Citations

Abstract Few medical decisions have a greater impact on the life of patients affected by either long QT syndrome (LQTS) or catecholaminergic polymorphic ventricular tachycardia (CPVT) as the one to recommend an implantable cardioverter defibrillator (ICD) or not. If the decision is correct, a life might be saved or a litany of ICD-related complications might be avoided. If it is wrong, well you can fill in the blanks. Many physicians take the fastest and simplest road by recommending an ICD which represents ‘double protection’: for the patients and for themselves. Our opinion is that this requires a very careful consideration about the pros and cons and should be taken neither lightly nor quickly. Moreover, there is another side to this moon, which also requires more thought than usually assumed. As to LQTS and CPVT, the current data strongly indicate that when high risk patients are treated with either combination drug therapy comprising beta blockers and mexiletine (LQTS) or beta blockers and flecainide (CPVT) or triple therapy with left cardiac sympathetic denervation as the treatment intensifier, mortality is close to zero and most patients have no life-threatening events. Thus, we stand by our view that most patients still do not need and should not receive an ICD. However, sometimes patients are desperately worried for the fear of dying suddenly and ask for an ICD despite being at low risk. Their request should be listened to, respected, and considered with empathy because immortality cannot be guaranteed. We believe that both expertise and compassion are quintessential to practicing the science and art of medicine.

BACKGROUND: Fontan conversion (FC) is associated with a lower risk of atrial arrhythmias and thromboembolism, but it is unknown whether FC improves long-term survival. The purpose of this study was to assess the impact of FC on transplant-free survival. METHOD: Adults with Fontan palliation were divided into 3 groups: (1) atriopulmonary Fontan connection; (2) atriopulmonary Fontan and subsequent FC to total cavopulmonary connection (TCPC); (3) TCPC at initial Fontan operation. The risk of death/transplant was compared between the 3 groups using Cox regression analysis. RESULTS: We studied 534 patients (age 27±9 years; males [N=298; 56%]). Patients were divided into atriopulmonary Fontan group (N=199, 37%); FC-TCPC (N=138, 26%); and TCPC (N=197, 37%). The FC-TCPC and TCPC groups have similar 15-year incidence of death/transplant (42% versus 47%; P =0.8), even after excluding the 8% operative mortality in the FC-TCPC group (38% versus 47%; P =0.3). On multivariable analyses, neither FC nor the type of Fontan connection was associated with death/transplant. Rather, the risk factors for death/transplant were older age, hepatorenal dysfunction, heart failure, and higher Fontan pressures. The prevalence and severity of these comorbidities increased with age, suggesting that these factors reflect the duration of Fontan physiology, rather than the type of Fontan connection. CONCLUSIONS: These findings, in addition to the high operative mortality associated with FC, suggest that this may not be the optimal treatment option for most adults with atriopulmonary Fontan presenting with Fontan failure. Duration of Fontan physiology rather than the type of Fontan connection may be the main determinant of outcomes.

Background Secondary lymphedema frequently occurs following surgery, malignancy, trauma, or radiation and is characterized by limb swelling, discomfort, and recurrent infections. Two advanced supermicrosurgical techniques—lymphovenous anastomosis (LVA) and vascularized lymph node transfer (VLNT)—have recently gained popularity as treatment options. However, long-term outcome data for these procedures remain limited. This systematic review and meta-analysis aim to evaluate the long-term efficacy of LVA and VLNT in patients with secondary lymphedema followed for more than 2 years postoperatively, focusing on outcomes such as cellulitis rates and limb circumference. Methods This study followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Inclusion criteria encompassed studies involving adult patients with secondary lymphedema treated with LVA or VLNT and with at least 24 months of follow-up. The primary outcomes were annual cellulitis incidence and limb circumference change, analyzed separately for upper and lower extremities. Meta-analysis was conducted using R version 4.3.1. Pooled effect sizes were estimated using random-effects models. Subgroup and sensitivity analyses were also performed. Results A total of 23 studies met the inclusion criteria, covering 648 limbs treated with either LVA (n = 216) or VLNT (n = 432). The weighted average patient age was 56.3 years, and the cohort was predominantly female (99.9%). For LVA, the pooled mean reduction in annual cellulitis events was −1.13 (95% confidence interval [CI], −1.70 to −0.57) for upper extremities and −1.32 (95% CI, −2.08 to −0.55) for lower extremities. VLNT yielded greater reductions in cellulitis, with pooled mean differences of −2.43 (95% CI, −3.36 to −1.50) and −1.38 (95% CI, −2.11 to −0.65) for upper and lower limbs, respectively. Additionally, VLNT reduced limb circumference by 42.7% (95% CI, 36.7–49.7) in upper extremities and 21.98% (95% CI, 19.8–24.4) in lower extremities. Conclusion LVA and VLNT both result in durable, long-term improvements in cellulitis rates, and VLNT was shown to reduce limb circumference. Given the significant impact on patient quality of life, these interventions should remain integral to the treatment algorithm for secondary lymphedema.

Abstract Objective This study reports development and validation of a deep learning seizure detection algorithm for two‐channel subscalp electroencephalographic (EEG) recordings. Ultra‐long‐term monitoring of people with epilepsy may produce new insights into the timing and pattern of their seizures and may pave the way for novel therapeutic options. Although EEG is the accepted standard for epilepsy monitoring, ultra‐long‐term EEG recordings generate a massive quantity of data and are not reasonably reviewable in full by human readers. Methods The convolutional neural network‐bidirectional long short‐term memory (CNN‐BiLSTM) hybrid algorithm uses nine layers, operating on channel spectrograms 5 min in length with 50% overlap. Retrospective subscalp EEG data from 16 patients recorded at three centers were available for algorithm development and testing. EEG was recorded for a median of 63 days (range = 9–508), and a median of 17 seizures (range = 0–96) were recorded. Training data were augmented with scalp EEG seizures, and performance was benchmarked against a conventional spectral power classifier algorithm. We also evaluated an intrapatient training–testing approach where the algorithm was trained on the first 45% of data. Results The CNN‐BiLSTM trained on scalp EEG and subscalp EEG achieved an area under the receiver operating characteristic curve (AUROC) of .98 and an area under the precision–recall curve (AUPRC) of .50, which correspond to 94% sensitivity with 1.11 false detections per day. The same model trained on iEEG achieved only AUROC = .94 and AUPRC = .36. The conventional spectral band power detector achieved AUROC = .93 and AUPRC = .38. The CNN‐BiLSTM detector trained on the earliest half of the subscalp EEG data achieved AUROC = .93 and AUPRC = .37, corresponding to 87% sensitivity and 5.9 false detections per day. Significance High sensitivity and specificity are possible in automated seizure detection in two‐channel subscalp EEG data using a CNN‐BiLSTM framework. Performance of the detector is superior using subcutaneous EEG data for training rather than intracranial EEG, but addition of scalp EEG seizures for training was helpful.

Abstract BACKGROUND Mirdametinib is the first FDA-approved MEK1/2 inhibitor for both adults and children (≥2 years) with NF1 who have symptomatic PN not amenable to complete resection. We report updated results from the LTFU phase of the pivotal, phase 2b ReNeu trial (NCT03962543) evaluating the efficacy and safety of mirdametinib. MATERIALS AND METHODS In ReNeu, mirdametinib capsules or tablets for oral suspension (2 mg/m2 BID, max 4 mg BID) are administered in 3-weeks-on/1-week-off 28-day cycles. Following the 24-cycle (~2 years) treatment phase, patients could continue mirdametinib in an optional LTFU phase. These analyses are inclusive of the treatment and LTFU phases (data cutoff: June 12, 2024; an additional 9 months of cumulative data following the primary analysis). Exploratory analyses reported here included confirmed objective response rate (ORR; proportion of patients with ≥20% reduction of target PN volume from baseline on consecutive MRI scans within 2 to 6 months, assessed by blinded independent central review), duration of response (DoR), change from baseline in target PN volume, and safety. RESULTS Fifty-eight adults and 56 children were dosed with mirdametinib. Median (range) duration of mirdametinib treatment was 21.8 (0.4, 54.4) months in adults and 25.4 (1.6, 48.5) months in children. Among LTFU-eligible patients, 26/31 (84%) adults and 32/37 (86%) children entered the LTFU. Confirmed ORR was 47% (27/58; 95% CI, 33%, 60%) in adults and 55% (31/56; 95% CI, 42%, 69%) in children. Of patients with a confirmed objective response, 18 adults and 19 children achieved a deep response (best target PN volume reduction from baseline of >50%). Median (range) best percentage change from baseline in target PN volume was -41% (-90%, 13%) in adults and -43% (-98%, 48%) in children. Median DoR was not reached. Treatment-related adverse events (TRAEs) in ≥25% of patients were dermatitis acneiform, diarrhoea, nausea, and vomiting in adults, and diarrhoea, dermatitis acneiform, and paronychia in children. Grade ≥3 TRAEs occurred in 17% of adults and 25% of children. Dose interruptions, dose reductions, and discontinuations due to TRAEs occurred in 9%, 17%, and 22%, respectively, of adults, and in 14%, 14%, and 9%, respectively, of children. CONCLUSIONS An increase in confirmed ORR was observed with longer duration of mirdametinib treatment, with additional deep responses achieved in both adults and children with NF1-PN. Mirdametinib continued to be well tolerated with a manageable safety profile and no new safety signals identified in the LTFU phase. SUPPORTED BY SpringWorks Therapeutics, Inc.

Abstract Background Pathogenic variants in the DMD gene are associated with Duchenne and Becker muscular dystrophy (DMD/BMD). Professional medical societies currently recommend DMD carrier screening for all patients who are pregnant or considering pregnancy. Such testing may identify intragenic duplications of DMD (i.e., involving one or more exons but fully contained with the gene) in patients without a personal or family history of DMD/BMD. These incidentally detected DMD intragenic duplications, however, pose significant challenges for variant interpretation. Pathogenicity of an intragenic duplication depends on its structural configuration. Tandem duplications may cause reading frame disruption and gene loss-of-function; conversely, non-tandem duplications may not disrupt gene function. Current carrier screening assays cannot determine the structural configuration of an intragenic duplication. The current guidelines (e.g., the ClinGen PVS1 decision tree) presume intragenic duplications are in tandem unless proven otherwise. If this presumption of tandem configuration is inaccurate, it may lead to overestimation of variant pathogenicity, potentially resulting in unnecessary invasive procedures (e.g., amniocentesis for prenatal diagnosis) and/or having other negative impacts with regards to prenatal decision-making. This study aims to evaluate the validity of this presumption for incidentally detected DMD intragenic duplications. Methods We performed high-coverage whole-genome long-read sequencing on the PromethION instrument (Oxford Nanopore Technologies) for 15 cases with previously identified DMD intragenic duplications. Among these cases, four had personal or family history of DMD/BMD, while 11 had no known history (i.e., incidentally detected). The structural configurations of the duplications were determined by an in-house bioinformatics tool and manual inspection of the alignment files. Results In all 4 cases with a known personal or family history of DMD/BMD, the DMD intragenic duplications were confirmed to be in tandem, aligning with expectations of their pathogenicity. Interestingly, among the 11 cases with incidentally detected DMD intragenic duplications, seven (64%) were found to involve interspersed duplications. In five of these seven interspersed duplication cases, the involved DMD exons were co-duplicated with distinct segments of the Xp arm located 0.5–30 Mb away, forming complex structural variants. In another case, the duplicated DMD exons have inserted into the Xq arm, about 90 Mb downstream of DMD. The final case involved the duplicated DMD exons inserted into a repetitive region most consistent with 9q12 (i.e., the 9qh region). Conclusions Our study reveals that while DMD intragenic duplications in patients with a personal or family history of DMD/BMD were consistently in tandem, a substantial 64% of incidentally detected DMD intragenic duplications were not in tandem. These findings have important implications for both clinicians and laboratorians. They challenge the presumption of tandem configuration for DMD intragenic duplications in individuals where the variants were identified incidentally, e.g., through carrier screening in those without a family history of DMD/BMD. In these cases, we recommend classifying the DMD intragenic duplications as variants of uncertain significance (VUS), unless there is evidence of tandem configuration.

AbstractThumb carpometacarpal (CMC) arthritis is a common and sometimes debilitating condition with a variety of surgical treatments. Pyrocarbon thumb CMC hemiarthroplasty is one option, which has demonstrated promise; however, no long-term outcomes have been reported.We performed a retrospective institutional review of 106 primary thumb CMC pyrocarbon hemiarthroplasties with a minimum of 1 year, median 6.1-year follow-up. We analyzed rates of pain relief, reoperation, and implant failure as well as biomechanical, radiographic, and patient-reported outcomes.Pain was significantly decreased after surgery. Radial and palmar abduction were modestly improved postoperatively (increased from 40–50 degrees). Implants showed high rates of radiographic osteolysis (53%) and subsidence (44%). Two-, 5-, and 10-year rates of reoperation (18, 21, 21%) and implant removal (15, 19, and 19%), respectively.Pyrocarbon thumb CMC hemiarthroplasty provides high rates of pain relief and preservation of pinch and grip strength. Patients had modest improvement in radial and palmar abduction; however, hemiarthroplasty was associated with moderate rates of reoperation and implant revision.Therapy Level IV.

(1) Background: Cranial neuropathy is a commonly encountered condition with various underlying etiologies. While carotid artery dissection (CAD) is a well-recognized cause of ischemic stroke, CAD-related cranial neuropathy is rare and poorly characterized. We have conducted a comprehensive review of the published literature to better characterize its clinical course and outcomes. (2) Methods: We systematically reviewed the PubMed, CENTRAL, Ovid MEDLINE, and Embase literature for CAD-related cranial neuropathy. Data extracted included demographics, affected cranial nerves, symptoms, time course, diagnostic approach, and therapeutic interventions. (3) Results: From 635 screened studies, 97 met the inclusion criteria, yielding data on 108 patients with CAD- or dissecting pseudoaneurysm (dPSA)-related cranial neuropathy. The hypoglossal nerve (CN XII) was most commonly affected (76%), and the distal cervical internal carotid artery was the most frequently involved segment (89%). Most patients (90%) were treated with antithrombotic therapy which included either antiplatelets (47%) or anticoagulants (43%). Thirteen patients (12%) underwent endovascular intervention, nearly all with a diagnosed dPSA (mean size, 14.8 mm). Outcomes were favorable, with 94% experiencing symptom improvement. (4) Conclusions: Despite inherent limitations, our study demonstrates that CAD-related cranial neuropathy is typically a benign condition that has excellent outcomes with medical management. Endovascular treatment is rarely performed and is primarily reserved for cases involving diagnosed dPSA.

Objectives: Non-steroidal anti-inflammatory drugs (NSAID) are widely used for pain control in musculoskeletal conditions. The purpose of this study was to determine if long-term use of NSAIDs increases the incidience of rotator cuff tears. Methods: A retrospective comparative study using a national insurance database was performed. All patients who had a diagnosis of long-term NSAID use with active records in the database for at least 1 year or 2 years were identified. These patients were matched 1:1 to controls without NSAID use based on age, gender, and Elixhauser comorbidity index. Rotator cuff tendon tear rates were compared between each group. Sub-group analyses in the following age-ranges for each sex was also done: 35-45, 46-55, 56-65, 66-75. Results: A total of 499,240 patients who had a history of long-term NSAID use were evaluated. 10,180 patients sustained a rotator cuff tear compared to 7,471 control patients (2.04% vs. 1.50%, respectively), with an adjusted OR of 1.18 (95% CI: 1.14-1.21; P<0.001). Male chronic NSAID users in the 46 to 55 age range had higher rates of rotator cuff tears compared to control patients of the same demographics (OR: 1.41; 95% CI 1.30 – 1.52; P<0.001). Female chronic NSAID users in the 46 to 55 age range had higher rates of rotator cuff tears compared to control patients of the same demographics (OR: 1.40; 95% CI 1.31 – 1.49; P<0.001). Comparable results were seen in the 56-65 age range for both males and females. Further, chronic NSAID users (n=1,888; 18.5%) underwent rotator cuff repair at higher rates compared to controls (n=1,223; 16.4%). Conclusions: Long-term NSAID use significantly increases the rates of rotator cuff tendon tears at the 1-year and 2-year follow-up periods, which is particularly notable in the middle-aged population. These findings suggest that middle aged patients with long-term NSAID use may be at a higher risk for rotator cuff tendon tears.