The influence of REM sleep and SWS on emotional memory consolidation in participants reporting depressive symptoms

Negative emotional memory bias is thought to play a causal role in the onset and maintenance of major depressive disorder. Rapid Eye Movement (REM) sleep has been shown to selectively consolidate negative emotional memories in healthy participants, and is greater in quantity and density in depressed patients. Slow-Wave Sleep (SWS) is typically associated with the consolidation of non-emotional memories. However, the effects of REM sleep and SWS on emotional memory consolidation have not been investigated in participants reporting depressive symptoms. In this study, we recruited two groups of healthy participants; one reporting mild-to-moderate depressive symptoms, and another reporting minimal depressive symptoms (assessed using the Beck Depression Inventory; BDI-II). Using a within-subjects split-night design, we measured consolidation of positive, neutral and negative images across a 3 h retention interval rich in either REM sleep or SWS. We found a significant sleep condition x image valence interaction in participants reporting depressive symptoms [F (2, 20) = 4.73, p = .021], but not participants reporting minimal depressive symptoms [F (2, 22) = 0.17, p = .845]. Participants reporting depressive symptoms consolidated significantly more neutral memories during SWS, and marginally more negative memories during REM sleep, than those reporting minimal depressive symptoms [t (21) = 2.44, p = .023; t (21) = 1.96, p = .064, respectively]. Our preliminary results demonstrate that REM sleep and SWS have differential effects on the consolidation of emotional and neutral images in participants reporting depressive symptoms. Further studies including larger sample sizes are required to investigate whether REM sleep alterations promote the development of negative memory bias in major depressive disorder

EQIP\u27s First Year: A Step Closer to Higher Quality in Surgical Education.

OBJECTIVE: To describe the first year of the Educational Quality Improvement Program (EQIP) DESIGN: The Educational Quality Improvement Program (EQIP) was formed by the Association of Program Directors in Surgery (APDS) in 2018 as a continuous educational quality improvement program. Over 18 months, thirteen discrete goals for the establishment of EQIP were refined and executed through a collaborative effort involving leaders in surgical education. Alpha and beta pilots were conducted to refine the data queries and collection processes. A highly-secure, doubly-deidentified database was created for the ingestion of resident and program data. SETTING & PARTICIPANTS: 36 surgical training programs with 1264 trainees and 1500 faculty members were included in the dataset. 51,516 ERAS applications to programs were also included. Uni- and multi-variable analysis was then conducted. RESULTS: EQIP was successfully deployed within the timeline described in 2020. Data from the ACGME, ABS, and ERAS were merged with manually entered data by programs and successfully ingested into the EQIP database. Interactive dashboards have been constructed for use by programs to compare to the national cohort. Risk-adjusted multivariable analysis suggests that increased time in a technical skills lab was associated with increased success on the ABS\u27s Qualifying Examination, alone. Increased time in a technical skills lab and the presence of a formal teaching curriculum were associated with increased success on both the ABS\u27s Qualifying and Certifying Examination. Program type may be of some consequence in predicting success on the Qualifying Examination. CONCLUSIONS: The APDS has proved the concept that a highly secure database for the purpose of continuous risk-adjusted quality improvement in surgical education can be successfully deployed. EQIP will continue to improve and hopes to include an increasing number of programs as the barriers to participation are overcome

Metformin in non-diabetic hyperglycaemia: the GLINT feasibility RCT.

BACKGROUND: The treatment of people with diabetes with metformin can reduce cardiovascular disease (CVD) and may reduce the risk of cancer. However, it is unknown whether or not metformin can reduce the risk of these outcomes in people with elevated blood glucose levels below the threshold for diabetes [i.e. non-diabetic hyperglycaemia (NDH)]. OBJECTIVE: To assess the feasibility of the Glucose Lowering In Non-diabetic hyperglycaemia Trial (GLINT) and to estimate the key parameters to inform the design of the full trial. These parameters include the recruitment strategy, randomisation, electronic data capture, postal drug distribution, retention, study medication adherence, safety monitoring and remote collection of outcome data. DESIGN: A multicentre, individually randomised, double-blind, parallel-group, pragmatic, primary prevention trial. Participants were individually randomised on a 1 : 1 basis, blocked within each site. SETTING: General practices and clinical research facilities in Cambridgeshire, Norfolk and Leicestershire. PARTICIPANTS: Males and females aged ≥ 40 years with NDH who had a high risk of CVD. INTERVENTIONS: Prolonged-release metformin (500 mg) (Glucophage® SR, Merck KGaA, Bedfont Cross, Middlesex, UK) or the matched placebo, up to three tablets per day, distributed by post. MAIN OUTCOME MEASURES: Recruitment rates; adherence to study medication; laboratory results at baseline and 3 and 6 months; reliability and acceptability of study drug delivery; questionnaire return rates; and quality of life. RESULTS: We sent 5251 invitations, with 511 individuals consenting to participate. Of these, 249 were eligible and were randomised between March and November 2015 (125 to the metformin group and 124 to the placebo group). Participants were followed up for 0.99 years [standard deviation (SD) 0.30 years]. The use of electronic medical records to identify potentially eligible individuals in individual practices was resource intensive. Participants were generally elderly [mean age 70 years (SD 6.7 years)], overweight [mean body mass index 30.1 kg/m2 (SD 4.5 kg/m2)] and male (88%), and the mean modelled 10-year CVD risk was 28.8% (SD 8.5%). Randomisation, postal delivery of the study drug and outcome assessment using registers/medical records were feasible and acceptable to participants. Most participants were able to take three tablets per day, but premature discontinuation of the study drug was common (≈30% of participants by 6 months), although there were no differences between the groups. All randomised participants returned questionnaires at baseline and 67% of participants returned questionnaires by the end of the study. There was no between-group difference in Short Form questionnaire-8 items or EuroQol-5 Dimensions scores. Compared with placebo, metformin was associated with small improvements in the mean glycated haemoglobin level [-0.82 mmol/mol, 95% confidence interval (CI) -1.39 to -0.24 mmol/mol], mean estimated glomerular filtration rate (2.31 ml/minute/1.73 m2, 95% CI -0.2 to 4.81 ml/minute/1.73 m2) and mean low-density lipoprotein cholesterol level (-0.11 mmol/l, 95% CI -0.25 to 0.02 mmol/l) and a reduction in mean plasma vitamin B12 level (-16.4 ng/l, 95% CI -32.9 to -0.01 ng/l). There were 35 serious adverse events (13 in the placebo group, 22 in the metformin group), with none deemed to be treatment related. LIMITATIONS: Changes to sponsorship reduced the study duration, the limited availability of information in medical records reduced recruitment efficiency and discontinuation of study medication exceeded forecasts. CONCLUSIONS: A large, pragmatic trial comparing the effects of prolonged-release metformin and placebo on the risk of CVD events is potentially feasible. However, changes to the study design and conduct are recommended to enable an efficient scaling up of the trial. Recommendations include changing the inclusion criteria to recruit people with pre-existing CVD to increase the recruitment and event rates, using large primary/secondary care databases to increase recruitment rates, conducting follow-up remotely to improve efficiency and including a run-in period prior to randomisation to optimise trial adherence. TRIAL REGISTRATION: Current Controlled Trials ISRCTN34875079. FUNDING: The project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 18. See the NIHR Journals Library website for further project information. Merck KGaA provided metformin and matching placebo

Ad astra per aspera (Through Hardships to the Stars): Lessons Learned from the First National Virtual APDS Meeting, 2020

This article is made available for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.Objective After COVID-19 rendered in-person meetings for national societies impossible in the spring of 2020, the leadership of the Association of Program Directors in Surgery (APDS) innovated via a virtual format in order to hold its national meeting. Design APDS leadership pre-emptively considered factors that would be important to attendees including cost, value, time, professional commitments, education, sharing of relevant and current information, and networking. Setting The meeting was conducted using a variety of virtual formats including a web portal for entry, pre-ecorded poster and oral presentations on the APDS website, interactive panels via a web conferencing platform, and livestreaming. Participants There were 298 registrants for the national meeting of the APDS, and 59 participants in the New Program Directors Workshop. The registrants and participants comprised medical students, residents, associate program directors, program directors, and others involved in surgical education nationally. Results There was no significant difference detected for high levels of participant satisfaction between 2019 and 2020 for the following items: overall program rating, topics and content meeting stated objectives, relevant content to educational needs, educational format conducive to learning, and agreement that the program will improve competence, performance, communication skills, patient outcomes, or processes of care/healthcare system performance. Conclusions A virtual format for a national society meeting can provide education, engagement, and community, and the lessons learned by the APDS in the process can be used by other societies for utilization and further improvement

Feasibility of identifying household contacts of rifampin-and multidrug-resistant tuberculosis cases at high risk of progression to tuberculosis disease

CITATION: Gupta, A. et al. 2020. Feasibility of identifying household contacts of rifampin-and multidrug-resistant tuberculosis cases at high risk of progression to tuberculosis disease. Clinical infectious diseases, 70(3): 425–435. doi:10.1093/cid/ciz235The original publication is available at https://academic.oup.com/cid/Background: We assessed multidrug-resistant tuberculosis (MDR-TB) cases and their household contacts (HHCs) to inform the development of an interventional clinical trial. Methods: We conducted a cross-sectional study of adult MDR-TB cases and their HHCs in 8 countries with high TB burdens. HHCs underwent symptom screenings, chest radiographies, sputum TB bacteriologies, TB infection (TBI) testing (tuberculin skin test [TST] and interferon gamma release assay [IGRA]), and human immunodeficiency virus (HIV) testing. Results: From October 2015 to April 2016, 1016 HHCs from 284 MDR-TB cases were enrolled. At diagnosis, 69% of MDR-TB cases were positive for acid-fast bacilli sputum smears and 43% had cavitary disease; at study entry, 35% remained smear positive after a median MDR-TB treatment duration of 8.8 weeks. There were 9 HHCs that were diagnosed with TB prior to entry and excluded. Of the remaining 1007 HHCs, 41% were male and the median age was 25 years. There were 121 (12%) HHCs that had new cases of TB identified: 17 (2%) were confirmed, 33 (3%) probable, and 71 (7%) possible TB cases. The TBI prevalence (defined as either TST or IGRA positivity) was 72% and varied by age, test used, and country. Of 1007 HHCs, 775 (77%) were considered high-risk per these mutually exclusive groups: 102 (10%) were aged <5 years; 63 (6%) were aged ≥5 and were infected with HIV; and 610 (61%) were aged ≥5 years, were negative for HIV or had an unknown HIV status, and were TBI positive. Only 21 (2%) HHCs were on preventive therapy. Conclusions: The majority of HHCs in these high-burden countries were at high risk of TB disease and infection, yet few were receiving routine preventive therapy. Trials of novel, preventive therapies are urgently needed to inform treatment policy and practice.https://academic.oup.com/cid/article/70/3/425/5426963?login=truePublishers versio

The ‘affect tagging and consolidation’ (ATaC) model of depression vulnerability

Since the 1960’s polysomnographic sleep research has demonstrated that depressive episodes are associated with REM sleep alterations. Some of these alterations, such as increased REM sleep density, have also been observed in first-degree relatives of patients and remitted patients, suggesting that they may be vulnerability markers of major depressive disorder (MDD), rather than mere epiphenomena of the disorder. Neuroimaging studies have revealed that depression is also associated with heightened amygdala reactivity to negative emotional stimuli, which may also be a vulnerability marker for MDD. Several models have been developed to explain the respective roles of REM sleep alterations and negatively-biased amygdala activity in the pathology of MDD, however the possible interaction between these two potential risk-factors remains uncharted. This paper reviews the roles of the amygdala and REM sleep in the encoding and consolidation of negative emotional memories, respectively. We present our ‘affect tagging and consolidation’ (ATaC) model, which argues that increased REM sleep density and negatively-biased amygdala activity are two separate, genetically influenced risk-factors for depression which interact to promote the development of negative memory bias – a well-known cognitive vulnerability marker for depression. Predictions of the ATaC model may motivate research aimed at improving our understanding of sleep dependent memory consolidation in depression aetiology

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Overnight retention of emotional memories is influenced by BDNF Val66Met but not 5-HTTLPR

Emotional memory may be modulated by BDNF Val66Met and 5-HTTLPR polymorphisms. However, the influence of these genetic variants on the overnight retention of emotional memories has not been investigated in humans. Thirty-six healthy female students were selected to participate in this study based on 5-HTTLPR genotype status (L’/L’, L’/S’, S’/S’). Participants were also genotyped for BDNF Val66Met (Val/Val, Met carriers). We measured recognition performance for positive, neutral and negative images before and after overnight sleep. We found a significant interaction between BDNF Val66Met genotype group and image valence on post-sleep recognition performance. This interaction was driven by greater memory for negative and positive images, relative to neutral images, in Met carriers. We also found that longer Rapid Eye Movement (REM) sleep duration predicted greater post-sleep recognition performance for negative images in Met carriers, but not in Val homozygotes. We observed no influence of 5-HTTLPR polymorphisms on post- sleep recognition performance for positive, neutral or negative images. Our findings support a modulatory role for BDNF Val66Met in overnight emotional memory retention in females. We discuss the implications of this finding for understanding the influence of BDNF Val66Met on depression vulnerability