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Abstract Background Surgical resection is integral for the treatment of neuroblastoma, the most common extracranial solid malignancy in children. Safely locating and resecting primary tumor and remote deposits of disease remains a significant challenge, resulting in high rates of complications and incomplete surgery, worsening outcomes. Intraoperative molecular imaging (IMI) uses targeted radioactive or fluorescent tracers to identify and visualize tumors intraoperatively. GD2 was selected as an IMI target, as it is highly overexpressed in neuroblastoma and minimally expressed in normal tissue. Methods GD2 expression in neuroblastoma cell lines was measured by flow cytometry. DTPA and IRDye® 800CW were conjugated to anti-GD2 antibody to generate DTPA-αGD2-IR800. Binding affinity (Kd) of the antibody and the non-radiolabeled tracer were then measured by ELISA assay. Human neuroblastoma SK-N-BE(2) cells were surgically injected into the left adrenal gland of 3.5-5-week-old nude mice and the orthotopic xenograft tumors grew for 5 weeks. 111In-αGD2-IR800 or isotype control tracer was administered via tail vein injection. After 4 and 6 days, mice were euthanized and gamma and fluorescence biodistributions were measured using a gamma counter and ImageJ analysis of acquired SPY-PHI fluorescence images of resected organs (including tumor, contralateral adrenal, kidneys, liver, muscle, blood, and others). Organ uptake was compared by one-way ANOVA (with a separate analysis for each tracer/day combination), and if significant, Sidak’s multiple comparison test was used to compare the uptake of each organ to the tumor. Handheld tools were also used to detect and visualize tumor in situ, and to assess for residual disease following non-guided resection. Results 111In-αGD2-IR800 was successfully synthesized with 0.75-2.0 DTPA and 2–3 IRDye® 800CW per antibody and retained adequate antigen-binding (Kd = 2.39 nM for aGD2 vs. 21.31 nM for DTPA-aGD2-IR800). The anti-GD2 tracer demonstrated antigen-specific uptake in mice with human neuroblastoma xenografts (gamma biodistribution tumor-to-blood ratios of 3.87 and 3.88 on days 4 and 6 with anti-GD2 tracer), while isotype control tracer did not accumulate (0.414 and 0.514 on days 4 and 6). Probe accumulation in xenografts was detected and visualized using widely available operative tools (Neoprobe® and SPY-PHI camera) and facilitated detection ofputative residual disease in the resection cavity following unguided resection. Conclusions We have developed a dual-labeled anti-GD2 antibody-based tracer that incorporates In-111 and IRDye® 800CW for radio- and fluorescence-guided surgery, respectively. The tracer adequately binds to GD2, specifically accumulates in GD2-expressing xenograft tumors, and enables tumor visualization with a hand-held NIR camera. These results encourage the development of 111In-αGD2-IR800 for future use in children with neuroblastoma, with the goal of improving patient safety, completeness of resection, and overall patient outcomes.

Abstract In Māori and Pacific adults, the CREBRF rs373863828 minor (A) allele is associated with increased body mass index (BMI) but reduced incidence of type-2 and gestational diabetes mellitus. In this prospective cohort study of Māori and Pacific infants, nested within a nutritional intervention trial for pregnant women with obesity and without pregestational diabetes, we investigated whether the rs373863828 A allele is associated with differences in growth and body composition from birth to 12–18 months’ corrected age. Infants with and without the variant allele were compared using generalised linear models adjusted for potential confounding by gestation length, sex, ethnicity and parity, and in a secondary analysis, additionally adjusted for gestational diabetes. Carriage of the rs373863828 A allele was not associated with altered growth and body composition from birth to 6 months. At 12–18 months, infants with the rs373863828 A allele had lower whole-body fat mass [FM 1.4 (0.7) vs. 1.7 (0.7) kg, aMD −0.4, 95% CI −0.7, 0.0, P = 0.05; FM index 2.2 (1.1) vs. 2.6 (1.0) kg/m2 aMD −0.6, 95% CI −1.2,0.0, P = 0.04]. However, this association was not significant after adjustment for gestational diabetes, suggesting that it may be mediated, at least in part, by the beneficial effect of CREBRF rs373863828 A allele on maternal glycemic status.

Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor. Currently, there are few effective treatment options for GBM beyond surgery and chemo-radiation, and even with these interventions, median patient survival remains poor. While immune checkpoint inhibitors (ICIs) have demonstrated therapeutic efficacy against non-central nervous system cancers, ICI trials for GBM have typically had poor outcomes. TIGIT is an immune checkpoint receptor that is expressed on activated T-cells and has a role in the suppression of T-cell and Natural Killer (NK) cell function. As TIGIT expression is reported as both prognostic and a biomarker for anti-TIGIT therapy, we constructed a molecular imaging agent, [89Zr]Zr-DFO-anti-TIGIT (89Zr-αTIGIT), to visualize TIGIT in preclinical GBM by immunoPET imaging. PET imaging and biodistribution analysis of 89Zr-αTIGIT demonstrated uptake in the tumor microenvironment of GBM-bearing mice. Blocking antibody and irrelevant antibody tracer studies demonstrated specificity of 89Zr-αTIGIT with significance at a late time point post-tracer injection. However, the magnitude of 89Zr-αTIGIT uptake in tumor, relative to the IgG tracer was minimal. These findings highlight the features and limitations of using 89Zr-αTIGIT to visualize TIGIT in the GBM microenvironment.

Introduction: Erythroblastic island (EBI) macrophages play an essential role in the production and maturation of the vast numbers of red blood cells (RBCs) that are produced throughout life. Their location within the bone marrow makes it difficult to study the cellular and molecular interactions associated with their action so we have used an in vitro model of the EBI niche using macrophages derived from human induced pluripotent stem cells (hiPSCs). We previously demonstrated that the activation of the transcription factor KLF1 enhanced the activity of hiPSC-derived EBI macrophages.Methods: To elucidate the mechanisms associated with EBI-like activity we carried out a quantitative proteomic analysis and assessed the role of extracellular vesicles using Nanosight Tracking analyses and media filtration.Results and Discussion: Gene ontology analysis showed that many of the proteins upregulated by KLF1 were protein-binding factors, some of which were associated with the cell membrane or extracellular vesicles We demonstrated that filtration of macrophage-conditioned media resulted in a reduction in the supportive effects on erythroid cell viability and maturation implying a role for extracellular vesicles but this was not KLF1 dependent. Pathway analyses of the proteomic data revealed that proteins upregulated by KLF1 were associated with the citric acid cycle, pyruvate metabolism and ATP synthesis indicating that KLF1-activated macrophages had a metabolic profile comparable to a pro-reparative phenotype. This study has generated a proteomic dataset that could provide new insights into the role of macrophages within the EBI niche and has indicated a potential role for extracellular vesicles in the differentiation and maturation of RBCs in vitro. Further research will aid in the production of RBCs in vitro for use in disease modelling and cell therapy.

Abstract Background Pre-exposure prophylaxis (PrEP) demonstrates effectiveness in decreasing new cases of HIV. However, few African Americans use PrEP, despite being disproportionately impacted by HIV. Understanding the influence of sociocultural and structural factors on PrEP use among multiple priority groups of African Americans, including but not limited to men who have sex with men, may improve PrEP engagement and uptake. The social ecological model (SEM) as a framework guided the understanding of how these factors operate on multiple levels to influence PrEP use among this population. Methods This study derived data from the Afya PrEP study consisting of eleven focus groups (N = 63) with 18-29-year-old African American sexual and gender minority and heterosexual individuals at heightened behavioral vulnerability to HIV. We employed constructivist grounded theory processes to inductively analyze the data. A pooled kappa score of 0.90 indicated excellent inter-rater agreement. Results Factors impacting PrEP engagement among African American young adults included: (1) Community/social network influences; (2) medical mistrust; (3) stigma; (4) PrEP availability and accessibility, which had two sub-categories: (a) cost and (b) where to obtain PrEP; and (5) PrEP engagement strategies, which had two sub-categories: (a) current AIDS service organizations’ PrEP engagement practices and (b) recommended future PrEP engagement strategies. Categories one through three represent sociocultural factors, and categories four and five represent structural factors that influence perceptions and attitudes of African American young adults regarding PrEP. Conclusion Our study highlights sociocultural and structural factors that act as barriers and facilitators to PrEP engagement. The SEM guided the understanding of how these factors operated on multiple levels. One of the sociocultural factors, community/social network influences operated at the interpersonal level of the SEM; the other two, stigma and medical mistrust, operated at the community level. The structural factors (PrEP availability, accessibility, and engagement strategies) operated at the institutional/organizational level. Thus, multi-level interventions are warranted to improve PrEP engagement among various African American young adult priority groups.

Screening, Brief Intervention, and Referral to Treatment (SBIRT) is a supplementary intervention that can be incorporated into the Pre-Exposure Prophylaxis (PrEP) Care Continuum, complementing initiatives and endeavors focused on Human Immunodeficiency Virus (HIV) prevention in clinical care and community-based work. Referencing the Transtheoretical Model of Change and the PrEP Awareness Continuum, this conceptual analysis highlights how SBIRT amplifies ongoing HIV prevention initiatives and presents a distinct chance to address identified gaps. SBIRT's mechanisms show promise of fit and feasibility through (a) implementing universal Screening (S), (b) administering a Brief Intervention (BI) grounded in motivational interviewing aimed at assisting individuals in recognizing the significance of PrEP in their lives, (c) providing an affirming and supportive Referral to Treatment (RT) to access clinical PrEP care, and (d) employing client-centered and destigmatized approaches. SBIRT is uniquely positioned to help address the complex challenges facing PrEP awareness and initiation efforts. Adapting the SBIRT model to integrate and amplify HIV prevention efforts merits further examination.

The connectivity of the hippocampus is essential to its functions. To gain a whole system view of intrahippocampal connectivity, ex vivo mesoscale (100 μm isotropic resolution) multi-shell diffusion MRI (11.7T) and tractography were performed on entire post-mortem human right hippocampi. Volumetric measurements indicated that the head region was largest followed by the body and tail regions. A unique anatomical organization in the head region reflected a complex organization of the granule cell layer (GCL) of the dentate gyrus. Tractography revealed the volumetric distribution of the perforant path, including both the tri-synaptic and temporoammonic pathways, as well as other well-established canonical connections, such as Schaffer collaterals. Visualization of the perforant path provided a means to verify the borders between the pro-subiculum and CA1, as well as between CA1/CA2. A specific angularity of different layers of fibers in the alveus was evident across the whole sample and allowed a separation of afferent and efferent connections based on their origin (i.e. entorhinal cortex) or destination (i.e. fimbria) using a cluster analysis of streamlines. Non-canonical translamellar connections running along the anterior-posterior axis were also discerned in the hilus. In line with “dentations” of the GCL, mossy fibers were bunching together in the sagittal plane revealing a unique lamellar organization and connections between these. In the head region, mossy fibers projected to the origin of the fimbria, which was distinct from the body and tail region. Mesoscale tractography provides an unprecedented systems view of intrahippocampal connections that underpin cognitive and emotional processing.

Abstract Differential microglial inflammatory responses play a role in regulation of differentiation and maturation of oligodendrocytes (OLs) in brain white matter. How microglia–OL crosstalk is altered by traumatic brain injury (TBI) and its impact on axonal myelination and neurological function impairment remain poorly understood. In this study, we investigated roles of a Na+/H+ exchanger (NHE1), an essential microglial pH regulatory protein, in microglial proinflammatory activation and OL survival and differentiation in a murine TBI model induced by controlled cortical impact. Similar TBI-induced contusion volumes were detected in the Cx3cr1-Cre ERT2 control (Ctrl) mice and selective microglial Nhe1 knockout (Cx3cr1-Cre ERT2 ;Nhe1 flox/flox , Nhe1 cKO) mice. Compared to the Ctrl mice, the Nhe1 cKO mice displayed increased resistance to initial TBI-induced white matter damage and accelerated chronic phase of OL regeneration at 30 days post-TBI. The cKO brains presented increased anti-inflammatory phenotypes of microglia and infiltrated myeloid cells, with reduced proinflammatory transcriptome profiles. Moreover, the cKO mice exhibited accelerated post-TBI sensorimotor and cognitive functional recovery than the Ctrl mice. These phenotypic outcomes in cKO mice were recapitulated in C57BL6J wild-type TBI mice receiving treatment of a potent NHE1 inhibitor HOE642 for 1–7 days post-TBI. Taken together, these findings collectively demonstrated that blocking NHE1 protein stimulates restorative microglial activation in oligodendrogenesis and neuroprotection, which contributes to accelerated brain repair and neurological function recovery after TBI.

Introduction: Congenital dyserythropoietic anaemia (CDA) type IV has been associated with an amino acid substitution, Glu325Lys (E325K), in the transcription factor KLF1. These patients present with a range of symptoms, including the persistence of nucleated red blood cells (RBCs) in the peripheral blood which reflects the known role for KLF1 within the erythroid cell lineage. The final stages of RBCs maturation and enucleation take place within the erythroblastic island (EBI) niche in close association with EBI macrophages. It is not known whether the detrimental effects of the E325K mutation in KLF1 are restricted to the erythroid lineage or whether deficiencies in macrophages associated with their niche also contribute to the disease pathology.Methods: To address this question, we generated an in vitro model of the human EBI niche using induced pluripotent stem cells (iPSCs) derived from one CDA type IV patient as well as two iPSC lines genetically modified to express an KLF1-E325K-ERT2 protein that could be activated with 4OH-tamoxifen. The one patient iPSC line was compared to control lines from two healthy donors and the KLF1-E325K-ERT2 iPSC line to one inducible KLF1-ERT2 line generated from the same parental iPSCS.Results: The CDA patient-derived iPSCs and iPSCs expressing the activated KLF1-E325K-ERT2 protein showed significant deficiencies in the production of erythroid cells with associated disruption of some known KLF1 target genes. Macrophages could be generated from all iPSC lines but when the E325K-ERT2 fusion protein was activated, we noted the generation of a slightly less mature macrophage population marked by CD93. A subtle trend in their reduced ability to support RBC enucleation was also associated with macrophages carrying the E325K-ERT2 transgene.Discussion: Taken together these data support the notion that the clinically significant effects of the KLF1-E325K mutation are primarily associated with deficiencies in the erythroid lineage but it is possible that deficiencies in the niche might have the potential to exacerbate the condition. The strategy we describe provides a powerful approach to assess the effects of other mutations in KLF1 as well as other factors associated with the EBI niche.

Recent research highlights the function of regulatory T cells (Tregs) in white matter integrity in CNS diseases. Approaches that expand the number of Tregs have been utilized to improve stroke recovery. However, it remains unclear if Treg augmentation preserves white matter integrity early after stroke or promotes white matter repair. This study evaluates the effect of Treg augmentation on white matter injury and repair after stroke. Adult male C57/BL6 mice randomly received Treg or splenocyte (2 million, iv) transfer 2 h after transient (60 min) middle cerebral artery occlusion (tMCAO). Immunostaining showed improved white matter recovery after tMCAO in Treg-treated mice compared to mice received splenocytes. In another group of mice, IL-2/IL-2 antibody complexes (IL-2/IL-2Ab) or isotype IgG were administered (i.p) for 3 consecutive days starting 6 h after tMCAO, and repeated on day 10, 20 and 30. The IL-2/IL-2Ab treatment boosted the number of Tregs in blood and spleen and increased Treg infiltration into the ischemic brain. Longitudinal in vivo and ex vivo diffusion tensor imaging analysis revealed an increase in fractional anisotropy 28d and 35d, but not 14d, after stroke in IL-2/IL-2Ab-treated mice compared to isotype-treated mice, suggesting a delayed improvement in white matter integrity. IL-2/IL-2Ab also improved sensorimotor functions (rotarod test and adhesive removal test) 35d after stroke. There were correlations between white matter integrity and behavior performance. Immunostaining confirmed the beneficial effects of IL-2/IL-2Ab on white matter structures 35d after tMCAO. IL-2/IL-2Ab treatment starting as late as 5d after stroke still improved white matter integrity 21d after tMCAO, suggesting long-term salutary effects of Tregs on the late-stage tissue repair. We also found that IL-2/IL-2Ab treatment reduced the number of dead/dying OPCs and oligodendrocytes in the brain 3d after tMCAO. To confirm the direct effect of Tregs on remyelination, Tregs were cocultured with lysophosphatidyl choline (LPC)-treated organotypic cerebella. LPC exposure for 17 h induced demyelination in organotypic cultures, followed by gradual spontaneous remyelination upon removal of LPC. Co-culture with Tregs accelerated remyelination in organotypic cultures 7d after LPC. In conclusion, Boosting the number of Tregs protects oligodendrocyte lineage cells early after stroke and promotes long-term white matter repair and functional recovery. IL-2/IL-2Ab represents a feasible approach of Treg expansion for stroke treatment.

Abstract Background Engineered versions of adeno-associated virus (AAV) are commonly used in gene therapy but evidence revealing a potential oncogenic role of natural AAV in hepatocellular carcinoma (HCC) has raised concerns. The frequency of potentially oncogenic integrations has been reported in only a few populations. AAV infection and host genome integration in another type of liver cancer, cholangiocarcinoma (CCA), has been studied only in one cohort. All reported oncogenic AAV integrations in HCC come from strains resembling the fully sequenced AAV2 and partly sequenced AAV13. When AAV integration occurs, only a fragment of the AAV genome is detectable in later DNA or RNA sequencing. The integrated fragment is typically from the 3’ end of the AAV genome, and this positional bias has been only partly explained. Three research groups searched for evidence of AAV integration in HCC RNAseq samples in the Cancer Genome Atlas (TCGA) but reported conflicting results. Results We collected and analyzed whole transcriptome and viral capture DNA sequencing in paired tumor and non-tumor samples from two liver cancer Asian cohorts from Thailand (N = 147, 47 HCC and 100 intrahepatic cholangiocarcinoma (iCCA)) and Mongolia (N = 70, all HCC). We found only one HCC patient with a potentially oncogenic integration of AAV, in contrast to higher frequency reported in European patients. There were no oncogenic AAV integrations in iCCA patients. AAV genomic segments are present preferentially in the non-tumor samples of Thai patients. By analyzing the AAV genome positions of oncogenic and non-oncogenic integrated fragments, we found that almost all the putative oncogenic integrations overlap the X gene, which is present and functional only in the strain AAV2 among all fully sequenced strains. This gene content difference could explain why putative oncogenic integrations from other AAV strains have not been reported. We resolved the discrepancies in previous analyses of AAV presence in TCGA HCC samples and extended it to CCA. There are 12 TCGA samples with an AAV segment and none are in Asian patients. AAV segments are present in preferentially in TCGA non-tumor samples, like what we observed in the Thai patients. Conclusions Our findings suggest a minimal AAV risk of hepatocarcinogenesis in Asian liver cancer patients. The partial genome presence and positional bias of AAV integrations into the human genome has complicated analysis of possible roles of AAV in liver cancer.

Abstract Background Late stillbirth continues to affect 3–4/1000 pregnancies in high-resource settings, with even higher rates in low-resource settings. Reduced foetal movements are frequently reported by women prior to foetal death, but there remains a poor understanding of the reasons and how to deal with this symptom clinically, particularly during the preterm phase of gestation. We aimed to determine which women are at the greatest odds of stillbirth in relation to the maternal report of foetal movements in late pregnancy (≥ 28 weeks’ gestation). Methods This is an individual participant data meta-analysis of all identified case-control studies of late stillbirth. Studies included in the IPD were two from New Zealand, one from Australia, one from the UK and an internet-based study based out of the USA. There were a total of 851 late stillbirths, and 2257 controls with ongoing pregnancies. Results Increasing strength of foetal movements was the most commonly reported (> 60%) pattern by women in late pregnancy, which were associated with a decreased odds of late stillbirth (adjusted odds ratio (aOR) = 0.20, 95% CI 0.15 to 0.27). Compared to no change in strength or frequency women reporting decreased frequency of movements in the last 2 weeks had increased odds of late stillbirth (aOR = 2.33, 95% CI 1.73 to 3.14). Interaction analysis showed increased strength of movements had a greater protective effect and decreased frequency of movements greater odds of late stillbirth at preterm gestations (28–36 weeks’ gestation). Foetal hiccups (aOR = 0.45, 95% CI 0.36 to 0.58) and regular episodes of vigorous movement (aOR = 0.67, 95% CI 0.52 to 0.87) were associated with decreased odds of late stillbirth. A single episode of unusually vigorous movement was associated with increased odds (aOR = 2.86, 95% CI 2.01 to 4.07), which was higher in women at term. Conclusions Reduced foetal movements are associated with late stillbirth, with the association strongest at preterm gestations. Foetal hiccups and multiple episodes of vigorous movements are reassuring at all gestations after 28 weeks’ gestation, whereas a single episode of vigorous movement is associated with stillbirth at term.

Abstract In secondary analyses of a randomised controlled trial of exercise during pregnancy, we examined associations between mid-pregnancy maternal body mass index (BMI) and excessive gestational weight gain (GWG) with offspring health. Follow-up data were available on 57 mother–child pairs at 1-year and 52 pairs at 7-year follow-ups. Clinical assessments included body composition and fasting blood tests. At age 1 year, increased maternal BMI in mid-gestation was associated with greater weight standard deviation scores (SDS) in the offspring (p = 0.035), with no observed associations for excessive GWG. At age 7 years, greater maternal BMI was associated with increased weight SDS (p

Prolactin and placental lactogens increase during pregnancy and are involved with many aspects of maternal metabolic adaptation to pregnancy, likely to impact on fetal growth. The aim of this study was to determine whether maternal plasma prolactin or placental lactogen concentrations at 20 weeks of gestation were associated with later birth of small-for-gestational-age babies (SGA). In a nested case–control study, prolactin and placental lactogen in plasma samples obtained at 20 weeks of gestation were compared between 40 women who gave birth to SGA babies and 40 women with uncomplicated pregnancies and size appropriate-for-gestation-age (AGA) babies. Samples were collected as part of the 'screening of pregnancy endpoints' (SCOPE) prospective cohort study. SGA was defined as birthweight

Abstract To quantify the urinary bladder wall T1 relaxation time (T1) before and after the instillation contrast mixture in rats previously subjected to water avoidance stress (WAS) and/or acute exposure to protamine sulfate (PS). Female Wistar rats were randomized to receive either sham (control) or 1 h of WAS for ten consecutive days before the evaluation of nocturnal urination pattern in metabolic cages. T1 mapping of urinary bladder wall at 9.4 T was performed pre- and post- instillation of 4 mM Gadobutrol in a mixture with 5 mM Ferumoxytol. Subsequently, either T1 mapping was repeated after brief intravesical PS exposure or the animals were sacrificed for histology and analyzing the mucosal levels of mRNA. Compared to the control group, WAS exposure decreased the single void urine volume and shortened the post-contrast T1 relaxation time of mucosa- used to compute relatively higher ingress of instilled Gadobutrol. Compromised permeability in WAS group was corroborated by the urothelial denudation, edema and ZO-1 downregulation. PS exposure doubled the baseline ingress of Gadobutrol in both groups. These findings confirm that psychological stress compromises the paracellular permeability of bladder mucosa and its non-invasive assay with MRI was validated by PS exposure.

Abstract Background Chronic cerebral hypoperfusion (CCH) causes white matter damage and cognitive impairment, in which astrogliosis is the major pathology. However, underlying cellular mechanisms are not well defined. Activation of Na+/H+ exchanger-1 (NHE1) in reactive astrocytes causes astrocytic hypertrophy and swelling. In this study, we examined the role of NHE1 protein in astrogliosis, white matter demyelination, and cognitive function in a murine CCH model with bilateral carotid artery stenosis (BCAS). Methods Sham, BCAS, or BCAS mice receiving vehicle or a selective NHE1 inhibitor HOE642 were monitored for changes of the regional cerebral blood flow and behavioral performance for 28 days. Ex vivo MRI-DTI was subsequently conducted to detect brain injury and demyelination. Astrogliosis and demyelination were further examined by immunofluorescence staining. Astrocytic transcriptional profiles were analyzed with bulk RNA-sequencing and RT-qPCR. Results Chronic cerebral blood flow reduction and spatial working memory deficits were detected in the BCAS mice, along with significantly reduced mean fractional anisotropy (FA) values in the corpus callosum, external capsule, and hippocampus in MRI DTI analysis. Compared with the sham control mice, the BCAS mice displayed demyelination and axonal damage and increased GFAP+ astrocytes and Iba1+ microglia. Pharmacological inhibition of NHE1 protein with its inhibitor HOE642 prevented the BCAS-induced gliosis, damage of white matter tracts and hippocampus, and significantly improved cognitive performance. Transcriptome and immunostaining analysis further revealed that NHE1 inhibition specifically attenuated pro-inflammatory pathways and NADPH oxidase activation. Conclusion Our study demonstrates that NHE1 protein is involved in astrogliosis with pro-inflammatory transformation induced by CCH, and its blockade has potentials for reducing astrogliosis, demyelination, and cognitive impairment.

This collaborative-participatory research aimed to develop the research agenda of the college of teacher education (CTE) of a state university in Zambales, Philippines from 2017 to 2021. The research involved the core research group, faculty researchers, campus and university officials, and stakeholders such as students, alumni, and partner agencies (department of education (DeEd) faculty and administrators). The study was carried out in the first quarter of 2017 to develop the CTE research agenda framework, identify the key research areas, and present to the stakeholders. During the third quarter of 2018, the developed research agenda was revisited and reformulated as the university was converted into a more comprehensive university. A total of six themes were included in the final CTE research agenda framework with corresponding theme descriptions and research topics. The use of participatory-collaborative research effectively develops a college research agenda of the CTE. The processes involved in research agenda setting can serve as a basis for other teacher education institutions (TEIs) in coming up with their respective research agenda geared towards uplifting the quality of teacher education. The study could also serve as a guide for other colleges in formulating and revisiting their research agenda.

BackgroundAddressing issues of diversity, equity, and inclusion (DEI) has become central in implementing inclusive and socially responsible rehabilitation education and clinical practice. Yet, the constructs of disability and d/Deaf identity and culture, as well as ableism and allyship are often overlooked. Or, these concepts are approached using outdated philosophical perspectives that pathologize disability and fail to prioritize the lived experiences, expertise, intersectionality, and self-identified needs of people with disabilities. A Critical Disability Studies (CDS) framework may provide a background for better understanding and responding to these issues through allyship.PurposeThis study employed a CDS framework to understand the lived experiences of ableism and allyship from faculty, staff, and students on University of Washington (UW) campuses who identify as d/Deaf, disabled/with a disability, or as having a chronic health condition.MethodsDuring 2020–2021, we conducted in-depth, semi-structured interviews and focus groups with 22 diverse undergraduate and graduate students, faculty, and staff with disabilities, one third who also identified as people of color. Encounters were audio-recorded, transcribed verbatim, and coded using constant comparison until themes emerged.ResultsFour major themes that emerged from the data are: (1) Ever-present ableism in healthcare, (2) Ableism at the intersections, (3) COVID: Surfacing ableism and expanding access, and (4) Disability allyship and healthcare partnership building. Experiences of ableism and allyship were identified at individual, group/unit, and institutional/systemic levels, though participants reported significantly fewer instances of allyship compared to experiences of ableism. Participants identified intersections between disability and other marginalized identities and juxtaposed the benefits of widespread adoption of many access-increasing practices and technologies due to the COVID-19 pandemic, while also highlighting ways in which the pandemic created new obstacles to inclusion.ConclusionsThis analysis provides insights into ways of implementing inclusive practices in rehabilitation education, practice, and beyond. Rehabilitation students, faculty, and staff may not be aware of how ableism affects their disabled peers or underpins their professional education. It is important to cultivate opportunities within professional education and clinical training to explicitly address our collective role in creating inclusive and accessible academic and healthcare experiences for our diverse community post COVID-19. Drawing on a CDS framework, the research team devised the mnemonic TRAC, which includes Training, Recognition and Representation, Attendance and Action, and Calling to account as strategic guidelines for operationalizing such opportunities.

Plain English Summary The purpose of involving the public and patients in research is to help them have a say in decisions about healthcare and enable patients or other people with relevant experience to contribute to how research is planned, carried out, and shared with a wider audience. The Partner Priority Programme (PPP) was developed by the National Health Service [NHS] and Local Authority partners to share information and experience on evaluating new services being offered to patients that were seeking to reduce health inequalities, improve people’s health and wellbeing and reduce emergency hospital admissions. In this paper, we explore an approach we developed for involving public advisors (service users/patients, and caregivers) as equal partners within the evaluation and decision-making processes of health and social care services research. The aim of this study was to identify how public advisors were included, the impact of their involvement, and identify the changes organisations made as a result of public advisor involvement. Most projects had not included public advisors in their teams before and initially did not understand how to involve them. By attending scheduled meetings, they had time to learn how to engage with public advisors (and what methods to use to recruit them to be part of their teams). Participants also learned the benefits of including public advisors within their teams. With the help and support provided as part of the programme, public advisors seemed to grow in confidence and take part in teams as equal partners.

Abstract Background Gestational diabetes mellitus (GDM) has lifelong implications for the woman and her infant. Treatment reduces adverse maternal and perinatal outcomes although uncertainty remains about the optimal diagnostic criteria. The GEMS Trial aims to assess whether detection and treatment of women with GDM using the lower International Association of Diabetes in Pregnancy Study Groups diagnostic criteria compared with the higher criteria recommended in New Zealand reduces infant morbidity without increasing maternal morbidity. Methods GEMS is a multicentre, randomised trial. Women with a singleton pregnancy at 24 to 34 weeks’ gestation are eligible who give written informed consent. Women are randomly allocated to the Lower Criteria Group or the Higher Criteria Group. Women with a normal OGTT by their allocated criteria receive routine care (Higher criteria: fasting plasma glucose 90th centile). Secondary outcomes for the infant include a composite of serious outcomes, gestational age, anthropometry, Apgar score

Human pluripotent stem cells (hPSCs) and mesenchymal stromal/stem cells (hMSCs) are clinically relevant sources for cellular therapies and for modeling human development and disease. Many stem cell-based applications rely on the ability to activate several endogenous genes simultaneously to modify cell fate. However, genetic intervention of these cells remains challenging. Several catalytically dead Cas9 (dCas9) proteins fused to distinct activation domains can modulate gene expression when directed to their regulatory regions by a specific single-guide RNA (sgRNA). In this study, we have compared the ability of the first-generation dCas9-VP64 activator and the second-generation systems, dCas9-SAM and dCas9-SunTag, to induce gene expression in hPSCs and hMSCs. Several stem cell lines were tested for single and multiplexed gene activation. When the activation of several genes was compared, all three systems induced specific and potent gene expression in both single and multiplexed settings, but the dCas9-SAM and dCas9-SunTag systems resulted in the highest and most consistent level of gene expression. Simultaneous targeting of the same gene with multiple sgRNAs did not result in additive levels of gene expression in hPSCs nor hMSCs. We demonstrate the robustness and specificity of second-generation dCas9 activators as tools to simultaneously activate several endogenous genes in clinically relevant human stem cells.

In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk.

Abstract Background Asymmetric fetal growth and male sex are both associated with adverse neonatal outcome. However, less is known about the influence of asymmetric growth and fetal sex within SGA neonates, a group of infants already at increased risk for adverse neonatal outcomes. The aim of the present study was to provide insight into variance in risk factors for SGA in a fetal sex- and growth symmetry-specific way. Methods For this prospective, multicenter cohort study, data from the Screening for Pregnancy Endpoints (SCOPE) study were used with 5628 nulliparous participants, of which 633 (11.3%) pregnancies were complicated with SGA and 3376 (60.0%) women had uncomplicated pregnancies. Association between risk factors for SGA, SGA subgroups, and uncomplicated pregnancies were assessed with multivariable analyses. Results Prevalence of asymmetric growth varied from 45.8% of SGA infants to 5.5% of infants with a customized birthweight > 90th percentile (p < 0.001). Significantly more SGA males had asymmetric growth compared to SGA female infants (51.2% vs 40.4%, p = 0.009). Maternal pre-pregnancy diet and BMI < 20 and ≥ 30 were significantly associated with symmetric SGA but not with asymmetric SGA. Asymmetric SGA infants had not only lower customized birthweight percentile (4.4 (SD 2.8) vs 5.0 (SD 3.0), p < 0.001), but also lower rates of stillbirth (p = 0.041) and less often Apgar scores < 7 (p = 0.060). Conclusions Among SGA infants, low customized birthweight percentiles and male sex are associated with asymmetric growth. Only symmetric SGA is significantly associated with maternal risk factors in early pregnancy. There is a substantial variance in risk factors and neonatal outcomes for SGA based on growth symmetry, implying a different pathogenesis. Trial registration ACTRN12607000551493

Abstract Background This study represents the first Scottish retrospective analysis of the microbiology of diabetic foot infections (DFIs). The aims were to compare the microbiological profile of DFIs treated at a Scottish tertiary hospital to that in the literature, gather data regarding antimicrobial resistance and investigate potential trends between the microbiological results and nature or site of the clinical sample taken and age or gender of the patients. Methods A retrospective analysis of wound microbiology results was performed, data were obtained from one multidisciplinary outpatient foot clinic during the 12 months of the year 2017. Seventy-three patients and 200 microbiological investigations were included. In cases of soft tissue infection, the deepest part of a cleansed and debrided wound was sampled. In cases of osteomyelitis a bone biopsy was obtained. Factors influencing the pattern of microbial growth or prevalence of Staphylococcus aureus were investigated. Results Of the 200 microbiological investigations, 62% were culture positive, of which 37.9% were polymicrobial and 62.1% monomicrobial. Among the monomicrobial results (n = 77), most were Gram positive isolates (96.1%) and the most frequently isolated bacteria was S. aureus (84.4%). No methicillin-resistant S. aureus was reported. The prevalence of S. aureus in DFIs was associated with increasing age (p = 0.021), but no evidence of association with gender, anatomical sample site or sample material was found. Conclusion The microbiological profile of DFIs in Scotland resembles that reported elsewhere in the UK. In this context, Gram positive organisms, primarily S. aureus, are most frequently isolated from DFIs. The S. aureus isolates identified were largely susceptible to antibiotic therapy. An association between increasing patient age and the prevalence of S. aureus in DFIs was observed.

SPAK kinase is a master regulator of cation-Cl− cotransporters. Here the authors describe a new SPAK inhibitor with robust protective effects in rodent hydrocephalous and ischemic stroke models.

No abstract avaialble.

Background: Trajectories of comorbidities among individuals at risk of Alzheimer’s disease (AD) may differ from those aging without AD clinical syndrome. Therefore, characterizing the comorbidity burden and pattern associated with AD risk may facilitate earlier detection, enable timely intervention, and help slow the rate of cognitive and functional decline in AD. This case-control study was performed to compare the prevalence of comorbidities between AD cases and controls during the 5 years prior to diagnosis (or index date for controls); and to identify comorbidities with a differential time-dependent prevalence trajectory during the 5 years prior to AD diagnosis.Methods: Incident AD cases and individually matched controls were identified in a United States claims database between January 1, 2000 and December 31, 2016. AD status and comorbidities were defined based on the presence of diagnosis codes in administrative claims records. Generalized estimating equations were used to assess evidence of changes over time and between AD and controls. A principal component analysis and hierarchical clustering was performed to identify groups of AD-related comorbidities with respect to prevalence changes over time (or trajectory), and differences between AD and controls.Results: Data from 186,064 individuals in the IBM MarketScan Commercial Claims and Medicare Supplementary databases were analyzed (93,032 AD cases and 93,032 non-AD controls). In total, there were 177 comorbidities with a ≥ 5% prevalence. Five main clusters of comorbidities were identified. Clusters differed between AD cases and controls in the overall magnitude of association with AD, in their diverging time trajectories, and in comorbidity prevalence. Three clusters contained comorbidities that notably increased in frequency over time in AD cases but not in controls during the 5-year period before AD diagnosis. Comorbidities in these clusters were related to the early signs and/or symptoms of AD, psychiatric and mood disorders, cerebrovascular disease, history of hazard and injuries, and metabolic, cardiovascular, and respiratory complaints.Conclusion: We demonstrated a greater comorbidity burden among those who later developed AD vs. controls, and identified comorbidity clusters that could distinguish these two groups. Further investigation of comorbidity burden is warranted to facilitate early detection of individuals at risk of developing AD.

Background: Malignant gliomas are deadly tumours with few therapeutic options. Although immunotherapy may be a promising therapeutic strategy for treating gliomas, a significant barrier is the CD11b+ tumour-associated myeloid cells (TAMCs), a heterogeneous glioma infiltrate comprising up to 40% of a glioma's cellular mass that inhibits anti-tumour T-cell function and promotes tumour progression. A theranostic approach uses a single molecule for targeted radiopharmaceutical therapy (TRT) and diagnostic imaging; however, there are few reports of theranostics targeting the tumour microenvironment. Methods: Utilizing a newly developed bifunctional chelator, Lumi804, an anti-CD11b antibody (αCD11b) was readily labelled with either Zr-89 or Lu-177, yielding functional radiolabelled conjugates for PET, SPECT, and TRT. Findings: 89Zr/177Lu-labeled Lumi804-αCD11b enabled non-invasive imaging of TAMCs in murine gliomas. Additionally, 177Lu-Lumi804-αCD11b treatment reduced TAMC populations in the spleen and tumour and improved the efficacy of checkpoint immunotherapy. Interpretation: 89Zr- and 177Lu-labeled Lumi804-αCD11b may be a promising theranostic pair for monitoring and reducing TAMCs in gliomas to improve immunotherapy responses. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Introduction: Excess body weight and low physical activity levels may be detrimental to cancer survivorship and to the development of diabetes and cardiovascular disease (CVD). This study aimed to test the feasibility and acceptability of an adapted Diabetes Prevention Programme (DPP) for cancer survivors who have risk factors for Type 2 diabetes mellitus and CVD. Methods: Overweight (BMI >25 kg/m²) adults aged 50–79 who were diagnosed with nonmetastatic breast or colon cancer within the prior 5 years were recruited through a research registry and oncology clinics. Eligible individuals enrolled in a 13-week group lifestyle programme with goals of 5–7% weight loss and 150 minutes of moderate-intensity physical activity. Programme attendance, adherence to recommended behaviours, weight, and physical activity information were collected. Results: A total of 44 individuals were screened for eligibility; 23 were eligible and 17 enrolled in the programme. Participants attended a median of 10 out of 13 lifestyle sessions and were able to meet dietary and activity goals 72.7% and 56.3% of the time, respectively. At the end of the programme, median weight loss was 4.5% and median activity was 297 minutes/week (median change +164 minutes/week). Conclusion: The modified DPP intervention was feasible to deliver to this group of cancer survivors who had risk factors for diabetes or CVD. Incorporating successful prevention programmes such as the DPP into cancer survivorship care has the potential to improve health behaviours and chronic disease risk factors in the cancer survivor population.

Abstract We investigated fetal movement quality and pattern and association with late stillbirth in this multicentre case-control study. Cases (n = 164) had experienced a non-anomalous singleton late stillbirth. Controls (n = 569) were at a similar gestation with non-anomalous singleton ongoing pregnancy. Data on perceived fetal movements were collected via interviewer-administered questionnaire. We compared categorical fetal movement variables between cases and controls using multivariable logistic regression, adjusting for possible confounders. In multivariable analysis, maternal perception of the following fetal movement variables was associated with decreased risk of late stillbirth; multiple instances of ‘more vigorous than usual’ fetal movement (aOR 0.52, 95% CI 0.32–0.82), daily perception of fetal hiccups (aOR 0.28, 95%CI 0.15–0.52), and perception of increased length of fetal movement clusters or ‘busy times’ (aOR 0.23, 95%CI 0.11–0.47). Conversely, the following maternally perceived fetal movement variables were associated with increased risk of late stillbirth; decreased frequency of fetal movements (aOR 2.29, 95%CI 1.31–4.0), and perception of ‘quiet or light’ fetal movement in the evening (aOR 3.82, 95%CI 1.57–9.31). In conclusion, women with stillbirth were more likely than controls to have experienced alterations in fetal movement, including decreased strength, frequency and in particular a fetus that was ‘quiet’ in the evening.

Background: Mortality dramatically rises with the onset of symptoms in patients with severe aortic stenosis (AS). Surgery is indicated when symptoms become apparent or when there is ventricular decompensation. Cardiopulmonary exercise testing (CPET) in combination with exercise echocardiography can unmask symptoms and provides valuable information regarding contractile reserve. The aim of the present study was to determine the prevalence of reduced exercise tolerance and the parameters predicting adverse cardiovascular events. Methods: Thirty-two patients with asymptomatic severe AS were included in this study. Patients were followed up as part of an enhanced surveillance clinic. Results: Age was 69 ± 15.7 years, 75% of patients were male. Patients had a raised NT-ProBNP of 301 pg/mL. VO2peak was 19.5 ± 6.2 mL/kg/min. Forty-one percent of patients had a reduced %VO2peak and this predicted unplanned cardiac hospitalisation (P = 0.005). Exercise systolic longitudinal velocity (S′) and age were the strongest independent predictors for VO2peak (R2 = 0.76; P < 0.0001). Exercise S′ was the strongest independent predictor for NT-ProBNP (R2 = 0.48; P = 0.001). Conclusion: A large proportion of patients had a lower than predicted VO2peak. The major determinant of exercise and NT-ProBNP is the ability of the left ventricle (LV) to augment S′ on exercise rather than the severity of aortic valve obstruction or resting structural remodelling of the LV. Reduced exercise tolerance and more adverse remodelling, rather than valve obstruction predicted unplanned hospitalisation. This study demonstrates that for those patients, in whom a watchful waiting is an agreed strategy, a detailed assessment should be undertaken including CPET, exercise echocardiography and biomarkers to ensure those with exercise limitation and risk of decompensation are detected early and treated appropriately.

Abstract Background Currently, there are no medications approved for the treatment of juvenile fibromyalgia (JFM). We evaluated the safety and efficacy of duloxetine 30/60 mg once daily (QD) versus placebo in adolescents with JFM. Methods In this Phase 3b, multisite (US, Argentina, Puerto Rico, and India) trial, patients aged 13–17 years with JFM and a score of ≥4 on the Brief Pain Inventory-Modified Short Form: Adolescent Version (BPI) 24-h average pain severity score were randomized to duloxetine or placebo for the 13-week double-blind period. The starting duloxetine dose was 30 mg, with a target dose of 60 mg QD, as tolerated. The primary endpoint was the mean change in 24-h average pain severity of the Brief Pain Inventory (BPI) from baseline to Week 13, analyzed using mixed-model repeated measures (MMRM) technique. Secondary measures were BPI severity and interference scores; treatment response (≥30%, ≥50% reductions on BPI average pain severity); Pediatric Pain Questionnaire; Clinical Global Impression of Severity: Overall and Mental Illness scales; Functional Disability Inventory: child and parent versions; Children’s Depression Inventory; Multidimensional Anxiety Scale for Children; and safety and tolerability. Continuous secondary efficacy measures were analyzed using analysis of covariance or MMRM, and categorical data using Cochran-Mantel-Haenszel test and Fisher’s exact test, where appropriate. Results A total of 184 patients with JFM received duloxetine (N = 91) or placebo (N = 93), of which 149 patients (81.0%) completed the 13-week double-blind treatment period. Baseline characteristics were comparable between groups; majority of the patients were Caucasian (77.17%) and females (75.0%), with a mean age of 15.53 years. For the primary measure, BPI average pain severity, the mean change was not statistically different between duloxetine and placebo (− 1.62 vs. -0.97, respectively; p = .052). For secondary efficacy outcomes, statistically significantly more duloxetine- versus placebo-treated patients had a treatment response (≥30% and ≥50% reductions on BPI average pain severity) and improvement of the general activity and relationships items on the BPI interference subscale. The percentage of patients reporting at least 1 treatment-emergent adverse event was higher in the duloxetine versus placebo groups (82.42% vs. 62.37%, respectively; p = .003). The overall safety profile of duloxetine in this study was similar to that reported previously in duloxetine pediatric trials of other indications. Conclusions The primary study outcome, mean change in 24-h BPI average pain severity rating from baseline to Week 13, did not significantly improve with duloxetine compared to placebo in patients with JFM. However, significantly more patients on duloxetine compared to placebo had a ≥30% and ≥50% reduction in pain severity. There were no new safety concerns related to duloxetine in the study population. Trial registration ClinicalTrials.gov Identifier: NCT01237587. Registered 08 November, /2010.

In vitro differentiation of red blood cells (RBCs) is a desirable therapy for various disorders. Here the authors develop a culture system using stem cell-derived macrophages to show that inducible expression of a transcription factor, KLF1, enhances RBC production, potentially through the induction of three soluble factors, ANGPTL7, IL33 and SERPINB2.

Introduction A ‘Sleep-On-Side When Baby’s Inside’ public health campaign was initiated in New Zealand in 2018. This was in response to evidence that maternal supine going-to-sleep position was an independent risk factor for stillbirth from 28 weeks’ gestation. We evaluated the success of the campaign on awareness and modification of late pregnancy going-to-sleep position through nationwide surveys.Methods and analysis Two web-based cross-sectional surveys were conducted over 12 weeks in 2019–2020 in a sample of (1) pregnant women ≥28 weeks, primary outcome of going-to-sleep position; and (2) health professionals providing pregnancy care, primary outcome of knowledge of going-to-sleep position and late stillbirth risk. Univariable logistic regression was performed to identify factors associated with supine going-to-sleep position.Discussion The survey of pregnant women comprised 1633 eligible participants. Going-to-sleep position last night was supine (30, 1.8%), non-supine (1597, 97.2%) and no recall (16, 1.0%). Supine position had decreased from 3.9% in our previous New Zealand-wide study (2012–2015). Most women (1412, 86.5%) had received sleep-on-side advice with no major resultant worry (1276, 90.4%). Two-thirds (918, 65.0%) had changed their going-to-sleep position based on advice, with most (611 of 918, 66.5%) reporting little difficulty. Supine position was associated with Māori (OR 5.05, 95% CI 2.10 to 12.1) and Asian-non-Indian (OR 4.20, 95% CI 1.27 to 13.90) ethnicity; single (OR 10.98, 95% CI 4.25 to 28.42) and cohabitating relationship status (OR 2.69, 95% CI 1.09 to 6.61); hospital-based maternity provider (OR 2.55, 95% CI 1.07 to 6.10); education overseas (OR 3.92, 95% CI 1.09 to 14.09) and primary-secondary level (OR 2.80, 95% CI 1.32 to 6.08); and not receiving sleep-on-side advice (OR 6.70, 95% CI 3.23 to 13.92). The majority of health professionals (709 eligible participants) reported awareness of supine going-to-sleep position and late stillbirth risk (543, 76.6%).Conclusion Most pregnant women had received and implemented sleep-on-side advice without major difficulty or concern. Some groups of women may need a tailored approach to acquisition of going-to-sleep position information.

Clostridioides difficile infection (CDI) is a problem in both developed and developing countries and is a common hospital-acquired infection. This guideline provides evidence-based practical recommendations for South Africa and other developing countries. The scope of the guideline includes CDI diagnostic approaches; adult, paediatric and special populations treatment options; and surveillance and infection prevention and control recommendations.

A high quality benchmark for small variants encompassing 88 to 90% of the reference genome has been developed for seven Genome in a Bottle (GIAB) reference samples. However a reliable benchmark for large indels and structural variants (SVs) is more challenging. In this study, we manually curated 1235 SVs, which can ultimately be used to evaluate SV callers or train machine learning models. We developed a crowdsourcing app-SVCurator-to help GIAB curators manually review large indels and SVs within the human genome, and report their genotype and size accuracy. SVCurator displays images from short, long, and linked read sequencing data from the GIAB Ashkenazi Jewish Trio son [NIST RM 8391/HG002]. We asked curators to assign labels describing SV type (deletion or insertion), size accuracy, and genotype for 1235 putative insertions and deletions sampled from different size bins between 20 and 892,149 bp. 'Expert' curators were 93% concordant with each other, and 37 of the 61 curators had at least 78% concordance with a set of 'expert' curators. The curators were least concordant for complex SVs and SVs that had inaccurate breakpoints or size predictions. After filtering events with low concordance among curators, we produced high confidence labels for 935 events. The SVCurator crowdsourced labels were 94.5% concordant with the heuristic-based draft benchmark SV callset from GIAB. We found that curators can successfully evaluate putative SVs when given evidence from multiple sequencing technologies.

Objective To examine the effects of a consultant-led, community-based chronic obstructive pulmonary disease (COPD) service, based in a highly deprived area on emergency hospital admissions.Design A longitudinal matched controlled study using difference-in-differences analysis to compare the change in outcomes in the intervention population to a matched comparison population, 5 years before and after implementation.Setting A deprived district in the North West of England between 2005 and 2016.Intervention A community-based, consultant-led COPD service providing diagnostics, treatment and rehabilitation from 2011 to 2016.Main outcome measures Emergency hospital admissions, length of stay per emergency admission and emergency readmissions for COPD.Results The intervention was associated with 24 fewer emergency COPD admissions per 100 000 population per year (95% CI −10.6 to 58.8, p=0.17) in the postintervention period, relative to the control group. There were significantly fewer emergency admissions in populations with medium levels of deprivation (64 per 100 000 per year; 95% CI 1.8 to 126.9) and among men (60 per 100 000 per year; 95% CI 12.3 to 107.3).Conclusion We found limited evidence that the service reduced emergency hospital admissions, after an initial decline the effect was not sustained. The service, however, may have been more effective in some subgroups.

Background and objectivesSleep-disordered breathing (SDB) affects up to one third of women during late pregnancy and is associated with adverse pregnancy outcomes, including hypertension, diabetes, impaired fetal growth, and preterm birth. However, it is unclear if SDB is associated with late stillbirth (≥28 weeks' gestation). The aim of this study was to investigate the relationship between self-reported symptoms of SDB and late stillbirth.MethodsData were obtained from five case-control studies (cases 851, controls 2257) from New Zealand (2 studies), Australia, the United Kingdom, and an international study. This was a secondary analysis of an individual participant data meta-analysis that investigated maternal going-to-sleep position and late stillbirth, with a one-stage approach stratified by study and site. Inclusion criteria: singleton, non-anomalous pregnancy, ≥28 weeks' gestation. Sleep data ('any' snoring, habitual snoring ≥3 nights per week, the Berlin Questionnaire [BQ], sleep quality, sleep duration, restless sleep, daytime sleepiness, and daytime naps) were collected by self-report for the month before stillbirth. Multivariable analysis adjusted for known major risk factors for stillbirth, including maternal age, body mass index (BMI kg/m2), ethnicity, parity, education, marital status, pre-existing hypertension and diabetes, smoking, recreational drug use, baby birthweight centile, fetal movement, supine going-to-sleep position, getting up to use the toilet, measures of SDB and maternal sleep patterns significant in univariable analysis (habitual snoring, the BQ, sleep duration, restless sleep, and daytime naps). Registration number: PROSPERO, CRD42017047703.ResultsIn the last month, a positive BQ (adjusted odds ratio [aOR] 1.44, 95% confidence interval [CI] 1.02-2.04), sleep duration >9 hours (aOR 1.82, 95% CI 1.14-2.90), daily daytime naps (aOR 1.52, 95% CI 1.02-2.28) and restless sleep greater than average (aOR 0.62, 95% CI 0.44-0.88) were independently related to the odds of late stillbirth. 'Any' snoring, habitual snoring, sleep quality, daytime sleepiness, and a positive BQ excluding the BMI criterion, were not associated.ConclusionA positive BQ, long sleep duration >9 hours, and daily daytime naps last month were associated with increased odds of late stillbirth, while sleep that is more restless than average was associated with reduced odds. Pregnant women may be reassured that the commonly reported restless sleep of late pregnancy may be physiological and associated with a reduced risk of late stillbirth.

Infections of diabetic foot ulcers are common, generally recalcitrant and often complicated by antibiotic resistance. Alternative antimicrobial strategies are needed. Phage therapy is a promising alternative that is being rediscovered. Despite phage therapy's 100-year history, there have been no investigations into patient thoughts and concerns. This study aimed to explore patient awareness of and concern about antibiotic resistance and gain insight into the perceptions of phage therapy among a patient group that could potentially benefit from phage therapy. Patients with an active or resolved (healed or amputated) diabetic foot ulcer were eligible to participate. A survey was distributed digitally to eligible patients across Scotland via the NHS Research Scotland Diabetes Network and hard copies were available in diabetic foot clinics at the Royal Infirmary of Edinburgh and Queen Elizabeth University Hospital, Glasgow. A focus group of five survey respondents was held in Glasgow. Fifty-five survey responses were obtained. There was a high level of awareness (76.4%; N = 55) and concern (83.3%; N = 54) about antibiotic resistance. While largely aware of viruses, most patients had not heard of phage or phage therapy. Patients were no more concerned about phage than antibiotic therapy, with most suggesting more information could alleviate any concerns. Patient acceptability of phage therapy was high, a finding confirmed by the focus group. Patients are concerned about antibiotic resistance and supportive of 'new' antimicrobials. We have demonstrated that patients are supportive, enthusiastic and accepting of phage therapy. Although 'Western' phage therapy remains in its infancy, an understanding of patient ideas, concerns and expectations will be important in eventually shaping and successfully reintroducing phage therapy.

Abstract Background Participation in bowel scope screening (BSS) is low (43%), limiting its potential to reduce colorectal cancer (CRC) incidence and mortality. This study aimed to quantify the prevalence of barriers to BSS and examine the extent to which these barriers differed according to non-participant profiles: non-responders to the BSS invitation, active decliners of the invitation, and non-attenders of confirmed appointments. Methods Individuals invited for BSS between March 2013 and December 2015, across 28 General Practices in England, were sent a questionnaire. Questions measured initial interest in BSS, engagement with the information booklet, BSS participation, and, where applicable, reasons for BSS non-attendance. Chi-square tests of independence were performed to examine the relationship between barriers, non-participant groups and socio-demographic variables. Results 1478 (45.8%) questionnaires were returned for analysis: 1230 (83.2%) attended screening, 114 (7.7%) were non-responders to the BSS invitation, 100 (6.8%) were active decliners, and 34 (2.3%) were non-attenders. Non-responders were less likely to have read the whole information booklet than active decliners (x 2 (2, N = 157) = 7.00, p = 0.008) and non-attenders (x 2 (2, N = 101) = 8.07, p = 0.005). Non-responders also had lower initial interest in having BSS than either active decliners (x 2 (2, N = 213) = 6.07, p = 0.014) or non-attenders (x2 (2, N = 146) = 32.93, p

The chromosome 15q25.1 locus is a leading susceptibility region for lung cancer. Here, the authors interrogate three GWAS cohorts with 42,901 individuals to investigate potential pathological pathways such as gated channel activity and neuroactive ligand receptor interaction in lung cancer etiology.

There is increasing interest in the development and deployment of digital solutions to improve patient care and facilitate monitoring in medical practice, e.g., by remote observation of disease symptoms in the patients’ home environment. Digital health solutions today range from non-regulated wellness applications and research-grade exploratory instruments to regulated software as a medical device (SaMD). This paper discusses the considerations and complexities in developing innovative, effective, and validated SaMD for multiple sclerosis (MS). The development of SaMD requires a formalised approach (design control), inclusive of technical verification and analytical validation to ensure reliability. SaMD must be clinically evaluated, characterised for benefit and risk, and must conform to regulatory requirements associated with device classification. Cybersecurity and data privacy are also critical. Careful consideration of patient and provider needs throughout the design and testing process help developers overcome challenges of adoption in medical practice. Here, we explore the development pathway for SaMD in MS, leveraging experiences from the development of Floodlight™ MS, a continually evolving bundled solution of SaMD for remote functional assessment of MS. The development process will be charted while reflecting on common challenges in the digital space, with a view to providing insights for future developers.

Abstract Background Uptake of colorectal cancer screening is low in the English NHS Bowel Cancer Screening Programme (BCSP). Participation in screening is strongly associated with socioeconomic status. The aim of this study was to determine whether a supplementary leaflet providing the ‘gist’ of guaiac-based Faecal Occult Blood test (gFOBt) screening for colorectal cancer could reduce the socioeconomic status (SES) gradient in uptake in the English NHS BCSP. Methods The trial was integrated within routine BCSP operations in November 2012. Using a cluster randomised controlled design all adults aged 59–74 years who were being routinely invited to complete the gFOBt were randomised based on day of invitation. The Index of Multiple Deprivation was used to create SES quintiles. The control group received the standard information booklet (‘SI’). The intervention group received the SI booklet and the Gist leaflet (‘SI + Gist’) which had been designed to help people with lower literacy engage with the invitation. Blinding of hubs was not possible and invited subjects were not made aware of a comparator condition. The primary outcome was the gradient in uptake across IMD quintiles. Results In November 2012, 163,525 individuals were allocated to either the ‘SI’ intervention (n = 79,104) or the ‘SI + Gist’ group (n = 84,421). Overall uptake was similar between the intervention and control groups (SI: 57.3% and SI + Gist: 57.6%; OR = 1.02, 95% CI: 0.92–1.13, p = 0.77). Uptake was 42.0% (SI) vs. 43.0% (SI + Gist) in the most deprived quintile and 65.6% vs. 65.8% in the least deprived quintile (interaction p = 0.48). The SES gradient in uptake was similar between the study groups within age, gender, hub and screening round sub-groups. Conclusions Providing supplementary simplified information in addition to the standard information booklet did not reduce the SES gradient in uptake in the NHS BCSP. The effectiveness of the Gist leaflet when used alone should be explored in future research. Trial registration ISRCTN74121020 , registered: 17/20/2012.

Abstract We have generated a drug-free, all-in-one dCAS9-SAM vector that can activate endogenous gene expression with the potential to modify cell fate. We demonstrate that this strategy can be used in a number of cell lines and avoids exceptionally high levels of gene expression that are observed in standard transgenic approaches. Compared to the multi-plasmid system, this all-in-one vector activates gene expression to a comparable level but the reduced overall DNA content results in significantly higher viability of transfected cells. This allowed us to use the RUNX1C-GFP human embryonic stem cell reporter cell line to monitor gene activation in individual cells and to show that activation could occur at all stages of the cell cycle.

Abstract Background The Auckland Stillbirth study demonstrated a two-fold increased risk of late stillbirth for women who did not go to sleep on their left side. Two further studies have confirmed an increased risk of late stillbirth with supine sleep position. As sleep position is modifiable, we surveyed self-reported late pregnancy sleep position, knowledge about sleep position, and views about changing going-to-sleep position. Methods Participants in this 2014 survey were pregnant women (n = 377) in their third trimester from South Auckland, New Zealand, a multi-ethnic and predominantly low socio-economic population. An ethnically-representative sample was obtained using random sampling. Multivariable logistic regression was performed to identify factors independently associated with non-left sided going-to-sleep position in late pregnancy. Results Respondents were 28 to 42 weeks’ gestation. Reported going-to-sleep position in the last week was left side (30%), right side (22%), supine (3%), either side (39%) and other (6%). Two thirds (68%) reported they had received advice about sleep position. Non-left sleepers were asked if they would be able to change to their left side if it was better for their baby; 87% reported they would have little or no difficulty changing. Women who reported a non-left going-to-sleep position were more likely to be of Maori (aOR 2.64 95% CI 1.23–5.66) or Pacific (aOR 2.91 95% CI 1.46–5.78) ethnicity; had a lower body mass index (BMI) (aOR 0.93 95% CI 0.89–0.96); and were less likely to sleep on the left-hand side of the bed (aOR 3.29 95% CI 2.03–5.32). Conclusions Maternal going-to-sleep position in the last week was side-lying in 91% of participants. The majority had received advice to sleep on their side or avoid supine sleep position. Sleeping on the left-hand side of the bed was associated with going-to-sleep on the left side. Most non-left sleepers reported their sleeping position could be modified to the left side suggesting a public health intervention about sleep position is likely to be feasible in other multi-ethnic communities.

Stem cell-derived macrophages could treat liver fibrosis Macrophages, a type of white blood cell, when derived from embryonic stem cells in the laboratory reduce fibrosis in chronic liver disease. Lesley Forrester and colleagues from the University of Edinburgh found murine embryonic stem-cell-derived macrophages (ESDM) were morphologically similar to bone marrow-derived macrophages (BMDM), previously found to reduce fibrosis and improve liver function in mice with induced liver injury. Using a novel technique, the team found ESDM engulfed fewer particles at a slower rate than BMDM, indicating ESDM were less inflammatory. A higher dose of ESDM was required to have the same effect of BMDM to help liver fibrosis regression. However, they were more efficient in repopulating mouse livers depleted of liver-specific macrophages and also significantly improved liver function, indicating ESDM were similar to resident macrophages in the liver and had therapeutic potential.

Abstract More than 10% of babies are born too early resulting in over 15 million preterm births and more than one million new-born deaths globally. Although women with a previous spontaneous preterm birth (SPTB) are considered at high risk for recurrence, the majority occur in women without prior history. Prediction of SPTB risk allows for improved care and potential for targeting novel and existing therapeutics to prevent SPTB, which may result in improved outcomes for infant and mother. In this pilot study, a miRNA array was used to analyse plasma from healthy women in their first pregnancy at 20 weeks of gestation who then went on to deliver either at term or experience SPTB at 28–32 weeks. We identified specific miRNA expression profiles that differentiated between those mothers who delivered at term or delivered following SPTB. miR302b, miR1253 and a clustering of miR548 miRNAs were underexpressed in SPTB cases compared to term controls. Conversely, miR223 was elevated in mothers that later experienced a SPTB. The circulating miRNAs identified in the present study may therefore be attractive candidates as non-invasive biomarkers for the early prediction of SPTB. Further larger studies are now warranted to investigate the potential clinical utility of these markers.

Abstract Background In Australia the health outcomes of remote dwelling Aboriginal infants are comparable to infants in developing countries. This research investigates service quality, from the clinicians’ perspective and as observed and recorded by the researcher, in two large Aboriginal communities in the Top End of northern Australia following health system changes. Methods Data were collected from semi-structured interviews with 25 clinicians providing or managing child health services in the two study sites. Thirty hours of participant observation was undertaken in the ‘baby-rooms’ at the two remote health centres between June and December 2012. The interview and observational data, as well as field notes were integrated and analysed thematically to explore clinicians’ perspectives of service delivery to infants in the remote health centres. Results A range of factors affecting the quality of care, mostly identified before health system changes were instigated, persisted. These factors included ineffective service delivery, inadequate staffing and culturally unsafe practices. The six themes identified in the data: ‘very adhoc’, ‘swallowed by acute’, ‘going under’, ‘a flux’, ‘a huge barrier’ and ‘them and us’ illustrate how these factors continue, and when combined portray a ‘very chaotic system’. Conclusion Service providers perceived service provision and quality to be inadequate, despite health system changes. Further work is urgently needed to improve the quality, cultural responsiveness and effectiveness of services to this population.