A fibroblast-dependent TGFß1/sFRP2 noncanonical Wnt signaling axis promotes epithelial metaplasia in idiopathic pulmonary fibrosis.

Reciprocal interactions between alveolar fibroblasts and epithelial cells are crucial for lung homeostasis, injury repair, and fibrogenesis, but underlying mechanisms remain unclear. To investigate, we administered the fibroblast-selective TGFß1 signaling inhibitor, epigallocatechin gallate (EGCG), to Interstitial Lung Disease (ILD) patients undergoing diagnostic lung biopsy and conducted single-cell RNA sequencing on spare tissue. Biopsies from untreated patients showed higher fibroblast TGFß1 signaling compared to non-disease donor or end-stage ILD tissues. In vivo, EGCG downregulated TGFß1 signaling and several pro-inflammatory and stress pathways in biopsy samples. Notably, EGCG reduced fibroblast secreted frizzle-like receptor protein 2 (sFRP2), an unrecognized TGFß1 fibroblast target gene induced near type II alveolar epithelial cells (AEC2s) in situ. Using AEC2-fibroblast coculture organoids and precision cut lung slices (PCLS) from non-diseased donors, we found TGFß1 signaling promotes a spread AEC2 KRT17+ basaloid state, whereupon sFRP2 then activates a mature Krt5+ basal cell program. Wnt-receptor Frizzled 5 (Fzd5) expression and downstream calcineurin signaling were required for sFRP2-induced nuclear NFATc3 accumulation and KRT5 expression. These findings highlight stage-specific TGFß1 signaling in ILD, the therapeutic potential of EGCG in reducing IPF-related transcriptional changes, and identify TGFß1-non-canonical Wnt pathway crosstalk via sFRP2 as a novel mechanism for dysfunctional epithelial signaling in Idiopathic Pulmonary Fibrosis/ILD.

A Narrative Review of Pain in Pediatric Oncology: The Opioid Option.

Opioid therapy is the mainstay for managing pain in pediatric oncology. This narrative review describes the current literature regarding opioids for pediatric cancer pain. The review explores the multifaceted landscape of opioid utilization in this population, including the role of opioids in certain clinical circumstances, modalities of opioid delivery, unique opioids, outpatient and at-home pain management strategies, and other key concepts such as breakthrough pain. This review highlights the importance of individualized dosing and multimodal approaches to enhance efficacy and minimize adverse effects. Drawing from a wide range of evidence, this review offers insights to optimize pediatric oncology pain management.

Congenital lymphatic dysplasia and severe bone disease in a term neonate with a novel homozygous PIEZO1 variant.

We report a patient with nonimmune fetal hydrops and multiple pathologic fractures. RNA analysis revealed a novel PIEZO1 variant. This report is the first to elucidate PIEZO1's role as a critical regulator of bone mass and strength.

Spatial lipidomics maps brain alterations associated with mild traumatic brain injury.

Traumatic brain injury (TBI) is a global public health problem with 50-60 million incidents per year, most of which are considered mild (mTBI) and many of these repetitive (rmTBI). Despite their massive implications, the pathologies of mTBI and rmTBI are not fully understood, with a paucity of information on brain lipid dysregulation following mild injury event(s). To gain more insight on mTBI and rmTBI pathology, a non-targeted spatial lipidomics workflow utilizing high resolution mass spectrometry imaging was developed to map brain region-specific lipid alterations in rats following injury. Discriminant multivariate models were created for regions of interest including the hippocampus, cortex, and corpus callosum to pinpoint lipid species that differentiated between injured and sham animals. A multivariate model focused on the hippocampus region differentiated injured brain tissues with an area under the curve of 0.99 using only four lipid species. Lipid classes that were consistently discriminant included polyunsaturated fatty acid-containing phosphatidylcholines (PC), lysophosphatidylcholines (LPC), LPC-plasmalogens (LPC-P) and PC potassium adducts. Many of the polyunsaturated fatty acid-containing PC and LPC-P selected have never been previously reported as altered in mTBI. The observed lipid alterations indicate that neuroinflammation and oxidative stress are important pathologies that could serve to explain cognitive deficits associated with rmTBI. Therapeutics which target or attenuate these pathologies may be beneficial to limit persistent damage following a mild brain injury event.

Measurement Properties of Backward Walking and Its Sensitivity and Feasibility in Predicting Falls in People With Multiple Sclerosis.

BACKGROUND: People with multiple sclerosis (MS) experience mobility impairments that elevate fall risk, increasing the need to identify clinical measures that accurately predict falls. Backward walking (BW) better differentiates fallers from nonfallers in MS. However, no studies have reported the measurement properties of the backward walking Timed 25-Foot Walk (B-T25-FW) and BW metrics, like BW velocity. Additionally, it is unknown whether BW can predict future falls in MS or its link to activity levels. This study assessed the reliability and responsiveness of B-T25-FW and BW metrics, including BW velocity. It also examined whether BW could predict falls at 3 and 6 months and its association with activity levels. METHODS: During 2 separate visits, 23 people with MS completed the forward walking Timed 25-Foot Walk (F-T25-FW) and B-T25-FW, as well as forward walking and BW assessments in which spatiotemporal measures were recorded. Test-retest reliability was determined with intraclass correlation coefficients, and minimum detectable changes were calculated. Correlation analyses explored the relationship between BW velocity, B-T25-FW, prospective falls, and activity levels. RESULTS: B-T25-FW and BW velocity exhibited excellent test-retest reliability. Large effect sizes to interpret clinically meaningful change in the B-T25-FW and BW velocity were also found. Both metrics demonstrated modest negative correlations with falls at 3 and 6 months and correlated strongly with very active minutes at 3- and 6-months post study. CONCLUSIONS: The B-T25-FW and BW velocity are effective and reliable in clinical use for evaluating functional mobility in people with MS, are sensitive enough to detect subtle changes, and may be a meaningful marker for tracking disease progression and treatment efficacy.

Phospholipid isotope tracing suggests ß-catenin-driven suppression of phosphatidylcholine metabolism in hepatocellular carcinoma.

Activating mutations in the CTNNB1 gene encoding ß-catenin are among the most frequently observed oncogenic alterations in hepatocellular carcinoma (HCC). Profound alterations in lipid metabolism, including increases in fatty acid oxidation and transformation of the phospholipidome, occur in HCC with CTNNB1 mutations, but it is unclear what mechanisms give rise to these changes. We employed untargeted lipidomics and targeted isotope tracing to measure phospholipid synthesis activity in an inducible human liver cell line expressing mutant ß-catenin, as well as in transgenic zebrafish with activated ß-catenin-driven HCC. In both models, activated ß-catenin expression was associated with large changes in the lipidome including conserved increases in acylcarnitines and ceramides and decreases in triglycerides. Lipid isotope tracing analysis in human cells revealed a reduction in phosphatidylcholine (PC) production rates as assayed by choline incorporation. We developed lipid isotope tracing analysis for zebrafish tumors and observed reductions in phosphatidylcholine synthesis by both the CDP-choline and PEMT pathways. The observed changes in the ß-catenin-driven HCC phospholipidome suggest that zebrafish can recapitulate conserved features of HCC lipid metabolism and may serve as a model for identifying future HCC-specific lipid metabolic targets.

Heart-to-heart: infant heart rate at 3 months is linked to infant-directed speech, mother-infant interaction, and later language outcomes.

Introduction: Previous studies underscore the importance of speech input, particularly infant-directed speech (IDS) during one-on-one (1:1) parent-infant interaction, for child language development. We hypothesize that infants' attention to speech input, specifically IDS, supports language acquisition. In infants, attention and orienting responses are associated with heart rate deceleration. We examined whether individual differences in infants' heart rate measured during 1:1 mother-infant interaction is related to speech input and later language development scores in a longitudinal study. Methods: Using a sample of 31 3-month-olds, we assessed infant heart rate during mother-infant face-to-face interaction in a laboratory setting. Multiple measures of speech input were gathered at 3 months of age during naturally occurring interactions at home using the Language ENvironment Analysis (LENA) system. Language outcome measures were assessed in the same children at 30 months of age using the MacArthur-Bates Communicative Development Inventory (CDI). Results: Two novel findings emerged. First, we found that higher maternal IDS in a 1:1 context at home, as well as more mother-infant conversational turns at home, are associated with a lower heart rate measured during mother-infant social interaction in the laboratory. Second, we found significant associations between infant heart rate during mother-infant interaction in the laboratory at 3 months and prospective language development (CDI scores) at 30 months of age. Discussion: Considering the current results in conjunction with other converging theoretical and neuroscientific data, we argue that high IDS input in the context of 1:1 social interaction increases infants' attention to speech and that infants' attention to speech in early development fosters their prospective language growth.

Exploring Gut Microbiota Alterations with Trimethoprim-Sulfamethoxazole and Dexamethasone in a Humanized Microbiome Mouse Model.

Along with the standard therapies for glioblastoma, patients are commonly prescribed trimethoprim-sulfamethoxazole (TMP-SMX) and dexamethasone for preventing infections and reducing cerebral edema, respectively. Because the gut microbiota impacts the efficacy of cancer therapies, it is important to understand how these medications impact the gut microbiota of patients. Using mice that have been colonized with human microbiota, this study sought to examine how TMP-SMX and dexamethasone affect the gut microbiome. Two lines of humanized microbiota (HuM) Rag1-/- mice, HuM1Rag and HuM2Rag, were treated with either TMP-SMX or dexamethasone via oral gavage once a day for a week. Fecal samples were collected pre-treatment (pre-txt), one week after treatment initiation (1 wk post txt), and three weeks post-treatment (3 wk post txt), and bacterial DNA was analyzed using 16S rRNA-sequencing. The HuM1Rag mice treated with TMP-SMX had significant shifts in alpha diversity, beta diversity, and functional pathways at all time points, whereas in the HuM2Rag mice, it resulted in minimal changes in the microbiome. Likewise, dexamethasone treatment resulted in significant changes in the microbiome of the HuM1Rag mice, whereas the microbiome of the HuM2Rag mice was mostly unaffected. The results of our study show that routine medications used during glioblastoma treatment can perturb gut microbiota, with some microbiome compositions being more sensitive than others, and these treatments could potentially affect the overall efficacy of standard-of-care therapy.

Mercury and selenium distribution in human brain tissue using synchrotron micro-X-ray fluorescence.

Mercury is a well-recognized environmental contaminant and neurotoxin, having been associated with a number of deleterious neurological conditions including neurodegenerative diseases, such as Alzheimer's disease. To investigate how mercury and other metals behave in the brain, we used synchrotron micro-X-ray fluorescence to map the distribution pattern and quantify concentrations of metals in human brain. Brain tissue was provided by the Rush Alzheimer's Disease Center and samples originated from individuals diagnosed with Alzheimer's disease and without cognitive impairment. Data were collected at the 2-ID-E beamline at the Advanced Photon Source at Argonne National Laboratory with an incident beam energy of 13 keV. Course scans were performed at low resolution to determine gross tissue features, after which smaller regions were selected to image at higher resolution. The findings revealed (1) the existence of mercury particles in the brain samples of two subjects; (2) co-localization and linear correlation of mercury and selenium in all particles; (3) co-localization of these particles with zinc structures; and (4) association with sulfur in some of these particles. These results suggest that selenium and sulfur may play protective roles against mercury in the brain, potentially binding with the metal to reduce the induced toxicity, although at different affinities. Our findings call for further studies to investigate the relationship between mercury, selenium, and sulfur, as well as the potential implications in Alzheimer's disease and related dementias.

Mother-infant social and language interactions at 3 months are associated with infants' productive language development in the third year of life.

Previous studies underscore the importance of social interactions for child language development-particularly interactions characterized by maternal sensitivity, infant-directed speech (IDS), and conversational turn-taking (CT) in one-on-one contexts. Although infants engage in such interactions from the third month after birth, the prospective link between speech input and maternal sensitivity in the first half year of life and later language development has been understudied. We hypothesized that social interactions embodying maternal sensitivity, IDS and CTs in the first 3 months of life, are significantly associated with later language development and tested this using a longitudinal design. Using a sample of 40 3-month-old infants, we assessed maternal sensitivity during a structured mother-infant one-on-one (1:1) interaction based on a well-validated scoring system (the Coding Interactive Behavior system). Language input (IDS, CT) was assessed during naturally occurring interactions at home using the Language ENvironment Analysis (LENA) system. Language outcome measures were obtained from 18 to 30 months of age using the MacArthur-Bates Communicative Development Inventory. Three novel findings emerged. First, maternal sensitivity at 3 months was significantly associated with infants' productive language scores at 18, 21, 24, 27, and 30 months of age. Second, LENA-recorded IDS during mother-infant 1:1 interaction in the home environment at 3 months of age was positively correlated with productive language scores at 24, 27, and 30 months of age. Third, mother-infant CTs during 1:1 interaction was significantly associated with infants' productive language scores at 27 and 30 months of age. We propose that infants' social attention to speech during this early period-enhanced by sensitive maternal one-on-one interactions and IDS-are potent factors in advancing language development.

Does everyday discrimination account for the increased risk of vasomotor symptoms in Black women?: the Study of Women's Health Across the Nation (SWAN).

OBJECTIVES: Vasomotor symptoms (VMS), including hot flashes and night sweats, are hallmark symptoms of the menopause transition. Previous research has documented greater frequency, duration, and severity of VMS in Black women compared with women from other racial/ethnic groups, even after accounting for other factors. This analysis examined the association between discrimination and VMS and the extent to which discrimination accounts for the disproportionate burden of VMS in Black women. METHODS: Using available discrimination and VMS data from the SWAN cohort study (n = 2,377, 48% White, 32% Black, 6% Japanese, 4% Chinese, and 9% Hispanic women) followed approximately yearly in midlife from premenopause (42-52 y) through postmenopause (~20 y), we assessed concurrent associations between discrimination and VMS frequency in the past 2 weeks using weighted generalized mixed models. We also assessed associations between chronic discrimination across first four visits and VMS trajectories from premenopause to postmenopause using weighted multinomial logistic regression. Models were adjusted for known risk factors for VMS. RESULTS: Higher levels of discrimination were associated with concurrent reporting of any (odds ratio [OR], 1.57 [1.31-1.89]) and frequent (≥6 d) VMS (OR, 1.55 [1.21-1.99]). After adjustment, associations remained significant for any (OR, 1.30 [1.09-1.54]) but not frequent VMS. For any VMS trajectories, chronic discrimination was associated with "continuously high" (OR, 1.69 [1.03-2.77]) and "high pre-FMP-decline post-FMP" (OR, 1.70 [1.01-2.88]) versus "FMP-onset low" trajectories. After adjusting for discrimination, odds of reporting any, frequent, and of being in the "continuously high" any VMS trajectory remained elevated for Black versus White women. CONCLUSIONS: Discrimination is associated with greater concurrent risk of any (but not frequent) VMS, and chronic discrimination is associated with a continuously high reporting of any VMS over time, independent of known risk factors. Adjusting for discrimination attenuates but does not eliminate the increased risk of VMS for Black women.

External validation of the SI2NCAL2C score for outcomes following cerebral venous thrombosis.

OBJECTIVES: Prognostication for cerebral venous thrombosis (CVT) remains difficult. We sought to validate the SI2NCAL2C score in an international cohort. MATERIALS AND METHODS: The SI2NCAL2C score was originally developed to predict poor outcome (modified Rankin Scale (mRS) 3-6) at 6 months, and mortality at 30 days and 1 year using data from the International CVT Consortium. The SI2NCAL2C score uses 9 variables: the absence of any female-sex-specific risk factors, intracerebral hemorrhage, central nervous system infection, focal neurological deficits, coma, age, lower level of hemoglobin, higher level of glucose, and cancer. The ACTION-CVT study was an international retrospective study that enrolled consecutive patients across 27 centers. The poor outcome score was validated using 90-day mRS due to lack of follow-up at the 6-month time-point in the ACTION-CVT cohort. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC) and calibration plots. Missing data were imputed using the additive regression and predictive mean matching methods. Bootstrapping was performed with 1000 iterations. RESULTS: Mortality data were available for 950 patients and poor outcome data were available for 587 of 1,025 patients enrolled in ACTION-CVT. Compared to the International CVT Consortium, the ACTION-CVT cohort was older, less often female, and with milder clinical presentation. Mortality was 2.5% by 30 days and 6.0% by one year. At 90-days, 16.7% had a poor outcome. The SI2NCAL2C score had an AUC of 0.74 [95% CI 0.69-0.79] for 90-day poor outcome, 0.72 [0.60-0.82] for mortality by 30 days, and 0.82 [0.76-0.88] for mortality by one year. CONCLUSIONS: The SI2NCAL2C score had acceptable to good performance in an international external validation cohort. The SI2NCAL2C score warrants additional validation studies in diverse populations and clinical implementation studies.

Occupational therapy students' perceptions of their experience in a role-emerging Level II fieldwork within higher education student services.

BACKGROUND: Role-emerging settings - those where occupational therapy (OT) services have not traditionally been provided - are common sites for practice placements of entry-level occupational therapy students. A growing body of literature has attempted to determine the value and drawbacks of such practice placements on the professional preparedness of OT students with mixed findings. Benefits have been identified, including increased cultural understanding, advocacy, creativity, initiative, and problem-solving skills. However, OT students have been reported to perceive such placement as limiting their professional growth and preparedness to practice compared to traditional placements. METHODS: A phenomenological study was conducted seeking the perceptions of OT students (n = 14) about their clinical placement at a role-emerging site. Recorded semi-structured interviews were conducted by trained interviewers within two weeks of the end of clinical placement. The recordings were transcribed verbatim and then coded using an iterative multi-coder inductive approach. Inter-coder agreement, reflectivity, and audit trail were maintained. RESULTS: Three themes emerged from the analysis: (1) integrating independence and support, (2) becoming occupational therapists, and (3) filling a gap. These themes reflect students' positive perceptions of their role-emerging clinical placement. They felt that this placement allowed them to develop self-confidence and professional identity as occupational therapists and learn new skills while simultaneously filling a gap in services for clients. Most importantly, they felt that this placement prepared them for their future OT practice. CONCLUSION: This finding and their resounding support of the experience suggest that OT students can perceive role-emerging placement as a solid foundation for clinical practice. Factors, included in this placement, that may have contributed to their experience include the level of support provided, time available for learning including space to make mistakes, and freedom from productivity and payor requirements.

Effects of age and sex on photoperiod modulation of nucleus accumbens monoamine content and release in adolescence and adulthood.

Day length, or photoperiod, is a reliable environmental cue encoded by the brain's circadian clock that indicates changing seasons and induces seasonal biological processes. In humans, photoperiod, age, and sex have been linked to seasonality in neuropsychiatric disorders, as seen in Seasonal Affective Disorder, Major Depressive Disorder, and Bipolar Disorder. The nucleus accumbens is a key locus for the regulation of motivated behaviors and neuropsychiatric disorders. Using periadolescent and young adult male and female mice, here we assessed photoperiod's effect on serotonin and dopamine tissue content in the nucleus accumbens core, as well as on accumbal synaptic dopamine release and uptake. We found greater serotonin and dopamine tissue content in the nucleus accumbens from young adult mice raised in a Short winter-like photoperiod. In addition, dopamine release and clearance were greater in the nucleus accumbens from young adult mice raised in a Long summer-like photoperiod. Importantly, we found that photoperiod's effects on accumbal dopamine tissue content and release were sex-specific to young adult females. These findings support that in mice there are interactions across age, sex, and photoperiod that impact critical monoamine neuromodulators in the nucleus accumbens which may provide mechanistic insight into the age and sex dependencies in seasonality of neuropsychiatric disorders in humans.

Pan-Enterovirus Characterization Reveals Cryptic Circulation of Clinically Relevant Subtypes in Arizona Wastewater.

Background: Most seasonally circulating enteroviruses result in asymptomatic or mildly symptomatic infections. In rare cases, however, infection with some subtypes can result in paralysis or death. Of the 300 subtypes known, only poliovirus is reportable, limiting our understanding of the distribution of other enteroviruses that can cause clinical disease. Objective: The overarching objectives of this study were to: 1) describe the distribution of enteroviruses in Arizona during the late summer and fall of 2022, the time of year when they are thought to be most abundant, and 2) demonstrate the utility of viral pan-assay approaches for semi-agnostic discovery that can be followed up by more targeted assays and phylogenomics. Methods: This study utilizes pooled nasal samples collected from school-aged children and long-term care facility residents, and wastewater from multiple locations in Arizona during July-October of 2022. We used PCR to amplify and sequence a region common to all enteroviruses, followed by species-level bioinformatic characterization using the QIIME 2 platform. For Enterovirus-D68 (EV-D68), detection was carried out using RT-qPCR, followed by confirmation using near-complete whole EV-D68 genome sequencing using a newly designed tiled amplicon approach. Results: In the late summer and early fall of 2022, multiple enterovirus species were identified in Arizona wastewater, with Coxsackievirus A6, EV-D68, and Coxsackievirus A19 composing 86% of the characterized reads sequenced. While EV-D68 was not identified in pooled human nasal samples, and the only reported acute flaccid myelitis case in Arizona did not test positive for the virus, an in-depth analysis of EV-D68 in wastewater revealed that the virus was circulating from August through mid-October. A phylogenetic analysis on this relatively limited dataset revealed just a few importations into the state, with a single clade indicating local circulation. Significance: This study further supports the utility of wastewater-based epidemiology to identify potential public health threats. Our further investigations into EV-D68 shows how these data might help inform healthcare diagnoses for children presenting with concerning neurological symptoms.

The COVID-19 pandemic's effects on mental and psychosocial health in the Philippines: A scoping review.

Low- and middle-income countries (LMICs) remained at elevated risk for the effects of the COVID-19 pandemic because of persistent stressors to their health systems. Simultaneously facing high infection rates, strict containment measures and natural disasters, the Philippines provides important grounds for health research in LMICs. This review examined how the COVID-19 pandemic affected mental and psychosocial health in the Philippines. This scoping review included literature in English from 2020 to mid-2022 from PubMed, PsycInfo and SCOPUS, and used the PRISMA-ScR and PCC-question model. Two independent reviewers conducted blind article screening and data extraction using COVIDENCE software, followed by consensus building, data charting and analyses. This work identified 405 publications across PubMed (N = 56), PsycInfo (N = 106) and SCOPUS (N = 243), of which 76 articles addressed the Philippines. Article types included 54 research articles, 10 opinion pieces, 4 literature reviews, 6 letters to journals, 1 study protocol and 1 other report. These findings focused primarily on health professionals (N = 23) and educators/learners (N = 22) and reported mostly on moderate-to-severe clinical outcomes such as fear, depression, anxiety or stress. Coping behaviors, like resiliency and other ways of adapting to the pandemic, including religious, spiritual and community-oriented approaches highlighted experiences with stringent infection prevention and control measures to contain COVID-19 in the Philippines. The COVID-19 pandemic brought severe challenges to mental and psychosocial health in the Philippines. The literature focused mostly on healthcare workers and educators/learners, and moderate-to-severe mental health outcomes in these groups. There is a need to expand studies to other sociodemographic groups and communities across the Philippines. Future work stands to benefit from more in-depth qualitative, mixed methods, longitudinal and representative quantitative research in LMICs following this pandemic. Literature reviews remain important to synthesize post-pandemic experiences by providing context for future studies and health practice in the Philippines and other LMICs.

Infants' brain responses to social interaction predict future language growth.

In face-to-face interactions with infants, human adults exhibit a species-specific communicative signal. Adults present a distinctive "social ensemble": they use infant-directed speech (parentese), respond contingently to infants' actions and vocalizations, and react positively through mutual eye-gaze and smiling. Studies suggest that this social ensemble is essential for initial language learning. Our hypothesis is that the social ensemble attracts attentional systems to speech and that sensorimotor systems prepare infants to respond vocally, both of which advance language learning. Using infant magnetoencephalography (MEG), we measure 5-month-old infants' neural responses during live verbal face-to-face (F2F) interaction with an adult (social condition) and during a control (nonsocial condition) in which the adult turns away from the infant to speak to another person. Using a longitudinal design, we tested whether infants' brain responses to these conditions at 5 months of age predicted their language growth at five future time points. Brain areas involved in attention (right hemisphere inferior frontal, right hemisphere superior temporal, and right hemisphere inferior parietal) show significantly higher theta activity in the social versus nonsocial condition. Critical to theory, we found that infants' neural activity in response to F2F interaction in attentional and sensorimotor regions significantly predicted future language development into the third year of life, more than 2 years after the initial measurements. We develop a view of early language acquisition that underscores the centrality of the social ensemble, and we offer new insight into the neurobiological components that link infants' language learning to their early brain functioning during social interaction.