United Kingdom using the National MHRA Yellow Card Scheme and OpenPrescribing databases. Experimental data from the ChEMBL database alongside physiochemical (PC) and pharmacokinetic (PK) profiles were extracted and interpreted. DPP4i show limited polypharmacology alongside low suspected ADR rates. We found a minimal statistical difference between the unique ADR profiles ascribed to the DPP4i except for total ADRs (χ2 ; p < .05). Alogliptin consistently showed the highest suspected ADR rate per 1 000 000 items prescribed. Saxagliptin showed the lowest suspected ADR rate across all organ classes but did not reach statistical difference (χ2 ; p > .05). We confirmed the Phase III clinical trial data that showed gastrointestinal and skin reactions are the most reported ADRs across the DPP4i class and postulated underlying mechanisms for this based on possible drug interactions. The main pharmacological mechanism behind the ADRs is attributed to interactions with DPP4 activity and/or structure homolog (DASH) proteins which augment the immune-inflammatory modulation of DPP4.

Alternate Pembrolizumab Dosing Interval in Advanced NSCLC with PD-L1 TPS ≥ 50%: 3 Weekly Compared to 6 Weekly Dosing.

BACKGROUND: A fixed dose of 200 mg of pembrolizumab every 3 weeks (Q3W) is the standard of care for patients with stage IV non-small cell lung cancer (NSCLC) and PDL1 ≥50%. In April 2020, based on pharmacokinetic modeling without formal comparative studies, the FDA approved 400 mg every 6 weeks (Q6W). Pharmacokinetic studies also suggested comparable target engagement with weight-based and flat dosing for the respective schedules. The objective of this study was to determine if overall survival (OS) differs based on the Q3W vs. Q6W dosing schedule of pembrolizumab. METHODS: BC Cancer patients with stage IV NSCLC and PDL1 ≥50% treated with pembrolizumab were retrospectively reviewed. Patients were treated with weight-based dosing, per institution standard, of pembrolizumab 2 mg/kg Q3W or 4 mg/kg Q6W. Patient demographics, treatment and outcome were recorded. Patients were assigned to Q3W or Q6W according to the schedule that was used for the majority of treatment (greater than 50%). RESULTS: 718 patients with NSCLC and PDL1 ≥50% received first-line pembrolizumab between 2017 and2021, Q3W/Q6W dosing 677/41 patients. Baseline characteristics with respect to age, sex, smoking status, histology and performance status (PS) were similar between groups. In the multivariate model, including age, sex, PS and dosing schedule, the hazard ratio for death (HR) for OS Q3W vs. Q6W was 0.759 (p = 0.230). A 2:1 case-matched analysis for OS was performed, controlling for sex, age ± 5 years, PS and duration on pembrolizumab ± 2 months for Q3W vs. Q6W (n = 113) with a HR 0.834 (p = 0.500). CONCLUSIONS: There was no OS difference demonstrated with pembrolizumab dosing Q3W compared to Q6W in a multivariate analysis that included age, sex and PS. A case-matched analysis that controlled for these variables and for duration of treatment confirmed these findings. This study supports the use of Q6W pembrolizumab dosing, allowing for less frequent interactions with the medical system.