Community pharmacist-led interventions for patients with type 2 diabetes in low-income and middle-income countries:A scoping review

BACKGROUND: Studies assessing community pharmacist-led interventions conducted in high-income countries indicate that community pharmacists are successful in taking opportunities to support diabetes management. It is not yet clear as to what extent this is also true for low-income and middle-income countries.OBJECTIVES: To provide an overview of the types of interventions performed by community pharmacists and available evidence about their effects on patients with type 2 diabetes mellitus in low-income and middle-income countries.METHODS: PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for (non) randomized controlled, before-and-after, and interrupted time series design studies. There was no restriction on publication language. Interventions to be included had to be delivered by community pharmacists in a primary care or community setting. Study quality was assessed using the National Institute of Health tools, with results analyzed qualitatively, and the review itself was conducted in accordance with guidelines for scoping reviews.RESULTS: Twenty-eight studies were included, representing 4,434 patients (mean age from 47.4 to 59.5 years, 55.4% female) from community pharmacies (16 studies), primary care centers (8 studies) or community setting (4 studies). Four studies were single-component and the remaining represented multi-component interventions. Face-to-face counseling of patients was the most common intervention, often combined with the provision of printed materials, remote consultations, or conducting medication reviews. Generally, studies showed improved outcomes in the intervention group, including clinical, patient-reported and medication safety outcomes. In most studies, at least one domain was judged to be of poor quality, with heterogeneity among studies.CONCLUSIONS: Community pharmacist-led interventions on type 2 diabetes mellitus patients showed various positive effects but the quality of the evidence was poor. Face-to-face counseling of varying intensity, often combined with other strategies and representing a multi-component intervention, was the most common type. Although these findings support the expansion of the community pharmacist's role in diabetes care in low-income and middle-income countries, better quality studies are needed to evaluate the impact of specific interventions.</p

Role of Elf3 in diabetic nephropathy

Diabetic nephropathy (DN) is among the most serious complications of diabetes mellitus, and often leads to end-stage renal disease ultimately requiring dialysis or renal transplantation. The loss of podocytes has been reported to have a role in the onset and progression of DN. Here, we addressed the activation mechanism of Smad3 signaling in podocytes. Expression of RII and activation of Smad3 were induced by AGE exposure (P<0.05). Reduction of the activation of RII-Smad3 signaling ameliorated podocyte injuries in Smad3-knockout diabetic mice. The bone morphogenetic protein 4 (BMP4) significantly regulated activation of RII-Smad3 signalings (P<0.05). Moreover, the epithelium-specific transcription factor, Elf3was induced by AGE stimulation and, subsequently, upregulated RII expression in cultured podocytes. Induction of Elf3 and activation of RII-Smad3 signaling, leading to a decrease in WT1 expression, were observed in podocytes in diabetic human kidneys. Moreover, AGE treatment induced the secretion of Elf3-containing exosomes from cultured podocytes, which was dependent on the activation of the TGF-β-Smad3 signaling pathway. In addition, exosomal Elf3 protein in urine could be measured only in urinary exosomes from patients with DN. The appearance of urinary exosomal Elf3 protein in patients with DN suggested the existence of irreversible injuries in podocytes. The rate of decline in the estimated Glomerular Filtration Rate (eGFR) after measurement of urinary exosomal Elf3 protein levels in patients with DN (R2 = 0.7259) might be useful as an early non-invasive marker for podocyte injuries in DN

A new paradigm to indicate antidepressant treatments

This article develops the idea that clinical depression can be seen as a typical human response, largely rooted in human culture, to events of loss or times of adversity. Various biological, psychological, and social factors may cause some individuals to have a depressive reaction that is ineffectually limited in time and/or severity. Recovery occurs mainly based on natural resilience mechanisms, which come into play spontaneously, but which are sometimes inhibited or blocked by specific pathological biopsychosocial mechanisms. One of the mechanisms for this could be the influence of the circuits that regulate pleasure and happiness, along the dorsal diencephalic connection (DDC) pathway from the forebrain to the midbrain via the habenula. Therapy works by undermining the biopsychosocial factors that prevent the natural recovery mechanism from working. Treatment should, therefore, be seen as facilitating rather than causing natural recovery. This approach is in line with the high recovery rate after placebo treatments and the positive influence of pharmacological treatments with completely different sites of action. Acceptance of this model means that when studying new treatments for depression, a new paradigm must be applied in which the relative value of antidepressant treatment is specifically weighted in terms of enabling the natural resilience process

Preliminary pharmacogenetic study to explore putative dopaminergic mechanisms of antidepressant action

Background: There is sufficient evidence that interference of dopaminergic neurotransmission contributes to the therapeutic effects of antidepressants in unipolar and bipolar depression. Methods: Hamilton depression rating scale (HAMD 17) scores of 163 at least moderately ill patients with major depressive disorders were used to establish treatment response. HAMD 17 score status was measured before initiation, after two weeks, and after four weeks of treatment with various antidepressants. The possible association between response and genotype in a total of 14 variants of dopamine neurotransmission-related proteins was investigated. Results: DRD4 rs11246226 CA heterozygous patients were found with a greater improvement of HAMD 17 score when compared to homozygous C patients during 0–2 weeks and 0–4 weeks. Patients with MAOB rs1799836 heterozygous GA and homozygous A also demonstrated improved scores during 2–4 weeks and 0–4 weeks. Conclusions: The results are preliminary due to the limited population size and the small number of variants. Further research into the involvement of habenular dopamine D4 receptors in the antidepressant response is desirable

Limited Associations Between 5-HT Receptor Gene Polymorphisms and Treatment Response in Antidepressant Treatment-Free Patients With Depression

Major depressive disorder has become a prominent cause of disability, as lifetime prevalence has increased to similar to 15% in the Western world. Pharmacological effects of serotonin (5-hydroxytryptamine, 5-HT) are mediated through 5-hydroxytryptamine receptor (5-HTR) binding. Serotonin regulation of amygdala activity is attained through activation of three 5-HT2 family receptor subtypes, 5-HT2A, 5-HT2B, and 5-HT2C. Specifically, HT2A and the HT2C receptors have similar gross cerebral distribution and function, with higher constitutive activity found in HT2C than in HT2A. We investigated the possible association of 5-HTR gene polymorphisms to specific and non-specific antidepressant treatment responses in treatment-free patients in Siberia. 156 patients, aged between 18-70 years and clinically diagnosed with depressive disorders, were treated with antidepressants for 4 weeks. Patients were genotyped for a subset of 29 SNPs from the following 5-HT Receptor genes: HTR1A, HTR1B, HTR2A, HTR2C, HTR3A, HTR3B and HTR6. Primary outcome was measured by differences in Hamilton Depression Rating Scale (Delta HAM-D 17) scores between baseline/week two, week two/week four and baseline/week four. Univariate linear regression was initially conducted to determine the 5-HTR SNPs to be studied within the multiple linear regression. Multiple linear regression analyses over the three time periods were conducted for Delta HAM-D 17 with independent factors including: age, gender, depression diagnosis, antidepressant treatment and selected 5-HTR SNPs. We found improved increment HAM-D 17 in patients taking tricyclic antidepressants (0-4 weeks: B = 4.85, p = 0.0002; 0-2 weeks: B = 3.58, p = 0.002) compared to patients taking SSRIs. Over the course of study, significant associations between 5-HT receptors SNPs and antidepressant response were not identified

Polymorphisms in the adrenergic neurotransmission pathway impact antidepressant response in depressed patients

Mood disorders are a prevalent mental health disorder. The adrenergic neurotransmission pathway presents an opportunity to determine whether genetic mutations impact antidepressant response. For this study, 163 patients with major depressive disorders were enrolled to measure treatment response using the Hamilton Depression Rating Scale (HAMD-17). More than half of the patients had never been treated with antidepressants previously. Patients were genotyped for 14 SNPs within ADRA1A, SLC6A2, ADRβ1, MAOA and COMT to determine the impact of adrenergic neurotransmission polymorphisms related in antidepressant response. Patients were treated mainly with SSRIs and TCAs. The difference in HAMD-17 scores between the measurement periods were defined as the outcome measure. Multiple linear regression was conducted to determine the association between the genotypes and difference in HAMD-17 across the study period. Covariates of age, sex, antidepressant medication and depression diagnoses were included in the regression. Throughout the study HAMD-17 scores were measured at initiation, at two weeks and at four weeks for each patient. The difference in HAMD-17 scores was found to be 11.2 ​± ​4.4 between initiation and two weeks, 7.8 ​± ​5.3 between two week and four week, and 19.0 ​± ​5.3 throughout the entire study. SLC6A2 rs1532701 homozygous G/G Patients were associated with improved ΔHAMD-17 across week 2–4 and the entire study (B ​= ​7.1, p ​= ​0.002; B ​= ​6.7, p ​= ​0.013) compared to homozygous A/A patients. SLC6A2 rs1532701 homozygous A/G patients were further associated with improved ΔHAMD-17 compared to homozygous A/A patients at week 2–4 (B ​= ​2.8, p ​= ​0.023). Through our investigation, we were able to determine the genes within the adrenergic pathway to investigate further. To further elucidate these findings, replication and combination with other neurotransmitter pathways to better map the mechanism of actions of antidepressant for tailored treatment would be suggested

Investigating the potential role of BDNF and PRL genotypes on antidepressant response in depression patients:A prospective inception cohort study in treatment-free patients

Background: Brain-derived neurotrophic factor (BDNF) is associated with response to antidepressant drugs in mood and anxiety disorders. Prolactin (PRL) is a pituitary hormone with behavioural effects, acting as a neurotrophic factor within the brain and may be involved in antidepressant response. Objectives: To investigate the relationship between BDNF and PRL genotypes with antidepressant drug response. Methods: Prospective inception cohort of 186 Russian treatment-free participants (28 men and 158 women) between 18 and 70 years clinically diagnosed with depressive disorder who initiated antidepressant medication. DNA polymorphisms were genotyped for PRL rs1341239, BDNF rs6265 and rs7124442. Primary outcome was measured by differences in Hamilton Depression Rating Scale (Delta HAM-D) scores between baseline/week two, week two/week four, and baseline/week four. Linear regression and independent t-test determined the significance between polymorphisms and Delta HAM-D. Results: Comparisons between genotypes did not reveal any significant differences in scores during the first two weeks of treatment. In the latter two weeks, BDNF rs7124442 homozygous C patients responded significantly worse in comparison to homozygous T patients during this period. Further analysis within women and in postmenopausal women found a similar comparison between alleles. Limitations: Study lasted four weeks, which may be considered short to associate genuine antidepressant effects. Conclusions: Patients taking tricylic antidepressants were noted to have a significant improvement in Delta HAM-D compared to patients taking SSRIs. Homozygous C BDNF rs712442 patients were found to respond significantly worse in the last two weeks of treatment

Influence of eight ABCB1 polymorphisms on antidepressant response in a prospective cohort of treatment-free Russian patients with moderate or severe depression:An explorative psychopharmacological study with naturalistic design

BACKGROUND: Many antidepressants are substrates of P-glycoprotein, an efflux transporter in the blood-brain-barrier encoded by the ABCB1 gene. Genetic variations might influence the transport rate of antidepressants and hence their pharmacological effects. This study investigates the influence of eight polymorphisms in the ABCB1 gene on antidepressant treatment response. METHOD: 152 patients were included from psychiatric departments of the Mental Health Research Institute in Tomsk. The difference in Hamilton-Depression-Rating-Scale (HAMD-17)-scores between baseline and week two, week two and four, and baseline and week four was used to estimate timing of improvement of depression. Associations between the ABCB1 gene-polymorphisms and reduction in HAMD-17 score were assessed using independent t-test and multiple linear regression. RESULTS: Tricyclic antidepressants were associated with a higher reduction of HAMD-17 score when compared to SSRIs. The SNP rs2235040 A-allele had a significant positive influence on the ΔHAMD-17(0→2W) score but a significant negative influence on the ΔHAMD-17(2→4W) score. The rs4148739 G-allele had a significant negative influence on the ΔHAMD-17(0→2W) score but a significant positive influence on the ΔHAMD-17(2→4W) score. The SNP rs2235015 T-allele is significant negatively related to the ΔHAMD-17(2→4W) score. CONCLUSION: ABCB1 Genetic variations appear to affect speed but not magnitude of antidepressant drug response

AGEを介したSmad1とSmad3のリン酸化を介した新規相互作用は糖尿病性腎症の進展を制御する

Diabetic nephropathy (DN) is the major cause of end-stage renal failure and is associated with increased morbidity and mortality compared with other causes of renal diseases. We previously found that Smad1 plays a critical role in the development of DN both in vitro and in vivo. However, functional interaction between Smad1 and Smad3 signaling in DN is unclear. Here, we addressed the molecular interplay between Smad1 and Smad3 signaling under a diabetic condition by using Smad3-knockout diabetic mice. Extracellular matrix (ECM) protein overexpression and Smad1 activation were observed in the glomeruli of db/db mice but were suppressed in the glomeruli of Smad3+/−; db/db mice. Smad3 activation enhanced the phosphorylation of Smad1 C-terminal domain but decreased the phosphorylation of linker domain, thus regulating Smad1 activation in advanced glycation end product-treated mesangial cells (MCs). However, forced phosphorylation of the Smad1 linker domain did not affect Smad3 activation in MCs. Phosphorylation of the Smad1 linker domain increased in Smad3+/−; db/db mice and probucol-treated db/db mice, which was consistent with the attenuation of ECM overproduction. These results indicate that Smad3 expression and activation or probucol treatment alters Smad1 phosphorylation, thus suggesting new molecular mechanisms underlying DN development and progression

Space Demonstration of Two-Layer Pop-Up Origami Deployable Membrane Reflectarray Antenna by 3U CubeSat OrigamiSat-2

3U CubeSat OrigamiSat-2 demonstrates a 50-cm × 50-cm two-layer pop-up Origami deployable membrane reflectarray antenna in space. The membrane has small stowage volume and high gain even though it has low flatness because of a large enough antenna area to cover its un-flatness. C-band transmitter is equipped in the CubeSat and offers 20-Mbps amateur satellite communication. In 3U size, a 1-m length deployable gravity gradient mast and magnetic torquer are equipped to stabilize and control its attitude. A camera is attached to the satellite to measure the shape of the membrane antenna. OrigamiSat-2 was selected as the Innovative Satellite Technology Demonstration-4 by Japan Aerospace Exploration Agency (JAXA) and is going to be launched in 2024 by Epsilon Launch Vehicle