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Abstract Background Treatment with immune-checkpoint inhibitors (ICI) may be associated with adverse cardiac events. Troponin elevation is part of the diagnostic criteria for ICI related myocarditis (ICIrM) and myocardial infarction (MI), however there is limited data for causes of troponin elevation independent of MI and ICIrM and their clinical outcomes with ICI therapy. Purpose To assess the diagnostic and prognostic value of high-sensitivity troponin T (hs-TnT) in patients treated with ICI based on different etiologies and association with cardiac events. Methods All patients treated with ICI who had hs-TnT measured at a multi-center institution from 2011 to 2022 were included. Medical records were reviewed for baseline characteristics and long-term outcomes, including cardiac death and MACE (MI, stroke, heart failure [HF]), and cause of hs-TnT elevation. Risk of cardiac events and mortality were compared for the different etiologies of hs-TnT elevation. Results Of 5,423 patients treated with ICI, 1669 had post-ICI hs-TnT measurement. Mean age was 68.7±11.3 years, 58.3% were male, with follow-up through one year from ICI first administration. Elevated hs-TnT was seen in 1136 patients, with the different causes for elevation depicted in Figure 1, panel A. ICIrM patients exhibited the highest median hs-TnT value of 364 ng/L (IQR 1096), followed by a median of 98 ng/L for MI/Type 2 ischemia, 61 ng/L for infection/sepsis, 51 ng/L for pulmonary embolus, 50 ng/L for HF and 27 ng/L for indeterminate causes, Figure 1, panel B. Additionally, median time from first ICI dose to hs-TnT elevation according to each of the diagnoses are depicted in Figure 1, panel C, with ICIrM showing the shortest median time of 44 days (IQR 74). Hs-TnT elevation in patients with ICIrM had the highest risk for cardiac death (HR 52.7, 95% CI 11.7-238.0, p<0.001), followed by hs-TnT elevation due to HF (HR 15.9, 95% CI 2.9-87.0, p=0.001), MI/type 2 ischemia (HR 11.6, 95% CI 2.4-56.1, p=0.002), and infection/sepsis (HR 5.7, 95% CI 1.0-31.0, p=0.045) compared to those with no hs-TnT elevation, Figure 2, panel A. Similarly, patients with ICIrM had highest risk for MACE (HR 8.2, 95% CI 4.4-15.3, p<0.001), followed by increased hs-TnT due to MI/type 2 ischemia (HR 8.1, 95% CI 5.0-13.1, p<0.001), HF (HR 7.6, 95% CI 4.2-13.7, p<0.001), pulmonary embolism (HR 5.1, 95% CI 2.5-10.8, p<0.001), infection/sepsis (HR 4.1, 95% CI 2.4-7.0, p<0.001), and indeterminate cause (HR 2.4, 95% CI 1.5-3.8, p<0.001), Figure 2, panel B. Conclusions Hs-TnT measurements have prognostic value for cardiac events in cancer patients receiving ICI therapy, including in those without ICIrM. Patients with ICIrM demonstrated the highest median hs-TnT levels and the poorest outcomes, with a graded response observed; the worst prognosis was seen in patients with hs-TnT elevation due to ICIrM, followed by other causes, and those without hs-TnT elevation had the best prognosis.Figure 1 Figure 2

Background Immune‐checkpoint inhibitors (ICI) are associated with adverse cardiac events. Although troponin elevation is a diagnostic criterion for ICI‐related myocarditis (ICIrM) and myocardial infarction, data on other causes of troponin elevation and their outcomes in ICI‐treated patients are limited. Methods All patients treated with ICI who had hs‐TnT (high‐sensitivity troponin T) measured at a multicenter institution from 2011 to 2022 were included. Clinical data, outcomes (cardiac death, heart failure (HF), major adverse cardiovascular events [myocardial infarction, stroke, heart failure]), and cause of hs‐TnT elevation were assessed. Risks of cardiac events were compared across hs‐TnT elevation causes. Results Of 5423 patients treated with ICI, 1669 had post‐ICI hs‐TnT measurement (mean age 68.7±11.3 years, 58.3% male), with 1‐year follow‐up. Hs‐TnT elevation in patients with ICIrM (n=59) was associated with the highest risk for cardiac death (hazard ratio [HR], 52.7 [95% CI, 11.7–238.0], P <0.001), followed by hs‐TnT elevation due to heart failure (HR, 15.9), myocardial infarction/type 2 ischemia (HR, 11.6), and infection/sepsis (HR, 5.7), compared with those with no hs‐TnT elevation. ICIrM also carried highest risk for major adverse cardiovascular events (HR, 8.2, [95% CI, 4.4–15.3], P <0.001), followed by myocardial infarction/type 2 ischemia (HR, 8.1), heart failure (HR, 7.6), pulmonary embolus (HR, 5.1), infection/sepsis (HR, 4.1), and indeterminate cause (HR, 2.4). Among ICIrM, HsTnT value >576 ng/L best predicted risk for cardiac death and >319 ng/L for major adverse cardiovascular events. Conclusions Hs‐TnT elevation after ICI therapy is associated with increased risk of cardiac events, particularly in ICIrM, and a graded prognostic association depending on the cause of hs‐TnT elevation. Identifying the underlying cause and troponin thresholds may guide risk stratification and management.

Importance There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN. Objective To present the long-term efficacy and safety of patisiran in adults with hATTR-PN. Design, Setting, and Participants This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE. Intervention Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years. Main Outcomes and Measures Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed. Results At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and –3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival. Conclusions and Relevance In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine. Trial Registration ClinicalTrials.gov Identifier: NCT02510261

Background: ICI-related myocarditis is challenging to diagnose and associated with adverse cardiovascular events and mortality. ICI therapy has also been associated with acute coronary events. There is limited data regarding cardiac troponin T (cTnT) and its association with these cardiovascular outcomes. Methods: All patients treated with ICI at a tertiary institution from 2011 to 2022 were identified, and the charts of those with cTnT measurements were reviewed. In patients with cTnT elevation (cutoff of >14 ng/L), if the Bonaca criteria for myocarditis were met, these patients were labeled as cTnT+/myocarditis+, otherwise as cTnT+/myocarditis-. Patients with non-elevated cTnT values were labeled cTnT-. Medical records were reviewed for baseline characteristics and long-term outcomes, including cardiac death, new heart failure (HF) diagnosis, and MACE (myocardial infarction, TIA/stroke, new HF diagnosis). Kaplan-Meier curves were created to plot the comparison between the three groups. Results: A total of 1669 cancer patients who received ICI therapy had post-ICI cTnT measurements. Mean age was 68.7±11.3, 58.3% were male, with follow-up at 1 year post ICI administration. Of these, 59 patients were cTnT+/myocarditis+, 1077 patients were cTnT+/myocarditis-, and 533 were cTnT-. Survival free of cardiac death, MACE and new HF diagnosis showed a graded response from worst in cTnT+/myocarditis+ patients and best in cTnT- patients; cTnT+/myocarditis- patients had a more favorable but still worse prognosis than cTnT- patients (Figure 1). A cTnT value of 95 ng/L was identified as the best cutoff for the diagnosis of ICI-related myocarditis (AUC 0.82, sensitivity 81.36%, specificity 81.62%). The optimal cTnT cutoff for cardiac death was 576 ng/L (0.70, sensitivity 72%, specificity of 61%) and for MACE 319 ng/L (AUC 0.61, sensitivity 70%, specificity of 52%). Conclusion: In cancer patients receiving ICI therapy cTnT elevations indicate a higher risk of MACE, HF, and cardiac mortality even in patients without myocarditis. Although worst outcomes are seen in those meeting diagnostic criteria for myocarditis.

Objectives: The performed hand-held echocardiography (HHE) was evaluated and interpreted by trained advanced practice providers (APPs) on hospitalized CHF patients for image quality and interpretation by comparing with expert echocardiographer and SE findings. Background: Congestive heart failure (CHF) is associated with increased hospital admissions and mortality. While a standard echocardiogram (SE) is the gold standard for cardiac assessment, it is not readily available. Hospitalized CHF patients require rapid assessment for expedited treatment. Methods: Over 6 months, five trained APPs performed HHE on hospitalized CHF patients and interpreted: (a) left ventricular (LV) size, (b) LV ejection fraction (LVEF), and (c) right atrial pressure (RAP). The study echocardiographer reviewed and blindly interpreted the HHE images and compared them with APPs and SE findings. Kappa statistics determined the degree of agreement between APPs and the study echocardiographer’s interpretation of the HHE images and SE. Results: A total of 80 CHF patients (age 73 ± 14 years, 58% males; LVEF (by SE) 45 ± 19%; 36.3% body mass indexes ≥ 30 kg/m2) were enrolled. HHE interpretation by APPs had a good agreement for LVEF (kappa 0.79) with the study echocardiographer and SE (kappa 0.74) and a good agreement for RAP (kappa 0.67) with the study echocardiographer. The correlation between the absolute LVEF interpretation by the study echocardiographer on HHE and SE was r = 0.88 (p < 0.0001). Conclusions: Trained APPs obtained diagnostic-quality HHE images and interpreted the LV function and RAP in CHF patients in good agreement with the study echocardiographer. LVEF by HHE correlated with LVEF by SE. Our study suggests trained APPs can use HHE to evaluate LVEF and RAP in CHF patients, leading to expedited and optimized treatment.

Background: Full-thickness acetabular cartilage lesions are common findings during primary surgical treatment of femoroacetabular impingement (FAI). Purpose: To evaluate clinical outcomes after acetabular microfracture performed during FAI surgery in a prospective, multicenter cohort. Study Design: Cohort Study; Level of evidence, 3. Methods: Patients with FAI who had failed nonoperative management were prospectively enrolled in a multicenter cohort. Preoperative and postoperative (mean follow-up, 4.3 years) patient-reported outcome measures were obtained with a follow-up rate of 81.6% (621/761 hips), including 54 patients who underwent acetabular microfracture. Patient characteristics, radiographic parameters, intraoperative disease severity, and operative procedures were analyzed. Propensity matching using linear regression was used to match 54 hips with microfracture to 162 control hips (1:3) to control for confounding variables. Subanalyses of hips ≤35 and >35 years of age with propensity matching were also performed. Results: Patients who underwent acetabular microfracture were more likely to be male (81.8% vs 40.9%; P < .001), be older in age (35.0 vs 29.9 years; P = .001), have a higher body mass index (27.2 vs 25.0; P = .001), and have a greater alpha angle (69.6° vs 62.3°; P < .001) compared with the nonmicrofracture cohort (n = 533). After propensity matching to control for covariates, patients treated with microfracture displayed no differences in the modified Harris Hip Score or Hip Disability and Osteoarthritis Outcome Score ( P = .22-.95) but were more likely to undergo total hip arthroplasty (THA) (13% [7/54] compared with 4% [6/162] in the control group; P = .002), and age >35 years was associated with conversion to THA after microfracture. Microfracture performed at or before 35 years of age portended good outcomes with no significant risk of conversion to THA at the most recent follow-up. Conclusion: Microfracture of acetabular cartilage defects appears to be safe and associated with reliably improved short- to mid-term results in younger patients; modified expectations should be realized when full-thickness chondral lesions are identified in patients >35 years of age.

ABSTRACTFemoroacetabular impingement (FAI) is a common femoral and/or acetabular abnormality that can cause progressive damage to the hip and osteoarthritis. FAI can be the result of femoral head/neck overgrowth, acetabular overgrowth or both femoral and acetabular abnormalities, resulting in a loss of native hip biomechanics and pain upon hip flexion and rotation. Radiographic evidence can include loss of sphericity of the femoral neck (cam impingement) and/or acetabular retroversion with focal or global overcoverage (pincer impingement). Operative intervention is indicated in symptomatic patients after failed conservative management with radiographic evidence of impingement and minimal arthritic changes of the hip, with the goal of restoring normal hip biomechanics and reducing pain. This is done by correcting the femoral head–neck relationship to the acetabulum through femoral and/or acetabular osteoplasty and treatment of concomitant hip pathology. In pincer impingement cases with small lunate surfaces, reverse periacetabular osteotomy is indicated as acetabular osteoplasty can decrease an already small articular surface. While surgical dislocation is regarded as the traditional gold standard, hip arthroscopy has become widely utilized in recent years. Studies comparing both open surgery and arthroscopy have shown comparable long-term pain reduction and improvements in clinical measures of hip function, as well as similar conversion rates to total hip arthroplasty. However, arthroscopy has trended toward earlier improvement, quicker recovery and faster return to sports. The purpose of this study was to review the recent literature on open and arthroscopic management of FAI.

Abstract Although neurogastroenterology and motility ( NGM ) disorders are some of the most frequent disorders encountered by practicing gastroenterologists, a structured competency‐based training curriculum developed by NGM experts is lacking. The American Neurogastroenterology and Motility Society ( ANMS ) and the European Society of Neurogastroenterology and Motility ( ESNM ) jointly evaluated the components of NGM training in North America and Europe. Eleven training domains were identified within NGM , consisting of functional gastrointestinal disorders, visceral hypersensitivity and pain pathways, motor disorders within anatomic areas (esophagus, stomach, small bowel and colon, anorectum), mucosal disorders (gastro‐esophageal reflux disease, other mucosal disorders), consequences of systemic disease, consequences of therapy (surgery, endoscopic intervention, medications, other therapy), and transition of pediatric patients into adult practice. A 3‐tiered training curriculum covering these domains is proposed here and endorsed by all NGM societies. Tier 1 NGM knowledge and training is expected of all gastroenterology trainees and practicing gastroenterologists. Tier 2 knowledge and training is appropriate for trainees who anticipate NGM disorder management and NGM function test interpretation being an important part of their careers, which may require competency assessment and credentialing of test interpretation skills. Tier 3 knowledge and training is undertaken by trainees interested in a dedicated NGM career and may be restricted to specific domains within the broad NGM field. The joint ANMS and ESNM task force anticipates that the NGM curriculum will streamline NGM training in North America and Europe and will lead to better identification of centers of excellence where Tier 2 and Tier 3 training can be accomplished.

AbstractYoung hip surgeons are often faced with the decision to either perform arthroscopic surgery or a periacetabular osteotomy (PAO) in patients with symptomatic mild hip dysplasia (MHD). There is, however, a paucity of data on the results of PAO in this group. The aim of this paper is to report the results of PAOs in patients with MHD and compare those to hips with more severe forms of hip dysplasia (SHD). This data can then be used to compare emerging data reporting the results of hip arthroscopy for MHD. From January, 1996 to May, 2009, 299 hips in 268 patients were identified that underwent PAO at one institution. After removing those with <2 years of follow-up, 182 hips were followed up. The average age of the cohort was 31 years, and 85% were female. Nineteen hips with lateral center edge (LCE) angle from 18 to 25° and a Tönnis angle (TA) between 10 and 15° were considered to have MHD. This group was compared with the rest of the cohort (SHD). The mean clinical follow-up for the MHD group was 121 months. There was no significant difference in demographic variables between the groups. There were no complications in the MHD cohort. Surgical correction resulted in significant improvements in all radiographic measurements consistent with hip dysplasia in both groups. The Harris Hip Score (HHS) improved significantly in both groups ([MHD: 52–92] [SHD: 66–89]). Two hips (10.5%) in the MHD group and 15 hips (9.2%) in the SHD group underwent future THA (p = 0.69). The survivorship free from THA was 100%, 100%, and 86% at 3, 5, and 10 years, respectively, in the MHD group. The corresponding rates for hips in the control group at 3, 5, and 10 years, respectively, were 99%, 95%, and 81%. PAO in patients with MHD provides predictable improvements in pain, function, and results that are durable and comparable to hips with SHD. This data should be used to compare the early and midterm results of arthroscopic surgery performed in mildly dysplastic hips.

Obesity is a risk factor for complications following many orthopaedic procedures. The purpose of this study was to investigate whether obesity was an independent risk factor increasing the rate of complications following periacetabular osteotomy (PAO) and to determine whether radiographic correction after PAO was affected by obesity.We retrospectively collected demographic, clinical and radiographic data on 280 patients (231 women; 82.5% and 49 men; 17.5%) who were followed for a mean of 48 months (12 to 60) after PAO. A total of 65 patients (23.2%) were obese (body mass index (BMI) > 30 kg/m2). Univariate and multivariate analysis demonstrated that BMI was an independent risk factor associated with the severity of the complications. The average probability of a patient developing a major complication was 22% (95% confidence interval (CI) 11.78 to 38.21) for an obese patient compared with 3% (95% CI 1.39 to 6.58) for a non-obese patient The odds of a patient developing a major complication were 11 times higher (95% CI 4.71 to 17.60, p < 0.0001) for an obese compared with a non-obese patient.Following PAO surgery, there was no difference in radiographic correction between obese and non-obese patients. PAO procedures in obese patients correct the deformity effectively but are associated with an increased rate of complications.Cite this article: Bone Joint J 2015;97-B:29–34.