Recommendations for risk allele evidence curation, classification, and reporting from the ClinGen Low Penetrance/Risk Allele Working Group.

PURPOSE: Genetic variants at the low end of the penetrance spectrum have historically been challenging to interpret because their high population frequencies exceed the disease prevalence of the associated condition, leading to a lack of clear segregation between the variant and disease. There is currently substantial variation in the classification of these variants, and no formal classification framework has been widely adopted. The Clinical Genome Resource Low Penetrance/Risk Allele Working Group was formed to address these challenges and promote harmonization within the clinical community. METHODS: The work presented here is the product of internal and community Likert-scaled surveys in combination with expert consensus within the Working Group. RESULTS: We formally recognize risk alleles and low-penetrance variants as distinct variant classes from those causing highly penetrant disease that require special considerations regarding their clinical classification and reporting. First, we provide a preferred terminology for these variants. Second, we focus on risk alleles and detail considerations for reviewing relevant studies and present a framework for the classification these variants. Finally, we discuss considerations for clinical reporting of risk alleles. CONCLUSION: These recommendations support harmonized interpretation, classification, and reporting of variants at the low end of the penetrance spectrum.

Cell-Based Therapies Induce Tolerance of Vascularized Composite Allotransplants: A Systematic Review.

INTRODUCTION: Vascularized composite allotransplantation (VCA) is the transplantation of multiple tissue types as a solution for devastating injuries. Despite the highly encouraging functional outcomes of VCA, the consequences of long-term immunosuppression remain the main obstacle in its application. In this review, we provide researchers and surgeons with a summary of the latest advances in the field of cell-based therapies for VCA tolerance. METHODS: Four electronic databases were searched: PubMed, Scopus, Cumulative Index to Nursing and Allied Health Literature , and Web of Science. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analysis as the basis of our organization. RESULTS: Hematopoietic stem cells prolonged VCA survival. A combination of immature dendritic cells and tacrolimus was superior to tacrolimus alone. T cell Ig domain and mucin domain modified mature dendritic cells increased VCA tolerance. Bone marrow-derived mesenchymal stem cells prolonged survival of VCAs. A combination of adipose-derived mesenchymal stem cells, cytotoxic T-lymphocyte antigen 4 immunoglobulin, and antilymphocyte serum significantly improved VCA tolerance. Ex-vivo allotransplant perfusion with recipient's bone marrow-derived mesenchymal stem cells increased VCA survival. Recipient's adipose-derived mesenchymal stem cells and systemic immunosuppression prolonged VCA survival more than any of those agents alone. Additionally, a combination of peripheral blood mononuclear cells shortly incubated in mitomycin and cyclosporine significantly improved VCA survival. Finally, a combination of donor recipient chimeric cells, anti-αß-T cell receptor (TCR), and cyclosporine significantly prolonged VCA tolerance. CONCLUSIONS: Evidence from animal studies shows that cell-based therapies can prolong survival of VCAs. However, there remain many obstacles for these therapies, and they require rigorous clinical research given the rarity of the subjects and the complexity of the therapies. The major limitations of cell-based therapies include the need for conditioning with immunosuppressive drugs and radiation, causing significant toxicity. Safety concerns also persist as most research is on animal models. While completely replacing traditional immunosuppression with cell-based methods is unlikely soon, these therapies could reduce the need for high doses of immunosuppressants and improve VCA tolerance.

Ultrasensitive detection of Ag+and Ce3+ions using highly fluorescent carboxyl-functionalized carbon nitride nanoparticles.

The fluorescence quenching of carboxyl-rich g-C3N4nanoparticles was found to be selective to Ag+and Ce3+with a limit of detection as low as 30 pM for Ag+ions. A solid-state thermal polycondensation reaction was used to produce g-C3N4nanoparticles with distinct green fluorescence and high water solubility. Dynamic light scattering indicated an average nanoparticle size of 95 nm. The photoluminescence absorption and emission maxima were centered at 405 nm and 540 nm respectively which resulted in a large Stokes shift. Among different metal ion species, the carboxyl-rich g-C3N4nanoparticles were selective to Ag+and Ce3+ions, as indicated by strong fluorescence quenching and a change in the fluorescence lifetime. The PL sensing of heavy metal ions followed modified Stern-Volmer kinetics, and CNNPs in the presence of Ag+/Ce3+resulted in a higher value ofKapp(8.9 × 104M-1) indicating a more efficient quenching process and stronger interaction between CNNP and mixed ions. Sensing was also demonstrated using commercial filter paper functionalized with g-C3N4nanoparticles, enabling practical on-site applications.

Identification of Potential Factors Associated with Cellulitis Following Lymphovenous Bypass Surgery in Breast Cancer Survivors.

BACKGROUND: Breast cancer is one of the most common types of cancer, with around 2.3 million cases diagnosed in 2020. One in five cancer patients develops chronic lymphedema caused by multifactorial triggers and treatment-related factors. This can lead to swelling, skin infections, and limb dysfunction, negatively affecting the patient's quality of life. This retrospective cohort study aimed to determine the associations between demographic and breast cancer characteristics and postoperative cellulitis in breast cancer survivors who underwent lymphovenous bypass surgery (LVB) at Mayo Clinic, Florida. METHODS: We performed a retrospective chart review. Data were collected retrospectively from 2016 to 2022. Sixty adult breast cancer survivors who underwent LVB were included in the final analysis based on specific inclusion and exclusion criteria. Patients were excluded if they did not meet the inclusion criteria or had incomplete follow-up data. Demographic and surgical data were extracted, including body mass index (BMI), type of anastomosis, number of anastomoses, and preoperative cellulitis status. Lymphedema measurements were performed using tape measurements. Fisher's exact test was used to determine statistically significant associations between variables and postoperative cellulitis. RESULTS: Postoperative cellulitis was more common in patients aged 60 to 69 years (43.2%), whites (75.0%), overweight or obese (90.9%), with one to four anastomoses (81.8%), and nonsmokers (79.5%). The mean International Society of Lymphology (ISL) criteria for both postoperative cellulitis and no postoperative cellulitis was 1.93. Statistically significant associations with postoperative cellulitis were found for the number of anastomoses (p = 0.021), smoking status (p = 0.049), preoperative cellulitis (p = 0.04), and the length of years with lymphedema diagnosis variable (p = 0.004). CONCLUSION: Our results suggest that a greater number of anastomoses, smoking, preoperative cellulitis, and years with lymphedema are significantly associated with an increased risk of postoperative cellulitis. Awareness of these risk factors is crucial for monitoring and early treatment of infections following surgery.

Evaluation of the Aging Effect on Peripheral Nerve Regeneration: A Systematic Review.

INTRODUCTION: Peripheral nerve injuries have been associated with increased healthcare costs and decreased patients' quality of life. Aging represents one factor that slows the speed of peripheral nervous system (PNS) regeneration. Since cellular homeostasis imbalance associated with aging lead to an increased failure in nerve regeneration in mammals of advanced age, this systematic review aims to determine the main molecular and cellular mechanisms involved in peripheral nerve regeneration in aged murine models after a peripheral nerve injuries. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a literature search of 4 databases was conducted in July 2022 for studies comparing the peripheral nerve regeneration capability between young and aged murine models. RESULTS: After the initial search yielded 744 publications, ten articles fulfilled the inclusion criteria. These studies show that age-related changes such as chronic inflammatory state, delayed macrophages' response to injury, dysfunctional Schwann Cells (SCs), and microenvironment alterations cause a reduction in the regenerative capability of the PNS in murine models. Furthermore, identifying altered gene expression patterns of SC after nerve damage can contribute to the understanding of physiological modifications produced by aging. CONCLUSIONS: The interaction between macrophages and SC plays a crucial role in the nerve regeneration of aged models. Therefore, studies aimed at developing new and promising therapies for nerve regeneration should focus on these cellular groups to enhance the regenerative capabilities of the PNS in elderly populations.

Enhanced luminescence sensing performance and increased intrachain order in blended films of P3HT and cellulose nanocrystals.

Blended films comprising poly(butyl acrylate) (PBA)-grafted cellulose nanocrystals (CNCs) and poly(3-hexylthiophene) (P3HT), exhibited more intense photoluminescence (PL) and longer PL emission lifetimes compared to pristine P3HT films. Optical absorption and photoluminescence spectra indicated reduced torsional disorder i.e. enhanced backbone planarity in the P3HT@CNC blended composites compared to the bare P3HT. Such molecule-level geometrical modification resulted in both smaller interchain and higher intrachain exciton bandwidth in the blended composites compared to the bare P3HT, because of reduced interchain interactions and enhanced intrachain order. These results indicate a potential switch of the aggregation behavior from dominant H-aggregates to J-aggregates, supported by Raman spectroscopy. The reorganization of micromolecular structure and concomitant macroscopic aggregation of the conjugated polymer chains resulted in a longer conjugation length for the P3HT@CNC blended composites compared to the bare P3HT. Additionally, this nanoscale morphological change produced a reduction in the highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) energy gap of the blends, evidenced from optical absorption spectra. Classical molecular dynamics simulation studies predicted the probability of enhanced planarity in the polymer backbone following interactions with CNC surfaces. Theoretical results from density functional theory calculations corroborate the experimentally observed reduction of optical bandgap in the blends compared to bare P3HT. The blended composite outperformed the bare P3HT in nitro-group PL sensing tests with a pronounced difference in the reaction kinetics. While the PL quenching dynamics for bare P3HT followed Stern-Volmer kinetics, the P3HT@CNC blended composite exhibited a drastic deviation from the same. This work shows the potential of a functionalized rod-like biopolymer in tuning the optoelectronic properties of a technologically important polymeric organic semiconductor through control of the nanoscale morphology.

Efficacy of topical versus oral analgesic medication compared to a placebo in injured athletes: A systematic review with meta-analysis.

BACKGROUND: Athletes are injured frequently and often take analgesic medication. Moreover, athletes commonly use non-prescription topical and oral medications with little guidance. Despite wide use, relatively few studies exist on the efficacy of pain medication in injured athletes compared to a placebo. OBJECTIVE: To determine efficacy of topical or oral medications in pain reduction compared to a placebo in injured athletes. STUDY DESIGN: A systematic review and meta-analysis. METHODS: We conducted an electronic search using Medline/Pubmed, Web of Science, Ovid, and SportDiscus for all literature relating to topical or oral medications in athletes for pain management post-injury. Two reviewers screened the studies and measured their quality. To determine efficacy, we calculated the Hedges' g value. We created forest plots with 95% CI to graphically summarize the meta-analyses. RESULTS: There was a significant pooled effect size reflecting a reduction in pain outcomes for the topical treatment versus placebo (g = -0.64; 95% CI [-0.89, -0.39]; p < 0.001). There was not a significant reduction in pain outcomes for the oral treatment versus placebo (g = -0.26; 95% CI [-0.60, 0.17]; p = 0.272). CONCLUSION: Topical medications were significantly better at reducing pain compared to oral medications versus a placebo in injured athletes. These results are different when compared to other studies that used experimentally induced pain versus musculoskeletal injuries. The results from our study suggest that athletes should use topical medications for pain reduction, as it is more effective, and there are less reported adverse effects compared to oral medication.

Severity of illness and risk of mortality in Mayo Clinic's virtual hybrid advanced care at home program: a retrospective cohort study.

BACKGROUND: In July 2020, Mayo Clinic launched Advanced Care at Home (ACH), a high-acuity virtual hybrid hospital-at-home model (HaH) of care at Mayo Clinic Florida and Northwest Wisconsin, an urban destination medical center and a rural community practice respectively. This study aims to describe demographic characteristics of ACH patients as well as their acuity of illness using severity of illness (SOI) and risk of mortality (ROM), to illustrate the complexity of patients in the program, taking into account the different diagnostic related groups. METHODS: Mayo Clinic uses All Patient Refined-Diagnosis Related Groups (APR-DRG) to calculate SOI and ROM on hospitalized patients. APR-DRG data, including SOI and ROM, were gathered from individual chart reviews from July 6, 2020, to March 31, 2022. RESULTS:  Out of 923 patients discharged from ACH, the average APR-DRG SOI was 2.89 (SD 0.81) and ROM was 2.73. (SD 0.92). Mean age was 70.88 (SD 14.46) years, 54.6% were male patients and the average length of stay was 4.10 days. The most frequent diagnosis was COVID-19 infection with 162 patients (17.6%), followed by heart failure exacerbation (12.7%) and septicemia (10.9%). The 30-day readmission rate after discharge from ACH was 11.2% (n = 103) and the 30-day mortality rate was 1.8% (n = 17). There were no in-program patient deaths. CONCLUSIONS: SOI and ROM from patients at the ACH program have been shown to be in the range of "moderate/major" according to the APR-DRG classification. The ACH program is capable of accepting and managing highly complex patients that require advanced therapeutic means. Furthermore, the ACH program has an in-program mortality rate of 0 to date. Therefore, ACH is rising as a capable alternative to the brick-and-mortar hospital.

Noninvasive muscle activity imaging using magnetography.

A spectroscopic paradigm has been developed that allows the magnetic field emissions generated by the electrical activity in the human body to be imaged in real time. The growing significance of imaging modalities in biology is evident by the almost exponential increase of their use in research, from the molecular to the ecological level. The method of analysis described here allows totally noninvasive imaging of muscular activity (heart, somatic musculature). Such imaging can be obtained without additional methodological steps such as the use of contrast media.

Patient Satisfaction With a Multisite, Multiregional Remote Patient Monitoring Program for Acute and Chronic Condition Management: Survey-Based Analysis.

BACKGROUND: Remote patient monitoring (RPM) is an option for continuously managing the care of patients in the comfort of their homes or locations outside hospitals and clinics. Patient engagement with RPM programs is essential for achieving successful outcomes and high quality of care. When relying on technology to facilitate monitoring and shifting disease management to the home environment, it is important to understand the patients' experiences to enable quality improvement. OBJECTIVE: This study aimed to describe patients' experiences and overall satisfaction with an RPM program for acute and chronic conditions in a multisite, multiregional health care system. METHODS: Between January 1, 2021, and August 31, 2022, a patient experience survey was delivered via email to all patients enrolled in the RPM program. The survey encompassed 19 questions across 4 categories regarding comfort, equipment, communication, and overall experience, as well as 2 open-ended questions. Descriptive analysis of the survey response data was performed using frequency distribution and percentages. RESULTS: Surveys were sent to 8535 patients. The survey response rate was 37.16% (3172/8535) and the completion rate was 95.23% (3172/3331). Survey results indicated that 88.97% (2783/3128) of participants agreed or strongly agreed that the program helped them feel comfortable managing their health from home. Furthermore, 93.58% (2873/3070) were satisfied with the RPM program and ready to graduate when meeting the program goals. In addition, patient confidence in this model of care was confirmed by 92.76% (2846/3068) of the participants who would recommend RPM to people with similar conditions. There were no differences in ease of technology use according to age. Those with high school or less education were more likely to agree that the equipment and educational materials helped them feel more informed about their care plans than those with higher education levels. CONCLUSIONS: This multisite, multiregional RPM program has become a reliable health care delivery model for the management of acute and chronic conditions outside hospitals and clinics. Program participants reported an excellent overall experience and a high level of satisfaction in managing their health from the comfort of their home environment.

Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death.

AIMS: Catecholaminergic polymorphic ventricular tachycardia (CPVT) and short QT syndrome (SQTS) are inherited arrhythmogenic disorders that can cause sudden death. Numerous genes have been reported to cause these conditions, but evidence supporting these gene-disease relationships varies considerably. To ensure appropriate utilization of genetic information for CPVT and SQTS patients, we applied an evidence-based reappraisal of previously reported genes. METHODS AND RESULTS: Three teams independently curated all published evidence for 11 CPVT and 9 SQTS implicated genes using the ClinGen gene curation framework. The results were reviewed by a Channelopathy Expert Panel who provided the final classifications. Seven genes had definitive to moderate evidence for disease causation in CPVT, with either autosomal dominant (RYR2, CALM1, CALM2, CALM3) or autosomal recessive (CASQ2, TRDN, TECRL) inheritance. Three of the four disputed genes for CPVT (KCNJ2, PKP2, SCN5A) were deemed by the Expert Panel to be reported for phenotypes that were not representative of CPVT, while reported variants in a fourth gene (ANK2) were too common in the population to be disease-causing. For SQTS, only one gene (KCNH2) was classified as definitive, with three others (KCNQ1, KCNJ2, SLC4A3) having strong to moderate evidence. The majority of genetic evidence for SQTS genes was derived from very few variants (five in KCNJ2, two in KCNH2, one in KCNQ1/SLC4A3). CONCLUSIONS: Seven CPVT and four SQTS genes have valid evidence for disease causation and should be included in genetic testing panels. Additional genes associated with conditions that may mimic clinical features of CPVT/SQTS have potential utility for differential diagnosis.

Avoiding Escalation to the Emergency Department by Activating an In-Home Rapid Response Team in the 30 Days After Hospital-at-Home Discharge.

BACKGROUND: Mayo Clinic's virtual hybrid hospital-at-home program, Advanced Care at Home (ACH) monitors acute and post-acute patients for signs of deterioration and institutes a rapid response (RR) system if detected. OBJECTIVE: This study aimed to describe Mayo Clinic's ACH RR team and its effect on emergency department (ED) use and readmission rates. METHODS: This was a retrospective review of all post-inpatient (restorative phase) ACH patients admitted from July 6, 2020 through June 30, 2021. If the restorative patient had a clinical decompensation, an RR was activated. All RR activations were analyzed for patient demographic characteristics, admitting and escalation diagnosis, time spent by virtual team on the RR, and whether the RR resulted in transport to the ED or hospital readmission. RESULTS: Three hundred and twenty patients were admitted to ACH during the study interval; 230 received restorative care. Seventy-two patients (31.3%) had events that triggered an RR. Fifty (69.4%) of the RR events were related to the admission diagnosis (p < 0.001; 95% CI 0.59-0.80). Twelve patients (16.7%) required transport to an ED for further treatment and were readmitted and 60 patients (83.3%) were able to be treated successfully in the home by the RR team (p < 0.001; 95% CI 0.08-0.25). CONCLUSIONS: The use of an ACH RR team was effective at limiting both escalations back to an ED and hospital readmissions, as 83% of deteriorating patients were successfully stabilized and managed in their homes. Implementing a hospital-at-home RR team can reduce the need for ED use by providing critical resources and carrying out required interventions to stabilize the patient's condition.

Smartphones and Threshold-Based Monitoring Methods Effectively Detect Falls Remotely: A Systematic Review.

In the US, at least one fall occurs in at least 28.7% of community-dwelling seniors 65 and older each year. Falls had medical costs of USD 51 billion in 2015 and are projected to reach USD 100 billion by 2030. This review aims to discuss the extent of smartphone (SP) usage in fall detection and prevention across a range of care settings. A computerized search was conducted on six electronic databases to investigate the use of remote sensing technology, wireless technology, and other related MeSH terms for detecting and preventing falls. After applying inclusion and exclusion criteria, 44 studies were included. Most of the studies targeted detecting falls, two focused on detecting and preventing falls, and one only looked at preventing falls. Accelerometers were employed in all the experiments for the detection and/or prevention of falls. The most frequent course of action following a fall event was an alarm to the guardian. Numerous studies investigated in this research used accelerometer data analysis, machine learning, and data from previous falls to devise a boundary and increase detection accuracy. SP was found to have potential as a fall detection system but is not widely implemented. Technology-based applications are being developed to protect at-risk individuals from falls, with the objective of providing more effective and efficient interventions than traditional means. Successful healthcare technology implementation requires cooperation between engineers, clinicians, and administrators.

Perceived Age as a Mortality and Comorbidity Predictor: A Systematic Review.

INTRODUCTION: Perceived age is defined as how old a person looks to external evaluators. It reflects the underlying biological age, which is a measure based on physical and physiological parameters reflecting a person's aging process more accurately than chronological age. People with a higher biological age have shorter lives compared to those with a lower biological age with the same chronological age. Our review aims to find whether increased perceived age is a risk factor for overall mortality risk or comorbidities. METHODS: A literature search of three databases was conducted following the PRISMA guidelines for studies analyzing perceived age or isolated facial characteristics of old age and their relationship to mortality risk or comorbidity outcomes. Data on the number of patients, type and characteristics of evaluation methods, evaluator characteristics, mean chronologic age, facial characteristics studied, measured outcomes, and study results were collected. RESULTS: Out of 977 studies, 15 fulfilled the inclusion criteria. These studies found an increase in mortality risk of 6-51% in older-looking people compared to controls (HR 1.06-1.51, p < 0.05). In addition, perceived age and some facial characteristics of old age were also associated with cardiovascular risk and myocardial infarction, cognitive function, bone mineral density, and chronic obstructive pulmonary disease (COPD). CONCLUSION: Perceived age promises to be a clinically useful predictor of overall mortality and cardiovascular, pulmonary, cognitive, and osseous comorbidities. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

High Satisfaction With a Virtual Assistant for Plastic Surgery Frequently Asked Questions.

BACKGROUND: Most of a surgeon's office time is dedicated to patient education, preventing an appropriate patient-physician relationship. Telephone-accessed artificial intelligent virtual assistants (AIVAs) that simulate a human conversation and answer preoperative frequently asked questions (FAQs) can be effective solutions to this matter. An AIVA capable of answering preoperative plastic surgery-related FAQs has previously been described by the authors. OBJECTIVES: The aim of this paper was to determine patients' perception and satisfaction with an AIVA. METHODS: Twenty-six adult patients from a plastic surgery service answered a 3-part survey consisting of: (1) an evaluation of the answers' correctness, (2) their agreement with the feasibility, usefulness, and future uses of the AIVA, and (3) a section on comments. The first part made it possible to measure the system's accuracy, and the second to evaluate perception and satisfaction. The data were analyzed with Microsoft Excel 2010 (Microsoft Corporation, Redmond, WA). RESULTS: The AIVA correctly answered the patients' questions 98.5% of the time, and the topic with the lowest accuracy was "nausea." Additionally, 88% of patients agreed with the statements of the second part of the survey. Thus, the patients' perception was positive and overall satisfaction with the AIVA was high. Patients agreed the least with using the AIVA to select their surgical procedure. The comments provided improvement areas for subsequent stages of the project. CONCLUSIONS: The results show that patients were satisfied and expressed a positive experience with using the AIVA to answer plastic surgery FAQs before surgery. The system is also highly accurate.

Comprehensive Genetic Testing for Pediatric Hypertrophic Cardiomyopathy Reveals Clinical Management Opportunities and Syndromic Conditions.

Hypertrophic cardiomyopathy (HCM) has historically been diagnosed phenotypically. Through genetic testing, identification of a molecular diagnosis (MolDx) is increasingly common but the impact on pediatric patients is unknown. This was a retrospective study of next-generation sequencing data for 602 pediatric patients with a clinician-reported history of HCM. Diagnostic yield was stratified by gene and self-reported race/ethnicity. A MolDx of HCM was identified in 242 (40%) individuals. Sarcomeric genes were the highest yielding, but pathogenic and/or likely pathogenic (P/LP) variants in syndromic genes were found in 36% of individuals with a MolDx, often in patients without documented clinical suspicion for a genetic syndrome. Among all MolDx, 73% were in genes with established clinical management recommendations and 2.9% were in genes that conferred eligibility for clinical trial enrollment. Black patients were the least likely to receive a MolDx. In the current era, genetic testing can impact management of HCM, beyond diagnostics or prognostics, through disease-specific guidelines or clinical trial eligibility. Genetic testing frequently can help identify syndromes in patients for whom syndromes may not be suspected. These findings highlight the importance of pursuing broad genetic testing, independent of suspicion based on phenotype. Lower rates of MolDx in Black patients may contribute to health inequities. Further research is needed evaluating the genetics of HCM in underrepresented/underserved populations. Additionally, research related to the impact of genetic testing on clinical management of other diseases is warranted.

Simulation and Artificial Intelligence in Rhinoplasty: A Systematic Review.

BACKGROUND: Rhinoplasty is one of the most popular cosmetic procedures. The complexity of the nasal structure and the substantial aesthetic and functional impact of the operation make rhinoplasty very challenging. The past few years have witnessed an increasing implementation of artificial intelligence (AI) and simulation systems into plastic surgery practice. This review explores the potential uses of AI and simulation models in rhinoplasty. METHODS: Five electronic databases were searched: PubMed, CINAHL, EMBASE, Scopus, and Web of Science. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analysis as our basis of organization. RESULTS: Several simulation models were described to predict the nasal shape that aesthetically matches the patient's face, indicate the implant size in augmentation rhinoplasty and construct three-dimensional (3D) facial images from two-dimensional images. Machine learning was used to learn surgeons' rhinoplasty styles and accurately simulate the outcomes. Deep learning was used to predict rhinoplasty status accurately and analyze the factors associated with increased facial attractiveness after rhinoplasty. Finally, a deep learning model was used to predict patients' age before and after rhinoplasty proving that the procedure made the patients look younger. CONCLUSION: 3D simulation models and AI models can revolutionalize the practice of functional and aesthetic rhinoplasty. Simulation systems can be beneficial in preoperative planning, intra-operative decision making, and postoperative evaluation. In addition, AI models can be trained to carry out tasks that are either challenging or time-consuming for surgeons. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome.

BACKGROUND: Long QT syndrome (LQTS) is the first described and most common inherited arrhythmia. Over the last 25 years, multiple genes have been reported to cause this condition and are routinely tested in patients. Because of dramatic changes in our understanding of human genetic variation, reappraisal of reported genetic causes for LQTS is required. METHODS: Utilizing an evidence-based framework, 3 gene curation teams blinded to each other's work scored the level of evidence for 17 genes reported to cause LQTS. A Clinical Domain Channelopathy Working Group provided a final classification of these genes for causation of LQTS after assessment of the evidence scored by the independent curation teams. RESULTS: Of 17 genes reported as being causative for LQTS, 9 (AKAP9, ANK2, CAV3, KCNE1, KCNE2, KCNJ2, KCNJ5, SCN4B, SNTA1) were classified as having limited or disputed evidence as LQTS-causative genes. Only 3 genes (KCNQ1, KCNH2, SCN5A) were curated as definitive genes for typical LQTS. Another 4 genes (CALM1, CALM2, CALM3, TRDN) were found to have strong or definitive evidence for causality in LQTS with atypical features, including neonatal atrioventricular block. The remaining gene (CACNA1C) had moderate level evidence for causing LQTS. CONCLUSIONS: More than half of the genes reported as causing LQTS have limited or disputed evidence to support their disease causation. Genetic variants in these genes should not be used for clinical decision-making, unless accompanied by new and sufficient genetic evidence. The findings of insufficient evidence to support gene-disease associations may extend to other disciplines of medicine and warrants a contemporary evidence-based evaluation for previously reported disease-causing genes to ensure their appropriate use in precision medicine.

The genetic architecture of Plakophilin 2 cardiomyopathy.

PURPOSE: The genetic architecture of Plakophilin 2 (PKP2) cardiomyopathy can inform our understanding of its variant pathogenicity and protein function. METHODS: We assess the gene-wide and regional association of truncating and missense variants in PKP2 with arrhythmogenic cardiomyopathy (ACM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) specifically. A discovery data set compares genetic testing requisitions to gnomAD. Validation is performed in a rigorously phenotyped definite ARVC cohort and non-ACM individuals in the Geisinger MyCode cohort. RESULTS: The etiologic fraction (EF) of ACM-related diagnoses from truncating variants in PKP2 is significant (0.85 [0.80,0.88], p < 2 × 10-16), increases for ARVC specifically (EF = 0.96 [0.94,0.97], p < 2 × 10-16), and is highest in definite ARVC versus non-ACM individuals (EF = 1.00 [1.00,1.00], p < 2 × 10-16). Regions of missense variation enriched for ACM probands include known functional domains and the C-terminus, which was not previously known to contain a functional domain. No regional enrichment was identified for truncating variants. CONCLUSION: This multicohort evaluation of the genetic architecture of PKP2 demonstrates the specificity of PKP2 truncating variants for ARVC within the ACM disease spectrum. We identify the PKP2 C-terminus as a potential functional domain and find that truncating variants likely cause disease irrespective of transcript position.

An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy.

The ACMG/AMP variant classification framework was intended for highly penetrant Mendelian conditions. While it is appreciated that clinically relevant variants exhibit a wide spectrum of penetrance, accurately assessing and expressing the pathogenicity of variants with lower penetrance can be challenging. The vinculin (VCL) gene illustrates these challenges. Model organism data provide evidence that loss of function of VCL may play a role in cardiomyopathy and aggregate case-control studies suggest low penetrance. VCL loss of function variants, however, are rarely identified in affected probands and therefore there is a paucity of family studies clarifying the clinical significance of individual variants. This study, which aggregated data from >18,000 individuals who underwent gene panel or exome testing for inherited cardiomyopathies, identified 32 probands with VCL loss-of-function variants and confirmed enrichment in probands with dilated cardiomyopathy (odds ratio [OR] = 9.01; confidence interval [CI] = 4.93-16.45). Our data revealed that the majority of these individuals (89.5%) had pediatric onset of disease. Family studies demonstrated that heterozygous loss of function of VCL alone is insufficient to cause cardiomyopathy but that these variants do contribute to disease risk. In conclusion, VCL loss-of-function variants should be reported in a diagnostic setting but need to be clearly distinguished as having lower penetrance.