Building a vertically integrated genomic learning health system: The biobank at the Colorado Center for Personalized Medicine.

Precision medicine initiatives across the globe have led to a revolution of repositories linking large-scale genomic data with electronic health records, enabling genomic analyses across the entire phenome. Many of these initiatives focus solely on research insights, leading to limited direct benefit to patients. We describe the biobank at the Colorado Center for Personalized Medicine (CCPM Biobank) that was jointly developed by the University of Colorado Anschutz Medical Campus and UCHealth to serve as a unique, dual-purpose research and clinical resource accelerating personalized medicine. This living resource currently has more than 200,000 participants with ongoing recruitment. We highlight the clinical, laboratory, regulatory, and HIPAA-compliant informatics infrastructure along with our stakeholder engagement, consent, recontact, and participant engagement strategies. We characterize aspects of genetic and geographic diversity unique to the Rocky Mountain region, the primary catchment area for CCPM Biobank participants. We leverage linked health and demographic information of the CCPM Biobank participant population to demonstrate the utility of the CCPM Biobank to replicate complex trait associations in the first 33,674 genotyped individuals across multiple disease domains. Finally, we describe our current efforts toward return of clinical genetic test results, including high-impact pathogenic variants and pharmacogenetic information, and our broader goals as the CCPM Biobank continues to grow. Bringing clinical and research interests together fosters unique clinical and translational questions that can be addressed from the large EHR-linked CCPM Biobank resource within a HIPAA- and CLIA-certified environment.

ß-Cell-specific ablation of sirtuin 4 does not affect nutrient-stimulated insulin secretion in mice.

Sirtuins are a family of proteins that regulate biological processes such as cellular stress and aging by removing posttranslational modifications (PTMs). We recently identified several novel PTMs that can be removed by sirtuin 4 (SIRT4), which is found in mitochondria. We showed that mice with a global loss of SIRT4 [SIRT4-knockout (KO) mice] developed an increase in glucose- and leucine-stimulated insulin secretion, and this was followed by accelerated age-induced glucose intolerance and insulin resistance. Because whole body SIRT4-KO mice had alterations to nutrient-stimulated insulin secretion, we hypothesized that SIRT4 plays a direct role in regulating pancreatic ß-cell function. Thus, we tested whether ß-cell-specific ablation of SIRT4 would recapitulate the elevated insulin secretion seen in mice with a global loss of SIRT4. Tamoxifen-inducible ß-cell-specific SIRT4-KO mice were generated, and their glucose tolerance and glucose- and leucine-stimulated insulin secretion were measured over time. These mice exhibited normal glucose- and leucine-stimulated insulin secretion and maintained normal glucose tolerance even as they aged. Furthermore, 832/13 ß-cells with a CRISPR/Cas9n-mediated loss of SIRT4 did not show any alterations in nutrient-stimulated insulin secretion. Despite the fact that whole body SIRT4-KO mice demonstrated an age-induced increase in glucose- and leucine-stimulated insulin secretion, our current data indicate that the loss of SIRT4 specifically in pancreatic ß-cells, both in vivo and in vitro, does not have a significant impact on nutrient-stimulated insulin secretion. These data suggest that SIRT4 controls nutrient-stimulated insulin secretion during aging by acting on tissues external to the ß-cell, which warrants further study.

Intracardiac ablation for atrioventricular nodal reentry tachycardia using a 6 mm distal electrode cryoablation catheter: Prospective, multicenter, North American study (ICY-AVNRT STUDY).

INTRODUCTION: Radiofrequency (RF) ablation is effective for slow pathway ablation, but carries a risk of inadvertent AV block requiring permanent pacing. By comparison, cryoablation with a 4-mm distal electrode catheter has not been reported to cause permanent AV block but has been shown to be less effective than RF ablation. We sought to define the safety and efficacy of a 6-mm distal electrode cryoablation catheter for slow pathway ablation in patients with atrioventricular nodal reentry tachycardia (AVNRT). METHODS AND RESULTS: Twenty-six U.S. and eight Canadian centers participated in the study. Patients with supraventricular tachycardia (SVT) thought likely to be AVNRT were enrolled. If AVNRT was inducible and confirmed to be the clinical SVT, then the slow pathway was targeted with a cryoablation catheter using a standardized protocol of best practices. Acute success was defined as inducibility of no more than one echo beat after cryoablation. Primary efficacy was defined as acute success and the absence of documented recurrent AVNRT over 6 months of follow-up. Primary safety was a composite of serious procedure-related adverse events and/or device-related complications. Note that 397 subjects met enrollment criteria after the EP study and received cryoablation. Mean ablation procedure duration (including a waiting period) was 89 ± 40 minutes, and mean fluoroscopy time was 4.8 ± 5.9 minutes. Isoproterenol was administered before cryoablation in 53% and after the last lesion in 85% of cases. Acute procedural success was realized in 95% (378 of 397) of subjects. No subject received a permanent pacemaker due to AV block. The slow pathway could not be ablated in 19 subjects, including: 12 due to inefficacy, 2 due to transient AV block, and 5 due to both inefficacy and transient AV block. RF ablation was used in the same procedure in 11 of 19 failed subjects, and was ineffective in 3 subjects. Among the group with acute success, 10 subjects (2.7%) had documented recurrent AVNRT over the 6-month follow-up period, and all occurred within 3 months of the index cryoablation. Serious procedure-related adverse events occurred in 4 subjects (1.0%), including one each: tamponade, pulmonary embolism, femoral vein hemorrhage, and diagnostic EP catheter knotting. None of these serious adverse events were related to use of the cryoablation catheter. Overall, 93% of subjects had successful slow pathway ablation at 6 months with the study cryoablation catheter. CONCLUSIONS: Cryoablation for AVNRT using a focal 6-mm catheter was safe and effective. It resulted in a low risk of recurrence over 6 months of follow-up with no incidence of AV block requiring permanent pacing.

Metabolomics applied to islet nutrient sensing mechanisms.

After multiple decades of investigation, the precise mechanisms involved in fuel-stimulated insulin secretion are still being revealed. One avenue for gaining deeper knowledge is to apply emergent tools of "metabolomics," involving mass spectrometry and nuclear magnetic resonance-based profiling of islet cells in their fuel-stimulated compared with basal states. The current article summarizes recent insights gained from application of metabolomics tools to the specific process of glucose-stimulated insulin secretion, revealing 2 new mechanisms that may provide targets for improving insulin secretion in diabetes.

Lack of current implantable cardioverter defibrillator guidelines application for primary prevention of sudden cardiac death in Latin American patients with heart failure: a cross-sectional study.

AIMS: This cross-sectional study evaluated the application of accepted international implantable cardioverter defibrillator (ICD) guidelines for primary prevention of sudden cardiac death in patients with heart failure. METHODS AND RESULTS: The PLASMA (Probabilidad de Sufrir Muerte Arritmica) study was designed to characterize management of cardiac patients in Latin America. Twelve centres included 1958 consecutively admitted patients in cardiology units in 2008 and 2009. Discharged patients were evaluated for primary prevention, ICD indication and prescription by general cardiologists. Of 1711 discharged patients, 1525 (89%) had data available for evaluating indication status. Class I indications for ICD therapy were met for 153 (10%) patients based on collected data. Only 20 (13%, 95% confidence interval: 7.7-18.4%) patients with indication were prescribed an ICD. Patients prescribed an ICD were younger than patients who were not prescribed an ICD (62 vs. 68 years, P < 0.01). The reasons given by cardiologists for not prescribing an ICD for 133 patients with an indication were: indication criteria not met (75%), life expectancy <1 year (9.7%), rejection by the patient (5.2%), no medical coverage paying for the device (3.7%), psychiatric patient (2.2%), and other reasons (4.2%). CONCLUSIONS: In Latin America, international guidelines for primary prevention ICD implantation are not well followed. The main reason is that cardiologists believe that patients do not meet indication criteria, even though study data confirm that criteria are met. This poses a significant challenge and underlines the importance of continuous and improved medical education.

Do baseline diastolic echocardiographic parameters predict outcome after resynchronization therapy? Results from the PROSPECT trial.

INTRODUCTION: Cardiac resynchronization therapy (CRT) can improve clinical and cardiac structural status in heart failure patients. The role of baseline diastolic echocardiographic parameters to characterize the likelihood of positive outcomes is not well known. We explored relationships between diastolic parameters and outcomes 6 months after CRT implant in the Predictors of Response to CRT (PROSPECT) Trial. HYPOTHESIS: We hypothesized that diastolic echocardiographic parameters were associated with clinical and structural outcomes in CRT patients. METHODS: For 426 patients in PROSPECT, a prospective observational trial of CRT, baseline E/A ratio, left atrial (LA) area, isovolumic relaxation time, left ventricular inflow deceleration time, E' velocity, and E/E' ratio were evaluated and related to 6-month clinical composite score (CCS) and left ventricular end-systolic volume (LVESV) reduction using Spearman rank-order correlations. Parameters associated with outcomes were analyzed further by discrete categorization. RESULTS: As continuous variables, only E/A ratio and LA area correlated with CCSs (P = 0.017, P = 0.045, respectively) and relative change in LVESV at 6 months (P < 0.0001, P = 0.001, respectively). As discrete variables, E/A ratio and LA area also correlated with CCSs and LVESV. CONCLUSION: Diastolic echo parameters E/A ratio and LA area were associated with clinical and structural outcomes in CRT patients at 6 months.

Does the Presence of a Physical Disability Affect Classification of Sexual Assault?

The occurrence of sexual assault is common and problematic, especially among those with disabilities. While many other characteristics of the victim, perpetrator, and situation involving a sexual assault have been shown to affect perceptions, only one study has examined the impact of a hypothetical victim with a physical disability. Therefore, the purpose of this study was to explore the effect that a victim and/or perpetrator's physical disability status has on individuals' classification of encounters as sexual assault.University students over the age of 18 (n = 207) completed an anonymous online survey which included reading an ambiguous scenario involving a sexual assault in which either the victim, perpetrator or neither was in a wheelchair. Participants classified the scenario as either representing a sexual assault or not and completed the Illinois Rape Myth Acceptance scale and demographic information. A binary logistic regression model was conducted to examine the effects of conditions, participant gender and RMA score on sexual assault classification.In the scenario with the victim in a wheelchair, 71.6% of participants agreed sexual assault occurred; when the perpetrator was in a wheelchair 58.6% classified the scenario as sexual assault. In the control condition 61.4% agreed sexual assault occurred. Condition was not associated with classification at a statistically significant level; however, the effect sizes indicate participants were more likely to classify sexual assault when the victim was in a wheelchair (OR = 1.41), but less likely to blame a perpetrator in a wheelchair (OR = 0.69) compared to the control condition.Despite a lack of statistical significance, the data show a clear trend away from blaming individuals with disabilities in sexual assault scenarios. These findings can have implications within the legal system where incorrect decisions may be made due to bias based on disability status.

Screening plateletpheresis donors for HLA antibodies on two high-throughput platforms and correlation with recipient outcome.

BACKGROUND: To determine the prevalence and impact of transfusing plasma containing white blood cell antibodies, we compared two high-throughput HLA antibody screening assays and prospectively examined the medical records of all platelet (PLT) recipients to detect subtle manifestations of transfusion-related acute lung injury and other transfusion reactions. STUDY DESIGN AND METHODS: Serum samples from 136 plateletpheresis donors were tested for HLA Class I and II antibodies using microbead (LABScreen PRA, One Lambda) and microchip (Dynachip, Invitrogen) assays. Electronic medical records of all recipients were reviewed for vital signs and nursing documentation before and after transfusion. RESULTS: In the microchip assay with a cutoff value of 0.25, 2.9% of samples were positive for Class I and 8.9% for Class II antibodies; with a cutoff value of 0.1, the results were 14.9 and 21.6%, respectively. In the microbead assay (normalized background ratio, 1.5), 15% were positive for Class I and 21% for Class II antibodies. The prevalence of HLA antibodies was 17% in donors without pregnancy or transfusion history and 47% in donors with such history. The PLTs were transfused in 265 episodes to 67 patients. There were no reported reactions; however, symptoms or vital sign changes were noted in seven transfusion episodes. The incidence of reactions was 2.7% (2/75) for antibody-positive units and 2.6% (5/190) for antibody-negative units. CONCLUSIONS: Microbead and microchip assays yielded similar results. The prevalence of HLA antibodies was greater in donors with a history of pregnancy or transfusion, but no increase in the incidence of transfusion reactions was noted in recipients of components from donors with HLA antibodies.

Prognostic significance of atrial arrhythmias in a primary prevention ICD population.

INTRODUCTION: We investigated whether primary prevention implantable cardioverter defibrillator (ICD) patients with atrial arrhythmias are at higher risk for ICD shocks and mortality compared to patients without atrial arrhythmias in a subanalysis of the PREPARE study. METHODS AND RESULTS: Details of the PREPARE study design and results have been previously reported. We now included 537 of the 700 patients enrolled in PREPARE. These patients had a dual or biventricular device and at least one device follow-up after implantation. Continuously collected device diagnostics data were used to classify patients into two groups during follow-up: with (n = 133) or without (n = 404) atrial tachycardia/atrial fibrillation (AT/AF). The primary outcomes were ICD shocks and mortality. Subjects were followed for a mean of 333 ± 73 (range 5-365) days. During a follow-up of 1 year, ICD shocks occurred in 44 (8%) patients. Significantly, more patients with AT/AF received a shock (13.0% vs 6.9%, P = 0.03), with inappropriate shocks accounting for the majority of the difference (6.9% vs 2.6%, P = 0.02). There was no difference in prevalence of shocks between patients with and without a history of AF. Mortality was similar in patients with and without AT/AF, whether detected during the study or prior to the study. In addition, the 34 subjects with high average ventricular rate (≥110 beats per minute) during AT/AF had a higher risk of an inappropriate shock (21.0% vs 2.1%, P < 0.01). CONCLUSION: Primary prevention ICD patients with AT/AF are more likely to receive shocks, especially inappropriate shocks. Mortality was not higher in AT/AF patients. (PACE 2011; 34:1070-1079).

Host methylation predicts SARS-CoV-2 infection and clinical outcome.

BACKGROUND: Since the onset of the SARS-CoV-2 pandemic, most clinical testing has focused on RT-PCR1. Host epigenome manipulation post coronavirus infection2-4 suggests that DNA methylation signatures may differentiate patients with SARS-CoV-2 infection from uninfected individuals, and help predict COVID-19 disease severity, even at initial presentation. METHODS: We customized Illumina's Infinium MethylationEPIC array to enhance immune response detection and profiled peripheral blood samples from 164 COVID-19 patients with longitudinal measurements of disease severity and 296 patient controls. RESULTS: Epigenome-wide association analysis revealed 13,033 genome-wide significant methylation sites for case-vs-control status. Genes and pathways involved in interferon signaling and viral response were significantly enriched among differentially methylated sites. We observe highly significant associations at genes previously reported in genetic association studies (e.g. IRF7, OAS1). Using machine learning techniques, models built using sparse regression yielded highly predictive findings: cross-validated best fit AUC was 93.6% for case-vs-control status, and 79.1%, 80.8%, and 84.4% for hospitalization, ICU admission, and progression to death, respectively. CONCLUSIONS: In summary, the strong COVID-19-specific epigenetic signature in peripheral blood driven by key immune-related pathways related to infection status, disease severity, and clinical deterioration provides insights useful for diagnosis and prognosis of patients with viral infections.

Host methylation predicts SARS-CoV-2 infection and clinical outcome.

BACKGROUND: Since the onset of the SARS-CoV-2 pandemic, most clinical testing has focused on RT-PCR1. Host epigenome manipulation post coronavirus infection2-4 suggests that DNA methylation signatures may differentiate patients with SARS-CoV-2 infection from uninfected individuals, and help predict COVID-19 disease severity, even at initial presentation. METHODS: We customized Illumina's Infinium MethylationEPIC array to enhance immune response detection and profiled peripheral blood samples from 164 COVID-19 patients with longitudinal measurements of disease severity and 296 patient controls. RESULTS: Epigenome-wide association analysis revealed 13,033 genome-wide significant methylation sites for case-vs-control status. Genes and pathways involved in interferon signaling and viral response were significantly enriched among differentially methylated sites. We observe highly significant associations at genes previously reported in genetic association studies (e.g. IRF7, OAS1). Using machine learning techniques, models built using sparse regression yielded highly predictive findings: cross-validated best fit AUC was 93.6% for case-vs-control status, and 79.1%, 80.8%, and 84.4% for hospitalization, ICU admission, and progression to death, respectively. CONCLUSIONS: In summary, the strong COVID-19-specific epigenetic signature in peripheral blood driven by key immune-related pathways related to infection status, disease severity, and clinical deterioration provides insights useful for diagnosis and prognosis of patients with viral infections.

Viral infections affect the body in many ways, including via changes to the epigenome, the sum of chemical modifications to an individual's collection of genes that affect gene activity. Here, we analyzed the epigenome in blood samples from people with and without COVID-19 to determine whether we could find changes consistent with SARS-CoV-2 infection. Using a combination of statistical and machine learning techniques, we identify markers of SARS-CoV-2 infection as well as of severity and progression of COVID-19 disease. These signals of disease progression were present from the initial blood draw when first walking into the hospital. Together, these approaches demonstrate the potential of measuring the epigenome for monitoring SARS-CoV-2 status and severity.

Identifying incident Parkinson's disease using administrative diagnostic codes: a validation study.

BACKGROUND: Administrative databases that capture diagnostic codes are increasingly being used worldwide for research because they can save time and reduce costs. However, assessing validity is necessary before defining diseases using only diagnostic codes in research applications. OBJECTIVE: Our objective was to assess the validity of using diagnostic codes to identify incident Parkinson's disease (PD) cases in Olmsted County, Minnesota using an established standard for comparison (1976-2005). METHODS: Cases were identified solely using computer programs applied to administrative diagnostic code indexes from the Rochester Epidemiology Project (REP). Two codes >30 days apart or one code on the death certificate constituted PD. The standard was a clinical diagnosis by movement disorders specialists based on medical record review. Validity was assessed using positive predictive value (PPV) and sensitivity. Numbers of incident cases and incidence rates were compared between the two ascertainment methods by sex. RESULTS: The codes only method over-counted the number of incident PD cases by 73% (804 versus 464), and this over-counting generally increased with calendar year. Sensitivity was 80% (95% CI [76%, 84%]) and PPV was 46% (95% CI [34%, 50%]). Disease status misclassification accounted for two-thirds of falsely identified cases, where individuals were found to not have PD (43%) or even parkinsonism (23%) after medical record review. The codes only method also over-estimated the incidence rate time trend for men and women by approximately two-fold. CONCLUSION: In our context, using administrative diagnostic codes only to identify incident PD cases is not recommended unless more accurate algorithms are developed.

Effect of menopausal hormone therapy on proteins associated with senescence and inflammation.

BACKGROUND: Estrogen may inhibit cell senescence that contributes to age-related disorders. This study determined the effects of menopausal hormone treatments on circulating levels of markers of cell senescence. METHODS: Growth differentiation factor 15 (GDF15), tumor necrosis factor receptor 1 (TNFR1), FAS, and macrophage inflammatory protein 1α (MIP1α) were measured in serum using multiplexed bead-based assays and compared among menopausal women participating in the Kronos Early Estrogen Prevention Study randomized to either placebo (n = 38), oral conjugated equine estrogen (oCEE, n = 37), or transdermal 17ß-estradiol (tE2, n = 34). Serum levels of the senescent markers for each treatment were compared to placebo 36 months after randomization using the Wilcoxon rank sum test. RESULTS: Serum levels of GDF15, TNFR1, and FAS, but not MIP1α, were lower in both the oCEE and tE2 groups compared to placebo. The difference in levels between treatment and placebo for GDF15, TNFR1, and FAS were greater for oCEE [-108 pg/mL (p = .008), -234 pg/mL (p = .0006), and -1374 pg/mL (p < .0001), respectively] than for tE2 [-76 pg/mL (p = .072), -105 pg/mL (p = .076), and -695 pg/mL (p = .036), respectively]. Additionally, TNFR1 showed a positive association with time past menopause (correlation = 0.255, p = .019). CONCLUSIONS: Circulating levels of some markers of cell senescence were lower in menopausal women treated with oCEE and tE2 compared to placebo. Differences in the magnitude of effect of the two active treatments may reflect the differences in circulating levels of estrogen metabolites due to formulation and mode of delivery. These data generate new hypotheses with regard to the effects of menopause on the biology of aging.

Complications of Radial Column Plating of the Distal Radius.

Background: Distal radius fractures treated with open reduction and internal fixation are commonly stabilized with a volar locking plate; however, more complex fracture patterns may require supplemental fixation with fragment-specific implants. The objective of this study was to evaluate the outcomes of distal radius fractures treated with radial column plates. Methods: A consecutive series of 61 patients who sustained distal radius fractures underwent radial column plating alone or in conjunction with other implants between August 2006 and January 2014. Thirty-one patients returned for follow-up or returned a mailed questionnaire at an average of 4.1 years. The outcomes measures included Visual Analog Scale (VAS); Disabilities of the Arm, Shoulder and Hand (DASH); and Patient-Rated Wrist Evaluation (PRWE) scores. Results: Sixty-one patients with a mean age of 55 years (range, 20-87) met inclusion criteria and were available for follow-up or chart review at an average of 5.2 years (range, 1.6-9.0 years). Seventeen of 61 (28%) underwent radial column plate removal. Twenty patients returned for final follow-up examination, and 11 completed questionnaires via mail. Subjective scores included a mean postoperative VAS of 0.72, DASH score of 17.2, and PRWE score of 15.7. Hardware sensitivity and wrist stiffness were the most common complications at final follow-up. Conclusions: Radial column plating of the distal radius is a safe treatment modality and a valuable adjunct in the setting of complex distal radius fractures, but patients should be counseled that there is a 28% chance that hardware removal may be required. Our retrospective review found evidence of few complications and objective scores consistent with return to normal function.

Remodeling of the Acetylproteome by SIRT3 Manipulation Fails to Affect Insulin Secretion or ß Cell Metabolism in the Absence of Overnutrition.

SIRT3 is a nicotinamide adenine dinucleotide (NAD+)-dependent mitochondrial protein deacetylase purported to influence metabolism through post-translational modification of metabolic enzymes. Fuel-stimulated insulin secretion, which involves mitochondrial metabolism, could be susceptible to SIRT3-mediated effects. We used CRISPR/Cas9 technology to manipulate SIRT3 expression in ß cells, resulting in widespread SIRT3-dependent changes in acetylation of key metabolic enzymes but no appreciable changes in glucose- or pyruvate-stimulated insulin secretion or metabolomic profile during glucose stimulation. Moreover, these broad changes in the SIRT3-targeted acetylproteome did not affect responses to nutritional or ER stress. We also studied mice with global SIRT3 knockout fed either standard chow (STD) or high-fat and high-sucrose (HFHS) diets. Only when chronically fed HFHS diet do SIRT3 KO animals exhibit a modest reduction in insulin secretion. We conclude that broad changes in mitochondrial protein acetylation in response to manipulation of SIRT3 are not sufficient to cause changes in islet function or metabolism.

Delayed apoptosis allows islet ß-cells to implement an autophagic mechanism to promote cell survival.

Increased ß-cell death coupled with the inability to replicate existing ß-cells drives the decline in ß-cell mass observed in the progression of both major forms of diabetes. Understanding endogenous mechanisms of islet cell survival could have considerable value for the development of novel strategies to limit ß-cell loss and thereby promote ß-cell recovery. Insulinoma cells have provided useful insight into ß-cell death pathways but observations made in cell lines sometimes fail to translate to primary islets. Here, we report dramatic differences in the temporal regulation and engagement of the apoptotic program in primary rodent islets relative to the INS-1 derived 832/13 cell line. As expected, 832/13 cells rapidly induced cell stress markers in response to ER stress or DNA damage and were fully committed to apoptosis, resulting in >80% cell death within 24 h. In contrast, primary rat islets were largely refractory to cell death in response to ER stress and DNA damage, despite rapid induction of stress markers, such as XBP-1(s), CHOP, and PUMA. Gene expression profiling revealed a general suppression of pro-apoptotic machinery, such as Apaf-1 and caspase 3, and sustained levels of pro-survival factors, such as cIAP-1, cIAP-2, and XIAP, in rat islets. Furthermore, we observed sustained induction of autophagy following chronic ER stress and found that inhibition of autophagy rendered islet ß-cells highly vulnerable to ER stress-induced cell death. We propose that islet ß-cells dampen the apoptotic response to delay the onset of cell death, providing a temporal window in which autophagy can be activated to limit cellular damage and promote survival.

Characterization of health care utilization in patients receiving implantable cardioverter-defibrillator therapies: An analysis of the managed ventricular pacing trial.

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) are effective in terminating lethal arrhythmias, but little is known about the degree of health care utilization (HCU) after ICD therapies. OBJECTIVE: Using data from the managed ventricular pacing trial, we sought to identify the incidence and types of HCU in ICD patients after receiving ICD therapy (shocks or antitachycardia pacing [ATP]). METHODS: We analyzed HCU events (ventricular tachyarrhythmia [VTA]-related, heart failure-related, ICD implant procedure-related, ICD system-related, or other) and their association with ICD therapies (shocked ventricular tachycardia episode, ATP-terminated ventricular tachycardia episode, and inappropriately shocked episode). RESULTS: A total of 1879 HCUs occurred in 695 of 1030 subjects (80% primary prevention) and were classified as follows: 133 (7%) VTA-related, 373 (20%) heart failure-related, 97 (5%) implant procedure-related, 115 (6%) system-related, and 1160 (62%) other. Of 2113 treated VTA episodes, 1680 (80%) received ATP only and 433 (20%) received shocks. Stratifying VTA-related HCUs on the basis of the type of ICD therapy delivered, there were 25 HCUs per 100 shocked VTA episodes compared with 1 HCU per 100 ATP-terminated episodes. Inappropriate ICD shocks occurred in 8.7% of the subjects and were associated with 115 HCUs. The majority of HCUs (52%) began in the emergency department, and 66% of all HCUs resulted in hospitalization. CONCLUSION: For VTA-related HCUs, shocks are associated with a 25-fold increase in HCUs compared to VTAs treated by ATP only. Application of evidence-based strategies and automated device-based algorithms to reduce ICD shocks (higher rate cutoffs, use of ATP, and arrhythmia detection) may help reduce HCUs.

SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion.

Sirtuins are NAD+-dependent protein deacylases that regulate several aspects of metabolism and aging. In contrast to the other mammalian sirtuins, the primary enzymatic activity of mitochondrial sirtuin 4 (SIRT4) and its overall role in metabolic control have remained enigmatic. Using a combination of phylogenetics, structural biology, and enzymology, we show that SIRT4 removes three acyl moieties from lysine residues: methylglutaryl (MG)-, hydroxymethylglutaryl (HMG)-, and 3-methylglutaconyl (MGc)-lysine. The metabolites leading to these post-translational modifications are intermediates in leucine oxidation, and we show a primary role for SIRT4 in controlling this pathway in mice. Furthermore, we find that dysregulated leucine metabolism in SIRT4KO mice leads to elevated basal and stimulated insulin secretion, which progressively develops into glucose intolerance and insulin resistance. These findings identify a robust enzymatic activity for SIRT4, uncover a mechanism controlling branched-chain amino acid flux, and position SIRT4 as a crucial player maintaining insulin secretion and glucose homeostasis during aging.

Carpal osteoarthrosis.

Despite improved understanding of carpal mechanics, increased awareness of intercarpal ligament injuries, and improved techniques for treating carpal instability, post-traumatic intercarpal osteoarthrosis remains a common problem. Osteoarthritis of the carpal bones, including scapholunate advance collapse wrist, scaphotrapeziotrapezoid arthritis, lunotriquetral arthritis, triquetrohamate arthritis, and pisotriquetral arthritis, follows specific unique patterns, but in each, the final common pathway leads to degenerative change. Injury or deformity leads to instability and altered kinematics, producing abnormal joint contact pressures. Cartilage injury and eventual degeneration of the join follow. The etiology, prevalence, and current evaluation and treatment of these conditions are of importance to hand surgeons.