Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.

Ion channel mutations are an important cause of rare Mendelian disorders affecting brain, heart, and other tissues. We performed parallel exome sequencing of 237 channel genes in a well-characterized human sample, comparing variant profiles of unaffected individuals to those with the most common neuronal excitability disorder, sporadic idiopathic epilepsy. Rare missense variation in known Mendelian disease genes is prevalent in both groups at similar complexity, revealing that even deleterious ion channel mutations confer uncertain risk to an individual depending on the other variants with which they are combined. Our findings indicate that variant discovery via large scale sequencing efforts is only a first step in illuminating the complex allelic architecture underlying personal disease risk. We propose that in silico modeling of channel variation in realistic cell and network models will be crucial to future strategies assessing mutation profile pathogenicity and drug response in individuals with a broad spectrum of excitability disorders.

Unintentional drug-related deaths in people with mental illness in NSW Australia, 2012-2016: a retrospective cohort study.

PURPOSE: People with mental illness are a vulnerable and stigmatised group with poor health outcomes including greater premature mortality. This study aimed to investigate trends and rates of change in unintentional drug-related deaths for people with mental illness, describe types of medicines involved, and identify populations at risk in a cohort from New South Wales, Australia. METHODS: Features of unintentional drug-related deaths for people with mental illness between 2012 and 2016 were identified in a retrospective review of data from the National Coronial Information System. RESULTS: A total of 495 unintentional drug-related deaths were identified (1.6 deaths/100,000 population), showing an upward trend (p < 0.01). The most common substance involved was diazepam in both genders (males 135/319, 42%, female 76/176, 43%) and more than one contributory drug was included in 80% of cases. Between 2012 and 2016, amphetamine-related deaths showed the highest increase (3.2-fold), followed by codeine (2.5-fold) and quetiapine (2.5-fold). Males (RR 1.8, 95% CI 1.5-2.2) and people aged 35-44 (RR 1.7, CI 1.3-2.2) were more likely to die from unintentional drug-related deaths compared with the reference (females and people aged 25-34). CONCLUSION: This study found that the drugs commonly involved in deaths are also the drugs commonly used by and prescribed to people with mental illness. There were also significant differences between gender, age group, and marital status in the trend and rate of unintentional drug-related deaths for people with mental illness. A multifaceted approach encompassing both pharmaceutical prescribing and targeted public health messaging is required to inform intervention and prevention strategies.

High levels of engagement with testing for HIV and sexually transmissible infection among gay Asian men in Sydney and Melbourne: an observational study.

Background Gay and other men who have sex with men of Asian background (GAM) have been identified as a key population in efforts to eradicate HIV in New South Wales. The aims of the present study were to evaluate current levels of engagement with HIV and sexually transmissible infection (STI) testing services, assess knowledge of pre- and post-exposure prophylaxis and to identify factors associated with service engagement in this group. METHODS: A survey of 604 GAM residing in Sydney and Melbourne was undertaken. RESULTS: The data identified that a significant proportion of non-HIV-positive men (i.e. HIV-negative men and men whose HIV status was unknown) surveyed (n = 567; 93.9%) had engaged in frequent HIV testing and comprehensive STI testing in the 12 months prior to the survey (n = 180; 31.7%). There were significant differences (P < 0.05) in sexual practices at the bivariate level between those who reported frequent and comprehensive HIV/STI testing and those who did not. Those who tested regularly were substantially more sexually active, were more likely to have multiple partners (P = 0.001) and were more likely to engage in condomless anal intercourse with both casual (P < 0.001) and regular (P = 0.002) partners. Those who engaged with testing initiatives were more likely to discuss HIV status with both regular (P = 0.008) and casual (P < 0.001) partners, and identified more reasons to test than their counterparts (P < 0.001). The data also highlighted key service venues, with gay men most likely to have used public sexual health clinics (46.9%) as their most recent testing venue. CONCLUSIONS: The data demonstrate an association between high levels of male-to-male sexual activity and engagement in frequent and comprehensive HIV and STI testing. This likely derives from both self-perceived notions of risk and current reliance on established gay community organisations to convey information around testing. Increasing engagement with testing initiatives beyond GAM who self-identify as being at high HIV and STI risk will require the use of novel routes by which to disseminate this information.

Osteopetrosis in TAK1-deficient mice owing to defective NF-κB and NOTCH signaling.

The MAP kinase TGFß-activated kinase (TAK1) plays a crucial role in physiologic and pathologic cellular functions including cell survival, differentiation, apoptosis, inflammation, and oncogenesis. However, the entire repertoire of its mechanism of action has not been elucidated. Here, we found that ablation of Tak1 in myeloid cells causes osteopetrosis in mice as a result of defective osteoclastogenesis. Mechanistically, Tak1 deficiency correlated with increased NUMB-like (NUMBL) levels. Accordingly, forced expression of Numbl abrogated osteoclastogenesis whereas its deletion partially restored osteoclastogenesis and reversed the phenotype of Tak1 deficiency. Tak1 deletion also down-regulated Notch intracellular domain (NICD), but increased the levels of the transcription factor recombinant recognition sequence binding protein at Jκ site (RBPJ), consistent with NUMBL regulating notch signaling through degradation of NICD, a modulator of RBPJ. Accordingly, deletion of Rbpj partially corrected osteopetrosis in Tak1-deficient mice. Furthermore, expression of active IKK2 in RBPJ/TAK1-deficient cells significantly restored osteoclastogenesis, indicating that activation of NF-κB is essential for complete rescue of the pathway. Thus, we propose that TAK1 regulates osteoclastogenesis by integrating activation of NF-κB and derepression of NOTCH/RBPJ in myeloid cells through inhibition of NUMBL.

Successful Treatment of Plantar Hyperkeratosis in the Form of Recurrent Corns With Split-Thickness Sole Skin Graft.

INTRODUCTION: Plantar hyperkeratosis, such as corns and calluses, is common in older people and associated with pain, mobility impairment, and functional limitations. It usually develops on the palms, knees, or soles of feet, especially under the heels or balls. There are several treatment methods for plantar hyperkeratosis, such as salicylic acid plaster and scalpel debridement, and conservative modalities, such as using a shoe insert and properly fitting shoes. METHODS: We present an effective method of reconstructing the wound after corn excision using a split-thickness sole skin graft (STSSG). We harvested the skin graft from the arch of the sole using the dermatome with a skin thickness of 14/1000th inches. RESULTS: Because the split-thickness skin graft, harvested from the sole arch near the distal sole, is much thicker than the split-thickness skin graft from the thigh, it is more resistant to weight and friction. The healed wound with STSSG coverage over the distal sole was intact, and the donor site over the sole arch had healed without complication during the outpatient follow-up, 3 months after surgery. CONCLUSIONS: The recovery time of STSSG for corn excision is shorter than that with traditional treatment. Therefore, STSSG can be a reliable alternative treatment for recurrent palmoplantar hyperkeratosis.

Breast Reconstruction Using Pedicled Latissimus Dorsi Myocutaneous Flaps in Asian Patients With Small Breasts.

BACKGROUND: The use of implants is still the most common procedure for breast reconstruction because they are easy, less painful than tissue transplants, and do not need a donor site. However, it is challenging to find a suitable implant for patients with small breasts, and some women fear foreign bodies and possible complications or reoperations. Autologous breast reconstruction using the pedicled latissimus dorsi (LD) myocutaneous flap without an implant provides a good option for Asian women with small breasts. MATERIALS AND METHODS: Between June 1992 and December 2015, 31 patients underwent breast reconstruction with 33 LD flaps (29 unilateral and 2 bilateral). The skin paddle of the flap was designed with an oblique or transverse pattern depending on the mastectomy defect and the elasticity of skin. The thoracodorsal nerve was divided during flap harvesting to prevent a "twitching breast" postoperatively. Patients refused to have contralateral breast augmentation except for 2 with bilateral simultaneous augmentation after mastectomy bilaterally. Outcome measures were flap survival, shape and contour, symmetry of breast, complication of flap and donor site, patient satisfaction, and any local tumor recurrence or metastasis. RESULTS: The mean patient age was 46.7 years (range, 27-72), and the mean body mass index was 22.5 kg/m (range, 18.6-30). The mean size of the harvested skin paddle was 11.9 × 5.0 cm (range, 10 × 3 cm to 15 × 9 cm). Mean operative times were 200.8 minutes (range, 112-230 minutes) and 305 minutes (range, 300-310 minutes) for unilateral and bilateral reconstructions, respectively. Pathology reports showed a negative safety margin in all cases. Most cases were of invasive duct carcinoma (58%). All LD flaps survived, and the wounds healed satisfactorily over a mean follow-up of 49.9 months (range, 3-161 months). Donor sites were closed primarily with a hidden linear scar under the dorsal bra strap. Donor site morbidities were mainly seromas (15%), which were treated conservatively in most patients. CONCLUSIONS: The LD flap produced good autologous tissue for reconstruction, and no implants were needed for Asian women with small breasts. The reconstructed breasts showed good shape, contour, and symmetry. The results of donor site were acceptable and no significant functional loss. There were no major complications, and patient satisfaction was high.

Postmastectomy Breast Reconstruction Combined With Contralateral Breast Augmentation for Taiwanese Women With Small Breasts.

BACKGROUND: Although autogenous tissue-based breast reconstruction has been widely used in the past decade, implant-based breast reconstruction is more often used in Taiwan because Asian women are generally slender with small breasts. For patients with very small breasts, it is hard to achieve the goal of reconstructing a similar breast to the contralateral one, even with the smallest size implant available commercially. Therefore, these patients need not only breast reconstruction but also contralateral breast augmentation. Here we report the surgical outcomes and cosmetic results of breast reconstruction using cohesive gel implants combined with simultaneous contralateral breast augmentation. MATERIALS AND METHODS: A retrospective chart review was conducted to identify all patients with AA-sized to B-sized breast cups undergoing expander-implant reconstruction combined with contralateral breast augmentation between 2002 and 2015. Thirty patients were included. For each patient, patient profile (age, body mass index, and initial breast size), type and stage of breast cancer, surgical information (including implant sizes and the type of reconstruction and augmentation), and postoperative subjective pain scales were recorded. Outcomes were analyzed by identifying complications, the need for surgical revision, the presence of local or distant metastases, and patient satisfaction ratings. RESULTS: At a mean 2.3-year follow-up (range, 4 months to 12 years), problems occurred in 7 of the 30 patients, with 9 complications in 8 reconstructed breasts and in 1 augmented breast. Complications were mostly capsule contracture. Aesthetic satisfaction was rated as "excellent" or "good" by most of the patients, and only 1 commented "poor" on both overall and reconstructed results because of postoperative radiotherapy-associated skin necrosis. The total mean subjective pain scale was 1.9/10; a higher mean pain scale of 3.08 was noted in those patients undergoing augmentation with no extra incision. CONCLUSIONS: This is the first report of implant-based breast reconstruction with simultaneous contralateral augmentation in Taiwan, showing its efficacy, safety, and good cosmetic outcomes with relatively low complication and revision rates.

A Biodegradable Hemostatic Gelatin/Polycaprolactone Composite for Surgical Hemostasis.

Massive bleeding is the leading cause of battlefield-related deaths and the second leading cause of deaths in civilian trauma centers. One of the challenges of managing severe wounds is the need to promote hemostasis as quickly as possible, which can be achieved by using hemostatic dressings. In this study, we fabricated 2 kinds of gelatin/polycaprolactone composites with 2 ratios of gelatin/polycaprolactone, 1:1 and 2:1 (GP11 and GP21, respectively). Scanning electron microscopy revealed that the GP11 composite exhibited rougher and more porous structure than the GP21 composite did. Furthermore, both composites showed similar biocompatibility as that of tissue culture polystyrene. Moreover, both GP composites tended to show a gradual decrease in contact angle to zero within 40 minutes. The in vitro blood plasma coagulation assay revealed that the prothrombin time was significantly longer for the GP composites than it was for the Quikclot composite, whereas the activated partial thromboplastin time of the GP11 composite was significantly shorter than that of the gauze. Furthermore, the GP11 had the largest platelet adsorption of all the composites. The in vivo coagulation test showed an obvious shortening of the bleeding time with the Quikclot and GP21 compared with gauze sample. In conclusion, the GP composites showed superior biocompatibility and hemostasis to the gauze and comparable effects with the Qickclot composite. Therefore, the GP composites have the potential for development as biodegradable surgical hemostatic agents.

Enhanced wound-healing performance of a phyto-polysaccharide-enriched dressing - a preclinical small and large animal study.

Alginate is a natural rich anionic polysaccharide (APS), commonly available as calcium alginate (CAPS). It can maintain a physiologically moist microenvironment, which minimises bacterial infection and facilitates wound healing at a wound site. Patients with burn injuries suffer from pain and an inflammatory response. In this study, we evaluated the CAPS dressing and traditional dressing containing carboxymethyl cellulose (CMC) for wound healing and scar tissue formation in a burn model of rat and swine. In our pilot study of a burn rat model to evaluate inflammatory response and wound healing, we found that the monocyte chemoattractant protein (MCP)-1 and transforming growth factor (TGF)-ß were up-regulated in the CAPS treatment group. Next, the burn swine models tested positive for MCP-1 in a Gram-positive bacterial infection, and there was overproduction of TGF-ß during the burn wound healing process. Rats were monitored daily for 1 week for cytokine assay and sacrificed on day 28 post-burn injury. The swine were monitored over 6 weeks. We further examined the pain and related factors and inflammatory cytokine expression in a rodent burns model monitored everyday for 7 days post-burn. Our results revealed that the efficacy of the dressing containing CAPS for wound repair post-burn was better than the CMC dressing with respect to natural wound healing and scar formation. The polysaccharide-enriched dressing exerted an antimicrobial effect on burn wounds, regulated the inflammatory response and stimulated anti-inflammatory cytokine release. However, one pain assessment method showed no significant difference in the reduction in levels of adenosine triphosphate in serum of rats after wound dressing in either the CAPS or CMC group. In conclusion, a polysaccharide-enriched dressing outperformed a traditional dressing in reducing wound size, minimising hypertrophic scar formation, regulating cytokines and maximising antimicrobial effects.

Selective Loss of Presynaptic Potassium Channel Clusters at the Cerebellar Basket Cell Terminal Pinceau in Adam11 Mutants Reveals Their Role in Ephaptic Control of Purkinje Cell Firing.

A specialized axonal ending, the basket cell "pinceau," encapsulates the Purkinje cell axon initial segment (AIS), exerting final inhibitory control over the integrated outflow of the cerebellar cortex. This nonconventional axo-axonic contact extends beyond the perisomatic chemical GABAergic synaptic boutons to the distal AIS, lacks both sodium channels and local exocytotic machinery, and yet contains a dense cluster of voltage-gated potassium channels whose functional contribution is unknown. Here, we show that ADAM11, a transmembrane noncatalytic disintegrin, is the first reported Kv1-interacting protein essential for localizing Kv1.1 and Kv1.2 subunit complexes to the distal terminal. Selective absence of these channels at the pinceau due to mutation of ADAM11 spares spontaneous GABA release from basket cells at the perisomatic synapse yet eliminates ultrarapid ephaptic inhibitory synchronization of Purkinje cell firing. Our findings identify a critical role for presynaptic K(+) channels at the pinceau in ephaptic control over the speed and stability of spike rate coding at the Purkinje cell AIS in mice. SIGNIFICANCE STATEMENT: This study identifies ADAM11 as the first essential molecule for the proper localization of potassium ion channels at presynaptic nerve terminals, where they modulate excitability and the release of neural transmitters. Genetic truncation of the transmembrane disintegrin and metalloproteinase protein ADAM11 resulted in the absence of Kv1 channels that are normally densely clustered at the terminals of basket cell axons in the cerebellar cortex. These specialized terminals are responsible for the release of the neurotransmitter GABA onto Purkinje cells and also display electrical signaling. In the ADAM11 mutant, GABAergic release was not altered, but the ultrarapid electrical signal was absent, demonstrating that the dense presynaptic cluster of Kv1 ion channels at these terminals mediate electrical transmission. Therefore, ADAM11 plays a critical role at this central synapse.

Partial Calcanectomy Facilitates Wound Closure of Heel Defects in High-Risk Patients.

BACKGROUND: Heel ulcers in patients with severe peripheral artery occlusive disease represent a challenge to the treating physician. They become more difficult to treat with underlying medical comorbidities. The purpose of this report is to document evidence that partial calcanectomy is simple to perform and clears infected bone, tissue, and ulceration. MATERIALS: Between July 2011 and August 2013, 30 consecutive patients presented to our department with heel wounds caused by diabetes mellitus and pressure. After evaluation by a vascular surgeon, 12 patients diagnosed with near total occlusive peripheral vascular disease were included in this report. Of the 12 patients, 7 were women. Their ages ranged from 65 to 79 years (mean, 73.3 years). After admission, surgical debridement was performed emergently with subsequent partial calcanectomy and wound closure. RESULTS: Eight heel wounds (75%) healed completely with no further surgery to achieve defect coverage. Wound dehiscence developed in 4 patients (25%). The mean number of debridements was 1.75 (range, 1-3) with a total operation time of 71.5 minutes (range, 45-114 min). One patient died of acute myocardial infarction 2 weeks after discharge. The mean length of hospital stay was 8.3 days (range, 5-16 days). CONCLUSION: In this study, we demonstrate that partial calcanectomy is practical for the treatment of plantar heel ulcers in patients with severe comorbidities. With proper surgical planning and postoperative care, partial calcanectomy is a viable alternative to below-the-knee amputation and may better serve the patient who would otherwise be restricted to a sedentary lifestyle.

Cranioplasty Using a Novel Osteoconductive Scaffold and Platelet Gel.

BACKGROUND: Commonly used materials for cranioplasty include autogenous bone grafts, methyl methacrylate, and titanium mesh. We evaluated a novel osteoconductive scaffold [N-isopropylacrylamide cross-linked with acrylic acid using γ-rays (ANa powder)] mixed with platelet gel for cranioplasty. METHODS: ANa powder mixed with platelet gel was implanted into a 15 × 15-mm, full-thickness calvarial bone defect in 5 New Zealand white rabbits. ANa powder mixed with phosphate-buffered saline was implanted in 5 rabbits. The calvarial bone defect was left unreconstructed in another 5 rabbits. Twelve weeks after surgery, computed tomography examination was used to evaluate the radiographic evidence of bone healing in vivo. Bone specimens were then retrieved for histologic study. RESULTS: The ANa scaffold mixed with platelet gel is biocompatible, biodegradable, and both osteoconductive and osteoinductive, leading to progressive growth of new bone into the calvarial bone defect. CONCLUSION: The use of this novel osteoconductive scaffold combined with osteoinductive platelet gel offers a valuable alternative for the reconstruction of calvarial bone defects.

Chylous ascites after pedicled transverse rectus abdominis myocutaneous flap harvest.

Chylous ascites is a rare clinical condition that occurs as a consequence of disruption of the abdominal lymphatics. Here, we present the case of a 58-year-old woman with sustained chylous ascites after pedicled transverse rectus abdominis myocutaneous (TRAM) flap harvest. The chylous ascites did not decrease despite conservative therapy. For the diagnosis and localization of the chyle leakage, lymphangiography with lipiodol delivery was performed. Chylous drainage continued in a decreasing manner for the next 4 d because lipiodol accumulated to the point of leakage outside the lymphatic vessel causing a regional inflammatory reaction and obstructing the lymphatic vessels. To our knowledge, there is no case of chylous ascites related to pedicled TRAM flap harvest that has been reported in the English literature, in which the chyle leakage spontaneously resolved after lymphangiography.

Bipedicled flap for the reconstruction of soft tissue defects of the Achilles tendon.

Soft tissue defects exposing the Achilles tendon are common in patients who have undergone trauma or in those with pressure ulcers associated with vascular diseases. The purpose of this article was to present our experience of 11 patients who underwent reconstruction of soft tissue defects of the Achilles tendon using bipedicled fasciocutaneous flaps. Between August 2008 and August 2012, 11 patients were admitted to our hospital, presenting with soft tissue defects overlying the Achilles tendon. After adequate debridement, the 11 patients underwent bipedicled fasciocutaneous flap placement to resurface the complex soft tissue defects and provide a gliding surface for the exposed Achilles tendon. The patients' age, comorbidity, etiology, defect size and location, wound culture, skin graft size, complications, surgery duration, and follow-up period were reviewed. The 11 fasciocutaneous bipedicled flaps survived completely, and the wounds healed satisfactorily at a mean follow-up period of 20.9 months (range, 6-48 months). Only 1 flap was complicated with wound dehiscence and superficial necrosis of its lateral edge, which healed conservatively. The donor sites were covered with split-thickness skin grafts and healed well without complications. The bipedicled fasciocutaneous flap is a reliable flap for coverage of defects overlying the Achilles tendon, especially in patients with vascular problems and/or elderly patients. The ease of handling, short operative time, and early recovery of mobilization function are of great benefit to patients. Thus, the bipedicled fasciocutaneous flap can be a valuable alternative for defect reconstructions overlying the Achilles tendon, with satisfactory results both functionally and cosmetically.

Oncological safety and outcomes of nipple-sparing mastectomy with breast reconstruction: a single-centered experience in Taiwan.

INTRODUCTION: Nipple-sparing mastectomy has become a contemporary surgical treatment that achieves improved cosmetic outcomes for patients with breast cancer in Western countries. We examined oncological and cosmetic outcomes in Asian women who underwent nipple-sparing mastectomy in Taiwan. METHODS: Between 2006 and 2011, 42 patients with breast cancer who underwent 44 nipple-sparing mastectomy operations with immediate reconstruction at the Tri-Service General Hospital were reviewed. The cancer type, tumor stage, reconstruction method, presence of local recurrence, presence of distant metastasis, mortality, and complications were assessed and documented. Questionnaires were used to assess and rate patients' satisfaction with regard to appearance, sensation, symmetry, color, arousal, and texture. RESULTS: The mean follow-up period was 40.9 months (median, 45.5 months; range, 13-72 months). Among the 42 cases, only one case (2.4%) of local recurrence was observed and treated by nipple-areola complex resection. The overall complication rate was 25%, with nipple necrosis comprising 13.6%. CONCLUSION: Nipple-sparing mastectomy is a safe procedure in properly selected patients with breast cancer. This procedure yields similar oncological safety and cosmetic outcomes among Asians and women from Western countries.

Histochemical and functional improvement of adipose-derived stem cell-based tissue-engineered cartilage by hyperbaric oxygen/air treatment in a rabbit articular defect model.

Cartilage is exposed to compression forces during joint loading. Therefore, exogenous stimuli are frequently used in cartilage tissue engineering strategies to enhance chondrocyte differentiation and extracellular matrix (ECM) secretion. In this study, human adipose-derived stem cells were seeded on a gelatin/polycaprolactone scaffold to evaluate the histochemical and functional improvement of tissue-engineered cartilage after hyperbaric oxygen/air treatment in a rabbit articular defect model. Behavior tests showed beneficial effects on weight-bearing and rear leg-supporting capacities after treatment of tissue-engineered cartilage with 2.5 ATA oxygen or air. Moreover, positron emission tomography images and immunohistochemistry staining demonstrated hydroxyapatite formation and increased ECM synthesis, respectively, at the tissue-engineered cartilage graft site after high pressure oxygen/air treatment. Based on these results, we concluded that hyperbaric oxygen and air treatment can improve the quality of tissue-engineered cartilage in vivo by increasing the synthesis of ECM.

IGF signaling directs ventricular cardiomyocyte proliferation during embryonic heart development.

Secreted factors from the epicardium are believed to be important in directing heart ventricular cardiomyocyte proliferation and morphogenesis, although the specific factors involved have not been identified or characterized adequately. We found that IGF2 is the most prominent mitogen made by primary mouse embryonic epicardial cells and by a newly derived immortalized mouse embryonic epicardial cell line called MEC1. In vivo, Igf2 is expressed in the embryonic mouse epicardium during midgestation heart development. Using a whole embryo culture assay in the presence of inhibitors, we confirmed that IGF signaling is required to activate the ERK proliferation pathway in the developing heart, and that the epicardium is required for this response. Global disruption of the Igf2 gene, or conditional disruption of the two IGF receptor genes Igf1r and Insr together in the myocardium, each resulted in a significant decrease in ventricular wall proliferation and in ventricular wall hypoplasia. Ventricular cardiomyocyte proliferation in mutant embryos was restored to normal at E14.5, concurrent with the establishment of coronary circulation. Our results define IGF2 as a previously unexplored epicardial mitogen that is required for normal ventricular chamber development.

High-resolution molecular genomic autopsy reveals complex sudden unexpected death in epilepsy risk profile.

Advanced variant detection in genes underlying risk of sudden unexpected death in epilepsy (SUDEP) can uncover extensive epistatic complexity and improve diagnostic accuracy of epilepsy-related mortality. However, the sensitivity and clinical utility of diagnostic panels based solely on established cardiac arrhythmia genes in the molecular autopsy of SUDEP is unknown. We applied the established clinical diagnostic panels, followed by sequencing and a high density copy number variant (CNV) detection array of an additional 253 related ion channel subunit genes to analyze the overall genomic variation in a SUDEP of the 3-year-old proband with severe myoclonic epilepsy of infancy (SMEI). We uncovered complex combinations of single nucleotide polymorphisms and CNVs in genes expressed in both neurocardiac and respiratory control pathways, including SCN1A, KCNA1, RYR3, and HTR2C. Our findings demonstrate the importance of comprehensive high-resolution variant analysis in the assessment of personally relevant SUDEP risk. In this case, the combination of de novo single nucleotide polymorphisms (SNPs) and CNVs in the SCN1A and KCNA1 genes, respectively, is suspected to be the principal risk factor for both epilepsy and premature death. However, consideration of the overall biologically relevant variant complexity with its extensive functional epistatic interactions reveals potential personal risk more accurately.

Evaluation of Collagen Dermal Filler with Lidocaine for the Correction of Nasolabial Folds: A Randomized, Double-Blind, Multicenter Clinical Trial.

Purpose: Porcine-based dermal injectable collagen is effective for nasolabial fold correction. In the present study, a new dermal injectable collagen, incorporating a novel cross-linking technology and premixed with lidocaine, was introduced. The study aimed to determine the efficacy of the new dermal injectable collagen in improving bilateral nasolabial fold wrinkles, and reducing pain during injection. Patients and Methods: This prospective, double-blind, multicenter, parallel-group, randomized trial enrolled participants with moderate-to-severe bilateral nasolabial fold wrinkles from February 2019 to March 2021. Participants were randomly assigned to the test group (new dermal injectable collagen with lidocaine featuring a novel cross-linking technology) or control group (traditionally cross-linked dermal injectable collagen with lidocaine). Participants were monitored for adverse events (AEs), and for pain using the Thermometer Pain Scale (TPS) and a visual analog scale (VAS). Efficacy was measured using the Wrinkle Severity Rating Scale (WSRS) and the Global Aesthetic Improvement Scale (GAIS). Results: On the poor or better sides, the 2 groups exhibited a significant decrease in WSRS scores at 4, 12, 24, and 36 weeks after treatment, compared to baseline WSRS scores (all, p < 0.05). Compared to the control group, the test group had a greater decrease in WSRS score (poor or better sides) at 12, 24, 36, and 52 weeks after treatment (all, p < 0.05). A similar observation was also found in the WSRS response rate and GAIS score of the 2 groups. VAS and TPS scores were not significantly different between the 2 groups (p > 0.05), indicating that pain reduction was similar in the 2 groups. All AEs were anticipated AEs associated with facial aesthetic injections, and most recovered within 0 to 30 days without sequelae. There were no differences in AEs between the 2 groups (all, p > 0.05). Conclusion: The new dermal injectable collagen with lidocaine exhibited better efficacy for correcting nasolabial fold wrinkles compared to the control group. Both relieved pain and produced only transient and tolerable AEs.