A direct interareal feedback-to-feedforward circuit in primate visual cortex

The mammalian sensory neocortex consists of hierarchically organized areas reciprocally connected via feedforward (FF) and feedback (FB) circuits. Several theories of hierarchical computation ascribe the bulk of the computational work of the cortex to looped FF-FB circuits between pairs of cortical areas. However, whether such corticocortical loops exist remains unclear. In higher mammals, individual FF-projection neurons send afferents almost exclusively to a single higher-level area. However, it is unclear whether FB-projection neurons show similar area-specificity, and whether they influence FF-projection neurons directly or indirectly. Using viral-mediated monosynaptic circuit tracing in macaque primary visual cortex (V1), we show that V1 neurons sending FF projections to area V2 receive monosynaptic FB inputs from V2, but not other V1-projecting areas. We also find monosynaptic FBto-FB neuron contacts as a second motif of FB connectivity. Our results support the existence of FF-FB loops in primate cortex, and suggest that FB can rapidly and selectively influence the activity of incoming FF signals

Social and Structural Factors Associated With Substance Use within the Support Network of Adults Living In Precarious Housing in A Socially Marginalized Neighborhood of Vancouver, Canada

Background The structure of a social network as well as peer behaviours are thought to affect personal substance use. Where substance use may create health risks, understanding the contribution of social networks to substance use may be valuable for the design and implementation of harm reduction or other interventions. We examined the social support network of people living in precarious housing in a socially marginalized neighborhood of Vancouver, and analysed associations between social network structure, personal substance use, and supporters’ substance use. Methods An ongoing, longitudinal study recruited 246 participants from four single room occupancy hotels, with 201 providing social network information aligned with a 6-month observation period. Use of tobacco, alcohol, cannabis, cocaine (crack and powder), methamphetamine, and heroin was recorded at monthly visits. Ego- and graph-level measures were calculated; the dispersion and prevalence of substances in the network was described. Logistic mixed effects models were used to estimate the association between ego substance use and peer substance use. Permutation analysis was done to test for randomness of substance use dispersion on the social network. Results The network topology corresponded to residence (Hotel) with two clusters differing in demographic characteristics (Cluster 1 –Hotel A: 94% of members, Cluster 2 –Hotel B: 95% of members). Dispersion of substance use across the network demonstrated differences according to network topology and specific substance. Methamphetamine use (overall 12%) was almost entirely limited to Cluster 1, and absent from Cluster 2. Different patterns were observed for other substances. Overall, ego substance use did not differ over the six-month period of observation. Ego heroin, cannabis, or crack cocaine use was associated with alter use of the same substances. Ego methamphetamine, powder cocaine, or alcohol use was not associated with alter use, with the exception for methamphetamine in a densely using part of the network. For alters using multiple substances, cannabis use was associated with lower ego heroin use, and lower ego crack cocaine use. Permutation analysis also provided evidence that dispersion of substance use, and the association between ego and alter use was not random for all substances. Conclusions In a socially marginalized neighborhood, social network topology was strongly influenced by residence, and in turn was associated with type(s) of substance use. Associations between personal use and supporter’s use of a substance differed across substances. These complex associations may merit consideration in the design of interventions to reduce risk and harms associated with substance use in people living in precarious housing

Quality assurance for Chinese herbal formulae: standardization of IBS-20, a 20-herb preparation

<p>Abstract</p> <p>Background</p> <p>The employment of well characterized test samples prepared from authenticated, high quality medicinal plant materials is key to reproducible herbal research. The present study aims to demonstrate a quality assurance program covering the acquisition, botanical validation, chemical standardization and good manufacturing practices (GMP) production of IBS-20, a 20-herb Chinese herbal formula under study as a potential agent for the treatment of irritable bowel syndrome.</p> <p>Methods</p> <p>Purity and contaminant tests for the presence of toxic metals, pesticide residues, mycotoxins and microorganisms were performed. Qualitative chemical fingerprint analysis and quantitation of marker compounds of the herbs, as well as that of the IBS-20 formula was carried out with high-performance liquid chromatography (HPLC). Extraction and manufacture of the 20-herb formula were carried out under GMP. Chemical standardization was performed with liquid chromatography-mass spectrometry (LC-MS) analysis. Stability of the formula was monitored with HPLC in real time.</p> <p>Results</p> <p>Quality component herbs, purchased from a GMP supplier were botanically and chemically authenticated and quantitative HPLC profiles (fingerprints) of each component herb and of the composite formula were established. An aqueous extract of the mixture of the 20 herbs was prepared and formulated into IBS-20, which was chemically standardized by LC-MS, with 20 chemical compounds serving as reference markers. The stability of the formula was monitored and shown to be stable at room temperature.</p> <p>Conclusion</p> <p>A quality assurance program has been developed for the preparation of a standardized 20-herb formulation for use in the clinical studies for the treatment of irritable bowel syndrome (IBS). The procedures developed in the present study will serve as a protocol for other poly-herbal Chinese medicine studies.</p

Who is Reached by HIV Self-Testing? Individual Factors Associated With Self-Testing Within a Community-Based Program in Rural Malawi.

INTRODUCTION: HIV self-testing (HIVST) is an alternative strategy for reaching population subgroups underserved by available HIV testing services. We assessed individual factors associated with ever HIVST within a community-based program. SETTING: Malawi. METHODS: We conducted secondary analysis of an end line survey administered under a cluster-randomized trial of community-based distribution of HIVST kits. We estimated prevalence differences and prevalence ratios (PRs) stratified by sex for the outcome: self-reported ever HIVST. RESULTS: Prevalence of ever HIVST was 45.0% (475/1055) among men and 40.1% (584/1456) among women. Age was associated with ever HIVST in both men and women, with evidence of a strong declining trend across categories of age. Compared with adults aged 25-39 years, HIVST was lowest among adults aged 40 years and older for both men [34.4%, 121/352; PR 0.74, 95% confidence interval (CI): 0.62 to 0.88] and women (30.0%, 136/454; PR 0.71, 95% CI: 0.6 to 0.84). Women who were married, had children, had higher levels of education, or were wealthier were more likely to self-test. Men who had condomless sex in the past 3 months (47.9%, 279/582) reported a higher HIVST prevalence compared with men who did not have recent condomless sex (43.1%, 94/218; adjusted PR 1.37, 95% CI: 1.06 to 1.76). Among men and women, the level of previous exposure to HIV testing and household HIVST uptake was associated with HIVST. CONCLUSIONS: Community-based HIVST reached men, younger age groups, and some at-risk individuals. HIVST was lowest among older adults and individuals with less previous exposure to HIV testing, suggesting the presence of ongoing barriers to HIV testing

How students cope with part-time study

This study provides a qualitative test and illustration of a model of how students cope with the demands of part-time study. The model shows that students who are successful in finding the time to complete the requirements of part-time courses do so by adopting three mechanisms; sacrifice, support and the negotiation of arrangements. All three mechanisms operate in four domains, namely work, family, social lives and the self. The mechanisms and domains were related together in a three by four matrix. Data to verify and illuminate the model were gathered by the researchers through an on-line forum discussion on the topic of coping with part-time study. The researchers themselves were studying part-time in a course called Adult Education and Professional Development. Analysis of the data showed that the work domain was very important but little adaptation was possible. The family was seen as the most important domain and all three mechanisms were used. Time was commonly found for part-time study by sacrificing social lives. The self-domain was interpreted as important in establishing motivation and self-determination

Autoimmune PaneLs as PrEdictors of Toxicity in Patients TReated with Immune Checkpoint InhibiTors (ALERT)

Background: Immune-checkpoint inhibitors (ICI) can lead to immune-related adverse events (irAEs) in a significant proportion of patients. The mechanisms underlying irAEs development are mostly unknown and might involve multiple immune effectors, such as T cells, B cells and autoantibodies (AutoAb). Methods: We used custom autoantigen (AutoAg) microarrays to profile AutoAb related to irAEs in patients receiving ICI. Plasma was collected before and after ICI from cancer patients participating in two clinical trials (NCT03686202, NCT02644369). A one-time collection was obtained from healthy controls for comparison. Custom arrays with 162 autoAg were used to detect IgG and IgM reactivities. Differences of median fluorescent intensity (MFI) were analyzed with Wilcoxon sign rank test and Kruskal–Wallis test. MFI 500 was used as threshold to define autoAb reactivity. Results: A total of 114 patients and 14 healthy controls were included in this study. irAEs of grade (G) ≥ 2 occurred in 37/114 patients (32%). We observed a greater number of IgG and IgM reactivities in pre-ICI collections from patients versus healthy controls (62 vs 32 p &lt; 0.001). Patients experiencing irAEs G ≥ 2 demonstrated pre-ICI IgG reactivity to a greater number of AutoAg than patients who did not develop irAEs (39 vs 33 p = 0.040). We observed post-treatment increase of IgM reactivities in subjects experiencing irAEs G ≥ 2 (29 vs 35, p = 0.021) and a decrease of IgG levels after steroids (38 vs 28, p = 0.009). Conclusions: Overall, these results support the potential role of autoAb in irAEs etiology and evolution. A prospective study is ongoing to validate our findings (NCT04107311)

Evolving concepts on the age-related changes in “muscle quality”

The deterioration of skeletal muscle with advancing age has long been anecdotally recognized and has been of scientific interest for more than 150 years. Over the past several decades, the scientific and medical communities have recognized that skeletal muscle dysfunction (e.g., muscle weakness, poor muscle coordination, etc.) is a debilitating and life-threatening condition in the elderly. For example, the age-associated loss of muscle strength is highly associated with both mortality and physical disability. It is well-accepted that voluntary muscle force production is not solely dependent upon muscle size, but rather results from a combination of neurologic and skeletal muscle factors, and that biologic properties of both of these systems are altered with aging. Accordingly, numerous scientists and clinicians have used the term “muscle quality” to describe the relationship between voluntary muscle strength and muscle size. In this review article, we discuss the age-associated changes in the neuromuscular system—starting at the level of the brain and proceeding down to the subcellular level of individual muscle fibers—that are potentially influential in the etiology of dynapenia (age-related loss of muscle strength and power)

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie