Antigen and checkpoint receptor engagement recalibrates T cell receptor signal strength.

How T cell receptor (TCR) signal strength modulates T cell function and to what extent this is modified by immune checkpoint blockade (ICB) are key questions in immunology. Using Nr4a3-Tocky mice, we characterized early quantitative and qualitative changes that occur in CD4+ T cells in relation to TCR signaling strength. We captured how dose- and time-dependent programming of distinct co-inhibitory receptors rapidly recalibrates T cell activation thresholds and visualized the immediate effects of ICB on T cell re-activation. Our findings reveal that anti-PD1 immunotherapy leads to an increased TCR signal strength. We defined a strong TCR signal metric of five genes upregulated by anti-PD1 in T cells (TCR.strong), which was superior to a canonical T cell activation gene signature in stratifying melanoma patient outcomes to anti-PD1 therapy. Our study therefore reveals how analysis of TCR signal strength-and its manipulation-can provide powerful metrics for monitoring outcomes to immunotherapy.

Hypertensive disorders of pregnancy and the risk of maternal dementia: a systematic review and meta-analysis.

OBJECTIVE: Hypertensive disorders of pregnancy, including preeclampsia, are associated with an increased risk for maternal cardiovascular disease, stroke, and chronic kidney disease. However, their association with subsequent maternal dementia or cognitive impairment is less well understood. This study aimed to review and synthesize the published literature on hypertensive disorders of pregnancy and the subsequent risk for maternal dementia or cognitive impairment. DATA SOURCES: PubMed, Web of Science, Pyschinfo, and CINAHL were searched from database inception until July 31, 2022, for observational studies of hypertensive disorders of pregnancy and maternal dementia or cognitive impairment. STUDY ELIGIBILITY CRITERIA: Selected studies included the following: a population of pregnant women, exposure to a hypertensive disorder of pregnancy of interest, and at least 1 primary outcome (dementia) or secondary outcome (cognitive impairment). Two reviewers were involved in study selection. METHODS: We followed the Meta-analyses of Observational Studies in Epidemiology guidelines throughout. Random-effects meta-analyses were used to calculate the overall pooled estimates. Bias was assessed using an adapted version of the validated Newcastle-Ottawa Quality Assessment tool. RESULTS: A total of 25 eligible studies were identified and included 2,501,673 women. Preeclampsia was associated with a significantly increased risk for vascular dementia (adjusted hazard ratio, 1.89; 95% confidence interval, 1.47-2.43), whereas no clear association was noted between preeclampsia and Alzheimer's disease (adjusted hazard ratio, 1.27; 95% confidence interval, 0.95-1.70), nor between preeclampsia and any (undifferentiated) dementia (adjusted hazard ratio, 1.18; 95% confidence interval, 0.95-1.47). However, in an analysis restricted to women aged 65 years and older, preeclampsia was associated with an increased risk for Alzheimer's disease (adjusted hazard ratio, 1.92; 95% confidence interval, 1.35-2.73) and any dementia (adjusted hazard ratio, 1.87; 95% confidence interval, 1.21-2.91). CONCLUSION: Women whose pregnancies were complicated by preeclampsia seem to be at a substantially increased future risk for vascular dementia. The longer-term risks among these women with regards to Alzheimer's disease and other forms of dementia are less clear.

Association between diabetes overtreatment in older multimorbid patients and clinical outcomes: an ancillary European multicentre study.

BACKGROUND: Diabetes overtreatment is a frequent and severe issue in multimorbid older patients with type 2 diabetes (T2D). OBJECTIVE: This study aimed at assessing the association between diabetes overtreatment and 1-year functional decline, hospitalisation and mortality in older inpatients with multimorbidity and polypharmacy. METHODS: Ancillary study of the European multicentre OPERAM project on multimorbid patients aged ≥70 years with T2D and glucose-lowering treatment (GLT). Diabetes overtreatment was defined according to the 2019 Endocrine Society guideline using HbA1c target range individualised according to the patient's overall health status and the use of GLT with a high risk of hypoglycaemia. Multivariable regressions were used to assess the association between diabetes overtreatment and the three outcomes. RESULTS: Among the 490 patients with T2D on GLT (median age: 78 years; 38% female), 168 (34.3%) had diabetes overtreatment. In patients with diabetes overtreatment as compared with those not overtreated, there was no difference in functional decline (29.3% vs 38.0%, P = 0.088) nor hospitalisation rates (107.3 vs 125.8/100 p-y, P = 0.115) but there was a higher mortality rate (32.8 vs 21.4/100 p-y, P = 0.033). In multivariable analyses, diabetes overtreatment was not associated with functional decline nor hospitalisation (hazard ratio, HR [95%CI]: 0.80 [0.63; 1.02]) but was associated with a higher mortality rate (HR [95%CI]: 1.64 [1.06; 2.52]). CONCLUSIONS: Diabetes overtreatment was associated with a higher mortality rate but not with hospitalisation or functional decline. Interventional studies should be undertaken to test the effect of de-intensifying GLT on clinical outcomes in overtreated patients.

In-hospital adverse drug reactions in older adults; prevalence, presentation and associated drugs-a systematic review and meta-analysis.

BACKGROUND: the prevalence of adverse drug reactions (ADRs) in hospitalised older patients, their clinical presentations, causative drugs, severity, preventability and measurable outcomes are unclear, ADRs being an increasing challenge to older patient safety. METHODS: we systematically searched PubMed, Embase, EBSCO-CINAHL, the Cochrane Library, 'rey' literature and relevant systematic review bibliographies, published from database inception to March 2020. We included any study reporting occurrence of in-hospital ADRs as primary or secondary outcomes in hospitalised older adults (mean age ≥ 65 years). Two authors independently extracted relevant information and appraised studies for bias. Study characteristics, ADR clinical presentations, causative drugs, severity, preventability and clinical outcomes were analysed. Study estimates were pooled using random-effects meta-analytic models. RESULTS: from 2,399 abstracts, we undertook full-text screening in 286, identifying 27 studies (29 papers). Final analysis yielded a pooled ADR prevalence of 16% (95%CI 12-22%, I2 98%,τ2 0.8585), in a population of 20,153 hospitalised patients aged ≥65 years of whom 2,479 patients experienced ≥ one ADR. ADR ascertainment was highly heterogeneous. Almost 48.3% of all ADRs involved five presentations: fluid/electrolyte disturbances (17.3%), gastrointestinal motility/defaecation disorders (13.3%), renal disorders (8.2%), hypotension/blood pressure dysregulation disorders/shock (5.5%) and delirium (4.1%). Four drug classes accounted for 57.8% of causative medications i.e. diuretics (19.8%), anti-bacterials (14.8%), antithrombotic agents (12.2%) and analgesics (10.9%). Pooled analysis of severity was not feasible. Four studies reported the majority of ADRs as preventable (55-95%). CONCLUSIONS: on average, 16% of hospitalised older patients experience significant ADRs, varying in severity and mostly preventable, with commonly prescribed drug classes accounting for most ADRs.

Kava for generalised anxiety disorder: A 16-week double-blind, randomised, placebo-controlled study.

OBJECTIVE: Previous randomised, double-blind, placebo-controlled studies have shown that Kava (a South Pacific medicinal plant) reduced anxiety during short-term administration. The objective of this randomised, double-blind, placebo-controlled study was to perform a larger, longer-term trial assessing the efficacy and safety of Kava in the treatment of generalised anxiety disorder and to determine whether gamma-aminobutyric acid transporter (SLC6A1) single-nucleotide polymorphisms were moderators of response. METHODS: The trial was a phase III, multi-site, two-arm, 16-week, randomised, double-blind, placebo-controlled study investigating an aqueous extract of dried Kava root administered twice per day in tablet form (standardised to 120 mg of kavalactones twice/day) in 171 currently non-medicated anxious participants with diagnosed generalised anxiety disorder. The trial took place in Australia. RESULTS: An analysis of 171 participants revealed a non-significant difference in anxiety reduction between the Kava and placebo groups (a relative reduction favouring placebo of 1.37 points; p = 0.25). At the conclusion of the controlled phase, 17.4% of the Kava group were classified as remitted (Hamilton Anxiety Rating Scale score < 7) compared to 23.8% of the placebo group (p = 0.46). No SLC6A1 polymorphisms were associated with treatment response, while carriers of the rs2601126 T allele preferentially respond to placebo (p = 0.006). Kava was well tolerated aside from poorer memory (Kava = 36 vs placebo = 23; p = 0.044) and tremor/shakiness (Kava = 36 vs placebo = 23; p = 0.024) occurring more frequently in the Kava group. Liver function test abnormalities were significantly more frequent in the Kava group, although no participant met criteria for herb-induced hepatic injury. CONCLUSION: While research has generally supported Kava in non-clinical populations (potentially for more 'situational' anxiety as a short-term anxiolytic), this particular extract was not effective for diagnosed generalised anxiety disorder.

Detection and prevention of adverse drug reactions in multi-morbid older patients.

Adverse drug reactions (ADRs) are a recognised unintentional form of iatrogenic harm, which commonly occur in older adults who have high levels of multi-morbidity and associated polypharmacy. Previous studies estimate that at least one in 10 hospitalised older patients will experience an ADR. While recent research indicates that this could be as high as 39% in hospitalised multi-morbid, older adults, up to two-thirds of these ADRs can be considered preventable and therefore potentially avoidable. In addition to increasing patient morbidity and contributing to avoidable mortality, there is an associated cost implication with ADR occurrence. This commentary summarises current mainstream research in terms of ADR detection, prediction and prevention in multi-morbid older patients. At present, the biggest barrier to understanding and comparing ADRs in the literature is the large heterogeneity that exists in the population and study methods. Furthermore, there is the lack of standardised universally accepted methodology for ADR prediction, detection, causality assessment and subsequent prevention in older people. Standard available methods of ADR prediction applied to a heterogeneous multi-morbid population are generally unsatisfactory. Without an instrument that consistently and reliably predicts ADR risk in a reproducible manner, ADR prevention in multi-morbid older patients is challenging. Further attention should be focused on the culprit drugs that commonly lead to major ADRs in older multi-morbid hospitalised patients with polypharmacy. Risk associated with particular drug classes may possibly predict ADR occurrence better than patient characteristics alone. Current research is examining this drug class focus for ADR prevention in multi-morbid older people.

The Impact of Running, Monofilament Barbed Suture for Subcutaneous Tissue Closure on Infection Rates in Total Hip Arthroplasty: A Retrospective Cohort Analysis.

BACKGROUND: Recently, running, monofilament barbed suture has become more popular as an efficient and economical alternative to traditional braided interrupted suture for wound closure following total joint arthroplasty. Its overall association with wound complications following surgery remains unknown at this time. Several studies have investigated its use in total knee arthroplasty (TKA), but there is limited literature surrounding use in total hip arthroplasty (THA). In this retrospective cohort study, our primary objective was to determine whether the use of monofilament barbed suture in THA was associated with reduced rates of postoperative infection when compared to traditional braided suture. METHODS: Patients who underwent primary unilateral THA between November 2011 and December 2017 by a single senior surgeon with closure using either monofilament barbed suture (162 patients) or braided interrupted suture (429 patients) were retrospectively reviewed for postoperative wound complications during the first 90 days after surgery. Demographics, comorbidities, and perioperative data were also included to assess for risk factors for infection. RESULTS: There was no difference between braided and barbed suture in overall rates of major complication, including periprosthetic joint infection (PJI) (0.47% vs 0.62%, P = .82) or revisions (1.86% vs 1.23%, P = .60). The overall rate of minor, superficial wound complications was also similar between both groups (6.1% vs 3.1%, P = .15). However, when superficial complications were categorized by type (dehiscence vs infection), the use of barbed suture was associated with a decreased rate of superficial wound infection (0% vs 5.4%, P = .003) and an increased rate of wound dehiscence (3.1% vs 0.7%, P = .04). CONCLUSION: The use of monofilament barbed suture for superficial skin closure in THA leads to similar overall rates of both major and minor wound complications when compared to traditional interrupted braided suture. However, while barbed suture was associated with fewer superficial infections, there was an increased incidence of wound dehiscence. Overall, barbed suture demonstrated a cumulatively equivalent rate of superficial wound complications compared to braided suture. Based on this investigation, barbed suture appears safe to use in THA and may represent an efficient and effective alternative to braided suture for wound closure. LEVEL OF EVIDENCE: Level IV; retrospective cohort study.

Transdermal Scopolamine as an Adjunct to Multimodal Pain Management in Patients Undergoing Total Joint Arthroplasty.

BACKGROUND: Postoperative nausea and vomiting (PONV) after surgery degrades patient experience, tolerance of pain medication, rehabilitation progress, and functional outcomes. Given the importance of early rehabilitation following total joint arthroplasty (TJA), we asked whether transdermal scopolamine is effective in reducing rates of PONV and improving functional outcomes following TJA. METHODS: We retrospectively reviewed the charts of 1580 consecutive patients who underwent TJA between 2014 and 2017 and compared patients before the addition of the scopolamine patch (control group) to those after the addition (study group). Patients were given the scopolamine patch in the holding area unless contraindicated. A total of 495 patients were excluded. Charts were reviewed for PONV, demographic information, surgical time, length of stay, distance walked with physical therapy, and Visual Analog Scale pain scores. Student t-test was used to compare continuous data and chi-square was used for categorical variables. RESULTS: The incidence of PONV was significantly lower in the study group compared to the control group (14.4% vs 29.3%, P < .0001). Patients who were given scopolamine had lower Visual Analog Scale pain scores on postoperative days (POD) 0 through 2 (P < .01), were able to walk further distances on POD 0 through 3 (P < .001), and received fewer morphine equivalents on POD 1 and 2 (P < .001). Greater morphine equivalents were received by the study group on POD 0. CONCLUSION: Use of a scopolamine patch was associated with significant reduction in PONV and improvement in functional outcomes following TJA. These data support the use of transdermal scopolamine as part of a multimodal, perioperative pain protocol in patients undergoing TJA.

The Learning Curve by Operative Time for Soft Tissue Balancing in Total Knee Arthroplasty Using Electronic Sensor Technology.

BACKGROUND: Electronic sensor devices can provide an objective assessment of soft tissue balancing in total knee arthroplasty (TKA) which may potentially decrease postoperative pain. We aim to quantify the learning curve for operative time (OT) for this technology. METHODS: Consecutive TKA cases balanced with an electronic sensor balancing device by one senior surgeon from 2013 to 2017 were included in this study. The OT (in minutes) was analyzed using the cumulative sum analysis to evaluate the learning curve for this technology. Further analysis was done by splitting the 287 patients into 7 cohorts, 41 patients each. RESULTS: Two hundred eighty-seven patients balanced with sensor technology were available for analysis. The cumulative sum OT learning curve estimated that this technology's learning curve was 41 cases. This curve consisted of 2 phases: phase 1 which includes the first 41 cases and phase 2 which includes the remaining 246 patients. The mean OT for the first and last sensor-assisted cohorts was 120.4 and 108.9 minutes (P = .021). The mean OT for the first sensor-assisted cohort and the control cohort was 120.4 versus 109 minutes (P = .023). The mean OT for the last sensor-assisted cohort and the control cohort was 108.9 versus 109 minutes (P = .94). CONCLUSION: Our findings suggest that it takes approximately 41 cases of sensor-assisted TKA cases to achieve OTs identical to manually balanced TKA cases. This is a relatively shallow learning curve for the sensor technology, and allows arthroplasty surgeons to objectively achieve soft tissue balancing without adding OT to the surgery.

Same-Day Physical Therapy Following Total Knee Arthroplasty Leads to Improved Inpatient Physical Therapy Performance and Decreased Inpatient Opioid Consumption.

BACKGROUND: Early ambulation with physical therapy (PT) following total knee arthroplasty (TKA) has demonstrated benefits in the literature. However, the impact of early PT on rehabilitation performance and opioid consumption has not been elucidated. We evaluate the effect of same-day PT on inhospital functional outcomes and opioid consumption. METHODS: We retrospectively identified 2 cohorts of primary TKA patients from July 2016 to December 2017: PT0 (n = 295) received PT on the day of surgery, and PT1 (n = 392) received PT on postoperative day (POD) 1. Outcomes studied included number of feet walked on POD0-3, visual analog scale pain scores, morphine equivalents (ME) consumed, length of stay, and discharge disposition. Analysis was conducted using the Student t-test and Fisher exact test. RESULTS: In comparison to the PT1 group, the PT0 group walked significantly more steps on POD1 (347.6 vs 167.4 ft, P < .0001), POD2 (342.1 vs 203.5 ft, P < .0001), and POD3 (190.3 vs 128.9 ft, P = .00028). There was no difference between the 2 groups for visual analog scale. The PT0 group also consumed significantly fewer total ME when compared to the PT1 group (149.0 vs 200.3 mg, P = .0002). The PT0 group had a significantly shorter length of stay when compared to the PT1 group (2.7 vs 3.2 days, P = .00075). More patients were discharged home in the PT0 group (81.7% vs 54.8%, P < .0001). CONCLUSION: We observed that initiation of PT on POD0 led to better PT performance, reduced ME during hospitalization, and more patients discharged home. LEVEL OF EVIDENCE: III, Retrospective cohort study.

Adrenal insufficiency of patients with graft versus host disease treated with extracorporeal photopheresis.

Graft versus host disease (GvHD) is a serious and common complication of allogenic haematopoietic stem cell transplant. Corticosteroids are considered the standard care for initial treatment of GvHD but a significant proportion of patients will need long-term steroid treatment for control of GvHD. Extracorporeal photopheresis (ECP) is a cell-based immunomodulatory therapy that is an accepted second line treatment in patients with steroid refractory, dependent or intolerant GvHD and has shown efficacy in allowing steroid dose reduction and discontinuation in this cohort of patients. Adrenal cortical insufficiency is defined by the inability of the adrenal cortex to produce sufficient amounts of glucocorticoids and/or mineralocorticoids leading to a severe and potentially life-threatening condition. The most common cause of drug-induced adrenal insufficiency is the suppression of the hypothalamic-pituitary-adrenal axis by exogenous glucocorticoid doses ≥5 mg prednisolone equivalent for more than 4 weeks. The aim of the study was to ascertain the number of patients with GvHD receiving ECP that are affected by adrenocortical insufficiency.

Does ROSE matter? Evaluation of final diagnostic, PD-L1 immunohistochemistry, and molecular testing yields of CT-guided lung biopsies performed before and after the onset of the COVID-19 pandemic.

INTRODUCTION: The onset of the COVID-19 pandemic, with urgent implementation of safety protocols limiting the number of on-site personnel, essentially terminated the use of rapid on-site evaluation (ROSE) for computed tomography (CT)--guided lung biopsies at our institution. The diminished use of ROSE during the pandemic prompted us to reevaluate the potential value of ROSE for CT-guided lung biopsies. MATERIALS AND METHODS: We retrospectively identified all CT-guided lung biopsies from 2017 to 2022. Associations between the use of ROSE, adequate diagnostic and ancillary testing (programmed death-ligand 1 immunohistochemistry and next-generation sequencing) outcomes, and other factors such as the number of passes performed and lesion size, were evaluated. RESULTS: Nine hundred twelve CT-guided lung biopsies were performed from 2017 to 2022; 171 (19%) utilized ROSE. The use of ROSE had been steadily decreasing prior to the pandemic but was essentially eliminated with the onset of the pandemic. By univariable analysis, the employment of ROSE was more likely to be associated with an adequate final diagnosis (odds ratio = 2.14, 95% confidence interval: [1.24-3.70], P = 0.006) and successful molecular testing (odds ratio = 2.16, 95% confidence interval: [1.11-4.21], P = 0.024). However, those associations were not present in multivariable analyses that incorporated the number of passes performed or lesion size. There were no differences in diagnostic adequacy or ancillary testing yields when comparing the periods 2017-2019 and 2020-2022, despite declining use of ROSE. CONCLUSIONS: If ROSE is not requested for CT-guided lung biopsies, proceduralists should err on the side of performing more, rather than fewer, passes, particularly for smaller lesions.

Association of Health Care Work With Anxiety and Depression During the COVID-19 Pandemic: Structural Topic Modeling Study.

BACKGROUND: Stressors for health care workers (HCWs) during the COVID-19 pandemic have been manifold, with high levels of depression and anxiety alongside gaps in care. Identifying the factors most tied to HCWs' psychological challenges is crucial to addressing HCWs' mental health needs effectively, now and for future large-scale events. OBJECTIVE: In this study, we used natural language processing methods to examine deidentified psychotherapy transcripts from telemedicine treatment during the initial wave of COVID-19 in the United States. Psychotherapy was delivered by licensed therapists while HCWs were managing increased clinical demands and elevated hospitalization rates, in addition to population-level social distancing measures and infection risks. Our goal was to identify specific concerns emerging in treatment for HCWs and to compare differences with matched non-HCW patients from the general population. METHODS: We conducted a case-control study with a sample of 820 HCWs and 820 non-HCW matched controls who received digitally delivered psychotherapy in 49 US states in the spring of 2020 during the first US wave of the COVID-19 pandemic. Depression was measured during the initial assessment using the Patient Health Questionnaire-9, and anxiety was measured using the General Anxiety Disorder-7 questionnaire. Structural topic models (STMs) were used to determine treatment topics from deidentified transcripts from the first 3 weeks of treatment. STM effect estimators were also used to examine topic prevalence in patients with moderate to severe anxiety and depression. RESULTS: The median treatment enrollment date was April 15, 2020 (IQR March 31 to April 27, 2020) for HCWs and April 19, 2020 (IQR April 5 to April 27, 2020) for matched controls. STM analysis of deidentified transcripts identified 4 treatment topics centered on health care and 5 on mental health for HCWs. For controls, 3 STM topics on pandemic-related disruptions and 5 on mental health were identified. Several STM treatment topics were significantly associated with moderate to severe anxiety and depression, including working on the hospital unit (topic prevalence 0.035, 95% CI 0.022-0.048; P<.001), mood disturbances (prevalence 0.014, 95% CI 0.002-0.026; P=.03), and sleep disturbances (prevalence 0.016, 95% CI 0.002-0.030; P=.02). No significant associations emerged between pandemic-related topics and moderate to severe anxiety and depression for non-HCW controls. CONCLUSIONS: The study provides large-scale quantitative evidence that during the initial wave of the COVID-19 pandemic, HCWs faced unique work-related challenges and stressors associated with anxiety and depression, which required dedicated treatment efforts. The study further demonstrates how natural language processing methods have the potential to surface clinically relevant markers of distress while preserving patient privacy.

Comparing Kundalini Yoga, cognitive behavioral therapy, and stress education for generalized anxiety disorder: Anxiety and depression symptom outcomes.

Increasingly, individuals with anxiety disorders are seeking mind-body interventions (e.g., yoga), but their effectiveness is unclear. This report summarizes seven additional, secondary outcomes measuring anxiety and depression symptoms from a study of 226 adults with generalized anxiety disorder who were randomized to 12-week Kundalini Yoga, Cognitive-Behavior Therapy (CBT) or stress education (control). At post-treatment, participants receiving CBT displayed significantly lower symptom severity, compared to those in the control group, on 6 of the 7 measures. Participants who received Yoga (vs. those in the control group) displayed lower symptom severity on 3 of the 7 measures. No significant differences were detected between participants receiving CBT vs those receiving Yoga. At the 6-month follow-up, participants from the CBT continued to display lower symptoms than the control group.

Prescribing, deprescribing and potential adverse effects of proton pump inhibitors in older patients with multimorbidity: an observational study.

BACKGROUND: Proton pump inhibitors (PPIs) contribute to polypharmacy and are associated with adverse effects. As prospective data on longitudinal patterns of PPI prescribing in older patients with multimorbidity are lacking, we sought to assess patterns of PPI prescribing and deprescribing, as well as the association of PPI use with hospital admissions over 1 year in this population. METHODS: We conducted a prospective, longitudinal cohort study using data from the Optimizing Therapy to Prevent Avoidable Hospital Admissions in Multimorbid Older Adults (OPERAM) trial, a randomized controlled trial testing an intervention to reduce inappropriate prescribing (2016-2018). This trial included adults aged 70 years and older with at least 3 chronic conditions and prescribed at least 5 chronic medications. We assessed prevalence of PPI use at time of hospital admission, and new prescriptions and deprescribing at discharge, and at 2 months and 1 year after discharge, by intervention group. We used a regression with competing risk for death to assess the association of PPI use with readmissions related to their potential adverse effects, and all-cause readmission. RESULTS: Overall, 1080 (57.4%) of 1879 patients (mean age 79 yr) had PPI prescriptions at admission, including 496 (45.9%) patients with a potentially inappropriate indication. At discharge, 133 (24.9%) of 534 patients in the intervention group and 92 (16.8%) of 546 patients in the control group who were using PPIs at admission had deprescribing. Among 680 patients who were not using PPIs at discharge, 47 (14.6%) of 321 patients in the intervention group and 40 (11.1%) of 359 patients in the control group had a PPI started within 2 months. Use of PPIs was associated with all-cause readmission (n = 770, subdistribution hazard ratio 1.31, 95% confidence interval 1.12-1.53). INTERPRETATION: Potentially inappropriate use of PPI, new PPI prescriptions and PPI deprescribing were frequent among older adults with multimorbidity and polypharmacy. These data suggest that persistent PPI use may be associated with clinically important adverse effects in this population.

Benzodiazepine Receptor Agonists Use and Cessation Among Multimorbid Older Adults with Polypharmacy: Secondary Analysis from the OPERAM Trial.

BACKGROUND: Benzodiazepine receptor agonists (BZRAs) are commonly prescribed in older adults despite an unfavorable risk-benefit ratio. Hospitalizations may provide a unique opportunity to initiate BZRA cessation, yet little is known about cessation during and after hospitalization. We aimed to measure the prevalence of BZRA use before hospitalization and the rate of cessation 6 months later, and to identify factors associated with these outcomes. METHODS: We conducted a secondary analysis of a cluster randomized controlled trial (OPtimising thERapy to prevent Avoidable hospital admissions in the Multimorbid elderly [OPERAM]), comparing usual care and in-hospital pharmacotherapy optimization in adults aged 70 years or over with multimorbidity and polypharmacy in four European countries. BZRA cessation was defined as taking one or more BZRA before hospitalization and not taking any BZRA at the 6-month follow-up. Multivariable logistic regression was performed to identify factors associated with BZRA use before hospitalization and with cessation at 6 months. RESULTS: Among 1601 participants with complete 6-month follow-up data, 378 (23.6%) were BZRA users before hospitalization. Female sex (odds ratio [OR] 1.52 [95% confidence interval 1.18-1.96]), a higher reported level of depression/anxiety (OR up to 2.45 [1.54-3.89]), a higher number of daily drugs (OR 1.08 [1.05-1.12]), use of an antidepressant (OR 1.74 [1.31-2.31]) or an antiepileptic (OR 1.46 [1.02-2.07]), and trial site were associated with BZRA use. Diabetes mellitus (OR 0.60 [0.44-0.80]) was associated with a lower probability of BZRA use. BZRA cessation occurred in 86 BZRA users (22.8%). Antidepressant use (OR 1.74 [1.06-2.86]) and a history of falling in the previous 12 months (OR 1.75 [1.10-2.78]) were associated with higher BZRA cessation, and chronic obstructive pulmonary disease (COPD) (OR 0.45 [0.20-0.91]) with lower BZRA cessation. CONCLUSION: BZRA prevalence was high among included multimorbid older adults, and BZRA cessation occurred in almost a quarter of them within 6 months after hospitalization. Targeted BZRA deprescribing programs could further enhance cessation. Specific attention is needed for females, central nervous system-acting co-medication, and COPD co-morbidity. REGISTRATION: ClinicalTrials.gov identifier: NCT02986425. December 8, 2016.

The Study of Ketamine for Youth Depression (SKY-D): study protocol for a randomised controlled trial of low-dose ketamine for young people with major depressive disorder.

BACKGROUND: Existing treatments for young people with severe depression have limited effectiveness. The aim of the Study of Ketamine for Youth Depression (SKY-D) trial is to determine whether a 4-week course of low-dose subcutaneous ketamine is an effective adjunct to treatment-as-usual in young people with major depressive disorder (MDD). METHODS: SKY-D is a double-masked, randomised controlled trial funded by the Australian Government's National Health and Medical Research Council (NHMRC). Participants aged between 16 and 25 years (inclusive) with moderate-to-severe MDD will be randomised to receive either low-dose ketamine (intervention) or midazolam (active control) via subcutaneous injection once per week for 4 weeks. The primary outcome is change in depressive symptoms on the Montgomery-Åsberg Depression Rating Scale (MADRS) after 4 weeks of treatment. Further follow-up assessment will occur at 8 and 26 weeks from treatment commencement to determine whether treatment effects are sustained and to investigate safety outcomes. DISCUSSION: Results from this trial will be important in determining whether low-dose subcutaneous ketamine is an effective treatment for young people with moderate-to-severe MDD. This will be the largest randomised trial to investigate the effects of ketamine to treat depression in young people. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ID: ACTRN12619000683134. Registered on May 7, 2019. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377513 .

Medication-related quality of life (MRQoL) in ambulatory older adults with multi-morbidity and polypharmacy.

PURPOSE: To assess medication-related quality-of-life (MRQoL) in multi-morbid older adults with polypharmacy and correlations with medications, frailty and health-related QoL. METHODS: With a cross sectional study of multi-morbid geriatric medicine outpatients, we assessed MRQoL (MRQol-LSv1), frailty status, potentially inappropriate medications, Medication Adherence Rating Scale (MARS), health-related-QoL (Short-Form 12, SF12) and medication burden (Living with Medicines Questionnaire, LMQv2). RESULTS: One-in-four (n = 59) of 234 outpatient attendees met inclusion criteria. Almost half (n = 106, 45%) were excluded due to cognition (MMSE < 26). Included participants (n = 27, mean age 80.2 years) experienced a median of 11 (IQR 9-13.5) co-morbidities and were prescribed a median of 10 (IQR 8-12.25) medications. Overall, MRQoL-LS.v.1 scores were low, suggesting good medication-related quality of life (median MRQoL-LS.v.1 score of 14, IQR 14-22). Correlations between MRQoL, number of daily medications, co-morbidity burden, LMQv2 score, SF12 scores and number of PIMs were non-significant. CONCLUSION: MRQoL-LSv.1 is unsuitable for most patients attending geriatric ambulatory services.

Nur77-Tempo mice reveal T cell steady state antigen recognition.

In lymphocytes, Nr4a gene expression is specifically regulated by antigen receptor signalling, making them ideal targets for use as distal T cell receptor (TCR) reporters. Nr4a3-Timer of cell kinetics and activity (Tocky) mice are a ground-breaking tool to report TCR-driven Nr4a3 expression using Fluorescent Timer protein (FT). FT undergoes a time-dependent shift in its emission spectrum following translation, allowing for the temporal reporting of transcriptional events. Our recent work suggested that Nr4a1/Nur77 may be a more sensitive gene to distal TCR signals compared to Nr4a3, so we, therefore, generated Nur77-Timer-rapidly-expressed-in-lymphocytes (Tempo) mice that express FT under the regulation of Nur77. We validated the ability of Nur77-Tempo mice to report TCR and B cell receptor signals and investigated the signals regulating Nur77-FT expression. We found that Nur77-FT was sensitive to low-strength TCR signals, and its brightness was graded in response to TCR signal strength. Nur77-FT detected positive selection signals in the thymus, and analysis of FT expression revealed that positive selection signals are often persistent in nature, with most thymic Treg expressing FT Blue. We found that active TCR signals in the spleen are low frequency, but CD69+ lymphoid T cells are enriched for FT Blue+ Red+ T cells, suggesting frequent TCR signalling. In non-lymphoid tissue, we saw a dissociation of FT protein from CD69 expression, indicating that tissue residency is not associated with tonic TCR signals. Nur77-Tempo mice, therefore, combine the temporal dynamics from the Tocky innovation with increased sensitivity of Nr4a1 to lower TCR signal strengths.

Detectability of Medication Errors With a STOPP/START-Based Medication Review in Older People Prior to a Potentially Preventable Drug-Related Hospital Admission.

INTRODUCTION: Multimorbidity and polypharmacy are risk factors for drug-related hospital admissions (DRAs) in the ageing population. DRAs caused by medication errors (MEs) are considered potentially preventable. The STOPP/START criteria were developed to detect potential MEs in older people. OBJECTIVE: The aim of this study was to assess the detectability of MEs with a STOPP/START-based in-hospital medication review in older people with polypharmacy and multimorbidity prior to a potentially preventable DRA. METHODS: Hospitalised older patients (n = 963) with polypharmacy and multimorbidity from the intervention arm of the OPERAM trial received a STOPP/START-based in-hospital medication review by a pharmacotherapy team. Readmissions within 1 year after the in-hospital medication review were adjudicated for drug-relatedness. A retrospective assessment was performed to determine whether MEs identified at the first DRA were detectable during the in-hospital medication review. RESULTS: In total, 84 of 963 OPERAM intervention patients (8.7%) were readmitted with a potentially preventable DRA, of which 72 patients (n = 77 MEs) were eligible for analysis. About half (48%, n = 37/77) of the MEs were not present during the in-hospital medication review and therefore were not detectable at that time. The pharmacotherapy team recommended a change in medication regimen in 50% (n = 20/40) of present MEs, which corresponds to 26% (n = 20/77) of the total identified MEs at readmission. However, these recommendations were not implemented. CONCLUSION: MEs identified at readmission were not addressed by a prior single in-hospital medication review because either these MEs occurred after the medication review (~50%), or no recommendation was given during the medication review (~25%), or the recommendation was not implemented (~25%). Future research should focus on optimisation of the timing and frequency of medication review and the implementation of proposed medication recommendations. REGISTRATION: ClinicalTrials.gov identifier: NCT02986425. December 8, 2016. FUNDING: European Union HORIZON 2020, Swiss State Secretariat for Education, Research and Innovation (SERI), Swiss National Science Foundation (SNSF).