ß-Catenin transcriptional activity is required for establishment of inner pillar cell identity during cochlear development.

The mammalian cochlea is composed of sensory hair cells as well as multiple different types of non-sensory supporting cells. Pillar cells are one type of supporting cell that form the tunnel of Corti and include two morphologically and functionally distinct subtypes: inner pillar cells (IPCs) and outer pillar cells (OPCs). The processes of specification and differentiation of inner versus outer pillar cells are still unclear. Here, we show that ß-Catenin is required for establishing IPC identity in the mammalian cochlea. To differentiate the transcriptional and adhesion roles of ß-Catenin in establishing IPC identity, we examined two different models of ß-Catenin deletion; one that deletes both transcriptional and structural functions and one which retains cell adhesion function but lacks transcriptional function. Here, we show that cochleae lacking ß-Catenin transcriptional function lost IPCs and displayed extranumerary OPCs, indicating its requirement for establishing IPC identity. Overexpression of ß-Catenin induced proliferation within IPCs but not ectopic IPCs. Single-cell transcriptomes of supporting cells lacking ß-Catenin transcriptional function show a loss of the IPC and gain of OPC signatures. Finally, targeted deletion of ß-Catenin in IPCs also led to the loss of IPC identity, indicating a cell autonomous role of ß-Catenin in establishing IPC identity. As IPCs have the capacity to regenerate sensory hair cells in the postnatal cochlea, our results will aid in future IPC-based hair cell regeneration strategies.

AbLEF: antibody language ensemble fusion for thermodynamically empowered property predictions.

MOTIVATION: Pre-trained protein language and/or structural models are often fine-tuned on drug development properties (i.e. developability properties) to accelerate drug discovery initiatives. However, these models generally rely on a single structural conformation and/or a single sequence as a molecular representation. We present a physics-based model, whereby 3D conformational ensemble representations are fused by a transformer-based architecture and concatenated to a language representation to predict antibody protein properties. Antibody language ensemble fusion enables the direct infusion of thermodynamic information into latent space and this enhances property prediction by explicitly infusing dynamic molecular behavior that occurs during experimental measurement. RESULTS: We showcase the antibody language ensemble fusion model on two developability properties: hydrophobic interaction chromatography retention time and temperature of aggregation (Tagg). We find that (i) 3D conformational ensembles that are generated from molecular simulation can further improve antibody property prediction for small datasets, (ii) the performance benefit from 3D conformational ensembles matches shallow machine learning methods in the small data regime, and (iii) fine-tuned large protein language models can match smaller antibody-specific language models at predicting antibody properties. AVAILABILITY AND IMPLEMENTATION: AbLEF codebase is available at https://github.com/merck/AbLEF.

Repair of surviving hair cells in the damaged mouse utricle.

Sensory hair cells (HCs) in the utricle are mechanoreceptors required to detect linear acceleration. After damage, the mammalian utricle partially restores the HC population and organ function, although regenerated HCs are primarily type II and immature. Whether native, surviving HCs can repair and contribute to this recovery is unclear. Here, we generated the Pou4f3DTR/+; Atoh1CreERTM/+; Rosa26RtdTomato/+ mouse to fate map HCs prior to ablation. After HC ablation, vestibular evoked potentials were abolished in all animals, with ∼57% later recovering responses. Relative to nonrecovery mice, recovery animals harbored more Atoh1-tdTomato+ surviving HCs. In both groups, surviving HCs displayed markers of both type I and type II subtypes and afferent synapses, despite distorted lamination and morphology. Surviving type II HCs remained innervated in both groups, whereas surviving type I HCs first lacked and later regained calyces in the recovery, but not the nonrecovery, group. Finally, surviving HCs initially displayed immature and subsequently mature-appearing bundles in the recovery group. These results demonstrate that surviving HCs are capable of self-repair and may contribute to the recovery of vestibular function.

AbMelt: Learning antibody thermostability from molecular dynamics.

Antibody thermostability is challenging to predict from sequence and/or structure. This difficulty is likely due to the absence of direct entropic information. Herein, we present AbMelt where we model the inherent flexibility of homologous antibody structures using molecular dynamics simulations at three temperatures and learn the relevant descriptors to predict the temperatures of aggregation (Tagg), melt onset (Tm,on), and melt (Tm). We observed that the radius of gyration deviation of the complementarity determining regions at 400 K is the highest Pearson correlated descriptor with aggregation temperature (rp = -0.68 ± 0.23) and the deviation of internal molecular contacts at 350 K is the highest correlated descriptor with both Tm,on (rp = -0.74 ± 0.04) as well as Tm (rp = -0.69 ± 0.03). Moreover, after descriptor selection and machine learning regression, we predict on a held-out test set containing both internal and public data and achieve robust performance for all endpoints compared with baseline models (Tagg R2 = 0.57 ± 0.11, Tm,on R2 = 0.56 ± 0.01, and Tm R2 = 0.60 ± 0.06). In addition, the robustness of the AbMelt molecular dynamics methodology is demonstrated by only training on <5% of the data and outperforming more traditional machine learning models trained on the entire data set of more than 500 internal antibodies. Users can predict thermostability measurements for antibody variable fragments by collecting descriptors and using AbMelt, which has been made available.

Opposing effects of Wnt/ß-catenin signaling on epithelial and mesenchymal cell fate in the developing cochlea.

During embryonic development, the otic epithelium and surrounding periotic mesenchymal cells originate from distinct lineages and coordinate to form the mammalian cochlea. Epithelial sensory precursors within the cochlear duct first undergo terminal mitosis before differentiating into sensory and non-sensory cells. In parallel, periotic mesenchymal cells differentiate to shape the lateral wall, modiolus and pericochlear spaces. Previously, Wnt activation was shown to promote proliferation and differentiation of both otic epithelial and mesenchymal cells. Here, we fate-mapped Wnt-responsive epithelial and mesenchymal cells in mice and found that Wnt activation resulted in opposing cell fates. In the post-mitotic cochlear epithelium, Wnt activation via ß-catenin stabilization induced clusters of proliferative cells that dedifferentiated and lost epithelial characteristics. In contrast, Wnt-activated periotic mesenchyme formed ectopic pericochlear spaces and cell clusters showing a loss of mesenchymal and gain of epithelial features. Finally, clonal analyses via multi-colored fate-mapping showed that Wnt-activated epithelial cells proliferated and formed clonal colonies, whereas Wnt-activated mesenchymal cells assembled as aggregates of mitotically quiescent cells. Together, we show that Wnt activation drives transition between epithelial and mesenchymal states in a cell type-dependent manner.

Lineage-tracing and translatomic analysis of damage-inducible mitotic cochlear progenitors identifies candidate genes regulating regeneration.

Cochlear supporting cells (SCs) are glia-like cells critical for hearing function. In the neonatal cochlea, the greater epithelial ridge (GER) is a mitotically quiescent and transient organ, which has been shown to nonmitotically regenerate SCs. Here, we ablated Lgr5+ SCs using Lgr5-DTR mice and found mitotic regeneration of SCs by GER cells in vivo. With lineage tracing, we show that the GER houses progenitor cells that robustly divide and migrate into the organ of Corti to replenish ablated SCs. Regenerated SCs display coordinated calcium transients, markers of the SC subtype inner phalangeal cells, and survive in the mature cochlea. Via RiboTag, RNA-sequencing, and gene clustering algorithms, we reveal 11 distinct gene clusters comprising markers of the quiescent and damaged GER, and damage-responsive genes driving cell migration and mitotic regeneration. Together, our study characterizes GER cells as mitotic progenitors with regenerative potential and unveils their quiescent and damaged translatomes.

Dual regulation of planar polarization by secreted Wnts and Vangl2 in the developing mouse cochlea.

Planar cell polarity (PCP) proteins localize asymmetrically to instruct cell polarity within the tissue plane, with defects leading to deformities of the limbs, neural tube and inner ear. Wnt proteins are evolutionarily conserved polarity cues, yet Wnt mutants display variable PCP defects; thus, how Wnts regulate PCP remains unresolved. Here, we have used the developing cochlea as a model system to show that secreted Wnts regulate PCP through polarizing a specific subset of PCP proteins. Conditional deletion of Wntless or porcupine, both of which are essential for secretion of Wnts, caused misrotated sensory cells and shortened cochlea - both hallmarks of PCP defects. Wntless-deficient cochleae lacked the polarized PCP components dishevelled 1/2 and frizzled 3/6, while other PCP proteins (Vangl1/2, Celsr1 and dishevelled 3) remained localized. We identified seven Wnt paralogues, including the major PCP regulator Wnt5a, which was, surprisingly, dispensable for planar polarization in the cochlea. Finally, Vangl2 haploinsufficiency markedly accentuated sensory cell polarization defects in Wntless-deficient cochlea. Together, our study indicates that secreted Wnts and Vangl2 coordinate to ensure proper tissue polarization during development.

Identifying targets to prevent aminoglycoside ototoxicity.

Aminoglycosides are potent antibiotics that are commonly prescribed worldwide. Their use carries significant risks of ototoxicity by directly causing inner ear hair cell degeneration. Despite their ototoxic side effects, there are currently no approved antidotes. Here we review recent advances in our understanding of aminoglycoside ototoxicity, mechanisms of drug transport, and promising sites for intervention to prevent ototoxicity.

Dissociating antibacterial from ototoxic effects of gentamicin C-subtypes.

Gentamicin is a potent broad-spectrum aminoglycoside antibiotic whose use is hampered by ototoxic side-effects. Hospital gentamicin is a mixture of five gentamicin C-subtypes and several impurities of various ranges of nonexact concentrations. We developed a purification strategy enabling assaying of individual C-subtypes and impurities for ototoxicity and antimicrobial activity. We found that C-subtypes displayed broad and potent in vitro antimicrobial activities comparable to the hospital gentamicin mixture. In contrast, they showed different degrees of ototoxicity in cochlear explants, with gentamicin C2b being the least and gentamicin C2 the most ototoxic. Structure-activity relationships identified sites in the C4'-C6' region on ring I that reduced ototoxicity while preserving antimicrobial activity, thus identifying targets for future drug design and mechanisms for hair cell toxicity. Structure-activity relationship data suggested and electrophysiological data showed that the C-subtypes both bind and permeate the hair cell mechanotransducer channel, with the stronger the binding the less ototoxic the compound. Finally, both individual and reformulated mixtures of C-subtypes demonstrated decreased ototoxicity while maintaining antimicrobial activity, thereby serving as a proof-of-concept of drug reformulation to minimizing ototoxicity of gentamicin in patients.

The impact of targeted ablation of one row of outer hair cells and Deiters' cells on cochlear amplification.

The mammalian cochlea contains three rows of outer hair cells (OHCs) that amplify the basilar membrane traveling wave with high gain and exquisite tuning. The pattern of OHC loss caused by typical methods of producing hearing loss in animal models (noise, ototoxic exposure, or aging) is variable and not consistent along the length of the cochlea. Thus, it is difficult to use these approaches to understand how forces from multiple OHCs summate to create normal cochlear amplification. Here, we selectively removed the third row of OHCs and Deiters' cells in adult mice and measured cochlear amplification. In the mature cochlear epithelia, expression of the Wnt target gene Lgr5 is restricted to the third row of Deiters' cells, the supporting cells directly underneath the OHCs. Diphtheria toxin administration to Lgr5DTR-EGFP/+ mice selectively ablated the third row of Deiters' cells and the third row of OHCs. Basilar membrane vibration in vivo demonstrated disproportionately lower reduction in cochlear amplification by about 13.5 dB. On a linear scale, this means that the 33% reduction in OHC number led to a 79% reduction in gain. Thus, these experimental data describe the impact of reducing the force of cochlear amplification by a specific amount. Furthermore, these data argue that because OHC forces progressively and sequentially amplify the traveling wave as it travels to its peak, the loss of even a relatively small number of OHCs, when evenly distributed longitudinally, will cause a substantial reduction in cochlear amplification.NEW & NOTEWORTHY Normal cochlear physiology involves force production from three rows of outer hair cells to amplify and tune the traveling wave. Here, we used a genetic approach to target and ablate the third row of outer hair cells in the mouse cochlea and found it reduced cochlear amplification by 79%. This means that the loss of even a relatively small number of OHCs, when evenly distributed, causes a substantial reduction in cochlear amplification.

Antibacterial Envelope to Prevent Cardiac Implantable Device Infection.

BACKGROUND: Infections after placement of cardiac implantable electronic devices (CIEDs) are associated with substantial morbidity and mortality. There is limited evidence on prophylactic strategies, other than the use of preoperative antibiotics, to prevent such infections. METHODS: We conducted a randomized, controlled clinical trial to assess the safety and efficacy of an absorbable, antibiotic-eluting envelope in reducing the incidence of infection associated with CIED implantations. Patients who were undergoing a CIED pocket revision, generator replacement, or system upgrade or an initial implantation of a cardiac resynchronization therapy defibrillator were randomly assigned, in a 1:1 ratio, to receive the envelope or not. Standard-of-care strategies to prevent infection were used in all patients. The primary end point was infection resulting in system extraction or revision, long-term antibiotic therapy with infection recurrence, or death, within 12 months after the CIED implantation procedure. The secondary end point for safety was procedure-related or system-related complications within 12 months. RESULTS: A total of 6983 patients underwent randomization: 3495 to the envelope group and 3488 to the control group. The primary end point occurred in 25 patients in the envelope group and 42 patients in the control group (12-month Kaplan-Meier estimated event rate, 0.7% and 1.2%, respectively; hazard ratio, 0.60; 95% confidence interval [CI], 0.36 to 0.98; P = 0.04). The safety end point occurred in 201 patients in the envelope group and 236 patients in the control group (12-month Kaplan-Meier estimated event rate, 6.0% and 6.9%, respectively; hazard ratio, 0.87; 95% CI, 0.72 to 1.06; P<0.001 for noninferiority). The mean (±SD) duration of follow-up was 20.7±8.5 months. Major CIED-related infections through the entire follow-up period occurred in 32 patients in the envelope group and 51 patients in the control group (hazard ratio, 0.63; 95% CI, 0.40 to 0.98). CONCLUSIONS: Adjunctive use of an antibacterial envelope resulted in a significantly lower incidence of major CIED infections than standard-of-care infection-prevention strategies alone, without a higher incidence of complications. (Funded by Medtronic; WRAP-IT ClinicalTrials.gov number, NCT02277990.).

Computed tomography imaging-identified location and electrocardiographic characteristics of left bundle branch area pacing in bradycardia patients.

INTRODUCTION: Left bundle branch area pacing (LBBAP) is a novel physiological pacing modality. The relationship between the pacing lead tip location and paced electrocardiographic (ECG) characteristics remains unclear. The objectives are to determine the lead tip location within the interventricular septum (IVS) and assess the location-based ECG QRS duration (QRSd) and left ventricular activation time (LVAT). METHODS: This multicenter study enrolled 50 consecutive bradycardia patients who met pacemaker therapy guidelines and received LBBAP implantation via the trans-ventricular septal approach. After at least 3 months postimplant, 12-lead ECGs and pacing parameters were obtained. Cardiac computed tomography (CT) imaging was performed to assess the LBBAP lead tip distance from the LV blood pool. RESULTS: Among the 50 patients, analyzable CT images were obtained in 42. In 23 of the 42 patients, the lead tips were within 2 mm to the LV blood pool (the LV subendocardial (LVSE) group), 13 between 2 and 4 mm (the Near-LVSE group), and the remaining 6 beyond 4 mm (the Mid-LV septal (Mid-LVS) group). No significant differences in paced QRSd were found among the three groups (LVSE, 107 ± 15 ms; Near-LVSE, 106 ± 13 ms; Mid-LVS, 104 ± 15 ms; p = .87). LVAT in the LVSE (64 ± 7 ms) was significantly shorter than in the Mid-LVS (72 ± 8 ms; p < .05), but not significantly different from that in the Near-LVSE (69 ± 8 ms; p > .05). CONCLUSION: In routine LBBAP practice, paced narrow QRSd and fast LVAT, indicative of physiological pacing, were consistently achieved for lead tip location in the LV subendocardial or near LV subendocardial region.

Uncoordinated maturation of developing and regenerating postnatal mammalian vestibular hair cells.

Sensory hair cells are mechanoreceptors required for hearing and balance functions. From embryonic development, hair cells acquire apical stereociliary bundles for mechanosensation, basolateral ion channels that shape receptor potential, and synaptic contacts for conveying information centrally. These key maturation steps are sequential and presumed coupled; however, whether hair cells emerging postnatally mature similarly is unknown. Here, we show that in vivo postnatally generated and regenerated hair cells in the utricle, a vestibular organ detecting linear acceleration, acquired some mature somatic features but hair bundles appeared nonfunctional and short. The utricle consists of two hair cell subtypes with distinct morphological, electrophysiological and synaptic features. In both the undamaged and damaged utricle, fate-mapping and electrophysiology experiments showed that Plp1+ supporting cells took on type II hair cell properties based on molecular markers, basolateral conductances and synaptic properties yet stereociliary bundles were absent, or small and nonfunctional. By contrast, Lgr5+ supporting cells regenerated hair cells with type I and II properties, representing a distinct hair cell precursor subtype. Lastly, direct physiological measurements showed that utricular function abolished by damage was partially regained during regeneration. Together, our data reveal a previously unrecognized aberrant maturation program for hair cells generated and regenerated postnatally and may have broad implications for inner ear regenerative therapies.

Evaluation of continuous glucose monitoring-derived person-specific HbA1c in the presence and absence of complications in type 1 diabetes.

AIM: To evaluate the accuracy of a novel kinetic model at predicting HbA1c in a real-world setting and to understand and explore the role of diabetes complications in altering the glucose-HbA1c relationship and the mechanisms involved. MATERIALS AND METHODS: Deidentified HbA1c and continuous glucose monitoring values were collected from 93 individuals with type 1 diabetes. Person-specific kinetic variables were used, including red blood cell (RBC) glucose uptake and lifespan, to characterize the relationship between glucose levels and HbA1c. The resulting calculated HbA1c (cHbA1c) was compared with glucose management indicator (GMI) for prospective agreement with laboratory HbA1c. RESULTS: The cohort (42 men and 51 women) had a median age (IQR) of 61 (43, 72) years and a diabetes duration of 21 (10, 33) years. A total of 24 459 days of continuous glucose monitoring (CGM) data were available and 357 laboratory HbA1c were used to assess the average glucose-HbA1c relationship. cHbA1c had a superior correlation with laboratory HbA1c compared with GMI with a mean absolute deviation of 1.7 and 6.7 mmol/mol, r2  = 0.85 and 0.44, respectively. The fraction within 10% of absolute relative deviation from laboratory HbA1c was 93% for cHbA1c and 63% for GMI. Macrovascular disease had no effect on the model's accuracy, whereas microvascular complications resulted in a trend towards higher HbA1c, secondary to increased RBC glucose uptake. CONCLUSIONS: cHbA1c, which takes into account RBC glucose uptake and lifespan, accurately reflects laboratory HbA1c in a real-world setting and can aid in the management of individuals with diabetes.

Exploring Deep Learning of Quantum Chemical Properties for Absorption, Distribution, Metabolism, and Excretion Predictions.

Quantum mechanical (QM) descriptors of small molecules have wide applicability in understanding organic reactivity and molecular properties, but the substantial compute cost required for ab initio QM calculations limits their broad usage. Here, we investigate the use of deep learning for predicting QM descriptors, with the goal of enabling usage of near-QM accuracy electronic properties on large molecular data sets such as those seen in drug discovery. Several deep learning approaches have previously been benchmarked on a published data set called QM9, where 12 ground-state properties have been calculated for molecules with up to nine heavy atoms, limited to C, H, N, O, and F elements. To advance the work beyond the QM9 chemical space and enable application to molecules encountered in drug discovery, we extend the QM9 data set by creating a QM9-extended data set covering an additional ∼20,000 molecules containing S and Cl atoms. Using this extended set, we generate new deep learning models as well as leverage ANI-2x models to provide predictions on larger, more diverse molecules common in drug discovery, and we find the models estimate 11 of 12 ground-state properties reasonably. We use the predicted QM descriptors to augment graph convolutional neural network (GCNN) models for selected ADME end points (rat microsomal clearance, hepatic clearance, total clearance, and P-glycoprotein efflux) and found varying degrees of performance improvement compared to nonaugmented GCNN models, including pronounced improvement in P-glycoprotein efflux prediction.

Changing indications and antenatal prognostic factors for ex-utero intrapartum treatment procedures.

OBJECTIVE: In cases of suspected neonatal airway obstruction, the ex-utero intrapartum treatment (EXIT) procedure is used to secure the airway while a fetus remains on placental circulation. We report indications and outcomes from all EXIT procedures at a tertiary obstetric unit between 1997 and 2020. METHOD: Retrospective cohort study with data collected from maternal and neonatal medical records. RESULTS: Indications for EXIT procedures were micrognathia (n = 7), lymphatic malformations (n = 5), cervical teratomas (n = 4), goiters (n = 2), and intra-oral epulis (n = 1). Infants with a fetal teratoma were delivered earliest due to 75% presenting with preterm premature rupture of membranes or preterm labor. Low birth weight was found in 75% of these neonates; they did not survive 1 year. Intubation at EXIT occurred for 58% (n = 11) of babies, and six neonates required a tracheostomy. In four cases of fetal micrognathia, the inferior facial angle (IFA) was noted to be <5th centile. All but one micrognathia case had polyhydramnios. Of the total cohort, 75% of neonates were alive at 1 year. CONCLUSION: Risks for neonatal demise with EXIT include fetal teratoma, low birth weight, and prematurity. Micrognathia has become an increasingly valid indication for the procedure. The combination of polyhydramnios and IFA <5% correlates well with severe airway obstruction and suggests consideration of EXIT.

ß-Catenin is required for radial cell patterning and identity in the developing mouse cochlea.

Development of multicellular organs requires the coordination of cell differentiation and patterning. Critical for sound detection, the mammalian organ of Corti contains functional units arranged tonotopically along the cochlear turns. Each unit consists of sensory hair cells intercalated by nonsensory supporting cells, both specified and radially patterned with exquisite precision during embryonic development. However, how cell identity and radial patterning are jointly controlled is poorly understood. Here we show that ß-catenin is required for specification of hair cell and supporting cell subtypes and radial patterning of the cochlea in vivo. In 2 mouse models of conditional ß-catenin deletion, early specification of Myosin7-expressing hair cells and Prox1-positive supporting cells was preserved. While ß-catenin-deficient cochleae expressed FGF8 and FGFR3, both of which are essential for pillar cell specification, the radial patterning of organ of Corti was disrupted, revealed by aberrant expression of cadherins and the pillar cell markers P75 and Lgr6. Moreover, ß-catenin ablation caused duplication of FGF8-positive inner hair cells and reduction of outer hair cells without affecting the overall hair cell density. In contrast, in another transgenic model with suppressed transcriptional activity of ß-catenin but preserved cell adhesion function, both specification and radial patterning of the organ of Corti were intact. Our study reveals specific functions of ß-catenin in governing cell identity and patterning mediated through cell adhesion in the developing cochlea.

Surgically Acquired Vocal Cord Palsy in Infants and Children with Congenital Heart Disease (CHD): Description of Feeding Outcomes.

Impaired swallowing in infants can impact upon the ability to feed orally, often resulting in dependency on supplementary feeding. Such difficulties can lead to an increased burden of care and associated costs. The primary aim of this study was to investigate the impact of vocal cord palsy (VCP), acquired intraoperatively during cardiac surgery, on the feeding outcomes of infants at a tertiary metropolitan children's hospital. An additional aim was to obtain preliminary information on the impact of feeding difficulties in this group on the quality of life of parents and families. A review of 48 patients who had been referred to the speech pathology service was undertaken. Participants presented with heterogeneous cardiac diagnoses, and had an initial Videofluoroscopic Swallow Study (VFSS) at a median corrected age of 3.6 weeks. Sixty percent of participants presented with silent aspiration on VFSS. Thirty percent of participants required supplementary tube feeding more than 6 months post-surgery. Six percent of participants with poor feeding progress and persistent aspiration required further surgical intervention to support nutrition. Findings revealed no significant relationship between participant factors and the presence of feeding difficulties, however, infants with concomitant genetic and syndromic conditions were found to be most at-risk for long-term feeding difficulties. Analysis of informal parent questionnaire responses indicated parents experienced stress and anxiety after their child's discharge. This was noted in regard to their child's feeding, which impacts quality of life across a number of domains. Findings of this study highlight the importance of communicating the potential feeding difficulties to parents of at-risk infants prior to cardiac surgery. This study further highlighted the importance of routine post-operative otorhinolaryngology examinations following high-risk surgeries, as well as speech pathology management for all infants and children identified with VCP. Post-operative input from appropriately trained Speech Pathologists is vital in assisting parents to support and mitigate their child's difficulties through the provision of early intervention for feeding difficulties.

Patients' and family members' perspectives on arrhythmias and sudden death in dialysis: the HeartLink focus groups pilot study.

BACKGROUND: Patients receiving dialysis face a high risk of cardiovascular disease, arrhythmia and sudden cardiac death. Few patients, however, are aware of this risk. Implantable cardiac monitors are currently available for clinical use and can continuously monitor cardiac rhythms without the need for transvenous leads. Our goal was to gauge patients' and family members' perceptions of these risks and to identify their concerns about cardiac monitors. METHODS: Two 90-minute focus groups were conducted: one with patients receiving in-center hemodialysis and one with their family members. Trained moderators assessed: (1) knowledge of cardiovascular disease; (2) cardiovascular disease risk in dialysis; (3) risk of death due to cardiovascular disease; (4) best ways to convey this risk to patients/families; and (5) concerns about cardiac monitors. The sessions were audiotaped, transcribed, and independently analyzed by two reviewers to identify core themes. Emblematic quotations were chosen to illustrate the final themes. RESULTS: Nine adult patients and three family members participated. Patients felt education was inadequate and had little knowledge of arrhythmias. Patients'/families' concerns regarding cardiac monitors were related to adverse effects, the notification process, and cosmetic effects. Patients/families felt that nephrologists, not dialysis staff, would be the best source for education. CONCLUSIONS: The preliminary data from this small study population suggest that patients/families are not well aware of the high risk of arrhythmia and sudden cardiac death in dialysis. Further investigation is required to gauge this awareness among patients/families and to assess their impressions of implantable cardiac monitors for arrhythmia detection and management.

Racial Differences in Sudden Cardiac Death.

BACKGROUND: Blacks have a higher incidence of out-of-hospital sudden cardiac death (SCD) in comparison with whites. However, the racial differences in the cumulative risk of SCD and the reasons for these differences have not been assessed in large-scale community-based cohorts. The objective of this study is to compare the lifetime cumulative risk of SCD among blacks and whites, and to evaluate the risk factors that may explain racial differences in SCD risk in the general population. METHODS: This is a cohort study of 3832 blacks and 11 237 whites participating in the Atherosclerosis Risk in Communities Study (ARIC). Race was self-reported. SCD was defined as a sudden pulseless condition from a cardiac cause in a previously stable individual, and SCD cases were adjudicated by an expert committee. Cumulative incidence was computed using competing risk models. Potential mediators included demographic and socioeconomic factors, cardiovascular risk factors, presence of coronary heart disease, and electrocardiographic parameters as time-varying factors. RESULTS: The mean (SD) age was 53.6 (5.8) years for blacks and 54.4 (5.7) years for whites. During 27.4 years of follow-up, 215 blacks and 332 whites experienced SCD. The lifetime cumulative incidence of SCD at age 85 years was 9.6, 6.6, 6.5, and 2.3% for black men, black women, white men, and white women, respectively. The sex-adjusted hazard ratio for SCD comparing blacks with whites was 2.12 (95% CI, 1.79-2.51). The association was attenuated but still statistically significant in fully adjusted models (hazard ratio, 1.38; 95% CI, 1.11-1.71). In mediation analysis, known factors explained 65.3% (95% CI 37.9-92.8%) of the excess risk of SCD in blacks in comparison with whites. The single most important factor explaining this difference was income (50.5%), followed by education (19.1%), hypertension (22.1%), and diabetes mellitus (19.6%). Racial differences were evident in both genders but stronger in women than in men. CONCLUSIONS: Blacks had a much higher risk for SCD in comparison with whites, particularly among women. Income, education, and traditional risk factors explained ≈65% of the race difference in SCD. The high burden of SCD and the racial-gender disparities observed in our study represent a major public health and clinical problem.