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Objectives: A prospective parallel cohort trial was conducted to compare outcomes of patients treated with maxillary protraction vs LeFort 1 maxillary advancement surgery.Setting and Sample Population: The primary site for the clinical trial is Children's Hospital Los Angeles; the satellite test site is Seattle Children's Hospital. All patients have isolated cleft lip and palate and a skeletal Class III malocclusion.Material and Methods: A total of 50 patients, ages 11-14, will be recruited for the maxillary protraction cohort. The maxillary surgery cohort consists of 50 patients, ages 16-21, who will undergo LeFort 1 maxillary advancement surgery. Patients with additional medical or cognitive handicaps were excluded from the study.Results: Current recruitment of patients is on track to complete the study within the proposed recruitment period.Conclusion: This observational trial is collecting information that will examine dental, skeletal, financial and quality-of-life issues from both research cohorts. [ABSTRACT FROM AUTHOR]

Objective: To determine the effects on weight loss of three abbreviated behavioral weight loss interventions with and without coaching and mobile technology.Methods: A randomized controlled efficacy study of three 6-month weight loss treatments was conducted in 96 adults with obesity: 1) self-guided (SELF), 2) standard (STND), or 3) technology-supported (TECH). STND and TECH received eight in-person group treatment sessions. SELF and STND used paper diaries to self-monitor diet, activity, and weight; TECH used a smartphone application with social networking features and wireless accelerometer.Results: Weight loss was greater for TECH and STND than SELF at 6 months (-5.7 kg [95% confidence interval: -7.2 to -4.1] vs. -2.7 kg [95% confidence interval: -5.1 to -0.3], P < 0.05) but not 12 months. TECH and STND did not differ except that more STND (59%) than TECH (34%) achieved ≥ 5% weight loss at 6 months (P < 0.05). Self-monitoring adherence was greater in TECH than STND (P < 0.001), greater in both interventions than SELF (P < 0.001), and covaried with weight loss (r(84) = 0.36-0.51, P < 0.001).Conclusions: Abbreviated behavioral counseling can produce clinically meaningful weight loss regardless of whether self-monitoring is performed on paper or smartphone, but long-term superiority over standard of care self-guided treatment is challenging to maintain. [ABSTRACT FROM AUTHOR]

Copyright of Developmental Medicine & Child Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Developmental Medicine & Child Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Surrogate endpoints play an important role in drug development when they can be used to measure treatment effect early compared to the final clinical outcome and to predict clinical benefit or harm. Such endpoints are assessed for their predictive value of clinical benefit by investigating the surrogate relationship between treatment effects on the surrogate and final outcomes using meta-analytic methods. When surrogate relationships vary across treatment classes, such validation may fail due to limited data within each treatment class. In this paper, two alternative Bayesian meta-analytic methods are introduced which allow for borrowing of information from other treatment classes when exploring the surrogacy in a particular class. The first approach extends a standard model for the evaluation of surrogate endpoints to a hierarchical meta-analysis model assuming full exchangeability of surrogate relationships across all the treatment classes, thus facilitating borrowing of information across the classes. The second method is able to relax this assumption by allowing for partial exchangeability of surrogate relationships across treatment classes to avoid excessive borrowing of information from distinctly different classes. We carried out a simulation study to assess the proposed methods in nine data scenarios and compared them with subgroup analysis using the standard model within each treatment class. We also applied the methods to an illustrative example in colorectal cancer which led to obtaining the parameters describing the surrogate relationships with higher precision. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate tolerability of and response to rituximab in children with myelin oligodendrocyte glycoprotein (MOG) antibody-positive relapsing neuroinflammatory disease. This was an observational study of prospectively collected data on 12 consecutive children (eight females, four males; median age at onset 10y 6mo [interquartile range {IQR} 7y 2mo-12y 5mo], median follow-up 2y 1mo [IQR 1y 7mo-2y 6mo]) with central nervous system inflammation and persistent serum MOG immunoglobulin G positivity more than 12 weeks after clinical presentation. Patients received a standardized rituximab treatment protocol. MOG antibody testing was performed following standardized cell-based methods. Median clinical follow-up after rituximab induction was 2 years (IQR 1y 7mo-2y 10mo). The relapse rate in the first 12 months posttreatment was 0 (IQR 0-0). After rituximab, two patients relapsed during B-cell suppression and four showed clinical or radiological disease recurrences at B-cell reconstitution. Mild-to-moderate infusion related adverse events occurred in two patients. Leukopenia developed in seven patients and serum immunoglobulin suppression in five patients with no significant age effect on the risk of their development. None developed severe life-threatening events. Rituximab-induced B-cell suppression was associated with absence of relapses in 10 patients who were MOG-positive with recurrent disease. Rituximab was well tolerated. The most frequent adverse effects were hypogammaglobulinemia and leukopenia. We recommend monitoring of complete blood counts and immunoglobulins in this population. WHAT THIS PAPER ADDS: Rituximab appears to control disease in most anti-myelin oligodendrocyte glycoprotein-positive patients with relapsing neuroinflammatory disease. Rituximab was associated with transitory, mild-to-moderate infusion-related effects. Half of patients treated with rituximab developed leukopenia or hypogammaglobulinemia. No opportunistic infections were observed. [ABSTRACT FROM AUTHOR]

Copyright of Developmental Medicine & Child Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Developmental Medicine & Child Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Developmental Medicine & Child Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Mediation analysis allows the examination of effects of a third variable in the pathway between an exposure and an outcome. The general multiple mediation analysis method, proposed by Yu et al, improves traditional methods (eg, estimation of natural and controlled direct effects) to enable consideration of multiple mediators/confounders simultaneously and the use of linear and nonlinear predictive models for estimating mediation/confounding effects. In this paper, we extend the method for time-to-event outcomes and apply the method to explore the racial disparity in breast cancer survivals. Breast cancer is the most common cancer and the second leading cause of cancer death among women of all races. Despite improvement of survival rates of breast cancer in the US, a significant difference between white and black women remains. Previous studies have found that more advanced and aggressive tumors and less than optimal treatment may explain the lower survival rates for black women as compared to white women. Due to limitations of current analytic methods and the lack of comprehensive data sets, researchers have not been able to differentiate the relative effect each factor contributes to the overall racial disparity. We use the CDC-funded Patterns of Care study to examine the determinants of racial disparities in breast cancer survival using a novel multiple mediation analysis. Using the proposed method, we applied the Cox hazard model and multiple additive regression trees as predictive models and found that all racial disparity in survival among Louisiana breast cancer patients were explained by factors included in the study. [ABSTRACT FROM AUTHOR]

In this paper, we propose a large-scale multiple testing procedure to find the significant sub-areas between two samples of curves automatically. The procedure is optimal in that it controls the directional false discovery rate at any specified level on a continuum asymptotically. By introducing a nonparametric Gaussian process regression model for the two-sided multiple test, the procedure is computationally inexpensive. It can cope with problems with multidimensional covariates and accommodate different sampling designs across the samples. We further propose the significant curve/surface, giving an insight on dynamic significant differences between two curves. Simulation studies demonstrate that the proposed procedure enjoys superior performance with strong power and good directional error control. The procedure is also illustrated with the application to two executive function studies in hemiplegia. [ABSTRACT FROM AUTHOR]

Copyright of Developmental Medicine & Child Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Developmental Medicine & Child Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

This paper considers the analysis of a repeat event outcome in clinical trials of chronic diseases in the context of dependent censoring (e.g. mortality). It has particular application in the context of recurrent heart failure hospitalisations in trials of heart failure. Semi-parametric joint frailty models (JFMs) simultaneously analyse recurrent heart failure hospitalisations and time to cardiovascular death, estimating distinct hazard ratios whilst individual-specific latent variables induce associations between the two processes. A simulation study was carried out to assess the suitability of the JFM versus marginal analyses of recurrent events and cardiovascular death using standard methods. Hazard ratios were consistently overestimated when marginal models were used, whilst the JFM produced good, well-estimated results. An application to the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity programme was considered. The JFM gave unbiased estimates of treatment effects in the presence of dependent censoring. We advocate the use of the JFM for future trials that consider recurrent events as the primary outcome. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

In clinical trials with survival endpoint, it is common to observe an overlap between two Kaplan-Meier curves of treatment and control groups during the early stage of the trials, indicating a potential delayed treatment effect. Formulas have been derived for the asymptotic power of the log-rank test in the presence of delayed treatment effect and its accompanying sample size calculation. In this paper, we first reformulate the alternative hypothesis with the delayed treatment effect in a rescaled time domain, which can yield a simplified sample size formula for the log-rank test in this context. We further propose an intersection-union test to examine the efficacy of treatment with delayed effect and show it to be more powerful than the log-rank test. Simulation studies are conducted to demonstrate the proposed methods. [ABSTRACT FROM AUTHOR]

Background and Aims: Baclofen, a selective γ-aminobutyric acid (GABA)B receptor agonist, has emerged as a potential treatment for alcohol use disorder with much unexplained variation in response to treatment efficacy and dose regimen. Several positive studies include patients with alcoholic liver disease (ALD) and/or history of heavy drinking. The aim of this paper was to examine the association of cortical GABA+ concentration with severity of liver disease (including markers of liver injury) and other clinical characteristics in alcohol patients.Methods: Proton magnetic resonance spectroscopy (1 H-MRS), from the parietal lobe, was analyzed to yield absolute concentration of GABA in 24 alcohol-dependent individuals. Diagnosis of ALD, markers of liver injury, severity of liver disease (Model for End-Stage Liver Disease [MELD]), and alcohol history were assessed. Covariates included concurrent medication, age, and recent alcohol consumption.Results: Multiple linear regression revealed that GABA+ concentration was significantly predicted by MELD scores (F = 5.02, R2  = 0.59, P = 0.01; MELD: B = -0.63, P = 0.02), when controlling for covariates concurrent medication, age, and recent alcohol consumption.Conclusion: Severity of ALD is associated with lower cortical concentrations of GABA+. These results may explain variations in response to the GABAB agonist, baclofen, in the alcohol-dependent population. [ABSTRACT FROM AUTHOR]

A dynamic treatment regime (DTR) is a sequence of decision rules, each of which recommends a treatment based on a patient's past and current health status. Sequential, multiple assignment, randomized trials (SMARTs) are multi-stage trial designs that yield data specifically for building effective DTRs. Modeling the marginal mean trajectories of a repeated-measures outcome arising from a SMART presents challenges, because traditional longitudinal models used for randomized clinical trials do not take into account the unique design features of SMART. We discuss modeling considerations for various forms of SMART designs, emphasizing the importance of considering the timing of repeated measures in relation to the treatment stages in a SMART. For illustration, we use data from three SMART case studies with increasing level of complexity, in autism, child attention deficit hyperactivity disorder, and adult alcoholism. In all three SMARTs, we illustrate how to accommodate the design features along with the timing of the repeated measures when comparing DTRs based on mean trajectories of the repeated-measures outcome. [ABSTRACT FROM AUTHOR]

Background and Objectives: We examined youth recovery outcomes at 6- and 9-months post-participation in an aftercare pilot study called Educating and Supporting inQuisitive Youth in Recovery (ESQYIR) that aimed to investigate the utility of a 12-week mobile texting recovery support intervention.Methods: A total of 80 youth [Mage 20.4 (SD = 3.5)] were randomized to a mobile texting aftercare intervention or an aftercare-as-usual control group. Both groups received identical data collection protocols with psychosocial and behavioral assessments occurring at baseline, during the trial (months 1 and 2), at discharge from the trial (month 3), and 3-, 6-, and 9-month post-intervention follow-ups.Results: Mixed modeling showed that youth who participated in the mobile texting aftercare intervention were less likely to test positive for their primary drug compared to youth in the aftercare-as-usual condition during 6- and 9-months follow-ups (p < .01). Additionally, youth in the aftercare intervention reported significantly higher self-efficacy/confidence to abstain during recovery (p < .05) and were more likely to participate in recovery-related behaviors (self-help and goal-directed extracurricular activities; p < .05) than those in aftercare-as-usual at the 6- and 9-month follow-ups.Conclusions: Results suggest that delivering a structured, behavioral-based wellness aftercare intervention using mobile texting can be an effective for sustaining recovery outcomes in youth over time compared to youth who receive aftercare-as-usual.Scientific Significance: This study shows that a mobile-texting aftercare intervention sustained effects at 6- and 9-months post-intervention for young people in substance use recovery. [ABSTRACT FROM AUTHOR]

Objective: To develop outcome measures that are more sensitive than current measures for evaluating primary or transitional care after hospitalizations, emergency department (ED) visits, or observation stays.Data Sources: Medicare claims data from January 1, 2015, to October 31, 2017, for 1 261 707 Medicare fee-for-service beneficiaries served by (a) primary care practices participating in Track 1 of the Comprehensive Primary Care Plus (CPC+) initiative, and (b) their matched comparison practices.Study Design: Given the poor statistical power in many studies to detect effects on readmissions, we developed two novel claims-based measures of unplanned acute care (UAC) following an index acute care event. The first measure assesses the proportion of hospitalizations followed by an unplanned readmission, ED visit, or observation stay within 30 days of discharge; the second assesses the proportion of ED visits and observation stays followed by a hospitalization, ED visit, or observation stay within 30 days. We calculate minimum detectable effects (MDEs) for both measures and for a conventional measure of 30-day unplanned readmissions, using CPC+ data.Principal Findings: Repeat UAC events are common among Medicare beneficiaries served by the CPC+ practices. In 2017, 22% of discharges and 21% of ED visits and observation stays had a UAC event within 30 days. Readmissions were the most common UAC event following discharge, whereas ED visits were most common following index ED visits or observation stays. MDEs are 25%-40% lower for the new measures than for the standard 30-day readmissions measure, indicating better statistical power to detect impacts of primary or transitional care interventions.Conclusions: This study introduces two new claims-based measures to assess quality of care during a patient's vulnerable period following acute care. The new measures complement existing measures, covering a broader range of UAC events than the standard 30-day readmissions measure, and yielding greater statistical power. [ABSTRACT FROM AUTHOR]

Background: Patient-reported outcomes have received a great deal of interest in periodontal plastic procedures. However, their evaluation has mainly been short-term. Thus, the aim of this study was to evaluate the impact of soft tissue grafting procedures conducted over a decade ago on the willingness of a patients to undergo the surgery again.Methods: Subjects that received an autogenous soft tissue graft over 10 years ago were screened and invited for a survey. Their response was only analyzed if they were able to correctly identify the sites of the surgical procedures. Dichotomous questions and visual analogue scales (VASs) were used to assess self-reported pain, willingness to retreat and satisfaction.Results: Fifty-two patients were included in the analyses. Higher pain was reported for mandibular sites, and treated areas including ≥ 3 teeth (P < 0.01). Willingness to retreatment was 84.6% and it was negatively associated with self-reported pain measures, the arch location (mandible), and number of treated sites (≥3 teeth) (P < 0.01). Mean satisfaction rate was 86.9 ± 13.65 (VAS) and showed a positive correlation with willingness to retreat (P < 0.01). Having a complete root coverage at the recall visit was also significantly associated with higher patient satisfaction scores (P < 0.01).Conclusions: Patient experience of previous autogenous soft tissue grafting has an influence on their decision to undergo future treatment. Willingness to retreat was negatively affected by mandibular sites, larger treated areas and the perceived pain, while presenting with complete root coverage was significantly associated with patient satisfaction. [ABSTRACT FROM AUTHOR]

Objective: Blood tests to monitor disease activity, attack severity, or treatment impact in neuromyelitis optica spectrum disorder (NMOSD) have not been developed. This study investigated the relationship between serum glial fibrillary acidic protein (sGFAP) concentration and NMOSD activity and assessed the impact of inebilizumab treatment.Methods: N-MOmentum was a prospective, multicenter, double-blind, placebo-controlled, randomized clinical trial in adults with NMOSD. sGFAP levels were measured by single-molecule arrays (SIMOA) in 1,260 serial and attack-related samples from 215 N-MOmentum participants (92% aquaporin 4-immunoglobulin G-seropositive) and in control samples (from healthy donors and patients with relapsing-remitting multiple sclerosis).Results: At baseline, 62 participants (29%) exhibited high sGFAP concentrations (≥170 pg/ml; ≥2 standard deviations above healthy donor mean concentration) and were more likely to experience an adjudicated attack than participants with lower baseline concentrations (hazard ratio [95% confidence interval], 3.09 [1.6-6.1], p = 0.001). Median (interquartile range [IQR]) concentrations increased within 1 week of an attack (baseline: 168.4, IQR = 128.9-449.7 pg/ml; attack: 2,160.1, IQR = 302.7-9,455.0 pg/ml, p = 0.0015) and correlated with attack severity (median fold change from baseline [FC], minor attacks: 1.06, IQR = 0.9-7.4; major attacks: 34.32, IQR = 8.7-107.5, p = 0.023). This attack-related increase in sGFAP occurred primarily in placebo-treated participants (FC: 20.2, IQR = 4.4-98.3, p = 0.001) and was not observed in inebilizumab-treated participants (FC: 1.1, IQR = 0.8-24.6, p > 0.05). Five participants (28%) with elevated baseline sGFAP reported neurological symptoms leading to nonadjudicated attack assessments.Interpretation: Serum GFAP may serve as a biomarker of NMOSD activity, attack risk, and treatment effects. ANN NEUROL 2021;89:895-910. [ABSTRACT FROM AUTHOR]

Objective: Dysferlinopathy is a muscular dystrophy with a highly variable clinical presentation and currently unpredictable progression. This variability and unpredictability presents difficulties for prognostication and clinical trial design. The Jain Clinical Outcomes Study of Dysferlinopathy aims to establish the validity of the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) scale and identify factors that influence the rate of disease progression using NSAD.Methods: We collected a longitudinal series of functional assessments from 187 patients with dysferlinopathy over 3 years. Rasch analysis was used to develop the NSAD, a motor performance scale suitable for ambulant and nonambulant patients. Generalized estimating equations were used to evaluate the impact of patient factors on outcome trajectories.Results: The NSAD detected significant change in clinical progression over 1 year. The steepest functional decline occurred during the first 10 years after symptom onset, with more rapid decline noted in patients who developed symptoms at a younger age (p = 0.04). The most rapidly deteriorating group over the study was patients 3 to 8 years post symptom onset at baseline.Interpretation: The NSAD is the first validated limb girdle specific scale of motor performance, suitable for use in clinical practice and clinical trials. Longitudinal analysis showed it may be possible to identify patient factors associated with greater functional decline both across the disease course and in the short-term for clinical trial preparation. Through further work and validation in this cohort, we anticipate that a disease model incorporating functional performance will allow for more accurate prognosis for patients with dysferlinopathy. ANN NEUROL 2021;89:967-978. [ABSTRACT FROM AUTHOR]

Background and Purpose: Rho kinase (ROCK) activation is involved in neuroinflammatory processes leading to progression of neurodegenerative diseases such as Parkinson's disease. Furthermore, ROCK plays a major role in angiogenesis. Neuroinflammation and angiogenesis are mechanisms involved in developing l-DOPA-induced dyskinesias (LID). However, it is not known whether ROCK plays a role in LID and whether ROCK inhibitors may be useful against LID.Experimental Approach: In rats, we performed short- and long-term dopaminergic lesions using 6-hydroxydopamine and developed a LID model. Effects of dopaminergic lesions and LID on the RhoA/ROCK levels were studied by western blot, real-time PCR analyses and ROCK activity assays in the substantia nigra and striatum. The effects of the ROCK inhibitor fasudil on LID were particularly investigated.Key Results: Short-term 6-hydroxydopamine lesions increased nigrostriatal RhoA/ROCK expression, apparently related to the active neuroinflammatory process. However, long-term dopaminergic denervation (completed and stabilized lesions) led to a decrease in RhoA/ROCK levels. Rats with LID showed a significant increase of RhoA and ROCK expression. The development of LID was reduced by the ROCK inhibitor fasudil (10 and 40 mg·kg-1 ), without interfering with the therapeutic effect of l-DOPA. Interestingly, treatment of 40 mg·kg-1 of fasudil also induced a significant reduction of dyskinesia in rats with previously established LID.Conclusion and Implications: The present results suggest that ROCK is involved in the pathophysiology of LID and that ROCK inhibitors such as fasudil may be a novel target for preventing or treating LID. Furthermore, previous studies have revealed neuroprotective effects of ROCK inhibitors. [ABSTRACT FROM AUTHOR]

Background and Purpose: Charcot-Marie-Tooth (CMT) disease is the most common hereditary peripheral neuropathy. CMT type 1A (CMT1A) accounts for approximately 50% of CMT patients and is linked to PMP22 gene duplication. Histone deacetylase-6 (HDAC6) has pleiotropic effects, such as regulating lipid homeostasis and cellular stress. Although HDAC6 has been regarded as a promising drug target for neurodegenerative diseases, its inhibition has not yet been tested in CMT1A. Here we have tested the therapeutic potential of CKD-504, a clinical stage HDAC6 inhibitor, in a mouse model of CMT1A EXPERIMENTAL APPROACH: The potency and selectivity of CKD-504 was evaluated, using a HDAC enzyme panel assay and western blots. The therapeutic potential of CKD-504 was evaluated using behavioural testing and electrophysiological assessments in the C22 mouse model of CMT1A. PMP22 protein expression and aggregation were analysed in mesenchymal stem cell-derived Schwann cells from CMT1A patients and sciatic nerves from C22 mice.Key Results: The HDAC6 inhibitor, CKD-504, modulated molecular chaperon proteins such as HSP90 and HSP70, which are involved in the folding/refolding of proteins such as PMP22. CKD-504 treatment restored myelination in both mesenchymal stem cell-derived Schwann cells from CMT1A patients and sciatic nerves of C22 mice and improved the axonal integrity of the sciatic nerve, leading to behavioural, electrophysiological, and histological improvements in C22 mice.Conclusion and Implications: A novel HDAC6 inhibitor, CKD-504, has potent therapeutic efficacy for CMT1A. [ABSTRACT FROM AUTHOR]

Background and Objectives: Adults experiencing homelessness with opioid use disorder (OUD) utilize buprenorphine (BUP), a first-line medication for OUD, at very low rates. Innovative and tailored approaches are needed to reduce barriers to treatment and increase utilization of BUP in this population. This study describes a pilot Mobile Community-based Access Team (M-CAT) that used mobile technology and FaceTime in addition to existing community-based case management programs to provide BUP treatment for veterans with OUD experiencing homelessness who had difficulties engaging in the regular BUP clinic.Methods: We conducted a retrospective chart review of veterans enrolled in M-CAT or the usual BUP clinic between January 2015 and December 2017 (N = 36). We abstracted demographic, medical, substance use, prescription, health care utilization, and drug use data from medical records.Results: Twelve veterans were enrolled in M-CAT and 24 were enrolled in BUP clinic. Mean retention in treatment was 19.2 months (standard deviation [SD] = 10.2) in M-CAT and 36 months (SD = 27.6) in BUP clinic. At the endpoint, 66.7% (n = 8) in M-CAT and 100% (n = 24) in BUP clinic remained on BUP.Discussion and Conclusion: M-CAT is an innovative and tailored pilot project that successfully integrated specific OUD medication treatment into existing case management programs for veterans experiencing homelessness using mobile technology and Facetime. M-CAT can potentially increase utilization of BUP for OUD among high-risk population of veterans experiencing homelessness who are otherwise not engaged in treatment.Scientific Significance: Integrating telemedicine, BUP treatment, and community-based case management to treat OUD among veterans experiencing homelessness is feasible with high treatment retention. (Am J Addict 2020;29:485-491). [ABSTRACT FROM AUTHOR]

Aim: To test the prediction of communication disorder severity at 5 years of age from characteristics at 2 years for children with cerebral palsy (CP) whose communication is giving cause for concern.Method: In this cohort study, 77 children (52 males; 25 females) with communication difficulties and CP were visited at home at 2 (mean 2y 4mo; SD 3mo) and 5 (mean 5y 5mo; SD 4mo) years of age. Information on the type and distribution of motor disorder, seizures, gross and fine motor function, hearing, and vision were collected from medical notes. Non-verbal cognition, language comprehension, language expression, spoken vocabulary, and methods of communication were assessed directly at age 2 years. At 5 years, communication and speech function were rated using the Communication Function Classification System (CFCS), Functional Communication Classification System (FCCS), and Viking Speech Scale (VSS).Results: In multivariable regression models, CP type, Gross Motor Function Classification System level, vision, the amount of speech understood by strangers, non-verbal cognition, and number of consonants produced at age 2 years predicted the CFCS level at age 5 years (R2 =0.54). CP type, Manual Ability Classification System level, amount of speech understood, vision, and number of consonants predicted the FCCS level (R2 =0.49). CP type, amount of speech understood by strangers, and number of consonants predicted the VSS level (R2 =0.50).Interpretation: Characteristics at 2 years of age predict communication and speech performance at 5 years, and should inform referral to speech and language therapy. [ABSTRACT FROM AUTHOR]

Objective: Troublesome hot flushes and night sweats (HFNS) are experienced by many women after treatment for breast cancer, impacting significantly on sleep and quality of life. Cognitive behavioural therapy (CBT) is known to be effective for the alleviation of HFNS. However, it is not known if it can effectively be delivered by specialist nurses. We investigated whether group CBT, delivered by breast care nurses (BCNs), can reduce the impact of HFNS.Methods: We recruited women with primary breast cancer following primary treatment with seven or more HFNS/week (including 4/10 or above on the HFNS problem rating scale), from six UK hospitals to an open, randomised, phase 3 effectiveness trial. Participants were randomised to Group CBT or usual care (UC). The primary endpoint was HFNS problem rating at 26 weeks after randomisation. Secondary outcomes included sleep, depression, anxiety and quality of life.Results: Between 2017 and 2018, 130 participants were recruited (CBT:63, control:67). We found a 46% (6.9-3.7) reduction in the mean HFNS problem rating score from randomisation to 26 weeks in the CBT arm and a 15% (6.5-5.5) reduction in the UC arm (adjusted mean difference -1.96, CI -3.68 to -0.23, P = .039). Secondary outcomes, including frequency of HFNS, sleep, anxiety and depression all improved significantly.Conclusion: Our results suggest that specialist nurses can be trained to deliver CBT effectively to alleviate troublesome menopausal hot flushes in women following breast cancer in the NHS setting. [ABSTRACT FROM AUTHOR]

Emergency laparotomy is associated with high mortality. Implementation of an evidence-based care bundle has been shown to improve patient outcomes. A quality improvement project to implement a six-component care bundle was undertaken between July 2015 and May 2018. As part of this project, we worked with 27 hospitals in the Emergency Laparotomy Collaborative. Previous pilot implementation of the same bundle in our hospital between December 2012 and July 2013 had shown marked improvement, maintained until April 2014, but then deterioration. Understanding the reasons for this deterioration informed our work to re-implement the bundle and sustain improvement. A cohort of 930 consecutive patients requiring emergency laparotomy between October 2014 and April 2019 were included. Baseline data were collected between October 2014 and June 2015, and the bundle was re-implemented in July 2015. Thirty-day mortality decreased from 11% in the baseline group to 7.3% after bundle implementation. Hospital length of stay decreased from 19.5 to 17.9 days. Full bundle compliance improved from < 60% to > 80% for all patients, with improvement in application of all individual bundle components. This study provides further evidence that outcomes for high-risk surgical patients can be improved with an evidence-based care bundle, but attention must be paid to maintaining bundle compliance. Issues around sustaining improvement must be considered from project initiation. [ABSTRACT FROM AUTHOR]

With heighted interest in causal inference based on real-world evidence, this empirical study sought to understand differences between the results of observational analyses and long-term randomized clinical trials. We hypothesized that patients deemed "eligible" for clinical trials would follow a different survival trajectory from those deemed "ineligible" and that this factor could partially explain results. In a large observational registry dataset, we estimated separate survival trajectories for hypothetically trial-eligible vs ineligible patients under both coronary artery bypass surgery (CABG) and percutaneous coronary intervention (PCI). We also explored whether results would depend on the causal inference method (inverse probability of treatment weighting vs optimal full propensity matching) or the approach to combine propensity scores from multiple imputations (the "across" vs "within" approaches). We found that, in this registry population of PCI/CABG multivessel patients, 32.5% would have been eligible for contemporaneous RCTs, suggesting that RCTs enroll selected populations. Additionally, we found treatment selection bias with different distributions of propensity scores between PCI and CABG patients. The different methodological approaches did not result in different conclusions. Overall, trial-eligible patients appeared to demonstrate at least marginally better survival than ineligible patients. Treatment comparisons by eligibility depended on disease severity. Among trial-eligible three-vessel diseased and trial-ineligible two-vessel diseased patients, CABG appeared to have at least a slight advantage with no treatment difference otherwise. In conclusion, our analyses suggest that RCTs enroll highly selected populations, and our findings are generally consistent with RCTs but less pronounced than major registry findings. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether laparoscopic sacrohysteropexy (LSH) is non-inferior to vaginal sacrospinous hysteropexy (SSHP) in the surgical treatment of uterine prolapse.Design: Multicentre randomised controlled, non-blinded non-inferiority trial.Setting: Five non-university teaching hospitals in the Netherlands, one university hospital in Belgium.Population: 126 women with uterine prolapse stage 2 or higher undergoing surgery without previous pelvic floor surgery.Methods: Randomisation in a 1:1 ratio to LSH or SSHP, stratified per centre and severity of the uterine prolapse. The predefined inferiority margin was an increase in surgical failure rate of 10%.Main Outcome Measures: Primary outcome was surgical failure, defined as recurrence of uterine prolapse (POP-Q ≥ 2) with bothersome bulging/protrusion symptoms and/or repeat surgery or pessary at 12 months postoperatively. Secondary outcomes were anatomical recurrence (any compartment), functional outcome and quality of life.Results: Laparoscopic sacrohysteropexy was non-inferior for surgical failure (n = 1, 1.6%) compared with SSHP (n = 2, 3.3%, difference -1.7%, 95% CI: -7.1 to 3.7) 12 months postoperatively. Overall, anatomical recurrences and quality of life did not differ. More bothersome symptoms of overactive bladder (OAB) and faecal incontinence were reported after LSH. Dyspareunia was more frequently reported after SSHP.Conclusion: Laparoscopic sacrohysteropexy was non-inferior to SSHP for surgical failure of the apical compartment at 12 months' follow up. Following LSH, bothersome OAB and faecal incontinence were more frequent, but dyspareunia was less frequent.Tweetable Abstract: Laparoscopic sacrohysteropexy and vaginal sacrospinous hysteropexy have equally good short-term outcomes. [ABSTRACT FROM AUTHOR]

Aim: To determine whether energy consumption changes after selective dorsal rhizotomy (SDR) among children with cerebral palsy (CP).Method: We retrospectively evaluated net nondimensional energy consumption during walking among 101 children with bilateral spastic CP who underwent SDR (59 males, 42 females; median age [5th centile, 95th centile] 5y 8mo [4y 2mo, 9y 4mo]) compared to a control group of children with CP who did not undergo SDR. The control group was matched by baseline age, spasticity, and energy consumption (56 males, 45 females; median age [5th centile, 95th centile] 5y 8mo [4y 1mo, 9y 6mo]). Outcomes were compared at baseline and follow-up (SDR: mean [SD] 1y 7mo [6mo], control: 1y 8mo [8mo]).Results: The SDR group had significantly greater decreases in spasticity compared to matched controls (-42% SDR vs -20% control, p<0.001). While both groups had a modest reduction in energy consumption between visits (-12% SDR, -7% control), there was no difference in change in energy consumption (p=0.11) or walking speed (p=0.56) between groups.Interpretation: The SDR group did not exhibit greater reductions in energy consumption compared to controls. The SDR group had significantly greater spasticity reduction, suggesting that spasticity had minimal impact on energy consumption during walking in CP. These results support prior findings that spasticity and energy consumption decrease with age in CP. Identifying matched control groups is critical for outcomes research involving children with CP to account for developmental changes. [ABSTRACT FROM AUTHOR]

Background: Patients undergoing emergency abdominal surgery are at high risk of post-operative complications. Although post-operative treatment at an intermediate care unit may improve early outcome, there is a lack of studies on the long-term effects of such therapy. The aim of this study was to assess the long-term effect of intermediate care versus standard surgical ward care on mortality in the Intermediate Care After Emergency Abdominal Surgery (InCare) trial.Methods: We included adult patients undergoing emergency major laparoscopy or laparotomy with an Acute Physiology and Chronic Health Evaluation (APACHE) II score of 10 or more, who participated in the InCare trial from October 2010 to November 2012. In the InCare trial, patients were randomized to either post-operative intermediate care or standard surgical ward care. The primary outcome was time to death within 6 years after surgery. We assessed mortality with Coxregression analysis.Results: A total of 286 patients were included. The all-cause 6-year landmark mortality was 52.8% (76 of 144 patients) in the intermediate care group and 47.9% (68 of 142 patients) in the ward care group. There was no statistically significant difference in mortality risk between the two groups (hazard ratio 1.06 (95% confidence interval 0.76-1.47), P = .73).Conclusion: We found no statistically significant difference in 6-year mortality between patients randomized to post-operative intermediate care or ward care after emergency abdominal surgery. However, we detected an absolute mortality risk reduction of 5% in favour of ward care, possibly due to random error. [ABSTRACT FROM AUTHOR]

Background: To evaluate the efficacy of synbiotic tablets on the clinical and biochemical parameters of smokers and non-smokers with gingivitis.Methods: Eighty patients with gingivitis [40 smokers (+), 40 non-smokers (-)] were randomly assigned to test (T) or control (C) groups. Four groups were defined: T(+), T(-), C(+) and C(-). The subjects daily chewed a synbiotic or placebo tablet for 30 days. The gingival crevicular fluid levels of interleukin (IL)-6, IL-8 and IL-10 were determined as the primary outcome variables.Results: The clinical and biochemical parameters for all groups significantly reduced compared with the baseline (P < 0.05). While there were no significant differences between the groups for gingival index, the plaque index was significantly higher in both smoker groups than that in the T(-) group during the second month (P < 0.05). IL-8 levels in C(-) and IL-6 levels in both control groups were significantly higher than those in the T(+) group. The IL-10 levels in both control groups were significantly higher than those in the T(-) group during the second month (P < 0.05).Conclusions: Adjunctive synbiotic tablets significantly reduce subclinical therapeutic outcomes for both smokers and non-smokers compared with placebo according to the biochemical parameters. [ABSTRACT FROM AUTHOR]

Aim: To establish the prevalence of dystonic pain in children and their response to deep brain stimulation (DBS).Method: Dystonic pain was assessed in a cohort of 140 children, 71 males and 69 females, median age 11 years 11 months (range 3y-19y 1mo), undergoing DBS in our centre over a period of 10 years. The cohort was divided into aetiological dystonia groups: 1a, inherited; 1b, heredodegenerative; 2, acquired; and 3, idiopathic. Motor responses were measured with the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS).Results: Dystonic pain was identified in 63 (45%) patients, 38% of whom had a diagnosis of cerebral palsy (CP). Dystonic pain improved in 90% of children and in all aetiological subgroups 1 year after DBS, while the BFMDRS motor score improved in 70%. Statistically significant improvement (p<0.01) was noted for the whole cohort on the Numerical Pain Rating Scale (n=27), Paediatric Pain Profile (n=17), and Caregivers Priorities and Child Health Index of Life with Disabilities questionnaire (n=48). There was reduction of pain severity, frequency, and analgesia requirement. Findings were similar for the whole cohort and aetiological subgroups other than the inherited heredodegenerative group where the improvement did not reach statistical significance.Interpretation: Dystonic pain is frequent in children with dystonia, including those with CP, who undergo DBS; this can be an important, realizable goal of surgery irrespective of aetiology. We encourage the use of multimodal approach in pain research to reduce the risk of bias. [ABSTRACT FROM AUTHOR]

Background: Approximately 50% of children with cancer in the United States who are aged <15 years receive primary treatment on a therapeutic clinical trial. To the authors' knowledge, it remains unknown whether trial enrollment has a clinical benefit compared with the best alternative standard therapy and/or off trial (ie, clinical trial effect). The authors conducted a retrospective matched cohort study to compare the morbidity and mortality of pediatric patients with cancer who are treated on a phase 3 clinical trial compared with those receiving standard therapy and/or off trial.Methods: Subjects were aged birth to 19 years; were diagnosed between 2000 and 2010 with acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), rhabdomyosarcoma, or neuroblastoma; and had received initial treatment at the Children's Hospital of Philadelphia. On-trial and off-trial subjects were matched based on age, race, ethnicity, a diagnosis of Down syndrome (for patients with ALL or AML), prognostic risk level, date of diagnosis, and tumor type.Results: A total of 428 participants were matched in 214 pairs (152 pairs for ALL, 24 pairs for AML, 32 pairs for rhabdomyosarcoma, and 6 pairs for neuroblastoma). The 5-year survival rate did not differ between those treated on trial versus those treated with standard therapy and/or off trial (86.9% vs 82.2%; P = .093). On-trial patients had a 32% lower odds of having worse (higher) mortality-morbidity composite scores, although this did not reach statistical significance (odds ratio, 0.68; 95% confidence interval, 0.45-1.03 [P = .070]).Conclusions: There was no statistically significant difference in outcomes noted between those patients treated on trial and those treated with standard therapy and/or off trial. However, in partial support of the clinical trial effect, the results of the current study indicate a trend toward more favorable outcomes in children treated on trial compared with those treated with standard therapy and/or off trial. These findings can support decision making regarding enrollment in pediatric phase 3 clinical trials. [ABSTRACT FROM AUTHOR]

Objective: The effect of surgical treatment for supratentorial spontaneous intracerebral hemorrhage (ICH) and whether it is modified by key baseline characteristics and timing remains uncertain.Methods: We performed a systematic review and meta-analysis of randomized controlled trials of surgical treatment of supratentorial spontaneous ICH aimed at clot removal. We searched MEDLINE, Embase, and Cochrane databases up to February 21, 2019. Primary outcome was good functional outcome at follow-up; secondary outcomes were death and serious adverse events. We analyzed all types of surgery combined and minimally invasive approaches separately. We pooled risk ratios with 95% confidence intervals and assessed the modifying effect of age, Glasgow Coma Scale, hematoma volume, and timing of surgery with meta-regression analysis.Results: We included 21 studies with 4,145 patients; 4 (19%) were of the highest quality. Risk ratio of good functional outcome after any type of surgery was 1.40 (95% confidence interval [CI] = 1.22-1.60, I2  = 46%, 20 studies), and after minimally invasive surgery it was 1.47 (95% CI = 1.26-1.72, I2  = 47%, 12 studies). For death, the risk ratio for any type of surgery was 0.77 (95% CI = 0.68-0.85, I2  = 23%, 21 studies), and for minimally invasive surgery it was 0.68 (95% CI = 0.56-0.83, I2  = 14%, 13 studies). Serious adverse events were reported infrequently. Surgery seemed more effective when performed sooner after symptom onset (p = 0.04, 12 studies). Age, Glasgow Coma Scale, and hematoma volume did not modify the effect of surgery.Interpretation: Surgical treatment of supratentorial spontaneous ICH may be beneficial, in particular with minimally invasive procedures and when performed soon after symptom onset. Further well-designed randomized trials are needed to demonstrate whether (minimally invasive) surgery improves functional outcome after ICH and to determine the optimal time window of the treatment after symptom onset. ANN NEUROL 2020;88:239-250. [ABSTRACT FROM AUTHOR]

Introduction and Aims: The Australian Treatment Outcomes Profile (ATOP) is a brief clinical tool measuring recent substance use, health and wellbeing among clients attending alcohol and other drug (AOD) treatment services. It has previously been assessed for concurrent validity and inter-rater reliability. In this study we examine whether it is suitable for administration over the telephone.Design and Methods: We recruited a sample of 107 AOD clients across public sector specialist AOD treatment services in New South Wales, Australia between 2016 and 2018. Participants had a mean age of 47 years and 46% were female. Participants completed a face-to-face ATOP and a phone ATOP with a researcher within 5 days. Comparisons between the two administration modes were undertaken using Spearman's rank correlation coefficient for continuous or ordinal variables, and Cohen's Kappa for nominal variables.Results: Among 107 participants, 59% were attending for alcohol treatment and 41% for opioid treatment. Most ATOP items (76%) reached above 0.7 (good) or 0.9 (excellent) agreement between face-to-face and telephone use.Discussion and Conclusions: Our findings suggest that the ATOP is a suitable instrument for telephone monitoring of recent substance use, health and social functioning among AOD clients. Its validation for remote use over the telephone will support staff to monitor clients' risks and outcomes-of particular relevance in response to the COVID-19 pandemic in which services are increasingly relying on telework approaches to client monitoring. [ABSTRACT FROM AUTHOR]

Background: At present, the severity of patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a focal point.Methods: To assess the factors associated with severity and prognosis of patients infected with SARS-CoV-2, we retrospectively investigated the clinical, imaging and laboratory characteristics of confirmed 280 cases of novel coronavirus disease (COVID-19) from 20 January to 20 February 2020.Results: The median age of patients in the mild group was 37.55 years, whilst that in the severe group was 63.04 years. The proportion of patients aged over 65 years in the severe group was significantly higher than that of the mild group (59.04% vs. 10.15%, P < 0.05). 85.54% of severe patients had diabetes or cardiovascular diseases, which was significantly higher than that of the mild group (51.81% vs. 7.11%, P = 0.025; 33.73% vs. 3.05%, P = 0.042). Patients in the mild group experienced earlier initiation of antiviral treatment (1.19 ± 0.45 vs. 2.65 ± 1.06 days in the severe group, P < 0.001). Our study showed that comorbidity, time from illness onset to antiviral treatment and age >=65 were three major risk factors for COVID-19 progression, whilst comorbidity and time from illness onset to antiviral treatment were two major risk factors for COVID-19 recovery.Conclusions: The elderly and patients with underlying diseases are more likely to experience a severe progression of COVID-19. It is recommended that timely antiviral treatment should be initiated to slow the disease progression and improve the prognosis. [ABSTRACT FROM AUTHOR]

Background: The optimal dose and timing of enteral nutrition (EN) in septic shock are unclear.Methods: We conducted a phase 3 single-center randomized controlled pilot trial comparing early trophic EN with "no EN" in mechanically ventilated adults with septic shock, with the hypothesis that implementing a protocol comparing early trophic EN with "no EN" in patients with septic shock would be feasible. Patients were randomized to early trophic EN or "no EN" until off vasopressor for 3 hours. The primary outcome was feasibility in achieving >75% consent and compliance rate and <10% contamination rate.Results: One hundred thirty-one patients were eligible for enrollment, and 49 were available for consent. Thirty-one (86%) consented and were randomized and 100% of patients in the early EN arm and 94% in the "no EN" arm completed their protocols. While on vasopressors, early EN group received median 384 kcal, and the "no EN" group received median 0 kcal. Contamination rate was 0 in the early trophic EN arm and 6% in the "no EN" arm. The early EN group had median 25 intensive care unit-free days, as compared with 12 in the "no EN" arm (P = .014). The early EN arm had median 27 ventilator-free days, compared with 14 in "no EN" arm (P = .009).Conclusion: Our protocol comparing early trophic EN with "no EN" in septic shock was feasible. Early trophic EN may be beneficial, but a larger multicenter trial is warranted to confirm the observed clinical benefits seen in this trial. [ABSTRACT FROM AUTHOR]

Objective: To assess real-world effectiveness of initial treatment with newer compared to injectable disease-modifying therapies (DMTs) on disease activity in pediatric multiple sclerosis (MS) and clinically isolated syndrome (CIS).Methods: This is a cohort study of children with MS/CIS followed at 12 clinics in the US Network of Pediatric MS Centers, who received initial therapy with newer (fingolimod, dimethyl fumarate, teriflunomide, natalizumab, rituximab, ocrelizumab) or injectable (interferon-β, glatiramer acetate) DMTs. Propensity scores (PSs) were computed, including preidentified confounders. Relapse rate while on initial DMT was modeled with negative binomial regression, adjusted for PS-quintile. Time to new/enlarging T2-hyperintense and gadolinium-enhancing lesions on brain magnetic resonance imaging were modeled with midpoint survival analyses, adjusted for PS-quintile.Results: A total of 741 children began therapy before 18 years, 197 with newer and 544 with injectable DMTs. Those started on newer DMTs were older (15.2 vs injectable 14.4 years, p = 0.001) and less likely to have a monofocal presentation. In PS-quintile-adjusted analysis, those on newer DMTs had a lower relapse rate than those on injectables (rate ratio = 0.45, 95% confidence interval (CI) = 0.29-0.70, p < 0.001; rate difference = 0.27, 95% CI = 0.14-0.40, p = 0.004). One would need to treat with newer rather than injectable DMTs for 3.7 person-years to prevent 1 relapse. Those started on newer DMTs had a lower rate of new/enlarging T2 (hazard ratio [HR] = 0.51, 95% CI = 0.36-0.72, p < 0.001) and gadolinium-enhancing lesions (HR = 0.38, 95% CI = 0.23-0.63, p < 0.001) than those on injectables.Interpretation: Initial treatment of pediatric MS/CIS with newer DMTs led to better disease activity control compared to injectables, supporting greater effectiveness of newer therapies. Long-term safety data for newer DMTs are required. ANN NEUROL 2020 ANN NEUROL 2020;88:42-55. [ABSTRACT FROM AUTHOR]

Objective: To compare standard (native tissue) repair with synthetic mesh inlays or mesh kits.Design: Randomised controlled trial.Setting: Thirty-three UK hospitals.Population: Women having surgery for recurrent prolapse.Methods: Women recruited using remote randomisation.Main Outcome Measures: Prolapse symptoms, condition-specific quality-of-life and serious adverse effects.Results: A Mean Pelvic Organ Prolapse Symptom Score at 1 year was similar for each comparison (standard 6.6 versus mesh inlay 6.1, mean difference [MD] -0.41, 95% CI -2.92 to 2.11: standard 6.6 versus mesh kit 5.9, MD -1.21 , 95% CI -4.13 to 1.72) but the confidence intervals did not exclude a minimally important clinical difference. There was no evidence of difference in any other outcome measure at 1 or 2 years. Serious adverse events, excluding mesh exposure, were similar at 1 year (standard 7/55 [13%] versus mesh inlay 5/52 [10%], risk ratio [RR] 1.05 [0.66-1.68]: standard 3/25 [12%] versus mesh kit 3/46 [7%], RR 0.49 [0.11-2.16]). Cumulative mesh exposure rates over 2 years were 7/52 (13%) in the mesh inlay arm, of whom four women required surgical revision; and 4/46 in the mesh kit arm (9%), of whom two required surgical revision.Conclusions: We did not find evidence of a difference in terms of prolapse symptoms from the use of mesh inlays or mesh kits in women undergoing repeat prolapse surgery. Although the sample size was too small to be conclusive, the results provide a substantive contribution to future meta-analysis.Tweetable Abstract: There is not enough evidence to support use of synthetic mesh inlay or mesh kits for repeat prolapse surgery. [ABSTRACT FROM AUTHOR]

Background: Percutaneous coronary intervention (PCI) is effective in treating patients with acute coronary syndrome (ACS) but is associated with some serious complications. Nicorandil is an anti-anginal agent acting to improve microvascular circulation and to increase coronary blood flow. The objective of this article is to evaluate the effects of intracoronary injection followed with continuous intravenous injection of nicorandil on ECG parameters in patients with unstable angina pectoris (UA) undergoing PCI.Methods: A single-center, self-controlled clinical trial was conducted at the Second Hospital of Tianjin Medical University between January 2019 and April 2019. Sixty-three consecutive patients with UA who received coronary angiography and selective PCI were enrolled. ECG was recorded and analyzed before and 24 hr after nicorandil infusion.Results: Patients were divided into three groups: control group (n = 23, aged 63.43 ± 12.55 years), short-term, and prolonged use with nicorandil group (n = 20 and 20, aged 66.45 ± 8.06 years and 65.80 ± 9.49 years, respectively). Clinical characteristics and ECG parameters were similar before PCI among three groups (p > .05). In nicorandil treatment groups, intervals of QTd and Tp-e in patients post-PCI were significantly shorter than that in control and pre-PCI (p < .05).Conclusions: Nicorandil infusion reduces QTd and Tp-e interval in patients with UA. Further studies will be needed to determine whether these electrophysiological changes are associated with a reduction of ventricular arrhythmias and improved outcomes. [ABSTRACT FROM AUTHOR]

Background and Purpose: Tetramethylpyrazine (TMP) was originally isolated from the traditional Chinese herb ligusticum and the fermented Japanese food natto and has since been synthesized. TMP has a long history of beneficial effects in the treatment of many cardiovascular diseases. Here we have evaluated the therapeutic effects of TMP on pulmonary hypertension (PH) in animal models and in patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH).Experimental Approach: Three well-defined models of PH -chronic hypoxia (10% O2 )-induced PH (HPH), monocrotaline-induced PH (MCT-PH) and Sugen 5416/hypoxia-induced PH (SuHx-PH) - were used in Sprague-Dawley rats, and assessed by echocardiography, along with haemodynamic and histological techniques. Primary cultures of rat distal pulmonary arterial smooth muscle cells (PASMCs) were used to study intracellular calcium levels. Western blots and RT-qPCR assays were also used. In the clinical cohort, patients with PAH or CTEPH were recruited. The effects of TMP were evaluated in all systems.Key Results: TMP (100 mg·kg-1 ·day-1 ) prevented rats from developing experimental PH and ameliorated three models of established PH: HPH, MCT-PH and SuHx-PH. The therapeutic effects of TMP were accompanied by inhibition of intracellular calcium homeostasis in PASMCs. In a small cohort of patients with PAH or CTEPH, oral administration of TMP (100 mg, t.i.d. for 16 weeks) increased the 6-min walk distance and improved the 1-min heart rate recovery.Conclusion and Implications: Our results suggest that TMP is a novel and inexpensive medication for treatment of PH. Clinical trial is registered with www.chictr.org.cn (ChiCTR-IPR-14005379). [ABSTRACT FROM AUTHOR]

Background: Imaging of glioblastoma patients after maximal safe resection and chemoradiation commonly demonstrates new enhancements that raise concerns about tumor progression. However, in 30% to 50% of patients, these enhancements primarily represent the effects of treatment, or pseudo-progression (PsP). We hypothesize that quantitative machine learning analysis of clinically acquired multiparametric magnetic resonance imaging (mpMRI) can identify subvisual imaging characteristics to provide robust, noninvasive imaging signatures that can distinguish true progression (TP) from PsP.Methods: We evaluated independent discovery (n = 40) and replication (n = 23) cohorts of glioblastoma patients who underwent second resection due to progressive radiographic changes suspicious for recurrence. Deep learning and conventional feature extraction methods were used to extract quantitative characteristics from the mpMRI scans. Multivariate analysis of these features revealed radiophenotypic signatures distinguishing among TP, PsP, and mixed response that compared with similar categories blindly defined by board-certified neuropathologists. Additionally, interinstitutional validation was performed on 20 new patients.Results: Patients who demonstrate TP on neuropathology are significantly different (P < .0001) from those with PsP, showing imaging features reflecting higher angiogenesis, higher cellularity, and lower water concentration. The accuracy of the proposed signature in leave-one-out cross-validation was 87% for predicting PsP (area under the curve [AUC], 0.92) and 84% for predicting TP (AUC, 0.83), whereas in the discovery/replication cohort, the accuracy was 87% for predicting PsP (AUC, 0.84) and 78% for TP (AUC, 0.80). The accuracy in the interinstitutional cohort was 75% (AUC, 0.80).Conclusion: Quantitative mpMRI analysis via machine learning reveals distinctive noninvasive signatures of TP versus PsP after treatment of glioblastoma. Integration of the proposed method into clinical studies can be performed using the freely available Cancer Imaging Phenomics Toolkit. [ABSTRACT FROM AUTHOR]

Objectives: To test whether providing psychological self-help materials would significantly lower the incidence of post-traumatic stress disorder (PTSD) at 6-12 weeks postnatally.Design: Open-label randomised controlled trial, with blinded outcome assessment.Setting: Community midwifery services in two National Health Service (NHS) trusts in the North West.Sample: A cohort of 2419 women receiving normal NHS postnatal care.Methods: Midwives screened women for traumatic birth experience; 678 women who screened positively (28.1%) were randomly allocated to self-help with usual care (n = 336) or to usual care alone (n = 342). The self-help materials were a leaflet and online film designed to prevent the development of PTSD after trauma exposure through explaining how to manage early psychological responses.Main Outcome Measure: The primary outcome was a composite of diagnostic and subdiagnostic PTSD at 6-12 weeks postnatally using the gold-standard Clinician-Administered PTSD Scale (CAPS-5) interview.Results: Of the 678 women correctly randomised plus the nine women randomised in error, 478 (70.5%) were followed up. Diagnostic or subdiagnostic PTSD rates at follow-up did not differ between groups who received self-help (26.7%, 65/243) or usual care alone (26.2%, 64/244) (intention-to-treat analysis: RR 1.02, 95% CI 0.68-1.53). Findings remained consistent in the per-protocol analysis (RR 1.04, 95% CI 0.85-1.27). Women viewed the materials very positively. There were no adverse effects. Health economic micro-costing indicated implementation would be very low cost.Conclusions: Many women experience a traumatic birth and risk developing PTSD, but self-help strategies without professional support are insufficient and should not be routinely introduced.Tweetable Abstract: Self-help information alone does not reduce the number of women developing PTSD after a traumatic childbirth. [ABSTRACT FROM AUTHOR]

Background and Purpose: There is a major unmet need to develop new therapies for migraine. We have previously demonstrated the therapeutic potential of the acid-sensing ion channel (ASIC) blockade in migraine, via an ASIC1 mechanism. ASIC3 is expressed in the trigeminal ganglion and its response is potentiated by NO that can trigger migraine attacks in patients. Thus we sought to explore the potential therapeutic effect of ASIC3 blockade in migraine.Experimental Approach: To investigate this, we utilised validated electrophysiological and behavioural rodent preclinical models. In rats, ASIC3 blockade using APETx2 (50 or 100 μg·kg-1 , i.v.) was measured by using durovascular and NO-evoked trigeminal nociceptive responses along with cortical spreading depression models. In mice, we sought to determine if periorbital mechanical sensitivity, induced by acute nitroglycerin (10 mg·kg-1 , i.p.), was attenuated by APETx2 (230 μg·kg-1 , i.p.), as well as latent sensitisation induced by bright light stress in a chronic nitroglycerin model.Key Results: Here, we show that the ASIC3 blocker APETx2 inhibits durovascular-evoked and NO-induced sensitisation of trigeminal nociceptive responses in rats. In agreement, acute and chronic periorbital mechanosensitivity induced in mice by nitroglycerin and subsequent bright light stress-evoked latent sensitivity as a model of chronic migraine are all reversed by APETx2.Conclusion and Implications: These results support the development of specific ASIC3 or combined ASIC1/3 blockers for migraine-related pain and point to a potential role for ASIC-dependent NO-mediated attack triggering. This has key implications for migraine, given the major unmet need for novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Background and Purpose: Pemphigus and pemphigoid diseases are characterized and caused predominantly by IgG autoantibodies targeting structural proteins of the skin. Their current treatment relies on general and prolonged immunosuppression that causes severe adverse events, including death. Hence, novel safe and more effective treatments are urgently needed. Due to its' physiological functions, the neonatal Fc receptor (FcRn) has emerged as a potential therapeutic target for pemphigus and pemphigoid, primarily because IgG is protected from proteolysis after uptake into endothelial cells. Thus, blockade of FcRn would reduce circulating autoantibody concentrations. However, long-term effects of pharmacological FcRn inhibition in therapeutic settings of autoimmune diseases are unknown.Experimental Approach: Therapeutic effects of FcRn blockade were investigated in a murine model of the prototypical autoantibody-mediated pemphigoid disease, epidermolysis bullosa acquisita (EBA). B6.SJL-H2s C3c/1CyJ mice with clinically active disease were randomized to receive either an anti-FcRn monoclonal antibody (4470) or an isotype control over 4 weeks.Key Results: While clinical disease continued to worsen in isotype control-treated mice, overall disease severity continuously decreased in mice injected with 4470, leading to almost complete remission in over 25% of treated mice. These clinical findings were paralleled by a reduction of autoantibody concentrations. Reduction of autoantibody concentrations, rather than modulating neutrophil activation, was responsible for the observed therapeutic effects.Conclusion and Implications: The clinical efficacy of anti-FcRn treatment in this prototypical autoantibody-mediated disease encourages further development of anti-FcRn antibodies for clinical use in pemphigoid diseases and potentially in other autoantibody mediated diseases. [ABSTRACT FROM AUTHOR]

Background: In Europe 700.000 new cases of sepsis occur annually and more than 100.000 of these patients die due to multiorgan failure (MOF). We have identified shock-induced endotheliopathy (SHINE) to be associated with development of MOF and mortality. Furthermore, in patients with septic shock those with circulating levels of thrombomodulin (TM) above 10 ng/mL have twice the mortality (56% vs 28%) than those with levels below this level. Pilot studies indicate that infusion of iloprost (1 ng/kg/min) is associated with improved endothelial function in patients with septic shock.Material and Methods: This is a multicenter, randomized, blinded, investigator-initiated, adaptive phase 2B trial in up to 384 patients with septic shock-induced endotheliopathy defined by TM > 10 ng/mL who are allocated 1:1 to 72 hours continuous infusion of iloprost 1 ng/kg/min or placebo (equal volume of saline). The primary outcome is the mean daily modified Sequential Organ Failure Assessment (SOFA) score in the ICU up to day 90. Secondary outcomes include 28- and 90-day all-cause mortality, days alive without vasopressor in the ICU within 90 days, days alive without mechanical ventilation in the ICU within 90 days, days alive without renal replacement therapy in the ICU within 90 days, numbers of serious adverse reactions, and the number of serious adverse events within the first 7 days.Discussion: This trial tests the safety and efficacy of iloprost vs placebo for 72 hours in patients with septic shock and SHINE. The outcome measures focus on the potential effect of the intervention to mitigate organ failure.Trial Registration: COMBAT-SHINE trial-EudraCT no. 2019-001131-31-Clinicaltrials.gov: NCT04123444-Ethics Committee no. H-19018258. [ABSTRACT FROM AUTHOR]

Background and Purpose: Gout arthritis, which is provoked by monosodium urate (MSU) crystal accumulation in the joint and periarticular tissues, induces severe pain and affects quality of life of the patients. Eucalyptol (1,8-cineol), the principal component in the essential oils of eucalyptus leaves, is known to possess anti-inflammatory and analgesic properties. We aimed to examine the therapeutic effects of eucalyptol on gout arthritis and related mechanisms.Experimental Approach: A mouse model of gout arthritis was established via MSU injection into the ankle joint. Ankle oedema, mechanical allodynia, neutrophil infiltration, oxidative stress, NLRP3 inflammasome, and TRPV1 expression were examined.Key Results: Eucalyptol attenuated MSU-induced mechanical allodynia and ankle oedema in dose-dependently, with effectiveness similar to indomethacin. Eucalyptol reduced inflammatory cell infiltrations in ankle tissues. Eucalyptol inhibited NLRP3 inflammasome activation and pro-inflammatory cytokine production induced by MSU in ankle tissues in vivo. Eucalyptol reduced oxidative stress induced by MSU in RAW264.7 cells in vitro as well as in ankle tissues in vivo, indicated by an increase in activities of antioxidant enzymes and reduction of ROS. Eucalyptol attenuated MSU-induced up-regulation of TRPV1 expression in ankle tissues and dorsal root ganglion neurons innervating the ankle. The in vivo effects of eucalyptol on ankle oedema, mechanical allodynia, NLRP3 inflammasome, IL-1β, and TRPV1 expression were mimicked by treating MSU-injected mice with antioxidants.Conclusion and Implications: Eucalyptol alleviates MSU-induced pain and inflammation via mechanisms possibly involving anti-oxidative effect. Eucalyptol and other antioxidants may represent promising therapeutic options for gout arthritis. [ABSTRACT FROM AUTHOR]

In failure-time settings, a competing event is any event that makes it impossible for the event of interest to occur. For example, cardiovascular disease death is a competing event for prostate cancer death because an individual cannot die of prostate cancer once he has died of cardiovascular disease. Various statistical estimands have been defined as possible targets of inference in the classical competing risks literature. Many reviews have described these statistical estimands and their estimating procedures with recommendations about their use. However, this previous work has not used a formal framework for characterizing causal effects and their identifying conditions, which makes it difficult to interpret effect estimates and assess recommendations regarding analytic choices. Here we use a counterfactual framework to explicitly define each of these classical estimands. We clarify that, depending on whether competing events are defined as censoring events, contrasts of risks can define a total effect of the treatment on the event of interest or a direct effect of the treatment on the event of interest not mediated by the competing event. In contrast, regardless of whether competing events are defined as censoring events, counterfactual hazard contrasts cannot generally be interpreted as causal effects. We illustrate how identifying assumptions for all of these counterfactual estimands can be represented in causal diagrams, in which competing events are depicted as time-varying covariates. We present an application of these ideas to data from a randomized trial designed to estimate the effect of estrogen therapy on prostate cancer mortality. [ABSTRACT FROM AUTHOR]