Sustained Functional Improvement Research Articles

Long-term effect of mavacamten in obstructive hypertrophic cardiomyopathy.

Long-term safety and efficacy of mavacamten in patients with obstructive hypertrophic cardiomyopathy (HCM) are unknown. MAVA-LTE (NCT03723655) is an ongoing, 5-year, open-label extension study designed to evaluate the long-term effects of mavacamten. Participants from EXPLORER-HCM (NCT03470545) could enrol in MAVA-LTE upon study completion. At the latest data cut-off, 211 (91.3%) of 231 patients originally enrolled in MAVA-LTE still received mavacamten. Median (range) time on study was 166.1 (6.0-228.1) weeks; 185 (80.1%) and 99 (42.9%) patients had completed the week 156 and 180 visits, respectively. Sustained reductions from baseline to week 180 occurred in left ventricular outflow tract gradients (mean [standard deviation]: resting, -40.3 [32.7] mmHg; Valsalva, -55.3 [33.7] mmHg), NT-proBNP (median [interquartile range]: -562 [-1162.5, -209] ng/L), and EQ-5D-5L score (mean [standard deviation]: 0.09 [0.17]). Mean left ventricular ejection fraction (LVEF) decreased from 73.9% (baseline) to 66.6% (week 24) and 63.9% (week 180). At week 180, 74 (77.9%) of 95 patients improved by at least one New York Heart Association class from baseline. Over 739 patient-years exposure, 20 patients (8.7%; exposure-adjusted incidence: 2.77/100 patient-years) experienced 22 transient reductions in LVEF to <50% resulting in temporary treatment interruption (all recovered LVEF of ≥50%). Five (2.2%) patients died (all considered unrelated to mavacamten). Long-term mavacamten treatment resulted in sustained improvements in cardiac function and symptoms in patients with obstructive HCM, with no new safety concerns identified. Transient, reversible reductions in LVEF were observed in a small proportion of patients during long-term follow-up.

53081 Dupilumab Treatment Provides Sustained Improvement in Skin Barrier Function, Clinical Outcomes, and Patient-Reported Outcomes in Patients Aged 6 to 11 Years With Moderate-to-Severe Atopic Dermatitis

53081 Dupilumab Treatment Provides Sustained Improvement in Skin Barrier Function, Clinical Outcomes, and Patient-Reported Outcomes in Patients Aged 6 to 11 Years With Moderate-to-Severe Atopic Dermatitis

Comparing autologous blood, corticosteroid, and a combined injection of both for treating lateral epicondylitis: a randomized clinical trial

BackgroundBecause lateral epicondylitis is a common musculoskeletal disorder that affects the forearm's extensor tendons, an effective therapeutic approach should reverse the degeneration and promote regeneration. This study aimed to compare the efficacies of autologous blood (AB) injection, corticosteroid (CS) injection, and a combined injection of both in treating lateral epicondylitis (LE), hypothesizing that the combined approach might offer immediate symptom resolution and a lower recurrence.Materials and methodsA total of 120 patients diagnosed with lateral epicondylitis were systematically distributed among three distinct therapeutic injection groups. Those in the AB group were administered 1 ml of autologous venous blood mixed with 2 ml of 2% prilocaine HCl. Participants in the CS category were given 1 ml of 40 mg methylprednisolone acetate mixed with 2 ml of 2% prilocaine HCl. Meanwhile, patients in the combined group received a mixture containing 1 ml each of autologous venous blood and 40 mg methylprednisolone acetate along with 1 ml of 2% prilocaine HCl. Prior to receiving their respective injections, a comprehensive assessment of all participants was carried out. Follow-up assessments were subsequently conducted on days 15, 30, and 90 utilizing metrics of the patient-rated tennis elbow evaluation (PRTEE) and measurements of hand grip strength (HGS).ResultsOne patient dropped out from the combined group, and 119 patients completed the trial. No complications were recorded during the course of follow-up. By day 15, all groups had demonstrated significant PRTEE improvement, with CS showing the most pronounced reduction (p = 0.001). However, the benefits of CS had deteriorated by day 30 and had deteriorated further by day 90. The AB and AB + CS groups demonstrated sustained improvement, with AB + CS revealing the most effective treatment, achieving a clinically significant improvement in 97.4% of the patients. The improved HGS parallelled the functional enhancements, as it was more substantial in the AB and AB + CS groups (p = 0.001), corroborating the sustained benefits of these treatments.ConclusionsThe study concluded that while AB and CS individually offer distinct benefits, a combined AB + CS approach optimizes therapeutic outcomes, providing swift and sustained functional improvement with a lower recurrence rate. These findings have substantial clinical implications, suggesting a balanced, multimodal treatment strategy for enhanced patient recovery in LE.Level of evidence: Randomized clinical trial, level 1 evidence.Trial registration: NCT06236178.

Effectiveness of vortioxetine in elderly patients with major depressive disorder in real-world clinical practice: Results from the RELIEVE study.

Data demonstrating the real-world, long-term effectiveness of vortioxetine in elderly patients with major depressive disorder (MDD) are clinically useful to confirm findings from randomized trials. RELIEVE was a multinational, 24-week, observational, prospective study in outpatients with MDD initiating vortioxetine treatment in routine care settings (NCT03555136). Here, we report data from a subgroup of 130 patients aged ⩾ 65 years. The primary study outcome was changed from baseline in patient functioning assessed using the Sheehan Disability Scale (SDS). Other clinical outcomes included depression severity (Patient Health Questionnaire-9 [PHQ-9] and Clinical Global Impressions-Severity [CGI-S]), cognitive performance (Digit Symbol Substitution Test [DSST]) and symptoms (Perceived Deficits Questionnaire - Depression-5 item [PDQ-D-5]), and health-related quality of life (HRQoL) (EuroQoL 5 Dimensions 5 Levels [EQ-5D-5L]). Clinically meaningful and statistically significant improvements in patient functioning, depressive symptoms, cognitive function, and HRQoL were observed at week 24. Least squares mean SDS, PHQ-9, CGI-S, PDQ-D-5, DSST, and EQ-5D-5L scores improved from baseline by 6.5, 5.7, 1.2, 3.2, 4.4, and 0.11 points, respectively (p < 0.01 for all). Adverse events were observed in 23.1% of patients. Consistent with previous clinical studies of vortioxetine, this study supports the effectiveness and safety of vortioxetine in treating elderly patients with MDD in a real-world setting over a 6-month period. Patients showed clinically relevant and sustained improvements in psychosocial functioning, depressive symptoms, and cognitive function after receiving vortioxetine, which was generally well tolerated. Main study limitations include the open-label study design and lack of a placebo or comparator group.

Sustained improvement in renal function with palopegteriparatide in adults with chronic hypoparathyroidism: 2-year results from the phase 3 PaTHway trial

Sustained improvement in renal function with palopegteriparatide in adults with chronic hypoparathyroidism: 2-year results from the phase 3 PaTHway trial

The Right Formula for Acne: Importance of Vehicle Formulation in Tazarotene 0.045% Lotion Design, Application, Tolerability, and Efficacy

The vehicles used for topical dermatological treatments can significantly contribute to treatment effects while also delivering ingredients to maintain skin barrier function and reduce irritation. Tazarotene 0.045% lotion was developed using proprietary polymeric emulsion technology to provide uniform and efficient delivery of the active ingredient as well as improved safety and tolerability compared to higher-dose tazarotene formulations. The lotion vehicle additionally provides rapid and sustained improvements in moisturization and skin barrier function with patient-friendly application and cosmetic properties. Compared with trifarotene 0.005% cream, tazarotene 0.045% lotion demonstrated ∼30% greater spreadability and a lower potential for irritation. In clinical trials and investigator-initiated studies, tazarotene 0.045% lotion demonstrated efficacy in the treatment of facial and truncal acne and improved skin oiliness. Facial acne improvements were similar among study participants grouped by sex, race, ethnicity, or age. In a head-to-head study, efficacy was comparable to tazarotene 0.1% cream with approximately half the rate of treatment-emergent adverse events. Tazarotene 0.045% lotion is a beneficial acne treatment option for patients of varying ages, races, ethnicities, and skin types, delivered in a formulation that can be easily used on the face, back, and chest.

288 Impact of Disc Degeneration on Clinical Outcomes After Fusion for Grade 1 Spondylolisthesis: A 5-year QOD Study

INTRODUCTION: Disc degeneration with loss of disc height can be an indication to fuse patients with lumbar spondylosis. However, its relevance for spondylolisthesis is unknown. METHODS: The Quality Outcomes Database was queried for adult patients who underwent fusion for single-level degenerative grade 1 lumbar spondylolisthesis. Pfirrmann grade at the level to be fused was assessed on preoperative sagittal T2-weighted MRI. VAS-back pain (BP-VAS), VAS-leg pain (LP-VAS), and ODI were collected preoperatively and at 3, 12, 24, 36, and 60 months postoperatively. RESULTS: The query returned 395 patients. Mean age (95% CI) was 60 (58.9-61.1) years; 39.5% were male. None had a Pfirrmann grade 1 disc. One (0.3%) had a grade 2 disc, 53 (13.4%) had a grade 3 disc, 245 (62%) had a grade 4 disc, and 96 (24.3%) had a grade 5 disc. Posterior-only approach was performed in 92.6%; interbody graft was placed in 92.7%. Mean BP-VAS (95% CI) at baseline, 3 months, 12 months, 24 months, 36 months, and 60 months were 7.1 (6.8-7.3) (n = 343), 3.1 (2.8-3.3) (n = 353), 2.9 (2.6-3.2) (n = 305), 3.2 (2.8-3.5) (n = 283), 3.5 (2.9-4.1) (n = 107), and 3.7 (3.3-4.0) (n = 324). Mean LP-VAS (95% CI) were 6.7 (6.4-7.0) (n = 392), 2.3 (2.0-2.6) (n = 353), 2.2 (1.9-2.6) (n = 306), 2.6 (2.2-2.9) (n = 284), 2.8 (2.2-3.4) (n = 107), and 2.8 (2.4-3.1) (n = 322). Mean ODI (95% CI) were 49.4 (47.8-51.1) (n = 392), 27.4 (25.3-29.5) (n = 347), 22.9 (20.6-25.2) (n = 313), 22.4 (20.1-24.8) (n = 291), 22.4 (18.3-26.4) (n = 97), and 25.9 (23.7-28.2) (n = 325). Utilizing linear regression, Pfirrmann grade was not associated with improvements in VAS-BP, VAS-LP, or ODI at any time point in unadjusted and adjusted analyses (p &gt; 0.05). CONCLUSIONS: Patients who undergo fusion for single-level grade 1 spondylolisthesis are likely to experience significant and sustained improvements in pain and function regardless of severity of disc degeneration.

Office-Based Carpal Tunnel Release With Ultrasound Guidance: 6-month Outcomes From the Multicenter ROBUST Trial

The purpose of this study was to determine the safety and effectiveness of office-based carpal tunnel release with ultrasound guidance (CTR-US). In this prospective multicenter observational study, patients were treated with CTR-US in an office setting. Outcomes were time to resume normal daily activities, time to return to work, Boston Carpal Tunnel Questionnaire Symptom Severity Scale and Functional Status Scale scores, Michigan Hand Questionnaire, Numeric Pain Scale, EuroQoL-5 Dimension 5-Level score, procedure satisfaction, and adverse events over 6 months. A total of 149 participants (226 hands) from seven centers underwent office-based CTR-US. The mean age was 58 years, 52% were women, and 68% were employed. The mean incision length was 5 mm, 52% had simultaneous bilateral procedures, and wide-awake local anesthesia no tourniquet was used in all cases. All procedures were completed as planned, with no conversions to open repair and mean intraoperative pain severity of 1.6 ± 1.5. The median time to resume normal activities was 2 days (interquartile range: 1-4 days) and return to work was 4 days (interquartile range: 1-5 days). Over 6 months, Boston Carpal Tunnel Questionnaire Symptom Severity Scale decreased by a mean of 1.7 points, Boston Carpal Tunnel Questionnaire Functional Status Scale decreased by 1.1 points, Michigan Hand Questionnaire Global score increased by 35 points, Numeric Pain Scale decreased by 3.7 points, and EuroQoL-5 Dimension 5-Level score increased by 0.11 points. At 6 months, 94% reported procedure satisfaction. Unilateral and simultaneous bilateral procedures were similarly effective. There was one (0.4%) adverse event, a nerve contusion treated with neurolysis and nerve wrap where the patient fully regained normal function within 7 weeks. There were no revisions for persistent or recurrent carpal tunnel syndrome symptoms. Office-based CTR-US, performed either unilaterally or as simultaneous bilateral procedures, is well tolerated with a low complication rate and associated with rapid recovery, sustained improvement in symptoms and function, and high procedure satisfaction. Therapeutic III.

Highly effective cystic fibrosis transmembrane conductance (regulator) modulator therapy: shifting the curve for most while leaving some further behind.

Traditional cystic fibrosis (CF) care had been focused on early intervention and symptom mitigation. With the advent of highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy (HEMT), in particular, the approval of elexacaftor/tezacaftor/ivacaftor in 2019, there has been a dramatic improvement in outcomes in CF. The purpose of this article is to review the benefits, limitations, and impact of HEMT as well as discuss the new implications, challenges, and hope that modulators bring to people with CF (pwCF). HEMT has demonstrated sustained improvement in lung function, nutrition, quality of life, and survival for over 90% of pwCF. As HEMT has delivered such promise, there is a small but significant portion of pwCF who do not benefit from HEMT due to ineligible mutations, intolerance, or lack of accessibility to modulators. HEMT has significantly improved outcomes, but continued research is needed to understand the new challenges and implications the era of HEMT will bring, as well as how to provide equitable care to those who are unable to benefit from HEMT.

Long-Term Improvement in Hippocampal-Dependent Learning Ability in Healthy, Aged Individuals Following High Intensity Interval Training.

Physical exercise may reduce dementia risk in aging, but varying reports on its effectiveness make it challenging to ascribe what level of exercise will have significant longer-term effects on important functions such as hippocampal-based learning and memory. This study compared the effect of three different 6-month exercise regimens on hippocampal-dependent cognition in healthy, elderly individuals. Participants, aged 65-85 with no cognitive deficits, were randomly assigned to one of three exercise interventions (low (LIT), medium (MIT), and High intensity interval training (HIIT), respectively). Each participant attended 72 supervised exercise sessions over a 6-month period. A total of 151 participants completed all sessions. Cognitive testing for hippocampal performance occurred monthly, as did blood collection, and continued for up to 5 years following initiation of the study. Multimodal 7 Tesla MRI scans were taken at commencement, 6 and 12 months. After 6 months, only the HIIT group displayed significant improvement in hippocampal function, as measured by paired associative learning (PAL). MRI from the HIIT group showed abrogation of the age-dependent volumetric decrease within several cortical regions including the hippocampus and improved functional connectivity between multiple neural networks not seen in the other groups. HIIT-mediated changes in the circulating levels of brain-derived neurotrophic factor (BDNF) and cortisol correlated to improved hippocampal-dependent cognitive ability. These findings demonstrate that HIIT significantly improves and prolongs the hippocampal-dependent cognitive health of aged individuals. Importantly, improvement was retained for at least 5 years following initiation of HIIT, suggesting that the changes seen in hippocampal volume and connectivity underpin this long-term maintenance. Sustained improvement in hippocampal function to this extent confirms that such exercise-based interventions can provide significant protection against hippocampal cognitive decline in the aged population. The changes in specific blood factor levels also may provide useful biomarkers for choosing the optimal exercise regimen to promote cognitive improvement.

Immediate and long-term electrophysiological biomarkers of antidepressant-like behavioral effects after subanesthetic ketamine and medial prefrontal cortex deep brain stimulation treatment.

Both ketamine (KET) and medial prefrontal cortex (mPFC) deep brain stimulation (DBS) are emerging therapies for treatment-resistant depression, yet our understanding of their electrophysiological mechanisms and biomarkers is incomplete. This study investigates aperiodic and periodic spectral parameters, and the signal complexity measure sample entropy, within mPFC local field potentials (LFP) in a chronic corticosterone (CORT) depression model after ketamine and/or mPFC DBS. Male rats were intraperitoneally administered CORT or vehicle for 21 days. Over the last 7 days, animals receiving CORT were treated with mPFC DBS, KET, both, or neither; then tested across an array of behavioral tasks for 9 days. We found that the depression-like behavioral and weight effects of CORT correlated with a decrease in aperiodic-adjusted theta power (5-10 Hz) and an increase in sample entropy during the administration phase, and an increase in theta peak frequency and a decrease in the aperiodic exponent once the depression-like phenotype had been induced. The remission-like behavioral effects of ketamine alone correlated with a post-treatment increase in the offset and exponent, and decrease in sample entropy, both immediately and up to eight days post-treatment. The remission-like behavioral effects of mPFC DBS alone correlated with an immediate decrease in sample entropy, an immediate and sustained increase in low gamma (20-50 Hz) peak width and aperiodic offset, and sustained improvements in cognitive function. Failure to fully induce remission-like behavior in the combinatorial treatment group correlated with a failure to suppress an increase in sample entropy immediately after treatment. Our findings therefore support the potential of periodic theta parameters as biomarkers of depression-severity; and periodic low gamma parameters and cognitive measures as biomarkers of mPFC DBS treatment efficacy. They also support sample entropy and the aperiodic spectral parameters as potential cross-modal biomarkers of depression severity and the therapeutic efficacy of mPFC DBS and/or ketamine. Study of these biomarkers is important as objective measures of disease severity and predictive measures of therapeutic efficacy can be used to personalize care and promote the translatability of research across studies, modalities, and species.

MID-TERM OUTCOMES OF TROCHLEOPLASTY IN THE TREATMENT OF SEVERE TROCHLEAR DYSPLASIA

IntroductionTrochleoplasty is an effective surgical procedure for patients with severe trochlear dysplasia and recurrent patella instability. Previous work has suggested patients demonstrate early improvements in knee function and quality of life. However, concerns regarding longer term outcomes due to the development of stiffness and patellofemoral osteoarthritis remain a concern for these patients. Our aim was to assess mid-term patient-reported outcome and quality of life measures for trochleoplasty performed at a single centre for severe trochlear dysplasia.MethodsRetrospective review of 28 knees (23 patients) having undergone trochleoplasty for severe trochlear dysplasia were reviewed. Due to the non-parametric nature of the data, median and interquartile range (IQR) were determined for pre-operative and mid-term follow-up scores. Statistically significant differences between groups were assessed using paired Wilcoxon-signed rank test with statistical significance set at p&lt;0.05. Data were analysed using a statistical software package (IBM® SPSS® Statistics 26.0).ResultsMedian time from surgery to follow-up for all patients in the series was 5.3 years (IQR 3.9 – 7.0 years). Median pre-operative Kujala score improved from 57.0 (IQR 45 – 66) to 96.3 (IQR 83 -100). Median pre-operative IKDC score improved from 42.6 (IQR 35.9 – 51.3) to 92.6 (IQR 71.6 – 98.7). Median EQ-5D score also improved from 0.691 (IQR 0.414 – 0.727) to 1.000 (IQR 0.8178 – 1.000). Improvement in Kujala scores, IKDC scores and EQ-5D were all statistically significant with p&lt;0.001 in all domains.DiscussionOur data suggests patients experience significant improvements in knee function and quality of life following trochleoplasty surgery for severe dysplasia. We demonstrate an absolute improvement in scores at a mean of 5.3 years follow-up of 39.3 points for Kujala, 50 for IKDC and 0.309 for EQ-5D. Minimal clinically important differences (MCID) have been reported to be in the region of 10 for the Kujala score, 8.8–15.6 for IKDC and 0.085 for EQ-5D. Our data shows improvements which far exceed the published MCID, suggesting trochleoplasty confers a large treatment effect and patients benefiting from sustained improvements in knee function and overall quality of life at mid-term follow-up.ConclusionFollowing trochleoplasty for severe trochlear dysplasia, patient reported outcomes demonstrate continued improvements in knee function and quality of life at mid-term (5-year) follow-up. There is a large absolute treatment effect which likely impacts on both physical and psychological wellbeing for these patients. Continued surveillance of patient reported outcomes in this clinically complex cohort is indicated.

Evaluating purified exosome product and its role in neurologic and functional recovery following spinal cord injury in female rats

Introduction Exosomes represent extracellular vesicles that mediate intercellular interactions and have been extensively studied for their therapeutic potential. Purified exosomes product (PEP) from human plasma is reported to aid in tissue repair but has never been evaluated as a potential therapy for spinal cord injury (SCI). Objective We aim to investigate the effects of PEP on axon myelination, reduction in cavity size, and functional improvements in rats following SCI. Methods Following T9-T10 laminectomy and contusion to the spinal cord, female rats received either intrathecal (IT) PEP, IT ringer-lactate solution (RL), intravenous (IV) PEP, or IV RL one day post injury. Rats underwent behavioral assessments each week for 10 weeks following SCI. After 10 weeks, histological evaluations were performed to quantity axon myelination and cavity size. Results The IT PEP group had significantly (P ≤ 0.05) more myelinated axons 1000 μm rostral to the injury, at the epicenter, and 1000 μm caudal of the injury (34.3 ± 3.1, 27.7 ± 2.1, and 32.0 ± 1.7, respectively) compared to the IT RL group (27.3 ± 2.5, 17.3 ± 2.5, and 23.3 ± 2.5, respectively). In addition, IT PEP rats had significantly reduced cavity size at the injury epicenter compared to controls (28.31%±1.74% vs. 34.39%±3.78%, respectively). Lastly, functional improvements were observed and sustained beginning at the 31 days following injury. The IV PEP group did not show sustained functional improvement compared to the IV RL rats. Conclusion Our results suggest that IT PEP injection may yield beneficial effects following SCI. However, further studies are warranted to investigate the role of PEP following SCI and to optimize its potential for clinical translation.

Adults with congenital heart disease and pulmonary arterial hypertension: Quantitative assessment of haemodynamic parameters under disease targeting therapy - A retrospective multicentre analysis

Abstract Background Pulmonary arterial hypertension (PAH) occurs in approximately 10% of adults with congenital heart disease (ACHD), usually develops secondary to intra- or extra-cardiac shunts resulting in pressure and/or volume overload in the pulmonary circulation, and is associated with increased morbidity and mortality. Treatment strategies for PAH-ACHD include disease targeting therapies (DTT), such as phosphodiesterase-5 inhibitors (PDE5i) and endothelin receptor antagonists (ERA). Data regarding the impact of DTT on cardiopulmonary haemodynamics in PAH-ACHD are scarce. Purpose Aim of this study was to quantify effects of DTT on cardiopulmonary haemodynamics (assessed by right heart catheterisation [RHC]) and on key non-invasive functional parameters contributing to ESC/ERS risk status in PAH-ACHD patients, as applied in real-world clinical practice. Methods We retrospectively analysed the effect of DTT in PAH-ACHD patients who had undergone RHC in adulthood at baseline (treatment-naïve) between 2000 and 2022, with at least one follow-up RHC during DTT, in six expert centres in Europe. Clinical characteristics (WHO functional class [WHO-FC], 6-minute walking distance [6MWD], N-terminal pro-brain natriuretic peptide [NTproBNP] and measures of RHC (systemic/ pulmonary cardiac output, systolic/diastolic/mean pulmonary arterial pressure [sPAP, dPAP, mPAP], and pulmonary arterial wedge pressure [PAWP]) were collected. Pulmonary vascular resistance/arterial compliance (PVR+PAC) and stroke volume index (SVI) were calculated. Results 44 patients (70% female, mean age 45±15 years) were included. Underlying CHD was a pre- or post-tricuspid shunt in 35% and 63%, respectively. 14% had complex CHD, 7% had innate left heart disease, and 21% presented with Eisenmenger´s syndrome. At baseline 71% were in WHO-FC III/IV, 6MWD was 371±105 m, and NTproBNP was 673 [446–1021] ng/l. On RHC, mPAP was 58±15 mmHg, PVR 11 [7–17] wood units (WU), SVI 32 [27–44] ml/min/m2, CI 2.7±1.0 l/min/m2, and PAC 1.0 [0.7–1.4] ml/mmHg. DTT was started in all patients after baseline RHC. 81% received monotherapy (34% PDE5i, 66% ERA) and 19% received upfront combination therapy (PDE5i+ERA). Follow-up RHC was performed 15 [5–33] months after baseline RHC. At follow-up, WHO-FC and NTproBNP (562 [428-762] ng/l) significantly improved (p&amp;lt;0.001 and p=0.021, respectively), as did hemodynamic measures: mPAP (53±15 mmHg, p&amp;lt;0.001), PVR (9 [5–10] WU, p&amp;lt;0.001), SVI (37 [30–49] ml/min/m2, p=0.010), PAC (1.3 [1.0–1.7] ml/mmHg, p&amp;lt;0.001), and CI (3.1±1.1 l/min/m2, p=0.001). In contrast, 6MWD showed subtle change (379±111 m, p=0.164). After follow-up RHC, DTT was escalated in 78% of patients. Conclusions In PAH-ACHD patients, DTT was associated with a moderate but sustained haemodynamic and functional improvement after 15 months. Repeat RHC triggered treatment escalation in most patients. Therefore, ongoing vigilance for PAH-ACHD patients and subsequent treatment optimisation is warranted.

Abstract 12927: Impact of AAV- MYBPC3 Gene Transfer on Heart Structure and Function in Human and Mouse Models of Hypertrophic Cardiomyopathy

Background: Hypertrophic cardiomyopathy (HCM) is a life-threatening inherited heart disease characterized by left ventricular hypertrophy and diastolic dysfunction. The most common cause of HCM is genetic variants in MYBPC3 , encoding cardiac myosin binding protein C (cMyBP-C), a sarcomeric protein with structural and regulatory roles. The majority of MYBPC3 gene variants are truncating leading to protein haploinsufficiency. Hypothesis: Transfer of a functional copy of MYBPC3 to heart muscle deficient in cMyBP-C will lead to sustained improvements in cardiac function. Aims: To determine whether BMN 293 (AAV-hMYBPC3) can restore cMyBP-C levels in the sarcomere and halt and/or reverse disease progression in non-clinical models of genetic HCM due to MYPBC3 deficiency. Methods: BMN 293 is an adeno-associated virus (AAV) vector that encodes wild-type human MYBPC3 under the control of a cardiomyocyte-selective promoter. We transduced human iPSC-derived cardiomyocytes and engineered heart tissues (EHTs) carrying a compound heterozygous truncating MYBPC3 mutation (MYBPC3 -/- ) with BMN 293 and assessed cMyBP-C levels and contractile parameters. We also systemically administered BMN 293 to MYBPC3 -/- mice and assessed cardiac distribution of human cMyBP-C by molecular and histological methods and determined its impact on left ventricular hypertrophy and function by echocardiography and other imaging techniques. Results: BMN 293 transduction of human iPSC MYBPC3 -/- cardiomyocytes and EHTs resulted in high levels of human MYBPC3 mRNA and cMyBP-C protein, correct incorporation of cMyBP-C into the sarcomere, and complete normalization of contractile kinetics. BMN 293 was well tolerated in MYBPC3 -/- mice and resulted in uniform restoration of cMyBP-C expression throughout the heart and significant correction of structural and functional cardiac abnormalities. Conclusions: A single IV infusion of BMN 293 to MYBPC3 -/- mice resulted in early and sustained reduction in left ventricular hypertrophy and durable improvements in diastolic function.

Deep brain stimulation in multiple sclerosis-associated tremor. A large, retrospective, longitudinal open label study, with long-term follow-up.

Tremor affects up to 25%-58% in multiple sclerosis (MS) population. Deep-brain stimulation (DBS) of the ventral-intermediate nucleus (VIM) of the thalamus is considered as a potential option following medical treatments. Long term DBS efficacy is not well known in these patients with a poor outcome mostly related to disease progression. To report a large and retrospective study of thalamic DBS in MS tremor. We conducted a large and retrospective study of patients with MS disabling and pharmacologically resistant upper limb tremor, who underwent thalamic DBS procedure from January 1992 to January 2015 in University Hospital of Henri Mondor, France. Demographic data, clinical assessment and activity daily living were collected. A three-month and twelve-month post-operative assessment with clinical and functional rating scales have been achieved, as well as long term follow-up for most patients. One hundred and four patients underwent DBS procedure. There were 71 female (68%) and 33 male (32%). At three-month post-operative assessment, 64% patients were improved clinically and functionally. Among these, 93% of patients kept a good efficacy at one-year post-operative assessment. Mean duration of follow-up for these patients was 6 years. We described a long-term sustained clinical and functional improvement in this large and retrospective report of thalamic DBS. This neuromodulation approach could be a therapeutic option for all severe upper extremity refractory tremor in MS patients.

Sirolimus Long-Term Tolerability and Impact on Kidney Function in Lung Transplantation: A Single-Center Experience

After lung transplant, 2 common complications are calcineurin inhibitor (CNI) induced nephrotoxicity and bronchiolitis obliterans syndrome. The objective of this study was to investigate the long-term effects of sirolimus conversion after lung transplantation. This was a retrospective cohort study of patients who had undergone lung transplantation at a single center from June 2003 to December 2016. We compared patients converted to a sirolimus-based regimen to those maintained on our standard tacrolimus-based regimen. Kidney function, pulmonary function, and immunosuppression concentrations were compared between the groups. Additionally, indications, toxicity monitoring parameters, and discontinuation rates for sirolimus were collected. During the study period, 176 of the 205 patients who underwent lung transplants were converted to a sirolimus-containing regimen (86%). The most common reason for sirolimus initiation was impairment of kidney function or CNI-associated neurotoxicity. Sirolimus was initiated at a median of 150 days post-transplantation and continued for a medium time of 5.02 (2.27-7.85) years. Of those patients converted to sirolimus, 39 (22%) had sirolimus subsequently discontinued secondary to an adverse event. No difference in pulmonary function was found between the groups at 1- and 3-years post-transplantation. In the sirolimus group, the median estimated glomerular filtration rate improved by 8.6 mL/min/1.73 m2 at 3 months post-conversion (P < .001), which was maintained at both 1 and 3 years (P=.014 and .025, respectively). Sirolimus is a viable immunosuppressant option after lung transplant, which successfully allows for the reduction or withdrawal of the CNI, resulting in sustained improvement in kidney function.

Long-term clinical outcomes of elexacaftor/tezacaftor/ivacaftor therapy in adults with cystic fibrosis and advanced pulmonary disease

BackgroundThe combination of cystic fibrosis transmembrane conductance regulator (CFTR) modulators elexacaftor, tezacaftor and ivacaftor (ELX/TEZ/IVA) has been approved for treatment of cystic fibrosis (CF) patients (pwCF) homozygous and heterozygous for Phe508del. We aim to assess the long-term effects of ELX/TEZ/IVA therapy on clinical outcomes in severe pwCF. MethodsLung function, pulmonary exacerbation (PEx), sweat chloride concentration, body mass index (BMI) and the respiratory domain of the cystic fibrosis questionnaire-revised (CFQ-R RD) were prospectively evaluated in a cohort of pwCF who were candidates for inclusion in a compassionate program of ELX/TEZ/IVA therapy. All procedures were performed at baseline and then at 12 and 24 months after initiation of modulator therapy. The number of PExs in the year before the study enrollment was collected from our records. ResultsThirty-six adult pwCF (median age 36.7 years; BMI 19.8 kg/m2; FEV1 36.5% predicted) were recruited from 2019. At 12 and 24 months after initiation, the absolute change in ppFEV1 (percent predicted forced expiratory volume in 1 s) from baseline was +12.5% (p < 0.0001) and +13% (p < 0.0001), respectively. A median of 4.0 exacerbations per patient was reported in the preceding year, while the median number of PExs was 0.0 and 1.0 after 12 and 24 months, respectively, of modulator therapy (both p < 0.0001). After 12 and 24 months of ELX/TEZ/IVA therapy, the CFQ-R RD score improved by 22.4 points (p < 0.0001) and 16.7 points (p < 0.0001), and sweat chloride levels decreased by 65.5 mmol/L (p < 0.0001) and 60 mmol/L (p < 0.0001), respectively. BMI significantly increased. ConclusionsLong-term ELX/TEZ/IVA combination therapy markedly impacts the clinical status of patients with severe CF, showing a sustained improvement in lung function and PEx rate.

Atrial septal defect-associated pulmonary hypertension with decompensated heart failure: outcomes after fenestrated device closure.

Up to 90% of adults with untreated atrial septal defect will be symptomatic by 4th decade, and 30-49% will develop heart failure. 8-10% of these patients have pulmonary arterial hypertension with a female predominance regardless of age. We aimed to demonstrate that fenestrated closure can be safely performed in patients with decompensated heart failure and atrial septal defect-associated pulmonary arterial hypertension with improved outcome. Transcatheter fenestrated atrial septal defect closures (Occlutech GmbH, Jena, Germany) were performed on a compassionate-use basis in 5 consecutive adult patients with atrial septal defect-associated pulmonary arterial hypertension and severe heart failure with prohibitive surgical mortality risks. Change in systemic oxygen saturation, 6-minute walk test, NYHA class, echocardiographic and haemodynamic parameters were used as parameters of outcome. All patients were female, mean age 48.8 ± 13.5 years, followed up for a median of 29 months (max 64 months). Significant improvements observed in the 6-minute walk test, and oxygen saturation comparing day 0 time point to all other follow-up time points data (B = 1.32, SE = 0.28, t (22.7) = -4.77, p = 0.0001); and in the haemodynamic data (including pulmonary vascular resistance and pulmonary pressure) (B = -0.60, SE = 0.22, t (40.2) = 2.74, p = .009). All patients showed improved right ventricular size and function along with NYHA class. There were no procedure-related complications. Fenestrated atrial septal defect closure is feasible in adults with decompensated heart failure and atrial septal defect-associated pulmonary arterial hypertension. It results in sustained haemodynamic and functional improvement.

Chronic PCSK9 inhibitor therapy leads to sustained improvements in endothelial function, arterial stiffness, and microvascular function.

Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) effectively decrease low-density lipoprotein cholesterol (LDL-C) and reduce cardiovascular events in patients at very high cardiovascular risk. Recent short-term studies suggest a partially LDL-C independent beneficial effect of PCSK9 inhibitor (PCSK9i) therapy on endothelial function and arterial stiffness, whereas it is unknown if this effect persists and what the effect is on microcirculation. To investigate the effects of PCSK9i therapy on vascular parameters beyond its lipid lowering effect. In this prospective trial, 32 patients at very high cardiovascular risk and indication for PCSK9i therapy were included. Measurements were performed at baseline and after 6 months of PCSK9i treatment. Endothelial function was assessed as flow-mediated dilation (FMD). Arterial stiffness was measured as pulse wave velocity (PWV) and aortic augmentation index (AIx). Peripheral tissue oxygenation (StO2) as a marker of microvascular function was assessed at the distal extremities using near-infrared spectroscopy camera. Six months of PCSK9i therapy decreased LDL-C levels from 141 ± 54 to 60 ± 30 mg/dl (-56 ± 21 %, p < 0.001), FMD significantly increased from 5.4 ± 1.7 % to 6.4 ± 1.9 % (+19 ± 10 %, p < 0.001), PWV decreased in male patients significantly from 8.9 ± 2.1 to 7.9 ± 1.5 m/s (-12 ± 9 %, p = 0.025). AIx decreased from 27.1 ± 10.4 % to 23.0 ± 9.7 % (-16 ± 14 %, p < 0.001), StO2 significantly increased from 67 ± 12 % to 71 ± 11 % (+7 ± 6 %, p = 0.012). Brachial and aortic blood pressure showed no significant changes after six months. There was no correlation between LDL-C reduction and changes in vascular parameters. Chronic PCSK9i therapy is associated with sustained improvements in endothelial function, arterial stiffness, and microvascular function independent from lipid lowering.