What factors indicate prognosis for adults with depression in primary care? A protocol for meta-analyses of individual patient data using the Dep-GP database [version 2; peer review: 2 approved]

BACKGROUND: Pre-treatment severity is a key indicator of prognosis for those with depression. Knowledge is limited on how best to encompass severity of disorders. A number of non-severity related factors such as social support and life events are also indicators of prognosis. It is not clear whether this holds true after adjusting for pre-treatment severity as a) a depressive symptom scale score, and b) a broader construct encompassing symptom severity and related indicators: “disorder severity”. In order to investigate this, data from the individual participants of clinical trials which have measured a breadth of “disorder severity” related factors are needed. AIMS: 1) To assess the association between outcomes for adults seeking treatment for depression and the severity of depression pre-treatment, considered both as i) depressive symptom severity only and ii) “disorder severity” which includes depressive symptom severity and comorbid anxiety, chronicity, history of depression, history of previous treatment, functional impairment and health-related quality of life. 2) To determine whether i) social support, ii) life events, iii) alcohol misuse, and iv) demographic factors (sex, age, ethnicity, marital status, employment status, level of educational attainment, and financial wellbeing) are prognostic indicators of outcomes, independent of baseline “disorder severity” and the type of treatment received. METHODS: Databases were searched for randomised clinical trials (RCTs) that recruited adults seeking treatment for depression from their general practitioners and used the same diagnostic and screening instrument to measure severity at baseline – the Revised Clinical Interview Schedule; outcome measures could differ between studies. Chief investigators of all studies meeting inclusion criteria were contacted and individual patient data (IPD) were requested. CONCLUSIONS: In total 15 RCTs met inclusion criteria. The Dep-GP database will include the 6271 participants from the 13 studies that provided IPD. This protocol outlines how these data will be analysed. REGISTRATION: PROSPERO CRD42019129512 (01/04/2019

Healthy Campus Trial: A multiphase optimization strategy (MOST) fully factorial trial to optimize the smartphone cognitive behavioral therapy (CBT) app for mental health promotion among university students: Study protocol for a randomized controlled trial

This is the final version. Available from the publisher via the DOI in this record.After the publication of the primary findings, the de-identified and completely anonymized individual participant-level dataset will be posted on the UMIN-ICDR website (http://www.umin.ac.jp/icdr/index-j.html) so that it can be accessed by qualified researchers.Background: Youth in general and college life in particular are characterized by new educational, vocational, and interpersonal challenges, opportunities, and substantial stress. It is estimated that 30-50% of university students meet criteria for some mental disorder, especially depression, in any given year. The university has traditionally provided many channels to promote students' mental health, but until now only a minority have sought such help, possibly owing to lack of time and/or to stigma related to mental illness. Smartphone-delivered cognitive behavioral therapy (CBT) shows promise for its accessibility and effectiveness. However, its most effective components and for whom it is more (or less) effective are not known. Methods/design: Based on the multiphase optimization strategy framework, this study is a parallel-group, multicenter, open, fully factorial trial examining five smartphone-delivered CBT components (self-monitoring, cognitive restructuring, behavioral activation, assertion training, and problem solving) among university students with elevated distress, defined as scoring 5 or more on the Patient Health Questionnaire-9 (PHQ-9). The primary outcome is change in PHQ-9 scores from baseline to week 8. We will estimate specific efficacy of the five components and their interactions through the mixed-effects repeated-measures analysis and propose the most effective and efficacious combinations of components. Effect modification by selected baseline characteristics will be examined in exploratory analyses. Discussion: The highly efficient experimental design will allow identification of the most effective components and the most efficient combinations thereof among the five components of smartphone CBT for university students. Pragmatically, the findings will help make the most efficacious CBT package accessible to a large number of distressed university students at reduced cost; theoretically, they will shed light on the underlying mechanisms of CBT and help further advance CBT for depression

Intracranial pressure in patients with papilloedema

OBJECTIVES: Papilloedema is a clinical manifestation of chronically raised intracranial pressure (ICP), often seen in idiopathic intracranial hypertension (IIH). However, the extent of intracranial hypertension required to produce papilloedema is not known. We compare ICP values in IIH patients who developed papilloedema and those who did not. We aim to identify a pathological ICP threshold predictive of the development of papilloedema in IIH patients. MATERIALS AND METHODS: Single-centre cohort of IIH patients (2006-2016) who underwent 24-hour ICP monitoring (ICPM) and ophthalmology assessments, prior to intervention. Papilloedema was graded according to the Frisén scale. An unpaired t-test compared 24-hour ICPM between papilloedema and no-papilloedema groups. Fisher's exact test was used to determine predictive value of ICP. RESULTS: Thirty-six patients with IIH (35 F: 1M), mean age 32.5 ± 9.49 years (mean ± SD) were included. Patients with papilloedema had a mean median 24-hour ICP of 10.4 ± 5.32 mm Hg (n = 25), significantly higher than the group without papilloedema 6.31 ± 3.30 mm Hg (n = 11) (P < .05). The papilloedema group were exposed to higher pressures (10 mm Hg) for 30 minutes or more. Using 24-hour median ICP of 10 mm Hg as a minimum cut-off predictive value gives a specificity = 91%, sensitivity = 48%, PPV = 92% and NPV = 44% of detecting papilloedema. CONCLUSIONS: A 24-hour ICP of 10 mmHg or more is a good predictor for papilloedema and reflects a pathological threshold. The range varied widely suggesting papilloedema can occur at even lower pressures. These results are consistent with emerging evidence suggest that pathologically "high" 24 hours ICP is lower than previously quoted

A Patient Stratification Approach to Identifying the Likelihood of Continued Chronic Depression and Relapse Following Treatment for Depression

BACKGROUND: Subgrouping methods have the potential to support treatment decision making for patients with depression. Such approaches have not been used to study the continued course of depression or likelihood of relapse following treatment. METHOD: Data from individual participants of seven randomised controlled trials were analysed. Latent profile analysis was used to identify subgroups based on baseline characteristics. Associations between profiles and odds of both continued chronic depression and relapse up to one year post-treatment were explored. Differences in outcomes were investigated within profiles for those treated with antidepressants, psychological therapy, and usual care. RESULTS: Seven profiles were identified; profiles with higher symptom severity and long durations of both anxiety and depression at baseline were at higher risk of relapse and of chronic depression. Members of profile five (likely long durations of depression and anxiety, moderately-severe symptoms, and past antidepressant use) appeared to have better outcomes with psychological therapies: antidepressants vs. psychological therapies (OR (95% CI) for relapse = 2.92 (1.24–6.87), chronic course = 2.27 (1.27–4.06)) and usual care vs. psychological therapies (relapse = 2.51 (1.16–5.40), chronic course = 1.98 (1.16–3.37)). CONCLUSIONS: Profiles at greater risk of poor outcomes could benefit from more intensive treatment and frequent monitoring. Patients in profile five may benefit more from psychological therapies than other treatments

Renal epithelial cells retain primary cilia during human acute renal allograft rejection injury

OBJECTIVES: Primary cilia are sensory organelles which co-ordinate several developmental/repair pathways including hedgehog signalling. Studies of human renal allografts suffering acute tubular necrosis have shown that length of primary cilia borne by epithelial cells doubles throughout the nephron and collecting duct, and then normalises as renal function returns. Conversely the loss of primary cilia has been reported in chronic allograft rejection and linked to defective hedgehog signalling. We investigated the fate of primary cilia in renal allografts suffering acute rejection. RESULTS: Here we observed that in renal allografts undergoing acute rejection, primary cilia were retained, with their length increasing 1 week after transplantation and remaining elevated. We used a mouse model of acute renal injury to demonstrate that elongated renal primary cilia in the injured renal tubule show evidence of smoothened accumulation, a biomarker for activation of hedgehog signalling. We conclude that primary cilium-mediated activation of hedgehog signalling is still possible during the acute phase of renal allograft rejection

Life events and treatment prognosis for depression: A systematic review and individual patient data meta-analysis

Objective: To investigate associations between major life events and prognosis independent of treatment type: (1) after adjusting for clinical prognostic factors and socio-demographics; (2) amongst patients with depressive episodes at least six-months long; and (3) patients with a first life-time depressive episode. // Methods: Six RCTs of adults seeking treatment for depression in primary care met eligibility criteria, individual patient data (IPD) were collated from all six (n = 2858). Participants were randomized to any treatment and completed the same baseline assessment of life events, demographics and clinical prognostic factors. Two-stage random effects meta-analyses were conducted. // Results: Reporting any major life events was associated with poorer prognosis regardless of treatment type. Controlling for baseline clinical factors, socio-demographics and social support resulted in minimal residual evidence of associations between life events and treatment prognosis. However, removing factors that might mediate the relationships between life events and outcomes reporting: arguments/disputes, problem debt, violent crime, losing one's job, and three or more life events were associated with considerably worse prognoses (percentage difference in 3–4 months depressive symptoms compared to no reported life events =30.3%(95%CI: 18.4–43.3)). // Conclusions: Assessing for clinical prognostic factors, social support, and socio-demographics is likely to be more informative for prognosis than assessing self-reported recent major life events. However, clinicians might find it useful to ask about such events, and if they are still affecting the patient, consider interventions to tackle problems related to those events (e.g. employment support, mediation, or debt advice). Further investigations of the efficacy of such interventions will be important

Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons

The perspective of neuroinflammation as an epiphenomenon following neuron damage is being replaced by the awareness of glia and their importance in neural functions and disorders. Systemic inflammation generates signals that communicate with the brain and leads to changes in metabolism and behavior, with microglia assuming a pro-inflammatory phenotype. Identification of potential peripheral-to-central cellular links is thus a critical step in designing effective therapeutics. Mast cells may fulfill such a role. These resident immune cells are found close to and within peripheral nerves and in brain parenchyma/meninges, where they exercise a key role in orchestrating the inflammatory process from initiation through chronic activation. Mast cells and glia engage in crosstalk that contributes to accelerate disease progression; such interactions become exaggerated with aging and increased cell sensitivity to stress. Emerging evidence for oligodendrocytes, independent of myelin and support of axonal integrity, points to their having strong immune functions, innate immune receptor expression, and production/response to chemokines and cytokines that modulate immune responses in the central nervous system while engaging in crosstalk with microglia and astrocytes. In this review, we summarize the findings related to our understanding of the biology and cellular signaling mechanisms of neuroinflammation, with emphasis on mast cell-glia interactions

Identification of a Cardiac Specific Protein Transduction Domain by In Vivo Biopanning Using a M13 Phage Peptide Display Library in Mice

Background: A peptide able to transduce cardiac tissue specifically, delivering cargoes to the heart, would be of significant therapeutic potential for delivery of small molecules, proteins and nucleic acids. In order to identify peptide(s) able to transduce heart tissue, biopanning was performed in cell culture and in vivo with a M13 phage peptide display library. Methods and Results: A cardiomyoblast cell line, H9C2, was incubated with a M13 phage 12 amino acid peptide display library. Internalized phage was recovered, amplified and then subjected to a total of three rounds of in vivo biopanning where infectious phage was isolated from cardiac tissue following intravenous injection. After the third round, 60% of sequenced plaques carried the peptide sequence APWHLSSQYSRT, termed cardiac targeting peptide (CTP). We demonstrate that CTP was able to transduce cardiomyocytes functionally in culture in a concentration and cell-type dependent manner. Mice injected with CTP showed significant transduction of heart tissue with minimal uptake by lung and kidney capillaries, and no uptake in liver, skeletal muscle, spleen or brain. The level of heart transduction by CTP also was greater than with a cationic transduction domain. Conclusions: Biopanning using a peptide phage display library identified a peptide able to transduce heart tissue in vivo efficiently and specifically. CTP could be used to deliver therapeutic peptides, proteins and nucleic acid specifically to the heart. © 2010 Zahid et al