Next-generation precision medicine for suicidality prevention.

Suicidality remains a clear and present danger in society in general, and for mental health patients in particular. Lack of widespread use of objective and/or quantitative information has hampered treatment and prevention efforts. Suicidality is a spectrum of severity from vague thoughts that life is not worth living, to ideation, plans, attempts, and completion. Blood biomarkers that track suicidality risk provide a window into the biology of suicidality, as well as could help with assessment and treatment. Previous studies by us were positive. Here we describe new studies we conducted transdiagnostically in psychiatric patients, starting with the whole genome, to expand the identification, prioritization, validation and testing of blood gene expression biomarkers for suicidality, using a multiple independent cohorts design. We found new as well as previously known biomarkers that were predictive of high suicidality states, and of future psychiatric hospitalizations related to them, using cross-sectional and longitudinal approaches. The overall top increased in expression biomarker was SLC6A4, the serotonin transporter. The top decreased biomarker was TINF2, a gene whose mutations result in very short telomeres. The top biological pathways were related to apoptosis. The top upstream regulator was prednisolone. Taken together, our data supports the possibility that biologically, suicidality is an extreme stress-driven form of active aging/death. Consistent with that, the top subtypes of suicidality identified by us just based on clinical measures had high stress and high anxiety. Top therapeutic matches overall were lithium, clozapine and ketamine, with lithium stronger in females and clozapine stronger in males. Drug repurposing bioinformatic analyses identified the potential of renin-angiotensin system modulators and of cyclooxygenase inhibitors. Additionally, we show how patient reports for doctors would look based on blood biomarkers testing, personalized by gender. We also integrated with the blood biomarker testing social determinants and psychological measures (CFI-S, suicidal ideation), showing synergy. Lastly, we compared that to machine learning approaches, to optimize predictive ability and identify key features. We propose that our findings and comprehensive approach can have transformative clinical utility.

Proposal and Rationale for a Cardioethics Curriculum.

The modern practice of cardiovascular medicine involves many ethical controversies in the care of our complex patients. Accordingly, we propose a framework for a practical, clinically based "cardioethics" curriculum that might be incorporated into fellowship training to prepare cardiologists to cope with increasingly complex ethical dilemmas. This work can also be adopted into continuing medical education for cardiologists and other cardiovascular practitioners given the critical importance of collaborative care in cardiology. We discuss heart transplant allocation, futility concerns, withdrawing care, advance care planning, conflicts of interests, and distributive justice. Sound ethical decision-making in cardiology requires a combination of extensive technical knowledge, nuanced appreciation of individual patient goals and values, and thoughtful application of ethical principles and reasoning. Cardiologists have an exceptionally broad toolkit of medications and interventions to address high-stakes disease states. We should maintain a similarly broad ethical toolkit to provide the best care for our patients.

In-situ X-ray monitoring of solidification and related processes of metal alloys.

X-ray radioscopy enables the in-situ monitoring of metal alloy processes and then gives access to crucial information on the dynamics of the underlying phenomena. In the last decade, the utilisation of this powerful imaging technique has been adapted to microgravity platforms such as sounding rockets and parabolic flights. The combination of microgravity experimentation with X-ray radioscopy has resulted in a leap in the understanding of fundamental science and has opened new paths in the fields of materials science. The present review focuses on the short history of this research, which includes facility developments, microgravity experiments and results obtained by partners of the XRMON (In-situ X-Ray MONitoring of advanced metallurgical processes under microgravity and terrestrial conditions) research project in the framework of the MAP (Microgravity Application Promotion) programme of the European Space Agency. Three illustrative research topics that were advanced significantly through the use of X-ray radioscopy will be detailed: solidification of metal alloys, metallic foam formation and diffusion in melts.

Case report of a breast granular cell tumor in a young transgender man.

INTRODUCTION AND IMPORTANCE: Granular cell tumors (GCTs) can be diagnostically challenging due to their rarity, diverse anatomic locations, and clinical and radiologic similarities to other more common entities. GCTs involving the breast are rare and are most commonly encountered in premenopausal cisgender women. We report an unusual case of a breast GCT in a young transgender man. CASE PRESENTATION: A 20-year-old transgender man who was on testosterone therapy for about 1 year presented with a painless, palpable mass in the right breast which radiologically resembled a lymph node. A fine needle aspiration showed morphology and immunohistochemistry consistent with a GCT. The tumor was excised by a mastectomy for therapeutic and gender-affirming purposes which confirmed the diagnosis of a breast GCT. CLINICAL DISCUSSION: Breast GCTs are most commonly found in cisgender women, however the mechanisms behind this relationship and whether transgender persons have an altered risk profile are not well understood. Breast GCTs are typically benign lesions with a low chance of recurrence following excision. CONCLUSION: GCTs are rare and poorly understood entities which have not been previously documented in transgender patients and can resemble other benign or malignant lesions.

Complementary Phenotyping of Maize Root System Architecture by Root Pulling Force and X-Ray Imaging.

The root system is critical for the survival of nearly all land plants and a key target for improving abiotic stress tolerance, nutrient accumulation, and yield in crop species. Although many methods of root phenotyping exist, within field studies, one of the most popular methods is the extraction and measurement of the upper portion of the root system, known as the root crown, followed by trait quantification based on manual measurements or 2D imaging. However, 2D techniques are inherently limited by the information available from single points of view. Here, we used X-ray computed tomography to generate highly accurate 3D models of maize root crowns and created computational pipelines capable of measuring 71 features from each sample. This approach improves estimates of the genetic contribution to root system architecture and is refined enough to detect various changes in global root system architecture over developmental time as well as more subtle changes in root distributions as a result of environmental differences. We demonstrate that root pulling force, a high-throughput method of root extraction that provides an estimate of root mass, is associated with multiple 3D traits from our pipeline. Our combined methodology can therefore be used to calibrate and interpret root pulling force measurements across a range of experimental contexts or scaled up as a stand-alone approach in large genetic studies of root system architecture.

Precision medicine for mood disorders: objective assessment, risk prediction, pharmacogenomics, and repurposed drugs.

Mood disorders (depression, bipolar disorders) are prevalent and disabling. They are also highly co-morbid with other psychiatric disorders. Currently there are no objective measures, such as blood tests, used in clinical practice, and available treatments do not work in everybody. The development of blood tests, as well as matching of patients with existing and new treatments, in a precise, personalized and preventive fashion, would make a significant difference at an individual and societal level. Early pilot studies by us to discover blood biomarkers for mood state were promising [1], and validated by others [2]. Recent work by us has identified blood gene expression biomarkers that track suicidality, a tragic behavioral outcome of mood disorders, using powerful longitudinal within-subject designs, validated them in suicide completers, and tested them in independent cohorts for ability to assess state (suicidal ideation), and ability to predict trait (future hospitalizations for suicidality) [3-6]. These studies showed good reproducibility with subsequent independent genetic studies [7]. More recently, we have conducted such studies also for pain [8], for stress disorders [9], and for memory/Alzheimer's Disease [10]. We endeavored to use a similar comprehensive approach to identify more definitive biomarkers for mood disorders, that are transdiagnostic, by studying mood in psychiatric disorders patients. First, we used a longitudinal within-subject design and whole-genome gene expression approach to discover biomarkers which track mood state in subjects who had diametric changes in mood state from low to high, from visit to visit, as measured by a simple visual analog scale that we had previously developed (SMS-7). Second, we prioritized these biomarkers using a convergent functional genomics (CFG) approach encompassing in a comprehensive fashion prior published evidence in the field. Third, we validated the biomarkers in an independent cohort of subjects with clinically severe depression (as measured by Hamilton Depression Scale, (HAMD)) and with clinically severe mania (as measured by the Young Mania Rating Scale (YMRS)). Adding the scores from the first three steps into an overall convergent functional evidence (CFE) score, we ended up with 26 top candidate blood gene expression biomarkers that had a CFE score as good as or better than SLC6A4, an empirical finding which we used as a de facto positive control and cutoff. Notably, there was among them an enrichment in genes involved in circadian mechanisms. We further analyzed the biological pathways and networks for the top candidate biomarkers, showing that circadian, neurotrophic, and cell differentiation functions are involved, along with serotonergic and glutamatergic signaling, supporting a view of mood as reflecting energy, activity and growth. Fourth, we tested in independent cohorts of psychiatric patients the ability of each of these 26 top candidate biomarkers to assess state (mood (SMS-7), depression (HAMD), mania (YMRS)), and to predict clinical course (future hospitalizations for depression, future hospitalizations for mania). We conducted our analyses across all patients, as well as personalized by gender and diagnosis, showing increased accuracy with the personalized approach, particularly in women. Again, using SLC6A4 as the cutoff, twelve top biomarkers had the strongest overall evidence for tracking and predicting depression after all four steps: NRG1, DOCK10, GLS, PRPS1, TMEM161B, GLO1, FANCF, HNRNPDL, CD47, OLFM1, SMAD7, and SLC6A4. Of them, six had the strongest overall evidence for tracking and predicting both depression and mania, hence bipolar mood disorders. There were also two biomarkers (RLP3 and SLC6A4) with the strongest overall evidence for mania. These panels of biomarkers have practical implications for distinguishing between depression and bipolar disorder. Next, we evaluated the evidence for our top biomarkers being targets of existing psychiatric drugs, which permits matching patients to medications in a targeted fashion, and the measuring of response to treatment. We also used the biomarker signatures to bioinformatically identify new/repurposed candidate drugs. Top drugs of interest as potential new antidepressants were pindolol, ciprofibrate, pioglitazone and adiphenine, as well as the natural compounds asiaticoside and chlorogenic acid. The last 3 had also been identified by our previous suicidality studies. Finally, we provide an example of how a report to doctors would look for a patient with depression, based on the panel of top biomarkers (12 for depression and bipolar, one for mania), with an objective depression score, risk for future depression, and risk for bipolar switching, as well as personalized lists of targeted prioritized existing psychiatric medications and new potential medications. Overall, our studies provide objective assessments, targeted therapeutics, and monitoring of response to treatment, that enable precision medicine for mood disorders.

Preimplantation genetic testing using Karyomapping for a paternally inherited reciprocal translocation: a case study.

PURPOSE: Preimplantation genetic testing (PGT) using Karyomapping is used to screen embryos for single gene disorders prior to implantation. While Karyomapping is not designed to screen for abnormalities in chromosome copy number, this testing is based upon a genome-wide analysis of single nucleotide polymorphisms (SNP) and, as such, some chromosome abnormalities are detected. The aim of this study was to validate whether Karyomapping could provide reliable and accurate PGT for a paternal 46,XY,t(10;19)(p15;p13.3) reciprocal translocation. METHODS: Feasibility/validation for PGT was performed using DNA from the couple, as well as DNA from the paternal parents and from a previous unbalanced pregnancy. Karyomapping was performed using Illumina's HumanKaryomap-12 BeadChip microarray technology. SNP analysis was performed using BlueFuse Multi software (Illumina). Transmission of the translocation was assessed through the analysis of SNP markers on the chromosome regions of interest. RESULTS: PGT-SR was determined to be feasible as chromosomal SNP analysis could reliably distinguish normal/balanced outcomes from all unbalanced outcomes. The couple transferred a normal/balanced embryo in an elective single embryo transfer procedure following 2 IVF/PGT-SR cycles. A clinical pregnancy was achieved. CONCLUSION: This is the first report of PGT-SR test validation using Karyomapping for a 46,XY,t(10;19)(p15;p13.3) reciprocal translocation. Karyomapping may offer a means of detecting unbalanced forms of chromosome rearrangements when other PGT platforms fail.

Defining the limits of detection for chromosome rearrangements in the preimplantation embryo using next generation sequencing.

STUDY QUESTION: Is next generation sequencing (NGS) capable of detecting smaller sub-chromosomal rearrangements in human embryos than the manufacturer's quoted resolution suggests? SUMMARY ANSWER: NGS was able to detect unbalanced chromosome segments smaller than the manufacturer's resolution. WHAT IS KNOWN ALREADY: Array Comparative Genomic Hybridization (array-CGH) has been the gold standard platform used for PGD of chromosome rearrangements. NGS is a viable alternative to array-CGH for PGD of chromosome arrangements given that the manufacturer's guidelines quote a resolution of ≥20 Mb. However, as many patients carry a chromosome rearrangement <20 Mb, the detection limits of NGS warrant further investigation. STUDY DESIGN, SIZE, DURATION: This study involved a retrospective assessment of stored DNA samples from embryos that had previously been diagnosed as unbalanced by array-CGH as part of routine PGD in two separate IVF clinics between November 2013 and April 2017. SurePlex whole genome amplification (WGA) products derived from DNA extracted from an embryo biopsy sample known to carry an unbalanced form of a chromosome rearrangement were subjected to a specific NGS workflow (VeriSeq PGS). The results from the two technologies were compared for each sample. PARTICIPANTS/MATERIALS, SETTING, METHODS: WGA products from 200 embryos known to carry unbalanced rearrangements were sequenced and analysed. These embryos had been created by 75 patients known to carry a chromosome rearrangement (68 reciprocal translocations, 3 pericentric inversions, 1 paracentric inversion, 2 insertions and 1 dual reciprocal and inversion). Each sample was assessed for the size of the segmental gain/loss (Mb), copy number for each segment and chromosome, segregation pattern, the number of bins in the analysis software used and concordance with array-CGH results. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 294 unbalanced chromosome segments were assessed. NGS was capable of detecting 285/294 (97%) unbalanced segments previously identified using array-CGH. The final PGD diagnosis was concordant for 200/200 (100%) embryos. In total, 44/75 (59%) patients contained an unbalanced chromosome segment below the quoted 20 Mb manufacturer's stated resolution. Of these, 35/44 (80%) patients had segments that were able to be detected using NGS, whilst maintaining clinical outcome concordance. LIMITATIONS, REASONS FOR CAUTION: Our study subset did not include any rearrangements involving the Y chromosome. NGS has less available bins per chromosome compared to the array-CGH platform used, thus it remains possible that chromosome rearrangements predicted to be small but still detectable by array-CGH may not be feasible for testing using NGS. This should be considered when undertaking a theoretical feasibility assessment for detecting the chromosome rearrangement in question. Only one specific workflow for WGA and NGS was investigated in this study. WIDER IMPLICATIONS OF THE FINDINGS: This study has shown that NGS is available for the detection of unbalanced chromosome rearrangements ≥10 Mb. STUDY FUNDING/COMPETING INTEREST(S): Part sponsorship of the VeriSeq PGS kits used was provided by Illumina. The remainder of the kits were provided by two commercial IVF clinics. None of the authors has any conflicting interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Development Review of the BACE1 Inhibitor Lanabecestat (AZD3293/LY3314814).

Several ongoing clinical development programs are investigating potential disease-modifying treatments for Alzheimer's disease (AD), including lanabecestat (AZD3293/LY3314814). Lanabecestat is a brain-permeable oral inhibitor of human beta-site amyloid (Aß) precursor protein-cleaving enzyme 1 (BACE1) that reduces Aß production. As a potent BACE1 inhibitor, lanabecestat significantly reduced soluble Aß species and soluble amyloid precursor proteins (sAPPß) in mouse, guinea pig, and dog in a time- and dose-dependent manner. Significant reductions in plasma and cerebrospinal fluid (CSF) Aß1-40 and Aß1-42 were observed in Phase 1 studies of healthy subjects and AD patients treated with lanabecestat. Three lanabecestat trials are ongoing and intended to support registration in Early AD: (1) Phase 2/3 study in patients with mild cognitive impairment (MCI) due to AD and mild AD dementia (AMARANTH, NCT02245737); (2) Delayed-start extension study (AMARANTH-EXTENSION, NCT02972658) for patients who have completed treatment in the AMARANTH Study; and (3) Phase 3 study in mild AD dementia (DAYBREAK-ALZ, NCT02783573). This review will discuss the development of lanabecestat, results from the completed nonclinical and clinical studies, as well as describe the ongoing Phase 3 clinical trials.

Biomechanical analysis of an interference screw and a novel twist lock screw design for bone graft fixation.

BACKGROUND: Malpositioning of an anterior cruciate ligament graft during reconstruction can occur during screw fixation. The purpose of this study is to compare the fixation biomechanics of a conventional interference screw with a novel Twist Lock Screw, a rectangular shaped locking screw that is designed to address limitations of graft positioning and tensioning. METHODS: Synthetic bone (10, 15, 20lb per cubic foot) were used simulating soft, moderate, and dense cancellous bone. Screw push-out and graft push-out tests were performed using conventional and twist lock screws. Maximum load and torque of insertion were measured. FINDINGS: Max load measured in screw push out with twist lock screw was 64%, 60%, 57% of that measured with conventional screw in soft, moderate and dense material, respectively. Twist lock max load was 78% and 82% of that with conventional screw in soft and moderate densities. In the highest bone density, max loads were comparable in the two systems. Torque of insertion with twist lock was significantly lower than with conventional interference screw. INTERPRETATION: Based on geometric consideration, the twist lock screw is expected to have 35% the holding power of a cylindrical screw. Yet, results indicate that holding power was greater than theoretical consideration, possibly due to lower friction and lower preloaded force. During graft push out in the densest material, comparable max loads were achieved with both systems, suggesting that fixation of higher density bone, which is observed in young athletes that require reconstruction, can be achieved with the twist lock screw.

Comparison of HER2 Dual-Color and Fluorescence In Situ Hybridization in Breast Cancer: A Cohort Study Emphasizing Equivocal Cases.

OBJECTIVES: Human epidermal growth factor receptor 2 (HER2; ERBB2 gene) is of prognostic and predictive significance in breast carcinoma. Both fluorescence in situ hybridization (FISH) and dual-color in situ hybridization (DISH) methods are available. DISH and FISH are highly concordant in validation studies, but differences may be more prevalent in the equivocal range. Our goal was to compare FISH and DISH on a cohort enriched for equivocal cases, with respect to HER2 determination. METHODS: The cohort was enriched for equivocal (2+) cases. DISH and FISH were evaluated using standard protocols and the results compared with respect to HER2 status, HER2 copy number, and HER2/chromosome 17 (Chr17) ratio. RESULTS: In total, 109 cases were identified. The agreement rate of DISH with FISH was 74%. The mean ± SD HER2/Chr17 ratio by DISH was 1.63 ± 0.08 vs 1.59 ± 0.26 by FISH (P = .45). The mean ± SD HER2 copy number by DISH was 4.56 ± 0.45 vs 4.75 ± 1.08 by FISH (P = .004). Individual signals were more easily resolved using FISH in cases with higher copy numbers. CONCLUSIONS: In our cohort enriched for equivocal cases, the numerical values of HER2 copy number were significantly lower using DISH, resulting in discordances. Although DISH is a valid method, variations with FISH may be expected in high-equivocal cases and in quality assurance activities.

Detecting intratumoral heterogeneity in routine breast-HER2 testing: low yield of testing multiple blocks.

BACKGROUND: Intratumoral heterogeneity can lead to uncertainty in breast carcinoma HER2 testing, both with respect to pathology reporting and clinical significance. The standard practice is to perform breast biomarker testing on a single representative section of tumor; however, concern over heterogeneity often leads to testing on additional tissue blocks. Our objective was to assess the diagnostic yield of testing multiple blocks of a single invasive breast carcinoma. METHODS: We performed a retrospective review of 139 consecutive cases (between 2006 and 2012) in which clinical HER2 testing was performed in multiple blocks. Tumor characteristics and HER2 studies (both immunohistochemistry and data from in situ hybridization) were reviewed. Regional differences in morphology and HER2 immunoreactivity were recorded. In situ hybridization was performed in 25 of 139 of the cases; patterns of genetic heterogeneity were reviewed. We audited discordances in HER2 result between blocks. RESULTS: Testing of multiple blocks yielded no additional HER2 information in 134 (96.4%) of 139 cases. Morphologic differences or heterogeneity in HER2 expression was observed in 22 (15.8%) of 139 of cases. Only 5 of these showed differences in HER2 between blocks, of which 4 were associated with equivocal HER2 immunohistochemistry, and 4 were high-grade. CONCLUSIONS: In the vast majority of cases, even those with heterogeneity, testing of a single block is sufficient for an accurate HER2 determination. High-grade tumors with equivocal HER2 status and observable heterogeneity are more likely to yield a different result on testing of additional blocks.

Understanding and predicting suicidality using a combined genomic and clinical risk assessment approach.

Worldwide, one person dies every 40 seconds by suicide, a potentially preventable tragedy. A limiting step in our ability to intervene is the lack of objective, reliable predictors. We have previously provided proof of principle for the use of blood gene expression biomarkers to predict future hospitalizations due to suicidality, in male bipolar disorder participants. We now generalize the discovery, prioritization, validation, and testing of such markers across major psychiatric disorders (bipolar disorder, major depressive disorder, schizoaffective disorder, and schizophrenia) in male participants, to understand commonalities and differences. We used a powerful within-participant discovery approach to identify genes that change in expression between no suicidal ideation and high suicidal ideation states (n=37 participants out of a cohort of 217 psychiatric participants followed longitudinally). We then used a convergent functional genomics (CFG) approach with existing prior evidence in the field to prioritize the candidate biomarkers identified in the discovery step. Next, we validated the top biomarkers from the prioritization step for relevance to suicidal behavior, in a demographically matched cohort of suicide completers from the coroner's office (n=26). The biomarkers for suicidal ideation only are enriched for genes involved in neuronal connectivity and schizophrenia, the biomarkers also validated for suicidal behavior are enriched for genes involved in neuronal activity and mood. The 76 biomarkers that survived Bonferroni correction after validation for suicidal behavior map to biological pathways involved in immune and inflammatory response, mTOR signaling and growth factor regulation. mTOR signaling is necessary for the effects of the rapid-acting antidepressant agent ketamine, providing a novel biological rationale for its possible use in treating acute suicidality. Similarly, MAOB, a target of antidepressant inhibitors, was one of the increased biomarkers for suicidality. We also identified other potential therapeutic targets or biomarkers for drugs known to mitigate suicidality, such as omega-3 fatty acids, lithium and clozapine. Overall, 14% of the top candidate biomarkers also had evidence for involvement in psychological stress response, and 19% for involvement in programmed cell death/cellular suicide (apoptosis). It may be that in the face of adversity (stress), death mechanisms are turned on at a cellular (apoptosis) and organismal level. Finally, we tested the top increased and decreased biomarkers from the discovery for suicidal ideation (CADM1, CLIP4, DTNA, KIF2C), prioritization with CFG for prior evidence (SAT1, SKA2, SLC4A4), and validation for behavior in suicide completers (IL6, MBP, JUN, KLHDC3) steps in a completely independent test cohort of psychiatric participants for prediction of suicidal ideation (n=108), and in a future follow-up cohort of psychiatric participants (n=157) for prediction of psychiatric hospitalizations due to suicidality. The best individual biomarker across psychiatric diagnoses for predicting suicidal ideation was SLC4A4, with a receiver operating characteristic (ROC) area under the curve (AUC) of 72%. For bipolar disorder in particular, SLC4A4 predicted suicidal ideation with an AUC of 93%, and future hospitalizations with an AUC of 70%. SLC4A4 is involved in brain extracellular space pH regulation. Brain pH has been implicated in the pathophysiology of acute panic attacks. We also describe two new clinical information apps, one for affective state (simplified affective state scale, SASS) and one for suicide risk factors (Convergent Functional Information for Suicide, CFI-S), and how well they predict suicidal ideation across psychiatric diagnoses (AUC of 85% for SASS, AUC of 89% for CFI-S). We hypothesized a priori, based on our previous work, that the integration of the top biomarkers and the clinical information into a universal predictive measure (UP-Suicide) would show broad-spectrum predictive ability across psychiatric diagnoses. Indeed, the UP-Suicide was able to predict suicidal ideation across psychiatric diagnoses with an AUC of 92%. For bipolar disorder, it predicted suicidal ideation with an AUC of 98%, and future hospitalizations with an AUC of 94%. Of note, both types of tests we developed (blood biomarkers and clinical information apps) do not require asking the individual assessed if they have thoughts of suicide, as individuals who are truly suicidal often do not share that information with clinicians. We propose that the widespread use of such risk prediction tests as part of routine or targeted healthcare assessments will lead to early disease interception followed by preventive lifestyle modifications and proactive treatment.

Successful Semi-Ambulatory Veno-Arterial Extracorporeal Membrane Oxygenation Bridge to Heart-Lung Transplantation in a Very Small Child.

Lung transplantation (LTx) may be denied for children on extracorporeal membrane oxygenation (ECMO) due to high risk of cerebral hemorrhage. Rarely has successful LTx been reported in children over 10 years of age receiving awake or ambulatory veno-venous ECMO. LTx following support with ambulatory veno-arterial ECMO (VA ECMO) in children has never been reported to our knowledge. We present the case of a 4-year-old, 12-kg child with heritable pulmonary artery hypertension and refractory right ventricular failure. She was successfully bridged to heart-lung transplantation (HLTx) using ambulatory VA ECMO. Initial resuscitation with standard VA ECMO was converted to an ambulatory circuit using Berlin heart cannulae. She was extubated and ambulating around her bed while on VA ECMO for 40 days. She received an HLTx from an oversized marginal lung donor. Despite a cardiac arrest and Grade 3 primary graft dysfunction, she made a full recovery without neurological deficits. She achieved 104% force expiratory volume in 1 s 33 months post-HLTx. Ambulatory VA ECMO may be a useful strategy to bridge very young children to LTx or HLTx. Patient tailored ECMO cannulation, minimization of hemorrhage, and thrombosis risks while on ECMO contributed to a successful HLTx in our patient.

A case report of living-donor lobar lung transplantation for scleroderma-associated usual interstitial pneumonia: eight years and counting.

INTRODUCTION: Scleroderma-associated interstitial lung disease is a life-limiting complication of scleroderma, often requiring lung transplantation. Living-donor lobar lung transplantation (LDLLT) is a viable alternative to deceased-donor lung transplantation in specialized centers under select circumstances. CLINICAL CASE: A 47-year-old female underwent LDLLT after nine years of symptomatic scleroderma-associated usual interstitial pneumonia and three years awaiting deceased-donor lung transplantation. Her manifestations of scleroderma included mild sclerodactyly, periungual erythema, Raynaud's phenomenon, and gastroesophageal reflux, with positive antinuclear autoantibodies. Several years post-transplantation, manometry revealed feeble lower esophageal sphincteric pressure with ineffective esophageal motility. Bronchiolitis obliterans syndrome developed 64 months post-transplantation without evidence of aspiration or reflux on transbronchial biopsy. Currently, she has normal renal function and good allograft function [FEV1 1.52 L (73% predicted) and FVC 2.50 L (99% predicted)]. RELEVANCE: This is the second reported case of LDLLT in scleroderma, and the first reporting long-term pulmonary, renal, and esophageal function post-transplantation.

Implications of the 2013 ACC/AHA cholesterol guidelines for adults in contemporary cardiovascular practice: insights from the NCDR PINNACLE registry.

BACKGROUND: In a significant update, the 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guidelines recommend fixed-dose statin therapy for those at risk and do not recommend nonstatin therapies or treatment to target low-density lipoprotein cholesterol (LDL-C) levels, limiting the need for repeated LDL-C testing. OBJECTIVES: The goal of this study was to examine the impact of the 2013 ACC/AHA cholesterol guidelines on current U.S. cardiovascular practice. METHODS: Using the NCDR PINNACLE (National Cardiovascular Data Registry Practice Innovation and Clinical Excellence) registry data from 2008 to 2012, we assessed current practice patterns as a function of the 2013 cholesterol guidelines. Lipid-lowering therapies and LDL-C testing patterns by patient risk group (atherosclerotic cardiovascular disease [ASCVD], diabetes, LDL-C ≥190 mg/dl, or an estimated 10-year ASCVD risk ≥7.5%) were described. RESULTS: Among a cohort of 1,174,545 patients, 1,129,205 (96.1%) were statin-eligible (91.2% ASCVD, 6.6% diabetes, 0.3% off-treatment LDL-C ≥190 mg/dl, 1.9% estimated 10-year ASCVD risk ≥7.5%). There were 377,311 patients (32.4%) not receiving statin therapy and 259,143 (22.6%) receiving nonstatin therapies. During the study period, 20.8% of patients had 2 or more LDL-C assessments, and 7.0% had more than 4. CONCLUSIONS: In U.S. cardiovascular practices, 32.4% of statin-eligible patients, as defined by the 2013 ACC/AHA cholesterol guidelines, were not currently receiving statins. In addition, 22.6% were receiving nonstatin lipid-lowering therapies and 20.8% had repeated LDL-C testing. Achieving concordance with the new cholesterol guidelines in patients treated in U.S. cardiovascular practices would result in significant increases in statin use, as well as significant reductions in nonstatin therapies and laboratory testing.

Impact of the 2014 expert panel recommendations for management of high blood pressure on contemporary cardiovascular practice: insights from the NCDR PINNACLE registry.

BACKGROUND: Since 2003, the Seventh Report of the Joint National Committee (JNC-7) has been the predominant guideline for blood pressure management. A 2014 expert panel recommended increasing the blood pressure targets for patients age 60 years and older, as well as those with diabetes or chronic kidney disease. OBJECTIVES: The purpose of this study was to examine the effect of the 2014 expert panel blood pressure management recommendations on patients managed in U.S. ambulatory cardiovascular practices. METHODS: Using the National Cardiovascular Data Registry PINNACLE Registry, we assessed the proportion of patients who met the 2003 and 2014 panel recommendations, highlighting the populations of patients for whom the blood pressure goals changed. RESULTS: Of 1,185,253 patients in the study cohort, 706,859 (59.6%) achieved the 2003 JNC-7 goals. Using the 2014 recommendations, 880,378 (74.3%) patients were at goal. Among the 173,519 (14.6%) for whom goal achievement changed, 40,323 (23.2%) had a prior stroke or transient ischemic attack, and 112,174 (64.6%) had coronary artery disease. In addition, the average Framingham risk score in this group was 8.5 ± 3.2%, and the 10-year ASCVD risk score was 28.0 ± 19.5%. CONCLUSIONS: Among U.S. ambulatory cardiology patients with hypertension, nearly 1 in 7 who did not meet JNC-7 recommendations would now meet the 2014 treatment goals. If the new recommendations are implemented in clinical practice, blood pressure target achievement and cardiovascular events will need careful monitoring, because many patients for whom the target blood pressure is now more permissive are at high cardiovascular risk.