Where's the Disconnect? Exploring Pathways to Healthcare Coordinated for Youth Experiencing Homelessness in Toronto, Canada, Using Grounded Theory Methodology.

About 900 youth experiencing homelessness (YEH) reside at an emergency youth shelter (EYS) in Toronto on any given night. Several EYSs offer access to healthcare based on youths' needs, including access to primary care, and mental health and addictions support. However, youth also require healthcare from the broader health system, which is often challenging to navigate and access. Currently, little is known about healthcare coordination efforts between the EYS and health systems for YEH. Using grounded theory methodology, we interviewed 24 stakeholders and concurrently analyzed and compared data to explore pathways to healthcare coordinated for youth who reside at an EYS in Toronto. We also investigated fundamental parts (i.e., norms, resources, regulations, and operations) within the EYS and health systems that influence these pathways to healthcare using thematic analysis. A significant healthcare coordination gap was found between these two systems, typically when youth experience crises, often resulting in a recurring loop of transition and discharge between EYSs and hospitals. Several parts within each system act interdependently in hindering adequate healthcare coordination between the EYS and health systems. Incorporating training for system staff on how to effectively coordinate healthcare and work with homeless populations who have complex health needs, and rethinking information-sharing policies within circles of care are examples of how system parts can be targeted to improve healthcare coordination for YEH. Establishing multidisciplinary healthcare teams specialized to serve the complex needs of YEH may also improve healthcare coordination between systems, and access and quality of healthcare for this population.

Acute-Phase Plasma Pigment Epithelium-Derived Factor Predicting Outcomes after Aneurysmal Subarachnoid Hemorrhage in the Elderly.

Aneurysmal subarachnoid hemorrhage (SAH) has increased with the aging of the population, but the outcome for elderly SAH patients is very poor. Therefore, predicting the outcome is important for determining whether to pursue aggressive treatment. Pigment epithelium-derived factor (PEDF) is a matricellular protein that is induced in the brain, and the plasma levels could be used as a biomarker for the severity of metabolic diseases. This study investigated whether acute-phase plasma PEDF levels could predict outcomes after aneurysmal SAH in the elderly. Plasma samples and clinical variables were collected over 1-3 days, post-SAH, from 56 consecutive elderly SAH patients ≥75 years of age registered in nine regional stroke centers in Japan between September 2013 and December 2016. The samples and variables were analyzed in terms of 3-month outcomes. Acute-phase plasma PEDF levels were significantly elevated in patients with ultimately poor outcomes, and the cutoff value of 12.6 µg/mL differentiated 3-month outcomes with high sensitivity (75.6%) and specificity (80.0%). Acute-phase plasma PEDF levels of ≥12.6 µg/mL were an independent and possibly better predictor of poor outcome than previously reported clinical variables. Acute-phase plasma PEDF levels may serve as the first biomarker to predict 3-month outcomes and to select elderly SAH patients who should be actively treated.

Effects of the Norfolk diabetes prevention lifestyle intervention (NDPS) on glycaemic control in screen-detected type 2 diabetes: a randomised controlled trial.

BACKGROUND: The purpose of this trial was to test if the Norfolk Diabetes Prevention Study (NDPS) lifestyle intervention, recently shown to reduce the incidence of type 2 diabetes in high-risk groups, also improved glycaemic control in people with newly diagnosed screen-detected type 2 diabetes. METHODS: We screened 12,778 participants at high risk of type 2 diabetes using a fasting plasma glucose and glycosylated haemoglobin (HbA1c). People with screen-detected type 2 diabetes were randomised in a parallel, three-arm, controlled trial with up to 46 months of follow-up, with a control arm (CON), a group-based lifestyle intervention of 6 core and up to 15 maintenance sessions (INT), or the same intervention with additional support from volunteers with type 2 diabetes trained to co-deliver the lifestyle intervention (INT-DPM). The pre-specified primary end point was mean HbA1c compared between groups at 12 months. RESULTS: We randomised 432 participants (CON 149; INT 142; INT-DPM 141) with a mean (SD) age of 63.5 (10.0) years, body mass index (BMI) of 32.4 (6.4) kg/m2, and HbA1c of 52.5 (10.2) mmol/mol. The primary outcome of mean HbA1c at 12 months (CON 48.5 (9.1) mmol/mol, INT 46.5 (8.1) mmol/mol, and INT-DPM 45.6 (6.0) mmol/mol) was significantly lower in the INT-DPM arm compared to CON (adjusted difference -2.57 mmol/mol; 95% CI -4.5, -0.6; p = 0.007) but not significantly different between the INT-DPM and INT arms (-0.55 mmol/mol; 95% CI -2.46, 1.35; p = 0.57), or INT vs CON arms (-2.14 mmol/mol; 95% CI -4.33, 0.05; p = 0.07). Subgroup analyses showed the intervention had greater effect in participants < 65 years old (difference in mean HbA1c compared to CON -4.76 mmol/mol; 95% CI -7.75, -1.78 mmol/mol) than in older participants (-0.46 mmol/mol; 95% CI -2.67, 1.75; interaction p = 0.02). This effect was most significant in the INT-DPM arm (-6.01 mmol/mol; 95% CI -9.56, -2.46 age < 65 years old and -0.22 mmol/mol; 95% CI -2.7, 2.25; aged > 65 years old; p = 0.007). The use of oral hypoglycaemic medication was associated with a significantly lower mean HbA1c but only within the INT-DPM arm compared to CON (-7.0 mmol/mol; 95% CI -11.5, -2.5; p = 0.003). CONCLUSION: The NDPS lifestyle intervention significantly improved glycaemic control after 12 months in people with screen-detected type 2 diabetes when supported by trained peer mentors with type 2 diabetes, particularly those receiving oral hypoglycaemics and those under 65 years old. The effect size was modest, however, and not sustained at 24 months. TRIAL REGISTRATION: ISRCTN34805606 . Retrospectively registered 14.4.16.

Mechanisms enhancing the protective functions of macular xanthophylls in the retina during oxidative stress.

Macular xanthophylls (MXs) are distinguished from other dietary carotenoids by their high membrane solubility and preferential transmembrane orientation. Additionally, these properties enhance the chemical and physical stability of MXs in the eye retina, and maximize their protective activities. The effectiveness of MXs' protection is also enhanced by their selective accumulation in the most vulnerable domains of retinal membranes. The retina is protected by MXs mainly through blue-light filtration, quenching of the excited triplet states of potent photosensitizers, and physical quenching of singlet oxygen. To perform these physical, photo-related actions, the structure of MXs should remain intact. However, the conjugated double-bond structure of MXs makes them highly chemically reactive and susceptible to oxidation. Chemical quenching of singlet oxygen and scavenging of free radicals destroy their intact structure and consume MXs. Consequently, their physical actions, which are critical to the protection of retina, are diminished. Thus, it is timely and important to identify mechanisms whereby the chemical destruction (bleaching) of MXs in retinal membranes can be reduced. It was shown that nitroxide free radicals (spin labels) located in membranes protect MXs against destruction, and their effect is especially pronounced during the light-induced formation of singlet oxygen. That should extend and enhance their positive action in the retina through physical processes. In this review, we will discuss possible applications of this new strategy during ophthalmological procedures, which can cause acute bleaching of MXs and damage the retina through oxidative processes.

Antiangiogenic and antifibrogenic activity of pigment epithelium-derived factor (PEDF) in bile duct-ligated portal hypertensive rats.

OBJECTIVE: Antiangiogenic strategies have been proposed as a promising new approach for the therapy of portal hypertension and chronic liver disease. Pigment epithelium-derived factor (PEDF) is a powerful endogenous angiogenesis inhibitor whose role in portal hypertension remains unknown. Therefore, we aimed at determining the involvement of PEDF in cirrhotic portal hypertension and the therapeutic efficacy of its supplementation. DESIGN: PEDF expression profiling and its relationship with vascular endothelial growth factor (VEGF), neovascularisation and fibrogenesis was determined in bile duct-ligated (BDL) rats and human cirrhotic livers. The ability of exogenous PEDF overexpression by adenovirus-mediated gene transfer (AdPEDF) to inhibit angiogenesis, fibrogenesis and portal pressure was also evaluated in BDL rats, following prevention and intervention trials. RESULTS: PEDF was upregulated in cirrhotic human and BDL rat livers. PEDF and VEGF protein expression and localisation in mesentery and liver increased in parallel with portal hypertension progression, being closely linked in time and space with mesenteric neovascularisation and liver fibrogenesis in BDL rats. Furthermore, AdPEDF increased PEDF bioavailability in BDL rats, shifting the net balance in the local abundance of positive (VEGF) and negative (PEDF) angiogenesis drivers in favour of attenuation of portal hypertension-associated pathological neovascularisation. The antiangiogenic effects of AdPEDF targeted only pathological angiogenesis, without affecting normal vasculature, and were observed during early stages of disease. AdPEDF also significantly decreased liver fibrogenesis (through metalloproteinase upregulation), portosystemic collateralisation and portal pressure in BDL rats. CONCLUSIONS: This study provides compelling experimental evidence indicating that PEDF could be a novel therapeutic agent worthy of assessment in portal hypertension and cirrhosis.

The circadian clock: pacemaker and tumour suppressor.

The circadian rhythms are daily oscillations in various biological processes that are regulated by an endogenous clock. Disruption of these rhythms has been associated with cancer in humans. One of the cellular processes that is regulated by circadian rhythm is cell proliferation, which often shows asynchrony between normal and malignant tissues. This asynchrony highlights the importance of the circadian clock in tumour suppression in vivo and is one of the theoretical foundations for cancer chronotherapy. Investigation of the mechanisms by which the circadian clock controls cell proliferation and other cellular functions might lead to new therapeutic targets.

A Multicenter, Phase II Trial of Schedule Modification for Nab-Paclitaxel in Combination with Ramucirumab for Patients with Previously Treated Advanced Gastric or Gastroesophageal Junction Cancer: The B-RAX Trial (JACCRO GC-09).

BACKGROUND: This study investigated whether schedule modification of bi-weekly nanoparticle albumin-bound paclitaxel (nab-PTX) plus ramucirumab (RAM) is efficacious against gastric cancer (GC) or gastroesophageal junction cancer (GJC). PATIENTS AND METHODS: Patients with unresectable GC or GJC who were previously treated with fluoropyrimidine-containing regimens received nab-PTX (100 mg/m2) on days 1, 8, and 15 and RAM (8 mg/kg) on days 1 and 15 of a 28-day cycle. Based on the incidence of severe adverse events (AEs) during the first cycle, patients were modified to bi-weekly therapy from the second cycle. The primary endpoint was progression-free survival (PFS) in the bi-weekly therapy population. Based on the hypothesis that bi-weekly nab-PTX plus RAM would improve PFS from 4.5 to 7.0 months, 40 patients were required for power of 0.8 with a one-sided α of 0.05. RESULTS: Of the 81 patients enrolled, 47 patients (58%) were assigned to bi-weekly therapy. Patient characteristics were Eastern Cooperative Oncology Group performance status of 1 (19%) and diffuse type (45%). Median PFS was 4.7 months (95% confidence interval [CI] 3.7-5.6 months) and overall response rate was 25% (95% CI 11-39%). Severe AEs of grade 3 or worse were mainly neutropenia (83%) and hypertension (23%). EQ-5D scores were maintained during the treatment. In patients who continued standard-schedule therapy, median PFS was 2.7 months (95% CI 1.8-4.0 months). CONCLUSIONS: The primary endpoint for PFS was statistically not met, but modification of nab-PTX plus RAM to a bi-weekly schedule might be a feasible treatment option as second-line treatment for advanced GC/GJC patients, especially elderly patients, with severe AEs during the first cycle.

The SARS-CoV-2 rS1-E-PLGA nanovaccine and evaluation of its immune effect in BALB/c mice.

OBJECTIVE: Vaccination is an important method for preventing COVID-19 infection. However, certain vaccines do not meet the current needs. To improve the vaccine effect, discard ineffective antigens, and focus on high-quality antigenic clusters, S1-E bivalent antigens were designed. MATERIALS AND METHODS: Vaccine delivery is performed using poly (lactic-co-glycolic acid) (PLGA). Here, the recombinant S1-E (rS1-E) was covered on PLGA and injected intramuscularly into mice. In total, 48 BALB/c mice were randomly divided into six groups with 8 mice in each group. The mice received intramuscular injections. Prior to vaccination, the hydrophobicity of the rS1-E and the antigenic site of the E protein were both analysed. The morphology, zeta potential, and particle size distribution of rS1-E-PLGA were examined. Anti-S1 and anti-E antibodies were detected in mouse serum by ELISA. Neutralising an-tibodies were detected by co-incubating the pseudovirus with the obtained serum. IL-2 and TNF-α levels were also measured. RESULTS: The designed recombinant S1-E protein was successfully coated on PLGA nanoparticles. rS1-E-PLGA nanovaccine has suitable size, shape, good stability, sustained release and other characteristics. Importantly, mice were stimulated with rS1-E-PLGA nanovaccines to produce high-titre antibodies and a good cellular immune response. CONCLUSIONS: Our results indicate that rS1-E-PLGA nanovaccine may provide a good protective effect, and the vaccine should be further investigated in human clinical trials for use in vaccination or as a booster.

High serum soluble tumor necrosis factor receptor 1 predicts poor treatment response in acute-stage schizophrenia.

Inflammation may be involved in the pathophysiology of schizophrenia. However, few cross-sectional or longitudinal studies have examined changes in biomarker expression to evaluate diagnostic and prognostic efficacy in acute-stage schizophrenia. We compared serum inflammatory biomarker concentrations in 87 patients with acute-stage schizophrenia on admission to 105 age-, sex-, and body mass index (BMI)-matched healthy controls. The measured biomarkers were soluble tumor necrosis factor receptor 1 (sTNFR1) and adiponectin, which are associated with inflammatory responses, and pigment epithelium-derived factor (PEDF), which has anti-inflammatory properties. We then investigated biomarker concentrations and associations with clinical factors in 213 patients (including 42 medication-free patients) and 110 unmatched healthy controls to model conditions typical of clinical practice. Clinical symptoms were assessed using the Brief Psychiatric Rating Scale and Global Assessment of Function. In 121 patients, biomarker levels and clinical status were evaluated at both admission and discharge. Serum sTNFR1 was significantly higher in patients with acute-stage schizophrenia compared to matched controls while no significant group differences were observed for the other markers. Serum sTNFR1 was also significantly higher in the 213 patients compared to unmatched controls. The 42 unmedicated patients had significantly lower PEDF levels compared to controls. Between admission and discharge, sTNFR1 levels decreased significantly; however, biomarker changes did not correlate with clinical symptoms. The discriminant accuracy of sTNFR1 was 93.2% between controls and patients, showing no symptom improvement during care. Inflammation and a low-level anti-inflammatory state may be involved in both schizophrenia pathogenesis and acute-stage onset. High serum sTNFR1 in the acute stage could be a useful prognostic biomarker for treatment response in clinical practice.

Study of Pigment Epithelium-derived Factor in Pathogenesis of Diabetic Retinopathy.

Diabetic retinopathy (DR), a major microvascular complication of diabetes, has emerged as a leading cause of visual impairment and blindness among adults worldwide. However, aside from pathological damage, the traditional laser and multi-needle operation treatments required for more advanced disease can cause further damage to the visual field and increase the operation risk. Therefore, the development of new therapeutic strategies for the prevention and treatment of DR is essential. Some emerging evidence now indicates that pigment epithelium-derived factor (PEDF), a multifunctional protein, can target multiple pathways to exert neurotropic, neuropro- tective, anti-angiogenic, anti-vasopermeability, anti-inflammation, anti-thrombogenic, and anti-oxidative effects against DR. This review addresses the functions of PEDF in different pathways that could lead to potential therapeutics for the treatment of DR.

Association of serum levels of secreted frizzled-related protein 5 and Wnt member 5a with glomerular filtration rate in patients with type 2 diabetes mellitus and chronic renal disease: a cross-sectional study

ABSTRACT BACKGROUND: Diabetic nephropathy is a common complication of chronic kidney disease (CKD). ­Inflammation in the kidneys is crucial for promoting development and progression of this complication. Wnt member 5a (Wnt5a) and secreted frizzled-related protein 5 (Sfrp5) are proinflammatory proteins associated with insulin resistance and chronic low-grade adipose tissue inflammation. OBJECTIVE: To determine the correlation between serum Sfrp5 and Wnt5a concentrations and glomerular filtration rate in patients with type 2 diabetes mellitus and CKD. DESIGN AND SETTING: Cross-sectional, comparative and observational study in the Department of Endocrinology, Civil Hospital, Culiacán, Sinaloa, Mexico. METHODS: Eighty individuals with chronic kidney disease were recruited. Their serum Sfrp5 and Wnt5a concentrations were quantified using the enzyme-linked immunosorbent assay (ELISA) test. The statistical analysis consisted of the Mann-Whitney U test for independent samples and Spearman correlation, with statistical significance of P < 0.05. RESULTS: Serum Sfrp5 concentration continually increased through the stages of CKD progression, whereas serum Wnt5a concentration presented its highest levels in stage 3 CKD. Negative correlations between estimated glomerular filtration rate (eGFR) and serum concentrations of Sfrp5 (r = -0434, P = 0.001) and Wnt5a (r = -0481, P = 0.001) were found. CONCLUSIONS: There were negative correlations between serum Sfrp5 and Wnt5a concentrations and eGFR at each stage of CKD, with higher levels in female patients. This phenomenon suggests that Sfrp5 and Wnt5a might be involved in development and evolution towards end-stage renal disease.

[Clinical and immunological signs of retinal lesions and possibilities of their correction by drugs in patients with chronic diffuse liver diseases of viral etiology and carriers of Australia antigen]. / Kliniko-immunologicheskie priznaki porazheniia setchatki i vozmozhnosti ikh farmakokorrektsii u bol'nykh s khronicheskimi diffuznymi zabolevaniiami pecheni virusnoi étiologii i nositelei avstraliiskogo antigena.

A total of 133 subjects aged 15 to 55 were followed up, the main group (n = 87), patients with chronic diffuse diseases of the liver caused by hepatitis B virus, and two reference groups, 26 patients with uveitis and 20 normal subjects, 13 and 4 subjects of each group, respectively, were Australian antigen (HBsAg) carriers. Functional disorders of the retina were detected in 93.2% of group 1 patients, as well as intensified local (tears) and total system (blood) autoimmune reactions to tissue-specific retinal S-antigen (mol.mass 48 kD). An increased detection rate of antibodies to S-antigen and its higher titers were found in healthy virus carriers as compared to HBsAg-seronegative donors. These data may be regarded as evidence of an increased risk of uveoretinal pathology in subjects infected with hepatitis B virus, this being confirmed by a higher incidence (50%) of latent virus carriership in the group of patients with uveoretinitis. Stabilizing effect of cavinton in functional changes of the retina was revealed, this recommending this drug for combined therapy of patients with chronic diffuse diseases of the liver and for prevention of ocular diseases. The majority of the examinees in whom retinal abnormalities were found being young, the authors draw attention to the social aspect of the problem.

[Soft contactlenses in general practice (author's transl)]. / Weiche Kontaklinsen in der Praxis Materialien, Stoffwechsel, Oberflächen, Reinigung, therapeutische Anwendung

In contrast to the hard lenses the soft lens has enough permeability for oxygen and water-soluble substances, whereas high molecular substances, bacteria and virus cannot penetrate the soft lenses, so long as their surfaces are intact. The two principal production methods, the spin cast method and the lathe-turned method are compared. The duration of wearing of the soft lens depends on the deposits of proteins from the tears on the surface of the lens and the desinfection method. The daily boiling of the lenses shortens their useful life, while chemical desinfection causes besides bacteriolysis, damage of the corneal cell protein. The new cleaners on the base of proteolytic plant enzymes promise good results. For the optical correction of astigmatism with more than 1 cyl, soft lenses with conic outer surface are used or combinations of a soft and a hard lens (Duosystem). The therapeutic use of soft lenses has as aim: protection of the cornea against mechanical irritation, release of pain, protracted administration output of medicaments. Further indications for use: aseptic corneal inflammation and corneal defects.

Human immunoglobulin preparations for intravenous use prevent endotoxin-induced uveitis in rats.

OBJECTIVE: We analyzed the preventive effect of immunoglobulins for intravenous use (IVIgs) in endotoxin-induced uveitis (EIU), a disease related to tumor necrosis factor alpha (TNF-alpha) production. MATERIALS AND METHODS: EIU was the experimental model in Lewis rats, injecting a systemic dose of 150 microg of lipopolysaccharide (LPS) into the rat's footpad. Half of them were treated with 5 serial intravenous doses of 100 mg of IVIg during the 5 days prior to LPS injection. Eyes were repeatedly examined with a slitlamp, rats were killed and their eyes enucleated for histopathologic study at the 2nd, 16th and 24th hours. TNF-alpha serum levels were measured in aqueous humor at several time intervals by a bioassay using L-929 mouse fibroblasts. Aqueous humor proteins were detected by the Bradford method. RESULTS: IVIg treatment prevented EIU development, treated animals showing a lower grade of ocular inflammation beyond the 2nd hour (Fisher test, p > 0.05). Inflammatory cell infiltration was significantly reduced in the iris, ciliary body and anterior chamber at a 24-hour interval (Wilcoxon test, p < 0.05). This protection was associated with lower levels of TNF-alpha in serum at all time intervals and in aqueous humor at 16 h (Student's t test, p < 0.05), while differences were not significant between the samples of aqueous humor collected at 2 h. Protein exudate was not reduced in the treated group. CONCLUSIONS: Repeated IVIg injections could be useful in the preventive treatment of EIU probably mediated by a decrease in TNF-alpha release.

The anti-IRBP IgG1 and IgG2a response does not correlate with susceptibility to experimental autoimmune uveitis

Susceptibility to experimental autoimmune uveitis (EAU) in inbred mice has been associated with a dominant Th1 response. Elevated anti-inter-photoreceptor retinoid-binding protein (anti-IRBP) IgG2a/IgG1 antibody ratios have been implicated as candidate markers to predict disease severity. In the present study, both the anti-IRBP antibody isotype and severity of EAU phenotypes were examined in 4 non-isogenic genetically selected mouse lines to determine if they can be used as general markers of disease. Mice between 8 and 12 weeks old selected for high (H III) or low (L III) antibody response and for maximum (AIR MAX) or minimum (AIR MIN) acute inflammatory reaction (AIR) were immunized with IRBP. Each experiment was performed with at least 5 mice per group. EAU was evaluated by histopathology 21 days after immunization and the minimal criterion was inflammatory cell infiltration of the ciliary body, choroid and retina. Serum IgG1- and IgG2a-specific antibodies were determined by ELISA. EAU was graded by histological examination of the enucleated eyes. The incidence of EAU was lower in AIR MIN mice whereas in the other strains approximately 40 percent of the animals developed the disease. Low responder animals did not produce anti-IRBP IgG2a antibodies or interferon-gamma. No correlation was observed between susceptibility to EAU and anti-IRBP isotype profiles. Susceptibility to EAU is related to the intrinsic capacity to mount higher inflammatory reactions and increased production of anti-IRBP IgG2a isotype is not necessarily a marker of this immunologic profile.