Scaling Up Maternal Mental healthcare by Increasing access to Treatment (SUMMIT) through non-specialist providers and telemedicine: a study protocol for a non-inferiority randomized controlled trial.

BACKGROUND: Depression and anxiety impact up to 1 in 5 pregnant and postpartum women worldwide. Yet, as few as 20% of these women are treated with frontline interventions such as evidence-based psychological treatments. Major barriers to uptake are the limited number of specialized mental health treatment providers in most settings, and problems with accessing in-person care, such as childcare or transportation. Task sharing of treatment to non-specialist providers with delivery on telemedicine platforms could address such barriers. However, the equivalence of these strategies to specialist and in-person models remains unproven. METHODS: This study protocol outlines the Scaling Up Maternal Mental healthcare by Increasing access to Treatment (SUMMIT) randomized trial. SUMMIT is a pragmatic, non-inferiority test of the comparable effectiveness of two types of providers (specialist vs. non-specialist) and delivery modes (telemedicine vs. in-person) of a brief, behavioral activation (BA) treatment for perinatal depressive and anxiety symptoms. Specialists (psychologists, psychiatrists, and social workers with ≥ 5 years of therapy experience) and non-specialists (nurses and midwives with no formal training in mental health care) were trained in the BA protocol, with the latter supervised by a BA expert during treatment delivery. Consenting pregnant and postpartum women with Edinburgh Postnatal Depression Scale (EPDS) score of ≥ 10 (N = 1368) will be randomized to one of four arms (telemedicine specialist, telemedicine non-specialist, in-person specialist, in-person non-specialist), stratified by pregnancy status (antenatal/postnatal) and study site. The primary outcome is participant-reported depressive symptoms (EPDS) at 3 months post-randomization. Secondary outcomes are maternal symptoms of anxiety and trauma symptoms, perceived social support, activation levels and quality of life at 3-, 6-, and 12-month post-randomization, and depressive symptoms at 6- and 12-month post-randomization. Primary analyses are per-protocol and intent-to-treat. The study has successfully continued despite the COVID-19 pandemic, with needed adaptations, including temporary suspension of the in-person arms and ongoing randomization to telemedicine arms. DISCUSSION: The SUMMIT trial is expected to generate evidence on the non-inferiority of BA delivered by a non-specialist provider compared to specialist and telemedicine compared to in-person. If confirmed, results could pave the way to a dramatic increase in access to treatment for perinatal depression and anxiety. TRIAL REGISTRATION: ClinicalTrials.gov NCT04153864 . Registered on November 6, 2019.

A phase II study of gemcitabine and cisplatin plus sorafenib in patients with advanced biliary adenocarcinomas.

BACKGROUND: This study evaluated the addition of sorafenib to gemcitabine and cisplatin in biliary adenocarcinoma first-line therapy. METHODS: Patients with advanced biliary adenocarcinomas received gemcitabine 1000 mg m(-2) and cisplatin 25 mg m(-2) on a 2 weeks on/1 week off cycle and sorafenib 400 mg twice daily. After the initial 16 patients were enrolled, the chemotherapy doses were amended in view of grade 3 and 4 hand-foot skin reaction and haematologic toxicity. Subsequently, 21 patients received gemcitabine 800 mg m(-2), cisplatin 20 mg m(-2) and sorafenib 400 mg. The primary end point was an improvement in 6-month progression-free survival (PFS6) from historical 57-77% (90% power, type I error of 10%). Pretreatment pERK, evaluated by immunostaining, was correlated with clinical outcome. RESULTS: A total of 39 patients were accrued. The most common grade 3-4 toxicities noted in >10% of patients were fatigue, elevated liver function tests and haematologic toxicities including thromboemboli, hyponatraemia and hypophosphataemia. Six-month progression-free survival was 51% (95% confidence interval (CI) 34-66%). Median PFS and overall survival were 6.5 (95% CI: 3.5-8.3) and 14.4 months (95% CI: 11.6-19.2 months), respectively. No correlation was observed between pERK and outcomes. CONCLUSION: The addition of sorafenib to gemcitabine and cisplatin in biliary adenocarcinomas did not improve efficacy over historical data, and toxicity was increased.

Bortezomib successfully reverses early recurrence of light-chain deposition disease in a renal allograft: a case report.

Light-Chain Deposition Disease (LCDD) frequently recurs after renal transplantation, displaying a pernicious course. Herein we have described a 39-year-old Caucasian man with a history of immunoglobulin G-kappa multiple myeloma who failed two chemotherapy regimens, but ultimately responded to the combination of thalidomide, bortezomib, and dexamethasone followed by high-dose melphalan and autologous stem cell transplantation 3 years prior to transplantation, during which time he showed no evidence of persistent or recurrent disease. At 3 days following spousal living related renal transplantation, he displayed a rapid deterioration of renal function requiring dialysis therapy. This episode failed to respond to empiric antirejection therapy including anti-thymocyte globulin, plasmapheresis, and anti-CD20 monoclonal antibody. Increasing evidence suggested recurrence of LCDD, including positive immunofluorescence staining of basement membranes and vessels for kappa light chains as well as free kappa light chains in his urine and serum. Following suspension of sirolimus, he was initiated on and responded to bortezomib (1.3 mg/m(2)) with discontinuation of dialysis within 3 weeks and progressively improving renal function. His maintenance therapy, in addition to six 2-week-long cycles of bortezomib separated by 1-week rest periods, includes cyclosporine (50 mg twice daily), prednisone (10 mg daily), and curcumin (9 g daily). In sum, bortezomib rescue therapy salvaged a spousal renal transplant afflicted with recurrent LCDD.

New insights into the heparan sulfate proteoglycan-binding activity of apolipoprotein E.

Defective binding of apolipoprotein E (apoE) to heparan sulfate proteoglycans (HSPGs) is associated with increased risk of atherosclerosis due to inefficient clearance of lipoprotein remnants by the liver. The interaction of apoE with HSPGs has also been implicated in the pathogenesis of Alzheimer's disease and may play a role in neuronal repair. To identify which residues in the heparin-binding site of apoE and which structural elements of heparan sulfate interact, we used a variety of approaches, including glycosaminoglycan specificity assays, (13)C nuclear magnetic resonance, and heparin affinity chromatography. The formation of the high affinity complex required Arg-142, Lys-143, Arg-145, Lys-146, and Arg-147 from apoE and N- and 6-O-sulfo groups of the glucosamine units from the heparin fragment. As shown by molecular modeling, using a high affinity binding octasaccharide fragment of heparin, these findings are consistent with a binding mode in which five saccharide residues of fully sulfated heparan sulfate lie in a shallow groove of the alpha-helix that contains the HSPG-binding site (helix 4 of the four-helix bundle of the 22-kDa fragment). This groove is lined with residues Arg-136, Ser-139, His-140, Arg-142, Lys-143, Arg-145, Lys-146, and Arg-147. In the model, all of these residues make direct contact with either the 2-O-sulfo groups of the iduronic acid monosaccharides or the N- and 6-O-sulfo groups of the glucosamine sulfate monosaccharides. This model indicates that apoE has an HSPG-binding site highly complementary to heparan sulfate rich in N- and O-sulfo groups such as that found in the liver and the brain.

The protein Hrb57A of Drosophila melanogaster closely related to hnRNP K from vertebrates is present at sites active in transcription and coprecipitates with four RNA-binding proteins.

The hnRNP K protein is among the major hnRNA-binding proteins with a strong preference for cytidine-rich sequences. We have cloned a Drosophila hnRNP protein closely related to this vertebrate protein. The protein first identified by the monoclonal antibody Q18 is encoded by a gene located in 57A on polytene chromosomes and has been consequently named Hrb57A. The amino acid sequence of the Hrb57A KH domains and their overall organisation in the protein are remarkably similar to the vertebrate proteins. As the hnRNP K in vertebrates the M(r) 55 000 Drosophila Hrb57A/Q18 protein strongly binds to poly(C) in vitro and is ubiquitously present in nuclei active in transcription. On polytene chromosomes it is found in many puffs and minipuffs. Hrb57A/Q18 specifically coprecipitates four other proteins: Hrb87F/P11 a Drosophila hnRNP A1 homologue, the hnRNA-binding protein S5, the RNA recognition motif-containing protein NonA and the RNA-binding zinc finger-containing protein on ecdysone puffs PEP/X4.

The development of sirolimus: The University of Texas-Houston experience.

The transplant team at The University of Texas-Houston has studied sirolimus from preclinical through pivotal Phase III trials to single-center Phase IV trials as we continue to refine algorithms for sirolimus therapy. The sirolimus/CsA combination produces a marked reduction in the occurrence and severity of acute allograft rejection episodes. A recently completed post hoc median effect analysis of drug blood concentrations displayed by patients in the 2 pivotal Phase III trials documented that the combination displays synergistic interactions. Patients in the sirolimus/CsA arms did not display an increased incidence of infectious or malignant complications. However, they did experience a range of nonimmune toxicities, including potentiation of putatively CsA-related adverse reactions, such as renal dysfunction and hypercholesterolemia, which appear to be mitigated by reduction or elimination of CsA. However, thrombocytopenia and to a lesser extent leukopenia and anemia appear to be sirolimus-related side effects. The occurrence and severity of these adverse reactions seem to be avoided or ameliorated in most patients by optimizing sirolimus exposure at concentrations (15 ng/mL or by dose reduction. Sirolimus thus appears to be a potent and unique agent for developing new immunosuppressive strategies in organ transplantation.

Phytoestrogens alter adrenocortical function: genistein and daidzein suppress glucocorticoid and stimulate androgen production by cultured adrenal cortical cells.

Phytoestrogens influence a variety of biological processes. As 17beta-estradiol alters adrenocortical cell function, we examined whether the dietary phytoestrogens, genistein and daidzein, have related effects. In cultured human fetal and postnatal adrenal cortical cells, genistein and daidzein (both 0.4-40 micromol/L) decreased ACTH-stimulated cortisol production to basal levels (ED50, 1-4 micromol/L). In the adult adrenocortical cell line, H295, genistein, daidzein, and 17beta-estradiol (10 micromol/L) decreased cAMP-stimulated cortisol synthesis in a similar fashion. Neither genistein nor daidzein altered basal or ACTH-stimulated dehydroepiandosterone sulfate (DHEA-S) production in fetal adrenocortical cells, whereas in postnatal adrenocortical cells, DHEA and DHEA-S were markedly increased (ED50, 1-4 micromol/L). In H295 cells, basal and cAMP-stimulated DHEA production were similarly increased by the phytoestrogens and 17beta-estradiol. Genistein and daidzein did not affect the expression of steroid-metabolizing enzymes. However, genistein and daidzein specifically inhibited the activity of 21-hydroxylase (P450c21); the activities of other steroidogenic enzymes were not affected. Thus, phytoestrogens may decrease cortisol synthesis by suppressing the activity of P450c21 and, as a consequence, increase DHEA/DHEA-S synthesis by shunting metabolites away from the glucocorticoid synthetic pathway. Therefore, consumption of foods containing phytoestrogens may alter adrenocortical function by decreasing cortisol and increasing androgen production.

Update in medical therapy in inflammatory bowel disease: a clinician's view.

Recent advances in the therapy of inflammatory bowel disease specifically directed against the inflammatory and immune mechanisms include an impressive and often overwhelming cornucopia of anti-inflammatory agents, immunomodulators, antibiotics, biologicals, topical therapies, nicotine, heparin, and nutritional supplements. The interface of one drug regimen into another may lead to confounding and often confusing programs of treatment. This review will attempt to offer a perspective of care and an update of specific remedies, but the aim is practicality and usefulness, not encyclopedic detail.

Dietary modification of high density lipoprotein phospholipid and influence on cellular cholesterol efflux.

African green monkeys fed fat-specific diets served as a model to investigate the effect of phospholipid acyl chain modification on high density lipoprotein (HDL)-mediated cellular cholesterol efflux. Diets enriched in saturated, monounsaturated, n-6 polyunsaturated, or n-3 polyunsaturated fats were provided during both low cholesterol and cholesterol-enriched stages; sera and HDL3 samples were obtained at specific points during the treatment period. Analysis of the HDL phospholipid composition revealed significant acyl chain modification, consistent with the respective fat-specific diet. Cholesterol efflux from mouse L-cell fibroblasts to HDL3 isolated from the specific diet groups was measured and revealed no differences in the abilities of the particles to accept cellular cholesterol; determination of the bidirectional flux of cholesterol between the cells and HDL3 species further demonstrated no effect of phospholipid acyl chain modification on this process. The effects of dietary modification of phospholipid acyl chains on cellular cholesterol efflux were directly examined by isolating the HDL phospholipid and combining it with human apolipoprotein A-I to form well-defined reconstituted HDL particles. These complexes did not display any differences with respect to their ability to stimulate cellular cholesterol efflux. Incubations with 5% sera further confirmed that the fat-specific diets do not influence cholesterol efflux. These results suggest that the established influences of specific dietary fats on the progression of atherosclerosis are due to effects on cholesterol metabolism other than the efflux of cellular cholesterol in the first step of reverse cholesterol transport.

Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DS) as therapeutic options in menopause.

In recent years, there has been increasing interest in the potential of androgen replacement in menopausal women and specifically adrenal androgen replacement. There is unfortunately increasing unmonitored use of dehydroepiandrosterone (DHEA) among adults in the United States with only limited and preliminary human data. An extensive body of literature in laboratory animals exists to suggest DHEA used in extremely large doses has multifaceted effects; though the inapplicability of this data to humans is not appreciated, as the physiology of adrenal androgens in humans and a few primates is unique. Currently, there is much international and multidisciplinary interest in the physiology and use of DHEA "replacement" in men and menopausal women. The scientific community anxiously await the results of these investigations, but in the interim DHEA and/or DHEA-Sulfate (DHEAS) supplementation is not recommended as a therapeutic option in menopause outside of clinical trials.

Integrating ongoing evaluation process for international pediatric nursing courses.

Two international pediatric courses for nurses from developing countries were planned and implemented in Israel during the past 2 years. The courses consisted of 53 RNs from 29 countries. The purpose of this article is to describe the ongoing evaluation and follow-up process of these courses. Findings indicated that the majority of nurses expressed: a) high satisfaction with the course and felt it enhanced their professional capacity and practice, and benefited their colleagues and superiors; b) high motivation and enthusiasm to improve nursing practices in their home countries; c) changes in attitudes and beliefs relating to pediatric nursing.

PIP: A total of 53 nurses from 29 developing countries participated in two 8-week pediatric nursing courses held in Israel in 1993 and 1994 under the auspices of the Center for International Cooperation of the Ministry of Foreign Affairs, Kupat Holim (Israel's largest health insurance institution), and the Dina School of Nursing. The course objectives were to increase knowledge of child growth and development, enhance awareness of the special needs of children and their families, impart specific clinical skills, and instill a holistic, multicultural perspective. Continuous evaluation of the 320-hour course was achieved through structured individual interviews with participants, periodic class discussions, and a written midterm examination on the materials covered. Final course evaluation was achieved through a written examination, class discussion, and completion of a questionnaire devised by the Foreign Ministry. One year after completion of the second course, a questionnaire was mailed to all participants in both courses. Of the 30 nurses (57%) who responded, the majority felt the course enhanced their professional knowledge and practice and agreed their institution, colleagues, and supervisors benefited from their participation. Although 21 nurses (69%) stated the course increased their chances for professional advancement, only 9 (31%) reported it had any impact on their professional status. A particularly notable outcome of course enrollment was increased awareness of the importance of parental participation in the care of hospitalized children.

Canadians' use of U.S. medical services.

To explore the extent of cross-border care seeking among Canadians, we analyzed the growth and distribution of Ontario Health Insurance Plan expenditures for medical care services provided in the United States to Ontario residents from 1987 to 1995. Although total out-of-province spending is low relative to in-province spending, there is evidence of cross-border care seeking for cardiovascular and orthopedic procedures, mental health services, and cancer treatments. However, combined with a preliminary investigation of cross-border patient care seeking using nonpublic funding sources, these analyses do not support the perception of widespread cross-border medical care seeking by Ontario residents.

Peroxidation of LDL from combined-hyperlipidemic male smokers supplied with omega-3 fatty acids and antioxidants.

The effects of marine omega-3 polyunsaturated fatty acids (FAs) and antioxidants on the oxidative modification of LDL were studied in a randomized, double-blind, placebo-controlled trial. Male smokers (n = 41) with combined hyperlipidemia were allocated to one of four groups receiving supplementation with omega-3 FAs (5 g eicosapentaenoic acid and docosahexaenoic acid per day), antioxidants (75 mg vitamin E, 150 mg vitamin C, 15 mg beta-carotene, and 30 mg coenzyme Q10 per day), both omega-3 FAs and antioxidants, or control oils. LDL and human mononuclear cells were isolated from the patients at baseline and after 6 weeks of supplementation. LDL was subjected to cell-mediated oxidation by the patients' own mononuclear cells, as well as to Cu(2+)-catalyzed and 2,2'-azobis-(2-amidinopropane hydrochloride) (AAPH)-initiated oxidation. Extent of LDL modification was measured as lag time, the formation rate of conjugated dienes (CDs), the maximum amount of CDs formed, formation of lipid peroxides, and the relative electrophoretic mobility of LDL on agarose gels. Dietary supplementation with omega-3 FAs increased the concentration of total omega-3 FAs in LDL and reduced the concentration of vitamin E in serum. The omega-3 FA-enriched LDL particles were not more susceptible to Cu(2+)-catalyzed, AAPH-initiated, or autologous cell-mediated oxidation than control LDL. In fact, enrichment with omega-3 FAs significantly reduced the formation rate of CDs when LDL was subjected to AAPH-induced oxidation. Supplementation with moderate amounts of antioxidants significantly increased the concentration of vitamin E in serum and increased the resistance of LDL to undergo Cu(2+)-catalyzed oxidation, measured as increased lag time, reduced formation of lipid peroxides, and reduced relative electrophoretic mobility compared with control LDL. Supplementation with omega-3 FAs/antioxidants showed oxidizability of LDL similar to that of control LDL and omega-3 FA-enriched LDL. In conclusion, omega-3 FAs neither rendered the LDL particles more susceptible to undergo in vitro oxidation nor influenced mononuclear cells' ability to oxidize autologous LDL, whereas moderate amounts of antioxidants protected LDL against oxidative modification.

Training improves endothelium-dependent vasodilation in resistance vessels of patients with heart failure.

The effects of physical training on endothelium-dependent vasodilation in skeletal muscle resistance vessels were investigated in patients with heart failure. Forearm blood flows (ml.min-1.100 ml-1) in response to brachial arterial administration of acetylcholine (5 x 10(-5) and 5 x 10(-4) M at 1 ml/min) and nitroglycerin (5 x 10(-6) and 5 x 10(-5) M at 1 ml/min) were determined by strain-gauge venous occlusion plethysmography before and after 8 wk of daily handgrip exercise in 12 patients with chronic heart failure. After 8 wk of daily handgrip exercise, the vasodilatory responses to acetylcholine significantly increased from pretraining values, i.e., 16.6 +/- 2.0 vs. 8.6 +/- 1.3 ml.min-1.100 ml-1 (P < 0.05) and 27.5 +/- 1.5 vs. 14.6 +/- 1.7 ml.min-1.100 ml-1 (P < 0.05), respectively, whereas the vasodilatory responses to nitroglycerin did not change. Handgrip exercise training appears to specifically enhance endothelium-dependent vasodilation in the forearm skeletal muscle circulation of patients with heart failure.

Developing tomorrow's integrated community health systems: a leadership challenge for public health and primary care.

As the nation's health system moves away from earlier models to one grounded in population health and market-based systems of care, new challenges arise for public health professionals, primary care practitioners, health plan and institutional managers, and community leaders. Among the challenges are the need to develop creative concepts of organization and accountability and to assure that dynamic, system-oriented structures support the new kind of leadership that is required. Developing tomorrow's integrated community health systems will challenge the leadership skills and integrative abilities of public health professionals, primary care practitioners, and managers. These leaders and their new organizations must, in turn, assume increased accountability for improving community health.

Physician relations in Canada: shooting inward as the circle closes.

As economic disputes between physicians become more frequent, discussions between physicians are becoming increasingly important. Those seeking insight into how physician organizations might mediate these disputes may be able to learn from others who have had negotiating responsibilities for over a quarter of a century--the provincial medical associations in Canada. In this article we examine the structure, process, and outcomes of negotiations between physicians, with a focus on responses to new physician expenditure caps in Ontario, Alberta, and British Columbia. Early negotiations between physicians over changes in relative fees favored general practitioners because they were the dominant voting block within the associations. Despite fewer gains in the fee arena, specialists were willing to remain in the associations because all physicians generally enjoyed similar income growth. Under new physician expenditure caps, however, physicians have been unable to resolve conflicts over how to allocate income limits across specialties. Negotiations between physicians face expanding economic issues and diverging interests as expenditure caps force physicians to concentrate on total costs.

Physician use in Ontario and the United States: The impact of socioeconomic status and health status.

OBJECTIVES: This study compared physician use in Ontario and the midwestern and northeastern United States for persons of different socioeconomic status and health status. The distribution of health problems associated with the most recent physician visit also was compared. METHODS: The design of the study was cross sectional; data derived from the 1990 Ontario Health Survey and the 1990 US National Health Interview Survey were used in analyses. RESULTS: Overall, persons in Ontario averaged 19% more visits than US residents, but differences varied markedly across income and health status. At each level of health status, low- income Canadians had 25% to 33% more visits than their US counterparts. However, among higher income persons, those in excellent or very good health had 22% more visits than Americans, while those in good, fair, or poor health had 10% fewer visits than Americans. Higher visit rates in Ontario were not associated with a greater prevalence of low- priority visits. CONCLUSIONS: Under the Canadian single- payer system, medical care in Ontario has been redistributed to low-income persons and the elderly. Compared with the United States, there has been a lower intensity of medical care for the sick higher income population.

The angiotensin II receptor antagonist losartan reduces blood pressure but not renal injury in obese Zucker rats.

Agents that interfere with the renin-angiotensin system (RAS) may ameliorate progressive renal injury, particularly in a setting where intrarenal RAS activity appears to be elevated. Whether RAS antagonists affect renal disease progression when intrarenal RAS activity is not increased is unclear. In this study, therefore, the effects of the angiotensin II receptor antagonist losartan on glomerular and tubulointerstitial injury were investigated in obese Zucker rats (OZR), an experimental model of progressive renal disease characterized by reduced intrarenal renin content and reduced plasma renin activity. Losartan (100 or 200 mg/L of drinking water) was administered to OZR beginning at 26 wk of age, when renal disease was established. At 38 and 44 wk of age, losartan-treated OZR demonstrated significant (P < 0.05) dose-related decreases in systolic blood pressure, compared with blood pressures in untreated, control OZR. Despite the reductions in blood pressure, losartan had no significant effects on albuminuria or glomerular or tubulointerstitial injury. At 44 wk of age, the percentage (mean +/- SE) of glomeruli with sclerosis was 51 +/- 11, 49 +/- 9, and 39 +/- 14% in control OZR, low-dose (100 mg/L) losartan-treated OZR, and high-dose (200 mg/L) losartan-treated OZR, respectively (P > 0.05). Similarly, the tubulointerstitial injury score (range, 0 to 4) in the three groups was, respectively, 1.7 +/- 0.4, 1.6 +/- 0.3, and 1.5 +/- 0.3 (P > 0.05). It was concluded that in a setting of chronic renal failure where intrarenal RAS activity does not appear to be increased, angiotensin II receptor antagonism may not be nephroprotective despite a reduction in blood pressure.