Arthroscopic subscapularis repair using the subscapularis interlocking (SICK)-stitch technique leads to restoration of clinical function with low complication and revision rates.

Background: The purpose of this study is to determine the mid-term outcome after arthroscopic subscapularis tendon (SCP) reconstruction using the subscapularis interlocking (SICK)-stitch technique. The hypotheses are that arthroscopically repaired SCP lesions using the SICK-stitch show a good restoration of shoulder function with low complication and failure rates. Methods: This is a retrospective monocentric study of n = 199 patients (n = 106 female) with arthroscopically treated SCP tears with the interlocking (SICK) stitch technique from July 2013 to October 2018. Inclusion criteria: minimum follow-up of 2 years. Exclusion criteria: irreparable and massive cuff tears, osteoarthritis, and fractures. The postoperative assessment consisted of the range of motion, constant score, simple shoulder test, simple shoulder value, disability of the shoulder and arm score, short form 12, and patient satisfaction. Results: Mean age was 61 years (25-83); n = 4 (2%) patients were lost to follow-up with mean follow-up time of 63.6 months (36-96). Additional supraspinatus tendon lesions (n = 147) were repaired in n = 101 cases. SCP grading (n = 69) (35% traumatic) (Fox/Romeo): n = 113 grade II, n = 71 grade III, n = 11 grade IV. A positive preoperative lift-off test (n = 132, 68%) was corrected in n = 124 (94%) of cases. Ninety seven percent of patients would undergo surgery again with a mean satisfaction score of 14.4/15. Results at final follow-up (data: mean pre; post; P value): lexion (130; 166; .001), abduction (123;159; .001), external rotation (35;82; .001), internal rotation (52; 68; .07), constant score (50; 82; .001), disability of the shoulder and arm score (40; 19; .001), simple shoulder test (5; 10; .001), and simple shoulder value (44; 83; .001) significantly improved. The mean physical health scale short form 12 was 46 (24-63) and 51 (15-66) for mental health. Age, body mass index, SCP-grading, and supraspinatus tendon repair did not significantly affect any outcome parameter. Three (1.5%) patients underwent revision surgery, of which 1 (0.5%) had an infection. Conclusion: Two years after arthroscopic SCP repair using the SICK-stitch technique, we observed excellent restoration of clinical function with low complication and revision rates. The SICK-stitch technique thus represents a good and reliable therapeutic option for the arthroscopic repair of SCP lesions.

Midterm outcomes of autologous bridging of rotator cuff tears with an autologous tendon patch (TEAR patch).

BACKGROUND: Large and massive rotator cuff tears and tears after failed surgical repair are a challenging clinical problem with different treatment options. The purpose of the study was to evaluate the midterm outcomes after rotator cuff repair (RCR) with autologous hamstring tendon graft bridging (tissue-enhanced autologous rotator cuff repair [TEAR] patch) with the hypothesis that outcomes would be reasonable and complication rates would be low. METHODS: This is a retrospective case series study of patients who underwent open RCR using a TEAR patch from June 2015 to March 2019. The exclusion criteria included evidence of cuff tear arthropathy, advanced fatty infiltration, moderate-to-severe arthropathy, and workers compensation board or litigation involved. Clinical outcome measures were Constant score; Disabilities of the Arm, Shoulder and Hand score; Simple Shoulder Test; Subjective Shoulder Value; range of motion (ROM); and manual muscle test for forward elevation, abduction, external and internal rotation, patient satisfaction, and willingness to perform the operation again. Radiographic outcome measures were magnetic resonance imaging, ultrasound, and radiographs: graft integrity and acromiohumeral distance (AHD). RESULTS: A total of 44 patients were followed (89%) for ≥2 years (45 shoulders, mean age 60.3 years [48-76 years], mean follow-up 4.3 years [2-6 years]). All clinical outcome measures (Constant score, Disabilities of the Arm, Shoulder and Hand score, Simple Shoulder Test, Subjective Shoulder Value, ROM, and manual muscle test) demonstrated significant improvement except active external and internal rotation. At 2 years of follow-up, the mean patient satisfaction was high (12.2 of 15 points), and 33 of 38 patients (73.3%) would perform the operation again. A perfect graft integration was observed in 30 (66.7%), a small gap in 7 (15.6%), a retear in 3 (7%), and a complete failure of the tendon patch in 5 (11%) patients. Graft integrity was strongly correlated with the postoperative AHD (r = 0.599, P = .001) and the gain in AHD (r = 0.599, P = .001) but not with ROM or patient-reported outcome measures or patient satisfaction. Four patients required revision surgeries (3 due to deep infection and 1 for poor function and pain). CONCLUSIONS: Midterm clinical and radiographic outcomes after RCR with graft bridging using a TEAR patch were reasonable. The procedure resulted in improved shoulder function and a high level of patient satisfaction. The revision rate is acceptable in view of the specific patient group and treatment alternatives. The described technique of the TEAR patch can be a valuable alternative to existing methods and a new autograft source for rotator cuff surgeries that need bridging of a tendon defect.

Clinical benefit, development, innovation, trials, epidemiology, and price for cancer drugs and indications with multiple special FDA designations.

BACKGROUND: This study analyzes the development, US Food and Drug Administration (FDA) approval, benefits, innovation, trials, epidemiology, and price of cancer drugs with multiple special designations: orphan, fast track, accelerated approval, priority review, and breakthrough therapy. METHODS: In total, 355 FDA-approved cancer drug indications with 841 special designations were identified (2012-2022). Trial, epidemiology, and price data were collected from FDA labels, the Global Burden of Disease study, and Medicare and Medicaid. The association between efficacy outcomes and indications' number of special designations were compared in meta-analyses. RESULTS: Median development times were 7.3, 7.8, and 5.4 months (P = .027) for drugs with 0 to 1, 2 to 3, and 4 to 5 special designations, respectively. Multiple special designations were associated with higher biotechnological and clinical innovation. Median patient enrollment in trials were 615, 471, 398, 168, 104, and 120 (P < .001) for indications with 0 to 5 special designations. Drugs for rare diseases supported by open-label phase 1/2 trials of single-arm design were granted more special designations. Hazard ratios for overall survival (0.80 vs 0.73 vs 0.73 vs 0.69 vs 0.56 vs 0.52; P = .003) and progression-free survival (0.70 vs 0.61 vs 0.59 vs 0.44 vs 0.37 vs 0.67; P < .001) substantially declined while tumor response increased with more special designations. Mean monthly prices increased for drugs with 0 to 4 but not 5 special designations ($21 596 vs $14 753 vs $32 410 vs $41 240 vs $38 703 vs $19 184). CONCLUSIONS: Multiple special designations are associated with faster clinical development and greater benefits for patients with unmet needs but also with nonrobust trial evidence and a tendency toward higher drug prices.

Special FDA designations for drug development: orphan, fast track, accelerated approval, priority review, and breakthrough therapy.

BACKGROUND: Over the past decades, US Congress enabled the US Food and Drug Administration (FDA) to facilitate and expedite drug development for serious conditions filling unmet medical needs with five special designations and review pathways: orphan, fast track, accelerated approval, priority review, and breakthrough therapy. OBJECTIVES: This study reviews the FDA's five special designations for drug development regarding their safety, efficacy/clinical benefit, clinical trials, innovation, economic incentives, development timelines, and price. METHODS: We conducted a keyword search to identify studies analyzing the impact of the FDA's special designations (orphan, fast track, accelerated approval, priority review, and breakthrough therapy) on the safety, efficacy/clinical benefit, trials, innovativeness, economic incentives, development times, and pricing of new drugs. Results were summarized in a narrative overview. RESULTS: Expedited approval reduces new drugs' time to market. However, faster drug development and regulatory review are associated with more unrecognized adverse events and post-marketing safety revisions. Clinical trials supporting special FDA approvals frequently use small, non-randomized, open-label designs. Required post-approval trials to monitor unknown adverse events are often delayed or not even initiated. Evidence suggests that drugs approved under special review pathways, marketed as "breakthroughs", are more innovative and deliver a higher clinical benefit than those receiving standard FDA approval. Special designations are an economically viable strategy for investors and pharmaceutical companies to develop drugs for rare diseases with unmet medical needs, due to financial incentives, expedited development timelines, higher clinical trial success rates, alongside greater prices. Nonetheless, patients, physicians, and insurers are concerned about spending money on drugs without a proven benefit or even on drugs that turn out to be ineffective. While European countries established performance- and financial-based managed entry agreements to account for this uncertainty in clinical trial evidence and cost-effectiveness, the pricing and reimbursement of these drugs remain largely unregulated in the US. CONCLUSION: Special FDA designations shorten clinical development and FDA approval times for new drugs treating rare and severe diseases with unmet medical needs. Special-designated drugs offer a greater clinical benefit to patients. However, physicians, patients, and insurers must be aware that special-designated drugs are often approved based on non-robust trials, associated with more unrecognized side effects, and sold for higher prices.

Gene regulation for inflammation and inflammation resolution differs between umbilical arterial and venous endothelial cells.

Systemic inflammation affects the whole vasculature, yet whether arterial and venous endothelial cells differ in their abilities to mediate inflammation and to return to homeostasis after an inflammatory stimulus has not been addressed thoroughly. We assessed gene-expression profiles in isolated endothelial cells from human umbilical arteries (HUAEC) or veins (HUVEC) under basal conditions, after TNF-α stimulation and various time points after TNF-α removal to allow reinstatement of homeostasis. TNF-α regulates the expression of different sets of transcripts that are significantly changed only in HUAEC, only in HUVEC or changed in both. We identified three types of gene regulation, i.e. genes that were significantly regulated after 24 h of TNF-α stimulation but no longer when TNF-α was removed (homeostatic regulation), genes that maintained significantly regulated after TNF-α removal (not homeostatic regulation) and genes that were only significantly regulated when TNF-α was removed (post-regulation). HUAEC and HUVEC quantitatively differed in these types of gene regulation, with relatively more genes being post-regulated in HUAEC. In conclusion our data demonstrate that HUAEC and HUVEC respond intrinsically different to an inflammatory insult. Whether this holds true for all endothelial cells and its relevance for inflammatory insults in different organs during systemic inflammation warrants further studies.

Arthroscopic Posterior HAGL Repair Using a Direct Transaxillary Portal.

Humeral avulsion of the glenohumeral ligament (HAGL lesion) is a challenging problem in surgery for shoulder instability. Open and arthroscopic approaches and techniques have been described to address this issue. Especially posterior HAGL lesions increase the surgical complexity, as open anterior approaches provide limited visibility and access for successful repair. This article describes an alternative technique using an arthroscopic transaxillary approach to deploy the suture anchor with a perpendicular angle to the humeral bone, thus, improving the ability to perfectly position the anchor at the anatomic insertion of the inferior humeral ligament.

Established and Emerging Lipid-Lowering Drugs for Primary and Secondary Cardiovascular Prevention.

Despite treatment with statins, patients with elevated low-density lipoprotein cholesterol (LDL-C) and triglycerides remain at increased risk for adverse cardiovascular events. Consequently, novel pharmaceutical drugs have been developed to control and modify the composition of blood lipids to ultimately prevent fatal cardiovascular events in patients with dyslipidaemia. This article reviews established and emerging lipid-lowering drugs regarding their mechanism of action, development stage, ongoing clinical trials, side effects, effect on blood lipids and reduction in cardiovascular morbidity and mortality. We conducted a keyword search to identify studies on established and emerging lipid modifying drugs. Results were summarized in a narrative overview. Established pharmaceutical treatment options include the Niemann-Pick-C1 like-1 protein (NPC1L1) inhibitor ezetimibe, the protein convertase subtilisin-kexin type 9 (PCSK9) inhibitors alirocumab and evolocumab, fibrates as peroxisome proliferator receptor alpha (PPAR-α) activators, and the omega-3 fatty acid icosapent ethyl. Statins are recommended as the first-line therapy for primary and secondary cardiovascular prevention in patients with hypercholesterinaemia and hypertriglyceridemia. For secondary prevention in hypercholesterinaemia, second-line options such as statin add-on or statin-intolerant treatments are ezetimibe, alirocumab and evolocumab. For secondary prevention in hypertriglyceridemia, second-line options such as statin add-on or statin-intolerant treatments are icosapent ethyl and fenofibrate. Robust data for these add-on therapeutics in primary cardiovascular prevention remains scarce. Recent biotechnological advances have led to the development of innovative small molecules (bempedoic acid, lomitapide, pemafibrate, docosapentaenoic and eicosapentaenoic acid), antibodies (evinacumab), antisense oligonucleotides (mipomersen, volanesorsen, pelcarsen, olezarsen), small interfering RNA (inclisiran, olpasiran), and gene therapies for patients with dyslipidemia. These molecules specifically target new cellular pathways, such as the adenosine triphosphate-citrate lyase (bempedoic acid), PCSK9 (inclisiran), angiopoietin-like 3 (ANGPTL3: evinacumab), microsomal triglyceride transfer protein (MTP: lomitapide), apolipoprotein B-100 (ApoB-100: mipomersen), apolipoprotein C-III (ApoC-III: volanesorsen, olezarsen), and lipoprotein (a) (Lp(a): pelcarsen, olpasiran). The authors are hopeful that the development of new treatment modalities alongside new therapeutic targets will further reduce patients' risk of adverse cardiovascular events. Apart from statins, data on new drugs' use in primary cardiovascular prevention remain scarce. For their swift adoption into clinical routine, these treatments must demonstrate safety and efficacy as well as cost-effectiveness in randomized cardiovascular outcome trials.

[Conversion of anatomic to reverse shoulder arthroplasty : Does it make sense?] / Konversion von anatomischer auf inverse Prothese : Macht das Sinn?

We can observe increasing numbers for the implantation of shoulder endoprostheses in developed industrial countries. This is accompanied by a certain number of revision surgeries. The conversion to reverse arthroplasty systems is by far the most common revision procedure. Depending on the primary implant and the individual situation, the surgical effort and consumption of resources can be substantial. Particularly favorable revision scenarios exist in the conversion of stemless primary implants that are part of a platform system and allow a partial exchange and easy conversion from anatomical to reverse implants.

A Preclinical Study on Brugada Syndrome with a CACNB2 Variant Using Human Cardiomyocytes from Induced Pluripotent Stem Cells.

Aims: Some gene variants in the sodium channels, as well as calcium channels, have been associated with Brugada syndrome (BrS). However, the investigation of the human cellular phenotype and the use of drugs for BrS in presence of variant in the calcium channel subunit is still lacking. Objectives: The objective of this study was to establish a cellular model of BrS in the presence of a CACNB2 variant of uncertain significance (c.425C > T/p.S142F) using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and test drug effects using this model. Methods and results: This study recruited cells from a patient with Brugada syndrome (BrS) and recurrent ventricular fibrillation carrying a missense variant in CACNB2 as well as from three healthy independent persons. These cells (hiPSC-CMs) generated from skin biopsies of healthy persons and the BrS patient (BrS-hiPSC-CMs) as well as CRISPR/Cas9 corrected cells (isogenic control, site-variant corrected) were used for this study. The hiPSC-CMs from the BrS patient showed a significantly reduced L-type calcium channel current (ICa-L) compared with the healthy control hiPSC-CMs. The inactivation curve was shifted to a more positive potential and the recovery from inactivation was accelerated. The protein expression of CACNB2 of the hiPSC-CMs from the BrS-patient was significantly decreased compared with healthy hiPSC-CMs. Moreover, the correction of the CACNB2 site-variant rescued the changes seen in the hiPSC-CMs of the BrS patient to the normal state. These data indicate that the CACNB2 gene variant led to loss-of-function of L-type calcium channels in hiPSC-CMs from the BrS patient. Strikingly, arrhythmia events were more frequently detected in BrS-hiPSC-CMs. Bisoprolol (beta-blockers) at low concentration and quinidine decreased arrhythmic events. Conclusions: The CACNB2 variant (c.425C > T/p.S142F) causes a loss-of-function of L-type calcium channels and is pathogenic for this type of BrS. Bisoprolol and quinidine may be effective for treating BrS with this variant.

Anterolateral Acromioplasty Does Not Change the Critical Shoulder Angle and Acromion Index in a Clinically Relevant Amount.

PURPOSE: Assessment on whether radiographic parameters of the acromion measured in radiographs change significantly after anterolateral acromioplasty. METHODS: This retrospective study included patients that underwent an arthroscopic anterolateral acromioplasty between January 2014 and September 2020. n = 435 subjects with high-quality preoperative and postoperative radiographs according to Suter-Henninger criteria were included in the final assessment. All measurements were independently performed by the first and second author in a blinded fashion using dicomPACS software: acromion index (AI), critical shoulder angle (CSA), lateral acromial angle (LAA), beta angle, acromio-humeral distance (AHD), Aoki angle, frontal supraspinatus outlet angle (FSOW), and acromion type, according to Bigliani. SPSS software was used for statistical analysis. RESULTS: The beta angle and the CSA did not significantly change after operation (alpha power 0.32 and 0.11, respectively). In a subgroup analysis of patients with a pathological CSA >35° (n = 194), the CSA changed from 38.62 (range: 35.08-47.52, SD 2.83) to 38.04 (range: 29.18-48.12, SD 3.77) postoperatively (P = .028) (Fig 8). All other parameters changed significantly after operation (AI, AHD, FSOW, and Aoki; P = .001, LAA; P = .039) (Fig. 9). The interobserver and intraobserver reliability was good to excellent in the majority of measured values. Mean patient age was 59.2 years (range: 18.1-87.1; SD 11.3), mean height was 1.73 meters (range: 1,50-1.98, SD 0.09), mean weight was 80.2 kg (range: 37.0-133.0, SD 16.68), and mean body mass index was 26.6 (range: 0.0-46.1, SD 4.73). CONCLUSION: Anterolateral acromioplasty producing a flat acromion undersurface did not result in a significant change of the CSA in the study population. Pathological preoperative CSA values of >35° were significantly reduced but not to normal values, but only by a small amount that puts the clinical relevance into question. LEVEL OF EVIDENCE: IV, diagnostic study, case series.

Socio-economic burden of disease: Survivorship costs for bladder cancer.

BACKGROUND: In this cost-of-illness study, we analysed the socio-economic burden of bladder cancer survivorship for the ten years after initial treatment in Germany during 2000, 2010 and 2020. METHODS: Bladder cancer follow-up guidelines were extracted from the European Association of Urology. Per patient costs were estimated with a micro-costing approach considering direct and indirect medical expenses derived from literature and official scales of tariffs. Three perspectives covering costs for patients, providers, and insurers were included to estimate societal costs. RESULTS: Mean 10-year follow-up costs per patient amounted to EUR 2214 for low-risk, EUR 4758 for medium-risk, and EUR 11,325 for high-risk non-muscle invasive bladder cancer (NMIBC) in 2020. The mean economic burden of muscle-invasive and metastatic bladder cancer (MIBC) was EUR 8994 per patient. Overall expenditure rose by 65% from 2000 to 2020 across all cancer stages (p < 0.001). While insurers covered 38% of costs in 2000, only 31% of costs were reimbursed in 2020 (p < 0.001). 58% of high-risk NMIBC follow-up resources were consumed by physician-patient visits and 17% by medical imaging (x-ray, CT-IVU, ultrasound). Spending was unevenly distributed across follow-up years (years 1-2: 43%, years 3-5: 29%, years 5-10: 28%). CONCLUSIONS: The rising socio-economic burden of follow-ups signifies the relevance of cancer survivorship for the healthcare system and society. This burden must be evenly distributed across stakeholders and considered in cost-effectiveness evaluations of novel anti-cancer drugs. Policy summary Personalized, equitable, and effective follow-up schedules covered by insurance funds are necessary to care for cancer survivors.

Socio-economic burden of disease: Survivorship costs for renal cell carcinoma.

OBJECTIVE: The objective of this study is to assess the risk-stratified 10-year socio-economic burden of renal cell carcinoma (RCC) follow-up costs after initial treatment in Germany from 2000 to 2020. METHODS: A micro-costing method considering direct and indirect medical expenditure associated with follow-up procedures was employed to calculate survivorship costs per patient. The frequencies of physician-patient visits, examinations and diagnostic tests were extracted from guidelines, whilst expenses were sourced from literature and official scales of tariffs. Societal costs were calculated based on three perspectives: patients, providers and insurers. RESULTS: Mean societal 10-year follow-up costs per patient amounted to EUR 3,377 (95%CI: 2,969-3,791) for low-risk, EUR 3,367 (95%CI: 3,003-3,692) for medium-risk and EUR 4,299 (95%CI: 3,807-4,755) for high-risk RCC in 2020. Spending increased by +32% from 2000 to 2020 for low-risk RCC, whilst medium-and high-risk RCC expenditure was cut by -39% and -22%, respectively. Patients shouldered 27%, providers 43% and insurers 35% of costs in 2020. Resources were consumed by medical imaging (52%), physician-patient consultations (31%), travel expenses (17%) and blood tests (1%). CONCLUSION: Results highlight the economic burden cancer survivorship poses for society. Cancer survivors require individualised, evidence-based and insurance-covered follow-up schedules to permit the early detection of side-effects, metastasis and secondary malignancies.

Medical education and mental health during COVID-19: a survey across 9 countries.

OBJECTIVES: To investigate students' experience with medical education alongside their mental and physical health since the onset of the COVID-19 pandemic across nine countries. METHODS: A cross-sectional online survey was distributed by local collaborators to 2,280 medical students across 148 medical schools in Brazil, Chile, Colombia, Germany, Italy, Japan, Mexico, Spain, and Venezuela using non-probability convenience sampling from June 22 to July 24, 2020. Students answered questions regarding teaching, internet use, COVID-19, physical and mental well-being. A multivariate logistic regression examined factors associated with depressed mood, insomnia, and headache. RESULTS: Academic teaching shifted to a virtual (67%, n=1,534) or hybrid environment (23%, n=531), whilst bedside teaching was suspended or cancelled (93%, n=2,120). Across all countries students were equally satisfied with the teaching modality, quantity, quality, and the evaluation system of in-person, hybrid, and online curricula. Negative changes in mental (40% (n=912) insomnia, 57% (n=1,300) emotional irritability, 47% (n=1,072) emotional instability, 41% (n=935) anhedonia, 40% (n=912) depressed mood) and physical (36% (n=821) headache, 57% (n=1,299) ocular tiredness, 49% (n=1,117) backache) health symptoms were frequently observed. Positive associations between the number of daily screen hours and depressed mood (adjusted odds ratio (AOR)=1.09, 95%CI: 1.05-1.12, p<.001), insomnia (AOR=1.08, 95%CI: 1.05-1.11, p<.001), and headache (AOR=1.11, 95%CI: 1.07-1.14, p<.001) were identified. CONCLUSIONS: Students' experience with digital and hybrid medical curricula was diverse during the pandemic. Education modality, quantity, and quality were positively evaluated. However, students' mental and physical health worsened. Besides bedside teaching, faculties ought to digitalize and strengthen social communities and extend support services for students.

Studying Brugada Syndrome With an SCN1B Variants in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

BACKGROUND: Among rare channelopathies BrS patients are at high risk of sudden cardiac death (SCD). SCN5A mutations are found in a quarter of patients. Other rare gene mutations including SCN1B have been implicated to BrS. Studying the human cellular phenotype of BrS associated with rare gene mutation remains lacking. OBJECTIVES: We sought to study the cellular phenotype of BrS with the SCN1B gene variants using human-induced pluripotent stem cell (hiPSCs)-derived cardiomyocytes (hiPSC-CMs). METHODS AND RESULTS: A BrS patient suffering from recurrent syncope harboring a two variants (c.629T > C and c.637C > A) in SCN1B, which encodes the function-modifying sodium channel beta1 subunit, and three independent healthy subjects were recruited and their skin biopsies were used to generate hiPSCs, which were differentiated into cardiomyocytes (hiPSC-CMs) for studying the cellular electrophysiology. A significantly reduced peak and late sodium channel current (INa) and a shift of activation curve to more positive potential as well as a shift of inactivation curve to more negative potential were detected in hiPSC-CMs of the BrS patient, indicating that the SCN1B variants impact the function of sodium channels in cardiomyocytes. The reduced INa led to a reduction of amplitude (APA) and upstroke velocity (V max ) of action potentials. Ajmaline, a sodium channel blocker, showed a stronger effect on APA and Vmax in BrS cells as compared to cells from healthy donors. Furthermore, carbachol was able to increase arrhythmia events and the beating frequency in BrS. CONCLUSION: Our hiPSC-CMs from a BrS-patient with two variants in SCN1B recapitulated some key phenotypic features of BrS and can provide a platform for studies on BrS with SCN1B variants.

A cellular model of Brugada syndrome with SCN10A variants using human-induced pluripotent stem cell-derived cardiomyocytes.

AIMS: Brugada syndrome (BrS) is associated with a pronounced risk to develop sudden cardiac death (SCD). Up to 21% of patients are related to mutations in SCN5A. Studies identified SCN10A as a contributor of BrS. However, the investigation of the human cellular phenotype of BrS in the presence of SCN10A mutations remains lacking. The objective of this study was to establish a cellular model of BrS in presence of SCN10A mutations using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). METHODS AND RESULTS: Dermal fibroblasts obtained from a BrS patient suffering from SCD harbouring the SCN10A double variants (c.3803G>A and c.3749G>A) and three independent healthy control subjects were reprogrammed to hiPSCs. Human-induced pluripotent stem cells were differentiated into cardiomyocytes (hiPSC-CMs).The hiPSC-CMs from the BrS patient showed a significantly reduced peak sodium channel current (INa) and a significantly reduced ATX II (sea anemone toxin, an enhancer of late INa) sensitive as well as A-887826 (a blocker of SCN10A channel) sensitive late sodium channel current (INa) when compared with the healthy control hiPSC-CMs, indicating loss-of-function of sodium channels. Consistent with reduced INa the action potential amplitude and upstroke velocity (Vmax) were significantly reduced, which may contribute to arrhythmogenesis of BrS. Moreover, Ajmaline effects on action potentials were stronger in BrS-hiPSC-CMs than in healthy control cells. This is in agreement with the higher susceptibility of patients to sodium channel blocking drugs in unmasking BrS. CONCLUSION: Patient-specific hiPSC-CMs are able to recapitulate single-cell phenotype features of BrS with SCN10A mutations and may provide novel opportunities to further elucidate the cellular disease mechanism.