Culturally adapted psychosocial interventions (CaPSI) for early psychosis in a low-resource setting: study protocol for a large multi-center RCT.

BACKGROUND: Psychosis treatment guidelines recommend cognitive behaviour therapy (CBT) and family intervention (FI), for all patients with first episode psychosis (FEP), though guidance borrows heavily from literature in adults from high income countries. To our knowledge, there are few randomized controlled trials (RCTs) examining the comparative effect of these commonly endorsed psychosocial interventions in individuals with early psychosis from high-income countries and no such trials from low and middle-income countries (LMICs). The present study aims to confirm the clinical-efficacy and cost-effectiveness of delivering culturally adapted CBT (CaCBT) and culturally adapted FI (CulFI) to individuals with FEP in Pakistan. METHOD: A multi-centre, three-arm RCT of CaCBT, CulFI, and treatment as usual (TAU) for individuals with FEP (n = 390), recruited from major centres across Pakistan. Reducing overall symptoms of FEP will be the primary outcome. Additional aims will include improving patient and carer outcomes and estimating the economic impact of delivering culturally appropriate psychosocial interventions in low-resource settings. This trial will assess the clinical-efficacy and cost-effectiveness of CaCBT and CulFI compared with TAU in improving patient (positive and negative symptoms of psychosis, general psychopathology, depressive symptoms, quality of life, cognition, general functioning, and insight) and carer related outcomes (carer experience, wellbeing, illness attitudes and symptoms of depression and anxiety). CONCLUSIONS: A successful trial may inform the rapid scale up of these interventions not only in Pakistan but other low-resource settings, to improve clinical outcomes, social and occupational functioning, and quality of life in South Asian and other minority groups with FEP. TRIAL REGISTRATION: NCT05814913.

The effect of melatonin on plasma markers of inflammation and on expression of nuclear factor-kappa beta in acetic acid-induced colitis in the rat.

BACKGROUND AND AIMS: Melatonin may be involved in gastrointestinal tract physiology and could affect inflammation-related gastrointestinal disorders. Rat models of ulcerative colitis imply melatonin is beneficial. To determine potential pathophysiological mechanisms, we assessed colonic nuclear factor-kappa beta expression and measured serum levels of pentraxin-3, lipid peroxides, and total thiols in an acetic acid model of this disease. MATERIALS AND METHODS: Thirty rats were divided into five groups: a control group, an acetic acid-induced colitis group, a group treated with melatonin before colitis induction, a group treated short-term after colitis induction, and a group treated long-term after colitis induction. After four weeks, blood samples were taken for measurement of pentraxin-3, lipid peroxide, and total thiols. Sections of the colon were taken for histopathological examination and immunohistochemical detection of nuclear factor-kappa beta expression. RESULTS: Melatonin administration reduced nuclear factor-kappa beta immunohistochemical expression, reduced serum levels of lipid peroxide and pentraxin-3, and maintained serum levels of total thiols. However, in long-term treatment the protective effect of melatonin was not as marked. CONCLUSION: Melatonin is effective in prevention and short-term treatment of the inflammatory process in acetic-acid induced colitis whereas the benefit of long-term treatment is unclear. Benefit may be linked to protection mechanisms against inflammatory processes by inhibiting the nuclear factor-kappa beta and conserving endogenous antioxidant reserves of total thiols, thus reducing the level of colonic damage possibly caused by lipid peroxides.

Impact of high-dose atorvastatin on endothelial, platelet, and angiogenic indices: effect of ethnicity, cardiovascular disease, and diabetes.

Lipid lowering with statins improves morbidity and mortality, particularly in diabetics, and may have additional nonlipid effects. South Asians (SAs) are at higher risk of cardiovascular disease and diabetes compared with white Europeans (WEs). We hypothesized that abnormal endothelial (marked by von Willebrand factor), angiogenesis (VEGF, angiopoietins 1 and 2) and platelet function (soluble P selectin, soluble CD40L) improve with statin treatment in diabetics in different ethnic groups. Plasma was obtained before and 8 weeks after treatment with atorvastatin (80 mg/day) by SAs and WEs with or without diabetes. Research indices were measured by enzyme-linked-immunosorbent assay (ELISA). Treatment increased angiopoietin-2 (P < .04) in all groups regardless of diabetes or ethnicity. In those free of diabetes, angiopoietin-2 increased 3-fold, whereas in diabetes, it increased 2-fold. We suggest that an additional effect of statins is to increase levels of growth factor angiopoietin-2 in the direction of normality. This effect is weaker in participants with diabetes.

Preprocedural hemoglobin predicts outcome in peripheral vascular disease patients undergoing percutaneous transluminal angioplasty.

BACKGROUND: Anemia is a risk factor for adverse outcome in patients with symptomatic cardiovascular disease. This study assessed the association of preprocedural hemoglobin with adverse outcome in patients with advanced peripheral vascular disease (PVD) undergoing percutaneous transluminal angioplasty (PTA). METHODS: Consecutive first-time procedures for patients with Rutherford category 4 or 5 PVD who underwent successful nonemergency PTA were analyzed in a retrospective cohort study. Cardiovascular risk factors, preprocedural hemoglobin, and angiographic data were recorded. Preprocedural (

Preprocedural neutrophil count predicts outcome in patients with advanced peripheral vascular disease undergoing percutaneous transluminal angioplasty.

BACKGROUND: The neutrophil count has been associated with adverse cardiovascular events after percutaneous coronary intervention. There are limited data on risk stratification of patients with advanced peripheral vascular disease (PVD) using white blood cell (WBC) subtypes. This study assessed the association of total and differential WBC counts with adverse outcome in patients with advanced PVD undergoing percutaneous transluminal angioplasty (PTA). METHODS: In a retrospective cohort study, consecutive de novo procedures were analyzed for patients with Rutherford category 4 or 5 PVD who underwent successful nonemergency PTA. Cardiovascular risk factors, baseline total and differential WBC counts, and angiographic data were recorded. Primary outcome was a composite of events of target vessel revascularization (repeat PTA or vascular bypass operation) or lower limb amputation. RESULTS: A total of 101 patients were studied. Their mean age was 76 +/- 10 years, 54% had diabetes mellitus, 68% were hypertensive, and 12% had had previous myocardial infarction. We observed 29 events during a median period of 14 months (interquartile range, 4-26). Cox regression analysis found diabetes mellitus (odds ratio [OR], 4.67; 95% confidence interval [CI], 1.35-16.14; P = .02), Rutherford category 5 (OR, 4.18; 95% CI, 1.06-16.51; P = .04), poor tibial runoff (OR, 4.42; 95% CI, 1.16-16.82; P = .03), and preprocedural neutrophil count in the third tertile (OR, 10.77; 95% CI, 2.19-52.91; P = .003) were independent predictors of outcome. CONCLUSIONS: The results suggest that the preprocedural neutrophil count could be used in global risk factor assessment of patients with advanced PVD who are being considered for PTA. The neutrophil count may reflect the burden of atherosclerosis and tissue damage, and so could identify patients who need more aggressive intervention for advanced PVD.

Indices of angiogenesis, platelet activation, and endothelial damage/dysfunction in relation to ethnicity and coronary artery disease: differences in central versus peripheral levels.

BACKGROUND: We hypothesized that indices of angiogenesis (vascular endothelial growth factor (VEGF), angiopoietins (Ang-1 and -2), platelet activation (soluble P-selectin)) and endothelial damage/dysfunction (von Willebrand factor (vWf)) would be more deranged in South Asians than in white Europeans when measured within the coronary sinus or coronary artery per se (that is, intracardiac sampling of blood supplying and draining the heart), as compared to measurements from the peripheral venous system. METHODS: To test this hypothesis, we performed a cross-sectional study of 87 subjects undergoing cardiac catheterization, where 43 were South Asian and 44 were white European. RESULTS: South Asian participants were younger (P = 0.01) but had a lower rate of self-reported smoking (P = 0.01). The extent of coronary atherosclerosis, assessed using presence of lesions > 50%, number of vessels diseased and Gensini score, was comparable between the two ethnic groups (all P = NS). When samples were analysed from the coronary circulation or the femoral vein in relation to South Asian and white European ethnicity, there were no significant differences in the levels of VEGF, angiopoietins 1 and 2, soluble P-selectin and vWf levels between the two ethnic groups. CONCLUSION: Indices of angiogenesis, platelet activation, and endothelial damage/dysfunction are comparable in South Asians and their white European counterparts. Our results suggest that their pathophysiological roles may be comparable in South Asians and white Europeans in the context of coronary artery disease.

Platelet activation in coronary artery disease: intracardiac vs peripheral venous levels and the effects of angioplasty.

BACKGROUND: Platelet activation and aggregation play a key role in coronary artery disease, with antiplatelet therapies leading to improved clinical outcomes. Limited data exist as to whether peripheral venous blood measurements of platelet physical indexes (eg, platelet count, volume, and granularity) and soluble markers of platelet activation (eg, P-selectin [sP-sel] and CD40 ligand [CD40L]) reflect the local (intracardiac) coronary environment. Furthermore, how percutaneous coronary interventions (PCIs) affect levels of peripheral/cardiac platelet indexes is unclear. METHODS: Blood samples were sequentially acquired from the coronary os, aortic root, coronary sinus, and the femoral vein, and where relevant, pre-PCI and post-PCI. Eighty-seven patients undergoing coronary angiography were recruited (mean [+/-SD] age, 59.8+/-10.8 years; 54 men [62%]), of whom 36 proceeded to PCI. Platelet physical indexes and plasma sP-sel and CD40L levels were measured (by enzyme-linked immunosorbent assay). RESULTS: At baseline, no intracardiac vs peripheral differences were noted in sP sel levels, while CD40L levels were elevated in the aorta compared to the coronary sinus and femoral venous. The mean platelet count (MPC) was similar at all four sites, but within the coronary sinus blood, mean platelet volume (MPV) was significantly lower and mean platelet granularity (MPG) was higher when compared to arterial levels. Though aortic and femoral levels of sP-sel were raised following PCI, transcardiac gradients of plasma sP-sel levels were unaffected. PCI was associated with lower CD40L, MPC, and MPV levels but with a higher MPG level in all sampling sites. CONCLUSIONS: sP-sel levels measured peripherally reflect the cardiac environment, unlike CD40L, MPC, MPV, and MPG. PCI leads to further platelet activation (raised sP-sel) despite aggressive antiplatelet therapy.

Systemic and intracardiac vascular endothelial growth factor and angiopoietin-1 and -2 levels in coronary artery disease: effects of angioplasty.

BACKGROUND: Vascular growth factors are involved in the pathophysiology of human atherosclerotic vascular disease and plaque destabilization. We hypothesized that in stable patients with coronary artery disease (CAD), plasma levels of vascular endothelial growth factor (VEGF) and angiopoietins 1 and 2 (as indices of angiogenesis) would be no higher in coronary sinus blood when compared to the aortic root, coronary ostium, and peripheral femoral vein. Secondly, we hypothesized that percutaneous coronary intervention (PCI; angioplasty+/-stenting) would increase intracardiac levels of these indices, perhaps by destabilizing coronary plaques. METHODS: Patients undergoing elective diagnostic coronary angiography (n = 70; mean age 58.8+/-11.2 years) of which 37 proceeded to PCI were recruited. Blood samples were obtained from the aortic root, coronary ostium, coronary sinus, and femoral vein. Plasma VEGF, angiopoietin-1 and angiopoietin-2 levels were measured by immunoassays. RESULTS: There were no significant differences in VEGF, angiopoietin-1 and angiopoietin-2 levels when aortic root, coronary ostium, coronary sinus, and femoral vein samples were compared (P = not significant (NS)). In patients undergoing PCI, peripheral angiopoietin-2 levels were increased significantly post PCI (P = 0.01). There was also a difference in intracardiac gradient (that is, aortic root-coronary sinus difference) in angiopoietin-1 (P = 0.02) following PCI. No significant changes in VEGF with PCI were noted. CONCLUSION: There were no differences in indices of angiogenesis when aortic root, coronary ostium, coronary sinus, and femoral vein levels of VEGF and angiopoietins are compared, suggesting that peripheral blood measurements of these indices are comparable to intracardiac levels. Although no immediate effects were observed in soluble VEGF levels, PCI affected intracardiac angiopoietin-1 with a systemic release of angiopoietin-2. Further investigations are necessary to determine the relative systemic and intracardiac effects of the angiopoietins in vascular remodelling post PCI.

Effects of low osmolar contrast (iomeprol) on haemorheology and platelet activation in patients with coronary artery disease.

BACKGROUND: Non-ionic low osmolar contrast agents are widely used during coronary angiography. As these agents cause activation of thrombotic pathways in vitro, this may have potentially significant clinical impact. However, limited evidence exists as to their in vivo effects from selective coronary cannulation. METHODS: We initially performed an in vitro experiment to assess the effect of serial contrast (Iomeprol 300, Bracco) dilution on platelet indices [mean platelet count (MPC), platelet volume (MPV), platelet granularity (MPG)]. The in vivo effect of contrast injection on platelet activation markers [soluble P-selectin (sPsel), soluble CD40 ligand (sCD40L)], MPC, MPV, MPG, haemoglobin and haematocrit was subsequently determined in 35 patients (mean age 58 +/- 11; 22 males) undergoing cardiac catheterisaton. RESULTS: No significant in vitro effect of contrast on MPC or MPV was seen but there was a significant increase in MPG (p = 0.40, 0.10 and 0.01, respectively). In the in vivo study, there was a reduction in mean haemoglobin and haematocrit levels, suggesting an average increase in plasma volume of 6.5 +/- 5.8%. The in vivo effect of Iomeprol was associated with an unadjusted reduction in sPsel concentrations (p = 0.04) and MPV (p < 0.05), with denser platelets (p < 0.05). There was no difference in MPC or sCD40L concentration (both p = NS). After adjustment for the haemodilution effect, no significant reduction in P-sel levels was seen with contrast (p = 0.27), although the adjusted post-contrast change in MPG (p = 0.01), MPC (p = 0.01) and sCD40L (p < 0.05) levels were significant. CONCLUSION: Low osmolar contrast led to a minimal effect on soluble and physical indices of platelets within the coronary artery, primarily due to plasma volume expansion.