Effect of a task-shared, collaborative care psychosocial intervention to improve depressive symptomatology among older adults in socioeconomically deprived areas of Brazil (PROACTIVE):cluster randomised controlled trial

BACKGROUND: There is an urgent need to reduce the burden of depression among older adults in low-income and middle-income countries (LMICs). We aimed to evaluate the efficacy of a task-shared, collaborative care psychosocial intervention for improving recovery from depression in older adults in Brazil. METHODS: PROACTIVE was a pragmatic, two-arm, parallel-group, cluster-randomised controlled trial conducted in Guarulhos, Brazil. Primary care clinics (clusters) were stratified by educational level and randomly allocated (1:1) to either enhanced usual care alone (control group) or to enhanced usual care plus the psychosocial intervention (intervention group), which involved a 17-week psychosocial programme based on psychoeducation and behavioural activation approaches. Individuals approached for the initial screening assessment were selected randomly from a list of individuals provided by the Health Secretariat of Guarulhos. Face-to-face baseline assessments were conducted among adults aged 60 years or older registered with one of the primary care clinics and identified with clinically significant depressive symptomatology (9-item Patient Health Questionnaire [PHQ-9] score ≥10). Community health workers delivered the programme through home sessions, supported by a dedicated tablet application. Masking of clinic staff and community health workers who delivered the intervention was not feasible; however, research assistants conducting recruitment and follow-up assessments were masked to trial allocation. The primary outcome was recovery from depression (PHQ-9 score <10) at 8-month follow-up. All primary analyses were performed by intention to treat with imputed data. Adaptations to the protocol were made due to the COVID-19 pandemic; recruitment and intervention home sessions were stopped, and follow-up assessments were conducted by telephone. This trial is registered with the ISRCTN registry, ISRCTN57805470. FINDINGS: We identified 24 primary care clinics in Guarulhos that were willing to participate, of which 20 were randomly allocated to either the control group (ten [50%] clusters) or to the intervention group (ten [50%] clusters). The four remaining eligible clusters were kept as reserves. Between May 23, 2019, and Feb 21, 2020, 8146 individuals were assessed for eligibility, of whom 715 (8·8%) participants were recruited: 355 (49·7%) in the control group and 360 (50·3%) in the intervention group. 284 (80·0%) participants in the control group and 253 (70·3%) in the intervention group completed follow-up at 8 months. At 8-month follow-up, 158 (62·5%) participants in the intervention group showed recovery from depression (PHQ-9 score <10) compared with 125 (44·0%) in the control group (adjusted odds ratio 2·16 [95% CI 1·47–3·18]; p<0·0001). These findings were maintained in the complete case analysis. No adverse events related to the intervention were observed. INTERPRETATION: Although the COVID-19 pandemic altered delivery of the intervention, the low-intensity psychosocial intervention delivered mainly by non-mental health professionals was highly efficacious in improving recovery from depression in older adults in Brazil. Our results support a low-resource intervention that could be useful to reduce the treatment gap for depression among older people in other LMICs. FUNDING: São Paulo Research Foundation and Joint Global Health Trials (UK Department for International Development, Medical Research Council, and the Wellcome Trust)

Increases in plasma sheet temperature with solar wind driving during substorm growth phases

During the substorm growth phase, magnetic reconnection extracts ~10^15 J from the solar wind through magnetic reconnection at the magnetopause, which is then stored in the magnetotail lobes. Plasma sheet pressure then increases to balance magnetic flux density increases in the lobes. We examine plasma sheet pressure, density and temperature during substorm growth phases using nine years of Cluster data (>316,000 data points). We show that plasma sheet pressure and temperature are higher during growth phases with higher solar wind driving whereas the density is approximately constant. We also show a weak correlation between plasma sheet temperature before onset and the minimum SuperMAG SML auroral index in the subsequent substorm. We discuss how energization of the plasma sheet before onset may result from thermodynamically adiabatic processes; how hotter plasma sheets may result in magnetotail instabilities and how this relates to the onset and size of the subsequent substorm expansion phase

Support for UNRWA's survival

The United Nations Relief and Works Agency for Palestine Refugees in the Near East (UNRWA) provides life-saving humanitarian aid for 5·4 million Palestine refugees now entering their eighth decade of statelessness and conflict. About a third of Palestine refugees still live in 58 recognised camps. UNRWA operates 702 schools and 144 health centres, some of which are affected by the ongoing humanitarian disasters in Syria and the Gaza Strip. It has dramatically reduced the prevalence of infectious diseases, mortality, and illiteracy. Its social services include rebuilding infrastructure and homes that have been destroyed by conflict and providing cash assistance and micro-finance loans for Palestinians whose rights are curtailed and who are denied the right of return to their homeland

Salicylic acid and salicylic acid glucoside in xylem sap of Brassica napus infected with Verticillium longisporum

Salicylic acid (SA) and its glucoside (SAG) were detected in xylem sap of Brassica napus by HPLC–MS. Concentrations of SA and SAG in xylem sap from the root and hypocotyl of the plant, and in extracts of shoots above the hypocotyl, increased after infection with the vascular pathogen Verticillium longisporum. Both concentrations were correlated with disease severity assessed as the reduction in shoot length. Furthermore, SAG levels in shoot extracts were correlated with the amount of V. longisporum DNA in the hypocotyls. Although the concentration of SAG (but not SA) in xylem sap of infected plants gradually declined from 14 to 35 days post infection, SAG levels remained significantly higher than in uninfected plants during the whole experiment. Jasmonic acid (JA) and abscisic acid (ABA) levels in xylem sap were not affected by infection with V. longisporum. SA and SAG extend the list of phytohormones potentially transported from root to shoot with the transpiration stream. The physiological relevance of this transport and its contribution to the distribution of SA in plants remain to be elucidated

HIV Risk Profiles Among HIV-Positive, Methamphetamine-Using Men Who Have Sex with Both Men and Women

This study examined demographic characteristics, sexual risk behaviors, sexual beliefs, and substance use patterns in HIV-positive, methamphetamine-using men who have sex with both men and women (MSMW) (n = 50) as compared to men who have sex with men only (MSM) (n = 150). Separate logistic regressions were conducted to predict group membership. In the final model, of 12 variables, eight were independently associated with group membership. Factors independently associated with MSMW were acquiring HIV through injection drug use, being an injection drug user, using hallucinogens, using crack, being less likely to have sex at a bathhouse, being less likely to be the receptive partner when high on methamphetamine, having greater intentions to use condoms for oral sex, and having more negative attitudes about HIV disclosure. These results suggest that, among HIV-positive methamphetamine users, MSMW differ significantly from MSM in terms of their HIV risk behaviors. Studies of gay men and HIV often also include bisexual men, grouping them all together as MSM, which may obscure important differences between MSMW and MSM. It is important that future studies consider MSM and MSMW separately in order to expand our knowledge about differential HIV prevention needs for both groups. This study showed that there were important differences in primary and secondary prevention needs of MSM and MSMW. These findings have implications for both primary and secondary HIV prevention among these high-risk populations

Polymorphisms in the multiple drug resistance protein 1 and in P-glycoprotein 1 are associated with time to event outcomes in patients with advanced multiple myeloma treated with bortezomib and pegylated liposomal doxorubicin

Single nucleotide polymorphisms (SNPs) in the multiple drug resistance protein 1 (MRP1) and P-glycoprotein 1 (MDR1) genes modulate their ability to mediate drug resistance. We therefore sought to retrospectively evaluate their influence on outcomes in relapsed and/or refractory myeloma patients treated with bortezomib or bortezomib with pegylated liposomal doxorubicin (PLD). The MRP1/R723Q polymorphism was found in five subjects among the 279 patient study population, all of whom received PLD + bortezomib. Its presence was associated with a longer time to progression (TTP; median 330 vs. 129 days; p = 0.0008), progression-free survival (PFS; median 338 vs. 129 days; p = 0.0006), and overall survival (p = 0.0045). MDR1/3435(C > T), which was in Hardy–Weinberg equilibrium, showed a trend of association with PFS (p = 0.0578), response rate (p = 0.0782) and TTP (p = 0.0923) in PLD + bortezomib patients, though no correlation was found in the bortezomib arm. In a recessive genetic model, MDR1/3435 T was significantly associated with a better TTP (p = 0.0405) and PFS (p = 0.0186) in PLD + bortezomib patients. These findings suggest a potential role for MRP1 and MDR1 SNPs in modulating the long-term outcome of relapsed and/or refractory myeloma patients treated with PLD + bortezomib. Moreover, they support prospective studies to determine if such data could be used to tailor therapy to the genetic makeup of individual patients

Hypoxia-Inducible Factor 1α Determines Gastric Cancer Chemosensitivity via Modulation of p53 and NF-κB

BACKGROUND: Reduced chemosensitivity of solid cancer cells represents a pivotal obstacle in clinical oncology. Hence, the molecular characterization of pathways regulating chemosensitivity is a central prerequisite to improve cancer therapy. The hypoxia-inducible factor HIF-1alpha has been linked to chemosensitivity while the underlying molecular mechanisms remain largely elusive. Therefore, we comprehensively analysed HIF-1alpha's role in determining chemosensitivity focussing on responsible molecular pathways. METHODOLOGY AND PRINCIPAL FINDINGS: RNA interference was applied to inactivate HIF-1alpha or p53 in the human gastric cancer cell lines AGS and MKN28. The chemotherapeutic agents 5-fluorouracil and cisplatin were used and chemosensitivity was assessed by cell proliferation assays as well as determination of cell cycle distribution and apoptosis. Expression of p53 and p53 target proteins was analyzed by western blot. NF-kappaB activity was characterized by means of electrophoretic mobility shift assay. Inactivation of HIF-1alpha in gastric cancer cells resulted in robust elevation of chemosensitivity. Accordingly, HIF-1alpha-competent cells displayed a significant reduction of chemotherapy-induced senescence and apoptosis. Remarkably, this phenotype was completely absent in p53 mutant cells while inactivation of p53 per se did not affect chemosensitivity. HIF-1alpha markedly suppressed chemotherapy-induced activation of p53 and p21 as well as the retinoblastoma protein, eventually resulting in cell cycle arrest. Reduced formation of reactive oxygen species in HIF-1alpha-competent cells was identified as the molecular mechanism of HIF-1alpha-mediated inhibition of p53. Furthermore, loss of HIF-1alpha abrogated, in a p53-dependent manner, chemotherapy-induced DNA-binding of NF-kappaB and expression of anti-apoptotic NF-kappaB target genes. Accordingly, reconstitution of the NF-kappaB subunit p65 reversed the increased chemosensitivity of HIF-1alpha-deficient cells. CONCLUSION AND SIGNIFICANCE: In summary, we identified HIF-1alpha as a potent regulator of p53 and NF-kappaB activity under conditions of genotoxic stress. We conclude that p53 mutations in human tumors hold the potential to confound the efficacy of HIF-1-inhibitors in cancer therapy

Corticosteroids and regional variations in thickness of the human cerebral cortex across the lifespan

International audienceExposures to life stressors accumulate across the lifespan, with possible impact on brain health. Little is known, however, about the mechanisms mediating age-related changes in brain structure. We use a lifespan sample of participants (n = 21 251; 4–97 years) to investigate the relationship between the thickness of cerebral cortex and the expression of the glucocorticoid- and the mineralocorticoid-receptor genes (NR3C1 and NR3C2, respectively), obtained from the Allen Human Brain Atlas. In all participants, cortical thickness correlated negatively with the expression of both NR3C1 and NR3C2 across 34 cortical regions. The magnitude of this correlation varied across the lifespan. From childhood through early adulthood, the profile similarity (between NR3C1/NR3C2 expression and thickness) increased with age. Conversely, both profile similarities decreased with age in late life. These variations do not reflect age-related changes in NR3C1 and NR3C2 expression, as observed in 5 databases of gene expression in the human cerebral cortex (502 donors). Based on the co-expression of NR3C1 (and NR3C2) with genes specific to neural cell types, we determine the potential involvement of microglia, astrocytes, and CA1 pyramidal cells in mediating the relationship between corticosteroid exposure and cortical thickness. Therefore, corticosteroids may influence brain structure to a variable degree throughout life

International collaborative study to assess cardiovascular risk and evaluate long-term health in cats with preclinical hypertrophic cardiomyopathy and apparently healthy cats:The REVEAL Study

Background: Hypertrophic cardiomyopathy is the most prevalent heart disorder in cats and principal cause of cardiovascular morbidity and mortality. Yet, the impact of preclinical disease is unresolved. Hypothesis/Objectives: Observational study to characterize cardiovascular morbidity and survival in cats with preclinical nonobstructive (HCM) and obstructive (HOCM) hypertrophic cardiomyopathy and in apparently healthy cats (AH). Animals: One thousand seven hundred and thirty client-owned cats (430 preclinical HCM; 578 preclinical HOCM; 722 AH). Methods: Retrospective multicenter, longitudinal, cohort study. Cats from 21 countries were followed through medical record review and owner or referring veterinarian interviews. Data were analyzed to compare long-term outcomes, incidence, and risk for congestive heart failure (CHF), arterial thromboembolism (ATE), and cardiovascular death. Results: During the study period, CHF, ATE, or both occurred in 30.5% and cardiovascular death in 27.9% of 1008 HCM/HOCM cats. Risk assessed at 1, 5, and 10 years after study entry was 7.0%/3.5%, 19.9%/9.7%, and 23.9%/11.3% for CHF/ATE, and 6.7%, 22.8%, and 28.3% for cardiovascular death, respectively. There were no statistically significant differences between HOCM compared with HCM for cardiovascular morbidity or mortality, time from diagnosis to development of morbidity, or cardiovascular survival. Cats that developed cardiovascular morbidity had short survival (mean \ub1 standard deviation, 1.3 \ub1 1.7 years). Overall, prolonged longevity was recorded in a minority of preclinical HCM/HOCM cats with 10% reaching 9-15 years. Conclusions and Clinical Importance: Preclinical HCM/HOCM is a global health problem of cats that carries substantial risk for CHF, ATE, and cardiovascular death. This finding underscores the need to identify therapies and monitoring strategies that decrease morbidity and mortality