APC is an RNA-binding protein, and its interactome provides a link to neural development and microtubule assembly.

Adenomatous polyposis coli (APC) is a microtubule plus-end scaffolding protein important in biology and disease. APC is implicated in RNA localization, although the mechanisms and functional significance remain unclear. We show APC is an RNA-binding protein and identify an RNA interactome by HITS-CLIP. Targets were highly enriched for APC-related functions, including microtubule organization, cell motility, cancer, and neurologic disease. Among the targets is ß2B-tubulin, known to be required in human neuron and axon migration. We show ß2B-tubulin is synthesized in axons and localizes preferentially to dynamic microtubules in the growth cone periphery. APC binds the ß2B-tubulin 3' UTR; experiments interfering with this interaction reduced ß2B-tubulin mRNA axonal localization and expression, depleted dynamic microtubules and the growth cone periphery, and impaired neuron migration. These results identify APC as a platform binding functionally related protein and RNA networks, and suggest a self-organizing model for the microtubule to localize synthesis of its own subunits.

IFN-γ and androgens disrupt mitochondrial function in murine myocytes.

The effect of cytokines on non-traditional immunological targets under conditions of chronic inflammation is an ongoing subject of study. Fatigue is a symptom often associated with autoimmune diseases. Chronic inflammatory response and activated cell-mediated immunity are associated with cardiovascular myopathies which can be driven by muscle weakness and fatigue. Thus, we hypothesize that immune dysfunction-driven changes in myocyte mitochondria may play a critical role in fatigue-related pathogenesis. We show that persistent low-level expression of IFN-γ in designated IFN-γ AU-Rich Element deletion mice (ARE mice) under androgen exposure resulted in mitochondrial and metabolic deficiencies in myocytes from male or castrated ARE mice. Most notably, echocardiography unveiled that low ejection fraction in the left ventricle post-stress correlated with mitochondrial deficiencies, explaining how heart function decreases under stress. We report that inefficiencies and structural changes in mitochondria, with changes to expression of mitochondrial genes, are linked to male-biased fatigue and acute cardiomyopathy under stress. Our work highlights how male androgen hormone backgrounds and active autoimmunity reduce mitochondrial function and the ability to cope with stress and how pharmacological blockade of stress signal protects heart function. These studies provide new insight into the diverse actions of IFN-γ in fatigue, energy metabolism, and autoimmunity. © 2023 The Pathological Society of Great Britain and Ireland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Ethical dilemmas in conducting qualitative, public health research on social media: using a study on Facebook as a case.

AIM: Platforms on social media are increasingly used for public health research. While social media provides an exceptional opportunity to explore communication about public health topics, this practice is not without ethical dilemmas. Our aim was to identify and unfold some of these dilemmas and to suggest possible solutions and ways forward for future research. METHODS: Using our own research within a closed forum for people experiencing suicidal thoughts as a case, we explored certain dilemmas and possible answers relating to whether what is to be researched falls under a public or private social media domain; we investigated avenues for obtaining access to participants in an evolving online environment; how to secure informed consent from participants; and ways of ensuring anonymity. RESULTS: We provide recommendations and reflections that we hope will offer inspiration for researchers embarking on similar social media public health research within and beyond suicide research. CONCLUSIONS: The ethical framework commonly referred to in health research, based on confidentiality, anonymity, informed consent and doing no harm must be adjusted to be relevant for a social media context where technologies and regulations are constantly being altered.

Risk of stillbirth and preterm birth among undocumented pregnant migrant women in Denmark: A retrospective case-control study.

AIMS: To examine the associations between undocumented pregnant migrant women and the risk of experiencing stillbirth or preterm birth. METHODS: A retrospective case-control study based on nationwide registers from Statistics Denmark and hospital journals from the seven largest hospital wards in Denmark from 1 January 2011 to 31 December 2018. A total of 882 undocumented pregnant migrant women and 3528 matched controls (both documented migrant and non-migrant women) were included. Logistic regression models were used to estimate the risk of undocumented pregnant migrant women experiencing (a) stillbirth and (b) preterm birth compared with the control group. RESULTS: Of the undocumented pregnant migrant women, 33.3% were EU citizens, 16.2% were applicants for residence and 50.5% had an unknown basis for residence. The mean age of the undocumented pregnant migrant women was 28.4 years, whereas the mean age of women in the control group was 30.9 years. Higher adjusted odds of experiencing stillbirth (aOR 3.50; 95% CI 1.31-9.38) and preterm birth (aOR 1.41; 95% CI 1.04-1.93) were observed among the undocumented pregnant migrant women compared with the control group. The basis of residence was not associated with higher odds of experiencing stillbirth or preterm birth. CONCLUSIONS: We found a higher risk of stillbirth and preterm birth among the undocumented pregnant migrant women than in the control group. Our findings suggest a need to increase the focus on providing access to antenatal care among those women currently excluded from this care.

Automatic Detection of Cognitive Impairment with Virtual Reality.

Cognitive impairment features in neuropsychiatric conditions and when undiagnosed can have a severe impact on the affected individual's safety and ability to perform daily tasks. Virtual Reality (VR) systems are increasingly being explored for the recognition, diagnosis and treatment of cognitive impairment. In this paper, we describe novel VR-derived measures of cognitive performance and show their correspondence with clinically-validated cognitive performance measures. We use an immersive VR environment called VStore where participants complete a simulated supermarket shopping task. People with psychosis (k=26) and non-patient controls (k=128) participated in the study, spanning ages 20-79 years. The individuals were split into two cohorts, a homogeneous non-patient cohort (k=99 non-patient participants) and a heterogeneous cohort (k=26 patients, k=29 non-patient participants). Participants' spatio-temporal behaviour in VStore is used to extract four features, namely, route optimality score, proportional distance score, execution error score, and hesitation score using the Traveling Salesman Problem and explore-exploit decision mathematics. These extracted features are mapped to seven validated cognitive performance scores, via linear regression models. The most statistically important feature is found to be the hesitation score. When combined with the remaining extracted features, the multiple linear regression model resulted in statistically significant results with R2 = 0.369, F-Stat = 7.158, p(F-Stat) = 0.000128.

The temporal dynamics of sleep disturbance and psychopathology in psychosis: a digital sampling study.

BACKGROUND: Sleep disruption is a common precursor to deterioration and relapse in people living with psychotic disorders. Understanding the temporal relationship between sleep and psychopathology is important for identifying and developing interventions which target key variables that contribute to relapse. METHODS: We used a purpose-built digital platform to sample self-reported sleep and psychopathology variables over 1 year, in 36 individuals with schizophrenia. Once-daily measures of sleep duration and sleep quality, and fluctuations in psychopathology (positive and negative affect, cognition and psychotic symptoms) were captured. We examined the temporal relationship between these variables using the Differential Time-Varying Effect (DTVEM) hybrid exploratory-confirmatory model. RESULTS: Poorer sleep quality and shorter sleep duration maximally predicted deterioration in psychosis symptoms over the subsequent 1-8 and 1-12 days, respectively. These relationships were also mediated by negative affect and cognitive symptoms. Psychopathology variables also predicted sleep quality, but not sleep duration, and the effect sizes were smaller and of shorter lag duration. CONCLUSIONS: Reduced sleep duration and poorer sleep quality anticipate the exacerbation of psychotic symptoms by approximately 1-2 weeks, and negative affect and cognitive symptoms mediate this relationship. We also observed a reciprocal relationship that was of shorter duration and smaller magnitude. Sleep disturbance may play a causal role in symptom exacerbation and relapse, and represents an important and tractable target for intervention. It warrants greater attention as an early warning sign of deterioration, and low-burden, user-friendly digital tools may play a role in its early detection.

Randomized pilot trial of praise text messages to improve medication adherence among adolescents and young adults with liver transplants.

BACKGROUND: AYA who have undergone liver transplantations often struggle to adhere to their post-transplant immunosuppressant medications, which can lead to serious health complications. The objective of this pilot study is to examine the acceptability and feasibility of a brief mobile health (mHealth) intervention and its impact on medication adherence among AYA liver transplant recipients. METHODS: Thirty-five AYAs (13-21 years old) were randomized to either (1) receive praise text messages whenever laboratory results indicated immunosuppressant medications within the expected range or (2) usual care. Motivation for adherence and adherence were assessed via self-report, and a MLVI was calculated based on values abstracted from the electronic health record. RESULTS: Multilevel, multivariate models showed significant associations between group assignment and some self-reported motivation and adherence outcomes but not MLVI. Specifically, AYA receiving the praise text messages were significantly more likely to report taking their prescribed doses (OR = 2.49, p = .03), taking their medicine according to the directions (OR = 2.39, p = .04), and being highly confident in taking their medication (OR = 2.46, p = .04), compared with the usual services group. Qualitative responses indicated praise texts were mostly helpful but could be improved. CONCLUSIONS: The results suggest texting patients about positive health indicators was acceptable and, with refinement, might promote AYA illness self-management.

Preoperative Liver Stiffness is Associated With Hospital Length of Stay After Cardiac Surgery.

OBJECTIVES: Risk assessment models for cardiac surgery do not account for the degrees of liver dysfunction. Ultrasound shear-wave elastography measures liver stiffness (LSM), a quantitative measurement related to fibrosis, congestion, and inflammation. The authors hypothesized that preoperative liver stiffness would be associated with hospital length of stay after cardiac surgery. DESIGN: Prospective observational study. SETTING: University hospital, single center. PARTICIPANTS: One hundred five adult patients undergoing nonemergent cardiac surgery. INTERVENTIONS: Preoperative liver stiffness measured by ultrasound elastography. MEASUREMENTS AND MAIN RESULTS: The associations were analyzed using linear mixed models, with adjustments for preoperative variables, duration of cardiopulmonary bypass, and type of surgery. Median liver stiffness was 6.4 kPa (range, 4.1-18.6 kPa). The median length of hospital stay was 6 days (range, 3-18 d). Each unit increase in liver stiffness, treated as a continuous variable, was associated with an increase of 0.32 ± 0.10 days in the hospital (p = 0.002). When treated as a categorical variable (<6 kPa, 6-9.4 kPa, and ≥9.5 kPa), LSM ≥9.5 kPa v LSM <6 kPa was associated strongly with an increase in hospital length of stay of 3.25 ± 0.87 days (p = 0.0003). CONCLUSIONS: A preoperative LSM ≥9.5 kPa was associated with a significantly longer postoperative hospital length of stay. This association appeared independent of preoperative comorbidities commonly associated with coronary disease. Preoperative liver stiffness is a novel risk metric that is associated with the postoperative hospital length of stay after cardiac surgery.

Creating "Plates" to Evaluate Canadians' Dietary Intake in Relation to the 2019 Canada's Food Guide.

PURPOSE: Explore Canadians' dietary intake in relation to the 2019 Canada's Food Guide (CFG) Plate using novel volume-based food analyses, by age and meal occasion. METHODS: Foods reported in 24-hour recalls by 20,456 Canadians in the 2015 Canadian Community Health Survey - Nutrition were classified as: Vegetables and Fruits, Whole Grain Foods, Protein Foods, Non-Whole Grain Foods or Other Foods (high in fat, sugar, sodium). Food volumes were used to calculate percent contributions of each grouping to total intake, stratified by age (1-6; 7-12; 13-17; 18-64; 65+years) and meal (breakfast, lunch, supper, snack), applying sample survey weights and bootstrapping. RESULTS: By volume, the Canadian population diet included: 29% Vegetables and Fruits, 22% Protein Foods, 7% Whole Grains, 24% Non-Whole Grain Foods, and 18% Other Foods. Intakes of Protein Foods (1-6 years) and Other Foods (7-12; 13-17 years) were higher in children than adults by volume, relative to total intake. Whole Grains intake was highest at breakfast. Other Foods intake was highest at snack. CONCLUSIONS: The volume-based population diet of Canadians reported on a single day includes a substantial proportion of non-recommended foods. There are opportunities to design interventions that target specific foods, ages, and meals to align intake with recommendations.

Five-Year Breast Surgeon Experience in LYMPHA at Time of ALND for Treatment of Clinical T1-4N1-3M0 Breast Cancer.

BACKGROUND: Breast cancer-related lymphedema (BCRL) is a source of postoperative morbidity for breast cancer survivors. Lymphatic microsurgical preventive healing approach (LYMPHA) is a technique used to prevent BCRL at the time of axillary lymph node dissection (ALND). We report the 5-year experience of a breast surgeon trained in LYMPHA and investigate the outcomes of patients who underwent LYMPHA following ALND for treatment of cT1-4N1-3M0 breast cancer. METHODS: A retrospective review of patients with cT1-4N1-3M0 breast cancer was performed in patients who underwent ALND with and without LYMPHA. Diagnosis of BCRL was made by certified lymphedema therapists. Descriptive statistics and lymphedema surveillance data were analyzed using results of Fisher's exact or Wilcoxon rank-sum tests. Logistic regression and propensity matching were performed to assess the reduction of BCRL occurrence following LYMPHA. RESULTS: In a 5-year period, 132 patients met inclusion criteria with 76 patients undergoing LYMPHA at the time of ALND and 56 patients undergoing ALND alone. Patients who underwent LYMPHA at the time of ALND were significantly less likely to develop BCRL than those who underwent ALND alone (p = 0.045). Risk factors associated with BCRL development were increased patient age (p = 0.007), body mass index (BMI) (p = 0.003), and, in patients undergoing LYMPHA, number of positive nodes (p = 0.026). CONCLUSIONS: LYMPHA may be successfully employed by breast surgeons trained in lymphatic-venous anastomosis at the time of ALND. While research efforts should continue to focus on prevention and surveillance of BCRL, LYMPHA remains an option to reduce BCRL and improve patient quality of life.

Does resilience moderate the effect of intimate partner violence on signs of depression among Tanzanian pregnant women: A cross-sectional study.

INTRODUCTION: Exposure to intimate partner violence (IPV) has been found to be associated with a multitude of poor health and quality of life outcomes. Among the risks exacerbated by IPV is prenatal depression. Resilience is hypothesized to protect against psychopathology after exposure to a traumatic influence. The present study aims to investigate resilience as a moderator of the effect of exposure to IPV on prenatal depression among pregnant women in Moshi, Tanzania. MATERIAL AND METHODS: In this cross-sectional study, nested within a larger longitudinal study, pregnant women receiving antenatal care were interviewed about exposure to IPV, signs of depression using the Edinburgh Postpartum Depression Scale, and resilience using the abbreviated Connor-Davidson Resilience Scale. Logistic regression was used to test the effect of the interaction term of resilience and exposure to IPV during pregnancy on the risk of high level of signs of depression. RESULTS: In total, 1013 women completed all interviews, 300 women reported exposure to IPV, and 113 had high levels of signs of depression. Mean resilience score was 14.26 (SD 9.45). Exposure to IPV was correlated with signs of depression (adjusted odds ratio 6.49, 95% CI 3.75-11.24). Resilience was not correlated with signs of depression, nor was the interaction term of resilience and exposure to IPV. CONCLUSIONS: The study did not find that resilience acted as a moderator of the effect of exposure to IPV during pregnancy on the risk of prenatal depression. The cross-sectional design of the study may not be well suited to investigate resilience, which could take time to manifest. The abbreviated Connor-Davidson Resilience Scale has not been validated in a Tanzanian setting, or in the Swahili version. Practitioners should take note that all women and families affected by IPV should be afforded relevant assistance from social services, law enforcement, healthcare practitioners, and other relevant services, regardless of their apparent level of resilience.

Intimate partner violence during pregnancy in Vietnam: role of husbands.

Intimate partner violence (IPV) perpetrators are often husbands. Understanding factors pertaining to women's male partners is essential for programming interventions against IPV. The objective of the study was to describe husband-related social and behavioural risk factors and assess how they are associated with IPV during pregnancy. Cross-sectional data were collected among 1309 pregnant women with husbands in Dong Anh district, Vietnam. Information on sociodemographic characteristics of husbands, the husband's behaviour and the husband's involvement in pregnancy care was indirectly collected via women's report at first antenatal care visit. Data on exposure to intimate partner violence during pregnancy were collected when the women returned for antenatal care in 30-34 gestational weeks. Logistic regression analyses were used to measure the relationships between IPV during pregnancy and risk factors from the husband. Pregnant women who had husbands who were younger or blue-collar worker/farmer/unemployed had more likelihood to be exposed to IPV. Women with husbands who drank alcohol before sexual intercourse and gambled were more likely to be exposed to IPV repeated times. Those with husbands who had intentions of having a child had over three times increased OR to be exposed to IPV once (AOR = 3.2, 95% CI 1.1-9.7). If the husband had a preference for sons, the woman had 1.5 times increased OR (AOR = 1.5; 95% CI 1.1-1.9) to be exposed to IPV repeated times during pregnancy. This study highlights significant associations between IPV and maternal perceptions of husbands' behaviours and involvement in pregnancy. Findings may help to identify at-risk pregnant women to IPV and guide the development of targeted interventions to prevent IPV from husbands.

Correction to: Skating on thin ice: pragmatic prescribing for medication refractory schizophrenia.

After publication of the original article [1], the authors have notified us that there was an oversight on acknowledging funding received for the study. They would like to mention that Professor Sukhi Shergill was funded by an ERC Consolidator Award.

An in vivo evaluation of the ontogeny of stereoselective fluoxetine metabolism and disposition in lambs from birth to one year of age.

1. The objective was to determine the ontogeny of stereoselective fluoxetine (FX) disposition in postnatal sheep from newborn to adulthood. 2. Catheters were implanted in a carotid artery and jugular vein. FX was administered intravenously, followed by serial arterial blood and cumulative urine collection. The concentrations of R,S-FX and R,S-norfluoxetine (R,S-NFX) in samples were measured using a validated enantioselective LC/MS/MS analytical method. 3. The metabolism of FX at 4.2 ± 0.4 days was limited compared to adults, but had developed compared to the fetus. Total body clearance (ClTB) did not significantly increase up to 33.6 ± 0.9 days, but significantly increased at 98.5 ± 2.0 days, with no further changes up to 397.3 ± 8.5 days. Up to 13.4 ± 0.8 days, the disposition of FX included Phase I metabolism to NFX and trifluoromethylphenol (TFMP), and renal elimination. At 32.9 ± 0.9 days, metabolism included Phase II conjugates of FX and NFX. Renal elimination of these compounds was low. 4. The elimination of FX increased in a non-linear manner during the first year in sheep. The metabolism and disposition of FX and NFX in plasma and urine were stereoselective and this appeared due to both stereoselective protein binding and metabolism.

Total sitting time, leisure time physical activity and risk of hospitalization due to low back pain: The Danish Health Examination Survey cohort 2007-2008.

AIMS: This study aimed to test the hypotheses that a high total sitting time and vigorous physical activity in leisure time increase the risk of low back pain and herniated lumbar disc disease. METHODS: A total of 76,438 adults answered questions regarding their total sitting time and physical activity during leisure time in the Danish Health Examination Survey 2007-2008. Information on low back pain diagnoses up to 10 September 2015 was obtained from The National Patient Register. The mean follow-up time was 7.4 years. Data were analysed using Cox regression analysis with adjustment for potential confounders. Multiple imputations were performed for missing values. RESULTS: During the follow-up period, 1796 individuals were diagnosed with low back pain, of whom 479 were diagnosed with herniated lumbar disc disease. Total sitting time was not associated with low back pain or herniated lumbar disc disease. However, moderate or vigorous physical activity, as compared to light physical activity, was associated with increased risk of low back pain (HR = 1.16, 95% CI: 1.03-1.30 and HR = 1.45, 95% CI: 1.15-1.83). Moderate, but not vigorous physical activity was associated with increased risk of herniated lumbar disc disease. CONCLUSIONS: The results suggest that total sitting time is not associated with low back pain, but moderate and vigorous physical activity is associated with increased risk of low back pain compared with light physical activity.

Probing Excitons, Trions, and Dark Excitons in Monolayer WS2 Using Resonance Raman Spectroscopy.

We present temperature-dependent resonance Raman measurements on monolayer WS2 for the temperature range 4-295 K using excitation photon energies from 1.9 to 2.15 eV in ∼7 meV steps. These are analyzed to determine the resonance profiles of five previously assigned phonon based Raman peaks (A1', E', 2ZA, LA, 2LA) and a previously unassigned peak at 485 cm-1 whose possible attributions are discussed. The resonance profiles obtained are fitted to a perturbation theory derived model and it is shown that both excitons and trions are required to explain the profiles. The model is used to separate the contribution of exciton-exciton, trion-trion, and exciton-trion scattering to each of the Raman peaks at 4 K. This separation allows the ratios of the rates of scattering involving the A1' and E' phonons for each of the three types of scattering to be determined. The explanation of the multiphonon Raman peaks requires the coupling of bright excitons and trions to large wavevector dark states. The fitting of the resonance Raman profiles for these Raman peaks demonstrates scattering of bright excitons to bright trions via these large wavevector dark states.

Uncertainty and anticipation in anxiety: an integrated neurobiological and psychological perspective.

Uncertainty about a possible future threat disrupts our ability to avoid it or to mitigate its negative impact and thus results in anxiety. Here, we focus the broad literature on the neurobiology of anxiety through the lens of uncertainty. We identify five processes that are essential for adaptive anticipatory responses to future threat uncertainty and propose that alterations in the neural instantiation of these processes result in maladaptive responses to uncertainty in pathological anxiety. This framework has the potential to advance the classification, diagnosis and treatment of clinical anxiety.

De novo variant in KIF26B is associated with pontocerebellar hypoplasia with infantile spinal muscular atrophy.

KIF26B is a member of the kinesin superfamily with evolutionarily conserved functions in controlling aspects of embryogenesis, including the development of the nervous system, though its function is incompletely understood. We describe an infant with progressive microcephaly, pontocerebellar hypoplasia, and arthrogryposis secondary to the involvement of anterior horn cells and ventral (motor) nerves. We performed whole exome sequencing on the trio and identified a de novo KIF26B missense variant, p.Gly546Ser, in the proband. This variant alters a highly conserved amino acid residue that is part of the phosphate-binding loop motif and motor-like domain and is deemed pathogenic by several in silico methods. Functional analysis of the variant protein in cultured cells revealed a reduction in the KIF26B protein's ability to promote cell adhesion, a defect that potentially contributes to its pathogenicity. Overall, KIF26B may play a critical role in the brain development and, when mutated, cause pontocerebellar hypoplasia with arthrogryposis.

Generalisation and specialisation in hoverfly (Syrphidae) grassland pollen transport networks revealed by DNA metabarcoding.

Pollination by insects is a key ecosystem service and important to wider ecosystem function. Most species-level pollination networks studied have a generalised structure, with plants having several potential pollinators, and pollinators in turn visiting a number of different plant species. This is in apparent contrast to a plant's need for efficient conspecific pollen transfer. The aim of this study was to investigate the structure of pollen transport networks at three levels of biological hierarchy: community, species and individual. We did this using hoverflies in the genus Eristalis, a key group of non-Hymenopteran pollinators. We constructed pollen transport networks using DNA metabarcoding to identify pollen. We captured hoverflies in conservation grasslands in west Wales, UK, removed external pollen loads, sequenced the pollen DNA on the Illumina MiSeq platform using the standard plant barcode rbcL, and matched sequences using a pre-existing plant DNA barcode reference library. We found that Eristalis hoverflies transport pollen from 65 plant taxa, more than previously appreciated. Networks were generalised at the site and species level, suggesting some degree of functional redundancy, and were more generalised in late summer compared to early summer. In contrast, pollen transport at the individual level showed some degree of specialisation. Hoverflies defined as "single-plant visitors" varied from 40% of those captured in early summer to 24% in late summer. Individual hoverflies became more generalised in late summer, possibly in response to an increase in floral resources. Rubus fruticosus agg. and Succisa pratensis were key plant species for hoverflies at our sites Our results contribute to resolving the apparent paradox of how generalised pollinator networks can provide efficient pollination to plant species. Generalised hoverfly pollen transport networks may result from a varied range of short-term specialised feeding bouts by individual insects. The generalisation and functional redundancy of Eristalis pollen transport networks may increase the stability of the pollination service they deliver.