Four-dimensional data assimilation and balanced dynamics

The problem of spurious excitation of gravity waves in the context of four-dimensional data assimilation is investigated using a simple model of balanced dynamics. The model admits a chaotic vortical mode coupled to a comparatively fast gravity wave mode, and can be initialized such that the model evolves on a so-called slow manifold, where the fast motion is suppressed. Identical twin assimilation experiments are performed, comparing the extended and ensemble Kalman filters (EKF and EnKF, respectively). The EKF uses a tangent linear model (TLM) to estimate the evolution of forecast error statistics in time, whereas the EnKF uses the statistics of an ensemble of nonlinear model integrations. Specifically, the case is examined where the true state is balanced, but observation errors project onto all degrees of freedom, including the fast modes. It is shown that the EKF and EnKF will assimilate observations in a balanced way only if certain assumptions hold, and that, outside of ideal cases (i.e., with very frequent observations), dynamical balance can easily be lost in the assimilation. For the EKF, the repeated adjustment of the covariances by the assimilation of observations can easily unbalance the TLM, and destroy the assumptions on which balanced assimilation rests. It is shown that an important factor is the choice of initial forecast error covariance matrix. A balance-constrained EKF is described and compared to the standard EKF, and shown to offer significant improvement for observation frequencies where balance in the standard EKF is lost. The EnKF is advantageous in that balance in the error covariances relies only on a balanced forecast ensemble, and that the analysis step is an ensemble-mean operation. Numerical experiments show that the EnKF may be preferable to the EKF in terms of balance, though its validity is limited by ensemble size. It is also found that overobserving can lead to a more unbalanced forecast ensemble and thus to an unbalanced analysis

Interventions for the prevention of adrenal crisis in adults with primary adrenal insufficiency : a systematic review

Objective: The incidence of adrenal crisis remains high, particularly for people with primary adrenal insufficiency, despite the introduction of behavioural interventions. The present study aimed to identify and evaluate available evidence of interventions aiming to prevent adrenal crisis in primary adrenal insufficiency. Design: Systematic review of literature and theoretical mapping. Methods: MEDLINE, MEDLINE in Process, EMBASE, ERIC, Cochrane CENTRAL, CINAHL, PsycINFO, the Health Management Information Consortium (HMIC) and trial registries were searched from inception to November 2021. Three reviewers independently selected studies and extracted data. Two reviewers appraised the studies for risk of bias. Results: Seven observational or mixed methods studies were identified where interventions were designed to prevent adrenal crisis in adrenal insufficiency. Patient education was the focus of all interventions and utilised the same two behaviour change techniques, instruction on how to perform a behaviour’ and ‘pharmacological support’. Barrier and facilitator themes aiding or hindering the intervention included: knowledge, behaviour, emotions, skills, social influences and environmental context and resources. Most studies did not measure effectiveness and assessment of knowledge was variable across studies. Study quality was moderate. Conclusion: This is an emerging field with limited studies available. Further research is required in relation to the development and assessment of different behaviour change interventions to prevent adrenal crisis

A low-order model investigation of the analysis of gravity waves in the ensemble Kalman filter.

The behavior of the ensemble Kalman filter (EnKF) is examined in the context of a model that exhibits a nonlinear chaotic (slow) vortical mode coupled to a linear (fast) gravity wave of a given amplitude and frequency. It is shown that accurate recovery of both modes is enhanced when covariances between fast and slow normal-mode variables (which reflect the slaving relations inherent in balanced dynamics) are modeled correctly. More ensemble members are needed to recover the fast, linear gravity wave than the slow, vortical motion. Although the EnKF tends to diverge in the analysis of the gravity wave, the filter divergence is stable and does not lead to a great loss of accuracy. Consequently, provided the ensemble is large enough and observations are made that reflect both time scales, the EnKF is able to recover both time scales more accurately than optimal interpolation (OI), which uses a static error covariance matrix. For OI it is also found to be problematic to observe the state at a frequency that is a subharmonic of the gravity wave frequency, a problem that is in part overcome by the EnKF.However, error in themodeled gravity wave parameters can be detrimental to the performance of the EnKF and remove its implied advantages, suggesting that a modified algorithm or a method for accounting for model error is needed

Longitudinal Cytokine Profiling Identifies GRO-α and EGF as Potential Biomarkers of Disease Progression in Essential Thrombocythemia.

Myeloproliferative neoplasms (MPNs) are characterized by deregulation of mature blood cell production and increased risk of myelofibrosis (MF) and leukemic transformation. Numerous driver mutations have been identified but substantial disease heterogeneity remains unexplained, implying the involvement of additional as yet unidentified factors. The inflammatory microenvironment has recently attracted attention as a crucial factor in MPN biology, in particular whether inflammatory cytokines and chemokines contribute to disease establishment or progression. Here we present a large-scale study of serum cytokine profiles in more than 400 MPN patients and identify an essential thrombocythemia (ET)-specific inflammatory cytokine signature consisting of Eotaxin, GRO-α, and EGF. Levels of 2 of these markers (GRO-α and EGF) in ET patients were associated with disease transformation in initial sample collection (GRO-α) or longitudinal sampling (EGF). In ET patients with extensive genomic profiling data (n = 183) cytokine levels added significant prognostic value for predicting transformation from ET to MF. Furthermore, CD56+CD14+ pro-inflammatory monocytes were identified as a novel source of increased GRO-α levels. These data implicate the immune cell microenvironment as a significant player in ET disease evolution and illustrate the utility of cytokines as potential biomarkers for reaching beyond genomic classification for disease stratification and monitoring.The serum cytokine studies were supported by a research grant from the Rosetrees Trust. NFØ was supported by grants from the Danish Lundbeck Foundation and Danish Cancer Society, J.G. was supported by fellowships from Bloodwise and the Kay Kendall Leukaemia Fund; and M.S.S. is the recipient of a Biotechnology and Biological Sciences Research Council Industrial Collaborative Awards in Science and Engineering PhD Studentship. Work in the R.C.S. laboratory was supported by grants from the Stiftung Blutspendezentrum SRK beider Basel, the Swiss National Science Foundation (31003A-147016/1 and 31003A_166613), and the Swiss Cancer League (KLS-2950-02-2012 and KFS-3655-02-2015). A.K. was supported by the Else Kröner-Fresenius Foundation. Work in the A.R.G. laboratory is supported by the Wellcome Trust, Bloodwise, Cancer Research UK, the Kay Kendall Leukaemia Fund, and the Leukemia and Lymphoma Society of America. Work in the D.G.K. laboratory is supported by a Bloodwise Bennett Fellowship (15008), a European Hematology Association Non-Clinical Advanced Research Fellowship, and an ERC Starting Grant (ERC-2016-STG–715371). D.G.K. and A.R.G. are supported by a core support grant from the Wellcome Trust and Medical Research Council to the Wellcome MRC Cambridge Stem Cell Institute, the National Institute for Health Research Cambridge Biomedical Research Centre, and the CRUK Cambridge Cancer Centre

Rising statin use and effect on ischemic stroke outcome

BACKGROUND: Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) have neuroprotective effects in experimental stroke models and are commonly prescribed in clinical practice. The aim of this study was to determine if patients taking statins before hospital admission for stroke had an improved clinical outcome. METHODS: This was an observational study of 436 patients admitted to the National Institutes of Health Suburban Hospital Stroke Program between July 2000 and December 2002. Self-reported risk factors for stroke were obtained on admission. Stroke severity was determined by the admission National Institutes of Health Stroke Scale score. Good outcome was defined as a Rankin score < 2 at discharge. Statistical analyses used univariate and multivariate logistic regression models. RESULTS: There were 436 patients with a final diagnosis of ischemic stroke; statin data were available for 433 of them. A total of 95/433 (22%) of patients were taking a statin when they were admitted, rising from 16% in 2000 to 26% in 2002. Fifty-one percent of patients taking statins had a good outcome compared to 38% of patients not taking statins (p = 0.03). After adjustment for confounding factors, statin pretreatment was associated with a 2.9 odds (95% CI: 1.2–6.7) of a good outcome at the time of hospital discharge. CONCLUSIONS: The proportion of patients taking statins when they are admitted with stroke is rising rapidly. Statin pretreatment was significantly associated with an improved functional outcome at discharge. This finding could support the early initiation of statin therapy after stroke

Supervised Treatment in Outpatients for Schizophrenia Plus (STOPS+): Protocol for a cluster randomised trial of a community-based intervention to improve treatment adherence and reduce the treatment gap for schizophrenia in Pakistan

Introduction: There is a significant treatment gap, with only a few community-based services for people with schizophrenia in Low- and Middle-Income countries. Poor treatment adherence in schizophrenia is associated with poorer health outcomes, suicide attempts and death. We previously reported the effectiveness of STOPS (Supervised Treatment in Outpatients for Schizophrenia) for improving treatment adherence in patients with schizophrenia. However, STOPS was evaluated in a tertiary care setting with no primary care involvement, limiting its generalisability to the wider at-risk population. We aim to evaluate the effectiveness of STOPS+ in scaling up the primary care treatment of schizophrenia to a real-world setting. Methods and analysis: The effectiveness of the STOPS+ intervention in improving the level of functioning and medication adherence in patients with schizophrenia in Pakistan will be evaluated using a cluster randomised controlled trial design. We aim to recruit 526 participants from 24 Primary Health Care Centres (PHCs) randomly allocated in 1:1 ratio to STOPS+ intervention and Enhanced Treatment as Usual (ETAU) arms. Participants will be followed-up for 12 months post recruitment. The sample size is estimated for two outcomes (i) The primary clinical outcome is level of functioning, measured using the Global Assessment of Functioning (GAF) scale, and (ii) the primary process outcome is adherence to treatment regimen measured using a validated measure. An intention-to-treat approach will be used for the primary analysis. Ethics and Dissemination: Ethical approval has been obtained from Keele University Ethical Review Panel (ref: MH-190017) and Khyber Medical University Ethical Review Board (ref: DIR-KMU-EB/ST/000648). The results of the STOPS+ trial will be reported in peer reviewed journals and academic conferences and disseminated to local stakeholders and policy makers

Association of Circulating Tumor DNA Testing Before Tissue Diagnosis With Time to Treatment Among Patients With Suspected Advanced Lung Cancer: The ACCELERATE Nonrandomized Clinical Trial.

IMPORTANCE Liquid biopsy has emerged as a complement to tumor tissue profiling for advanced non-small cell lung cancer (NSCLC). The optimal way to integrate liquid biopsy into the diagnostic algorithm for patients with newly diagnosed advanced NSCLC remains unclear. OBJECTIVE To evaluate the use of circulating tumor DNA (ctDNA) genotyping before tissue diagnosis among patients with suspected advanced NSCLC and its association with time to treatment. DESIGN, SETTING, AND PARTICIPANTS This single-group nonrandomized clinical trial was conducted among 150 patients at the Princess Margaret Cancer Centre-University Health Network (Toronto, Ontario, Canada) between July 1, 2021, and November 30, 2022. Patients referred for investigation and diagnosis of lung cancer were eligible if they had radiologic evidence of advanced lung cancer prior to a tissue diagnosis. INTERVENTIONS Patients underwent plasma ctDNA testing with a next-generation sequencing (NGS) assay before lung cancer diagnosis. Diagnostic biopsy and tissue NGS were performed per standard of care. MAIN OUTCOME AND MEASURES The primary end point was time from referral to treatment initiation among patients with advanced nonsquamous NSCLC using ctDNA testing before diagnosis (ACCELERATE [Accelerating Lung Cancer Diagnosis Through Liquid Biopsy] cohort). This cohort was compared with a reference cohort using standard tissue genotyping after tissue diagnosis. RESULTS Of the 150 patients (median age at diagnosis, 68 years [range, 33-91 years]; 80 men [53%]) enrolled, 90 (60%) had advanced nonsquamous NSCLC. The median time to treatment was 39 days (IQR, 27-52 days) for the ACCELERATE cohort vs 62 days (IQR, 44-82 days) for the reference cohort (P < .001). Among the ACCELERATE cohort, the median turnaround time from sample collection to genotyping results was 7 days (IQR, 6-9 days) for plasma and 23 days (IQR, 18-28 days) for tissue NGS (P < .001). Of the 90 patients with advanced nonsquamous NSCLC, 21 (23%) started targeted therapy before tissue NGS results were available, and 11 (12%) had actionable alterations identified only through plasma testing. CONCLUSIONS AND RELEVANCE This nonrandomized clinical trial found that the use of plasma ctDNA genotyping before tissue diagnosis among patients with suspected advanced NSCLC was associated with accelerated time to treatment compared with a reference cohort undergoing standard tissue testing. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04863924

The PULSAR Specialist Care protocol: a stepped-wedge cluster randomized control trial a training intervention for community mental health teams in recovery-oriented practice

Background: Recovery features strongly in Australian mental health policy; however, evidence is limited for the efficacy of recovery-oriented practice at the service level. This paper describes the Principles Unite Local Services Assisting Recovery (PULSAR) Specialist Care trial protocol for a recovery-oriented practice training intervention delivered to specialist mental health services staff. The primary aim is to evaluate whether adult consumers accessing services where staff have received the intervention report superior recovery outcomes compared to adult consumers accessing services where staff have not yet received the intervention. A qualitative sub-study aims to examine staff and consumer views on implementing recovery-oriented practice. A process evaluation sub-study aims to articulate important explanatory variables affecting the interventions rollout and outcomes. Methods: The mixed methods design incorporates a two-step stepped-wedge cluster randomized controlled trial (cRCT) examining cross-sectional data from three phases, and nested qualitative and process evaluation sub-studies. Participating specialist mental health care services in Melbourne, Victoria are divided into 14 clusters with half randomly allocated to receive the staff training in year one and half in year two. Research participants are consumers aged 18-75 years who attended the cluster within a previous three-month period either at baseline, 12 (step 1) or 24 months (step 2). In the two nested sub-studies, participation extends to cluster staff. The primary outcome is the Questionnaire about the Process of Recovery collected from 756 consumers (252 each at baseline, step 1, step 2). Secondary and other outcomes measuring well-being, service satisfaction and health economic impact are collected from a subset of 252 consumers (63 at baseline; 126 at step 1; 63 at step 2) via interviews. Interview based longitudinal data are also collected 12 months apart from 88 consumers with a psychotic disorder diagnosis (44 at baseline, step 1; 44 at step 1, step 2). cRCT data will be analyzed using multilevel mixed-effects modelling to account for clustering and some repeated measures, supplemented by thematic analysis of qualitative interview data. The process evaluation will draw on qualitative, quantitative and documentary data. Discussion: Findings will provide an evidence-base for the continued transformation of Australian mental health service frameworks toward recovery