Social prescribing for people living with dementia (PLWD) and their carers: what works, for whom, under what circumstances and why - protocol for a complex intervention systematic review.

INTRODUCTION: Dementia is a complex medical condition that poses significant challenges to healthcare systems and support services. People living with dementia (PLWD) and their carers experience complex needs often exacerbated by social isolation and challenges in accessing support. Social prescribing (SP) seeks to enable PLWD and their carers to access community and voluntary sector resources to support them address such needs. Existing research, however, does not describe what SP interventions are currently in place in dementia care. Little is known about the needs these interventions are designed to address, the reasons that lead PLWD and their carers to participate in them, their effectiveness and the extent to which they could increase positive health outcomes if adopted and how. METHODS AND ANALYSIS: A complex intervention systematic review of SP for PLWD and/or their carers will be conducted using an iterative logic model approach. Six electronic (MEDLINE, EMBASE, PsycINFO, CINAHL, Scopus and Cochrane/CENTRAL) and two grey literature databases (EThOS and CORE) were searched for publications between 1 January 2003 and June 2023, supplemented by handsearching of reference lists of included studies. Study selection, data extraction and risk of bias assessment, using Gough's Weight of Evidence Framework, will be independently performed by two reviewers. A narrative approach will be employed to synthesise and report quantitative and qualitative data. Reporting will be informed by the Preferred Reporting Items for Systematic Review and Meta-Analysis Complex Interventions extension statement and checklist. ETHICS AND DISSEMINATION: No ethical approval is required due to this systematic review operating only with secondary sources. Findings will be disseminated through peer-reviewed publications, conference presentations and meetings with key stakeholders including healthcare professionals, patient and carer groups, community organisations (eg, the Social Prescribing Network and the Evidence Collaborative at the National Academy for Social Prescribing), policymakers and funding bodies. PROSPERO REGISTRATION NUMBER: CRD42023428625.

A comparison of dermal toxicity models; assessing suitability for safe(r)-by-design decision-making and for screening nanomaterial hazards.

The objective of Safe-by-Design (SbD) is to support the development of safer products and production processes, and enable safe use throughout a materials' life cycle; an intervention at an early stage of innovation can greatly benefit industry by reducing costs associated with the development of products later found to elicit harmful effects. Early hazard screening can support this process, and is needed for all of the expected nanomaterial exposure routes, including inhalation, ingestion and dermal. In this study, we compare in vitro and ex vivo cell models that represent dermal exposures (including HaCaT cells, primary keratinocytes, and reconstructed human epidermis (RhE)), and when possible consider these in the context of regulatory accepted OECD TG for in vitro dermal irritation. Various benchmark nanomaterials were used to assess markers of cell stress in each cell model. In addition, we evaluated different dosing strategies that have been used when applying the OECD TG for dermal irritation in assessment of nanomaterials, and how inconsistencies in the approach used can have considerable impact of the conclusions made. Although we could not demonstrate alignment of all models used, there was an indication that the simpler in vitro cell model aligned more closely with RhE tissue than ex vivo primary keratinocytes, supporting the use of HaCaT cells for screening of dermal toxicity of nanomaterials and in early-stage SbD decision-making.

Semantic fluency in primary school-age children with vision impairment.

PURPOSE: Semantic fluency is potentially a useful tool for vocabulary assessment in children with vision impairment because it contains no visual test stimuli. It is not known whether in the primary school years children with vision impairment perform more poorly on semantic fluency tasks compared to their sighted peers. METHOD: We compared semantic fluency performance of two groups of 5- to 11-year-old British English speaking children-one group with vision impairment and one without. We also investigated within-group differences in performance, based on severity of vision impairment. We administered one category (animals) to children with vision impairment (n = 45) and sighted children (n = 30). Participants had one minute to respond. Responses were coded for accuracy, error type, clusters, and switches. RESULT: Correct responses increased with age within each group. Groups did not differ significantly on any outcome measure. Severity of vision impairment did not impact task performance. CONCLUSION: Results suggested that semantic fluency performance-at least for the category animals-is not different in children with vision impairment compared to sighted children. Findings also suggest that semantic fluency could be a suitable addition to the tools that speech-language pathologists use to assess language abilities in children with vision impairment.

White Kids on the Block: On Race, Identity and Criminality Among Incarcerated White Youth.

This study contributes to efforts already underway to attend to the reproduction of white supremacy and the ways whiteness manifests across contexts. We examine whiteness and white racial identity development among incarcerated youth, both a group and place not often studied in relation to these two concepts. Using critical ethnographic methods, we explore how processes of white identity development unfold among incarcerated white youth and the ways in which whiteness is lived, negotiated, and challenged within the carceral context. Findings suggest that white youth used pre-existing racial scripts about race, whiteness, and criminality to make sense of and navigate life in the carceral context. Still, we found that these racial scripts were often seeped in anti-black racist logics about criminality in service of whiteness and the construction of superior white identities.

Glycolytic inhibition with 3-bromopyruvate suppresses tumor growth and improves survival in a murine model of anaplastic thyroid cancer.

BACKGROUND: Anaplastic thyroid cancer is a rare but devastating malignancy. Anaplastic thyroid cancer cells exhibit the Warburg effect by preferentially undergoing glycolysis even in aerobic conditions, leading to high glucose use. Here we assess if targeted inhibition of glycolysis can diminish anaplastic thyroid cancer growth and improve outcomes. METHODS: Human anaplastic thyroid cancer cell line 8505C was grown in medium containing high (25 mmol/L) or low (3 mmol/L) glucose concentration and hexokinase II inhibitor 3-bromopyruvate (200 µM). Cellular proliferation, migration, and invasion were measured. An orthotopic xenograft model of anaplastic thyroid cancer was generated in nude mice using 8505C cells. Animals were provided standard chow or a ketogenic diet and treated with 3-bromopyruvate (1.8 mg/kg). Overall survival time was monitored. Necropsies were performed to harvest tumors for analysis. RESULTS: Growth of 8505C in low-glucose medium with 3-bromopyruvate decreased cell proliferation by 89%, migration by 44%, and invasion by 73% (P < .001 for all) compared with high glucose. Animals concomitantly receiving a ketogenic diet and 3-bromopyruvate exhibited smaller tumor volumes (P = .03), slower tumor growth rates (P = .01), and improved overall survival (P = .006) compared with standard-diet control subjects. Monotherapy with a ketogenic diet or 3-bromopyruvate alone did not reduce tumor size or increase survival over the standard-diet control group. CONCLUSION: Glycolytic inhibition with 3-bromopyruvate inhibits tumor growth and extends survival in a murine model of anaplastic thyroid cancer when combined with the ketogenic diet. Thus, targeted glycolytic inhibition of anaplastic thyroid cancer exhibits context-specific utility and may only be effective during ketosis induced by dietary restriction of glycolytic inputs.

Insulin-Like Growth Factor-1 Differentially Modulates Glutamate-Induced Toxicity and Stress in Cells of the Neurogliovascular Unit.

The age-related reduction in circulating levels of insulin-like growth factor-1 (IGF-1) is associated with increased risk of stroke and neurodegenerative diseases in advanced age. Numerous reports highlight behavioral and physiological deficits in blood-brain barrier function and neurovascular communication when IGF-1 levels are low. Administration of exogenous IGF-1 reduces the extent of tissue damage and sensorimotor deficits in animal models of ischemic stroke, highlighting the critical role of IGF-1 as a regulator of neurovascular health. The beneficial effects of IGF-1 in the nervous system are often attributed to direct actions on neurons; however, glial cells and the cerebrovasculature are also modulated by IGF-1, and systemic reductions in circulating IGF-1 likely influence the viability and function of the entire neuro-glio-vascular unit. We recently observed that reduced IGF-1 led to impaired glutamate handling in astrocytes. Considering glutamate excitotoxicity is one of the main drivers of neurodegeneration following ischemic stroke, the age-related loss of IGF-1 may also compromise neural function indirectly by altering the function of supporting glia and vasculature. In this study, we assess and compare the effects of IGF-1 signaling on glutamate-induced toxicity and reactive oxygen species (ROS)-produced oxidative stress in primary neuron, astrocyte, and brain microvascular endothelial cell cultures. Our findings verify that neurons are highly susceptible to excitotoxicity, in comparison to astrocytes or endothelial cells, and that a prolonged reduction in IGFR activation increases the extent of toxicity. Moreover, prolonged IGFR inhibition increased the susceptibility of astrocytes to glutamate-induced toxicity and lessened their ability to protect neurons from excitotoxicity. Thus, IGF-1 promotes neuronal survival by acting directly on neurons and indirectly on astrocytes. Despite increased resistance to excitotoxic death, both astrocytes and cerebrovascular endothelial cells exhibit acute increases in glutamate-induced ROS production and mitochondrial dysfunction when IGFR is inhibited at the time of glutamate stimulation. Together these data highlight that each cell type within the neuro-glio-vascular unit differentially responds to stress when IGF-1 signaling was impaired. Therefore, the reductions in circulating IGF-1 observed in advanced age are likely detrimental to the health and function of the entire neuro-glio-vascular unit.

Non-ambient X-ray and neutron diffraction of novel relaxor ferroelectric xBi2(Zn2/3,Nb1/3)O3-(1 - x)BaTiO3.

The first determination of the phase diagram of the novel ferroelectric relaxor xBi(Zn2/3Nb1/3)O3-(1 - x)BaTiO3 (BZN-BT) has been achieved with a combination of high-resolution X-ray and neutron diffraction up to the miscibility limit near x(BZN) = 20.0% over a temperature range 20 < T < 400 K. The combined X-ray and neutron data show that the instability within the xBZN-(1-x)BT system reaches a maximum at x = 3.9% and is driven by B-site displacement and distortion of the oxygen octahedra in the polar phases. Composition-dependent effects include a narrow Amm2-dominated region focused at x = 3.9%, significant convergence of the lattice parameters in both P4mm and Amm2 phases, and sharp maxima in piezoelectric coefficient d 33 and maximum polarization P max. Lattice parameter dilation at x ≥ 4.0% was observed for both P4mm and Amm2 unit cells, alongside the first appearance of Pm 3 m at 295 K and the onset of significant dielectric relaxation. Low-temperature neutron diffraction indicated a weak or non-existent temperature dependence on the transition from ferroelectric at x = 3.9% to ferroelectric relaxor at x = 4.0%. Temperature-dependent phase transitions were eliminated near x = 3.0%, with the ferroelectric limit observed at x = 5.0% and a transition to a low-loss relaxor dielectric near x = 8.0%.

Challenges for Family Medicine Residents in Attaining the CanMEDS Professional Role: A Thematic Analysis of Preceptor Field Notes.

PURPOSE: Among the roles of the competent physician is that of a professional, according to the Canadian Medical Education Directives for Specialists (CanMEDS) framework, which describes the abilities physicians require to effectively meet the health care needs of the people they serve. Through examination of preceptor field notes on resident performance, the authors identified aspects of this role with which family medicine residents struggle. METHOD: The authors used a structured thematic analysis in this qualitative study to explore the written feedback postgraduate medical learners receive at the University of Toronto Department of Family and Community Medicine. Seventy field notes written between 2015 and 2017 by clinical educators for residents who scored "below expectation" in the CanMEDS professional role were analyzed. From free-text comments, the authors derived inductive codes, amalgamated the codes into themes, and measured the frequency of the occurrence of the codes. The authors then mapped the themes to the key competencies of the CanMEDS professional role. RESULTS: From the field notes, 7 themes emerged that described reasons for poor performance. Lack of collegiality, failure to adhere to standards of practice or legal guidelines, and lack of reflection or self-learning were identified as major issues. Other themes were failure to maintain boundaries, taking actions that could have a negative impact on patient care, failure to maintain patient confidentiality, and failure to engage in self-care. When the themes were mapped to the key competencies in the CanMEDS professional role, most related to the competency "commitment to the profession." CONCLUSIONS: This study highlights aspects of professional conduct with which residents struggle and suggests that the way professionalism is taught in residency programs-and at all medical training levels-should be reassessed. Educational interventions that emphasize learners' commitment to the profession could enhance the development of more practitioners who are consummate professionals.

Lights Out: Examining Sleep in Children with Vision Impairment.

Sleep is crucial for development across cognitive, physical, and social-emotional domains. Sleep quality and quantity impact domains of daytime functioning, attainment, and global development. Previous work has explored sleep profiles in typically developing children and children with developmental disorders such as Down syndrome and Williams Syndrome, yet there is a complete absence of published work regarding the sleep profiles of children with vision impairment aged 4-11 years. This is the first known study that examines the sleep profiles in children with vision impairment (n = 58) in comparison to 58 typically developing children (aged 4-11 years) in the UK. Sleep was measured using the Childhood Sleep Habits Questionnaire (CSHQ; parental report), actigraphy and sleep diaries. Results showed group differences in subjective CSHQ scores but not objective actigraphy measures. Surprisingly, the findings revealed disordered sleep (namely, poor sleep quantity) in both groups. Discordance between CSHQ and actigraphy measures could represent heightened awareness of sleeping problems in parents/caregivers of children with vision impairment. The implications of this study extend beyond group comparison, examining disordered sleep in 'typically developing' children, exploring the potential role of light perception and the importance of sleep quality and quantity in both groups.

A network pharmacology study on analgesic mechanism of Yuanhu-Baizhi herb pair.

BACKGROUND: Millions of people are suffering from chronic pain conditions, such as headache, arthritis, cancer. Apart from western medicines, traditional Chinese medicines are also well accepted for pain management, especially in Asian countries. Yuanhu-Baizhi herb pair (YB) is a typical herb pair applied to the treatment of stomach pain, hypochondriac pain, headache, and dysmenorrhea, due to its effects on analgesia and sedation. This study is to identify potentially active compounds and the underlying mechanisms of YB in the treatment of pain. METHODS: Compounds in YB were collected from 3 online databases and then screened by bioavailability and drug likeness parameters. Swiss target prediction was applied to obtain targets information of the active compounds. Pain-related genes were conducted for Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Protein-protein interaction (PPI) networks of the genes were constructed using Cytoscape software. In addition, the hub genes were screened using maximal clique centrality (MCC) algorithm. RESULTS: In total, 31 compounds from Yuanhu were screened out with 35 putative target genes, while 26 compounds in Baizhi with 43 target genes were discovered. Hence, 78 potential target genes of YB were selected for further study. After overlap analysis of the 78 genes of YB and 2408 pain-associated genes, we finally achieved 34 YB-pain target genes, as well as 10 hub genes and 23 core compounds. Go enrichment and KEGG pathway analysis indicated that YB had a strong integration with neuro system, which might significantly contribute to antinociceptive effect. CONCLUSION: Our data provide deep understanding of the pharmacological mechanisms of YB in attenuating pain. The discovery shed new light on the development of active compounds of YB for the treatment of pain.

Age-dependent hormesis-like effects of the synthetic cannabinoid CP55940 in C57BL/6 mice.

Use of cannabis and cannabinoid-containing substances is increasing among geriatric patients, despite relatively sparse preclinical evidence in aged models. To better understand the effects of exogenous cannabinoids on aging male and female rodents, we compared the age- and dose-dependent physiological and behavioral effects of the synthetic cannabinoid CP55940 in young-adult and aged C57BL/6 mice. Locomotion, body temperature, thermal nociception, and fecal output were measured following CP55940 administration. Our findings indicate that CP55940 is more potent and efficacious in older mice, evidenced by exaggerated antinociception and locomotor inhibition when compared to younger adult mice. In addition, we report that low doses of CP55940 paradoxically stimulate locomotion in young-adult (4 m) mice; however, this hormesis-like response is not as evident in aged animals (21-24 m). These bidirectional effects appear to be mediated via the endocannabinoid CB1 and CB2 receptors.

Fecal microbiota transplantation from high caloric-fed donors alters glucose metabolism in recipient mice, independently of adiposity or exercise status.

Studies suggest the gut microbiota contributes to the development of obesity and metabolic syndrome. Exercise alters microbiota composition and diversity and is protective of these maladies. We tested whether the protective metabolic effects of exercise are mediated through fecal components through assessment of body composition and metabolism in recipients of fecal microbiota transplantation (FMT) from exercise-trained (ET) mice fed normal or high-energy diets. Donor C57BL/6J mice were fed a chow or high-fat, high-sucrose diet (HFHS) for 4 wk to induce obesity and glucose intolerance. Mice were divided into sedentary (Sed) or ET groups (6 wk treadmill-based ET) while maintaining their diets, resulting in four donor groups: chow sedentary (NC-Sed) or ET (NC-ET) and HFHS sedentary (HFHS-Sed) or ET (HFHS-ET). Chow-fed recipient mice were gavaged with feces from the respective donor groups weekly, creating four groups (NC-Sed-R, NC-ET-R, HFHS-Sed-R, HFHS-ET-R), and body composition and metabolism were assessed. The HFHS diet led to glucose intolerance and obesity in the donors, whereas exercise training (ET) restrained adiposity and improved glucose tolerance. No donor group FMT altered recipient body composition. Despite unaltered adiposity, glucose levels were disrupted when challenged in mice receiving feces from HFHS-fed donors, irrespective of donor-ET status, with a decrease in insulin-stimulated glucose clearance into white adipose tissue and large intestine and specific changes in the recipient's microbiota composition observed. FMT can transmit HFHS-induced disrupted glucose metabolism to recipient mice independently of any change in adiposity. However, the protective metabolic effect of ET on glucose metabolism is not mediated through fecal factors.

Loss of insulin-like growth factor-1 signaling in astrocytes disrupts glutamate handling.

Insulin-like Growth Factor-1 (IGF-1) has been studied extensively for its ability to promote neuronal growth and excitability. Declining levels of IGF-1 have been correlated with impaired learning and memory as well as an increased risk of neurodegenerative diseases. While neuronal regulation by IGF-1 is well understood, the role of IGF-1 in influencing astrocyte function requires further exploration. Astrocytes regulate many aspects of the brain microenvironment, including controlling glutamate-glutamine cycling, which ultimately supports neuronal metabolism, neurotransmission, and protection from over stimulation. In this study, we examined whether IGF-1 acts through its cognate receptor, IGFR, to alter astrocytic glutamate handling. We utilized both small molecule IGFR inhibitors and Cre-driven genetic approaches to reduce IGFR in vivo and in cultured rodent astrocytes. When IGFR was knocked out of primary astrocytes derived from igfrf/f mice using AAV5-CMV-Cre, significant reductions in glutamate uptake were observed. Similarly, inhibition of IGFR with picropodophyllotoxin for 2 h, as well as 24 h, reduced glutamate uptake in vitro. Mechanistically, short-term inhibition of IGFR resulted in a significant decrease in glutamate transporter availability on the cell surface, as assessed by biotinylation. Long-term inhibition of IGFR led to significant reductions in mRNA expression of glutamate transport machinery, as assessed with qPCR. Reduced glutamate transporter mRNA was also observed in the brains of astrocyte-specific IGFR-deficient mice, three to four months after knock-out was induced with tamoxifen. Interestingly, long-term IGF-1 inhibition also resulted in an increase in adenosine triphosphate-stimulated glutamate release, though no change in adenosine triphosphate-stimulated calcium flux was observed nor were any changes in purinergic receptor protein expression. Together, these data suggest that reduced IGF-1 signaling will favor an accumulation of extrasynaptic glutamate, which may contribute to neurodegeneration in disease states where IGF-1 levels are low. Cover Image for this issue: doi: 10.1111/jnc.14534.

Warfarin-Induced Skin Necrosis in the Presence of Acute Hepatic Injury and May-Thurner Syndrome.

Purpose: The purpose of the report is to describe a patient with warfarin-induced skin necrosis in the presence of acute hepatic injury and significant risk factors for venous thromboembolism, including protein C deficiency and May-Thurner syndrome. Summary: A 44-year-old female with multiple comorbidities presented to the emergency department with a significantly elevated international normalized ratio (INR > 15.9) rapidly reversed with vitamin K and fresh frozen plasma. Due to the findings of bilateral acute on chronic deep vein thromboses (DVTs) and suspected warfarin-induced skin necrosis, a heparin infusion was initiated but later discontinued due to endogenous partial thromboplastin times (PTT) elevations despite dose reductions. Although the necrosis encompassed large areas of the fatty tissue, the depth of necrosis remained mostly superficial. Supportive care and wound management were provided following warfarin reversal; no skin grafts or amputations were performed. Conclusion: A 44-year-old female developed a complicated probable warfarin-induced skin necrosis in the setting of acute liver failure, septic shock, May-Thurner syndrome, previously failed anticoagulation, and acute deep vein thrombosis.

Skeletal muscle-specific overexpression of heat shock protein 72 improves skeletal muscle insulin-stimulated glucose uptake but does not alter whole body metabolism.

AIMS: The induction of heat shock protein 72 (Hsp72) via heating, genetic manipulation or pharmacological activation is metabolically protective in the setting of obesity-induced insulin resistance across mammalian species. In this study, we set out to determine whether the overexpression of Hsp72, specifically in skeletal muscle, can protect against high-fat diet (HFD)-induced obesity and insulin resistance. MATERIALS AND METHODS: An Adeno-Associated Viral vector (AAV), designed to overexpress Hsp72 in skeletal muscle only, was used to study the effects of increasing Hsp72 levels on various metabolic parameters. Two studies were conducted, the first with direct intramuscular (IM) injection of the AAV:Hsp72 into the tibialis anterior hind-limb muscle and the second with a systemic injection to enable body-wide skeletal muscle transduction. RESULTS: IM injection of the AAV:Hsp72 significantly improved skeletal muscle insulin-stimulated glucose clearance in treated hind-limb muscles, as compared with untreated muscles of the contralateral leg when mice were fed an HFD. Despite this finding, systemic administration of AAV:Hsp72 did not improve body composition parameters such as body weight, fat mass or percentage body fat, nor did it lead to an improvement in fasting glucose levels or glucose tolerance. Furthermore, no differences were observed for other metabolic parameters such as whole-body oxygen consumption, energy expenditure or physical activity levels. CONCLUSIONS: At the levels of Hsp72 over-expression reported herein, skeletal muscle-specific Hsp72 overexpression via IM injection has the capacity to increase insulin-stimulated glucose clearance in this muscle. However, upon systemic injection, which results in lower muscle Hsp72 overexpression, no beneficial effects on whole-body metabolism are observed.

Colo-ovarian fistula.

Colo-ovarian fistula is a rare entity. The case of a 54-year-old female with a colo-ovarian fistula is presented. We describe our experience in managing this complication of diverticulitis and propose a workup and treatment plan. Initial imaging and diagnostic studies are described. En-bloc resection of the sigmoid colon and ovary was performed. A review of the literature is presented.

A Trial of Telephone Support Services to Prevent Further Intimate Partner Violence.

We conducted a randomized-controlled trial of telephone support services (TSS) versus enhanced usual care (EUC) for women who had reported intimate partner violence (IPV) within the past year during a visit to a pediatric emergency department. TSS nurse interventionists identified appropriate referrals to community programs, helped participants by problem-solving barriers to obtaining these local services, and provided social support. Three hundred women, ages 18 years and above were recruited. The TSS and EUC groups did not differ on any outcome variable, including IPV victimization, feelings of chronic vulnerability to a perpetrator, depressive symptoms, and posttraumatic stress disorder symptoms.