Aveir VR, retrievable leadless pacing in the young.

INTRODUCTION: Successful implantations of the Aveir VR, have been effectively demonstrated in adults; however, there remain limited reports supporting safe and feasible implantation of the Aveir VR in the young population. METHODS: Retrospective, observational study of Aveir VR implantation of young patients (≦21 years old) at UC Davis Medical Center from November 2022 to January 2024 via the internal jugular or femoral vein implantation approaches. Indications for pacing, patient demographics, pacing thresholds and longevity were reported at the time of implantation and last follow-up. RESULTS: A total of 10 patients received the Aveir VR with a median age of years (IQR 12.5-17) and median weight of 50.8 kg (IQR 44.6-60.9) kg. The majority were male (80%). Aveir VR leadless pacemaker occurred via internal jugular venous (90%) or femoral venous (10%) approaches. Indications for placement were intermittent complete heart block (60%) and sinus pauses (40%). Adequate impedance, sensing and thresholds were maintained from implantation to a median follow-up of 9 months. Predicted pacemaker longevity at follow-up median was 23.8 years. There were no complications in any of the 10 patients. CONCLUSION: Aveir VR implantation via the internal jugular and femoral veins is feasible in the young patient population with stable pacing parameters at follow-up.

Vectorcardiography signs of a failing Fontan: Heart rate, PR interval, RtQRSvm, QRSvm and SPQRS-T angle as noninvasive markers of late Fontan complications and mortality.

BACKGROUND: Limited data exists on interpreting vectorcardiography (VCG) parameters in the Fontan population. OBJECTIVE: The purpose of this study was to demonstrate the associations between ECG/VCG parameters and Fontan failure (FF). METHODS/RESULTS: 107 patients with a Fontan operation after 1990 and without significant ventricular pacing were included. FF and Fontan survival (FS) groups were compared. The average follow-up after Fontan operation was 11.8 years ±7.1 years. 14 patients had FF (13.1%) which was defined as having protein-losing-enteropathy (1.9%), plastic bronchitis (2.8%), Fontan takedown (1.9%), heart transplant (5.6%), NYHA class III-IV (2.8%) or death (0.9%). A 12­lead ECG at last follow up or prior to FF was assessed for heart rate, PR interval, QRS duration, Qtc and left/right sided precordial measures (P-wave, QRS and T-wave vector magnitudes, spatial P-R and QRS-T angles). Transthoracic echocardiogram evaluated atrioventricular valve regurgitation and ventricular dysfunction at FF or last follow up. A cox multivariate regression analysis adjusted for LV dominance, ventricular dysfunction, HR, PR, QTc, Pvm, QRSvm, SPQRST-angle, RtPvm, RtQRSvm and RtTvm. Ventricular dysfunction, increased heart rate and prolonged PR interval were significantly associated to FF at the multivariate analysis. ROC analysis and Kaplan-meier analysis revealed an increased total mortality associated with a heart rate > 93 bpm, PR interval > 155 mv, QRSvm >1.91 mV, RtQRSvm >1.8 mV and SPQRST angle >92.3 mV with p values <0.001 to 0.018. CONCLUSION: We demonstrate the importance of ECG/VCG monitoring in the Fontan population and suggest specific indicators of late complications and mortality.

Comparison of the in vivo kinematics between robotic-assisted Bi-cruciate retaining and Bi-cruciate stabilised total knee arthroplasty.

BACKGROUND: Up to 20% of patients remain unsatisfied after total knee arthroplasty (TKA), prompting the development of new implants. Bi-Cruciate Retaining (BCR) TKA preserves both the anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL), with the ACL beneficial for its proprioceptive qualities. The Bi-Cruciate Stabilised (BCS) TKA substitutes the ACL and PCL with a unique dual cam-post mechanism. Robotics improve accuracy and facilitate technically demanding TKA. METHODS: This was a retrospective case-control study recruited from two centres. Measured outcomes included kinematic analysis, proprioception, and functional outcomes. RESULTS: There was a significantly larger maximum flexion angle and range of flexion to extension in sit-to-stand and stairs in BCR when compared to BCS. Further analysis revealed more similarities between BCR and normal native knees. Proprioception and functional scores did not have any statistical difference. CONCLUSION: BCR TKA demonstrated better knee flexion in weight-bearing active range of motion and showed similarities with normal knee kinematics.

Prospects for the computational humanization of antibodies and nanobodies.

To be viable therapeutics, antibodies must be tolerated by the human immune system. Rational approaches to reduce the risk of unwanted immunogenicity involve maximizing the 'humanness' of the candidate drug. However, despite the emergence of new discovery technologies, many of which start from entirely human gene fragments, most antibody therapeutics continue to be derived from non-human sources with concomitant humanization to increase their human compatibility. Early experimental humanization strategies that focus on CDR loop grafting onto human frameworks have been critical to the dominance of this discovery route but do not consider the context of each antibody sequence, impacting their success rate. Other challenges include the simultaneous optimization of other drug-like properties alongside humanness and the humanization of fundamentally non-human modalities such as nanobodies. Significant efforts have been made to develop in silico methodologies able to address these issues, most recently incorporating machine learning techniques. Here, we outline these recent advancements in antibody and nanobody humanization, focusing on computational strategies that make use of the increasing volume of sequence and structural data available and the validation of these tools. We highlight that structural distinctions between antibodies and nanobodies make the application of antibody-focused in silico tools to nanobody humanization non-trivial. Furthermore, we discuss the effects of humanizing mutations on other essential drug-like properties such as binding affinity and developability, and methods that aim to tackle this multi-parameter optimization problem.

Stories to Prevent Cancer: A Pilot Study Using Cancer Survivor Narratives to Increase Human Papillomavirus Vaccine Intentions.

INTRODUCTION: Human papillomavirus (HPV) vaccination rates are lower than other recommended adolescent vaccines. Cancer survivor narratives are used to promote cancer prevention and control, but little is known about their impact on adolescent HPV vaccination. OBJECTIVE: This pilot study explored the feasibility and effects of a video education intervention using a cancer survivor narrative to improve parents' attitudes toward and intentions to get the HPV vaccine. METHODS: This study utilized a one-group design; participants completed a pre-intervention survey, watched the video before attending their sons' wellness visits, and completed a post-intervention survey within one week of their appointment. Using the narrative persuasion framework, we developed a 4-minute video of a local HPV-related cancer survivor to promote the HPV vaccine as cancer prevention. We recruited 37 participants between June and October 2020. Participants were parents of males ages 9-17 who had not yet initiated HPV vaccination. RESULTS: After the video, more parents agreed that HPV vaccination is safe (pre: 66% vs. post: 82%; P = .045) and that their child's chances of getting HPV-related cancer in the future are high (pre: 24% vs. post: 46%; P = .014). Overall, 91% of parents felt the cancer survivor story helped them understand the risks of HPV cancers, and 52% said the story influenced their decision to start HPV vaccination for their child. CONCLUSIONS: Our findings suggest that cancer survivor narratives influence parents' vaccine opinions and understanding of their child's risk of HPV infection, leading to increased parental intent to get the HPV vaccine for their adolescent males.

Exploratory Analysis of Concordance Between Clinician-Collected and Self-Sampled Human Papillomavirus Tests in a Small Cohort of Average- and High-Risk Patients.

Objectives: Cervical cancer screening rates have stagnated, but self-sampling modalities have the potential to increase uptake. This study compares the test characteristics of self-sampled high-risk human papillomavirus (hrHPV) tests with clinician-collected hrHPV tests in average-risk (i.e., undergoing routine screening) and high-risk patients (i.e., receiving follow-up after abnormal screening results). Methods: In this cross-sectional study, a relatively small cohort of average-risk (n = 35) and high-risk (n = 12) participants completed both clinician-collected and self-sampled hrHPV testing, along with a brief phone survey. We assessed hrHPV positivity, concordance, positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity across both methods (for types 16, 18, or other hrHPV). We also explored the relationship between test concordance and sociodemographic/behavioral factors. Results: Among average-risk participants, hrHPV positivity was 6% for both test methods (i.e., hrHPV-positive cases: n = 2), resulting in reported concordance, PPV, NPV, sensitivity, and specificity of 100%. Among high-risk participants, hrHPV positivity was 100% for clinician-collected tests but only 67% for self-sampled tests, showing varied concordance and sensitivity. Concordance was not associated with sociodemographic or behavioral factors. Conclusions: Self-sampled hrHPV testing demonstrated high accuracy for average-risk patients in this exploratory study. However, its performance was less consistent in high-risk patients who had already received an abnormal screening result, which could be attributed to spontaneous viral clearance over time. The limited number of participants, particularly HPV-positive cases, suggests caution in interpreting these results. Further research with larger cohorts is necessary to validate these findings and to explore the integration of self-sampled hrHPV testing into routine clinical care, particularly for patients with a history of cervical abnormalities. Clinical Trial Registration: NCT04591977, NCT04585243.

SIRT2 transgenic over-expression does not impact lifespan in mice.

The NAD+ -dependent deacylase family of sirtuin enzymes have been implicated in biological ageing, late-life health and overall lifespan, though of these members, a role for sirtuin-2 (SIRT2) is less clear. Transgenic overexpression of SIRT2 in the BubR1 hypomorph model of progeria can rescue many aspects of health and increase overall lifespan, due to a specific interaction between SIRT2 and BubR1 that improves the stability of this protein. It is less clear whether SIRT2 is relevant to biological ageing outside of a model where BubR1 is under-expressed. Here, we sought to test whether SIRT2 over-expression would impact the overall health and lifespan of mice on a nonprogeroid, wild-type background. While we previously found that SIRT2 transgenic overexpression prolonged female fertility, here, we did not observe any additional impact on health or lifespan, which was measured in both male and female mice on standard chow diets, and in males challenged with a high-fat diet. At the biochemical level, NMR studies revealed an increase in total levels of a number of metabolites in the brain of SIRT2-Tg animals, pointing to a potential impact in cell composition; however, this did not translate into functional differences. Overall, we conclude that strategies to enhance SIRT2 protein levels may not lead to increased longevity.

Looking Back to Move Forward: The Current State of Research on the Clinical Applications of Camphor- and Menthol-Containing Agents.

Topically applied compounds containing camphor and menthol have been used to alleviate pain, cold symptoms, and pruritus, historically predominantly in East Asia. Being not studied well, they are less recognized in Western medicine. Given the commonality of pain, pruritus, and cold symptoms in addition to the growing need for non-opioid treatment options, the authors investigated clinical applications of such compounds for their over-counter usage. The purpose was to analyze current clinical research and applications regarding the use of these topical agents. This study involved a bibliometric analysis of peer-reviewed articles, published in English and indexed in PubMed from 2010 to 2022, pertaining to camphor- and menthol-containing compounds. There were 103 results, of which 15 (14.6%) articles were related to the treatment of disorders related to health, such as upper respiratory infection, pain, and pruritus. Excluded were "non-research" articles (e.g., letters to the editor), articles that do not involve human subjects, reports of improper application or misuse (e.g., ingestion), and articles pertaining to intraoral, intranasal, and ophthalmic agents. Of these articles, the originating journals, respective journal impact factor scores, publication years, study designs, and study topics were identified. Underlying trends and themes regarding clinically relevant research on these compounds were subsequently discerned. Based on this analysis, topical agents containing camphor and menthol are potentially effective at treating pain, upper respiratory infection symptoms, and pruritus in addition to potentially functioning as an antimicrobial. However, with a limited number of studies addressing these compounds' uses in each application, no definitive recommendation can be made regarding their use. Given the promising results of earlier studies, the authors recommend that more primary research, particularly randomized, double-blind controlled studies, be done regarding clinical applications of these substances.

Loop recorder implantation in patients as young as 3-months of age; the benefit of the sub-scapular approach.

BACKGROUND: Loop recorder implants may have value in pediatric patients; however, size limitations exist due to the risk of erosion. METHODS: Retrospective review of five patients who underwent subscapular loop recorder implantation were reviewed. RESULTS: No complications occurred. Stable R-waves were noted but could be positional but with adequate diagnostics provided. CONCLUSION: Subscapular loop recorder implantation is feasible in patients as young as 3 months of age.

First report of an Aveir retrievable leadless pacemaker in a pediatric patient, via internal jugular vein access.

BACKGROUND: The Aveir device allows retrievability and mapping prior to fixation over alternative leadless pacemakers. CASE SUMMARY: We describe the first case of Aveir leadless pacemaker implantation into a 44.5 kg, pediatric patient with symptomatic sinus dysfunction. Access by the right internal jugular vein (RIJ) with 1st attempt implantation into the septal location. DISCUSSION: Placement of the Aveir leadless pacemaker is feasible in a 44.5 kg pediatric patient via a RIJ approach.

Leadless pacemaker implantation for pediatric patients through internal jugular vein approach: A case series of under 30 kg.

BACKGROUND: We demonstrate a case series of 8 pediatric patients, all under 30 kg, who had leadless pacemaker implants via the internal jugular vein. METHODS: A retrospective review of pediatric leadless pacing placement via the internal jugular vein at the University of Minnesota Masonic Children's Hospital and UC Davis Medical Center from 2018 through 2021 was performed. Rationales for pacing, demographics of patients, pacing thresholds, and longevity of devices were recorded. RESULTS: Eight internal jugular pacemaker insertions were performed successfully in patients weighing between 10.9 kg and 29 kg. Five patients had Micra implantation via the right internal jugular vein, whereas 3 patients had insertion via the left internal jugular vein. No surgical cut-downs were performed. No venous complications occurred. Up to 3 years of follow-up were noted. CONCLUSION: Leadless pacemaker implantation, via left or right internal jugular veins, is feasible without surgical cutdown in patients <30 kg.

Modified Frailty Index Does Not Provide Additional Value in Predicting Outcomes in Patients Undergoing Elective Transforaminal Lumbar Interbody Fusion.

OBJECTIVE: To determine the predictive value of the modified Frailty Index (mFI) in evaluating sarcopenia and clinical outcomes in patients undergoing 1-level or 2-level transforaminal lumbar interbody fusion (TLIF). METHODS: Patients who underwent a 1-level or 2-level TLIF between 2012 and 2020 were retrospectively identified. Frailty was compared among groups using mFI, and sarcopenia was classified by the psoas muscle cross-sectional area. Bivariate statistics compared demographics, comorbidities, and clinical outcomes. A linear regression model was developed using the Charlson Comorbidity Index (CCI) or mFI as independent variables to determine potential predictors for improvement in 1-year patient-reported outcomes. RESULTS: Of 488 included patients, 60 were severely frail and 60 patients had sarcopenia, but sarcopenia was not associated with patient frailty (P = 0.469). Severely frail patients had worse baseline Oswestry Disability Index (ODI) (P < 0.001), Mental Component Score-12 (P = 0.001), and Physical Component Score-12 (P < 0.001), and worse improvement in ODI (P = 0.037), Physical Component Score-12 (P < 0.001), and visual analog scale (VAS) back (P = 0.007). mFI was an independent predictor of poorer improvement in VAS back and ODI, whereas age + CCI in addition predicted poorer improvement in VAS leg. Patients with higher mFI experienced longer length of stay, less frequent home discharge, and higher rates of complications, but similar readmission and reoperation rates. CONCLUSIONS: Frailer patients experience poorer improvement in back pain, physical functioning, and disability after TLIF. mFI and the combination of age and CCI comparably predict patient-reported outcomes but do not correlate to baseline sarcopenia. Frailty increased the risk of complications, length of hospital stay, and risk of nonhome discharge.

Combined X-linked familial exudative vitreoretinopathy and retinopathy of prematurity phenotype in an infant with mosaic turner syndrome with ring X chromosome.

BACKGROUND: Retinopathy of prematurity (ROP) and familial exudative vitreoretinopathy (FEVR) are two distinct pathologies of retinal angiogenesis with overlapping clinical features. METHODS: Examination, multimodal imaging, and genetic testing were used to guide diagnosis and treatment. RESULTS: We report a combined phenotype of X-linked FEVR and ROP in a 4-month-old girl with mosaic Turner syndrome with ring X chromosome born at 26 weeks gestational age. She was initially diagnosed with atypical ROP with a vitreous band causing a localized traction retinal detachment, inferotemporal to the macula in the right eye, vessels to posterior zone 2 with no clear ridge temporally in the left eye, and fluorescein leakage in both eyes. Due to the suspicion of concurrent FEVR, genetic testing using a vitreoretinopathy panel was performed which revealed a mosaic Turner syndrome associated with 45,X/46,X,r(X), subsequently confirmed by chromosome analysis. The deleted region in the ring X chromosome included the NDP and RS1 genes. The patient was treated with laser photocoagulation of the peripheral avascular retina and sub-Tenon's triamcinolone injection in both eyes, intravitreal injection of bevacizumab in the left eye, and pars plicata vitrectomy in the right eye. CONCLUSIONS: In premature neonates with atypical ROP, a clinical suspicion of concurrent FEVR or similar vasculopathy is important and genetic testing may elucidate a genetic etiology, which could influence management and prognosis. Turner syndrome can be connected with co-occurring Mendelian gene disorders, particularly in individuals with mosaicism. The concurrence of FEVR and ROP appears to result in atypical and possibly more severe phenotypes.

Selective inhibitors of JAK1 targeting an isoform-restricted allosteric cysteine.

The Janus tyrosine kinase (JAK) family of non-receptor tyrosine kinases includes four isoforms (JAK1, JAK2, JAK3, and TYK2) and is responsible for signal transduction downstream of diverse cytokine receptors. JAK inhibitors have emerged as important therapies for immun(onc)ological disorders, but their use is limited by undesirable side effects presumed to arise from poor isoform selectivity, a common challenge for inhibitors targeting the ATP-binding pocket of kinases. Here we describe the chemical proteomic discovery of a druggable allosteric cysteine present in the non-catalytic pseudokinase domain of JAK1 (C817) and TYK2 (C838), but absent from JAK2 or JAK3. Electrophilic compounds selectively engaging this site block JAK1-dependent trans-phosphorylation and cytokine signaling, while appearing to act largely as 'silent' ligands for TYK2. Importantly, the allosteric JAK1 inhibitors do not impair JAK2-dependent cytokine signaling and are inactive in cells expressing a C817A JAK1 mutant. Our findings thus reveal an allosteric approach for inhibiting JAK1 with unprecedented isoform selectivity.

Examination of the Cell Cycle Dependence of Cytosine and Adenine Base Editors.

Base editors (BEs) are genome editing agents that install point mutations with high efficiency and specificity. Due to their reliance on uracil and inosine DNA damage intermediates (rather than double-strand DNA breaks, or DSBs), it has been hypothesized that BEs rely on more ubiquitous DNA repair pathways than DSB-reliant genome editing methods, which require processes that are only active during certain phases of the cell cycle. We report here the first systematic study of the cell cycle-dependence of base editing using cell synchronization experiments. We find that nickase-derived BEs (which introduce DNA backbone nicks opposite the uracil or inosine base) function independently of the cell cycle, while non-nicking BEs are highly dependent on S-phase (DNA synthesis phase). We found that synchronization in G1 (growth phase) during the process of cytosine base editing causes significant increases in C•G to A•T "byproduct" introduction rates, which can be leveraged to discover new strategies for precise C•G to A•T base editing. We observe that endogenous expression levels of DNA damage repair pathways are sufficient to process base editing intermediates into desired editing outcomes, and the process of base editing does not significantly perturb transcription levels. Overall, our study provides mechanistic data demonstrating the robustness of nickase-derived BEs for performing genome editing across the cell cycle.

Modulation of Deiodinase Types 2 and 3 during Skeletal Muscle Regeneration.

The muscle stem-cell niche comprises numerous cell types, which coordinate the regeneration process after injury. Thyroid hormones are one of the main factors that regulate genes linked to skeletal muscle. In this way, deiodinase types 2 and 3 are responsible for the fine-tuning regulation of the local T3 amount. Although their expression and activity have already been identified during muscle regeneration, it is of utmost importance to identify the cell type and temporal pattern of expression after injury to thoroughly comprehend their therapeutic potential. Here, we confirmed the expression of Dio2 and Dio3 in the whole tibialis anterior muscle. We identified, on a single-cell basis, that Dio2 is present in paired box 7 (PAX7)-positive cells starting from day 5 after injury. Dio2 is present in platelet derived growth factor subunit A (PDGFA)-expressing fibro-adipogenic progenitor cells between days 7 and 14 after injury. Dio3 is detected in myogenic differentiation (MYOD)-positive stem cells and in macrophages immediately post injury and thereafter. Interestingly, Dio2 and Dio3 RNA do not appear to be present in the same type of cell throughout the process. These results provide further insight into previously unseen aspects of the crosstalk and synchronized regulation of T3 in injured muscle mediated by deiodinases. The set of findings described here further define the role of deiodinases in muscle repair, shedding light on potential new forms of treatment for sarcopenia and other muscular diseases.

An additional patient with SMAD4-Juvenile Polyposis-Hereditary hemorrhagic telangiectasia and connective tissue abnormalities: SMAD4 loss-of-function and gain-of-function pathogenic variants result in contrasting phenotypes.

Loss-of-function pathogenic variants in somatic and germline cells in SMAD4 may cause cancer and juvenile polyposis-Hereditary Hemorrhagic Telangiectasia (SMAD4-JP-HHT), respectively. In a similar manner, gain-of-function somatic and germline pathogenic variants in SMAD4 can cause various forms of cancer as well as Myhre syndrome. The different SMAD4 molecular mechanisms result in contrasting clinical phenotypes demonstrated by SMAD4-JP-HHT and Myhre syndrome. We report an additional patient with SMAD4-JP-HHT and aortopathy, and expand the phenotype to include severe valvulopathy, cutaneous, ophthalmologic, and musculoskeletal features consistent with an inherited disorder of connective tissue. We compared this 70-year-old man with SMAD4-JP-HHT to 18 additional literature cases, and also compared patients with SMAD4-JP-HHT to those with Myhre syndrome. In contrast to aorta dilation, hypermobility, and loose skin in SMAD4-JP-HHT, Myhre syndrome has aorta hypoplasia, stiff joints, and firm skin representing an intriguing phenotypic contrast, which can be attributed to different molecular mechanisms involving SMAD4. We remind clinicians about the possibility of significant cardiac valvulopathy and aortopathy, as well as connective tissue disease in SMAD4-JP-HHT. Additional patients and longer follow-up will help determine if more intensive surveillance improves care amongst these patients.

Phenotypic spectrum of the recurrent TRPM3 p.(Val837Met) substitution in seven individuals with global developmental delay and hypotonia.

TRPM3 encodes a transient receptor potential cation channel of the melastatin family, expressed in the central nervous system and in peripheral sensory neurons of the dorsal root ganglia. The recurrent substitution in TRPM3: c.2509G>A, p.(Val837Met) has been associated with syndromic intellectual disability and seizures. In this report, we present the clinical and molecular features of seven previously unreported individuals, identified by exome sequencing, with the recurrent p.(Val837Met) variant and global developmental delay. Other shared clinical features included congenital hypotonia, dysmorphic facial features (broad forehead, deep-set eyes, and down turned mouth), exotropia, and musculoskeletal issues (hip dysplasia, hip dislocation, scoliosis). Seizures were observed in two of seven individuals (febrile seizure in one and generalized tonic-clonic seizures with atonic drops in another), and epileptiform activity was observed in an additional two individuals. This report extends the number of affected individuals to 16 who are heterozygous for the de novo recurrent substitution p.(Val837Met). In contrast with the initial report, epilepsy was not a mandatory feature observed in this series. TRPM3 pathogenic variation should be considered in individuals with global developmental delays, moderate-severe intellectual disability with, or without, childhood-onset epilepsy.