The CINCH-FMR postmarket registry: Real-world long-term outcomes with percutaneous mitral valve repair with the Carillon Mitral Contour System®.

BACKGROUND: The Carillon® Mitral Contour System® has been studied in 4 prospective controlled studies in the treatment of functional mitral regurgitation (FMR) where it has been found to reduce mitral regurgitation, reduce left ventricular and atrial volumes, and be associated with improvements in clinical parameters. AIMS: The CINCH post-market registry is designed to evaluate immediate, mid-term and long-term outcomes from a post-approval study of the Carillon® device evaluated in real-world practice. METHODS: The CINCH post-market registry is a single-arm study of percutaneous mitral annuloplasty with the Carillon device in patients with functional (secondary) mitral regurgitation and symptomatic congestive heart failure when utilized in real-world conditions. Patient selection, echocardiographic hemodynamic measurements, and patient follow-up requirements were performed per standard of care at each institution. RESULTS: A total of 101 patients treated with the Carillon device at 13 sites in Germany were enrolled in the CINCH registry. The mean age was 75 ± 9 years, 57 % were male, and patient presentation included primarily NYHA class III (69 %) with MR grade 3 (68 %). Over 5 years of follow-up, all-cause mortality was 40.1 %, the incidence of HFH was 53.9 %, and the composite outcome of HFH or death was 66.4 %. At each follow-up interval through 5 years, statistically significant reductions in NYHA class (p < 0.05) and MR grade (p < 0.01) were reported. CONCLUSIONS: In this "real world" registry of the Carillon Mitral Contour System, procedural safety and medium-term follow-up outcomes is similar to the outcomes seen in the prospective, controlled clinical trials, despite being used in populations of patients that extend outside of those studied in the trials. The use of this therapy in patients with atrial functional mitral regurgitation, and heart failure with preserved ejection fraction, was notable, since these types of patients were excluded from the prospective, controlled trials. This supports possible additional patient populations who might benefit from this type of mechanical therapy. The safety profile of this therapy in this registry and in the earlier trials may support a potential role in earlier forms of secondary mitral regurgitation.

Identification of highly selective SIK1/2 inhibitors that modulate innate immune activation and suppress intestinal inflammation.

The salt-inducible kinases (SIK) 1-3 are key regulators of pro- versus anti-inflammatory cytokine responses during innate immune activation. The lack of highly SIK-family or SIK isoform-selective inhibitors suitable for repeat, oral dosing has limited the study of the optimal SIK isoform selectivity profile for suppressing inflammation in vivo. To overcome this challenge, we devised a structure-based design strategy for developing potent SIK inhibitors that are highly selective against other kinases by engaging two differentiating features of the SIK catalytic site. This effort resulted in SIK1/2-selective probes that inhibit key intracellular proximal signaling events including reducing phosphorylation of the SIK substrate cAMP response element binding protein (CREB) regulated transcription coactivator 3 (CRTC3) as detected with an internally generated phospho-Ser329-CRTC3-specific antibody. These inhibitors also suppress production of pro-inflammatory cytokines while inducing anti-inflammatory interleukin-10 in activated human and murine myeloid cells and in mice following a lipopolysaccharide challenge. Oral dosing of these compounds ameliorates disease in a murine colitis model. These findings define an approach to generate highly selective SIK1/2 inhibitors and establish that targeting these isoforms may be a useful strategy to suppress pathological inflammation.

Percutaneous mitral annuloplasty with the Carillon device: Outcomes in proportionate and disproportionate functional mitral regurgitation.

BACKGROUND: It has been suggested that the disparity of outcomes between the studies of transcutaneous edge-to-edge repair (TEER) for functional mitral regurgitation (FMR) in heart failure with reduced ejection fraction (HFrEF) could be due to systematic differences in the populations studied. One proposal is that there are 2 broad groups: those with proportional FMR who respond less favorably, and those in whom the FMR is greater than expected (disproportionate) FMR where edge-to-edge TEER seems to be more effective. Whether this grouping is relevant for other percutaneous interventions for FMR is unknown. OBJECTIVES: We sought to compare clinical and echocardiographic outcomes of patients with HFrEF and proportionate and disproportionate FMR treated with indirect annuloplasty using the Carillon device. METHODS: This is a pooled analysis from 3 trials of patients with FMR. Key patient eligibility in these trials specified persistent grade 2+ to 4+ FMR with >5.5 cm left ventricular (LV) end-diastolic diameter (LVEDD) and reduced ejection fraction. Patients with an effective regurgitant orifice area/LV end-diastolic volume (EROA/LVEDV) ratio under 0.15 were assigned to the proportionate FMR group (n = 74;65%) and those with a ratio above 0.15 were classed as having disproportionate FMR (n = 39;35%). RESULTS: At 12 months following treatment, both groups showed improvements in all MR variables including regurgitation volume, EROA and vena contracta. Moreover, in patients with proportionate MR there were clinically relevant and statistically significant improvements in LV volumes and diameters. There was no independent relationship between the degree of proportionality as a continuous variable and the remodeling response to Carillon therapy (change in LVEDV r = 0.17; change in LVESV r = 0.14). CONCLUSION: Percutaneous mitral annuloplasty with the Carillon device reduces MR in patients with both proportionate and disproportionate FMR, and also results in LV reverse remodeling in those with proportionate FMR. The effect on remodeling remains to be verified in a large-scale trial.

Prediction of Future Medical Costs by Modifiable Measures of Health.

Introduction: Strategies to mitigate rising health-care costs are a priority for patients, employers, and health insurers. Yet gaps currently exist in whether health risk assessment can forecast medical claims costs. This study examined the ability of a health quotient (HQ) based on modifiable risk factors, age, sex, and chronic conditions to predict future medical claims spending. Methods: The study included 18,695 employees and adult dependents who participated in health assessments and were enrolled in an employer-sponsored health plan. Linear mixed effect models stratified by chronic conditions and adjusted for age and sex were utilized to evaluate the relationship between the health quotient (score of 0-100) and future medical claims spending. Results: Lower baseline health quotient was associated with higher medical claims cost over 2 years of follow up. For participants with chronic condition(s), costs were $3628 higher for those with a low health quotient (<73; N = 2673) compared to those with high health quotient (>85; N = 1045), after adjustment for age and sex (P value = 0.004). Each one-unit increase in health quotient was associated with a decrease of $154 (95% CI: 87.4, 220.3) in average yearly medical claims costs during follow up. Discussion: This study used a large employee population with 2 years of follow-up data, which provides insights that are applicable to other large employers. Results of this analysis contribute to our ability to predict health-care costs using modifiable aspects of health, objective laboratory testing and chronic condition status.

Target 2035 - an update on private sector contributions.

Target 2035, an international federation of biomedical scientists from the public and private sectors, is leveraging 'open' principles to develop a pharmacological tool for every human protein. These tools are important reagents for scientists studying human health and disease and will facilitate the development of new medicines. It is therefore not surprising that pharmaceutical companies are joining Target 2035, contributing both knowledge and reagents to study novel proteins. Here, we present a brief progress update on Target 2035 and highlight some of industry's contributions.

Botulinum Toxin A and B Improve Perfusion, Increase Flap Survival, Cause Vasodilation, and Prevent Thrombosis: A Systematic Review and Meta-analysis of Controlled Animal Studies.

BACKGROUND: A systematic review and meta-analysis of case-control animal model studies will help clarify the vascular effects of botulinum toxin (BTX). METHODS: Preferred Reporting Items of Systematic reviews and Meta-Analyses guidelines were used to identify all animal case-control studies published before September 13, 2020, evaluating the vascular effects of BTX. Primary parameters included the following: perfusion, flap survival, arterial and venous dilation, and arterial and venous thrombosis. RESULTS: Thirty-six studies with 1032 animals met the systematic review inclusion criteria. Twenty-nine studies had quantifiable data for statistical analysis. Statistically significant increases in perfusion with BTX over saline were detected within 1 day and sustained up to 8 weeks. The following represent weighted mean data from the meta-analysis. The administration of BTX has a 26% increase in both random pattern and pedicled flap survival area over controls. Botulinum toxin causes vasodilation. Botulinum toxin increases vessel diameter in arteries by 40% and in veins by 46% compared with saline controls. The administration of BTX reduces thrombosis by 85% in arteries and by 79% in veins compared with saline controls. Vascular effects were consistent across both BTX-A and BTX-B serotypes, multiple animal species, and various doses. No clear relationships between vascular effects and BTX pretreatment time were identified. CONCLUSIONS: Perivascular BTX administration intraoperatively or as a chemical delay pretreatment several days before surgery in multiple animal species and models shows multiple changes to the vascular system. Extrapolation of lessons learned from this systematic review and meta-analysis of animal models could expand research and clinical use of BTX in human vascular disease and surgery.

Role of Pharmacogenomics in Comprehensive Medication Management: Considerations for Employers.

Rising prescription costs, poor medication adherence, and safety issues pose persistent challenges to employer-sponsored health care plans and their beneficiaries. Comprehensive medication management (CMM), a patient-centered approach to medication optimization, enriched by pharmacogenomics (PGx), has been shown to improve the efficacy and safety of pharmaceutical regimens. This has contributed to improved health care outcomes, reduced costs of treatments, better adherence, shorter durations of treatment, and fewer adverse effects from drug therapy. Despite compelling clinical and economic evidence to justify the application of CMM guided by PGx, implementation in clinical settings remains sparse; notable barriers include limited physician adoption and health insurance coverage. Ultimately, these challenges may be overcome through comprehensive programs that include clinical decision support systems and education through employer-sponsored population health management channels to the benefit of the employees, employers, health care providers, and health care systems. This article discusses benefits, considerations, and barriers of scalable PGx-enriched CMM programs in the context of self-insured employers.

Early Insights From a Pharmacogenomic-Enriched Comprehensive Medication Management Program Implementation in an Adult Employee Population.

OBJECTIVES: The aims of the study are to assess adoption of a pharmacogenomic-enriched comprehensive medication management program in a self-insured employer setting and to better understand medication risks that affect employees. METHODS: Employees were identified to be at high risk of medication mismanagement and were subsequently provided with a program and process to improve their health. DNA testing, a clinical decision support system, and pharmacists were used to identify medication safety and effectiveness issues and to recommend appropriate changes. RESULTS: A total of 10.6% of the invited employees enrolled in the program. Actionable recommendations were suggested by pharmacists for 85.8% of employees who completed the program, averaging 5.2 recommendations per person. CONCLUSIONS: Implementation of a PGx + CMM program in a self-insured employer setting is feasible, detects risks in prescription regimens, and offers opportunities to improve medication management and reduce the burden of healthcare expenses.

Technical note: subscapularis-sparing approach to perform anatomic total shoulder arthroplasty using a multiplanar humeral osteotomy and angled glenoid instruments.

BACKGROUND: Anatomic total shoulder arthroplasty is typically performed through the deltopectoral approach followed by either a subscapularis tenotomy, tendon peel, or lesser tuberosity osteotomy to provide adequate exposure. These subscapularis-takedown methods have been associated with incomplete subscapularis healing, however, and as a result often lead to functional deficits and complications. Subscapularis-sparing approaches have been introduced to mitigate these complications, but thus far have either been limited to hemiarthroplasty or resulted in residual inferior humeral head osteophytes and humeral component size mismatch. The present technique demonstrates the possibility for surgeons to capitalize on the improved patient outcomes that are afforded by subscapularis-sparing approaches, while still utilizing the deltopectoral interval to perform a total glenohumeral joint arthroplasty. METHODS: This article describes in detail the placement of a stemless anatomic TSA with the use of angled glenoid instruments through a subscapularis-sparing deltopectoral approach. Postoperatively, patients are placed in a sling but are instructed to remove as tolerated, as early as the 1st postoperative week. Physical therapy is started at week 1 with a 4-phase progression. CONCLUSIONS: This technique using a TSA system with a polyaxial glenoid reamer and angled pegs on the backside of the glenoid allows the potential for maintenance of the strong postoperative radiographic and patient-reported outcomes that are achieved using traditional TSA approaches, with the advantage of accelerated rehabilitation protocols and decreased risk of subscapularis insufficiency that result from the use of subscapularis-sparing approaches.

Treating symptoms and reversing remodelling: clinical and echocardiographic 1-year outcomes with percutaneous mitral annuloplasty for mild to moderate secondary mitral regurgitation.

AIMS: To determine the effects of percutaneous mitral annuloplasty on symptoms, walk distance and left ventricular (LV) structure and function in patients with mild or moderate secondary mitral regurgitation (SMR). METHODS AND RESULTS: This was a pooled analysis of patients (n = 68) who, despite guideline-directed medical therapy had symptomatic heart failure (HF) with mild (n = 25) or moderate (n = 43) SMR treated with percutaneous mitral annuloplasty as part of the TITAN, TITAN II, or REDUCE-FMR trials. Primary outcomes were changes in symptoms, 6-min walk distance, and quality of life assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) after 1 year. Secondary analyses included changes in LV structure and function. At 1 year, New York Heart Association class status was maintained (48%) or improved (46%) in most patients, mean KCCQ scores increased from baseline by 10 units [95% confidence interval (CI) 3 to17; P < 0.01] and mean 6-min walk test distance increased by 34 m (95% CI 12 to 57; P < 0.01). SMR grade improved in 25% of patients and was maintained in 58% of patients with changes in mean regurgitant volume of -7 mL (95% CI -11 to -3; P < 0.001), vena contracta -0.11 cm (95% CI -0.20 to -0.02; P < 0.05), and effective regurgitant orifice area -0.03 cm2 (95% CI -0.06 to -0.01; P < 0.05). There were non-significant improvements in LV ejection fraction and volumes. Survival over 1 year was 89% with no difference between mild (96%) and moderate (86%) SMR (log-rank P = 0.22). Progression-free survival was 70% (82% in mild vs. 63% in moderate SMR; P = 0.16). Freedom from HF hospitalization was 73% (87% in mild SMR vs. 66% in moderate SMR; P = 0.07). CONCLUSION: Among patients with symptomatic HF and mild or moderate SMR on guideline-directed medical therapy, percutaneous mitral annuloplasty was associated with improvements in symptoms, SMR, a stabilization of LV structure and function, and high survival rates.

The Ability of Upper Extremity Surgeons to Assess Patient's Functional Status.

PURPOSE: To compare surgeon and patient assessment of upper extremity functional status at the time of initial consultation. We hypothesized that surgeons and patients demonstrate low levels of agreement with respect to assessing pain scores, functional status, and self-efficacy. METHODS: One hundred forty-three consecutive new patients were evaluated by 1 of 5 fellowship-trained upper extremity surgeons. Patients completed a Numeric Pain Rating Scale as well as the Patient-Reported Outcomes Measurement Information System (PROMIS) Upper Extremity (UE), Pain Interference (PI), and Self-Efficacy (SE) instruments. Surgeons provided their own estimates of patient function on each questionnaire at the conclusion of the visit and were blinded to the results of the patient-reported outcome measures (PROMs) for the duration of the study. Estimation errors, which represent the absolute value of the difference between the patient's actual score and the surgeon's estimated score on each questionnaire, were calculated for each questionnaire. RESULTS: As a group, surgeons assumed that the PROMIS UE and SE scores were higher than the patients' actual scores and assumed that patients had lower PROMIS PI scores than were actually reported. Mean estimation errors for all PROMIS instruments were greater than 10 points and larger than the SD for these instruments in the general population. CONCLUSIONS: Upper extremity surgeons demonstrate difficulty assessing their patient's self-reported functional status, pain interference, and level of self-efficacy during initial consultations. CLINICAL RELEVANCE: Although formalized PROMs are infrequently administered in orthopedic clinics, increased utilization of these questionnaires would allow for a more accurate baseline functional assessment. When evaluating new patients in the outpatient clinic, surgeons should recognize the potential limitations of their assessments of patient-reported function.

Model for Mitigation of Workplace Transmission of COVID-19 Through Population-Based Testing and Surveillance.

The coronavirus disease-2019 (COVID-19) pandemic is having a widespread impact on societies across the globe. As part of the effort to control transmission in the United States, many businesses either closed or instituted nonpharmaceutical control measures and allowed only essential workers on-site. During summer and fall of 2020, employers began formulating "return to work" strategies designed to mitigate the risk of transmission among employees. On a population level, several countries implemented national testing and surveillance strategies that proved effective in mitigating citizen-to-citizen transmission and contributed to suppressing COVID-19. A crucial component of many such strategies is population-based testing to identify and engage individuals with asymptomatic or presymptomatic infection, which also is relevant to return-to-work strategies. The authors describe an approach that multisite employers might use to help mitigate transmission of COVID-19 in the workplace. This approach leverages a bioinformatics platform informed by real-time PCR test data at the county and subcounty (eg, Public Use Microdata Area) level, allowing for population-based testing to be selectively targeted for employees in geographies with elevated SARS-CoV-2 positivity. A "Command Center" application integrates data from multiple sources (eg, local infection trends, employee symptom diaries, Bluetooth thermometers) in real time, which can be used to inform decisions regarding surveillance and employee self-isolation or quarantine; a mobile phone-based application provides for rapid, secure communication with employees. This overview is based on peer-reviewed literature and the early experience of a large employer with implementing bioinformatics tools to mitigate the impact of the pandemic on the workplace.

Anatomic total shoulder arthroplasty using a stem-free ellipsoid humeral implant in patients of all ages.

BACKGROUND: Stem-free shoulder arthroplasty has recently been shown to have comparable results to stemmed arthroplasty, though stemless designs are typically used in a younger patient population. Additionally, although the native humeral head is elliptical in shape, clinical results with ellipsoid implants in shoulder arthroplasty have not been reported on previously. This case series reports on the outcomes of a recently introduced anatomic total shoulder arthroplasty with an ellipsoid-shaped articular surface and unique multiplanar platform type of stemless fixation. METHODS: This retrospective case series examines the initial cohort of patients who received an anatomic total shoulder arthroplasty using an ellipsoid stem-free humeral prosthesis and an all-polyethylene glenoid component from the Catalyst CSR Total Shoulder System (Catalyst OrthoScience) over a 1-year period. Inclusion criteria were patients with a diagnosis of advanced glenohumeral joint arthritis with an intact rotator cuff, regardless of patient age. Clinical outcomes including shoulder range of motion and patient-reported outcome measures, as well as radiographs, were evaluated at multiple time points postoperatively, with minimum 2-year follow-up. RESULTS: Sixty-three shoulders in 57 patients with a mean age of 73.0 years (range 60-85 years) were included in the study with a mean follow-up period of 30.5 months (range 24-41 months). Forward elevation improved from 121° to 150° (P < .0001), external rotation improved from 28° to 48° (P < .0001), and internal rotation improved from L3 to L1 (P < .001). There were statistically significant improvements exceeding the minimal clinically important difference (MCID) in the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) score (37 to 94, P < .001), Single Assessment Numeric Evaluation (SANE) (40 to 93, P < .001), visual analog scale (6.3 to 0.4, P < .001), and Patient-Reported Outcomes Measurement Information System physical domain T score (44 to 57, P < .001). The improvement in the ASES score also exceeded the threshold for the substantial clinical benefit. Age, sex, and preoperative glenoid morphology did not appear to have an effect on the clinical outcome scores. There were no implant failures or evidence of radiographic loosening of the humerus component in any patients. CONCLUSION: At 2-year minimum follow-up, this stem-free ellipsoid humerus total shoulder arthroplasty provides very good results with high patient satisfaction, clinical improvement in all outcome measures studied, and no signs of loosening.