CSF MicroRNAs Reveal Impairment of Angiogenesis and Autophagy in Parkinson Disease.

BACKGROUND AND OBJECTIVES: We assessed longitudinal changes in CSF microRNAs (miRNAs) in patients with moderately severe Parkinson disease. METHODS: We used next-generation whole-genome miRNA sequencing to determine CSF miRNA expression in 75 patients with Parkinson disease after single random ascending doses of nilotinib and longitudinal miRNA expression after daily nilotinib, 150 and 300 mg, vs placebo for 1 year. RESULTS: Significant changes in the expression of miRNAs that control genes and pathways that regulate angiogenesis, autophagy, and the blood-brain-barrier components, primarily collagen, were observed over 1 year, suggesting impairment of these pathways in Parkinson progression in these patients. Different miRNAs that indicate activation of genes associated with autophagy flux and clearance and angiogenesis were significantly altered in the nilotinib, 300 mg vs 150 mg, or placebo group, and these changes correlated with clinical outcomes. No changes were observed in miRNAs after a single dose of nilotinib vs placebo. DISCUSSION: This study suggests vascular and autophagy defects in Parkinson progression. Nilotinib, 300 mg, reverses these effects via alteration of miRNA expression, suggesting epigenomic changes that may underlie long-term disease-modifying effects. TRIAL REGISTRATION INFORMATION: Clinical trial registration number: NCT02954978.

Phenomic Analysis of Chronic Granulomatous Disease Reveals More Severe Integumentary Infections in X-Linked Compared With Autosomal Recessive Chronic Granulomatous Disease.

Background: Chronic granulomatous disease (CGD) is an inborn error of immunity (IEI), characterised by recurrent bacterial and fungal infections. It is inherited either in an X-linked (XL) or autosomal recessive (AR) mode. Phenome refers to the entire set of phenotypes expressed, and its study allows us to generate new knowledge of the disease. The objective of the study is to reveal the phenomic differences between XL and AR-CGD by using Human Phenotype Ontology (HPO) terms. Methods: We collected data on 117 patients with genetically diagnosed CGD from Asia and Africa referred to the Asian Primary Immunodeficiency Network (APID network). Only 90 patients with sufficient clinical information were included for phenomic analysis. We used HPO terms to describe all phenotypes manifested in the patients. Results: XL-CGD patients had a lower age of onset, referral, clinical diagnosis, and genetic diagnosis compared with AR-CGD patients. The integument and central nervous system were more frequently affected in XL-CGD patients. Regarding HPO terms, perianal abscess, cutaneous abscess, and elevated hepatic transaminase were correlated with XL-CGD. A higher percentage of XL-CGD patients presented with BCGitis/BCGosis as their first manifestation. Among our CGD patients, lung was the most frequently infected organ, with gastrointestinal system and skin ranking second and third, respectively. Aspergillus species, Mycobacterium bovis, and Mycobacteirum tuberculosis were the most frequent pathogens to be found. Conclusion: Phenomic analysis confirmed that XL-CGD patients have more recurrent and aggressive infections compared with AR-CGD patients. Various phenotypic differences listed out can be used as clinical handles to distinguish XL or AR-CGD based on clinical features.

Discoidin Domain Receptor 1 is a therapeutic target for neurodegenerative diseases.

The role of Discoidin Domain Receptors (DDRs) is poorly understood in neurodegeneration. DDRs are upregulated in Alzheimer's and Parkinson's disease (PD), and DDRs knockdown reduces neurotoxic protein levels. Here we show that potent and preferential DDR1 inhibitors reduce neurotoxic protein levels in vitro and in vivo. Partial or complete deletion or inhibition of DDR1 in a mouse model challenged with α-synuclein increases autophagy and reduces inflammation and neurotoxic proteins. Significant changes of cerebrospinal fluid microRNAs that control inflammation, neuronal injury, autophagy and vesicular transport genes are observed in PD with and without dementia and Lewy body dementia, but these changes are attenuated or reversed after treatment with the DDR1 inhibitor, nilotinib. Collectively, these data demonstrate that DDR1 regulates autophagy and reduces neurotoxic proteins and inflammation and is a therapeutic target in neurodegeneration.

Immune-related Adverse Effects Associated with Programmed Death-1 Inhibitor Therapy in the Treatment of Non-Small Cell Lung Cancer: Incidence, Management, and Effect on Outcomes.

BACKGROUND: The programmed death 1 (PD-1) inhibitors may improve survival outcomes of non-small cell lung cancer (NSCLC) patients but are associated with immune-related adverse effects (IRAEs). Management of IRAEs may include immunosuppression (ie, corticosteroids), but there is concern that this may affect efficacy. This study evaluated the influence of IRAEs and immunosuppression for IRAEs on survival outcomes of NSCLC patients treated with PD-1 inhibitors (pembrolizumab and nivolumab). METHODS: We retrospectively examined data from Kaiser Permanente Southern and Northern California members diagnosed with NSCLC who received a PD-1 inhibitor from March 1, 2011 to September 30, 2016. Our primary goal was to evaluate the effects and management of IRAEs on survival with PD-1 inhibitors. Electronic database records were used to identify the occurrence of IRAEs, medication utilization, and death. Cox proportional hazard models were used to evaluate variables for association with increased risk of death. RESULTS: A total of 662 patients were included in the study (median age = 68 years) (interquartile range 61-74). IRAEs were identified in 18% of patients, of which 62% received immunosuppression. Median overall survival was 10 months (interquartile range = 4 months to not reached). Adjusting for covariates, use of immunosuppression during PD-1 inhibitor treatment was not associated with a significantly higher risk of death (hazard ratio = 1.04, 95% confidence interval = 0.84-1.29), whereas corticosteroid use before initiating PD-1 inhibitor therapy was (hazard ratio = 1.48, 95% confidence interval = 1.14-1.91). CONCLUSIONS: In a large, real-world cohort from an integrated healthcare system, use of corticosteroids prior to PD-1 inhibitors was associated with worse survival outcomes, whereas concomitant treatment was not.

Impact of disinvestment from weekend allied health services across acute medical and surgical wards: 2 stepped-wedge cluster randomised controlled trials.

BACKGROUND: Disinvestment (removal, reduction, or reallocation) of routinely provided health services can be difficult when there is little published evidence examining whether the services are effective or not. Evidence is required to understand if removing these services produces outcomes that are inferior to keeping such services in place. However, organisational imperatives, such as budget cuts, may force healthcare providers to disinvest from these services before the required evidence becomes available. There are presently no experimental studies examining the effectiveness of allied health services (e.g., physical therapy, occupational therapy, and social work) provided on weekends across acute medical and surgical hospital wards, despite these services being routinely provided internationally. The aim of this study was to understand the impact of removing weekend allied health services from acute medical and surgical wards using a disinvestment-specific non-inferiority research design. METHODS AND FINDINGS: We conducted 2 stepped-wedge cluster randomised controlled trials between 1 February 2014 and 30 April 2015 among patients on 12 acute medical or surgical hospital wards spread across 2 hospitals. The hospitals involved were 2 metropolitan teaching hospitals in Melbourne, Australia. Data from n = 14,834 patients were collected for inclusion in Trial 1, and n = 12,674 in Trial 2. Trial 1 was a disinvestment-specific non-inferiority stepped-wedge trial where the 'current' weekend allied health service was incrementally removed from participating wards each calendar month, in a random order, while Trial 2 used a conventional non-inferiority stepped-wedge design, where a 'newly developed' service was incrementally reinstated on the same wards as in Trial 1. Primary outcome measures were patient length of stay (proportion staying longer than expected and mean length of stay), the proportion of patients experiencing any adverse event, and the proportion with an unplanned readmission within 28 days of discharge. The 'no weekend allied health service' condition was considered to be not inferior if the 95% CIs of the differences between this condition and the condition with weekend allied health service delivery were below a 2% increase in the proportion of patients who stayed in hospital longer than expected, a 2% increase in the proportion who had an unplanned readmission within 28 days, a 2% increase in the proportion who had any adverse event, and a 1-day increase in the mean length of stay. The current weekend allied health service included physical therapy, occupational therapy, speech therapy, dietetics, social work, and allied health assistant services in line with usual care at the participating sites. The newly developed weekend allied health service allowed managers at each site to reprioritise tasks being performed and the balance of hours provided by each professional group and on which days they were provided. Analyses conducted on an intention-to-treat basis demonstrated that there was no estimated effect size difference between groups in the proportion of patients staying longer than expected (weekend versus no weekend; estimated effect size difference [95% CI], p-value) in Trial 1 (0.40 versus 0.38; estimated effect size difference 0.01 [-0.01 to 0.04], p = 0.31, CI was both above and below non-inferiority margin), but the proportion staying longer than expected was greater with the newly developed service compared to its no weekend service control condition (0.39 versus 0.40; estimated effect size difference 0.02 [0.01 to 0.04], p = 0.04, CI was completely below non-inferiority margin) in Trial 2. Trial 1 and 2 findings were discordant for the mean length of stay outcome (Trial 1: 5.5 versus 6.3 days; estimated effect size difference 1.3 days [0.9 to 1.8], p < 0.001, CI was both above and below non-inferiority margin; Trial 2: 5.9 versus 5.0 days; estimated effect size difference -1.6 days [-2.0 to -1.1], p < 0.001, CI was completely below non-inferiority margin). There was no difference between conditions for the proportion who had an unplanned readmission within 28 days in either trial (Trial 1: 0.01 [-0.01 to 0.03], p = 0.18, CI was both above and below non-inferiority margin; Trial 2: -0.01 [-0.02 to 0.01], p = 0.62, CI completely below non-inferiority margin). There was no difference between conditions in the proportion of patients who experienced any adverse event in Trial 1 (0.01 [-0.01 to 0.03], p = 0.33, CI was both above and below non-inferiority margin), but a lower proportion of patients had an adverse event in Trial 2 when exposed to the no weekend allied health condition (-0.03 [-0.05 to -0.004], p = 0.02, CI completely below non-inferiority margin). Limitations of this research were that 1 of the trial wards was closed by the healthcare provider after Trial 1 and could not be included in Trial 2, and that both withdrawing the current weekend allied health service model and installing a new one may have led to an accommodation period for staff to adapt to the new service settings. Stepped-wedge trials are potentially susceptible to bias from naturally occurring change over time at the service level; however, this was adjusted for in our analyses. CONCLUSIONS: In Trial 1, criteria to say that the no weekend allied health condition was non-inferior to current weekend allied health condition were not met, while neither the no weekend nor current weekend allied health condition demonstrated superiority. In Trial 2, the no weekend allied health condition was non-inferior to the newly developed weekend allied health condition across all primary outcomes, and superior for the outcomes proportion of patients staying longer than expected, proportion experiencing any adverse event, and mean length of stay. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12613001231730 and ACTRN12613001361796.

Study protocol for two randomized controlled trials examining the effectiveness and safety of current weekend allied health services and a new stakeholder-driven model for acute medical/surgical patients versus no weekend allied health services.

BACKGROUND: Disinvestment from inefficient or ineffective health services is a growing priority for health care systems. Provision of allied health services over the weekend is now commonplace despite a relative paucity of evidence supporting their provision. The relatively high cost of providing this service combined with the paucity of evidence supporting its provision makes this a potential candidate for disinvestment so that resources consumed can be used in other areas. This study aims to determine the effectiveness, cost-effectiveness and safety of the current model of weekend allied health service and a new stakeholder-driven model of weekend allied health service delivery on acute medical and surgical wards compared to having no weekend allied health service. METHODS/DESIGN: Two stepped wedge, cluster randomised trials of weekend allied health services will be conducted in six acute medical/surgical wards across two public metropolitan hospitals in Melbourne (Australia). Wards have been chosen to participate by management teams at each hospital. The allied health services to be investigated will include physiotherapy, occupational therapy, speech therapy, dietetics, social work and allied health assistants. At baseline, all wards will be receiving weekend allied health services. Study 1 intervention will be the sequential disinvestment (roll-in) of the current weekend allied health service model from each participating ward in monthly intervals and study 2 will be the roll-out of a new stakeholder-driven model of weekend allied health service delivery. The order in which weekend allied health services will be rolled in and out amongst participating wards will be determined randomly. This trial will be conducted in each of the two participating hospitals at a different time interval. Primary outcomes will be length of stay, rate of unplanned hospital readmission within 28 days and rate of adverse events. Secondary outcomes will be number of complaints and compliments, staff absenteeism, and patient discharge destination, satisfaction, and functional independence at discharge. DISCUSSION: This is the world's first application of the recently described non-inferiority (roll-in) stepped wedge trial design, and the largest investigation of the effectiveness of weekend allied health services on acute medical surgical wards to date. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry. REGISTRATION NUMBER: ACTRN12613001231730 (first study) and ACTRN12613001361796 (second study). Was this trial prospectively registered?: Yes. Date registered: 8 November 2013 (first study), 12 December 2013 (second study). Anticipated completion: June 2015. Protocol version: 1. Role of trial sponsor: KP and DL are directly employed by one of the trial sponsors, their roles were: KP assisted with overall development of research design and assisted with overall project management; DL contributed to project management, administration and communications strategy.

Clinical implication of immunoglobulin G levels in the management of patients with Helicobacter pylori infection.

OBJECTIVE: The objective of this research was to gauge the diagnostic utility of serology tests compared with urea breaths tests (UBTs) and determine reliable threshold values/ranges for diagnosis of Helicobacter pylori infection using only immunoglobulin (Ig) G results. METHODS: Data were obtained from 371 patients with UBTs and/or serology tests. Quantitative results were converted to multiple of minimum positive value (MMPV). Results were paralleled to obtain percentage change in serum IgG levels and 95% confidence intervals were obtained to establish new ranges for diagnosis. RESULTS: Treated patients with only serology tests in a time frame of 3 to 6 months after final treatment displayed a 68.33% ± 2.95% decrease in 95% confidence interval of serum IgG. Uninfected patients with serology and UBT results within 2 weeks displayed a range of 1.32 ± 0.23 MMPV; infected patients produced a range of 3.32 ± 0.88 MMPV. CONCLUSION: Treated patients should display a 65.38% to 71.28% decrease in serum IgG levels, along with an ending IgG level of ≤1.75 U/mL or ≤4.025 EV (ELISA value). Before treatment or exposure, patients with serum IgG values of 1.09 to 1.55 U/mL or 2.507 to 3.565 EV or lower are generally uninfected. Because of the lower cost and high confidence of results, we believe that IgG testing should be considered as a reasonable and even perhaps preferred method of monitoring H. pylori infections.