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Abstract Background Depressive symptoms are common in patients with Parkinson’s disease and depression is a significant predictor of functional impairment, reduced quality of life and general well-being in Parkinson's disease. Despite the high prevalence of depression, evidence on the effectiveness and tolerability of antidepressants in this population is limited. The primary aim of this trial is to establish the clinical and cost effectiveness of escitalopram and nortriptyline for the treatment of depression in Parkinson’s disease. Methods This is a multi-centre, double-blind, randomised placebo-controlled trial in 408 people with Parkinson’s disease with subsyndromal depression, major depressive disorder or persistent depressive disorder and a Beck Depression Inventory-II (BDI-II) score of 14 or above. Participants will be randomised into one of three groups, receiving either escitalopram, nortriptyline or placebo for 12 months. Trial participation is face-to-face, hybrid or remote. The primary outcome measure is the BDI-II score following 8 weeks of treatment. Secondary outcomes will be collected at baseline, 8, 26 and 52 weeks and following withdrawal, including severity of anxiety and depression scores as well as Parkinson’s disease motor severity, and ratings of non-motor symptoms, cognitive function, health-related quality of life, levodopa-equivalence dose, changes in medication, overall clinical effectiveness, capability, health and social care resource use, carer health-related quality of life, adverse effects and number of dropouts. Discussion This trial aims to determine the effectiveness of escitalopram and nortriptyline for reducing depressive symptoms in Parkinson’s disease over 8 weeks, to provide information on the effect of these medications on anxiety and other non-motor symptoms in PD and on impact on patients and caregivers, and to examine their effect on change in motor severity. Trial registration ClinicalTrials.gov Identifier: NCT03652870 Date of registration – 29th August 2018

Abstract Background Electronic patient-reported outcome (ePRO)-based symptom management improves cancer patients’ outcomes. However, implementation of ePROs is challenging, requiring technical resources for integration into clinical systems, substantial buy-in from clinicians and patients, novel workflows to support between-visit symptom management, and institutional investment. Methods The SIMPRO Research Consortium developed eSyM, an electronic health record-integrated, ePRO-based symptom management program for medical oncology and surgery patients and deployed it at six cancer centers between August 2019 and April 2022 in a type II hybrid effectiveness-implementation cluster randomized stepped-wedge study. Sites documented implementation strategies monthly using REDCap, itemized them using the Expert Recommendations for Implementation Change (ERIC) list and mapped their target barriers using the Consolidated Framework for Implementation Research (CFIR) to inform eSyM program enhancement, facilitate inter-consortium knowledge sharing and guide future deployment efforts. Results We documented 226 implementation strategies: 35 ‘foundational’ strategies were applied consortium-wide by the coordinating center and 191 other strategies were developed by individual sites. We consolidated these 191 site-developed strategies into 64 unique strategies (i.e., removed duplicates) and classified the remainder as either ‘universal’, consistently used by multiple sites (N = 29), or ‘adaptive’, used only by individual sites (N = 35). Universal strategies were perceived as having the highest impact; they addressed eSyM clinical preparation, training, engagement of patients/clinicians, and program evaluation. Across all documented SIMPRO strategies, 44 of the 73 ERIC strategies were addressed and all 5 CFIR barriers were addressed. Conclusion Methodical collection of theory-based implementation strategies fostered the identification of universal, high-impact strategies that facilitated adoption of a novel care-delivery intervention by patients, clinicians, and institutions. Attention to the high-impact strategies identified in this project could support implementation of ePROs as a component of routine cancer care at other institutions. Trial registration ClinicalTrials.gov. NCT03850912. February 22, 2019. https://clinicaltrials.gov/ct2/show/NCT03850912?term=hassett&draw=2&rank=1

Abstract Databases that link molecular data to clinical outcomes can inform precision cancer research into novel prognostic and predictive biomarkers. However, outside of clinical trials, cancer outcomes are typically recorded only in text form within electronic health records (EHRs). Artificial intelligence (AI) models have been trained to extract outcomes from individual EHRs. However, patient privacy restrictions have historically precluded dissemination of these models beyond the centers at which they were trained. In this study, the vulnerability of text classification models trained directly on protected health information to membership inference attacks is confirmed. A teacher-student distillation approach is applied to develop shareable models for annotating outcomes from imaging reports and medical oncologist notes. ‘Teacher’ models trained on EHR data from Dana-Farber Cancer Institute (DFCI) are used to label imaging reports and discharge summaries from the Medical Information Mart for Intensive Care (MIMIC)-IV dataset. ‘Student’ models are trained to use these MIMIC documents to predict the labels assigned by teacher models and sent to Memorial Sloan Kettering (MSK) for evaluation. The student models exhibit high discrimination across outcomes in both the DFCI and MSK test sets. Leveraging private labeling of public datasets to distill publishable clinical AI models from academic centers could facilitate deployment of machine learning to accelerate precision oncology research.

The biomedical sciences must maintain and enhance a research culture that prioritizes rigour and transparency. The US National Institute of Neurological Disorders and Stroke convened a workshop entitled Catalyzing Communities of Research Rigor Champions that brought together a diverse group of leaders in promoting research rigour and transparency (identified as rigour champions) to discuss strategies, barriers and resources for catalyzing technical, cultural and educational changes in the biomedical sciences. This article summarizes 2 days of panels and discussions and provides an overview of critical barriers to research rigour, perspectives behind reform initiatives and considerations for stakeholders across science. Additionally, we describe applications of network science to foster, maintain and expand cultural changes related to scientific rigour and opportunities to embed rigourous practices into didactic courses, training experiences and degree programme requirements. We hope this piece provides a primer for the wider research community on current discussions and actions and inspires individuals to build, join or expand collaborative networks within their own institutions that prioritize rigourous research practices.

The optimal management of locally advanced rectal cancer is rapidly evolving. The National Cancer Institute Rectal-Anal Task Force convened an expert panel to develop consensus on the design of future clinical trials of patients with rectal cancer. A series of 82 questions and subquestions, which addressed radiation and neoadjuvant therapy, patient perceptions, rectal cancer populations of special interest, and unique design elements, were subject to iterative review using a Delphi analytical approach to define areas of consensus and those in which consensus is not established. The task force achieved consensus on several areas, including the following: 1) the use of total neoadjuvant therapy with long-course radiation therapy either before or after chemotherapy, as well as short-course radiation therapy followed by chemotherapy, as the control arm of clinical trials; 2) the need for greater emphasis on patient involvement in treatment choices within the context of trial design; 3) efforts to identify those patients likely, or unlikely, to benefit from nonoperative management or minimally invasive surgery; 4) investigation of the utility of circulating tumor DNA measurements for tailoring treatment and surveillance; and 5) the need for identification of appropriate end points and recognition of challenges of data management for patients who enter nonoperative management trial arms. Substantial agreement was reached on priorities affecting the design of future clinical trials in patients with locally advanced rectal cancer.

Within the healthcare system, identification and intervention for intimate partner violence (IPV) are critical, yet often hindered by siloed operations among healthcare workers. Effective interprofessional collaboration is pivotal for timely and appropriate interventions. This article describes an interprofessional educational simulation involving nursing and social work students. Pairs engaged in risk assessment and safety planning for IPV. In the pilot run with 140 nursing and 137 social work students, post-simulation results increased confidence (t = 5.25, p = 0.001) and positive evaluation of IPV knowledge (t = 63.22, p = 0.001). Focus groups underscored team synergy, communication skills, and prior experiences as critical elements. Future projects should expand simulation scopes to address diverse situations and include additional professions interacting with survivors.

ABSTRACTMeasurement of IgG antibodies against group B streptococcus (GBS) capsular polysaccharide (CPS) by use of a standardized and internationally accepted multiplex immunoassay is important for the evaluation of candidate maternal GBS vaccines in order to compare results across studies. A standardized assay is also required if serocorrelates of protection against invasive GBS disease are to be established in infant sera for the six predominant GBS serotypes since it would permit the comparison of results across the six serotypes. We undertook an interlaboratory study across five laboratories that used standardized assay reagents and protocols with a panel of 44 human sera to measure IgG antibodies against GBS CPS serotypes Ia, Ib, II, III, IV, and V. The within-laboratory intermediate precision, which included factors like the lot of coated beads, laboratory analyst, and day, was generally below 20% relative standard deviation (RSD) for all six serotypes, across all five laboratories. The cross-laboratory reproducibility was

COVID-19 reveals the way single causes have multiple effects on children. Proponents of evidence-based education, like their colleagues in medicine, need to attend to the inevitable side effects produced by programs and policies. I explain why continuing motivation to learn is one outcome that no responsible evaluation should omit.

Abstract The effects of subthalamic nucleus deep brain stimulation (STN-DBS) on anxiety in Parkinson’s disease (PD) are understudied. We identified clinical predictors of STN-DBS effects on anxiety in this study. In this prospective, open-label, multicentre study, we assessed patients with anxiety undergoing STN-DBS for PD preoperatively and at 6-month follow-up postoperatively. We assessed the Hospital Anxiety and Depression Scale (HADS-anxiety and depression subscales), Unified PD Rating Scale-motor examination, Scales for Outcomes in PD-motor (SCOPA-M)-activities of daily living (ADL) and -motor complications, Non-Motor Symptom Scale (NMSS), PDQuestionnaire-8 (PDQ-8), and levodopa-equivalent daily dose. We tested changes at follow-up with Wilcoxon signed-rank test and corrected for multiple comparisons (Bonferroni method). We identified patients with a clinically relevant anxiety improvement of anxiety based on a designated threshold of ½ standard deviation of baseline HADS-anxiety. Moreover, we investigated predictors of HADS-anxiety changes with correlations and linear regressions. We included 50 patients with clinically relevant baseline anxiety (i.e., HADS-anxiety ≥ 8) aged 63.1 years ± 8.3 with 10.4 years ± 4.5 PD duration. HADS-anxiety improved significantly at 6-month follow-up as 80% of our cohort experienced clinically relevant anxiety improvement. In predictor analyses, worse baseline SCOPA-ADL and NMSS-urinary domain were associated with greater HADS-anxiety improvements. HADS-anxiety and PDQ-8 changes correlated moderately. Worse preoperative ADL and urinary symptoms predicted favourable postoperative anxiety outcome, which in turn was directly proportionate to greater QoL improvement. This study highlights the importance of detailed anxiety assessments alongside other non-motor and motor symptoms when advising and monitoring patients undergoing STN-DBS for PD.

NCCN guidelines indicate that cancer clinical trials (CCTs) are the best management for patients with cancer. However, only 5% of patients enroll in them. We examined oncologists’ perceived barriers and facilitators to discussing CCTs. This qualitative study was part of the ASCO-ACCC Initiative to Increase Racial and Ethnic Diversity in Clinical Trials. Barriers and facilitators at the system, trial, provider, and patient levels were examined. To achieve triangulation, patient encounters were reviewed using chart-stimulated recall (CSR) methods, thereby obtaining a valid assessment of physician performance. Ten oncology providers participated in this study. Nine were oncologists, and one was a clinical research coordinator; five were female; four were White; three were Asian; and three were Black. Barriers to offering CCTs were a lack of trial availability; ineligibility; a lack of knowledge; assumptions about patient interest, benefits, or harms; patient’s disease factors; and negative attitudes. Facilitators of offering CCTs were a physical space to discuss trials; greater trial availability; a systematic approach to offering trials; patient factors; patients seeking trials; a lack of comorbidities; patients being younger in age; patients being aware of, asking about, or hearing of trials from their surgeon; and higher levels of altruism. Many of the cited barriers are addressable with the cited facilitators. A larger study is needed to generalize and validate these findings.

BACKGROUND: Descriptions of changes in invasive bacterial disease (IBD) epidemiology during the coronavirus disease 2019 (COVID-19) pandemic in the United States are limited. METHODS: We investigated changes in the incidence of IBD due to Streptococcus pneumoniae, Haemophilus influenzae, group A Streptococcus (GAS), and group B Streptococcus (GBS). We defined the COVID-19 pandemic period as 1 March to 31 December 2020. We compared observed IBD incidences during the pandemic to expected incidences, consistent with January 2014 to February 2020 trends. We conducted secondary analysis of a health care database to assess changes in testing by blood and cerebrospinal fluid (CSF) culture during the pandemic. RESULTS: Compared with expected incidences, the observed incidences of IBD due to S. pneumoniae, H. influenzae, GAS, and GBS were 58%, 60%, 28%, and 12% lower during the pandemic period of 2020, respectively. Declines from expected incidences corresponded closely with implementation of COVID-19-associated nonpharmaceutical interventions (NPIs). Significant declines were observed across all age and race groups, and surveillance sites for S. pneumoniae and H. influenzae. Blood and CSF culture testing rates during the pandemic were comparable to previous years. CONCLUSIONS: NPIs likely contributed to the decline in IBD incidence in the United States in 2020; observed declines were unlikely to be driven by reductions in testing.

Astrocytes become reactive in response to insults to the central nervous system by adopting context-specific cellular signatures and outputs, but a systematic understanding of the underlying molecular mechanisms is lacking. In this study, we developed CRISPR interference screening in human induced pluripotent stem cell-derived astrocytes coupled to single-cell transcriptomics to systematically interrogate cytokine-induced inflammatory astrocyte reactivity. We found that autocrine-paracrine IL-6 and interferon signaling downstream of canonical NF-κB activation drove two distinct inflammatory reactive signatures, one promoted by STAT3 and the other inhibited by STAT3. These signatures overlapped with those observed in other experimental contexts, including mouse models, and their markers were upregulated in human brains in Alzheimer's disease and hypoxic-ischemic encephalopathy. Furthermore, we validated that markers of these signatures were regulated by STAT3 in vivo using a mouse model of neuroinflammation. These results and the platform that we established have the potential to guide the development of therapeutics to selectively modulate different aspects of inflammatory astrocyte reactivity.

BackgroundThere is evidence that social interaction has an inverse association with the development of neurodegenerative diseases. PREDICT-Parkinson Disease (PREDICT-PD) is an online UK cohort study that stratifies participants for risk of future Parkinson disease (PD). ObjectiveThis study aims to explore the methodological approach and feasibility of assessing the digital social characteristics of people at risk of developing PD and their social capital within the PREDICT-PD platform, making hypotheses about the relationship between web-based social engagement and potential predictive risk indicators of PD. MethodsA web-based application was built to enable social interaction through the PREDICT-PD portal. Feedback from existing members of the cohort was sought and informed the design of the pilot. Dedicated staff used weekly engagement activities, consisting of PD-related research, facts, and queries, to stimulate discussion. Data were collected by the hosting platform. We examined the pattern of connections generated over time through the cumulative number of posts and replies and ego networks using social network analysis. We used network metrics to describe the bonding, bridging, and linking of social capital among participants on the platform. Relevant demographic data and Parkinson risk scores (expressed as an odd 1:x) were analyzed using descriptive statistics. Regression analysis was conducted to estimate the relationship between risk scores (after log transformation) and network measures. ResultsOverall, 219 participants took part in a 4-month pilot forum embedded in the study website. In it, 200 people (n=80, 40% male and n=113, 57% female) connected in a large group, where most pairs of users could reach one another either directly or indirectly through other users. A total of 59% (20/34) of discussions were spontaneously started by participants. Participation was asynchronous, with some individuals acting as “brokers” between groups of discussions. As more participants joined the forum and connected to one another through online posts, distinct groups of connected users started to emerge. This pilot showed that a forum application within the cohort web platform was feasible and acceptable and fostered digital social interaction. Matching participants’ web-based social engagement with previously collected data at individual level in the PREDICT-PD study was feasible, showing potential for future analyses correlating online network characteristics with the risk of PD over time, as well as testing digital social engagement as an intervention to modify the risk of developing neurodegenerative diseases. ConclusionsThe results from the pilot suggest that an online forum can serve as an intervention to enhance social connectedness and investigate whether patterns of online engagement can impact the risk of developing PD through long-term follow-up. This highlights the potential of leveraging online platforms to study the role of social capital in moderating PD risk and underscores the feasibility of such approaches in future research or interventions.

Vaccine effectiveness (VE) against COVID-19 hospitalization was evaluated among immunocompetent adults (≥18 years) during March-August 2021 using a case-control design. Among 1669 hospitalized COVID-19 cases (11% fully vaccinated) and 1950 RT-PCR-negative controls (54% fully vaccinated), VE was 96% (95% confidence interval [CI], 93%-98%) among patients with no chronic medical conditions and 83% (95% CI, 76%-88%) among patients with ≥ 3 categories of conditions. VE was similar between those aged 18-64 years versus ≥65 years (P > .05). VE against severe COVID-19 was very high among adults without chronic conditions and lessened with increasing comorbidity burden.

BackgroundAs severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination coverage increases in the United States, there is a need to understand the real-world effectiveness against severe coronavirus disease 2019 (COVID-19) and among people at increased risk for poor outcomes.MethodsIn a multicenter case-control analysis of US adults hospitalized March 11-May 5, 2021, we evaluated vaccine effectiveness to prevent COVID-19 hospitalizations by comparing odds of prior vaccination with a messenger RNA (mRNA) vaccine (Pfizer-BioNTech or Moderna) between cases hospitalized with COVID-19 and hospital-based controls who tested negative for SARS-CoV-2.ResultsAmong 1212 participants, including 593 cases and 619 controls, median age was 58 years, 22.8% were Black, 13.9% were Hispanic, and 21.0% had immunosuppression. SARS-CoV-2 lineage B0.1.1.7 (Alpha) was the most common variant (67.9% of viruses with lineage determined). Full vaccination (receipt of 2 vaccine doses ≥14 days before illness onset) had been received by 8.2% of cases and 36.4% of controls. Overall vaccine effectiveness was 87.1% (95% confidence interval [CI], 80.7-91.3). Vaccine effectiveness was similar for Pfizer-BioNTech and Moderna vaccines, and highest in adults aged 18-49 years (97.4%; 95% CI, 79.3-9.7). Among 45 patients with vaccine-breakthrough COVID hospitalizations, 44 (97.8%) were ≥50 years old and 20 (44.4%) had immunosuppression. Vaccine effectiveness was lower among patients with immunosuppression (62.9%; 95% CI,20.8-82.6) than without immunosuppression (91.3%; 95% CI, 85.6-94.8).ConclusionDuring March-May 2021, SARS-CoV-2 mRNA vaccines were highly effective for preventing COVID-19 hospitalizations among US adults. SARS-CoV-2 vaccination was beneficial for patients with immunosuppression, but effectiveness was lower in the immunosuppressed population.

Abstract Introduction Self-management interventions consist of multiple components to support people in the management of medical, emotional, and behavioural aspects of their condition, and aim to improve quality of life, function, and other outcomes. A systematic review of self-management interventions in Parkinson’s showed no conclusive evidence for effectiveness of specific self-management approaches in Parkinson’s to date but identified several potentially useful components. Aim To identify the key required components for self-management in people with Parkinson’s by synthesising evidence from a body of primary qualitative evidence and systematic reviews, and to explore which of these key components should be incorporated into trials of self-management in Parkinson’s. Method A mixed-methods synthesis was conducted. We combined data from two primary qualitative studies and a systematic review of qualitative studies that focused on self-management in Parkinson’s to identify key intervention components. These were then mapped onto the results of a systematic review of Randomised Controlled Trials (RCTs) using matrices. First, data were extracted from the qualitative studies with people with Parkinson’s and healthcare professionals on the key self-management components in this population. Second, a matrix table was created to map the identified Parkinson’s specific self-management components against potential effectiveness from published RCTs of self-management interventions. Results Synthesis of qualitative data identified 15 potential self-management components. These 15 components included components needed to start self-managing (e.g., information, skill acquirement) and components needed to maintain self-managing (e.g., self-motoring, increasing motivation). From 18 RCTs, interventions varied in how many components were included (range 1–10). Trials reporting significant beneficial effects of their intervention included a higher number of components (4 or more self-management components) than trials without significant findings (1–3 self-management components). Conclusion Fifteen key self-management components were identified that should be incorporated into interventions or programs of self-management in Parkinson’s. No current trial has incorporated all aspects, but a higher number of these key components appears to make trials of self-management interventions more likely to be successful.

Abstract We report the case of a 79-year-old woman with Alzheimer’s disease who participated in a Phase III randomized controlled trial called CLARITY-AD testing the experimental drug lecanemab. She was randomized to the placebo group and subsequently enrolled in an open-label extension which guaranteed she received the active drug. After the third biweekly infusion, she suffered a seizure characterized by speech arrest and a generalized convulsion. Magnetic resonance imaging revealed she had multifocal swelling and a marked increase in the number of cerebral microhemorrhages. She was treated with an antiepileptic regimen and high-dose intravenous corticosteroids but continued to worsen and died after 5 days. Post-mortem MRI confirmed extensive microhemorrhages in the temporal, parietal and occipital lobes. The autopsy confirmed the presence of two copies of APOE4, a gene associated with a higher risk of Alzheimer’s disease, and neuropathological features of moderate severity Alzheimer’s disease and severe cerebral amyloid angiopathy with perivascular lymphocytic infiltrates, reactive macrophages and fibrinoid degeneration of vessel walls. There were deposits of β-amyloid in meningeal vessels and penetrating arterioles with numerous microaneurysms. We conclude that the patient likely died as a result of severe cerebral amyloid-related inflammation.

Abstract Background The Live Well with Parkinson’s Self-Management Toolkit is designed for use in the NHS to support people with Parkinson’s, their carers and health professionals in managing motor and non-motor symptoms and promoting well-being. The Toolkit was developed based on theory-based behaviour change and self-management techniques in consultation with people living with Parkinson’s and health and social care practitioners. There are digital (e-Toolkit) and paper (manual) versions. Methods Single-blind two-arm randomised controlled trial RCT of clinical effectiveness and cost-effectiveness of the Toolkit, facilitated by up to six sessions with a trained non-specialist supporter, in improving quality of life. People with Parkinson’s will be assessed at baseline, 6 and 12 months. Assessors will be blind to the treatment group. The primary outcome measure is the Parkinson’s Disease Questionnaire (PDQ-39, Parkinson’s related quality of life) score at 12 months. Secondary outcome measures include the MDS Unified Parkinson’s Disease Rating Scale (Part I, II, III, IV), EQ-5D, and a Client Service Receipt Inventory shortened, adapted for Parkinson’s. Carer outcomes include the Zarit Carer Burden Inventory and Carer Quality of Life Questionnaire for Parkinsonism. A total of 338 people with Parkinson’s, and their carers if appropriate, will be recruited from diverse settings across England. Those with advanced dementia, at end-of-life or with atypical Parkinsonism will be excluded. A parallel mixed methods process evaluation will explore the factors promoting or inhibiting implementation, uptake, use, effectiveness and cost-effectiveness of the Toolkit and sessions. Discussion If successful, the Live Well with Parkinson’s Toolkit could be used as a model for other complex long-term disorders, including dementia. This would bridge existing gaps in the NHS (as shown by the national Parkinson’s audit data), by enabling patients and carers to access personalised information, advice and support on symptom management and ‘living well’ with Parkinson’s. Trial registration ISRCTN92831552. Registered on 26th Oct 2021.