What Huntington's Disease Patients Say About Their Illness: An Online Direct-to-Participant Pilot Study.

Background: Direct-to-participant online reporting facilitates the conduct of clinical research by increasing access and clinically meaningful patient engagement. Objective: We assessed feasibility of online data collection from adults with diagnosed Huntington's disease (HD) who directly reported their problems and impact in their own words. Methods: Data were collected online from consenting United States residents who self-identified as 1) having been diagnosed with Huntington's disease, 2) able to ambulate independently, and 3) self-sufficient for most daily needs. Data for this pilot study were collected using the Huntington Study Group myHDstory online research platform. The Huntington Disease Patient Report of Problems (HD-PROP), an open-ended questionnaire, was used to capture verbatim bothersome problems and functional impact. Natural language processing, human-in-the-loop curation of verbatim reports involving clinical and experience experts, and machine learning classified verbatim-reports into clinically meaningful symptoms. Results: All 8 questionnaires in the online pilot study were completed by 345 participants who were 60.9% men, 34.5±9.9 (mean±SD) years old, and 9.5±8.4 years since HD diagnosis. Racial self-identification was 46.4% Caucasian, 28.7% African American, 15.4% American Indian/Alaska Native, and 9.5% other. Accuracy of verbatim classification was 99%. Non-motor problems were the most frequently reported symptoms; depression and cognitive impairment were the most common. Conclusions: Online research participation was feasible for a diverse cohort of adults who self-reported an HD diagnosis and predominantly non-motor symptoms related to mood and cognition. Online research tools can help inform what bothers HD patients, identify clinically meaningful outcomes, and facilitate participation by diverse and under-represented populations.

Reduction in Ventricular Tachyarrhythmia Burden in Patients Enrolled in the RAID Trial.

BACKGROUND: The RAID (Ranolazine Implantable Cardioverter-Defibrillator) randomized placebo-controlled trial showed that ranolazine treatment was associated with reduction in recurrent ventricular tachycardia (VT) requiring appropriate implantable cardioverter-defibrillator (ICD) therapy. OBJECTIVES: This study aimed to identify groups of patients in whom ranolazine treatment would result in the highest reduction of ventricular tachyarrhythmia (VTA) burden. METHODS: Andersen-Gill analyses were performed to identify variables associated with risk for VTA burden among 1,012 patients enrolled in RAID. The primary endpoint was VTA burden defined as VTA episodes requiring appropriate treatment. RESULTS: Multivariate analysis identified 7 factors associated with increased VTA burden: history of VTA, age ≥65 years, New York Heart Association functional class ≥III, QRS complex (≥130 ms), low ejection fraction (<30%), atrial fibrillation (AF), and concomitant antiarrhythmic drug (AAD) therapy. The effect of ranolazine on VTA burden was seen among patients without concomitant AAD therapy (HR [HR]: 0.68; 95% CI: 0.55-0.84; P < 0.001), whereas no effect was seen among those who are concomitantly treated with other AADs (HR: 1.33; 95% CI: 0.90-1.96; P = 0.16); P = 0.003 for interaction. In patients with cardiac resynchronization therapy (CRT) ICDs, ranolazine treatment was associated with a 36% risk reduction for VTA recurrence (HR: 0.64; 95% CI: 0.47-0.86; P < 0.001), whereas among patients with ICDs without CRT no significant effect was noted (HR: 0.94; 95% CI: 0.74-1.18; P = 0.57); P = 0.047 for interaction. CONCLUSIONS: In patients with high risk for VTA, ranolazine is effective in reducing VTA burden, with significantly greater effect in CRT-treated patients, those without AF, and those not treated with concomitant AADs. In patients already on AADs or those with AF, the addition of ranolazine did not affect VTA burden. (Ranolazine Implantable Cardioverter-Defibrillator Trial [RAID]; NCT01215253).

Low albumin level is more strongly associated with adverse outcomes and Staphylococcus aureus infection than hemoglobin A1C or smoking tobacco.

Postsurgical deep musculoskeletal infections are a major clinical problem in Orthopaedic Surgery. A serum-based nomogram, which can objectively risk-stratify patients, and aid surgeons in delineating infection risk associated with orthopedic surgical interventions, would be immensely helpful. Here, we constructed a multi-parametric nomogram based on serum anti-Staphylococcus aureus antibody responses, patient characteristics including demographics and standard clinical tests. This nomogram was formally tested in a prospective cohort study comparing 303 hospitalized patients with culture-confirmed S. aureus infection compared with a cohort of 223 healthy screened preoperative patients. Serum anti-S. aureus antibody responses, standard of care clinical tests, and patient demographic data were utilized to perform multivariate logistic regression analysis to quantify the presence of infection and adverse outcome using odds ratios (OR) and to assess predictive ability via area under the ROC curve (AUC). At enrollment, high anti-S. aureus IgG titers were predictive of infection. Remarkably, low serum albumin was found to be significantly associated with infection (OR = 479.963, 95% CI 61.59 - 3740.33, p < 0.0001) and this finding was surprisingly higher than BMI or HbA1c-associations. Combining all risk factors in the nomogram yielded a diagnostic AUC of 0.949 for predicting S. aureus infection. Our results indicate that a serum-based multi-parametric nomogram can be useful in diagnosing S. aureus infections, and importantly, malnourishment is significantly associated with these infections.

StaphAIR: A Label-Free Antigen Microarray Approach to Detecting Anti-Staphylococcus aureus Antibody Responses in Orthopedic Infections.

Arrayed imaging reflectometry (AIR) is an optical biosensor platform for simple, multiplex measurement of antigen-specific antibody responses in patient blood samples. Here, we report the development of StaphAIR, an 8-plex Staphylococcus aureus antigen array on the AIR platform for profiling antigen-specific anti-S. aureus humoral immune responses. Initial validation experiments with mouse and humanized monoclonal antibodies against the S. aureus autolysin glucosaminidase (Gmd) domain, and subsequent testing with dilution series of pooled positive human serum confirmed analytically robust behavior of the array, with all antigens displaying Langmuir-type dose-response curves. Testing a cohort of 82 patients with S. aureus musculoskeletal infections (MSKI) and 30 healthy individuals enabled discrimination of individual patient responses to different S. aureus antigens, with statistical significance between osteomyelitis patients and controls obtained overall for four individual antigens (IsdA, IsdB, Gmd, and SCIN). Multivariate analyses of the antibody titers obtained from StaphAIR revealed its utility as a potential diagnostic tool for detecting S. aureus MSKI (area under the receiver operating characteristic curve (AUC) > 0.85). We conclude that StaphAIR has utility as a high-throughput immunoassay for studying and diagnosing osteomyelitis in patients.

Increased myocellular lipid and IGFBP-3 expression in a pre-clinical model of pancreatic cancer-related skeletal muscle wasting.

BACKGROUND: Skeletal muscle wasting (SMW) in cancer patients is associated with increased morbidity, mortality, treatment intolerance and discontinuation, and poor quality of life. This is particularly true for patients with pancreatic ductal adenocarcinoma (PDAC), as over 85% experience SMW, which is responsible for ~30% of patient deaths. While the established paradigm to explain SMW posits that muscle catabolism from systemic inflammation and nutritional deficiencies, the cause of death, and the cellular and molecular mechanisms responsible remain to be elucidated. To address this, we investigated the relationship between tumour burden and survival in the KCKO murine PDAC model. METHODS: Female C57BL/6J mice 6-8 weeks of age underwent orthotopic injection with KCKO-luc tumour cells. Solid tumour was verified on Day 5, post-tumour inoculation. In vivo, longitudinal lean mass and tumour burden were assessed via dual-energy X-ray absorptiometry and IVIS imaging, respectively, and total body weight was assessed, weekly. Animals were sacrificed at a designated end point of 'failure to thrive'. After sacrifice, lower limb hind muscles were harvested for histology and RNA extraction. RESULTS: We found a strong correlation between primary tumour size and survival (r2  = 0.83, P < 0.0001). A significant decrease in lower limb lean mass was first detected at Day 38 post-implantation vs. no tumour controls (NTCs) (P < 0.0001). SMW was confirmed by histology, which demonstrated a 38%, 32.7%, and 39.9% decrease in fibre size of extensor digitorum longus, soleus, and tibialis anterior muscles, respectively, in PDAC mice vs. NTC (P < 0.002). Histology also revealed a 67.6% increase in haematopoietic cells within the muscle of PDAC mice when compared with NTC. Bulk RNAseq on muscles from PDAC mice vs. NTC revealed significant increases in c/ebpß/Δ, il-1, il-6, and tnf gene expression. Pathway analyses to identify potential upstream factors revealed increased adipogenic gene expression, including a four-fold increase in igfbp-3. Histomorphometry of Oil Red-O staining for fat content in tibialis anterior muscles demonstrated a 95.5% increase in positively stained fibres from PDAC mice vs. NTC. CONCLUSIONS: Together, these findings support a novel model of PDAC-associated SMW and mortality in which systemic inflammation leads to inflammatory cell infiltration into skeletal muscle with up-regulated myocellular lipids.

Mexiletine in Myotonic Dystrophy Type 1: A Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: To assess mexiletine's long-term safety and effect on 6-minute walk distance in a well-defined cohort of patients with myotonic dystrophy type 1 (DM1). METHODS: We performed a randomized, double-blind, placebo-controlled trial of mexiletine (150 mg 3 times daily) to evaluate its efficacy and safety in a homogenous cohort of adult ambulatory patients with DM1. The primary outcome was change in 6-minute walk distance at 6 months. Secondary outcomes included changes in hand grip myotonia, strength, swallowing, forced vital capacity, lean muscle mass, Myotonic Dystrophy Health Index scores, and 24-hour Holter and ECG results at 3 and 6 months. RESULTS: Forty-two participants were randomized and 40 completed the 6-month follow-up (n = 20 in both groups). No significant effects of mexiletine were observed on 6-minute walk distance, but hand grip myotonia was improved with mexiletine treatment. There were no differences between the mexiletine and placebo groups with respect to the frequency or type of adverse events. Changes in PR, QRS, and QTc intervals were similar in mexiletine- and placebo-treated participants. CONCLUSIONS: There was no benefit of mexiletine on 6-minute walk distance at 6 months. Although mexiletine had a sustained positive effect on objectively measured hand grip myotonia, this was not seen in measures reflecting participants' perceptions of their myotonia. No effects of mexiletine on cardiac conduction measures were seen over the 6-month follow-up period. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for ambulatory patients with DM1, mexiletine does not significantly change 6-minute walk distance at 6 months.

Serum antibodies against Staphylococcus aureus can prognose treatment success in patients with bone infections.

Prognosing life-threatening orthopedic infections caused by Staphylococcus aureus remains a major clinical challenge. To address this, we developed a multiplex assay to assess the humoral immune proteome against S. aureus in patients with musculoskeletal infections. We found initial evidence that antibodies against some antigens (autolysins: Amd, Gmd; secreted immunotoxins: CHIPS, SCIN, Hla) were associated with protection, whereas antibodies against the iron-regulated surface determinant (Isd) proteins (IsdA, IsdB, IsdH) were aligned with adverse outcomes. To formally test this, we analyzed antibody levels and 1-year clinical outcomes of 194 patients with confirmed S. aureus bone infections (AO Trauma Clinical Priority Program [CPP] Bone Infection Registry). A staggering 20.6% of the enrolled patients experienced adverse clinical outcomes (arthrodesis, reinfection, amputation, and septic death) after 1-year. At enrollment, anti-S. aureus immunoglobulin G (IgG) levels in patients with adverse outcomes were 1.35-fold lower than those in patients whose infections were successfully controlled (p < 0.0001). Overall, there was a 51%-69% reduction in adverse outcome risk for every 10-fold increase in initial IgG concentration against Gmd, Amd, IsdH, CHIPS, SCIN, and Hla (p < 0.05). Notably, anti-IsdB antibodies remained elevated in patients with adverse outcomes; for every 10-fold change in the ratio of circulating anti-Isd to anti-Atl IgG at enrollment, there was a trending 2.6-fold increased risk (odds ratio = 2.555) of an adverse event (p = 0.105). Moreover, antibody increases over time correlated with adverse outcomes and decreases with positive outcomes. These studies demonstrate the potential of the humoral immune response against S. aureus as a prognostic indicator for assessing treatment success and identifying patients requiring additional interventions.

Clinical utilization of species-specific immunoassays for identification of Staphylococcus aureus and Streptococcus agalactiae in orthopedic infections.

Staphylococcus aureus and Streptococcus agalactiae (Group B streptococcus, GBS) are common causes of deep musculoskeletal infections (MSKI) and result in significant patient morbidity and cost to the healthcare system. One of the major challenges with MSKI is the lack of faithful diagnostics to correctly identify the primary pathogen, as standard culture-based assays are prone to false positives in the case of polymicrobial infections, and false negatives due to limitations in sample acquisition and antibiotic use before presentation. To improve upon our current diagnostic methods for MSKI, we developed a multiplex immunoassay for antigen-specific IgGs in serum (Luminex), and medium enriched for newly synthesized antibodies (MENSA) for anti-S. aureus and GBS generated from cultured peripheral blood mononuclear cells (PBMCs) of orthopedic infection patients undergoing surgical treatment. Samples were obtained from 110 MSKI patients: 80 diabetic foot ulcer, 21 periprosthetic joint infection, 5 septic arthritis, 2 spine, 1 hand, and 1 fracture-related infection (FRI). Anti-S. aureus and anti-GBS antibody titers were compared to culture results to assess their concordance in identifying the pathogens. Immunoassay, particularly MENSA, showed high diagnostic potential for monomicrobial S. aureus and GBS orthopedic infections (AUC > 0.95). MENSA also demonstrated diagnostic potential for GBS polymicrobial orthopedic infection and for GBS DFU (AUC > 0.83 for both). Serum showed high diagnostic potential for S. aureus PJI (AUC > 0.95). Taken together, these findings support the development of species-specific immunoassays for the identification of causal pathogens in active MSKI, especially in conjunction with standard culture.

Species-Specific Immunoassay Aids Identification of Pathogen and Tracks Infectivity in Foot Infection.

BACKGROUND: Conventional bacterial cultures frequently fail to identify the dominant pathogen in polymicrobial foot infections, in which Staphylococcus aureus is the most common infecting pathogen. Previous work has shown that species-specific immunoassays may be able to identify the main pathogen in musculoskeletal infections. We sought to investigate the clinical applicability of a S. aureus immunoassay to accurately identify the infecting pathogen and monitor its infectivity longitudinally in foot infection. We hypothesized that this species-specific immunoassay could aid in the diagnosis of S. aureus and track the therapeutic response in foot infections. METHODS: From July 2015 to July 2019, 83 infected foot ulcer patients undergoing surgical intervention (debridement or amputation) were recruited and blood was drawn at 0, 4, 8, and 12 weeks. Whole blood was analyzed for S. aureus-specific serum antibodies (mix of historic and new antibodies) and plasmablasts were isolated and cultured to quantify titers of newly synthesized antibodies (NSAs). Anti-S. aureus antibody titers were compared with culture results to assess their concordance in identifying S. aureus as the pathogen. The NSA titer changes at follow-ups were compared with wound healing status to evaluate concordance between evolving host immune response and clinically resolving or relapsing infection. RESULTS: Analysis of serum for anti-S. aureus antibodies showed significantly increased titers of 3 different anti-S. aureus antibodies, IsdH (P = .037), ClfB (P = .025), and SCIN (P = .005), in S. aureus culture-positive patients compared with culture-negative patients. Comparative analysis of combining antigens for S. aureus infection diagnosis increased the concordance further. During follow-up, changes of NSA titers against a single or combination of S. aureus antigens significantly correlated with clinically resolving or recurring infection represented by wound healing status. CONCLUSION: In the management of foot infection, the use of S. aureus-specific immunoassay may aid in diagnosis of the dominant pathogen and monitoring of the host immune response against a specific pathogen in response to treatment. Importantly, this immunoassay could detect recurrent foot infection, which may guide a surgeon's decision to intervene. LEVEL OF EVIDENCE: Level II, prospective comparative study.

Lack of Humoral Immunity Against Glucosaminidase Is Associated with Postoperative Complications in Staphylococcus aureus Osteomyelitis.

BACKGROUND: Glucosaminidase (Gmd) is known to be a protective antigen in animal models of Staphylococcus aureus osteomyelitis. We compared the endogenous anti-Gmd antibody levels in sera of patients with culture-confirmed S. aureus bone infections to their sera at 1 year after operative treatment of the infection. METHODS: A novel global biospecimen registry of 297 patients with deep-wound culture-confirmed S. aureus osteomyelitis was analyzed to assess relationships between baseline anti-Gmd serum titers (via custom Luminex assay), known host risk factors for infection, and 1-year postoperative clinical outcomes (e.g., infection control, inconclusive, refracture, persistent infection, septic nonunion, amputation, and septic death). RESULTS: All patients had measurable humoral immunity against some S. aureus antigens, but only 20 patients (6.7%; p < 0.0001) had high levels of anti-Gmd antibodies (>10 ng/mL) in serum at baseline. A subset of 194 patients (65.3%) who completed 1 year of follow-up was divided into groups based on anti-Gmd level: low (<1 ng/mL, 54 patients; 27.8%), intermediate (<10 ng/mL, 122 patients; 62.9%), and high (>10 ng/mL, 18 patients; 9.3%), and infection control rates were 40.7%, 50.0%, and 66.7%, respectively. The incidence of adverse outcomes in these groups was 33.3%, 16.4%, and 11.1%, respectively. Assessing anti-Gmd level as a continuous variable showed a 60% reduction in adverse-event odds (p = 0.04) for every tenfold increase in concentration. No differences in patient demographics, body mass index of >40 kg/m, diabetes status, age of ≥70 years, male sex, Charlson Comorbidity Index of >1, or Cierny-Mader host type were observed between groups, and these risk factors were not associated with adverse events. Patients with low anti-Gmd titer demonstrated a significant 2.68-fold increased odds of adverse outcomes (p = 0.008). CONCLUSIONS: Deficiency in circulating anti-Gmd antibodies was associated serious adverse outcomes following operative treatment of S. aureus osteomyelitis. At 1 year, high levels of anti-Gmd antibodies were associated with a nearly 3-fold increase in infection-control odds. Additional prospective studies clarifying Gmd immunization for osteomyelitis are needed. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Dual Energy X-ray Absorptiometry (DEXA) as a longitudinal outcome measure of cancer-related muscle wasting in mice.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is notorious for its associated skeletal muscle wasting (SMW) and mortality. Currently, the relationships between PDAC, SMW, and survival are poorly understood. Thus, there is great need for a faithful small animal model with quantitative longitudinal outcome measures that recapitulate clinical PDAC, to define SMW onset and assess progression. Therefore, we aimed to validate dual energy X-ray absorptiometry (DEXA) as a longitudinal measure of lean mass, and demonstrate its utility to quantify SMW in the KCKO murine model of PDAC. METHODS: In vivo body composition of: 1) untreated mice at 5, 8, 12, 18, and 22 weeks of age (n = 4) and 2) a cohort of mice with (n = 5) and without PDAC (n = 5), was determined via DEXA and lean mass of the lower hind limbs was predicted via a region of interest analysis by two-independent observers. Total body weight was determined. Tibialis anterior (TA) muscles were weighed and processed for histomorphometry immediately post-mortem. Statistical differences between groups were assessed using ANOVA and Student's t-tests. Linear regression models and correlation analysis were used to measure the association between TA and DEXA mass, and reproducibility of DEXA was quantified via the intraclass correlation coefficient (ICC). RESULTS: Lean mass in growing untreated mice determined by DEXA correlated with TA mass (r2 = 0.94; p <0.0001) and body weight (r2 = 0.89; p <0.0001). DEXA measurements were highly reproducible between observers (ICC = 0.95; 95% CI: 0.89-0.98). DEXA and TA mass also correlated in the PDAC cohort (r2 = 0.76; p <0.0001). Significant SMW in tumor-bearing mice was detected within 38 days of implantation, by DEXA, TA mass, and histomorphometry. CONCLUSIONS: DEXA is a longitudinal outcome measure of lean mass in mice. The KCKO syngeneic model is a bona fide model of PDAC associated SMW that can be quantified with longitudinal DEXA.

A Bioinformatic Approach to Utilize a Patient's Antibody-Secreting Cells against Staphylococcus aureus to Detect Challenging Musculoskeletal Infections.

Noninvasive diagnostics for Staphylococcus aureus musculoskeletal infections (MSKI) remain challenging. Abs from newly activated, pathogen-specific plasmablasts in human blood, which emerge during an ongoing infection, can be used for diagnosing and tracking treatment response in diabetic foot infections. Using multianalyte immunoassays on medium enriched for newly synthesized Abs (MENSA) from Ab-secreting cells, we assessed anti-S. aureus IgG responses in 101 MSKI patients (63 culture-confirmed S. aureus, 38 S. aureus-negative) and 52 healthy controls. MENSA IgG levels were assessed for their ability to identify the presence and type of S. aureus MSKI using machine learning and multivariate receiver operating characteristic curves. Eleven S. aureus-infected patients were presented with prosthetic joint infections, 15 with fracture-related infections, 5 with native joint septic arthritis, 15 with diabetic foot infections, and 17 with suspected orthopedic infections in the soft tissue. Anti-S. aureus MENSA IgG levels in patients with non-S. aureus infections and healthy controls were 4-fold (***p = 0.0002) and 8-fold (****p < 0.0001) lower, respectively, compared with those with culture-confirmed S. aureus infections. Comparison of MENSA IgG responses among S. aureus culture-positive patients revealed Ags predictive of active MSKI (IsdB, SCIN, Gmd) and Ags predictive of MSKI type (IsdB, IsdH, Amd, Hla). When combined, IsdB, IsdH, Gmd, Amd, SCIN, and Hla were highly discriminatory of S. aureus MSKI (area under the ROC curve = 0.89 [95% confidence interval 0.82-0.93, p < 0.01]). Collectively, these results demonstrate the feasibility of a bioinformatic approach to use a patient's active immune proteome against S. aureus to diagnose challenging MSKI.

AnaLysIs of Both sex and device specific factoRs on outcomes in pAtients with non-ischemic cardiomyopathy (BIO-LIBRA): Design and clinical protocol.

BACKGROUND: Outcomes of patients with nonischemic cardiomyopathy and low ejection fraction implanted with an implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy with a defibrillator (CRT-D), especially in contemporary, real-life cohorts, are not fully understood. OBJECTIVE: We aimed to better characterize outcomes of death and ventricular tachyarrhythmias in patients with nonischemic cardiomyopathy, implanted with an ICD or CRT-D, and specifically assess differences by sex. METHODS: The AnaLysIs of Both Sex and Device Specific FactoRs on Outcomes in PAtients with Non-Ischemic Cardiomyopathy (BIO-LIBRA) study was designed to prospectively assess outcomes of device-treated ventricular tachyarrhythmias and all-cause mortality events in nonischemic cardiomyopathy patients, indicated for an ICD or CRT-D implantation for the primary prevention of sudden cardiac death (SCD), with a specific focus on sex differences. We will enroll a total of 1000 subjects across 50 U.S. sites and follow patients for up to 3 years. RESULTS: The primary objective of BIO-LIBRA is to evaluate the combined risk of all-cause mortality and treated ventricular tachycardia (VT) or ventricular fibrillation (VF) events by subject sex and by implanted device type. We will also assess all-cause mortality, VT or VF alone, cardiac death, and SCD in the total cohort, as well as by subject sex and by the implanted device type. In addition, the previously validated Seattle Proportional Risk Model (SPRM) will be used to compare the SPRM predicted incidence of SCD to the observed incidence. CONCLUSIONS: The BIO-LIBRA study will provide novel and contemporary information regarding outcomes in patients with a NICM who receive a defibrillator.

Association of Cardiac Resynchronization Therapy With Change in Left Ventricular Ejection Fraction in Patients With Chemotherapy-Induced Cardiomyopathy.

Importance: The incidence of chemotherapy-induced cardiomyopathy is increasing and is associated with poor clinical outcomes. Objective: To assess the association of cardiac resynchronization therapy (CRT) with improvement in cardiac function, as well as clinical improvement in patients with chemotherapy-induced cardiomyopathy. Design, Setting, and Participants: The Multicenter Automatic Defibrillator Implantation Trial-Chemotherapy-Induced Cardiomyopathy was an uncontrolled, prospective, cohort study conducted between November 21, 2014, and June 21, 2018, at 12 tertiary centers with cardio-oncology programs in the United States. Thirty patients were implanted with CRT owing to reduced left ventricular ejection fraction (LVEF≤35%), New York Heart Association class II-IV heart failure symptoms, and wide QRS complex, with established chemotherapy-induced cardiomyopathy and were followed up for 6 months after CRT implantation. The date of final follow-up was February 6, 2019. Exposures: CRT implantation according to standard of care. Main Outcomes and Measures: The primary end point was change in LVEF from baseline to 6 months after initiating CRT. Secondary outcomes included all-cause mortality and change in left ventricular end-systolic volume and end-diastolic volume. Results: Among 30 patients who were enrolled (mean [SD] age, 64 [11] years; 26 women [87%]; 73% had a history of breast cancer; 20% had a history of lymphoma or leukemia), primary end point data were available for 26 patients and secondary end point data were available for 23 patients. Patients had nonischemic cardiomyopathy with left bundle branch block, median LVEF of 29%, and a mean QRS duration of 152 ms. Patients with CRT experienced a statistically significant improvement in mean LVEF at 6 months from 28% to 39% (difference, 10.6% [95% CI, 8.0%-13.3%]; P < .001). This was accompanied by a reduction in LV end-systolic volume from 122.7 to 89.0 mL (difference, 37.0 mL [95% CI, 28.2-45.8]) and reduction in LV end-diastolic volume from 171.0 to 143.2 mL (difference, 31.9 mL [95% CI, 22.1-41.6]) (both P < .001). Adverse events included a procedure-related pneumothorax (1 patient), a device pocket infection (1 patient), and heart failure requiring hospitalization during follow-up (1 patient). Conclusions and Relevance: In this preliminary study of patients with chemotherapy-induced cardiomyopathy, CRT was associated with improvement in LVEF after 6 months. The findings are limited by the small sample size, short follow-up, and absence of a control group. Trial Registration: ClinicalTrials.gov Identifier: NCT02164721.

Short-Term Administration of Mycophenolate Is Well-Tolerated in CLN3 Disease (Juvenile Neuronal Ceroid Lipofuscinosis).

Mycophenolate, an immunosuppressant, is commonly used off-label for autoimmune neurological conditions. In CLN3 disease, a neurodegenerative disorder of childhood, preclinical and clinical data suggest secondary autoimmunity and inflammation throughout the central nervous system are key components of pathogenesis. We tested the short-term tolerability of mycophenolate in individuals with CLN3 disease, in preparation for possible long-term efficacy trials of this drug. We conducted a randomized, double-blind, placebo-controlled, crossover study of mycophenolate in 19 ambulatory individuals with CLN3 disease to determine the safety and tolerability of short-term administration (NCT01399047). The study included two 8-week treatment periods with a 4-week intervening washout. Mycophenolate was well tolerated. 89.5% of participants completed the mycophenolate arm, on the assigned study dose (95% CI: 66.9-98.7%), and there were no significant differences in tolerability rates between mycophenolate and placebo arms (10.5%; 95% CI: -3.3-24.3%, p = 0.21). All reported adverse events were mild in severity; the most common adverse events on mycophenolate were vomiting (31.6%; 95% CI: 12.6-56.6%), diarrhea (15.8%; 95% CI: 3.4-39.6%), and cough (15.8%; 95% CI: 3.4-39.6%). These did not occur at a significantly increased frequency above placebo. There were no definite effects on measured autoimmunity or clinical outcomes in the setting of short-term administration. Study of long-term exposure is needed to test the impact of mycophenolate on key clinical features and CLN3 disease trajectory.

Tracking Anti-Staphylococcus aureus Antibodies Produced In Vivo and Ex Vivo during Foot Salvage Therapy for Diabetic Foot Infections Reveals Prognostic Insights and Evidence of Diversified Humoral Immunity.

Management of foot salvage therapy (FST) for diabetic foot infections (DFI) is challenging due to the absence of reliable diagnostics to identify the etiologic agent and prognostics to justify aggressive treatments. As Staphylococcus aureus is the most common pathogen associated with DFI, we aimed to develop a multiplex immunoassay of IgG in serum and medium enriched for newly synthesized anti-S. aureus antibodies (MENSA) generated from cultured peripheral blood mononuclear cells of DFI patients undergoing FST. Wound samples were collected from 26 DFI patients to identify the infecting bacterial species via 16S rRNA sequencing. Blood was obtained over 12 weeks of FST to assess anti-S. aureus IgG levels in sera and MENSA. The results showed that 17 out of 26 infections were polymicrobial and 12 were positive for S. aureus While antibody titers in serum and MENSA displayed similar diagnostic potentials to detect S. aureus infection, MENSA showed a 2-fold-greater signal-to-background ratio. Multivariate analyses revealed increases in predictive power of diagnosing S. aureus infections (area under the receiver operating characteristic curve [AUC] > 0.85) only when combining titers against different classes of antigens, suggesting cross-functional antigenic diversity. Anti-S. aureus IgG levels in MENSA decreased with successful FST and rose with reinfection. In contrast, IgG levels in serum remained unchanged throughout the 12-week FST. Collectively, these results demonstrate the applicability of serum and MENSA for diagnosis of S. aureus DFI with increased power by combining functionally distinct titers. We also found that tracking MENSA has prognostic potential to guide clinical decisions during FST.

Ranolazine in High-Risk Patients With Implanted Cardioverter-Defibrillators: The RAID Trial.

BACKGROUND: Ventricular tachycardia (VT) and ventricular fibrillation (VF) remain a challenging problem in patients with implantable cardioverter-defibrillators (ICDs). OBJECTIVES: This study aimed to determine whether ranolazine administration decreases the likelihood of VT, VF, or death in patients with an ICD. METHODS: This was double-blind, placebo-controlled clinical trial in which high-risk ICD patients with ischemic or nonischemic cardiomyopathy were randomized to 1,000 mg ranolazine twice a day or placebo. The primary endpoint was VT or VF requiring appropriate ICD therapy or death, whichever occurred first. Pre-specified secondary endpoints included ICD shock for VT, VF, or death and recurrent VT or VF requiring ICD therapy. RESULTS: Among 1,012 ICD patients (510 randomized to ranolazine and 502 to placebo) the mean age was 64 ± 10 years and 18% were women. During 28 ± 16 months of follow-up there were 372 (37%) patients with primary endpoint, 270 (27%) patients with VT or VF, and 148 (15%) deaths. The blinded study drug was discontinued in 199 (39.6%) patients receiving placebo and in 253 (49.6%) patients receiving ranolazine (p = 0.001). The hazard ratio for ranolazine versus placebo was 0.84 (95% confidence interval: 0.67 to 1.05; p = 0.117) for VT, VF, or death. In a pre-specified secondary analysis, patients randomized to ranolazine had a marginally significant lower risk of ICD therapies for recurrent VT or VF (hazard ratio: 0.70; 95% confidence interval: 0.51 to 0.96; p = 0.028). There were no other significant treatment effects in other pre-specified secondary analyses, which included individual components of the primary endpoint, inappropriate shocks, cardiac hospitalizations, and quality of life. CONCLUSIONS: In high-risk ICD patients, treatment with ranolazine did not significantly reduce the incidence of the first VT or VF, or death. However, the study was underpowered to detect a difference in the primary endpoint. In prespecified secondary endpoint analyses, ranolazine administration was associated with a significant reduction in recurrent VT or VF requiring ICD therapy without evidence for increased mortality. (Ranolazine Implantable Cardioverter-Defibrillator Trial [RAID]; NCT01215253).

Immunotherapy synergizes with debridement and antibiotic therapy in a murine 1-stage exchange model of MRSA implant-associated osteomyelitis.

Methicillin-resistant Staphylococcus aureus (MRSA) reinfection following revision surgery remains a major orthopaedic problem. Toward the development of immunotherapy with anti-glucosaminidase monoclonal antibodies (anti-Gmd), we aimed to: (i) develop a murine 1-stage exchange model of bioluminescent MRSA (USA300LAC::lux) contaminated femoral implants; and (ii) utilize this model to demonstrate the synergistic effects of combination vancomycin and anti-Gmd therapy on reinfection and bone healing. Following an infection surgery, the original plate and two screws were removed on day 7, and exchanged with sterile implants. Mice were randomized to five groups: (i) no infection control; (ii) infected placebo; (iii) anti-Gmd; (iv) vancomycin; and (v) combination therapy. Bioluminescent imaging (BLI) was performed on days 0, 1, 3, 5, 7, 8, 10, 12, and 14. Mice were euthanized on day 14 (day 7 post-revision), and efficacy was assessed via colony forming units (CFU) on explanted hardware, micro-CT, and histology. As monotherapies, anti-Gmd inhibited Staphylococcus abscess communities, and vancomycin reduced CFU on the implants. However, only combination therapy prevented increased BLI post-revision surgery, with a significant 6.5-fold reduction on day 10 (p < 0.05 vs. placebo), and achieved sterile implant levels by day 12. Synergistic effects were also apparent from reduced osteolysis and increased new bone formation around the screws only observed following combination therapy. Taken together, we find that: (i) this murine femoral plate 1-stage revision model can efficiently evaluate therapies to prevent reinfection; and (ii) immunotherapy plays a distinct role from antibiotics to reduce reinfection following revision surgery, such that synergy to achieve osseointegration is possible. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1590-1598, 2018.

Teriparatide (human PTH1-34) compensates for impaired fracture healing in COX-2 deficient mice.

Genetic ablation of cyclooxygenase-2 (COX-2) in mice is known to impair fracture healing. To determine if teriparatide (human PTH1-34) can promote healing of Cox-2-deficient fractures, we performed detailed in vivo analyses using a murine stabilized tibia fracture model. Periosteal progenitor cell proliferation as well as bony callus formation was markedly reduced in Cox-2-/- mice at day 10 post-fracture. Remarkably, intermittent PTH1-34 administration increased proliferation of periosteal progenitor cells, restored callus formation on day 7, and enhanced bone formation on days 10, 14 and 21 in Cox-2-deficient mice. PTH1-34 also increased biomechanical torsional properties at days 10 or 14 in all genotypes, consistent with enhanced bony callus formation by radiologic examinations. To determine the effects of intermittent PTH1-34 for callus remodeling, TRAP staining was performed. Intermittent PTH1-34 treatment increased the number of TRAP positive cells per total callus area on day 21 in Cox-2-/- fractures. Taken together, the present findings indicate that intermittent PTH1-34 treatment could compensate for COX-2 deficiency and improve impaired fracture healing in Cox-2-deficient mice.

Telemedicine for Parkinson's Disease: Limited Engagement Between Local Clinicians and Remote Specialists.

INTRODUCTION: The integration of remote specialists into local care teams has not been widely evaluated. METHODS: Therefore, we surveyed clinicians whose patients with Parkinson's disease had participated in a national randomized controlled trial of video visits to determine (1) whether clinicians received recommendations from remote specialists; (2) whether those recommendations were implemented; (3) what barriers to specialty care local clinicians perceived; and (4) whether they would recommend video visits. RESULTS: Of 183 clinicians surveyed, 89 (49%) responded. Less than half received the recommendations of remote specialists, but they implemented most of the recommendations they received and found them to be beneficial. CONCLUSION: The greatest perceived barrier among respondents was distance from patient to specialist, and 40% of local clinicians would recommend video visits. As telemedicine grows, improved communication between remote specialists and local clinicians is likely needed.