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A total of 264 implants was placed in 143 patients using different immediate or delayed-immediate implant placement techniques in 12 different centers participating in a prospective multicenter study. The reason for tooth extraction was evaluated; bone quality and quantity were classified; socket depths were registered; and data on implant type, size, and position were collected. One hundred thirty-nine suprastructures were placed on 228 implants in 126 patients. A follow-up evaluation was done on 125 patients after 1 year of loading and on 107 patients after 3 years of loading. Clinical parameters (bleeding or not bleeding, pocket depth, and implant mobility) were evaluated after 1 and 3 years, and the marginal bone level after 1 year of loading was measured on radiographs. Clinical comparisons were performed to evaluate implant loss in relation to implant type, size, position, bone quality and quantity, socket depth, reason for tooth extraction, and placement method. In addition, life table analysis was done for cumulative implant survival rates. There was no clinical difference with respect to socket depth or when comparing the different placement methods. A higher failure rate was found for short implants in the posterior region of the maxilla and when periodontitis was cited as a reason for tooth extraction. Mean marginal bone resorption from the time of loading to the 1-year follow-up was 0.8 mm in the maxilla and 0.5 mm in the mandible. Over a period of 3 years, the implant survival rate was 92.4% in the maxilla and 94.7% in the mandible. [ABSTRACT FROM AUTHOR]

Increased susceptibility to distraction is a symptom of normal aging and several clinical syndromes, including Alzheimer's disease and attention deficit disorders. In the present study, aged and young adult macaques were well-trained to perform an automated delayed matching-to-sample (DMTS) task which assesses both attention and short-term memory. On 19% of all trials, a task-relevant distracting stimulus was presented during either the initial 1 or 3 s of delay intervals (early onset) or the final 1 or 3 s of delay intervals (late onset). In aged monkeys, both early and late onset distractors lasting 1 or 3 s impaired delayed recall on trials with the shortest delay intervals, but did not affect accuracy on trials with long delay intervals. In contrast, young adult monkeys were impaired only by the presence of an early onset distractor lasting 3 s. Impairment was selective for only those trials with the shortest delay intervals. Late onset distractors were relatively ineffective in producing distractibility in young adult animals. Methylphenidate (MPH; 0.005-1.0 mg/kg) failed to reduce distractibility in aged monkeys, producing locomotor abnormalities and hypophagia at doses ranging from 0.25 to 1.0 mg/kg. In young adult monkeys, however, distractibility was significantly attenuated by administration of the 0.125 mg/kg dose. Habituation to the distracting stimulus (under saline conditions) was assessed throughout the study and was not evident at any time point of testing. These data indicate that attention and recall after brief delays are impaired following exposure to task-relevant distracting stimulus in both aged and young adult monkeys, but that aged monkeys are more susceptible to distraction and do not receive significant benefit from MPH administration. [ABSTRACT FROM AUTHOR]

In the diagnostic workup of poorly differentiated tumors, T-cell receptor (TCR) clonality has long been considered as evidence of T-cell lymphoma. MET exon 14 skipping ( METex14 ) is a mutation typically seen in lung adenocarcinoma. Herein, we present the first report of METex14 lung adenocarcinoma with isolated monoclonal TCRγ gene rearrangement. A 69-year-old woman presented to an outside hospital with pleural effusions. A pleural decortication demonstrated malignant cells positive for CD30 and CD138 but negative for BerEP4, KRT5, and EMA. An equivocal HHV8 staining was interpreted as positive, leading to the erroneous outside diagnosis of primary effusion lymphoma. Additional workup at our institution revealed a lack of HHV8 and T-cell markers but the presence of TCRγ clonality, pankeratin, and TTF1 expression. Repeat TCRγ testing on the in-house biopsy was negative for clonality. Next-generation sequencing detected METex14 , confirming the diagnosis of lung adenocarcinoma. The potential diagnostic pitfall and prognostic/predictive implications are discussed., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: This study examines innovation configurations (i.e. sets of product/service, social and business model innovations) and configuration linkages (i.e. factors that help to combine innovations) across six organizations as contingent upon organizational structure., Design/methodology/approach: Using semi-structured interviews and available public information, qualitative data were collected and examined using content analysis to characterize innovation configurations and linkages in three local/private organizations and three foreign-led/public-private partnerships in Repiblik Ayiti (Haiti)., Findings: Organizations tend to combine product/service, social, and business model innovations simultaneously in locally founded private organizations and sequentially in foreign-based public-private partnerships. Linkages for simultaneous combination include limited external support, determined autonomy and shifting from a "beneficiary mindset," and financial need identification. Sequential combination linkages include social need identification, community connections and flexibility., Research Limitations/implications: The generalizability of our findings for this qualitative study is subject to additional quantitative studies to empirically test the suggested factors and to examine other health care organizations and countries., Practical Implications: Locally led private organizations in low- and middle-income settings may benefit from considering how their innovations are in service to one another as they may have limited resources. Foreign based public-private partnerships may benefit from pacing their efforts alongside a broader set of stakeholders and ecosystem partners., Originality/value: This study is the first, to our knowledge, to examine how organizations combine sets of innovations, i.e. innovation configurations, in a healthcare setting and the first of any setting to examine innovation configuration linkages., (© Wiljeana Jackson Glover, Sabrina JeanPierre Jacques, Rebecca Rosemé Obounou, Ernest Barthélemy and Wilnick Richard.)

Objective: This is the first systematic review aims to build the evidence for the impact of accreditation on quality improvement of healthcare services, as well as identify and develop an understanding of the contextual factors influencing accreditation implementation in the hospital setting through the lens of Normalisation Process Theory (NPT)., Data Sources: Data were gathered from five databases; MEDLINE, PUBMED, EMBASE, CINAHL, and the Cochrane Library. And supplemental sources., Study Design: This systematic review is reported following PRISMA guidelines with a quality assessment. Data were analysed using a thematic analysis guided by the NPT theoretical framework., Data Collection/extraction Methods: Data were extracted and summarized using prespecified inclusion/exclusion criteria and a data extraction sheet encompassing all necessary information about the studies included in the review., Principal Findings: There are inconsistent findings about the impact of accreditation on improving healthcare quality and outcomes, and there is scant evidence about its effectiveness. The findings also provide valuable insights into the key factors that may influence hospital accreditation implementation and develop a better understanding of their potential implications. Using the NPT shows a growing emphasis on the enactment work of the accreditation process and how this may drive improving the quality of healthcare services. However, little focus is given to accreditation's effects on health professionals' roles and responsibilities, strategies and ways for engaging health professionals for effective implementation, and ensuring that the goals and potential benefits of accreditation are made clear and transparent through ongoing evaluation and feedback to all health professionals involved in the accreditation process., Conclusions: While there are contradictory findings about the impact of accreditation on improving the quality of healthcare services, accreditation continues to gain acceptance internationally as a quality assurance tool to support best practices in evaluating the quality outcomes of healthcare delivered. Policymakers, healthcare organisations, and researchers should proactively consider a set of key factors for the future implementation of accreditation programmes if they are to be effectively implemented and sustained within the hospital setting. Systematic review registration: International Prospective Register of Systematic Reviews PROSPERO 2020 CRD42020172390 Available from: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=172390., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Alhawajreh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This study aims to evaluate if race and ethnicity affect rates of tympanostomy tube (TT) placement during inpatient pediatric admissions in children with otologic conditions. A review of the 2016 Kids' Inpatient Database was conducted based on the International Classification of Diseases, 10th revision, Clinical Modification (ICD-10-CM) codes for common otologic conditions. Among 85 827 weighted pediatric inpatient discharges with ICD-10-CM codes for common otologic conditions, 213 underwent TT placement. Odds ratios (ORs) for children of Hispanic ethnicity and Asian or Pacific Islander race undergoing TT placement when compared to other ethnicities and races were 0.60 ( P = .011) and 0.21 ( P = .040), respectively. Multiple logistic regression showed Hispanic ethnicity was associated with lower rates of TT placement when compared to non-Hispanic white children (OR = 0.62; 95% confidence interval = 0.40-0.96). Future studies should assess why these differences exist and if these differences are associated with racial/ethnic bias or attributed to patient/family preference., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction  Expanding access to care has been shown to impact patient care and disease epidemiology for different disease states, but has not been studied in pituitary adenoma. We hypothesize that increasing access to care-which includes diagnostics-through the Affordable Care Act (ACA) and Medicaid expansion has increased identification of pituitary adenomas. Methods  The National Cancer Institute's Surveillance, Epidemiology, and End Results database was utilized to identify patients with pituitary adenomas from 2007-to 2016 yielding 39,120 cases. Demographic, histologic, and insurance data were extracted. After stratification based on their insurance status, they were plotted to examine trends in insurance status after introduction of the ACA and Medicaid expansion. Magnetic resonance imaging (MRI) data was gathered from the Organization for Economic Co-operation and Development. A linear regression model was developed to describe the relationship between pituitary adenoma discovery and the number of MRI exams. Results  Pituitary adenoma diagnoses (37.6%) and MRI examinations per 1,000 in the U.S. (32.3%) increased concurrently from 2007 to 2016. Linear regression analysis revealed a statistically significant relationship ( p  = 0.0004). Those patients without insurance diagnosed with pituitary adenomas decreased 36.8% after Medicaid expansion ( p  = 0.023). With respect to Medicaid utilization, significant increases of 28.5% ( p  = 0.014) and 30.3% ( p  = 0.00096) were noted after both the ACA enactment and Medicaid expansion, respectively. Conclusion  The ACA has expanded health care access which has increased the ability to identify patients with pituitary adenomas. The present study also provides evidence that access to care is important for less prevalent diseases such as pituitary adenomas., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. The RAS pathway is activated in more than 55% of CRC and has been targeted for therapeutic intervention with MEK inhibitors. Unfortunately, many patients have de novo resistance, or can develop resistance to this new class of drugs. We have hypothesized that much of this resistance may pass through SRC as a common signal transduction node, and that inhibition of SRC may suppress MEK inhibition resistance mechanisms. CRC tumors of the Consensus Molecular Subtype (CMS) 4, enriched in stem cells, are difficult to successfully treat and have been suggested to evade traditional chemotherapy agents through resistance mechanisms. Here, we evaluate targeting two pathways simultaneously to produce an effective treatment by overcoming resistance. We show that combining Trametinib (MEKi) with Dasatinib (SRCi) provides enhanced cell death in 8 of the 16 tested CRC cell lines compared to treatment with either agent alone. To be able to select sensitive cells, we simultaneously evaluated a validated 18-gene RAS pathway activation signature score along with a 13-gene MEKi resistance signature score, which we hypothesize predict tumor sensitivity to this dual targeted therapy. We found the cell lines that were sensitive to the dual treatment were predominantly CMS4 and had both a high 18-gene and a high 13-gene score, suggesting these cell lines had potential for de novo MEKi sensitivity but were subject to the rapid development of MEKi resistance. The 13-gene score is highly correlated to a score for SRC activation, suggesting resistance is dependent on SRC. Our data show that gene expression signature scores for RAS pathway activation and for MEKi resistance may be useful in determining which CRC tumors will respond to the novel drug combination of MEKi and SRCi.

Background: Acute rejection remains a vexing problem in vascularized composite allotransplantation (VCA). Available immunosuppressive regimens are successful at minimizing alloimmune response and allowing VCA in humans. However, repeated rejection episodes are common, and systemic side effects of the current standard regimen (Tacrolimus, MMF, Prednisone) are dose limiting. Novel immunomodulatory approaches to improve allograft acceptance and minimize systemic toxicity are continuously explored in preclinical models. We aimed to systematically summarize past and current approaches to help guide future research in this complex field., Methods: We conducted a systematic review of manuscripts listed in the MEDLINE and PubMed databases. For inclusion, articles had to primarily investigate the effect of a therapeutic approach on prolonging the survival of a skin-containing preclinical VCA model. Non-VCA studies, human trials, anatomical and feasibility studies, and articles written in a language other than English were excluded. We followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines., Results: The search retrieved 980 articles of which 112 articles were ultimately included. The majority of investigations used a rat model. An orthotopic hind limb VCA model was used in 53% of the studies. Cell and drug-based approaches were investigated 58 and 52 times, respectively. We provide a comprehensive review of immunomodulatory strategies used in VCA preclinical research over a timeframe of 44 years., Conclusion: We identify a transition from anatomically non-specific to anatomical models mimicking clinical needs. As limb transplants have been most frequently performed, preclinical research focused on using the hind limb model. We also identify a transition from drug-based suppression therapies to cell-based immunomodulation strategies., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Improvised explosive devices (IEDs), during military operations, has increased the incidence of blast-induced traumatic brain injuries (bTBI). The shock wave is created following detonation of the IED. This shock wave propagates through the atmosphere and may cause bTBI. As a result, bTBI research has gained increased attention since this injury's mechanism is not thoroughly understood. To develop better protection and treatment against bTBI, further studies of soft material (e.g. brain and brain surrogate) deformation due to shock wave exposure are essential. However, the dynamic mechanical behavior of soft materials, subjected to high strain rates from shock wave exposure, remains unknown. Thus, an experimental approach was applied to study the interaction between the shock wave and an unconfined brain surrogate fabricated from a biomaterial (i.e. polydimethylsiloxane (PDMS)). The 1:70 ratio of curing agent-to-base determined the stiffness of the PDMS (Sylgard 184, Dow Corning Corporation). A stretched NACA 2414 (upper airfoil surface) geometry was utilized to resemble the shape of a porcine brain. Digital image correlation (DIC) technique was applied to measure the deformation on the brain surrogate's surface following shock wave exposure. A shock tube was utilized to create the shock wave and pressure transducers measured the pressure in the vicinity of the brain surrogate. A transient structural analysis using ANSYS Workbench was performed to predict the elastic modulus of 1:70 airfoil-shaped PDMS, at a strain rate on the order of 6 × 10 3  s -1 . Both compression and protrusion of the PDMS surface were found due to the shock wave exposure. Negative pressure was found in a semi-ring area, which was the cause of protrusion. Oscillation of the brain surrogate, due to the shock wave loading, was found. The frequency of oscillation does not depend on the geometry. This work will add to the limited data describing the dynamic behavior of soft materials due to shock wave loading., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Summary: Skin is one of the target tissues of rejection in face transplants and, because of its easy accessibility, has become the gold standard in the diagnosis of rejection. The allograft contains deeper tissues where rejection can occur, but samples cannot be obtained because of difficult access. Deep tissue changes were monitored on computed tomographic scans of the midface in six face transplant recipients with the help of image segmentation. The maxillary sinus was identified as a dynamic anatomical compartment. Observed changes in volume of the aeration relative to the opacification (aeration coefficient) of the maxillary sinus were quantified with the help of image segmentation. Changes in the aeration coefficient as a surrogate of mucosal swelling were quantified and related to time, treatment, and skin rejection grade. Lower aeration coefficients were found only in patients with transplanted maxillary sinus mucosa. Pathologic changes were not observed in face transplant recipients with a native maxillary sinus. The data show that the aeration coefficient was significantly lower at the time of biopsy-proven allograft rejection. Neither mechanical, nor infectious, nor medication side effects sufficiently explain the findings presented herein. The authors' findings are important to consider for clinical management of face transplant patients who receive parts of the sinonasal tract. The authors identify a potential radiologic biomarker of deep tissue allograft rejection. In the future, the proposed methodology might prove useful in monitoring deeper dynamic tissue changes in vascularized composite allografts and might help in designing patient-specific, individualized treatment strategies., Competing Interests: Disclosure:No author states any conflicts of interest., (Copyright © 2021 by the American Society of Plastic Surgeons.)

Background: Local immunosuppression in vascularized composite allotransplantation (VCA) aims to minimize immunosuppressant-related toxic and malignant side effects. Promising allograft survival data have been published by multiple workgroups. In this systematic review, we examine preclinical animal studies that investigated local immunosuppression in VCA., Material and Methods: We conducted a systematic review of manuscripts listed in the MEDLINE and PubMed database concerning preclinical VCA models. Papers included had to be available as full-text and written in English. Non-VCA studies, human trials, and studies using cell-based therapy strategies were excluded. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines., Results: Literature research retrieved 980 articles. Ten studies published between 2010 and 2019 met the inclusion and exclusion criteria. Seven out of ten articles demonstrated a significant prolongation of allograft survival by using local immunosuppression. Five articles employed tacrolimus (TAC) as the main immunosuppressive agent. Seven studies performed hind-limb VCA in a rat model., Conclusion: The easily accessible location of skin containing VCAs makes it an ideal candidate for local immunosuppression. Published preclinical data are very promising in terms of improved allograft survival and reduced systemic toxicity., Competing Interests: Declaration of Competing Interest None., (Published by Elsevier Ltd.)

Background: Facial vascularized composite allotransplantation (fVCA) presents an established approach to restore form and function of patients with catastrophic facial defects. Skin is one of the target tissues of the rejection process, and due to its easy accessibility has become the gold standard in the diagnosis of rejection. Mucosal rejection frequently occurs; however, the added value of mucosal rejection assessment for patient management is unknown., Methods: We conducted a systematic review of manuscripts listed in the MEDLINE/PubMed and GoogleScholar databases to identify articles that provide data on mucosal rejection following fVCA. For inclusion, papers had to be available as full-text and written in English. Non-VCA studies and animal studies were excluded. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines., Results: We included 17 articles that described changes in allotransplanted mucosa of fVCAs. These articles yielded data on 168 BANFF graded biopsies of corresponding skin and mucosa biopsies. Rejection grades were consistently higher in mucosal biopsies. Concordance between allograft skin and mucosa biopsy grades increased with an increasing skin-BANFF grade. Mucosa rejection grades were on average lower in the early stages of the posttransplant period (postoperative mo 12)., Conclusions: The mucosa of facial allotransplants is one of the primary targets of rejection. The data indicates that higher-grade skin rejection does not occur in absence of mucosal rejection. Further investigations are needed to elucidate the exact role of mucosal biopsies for fVCA patient management.

Background: We are in an innovation age for healthcare delivery. Some note that the complexity of healthcare delivery may make innovation in this setting more difficult and may require more adaptive solutions. The aim of this study is to examine the relationship between unit complexity and innovation, using a complex adaptive systems approach in a hospital setting., Methods: We conducted a quantitative study of 31 hospital units within one hospital and use complex adaptive systems (CAS) theory to examine how two CAS factors, autonomy and performance orientation, moderate the relationship between unit complexity and innovation., Results: We find that unit complexity is associated with higher innovation performance when autonomy is low rather than high. We also find that unit complexity is associated with higher innovation performance when performance orientation is high rather than low. Our findings make three distinct contributions: we quantify the influence of complexity on innovation success in the health care sector, we examine the impact of autonomy on innovation in health care, and we are the first to examine performance orientation on innovation in health care., Conclusions: This study tackles the long debate about the influence of complexity on healthcare delivery, particularly innovation. Instead of being subject to the influence of complexity with no means of making progress or gaining control, hospitals looking to implement innovation programs should provide guidance to teams and departments regarding the type of innovation sought and provide support in terms of time and management commitment. Hospitals should also find ways to promote and make successful pilot implementations of such innovations visible in the organization. A close connection between the targeted innovation and the overall success and performance of the hospital unit is ideal.

Traumatic brain injuries (TBI) affect millions of people each year. While research has been dedicated to determining the mechanical properties of the uninjured brain, there has been a lack of investigation on the mechanical properties of the brain after experiencing a primary blast-induced TBI. In this paper, whole porcine brains were exposed to a shock wave to simulate blast-induced TBI. First, ten (10) brains were subjected to unconfined compression experiments immediately following shock wave exposure. In addition, 22 brains exposed to a shock wave were placed in saline solution and refrigerated between 30 minutes and 6.0 hours before undergoing unconfined compression experiments. This study aimed to investigate the effect of a time delay on the viscoelastic properties in the event that an experiment cannot be completed immediately. Samples from both soaked and freshly extracted brains were subjected to compressive rates of 5, 50, and 500 mm/min during the unconfined compression experiments. The fractional Zener (FZ) viscoelastic model was applied to obtain the brain's material properties. The length of time in the solution statistically influenced three of the four FZ coefficients, E 0 (instantaneous elastic response), τ 0 (relaxation time), and α (fractional order). Further, the compressive rate statistically influenced τ 0 and α., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Traumatic brain injuries (TBI) affect millions of people each year and can result in long-term difficulties in thinking or focusing. Due to the number of people affected by these injuries, significant research has been dedicated to determining the mechanical properties of the brain using postmortem tissue from animals harvested within 24 h. The postmortem brain tissue is often stored in a solution until a rheological experiment is ready to begin. However, the effect of storage duration on the mechanical behavior of brain tissue is not understood. In this paper, postmortem porcine brains were placed in normal saline solution (0.9% NaCl) and refrigerated between 30 min and 6.5 h to allow the brain to absorb the solution. Afterwards, samples from both soaked and freshly extracted brains were subjected to unconfined compression tests at compressive rates of 5, 50, and 500 mm/min. The fractional Zener viscoelastic model was applied to obtain the brain's mechanical properties. While the results did not show a significant relationship between absorption and the long-term stiffness (E ∞ ), both the relaxation time (τ 0 ) and fractional order (α) were statistically influenced by both the length of time in the solution and compressive rate. Further, the instantaneous stiffness (E 0 ) was statistically influenced by the length of time in solution, though not the compressive rate., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: HIV positive individuals infected with viral hepatitis B (HBV) or C (HCV) are at an increased risk of progression to kidney and liver failures. Therefore, prior to initiation of antiretroviral therapy, early diagnosis and initiation of appropriate treatment protocols are imperative for co-infected individuals. This study evaluated the prevalence of HBV and HCV, and extent of liver and renal dysfunction among 90 newly diagnosed HIV patients attending the Cape Coast Teaching Hospital HIV clinic., Results: Levels of alanine aminotransferase, aspartate-platelet ratio index and estimated glomerular filtration rate were used respectively to diagnose hepatotoxicity, liver fibrosis and chronic kidney disease (CKD). Association analyses were evaluated by Pearson's Chi-square test or Fisher's exact test and considered significant at p < 0.05. Using rapid diagnostic tests, 75.6% (n = 68) had HIV1 mono-infection, 24.4% (n = 22) had HIV1/HBV co-infection while 0.0% (n = 0) had HIV1/HCV co-infection. The prevalence of hepatotoxicity, liver fibrosis, and CKD were 7.8% (n = 7), 2.2% (n = 2), and 15.5% (n = 14) respectively. Similar proportions of HIV1/HBV and HIV1 were diagnosed with liver fibrosis (p = 0.431). In relation to hepatotoxicity Grade, a high proportion of HIV1/HBV were diagnosed with Grade 2 (p = 0.042). Also, severely reduced kidney function (CKD stage 4) was observed in only HIV1/HBV (n = 2, 9.1%, p = 0.053).

The ongoing conflict against terrorism has resulted in an escalation of blast-induced traumatic brain injuries (bTBI) caused by improvised explosive devices (IEDs). The destructive IEDs create a blast wave that travels through the atmosphere. Blast-induced traumatic brain injuries, attributed to the blast wave, can cause life-threatening injuries and fatalities. This study aims to find a surrogate brain material for assessing the effectiveness of head protection systems designed to mitigate bTBI. Polydimethylsiloxane (PDMS) is considered as the surrogate brain material. The stiffness of PDMS (Sylgard 184, Dow Corning Corp.) can be controlled by varying the ratio of base and curing agent. Cylindrical PDMS specimen with ratios of 1:10, 1:70, and 1:80 were subjected to unconfined compression experiments at linear rates of 5 mm/min, 50 mm/min, and 500 mm/min. A ramp-hold strain profile was used to simulate a stress relaxation experiment. The fractional Zener viscoelastic model was used to describe the stress relaxation response, after optimization of the material constants for the brain surrogate and shock wave exposure brain tissue. The results show that the low cost PDMS can be used as a surrogate brain material to study the dynamic brain response to blast wave exposure., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Motivation . Microbiome sequencing allows defining clusters of samples with shared composition. However, this paradigm poorly accounts for samples whose composition is a mixture of cluster-characterizing ones and which therefore lie in between them in the cluster space. This paper addresses unsupervised learning of 2-way clusters. It defines a mixture model that allows 2-way cluster assignment and describes a variant of generalized k -means for learning such a model. We demonstrate applicability to microbial 16S rDNA sequencing data from the Human Vaginal Microbiome Project.

p27(Kip1) was first discovered as a key regulator of cell proliferation. The canonical function of p27(Kip1) is inhibition of cyclin-dependent kinase (CDK) activity. In addition to its initial identification as a CDK inhibitor, p27(Kip1) has also emerged as an intrinsically unstructured, multifunctional protein with numerous non-canonical, CDK-independent functions that exert influence on key processes such as cell cycle regulation, cytoskeletal dynamics and cellular plasticity, cell migration, and stem-cell proliferation and differentiation. Many of these non-canonical functions, depending on the cell-specific contexts such as oncogenic activation of signaling pathways, have the ability to turn pro-oncogenic in nature and even contribute to tumor-aggressiveness and metastasis. This review discusses the various non-canonical, CDK-independent mechanisms by which p27(Kip1) functions either as a tumor-suppressor or tumor-promoter.

The Triple Aim has become the guiding light and benchmark by which healthcare organizations plan their future efforts. It has been adopted into healthcare policies with little regard for including the skill sets of compassion and emotional intelligence. The multiple increasing demands on providers of healthcare are unsustainable and will cripple the system, resulting in outcomes that are counter to the Triple Aim goals. Patient engagement with shared decision-making should become the primary focus of care delivery. New delivery models and care plans are unaffordable to far too many patients and payers, despite the efforts of futurists who seek to advance quality and lower costs. Clinical care delivery and patient engagement efforts must be drastically redirected to innovative and sustainable value-based delivery models that support the goals of the Triple Aim.

The cyclin-dependent kinase (CDK) inhibitor p27Kip1 has been shown to regulate cellular proliferation via inhibition of CDK activities. It is now recognized that p27Kip1 can regulate cellular processes through non-canonical, CDK-independent mechanisms. We have developed an inducible p27Kip1 model in cultured cells to explore CDK-independent p27Kip1 regulation of biological processes. We present evidence that p27Kip1 can function in a CDK-independent manner to inhibit entry and/or progression of S phase. Even though this p27Kip1 mechanism is non-canonical it does requires the intact cyclin-binding motif in p27Kip1. We suggest a mechanism similar to that proposed in post-mitotic neural cells whereby p27Kip1 functions to coordinate growth arrest and apoptosis. Our hypothesis supports the concept that p27Kip1 is a gatekeeper for the entry and progression of S phase through interaction with specific protein(s) or via binding to specific DNA sequences in a CDK-independent manner.

Background: There are limited data on the prognostic implications of brain natriuretic peptide (BNP) assessment in patients with mildly symptomatic heart failure (HF) who receive cardiac resynchronization therapy with a defibrillator (CRT-D)., Methods and Results: The effect of elevated baseline and 1-year BNP levels (dichotomized at the upper tertile BNP of 120 pg/mL) on the risk of HF or death was assessed among the cohort of 1197 patients with baseline BNP data enrolled in MADIT (Multicenter Automated Defibrillator Implantation Trial)-CRT. Elevated baseline BNP was associated with a significant 68% (P=0.007) and 58% (P=0.02) increase in the risk of HF or death among MADIT-CRT patients allocated to CRT-D and implantable cardioverter defibrillator-only therapy, respectively. At 1 year of follow-up, patients allocated to CRT-D displayed significantly greater reductions in BNP (26% reduction) levels compared with implantable cardioverter defibrillator-only patients (8% increase; P=0.005). Patients with CRT-D in whom 1-year BNP levels were reduced or remained low experienced a significantly lower risk of subsequent HF or death as compared with patients in whom 1-year BNP levels were high. Similarly, the echocardiographic response to CRT-D was highest among those who maintained low BNP levels or in whom BNP level at 1-year was reduced., Conclusions: Our findings suggest that assessment of baseline and follow-up BNP provides important prognostic implications in patients with mildly symptomatic HF who receive CRT.

Background: Right ventricular function (RVF) is an important determinant of outcome in patients with heart failure, and those with severe RV dysfunction have worse outcome after cardiac resynchronization therapy (CRT). We used data from the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) Trial to determine whether therapy with CRT is influenced by or affects RV function and to define the relationship between RV function and outcomes., Methods and Results: A total of 1820 patients were randomly assigned to CRT plus implantable cardioverter defibrillator or implantable cardioverter defibrillator-only in a 3:2 ratio. We assessed RVF as RV fractional area change by echocardiography at baseline and after 1 year of therapy (n=1511 and 1273, respectively). The median RV fractional area change was 41%, with 10.9% of patients <35% at baseline. Baseline RVF did not modify the treatment effect of CRT on the primary outcome (interaction P=0.19). Randomization to CRT-implantable cardioverter defibrillator was associated with a greater improvement in RVF (ΔRV fractional area change 8.1% versus 5.4%; P<0.001), and improvement in RVF was related to subsequent outcomes. Every 5-point increase in RV fractional area change was associated with a 22% reduction in event rates (hazard ratio, 0.78; 95% confidence interval, 0.66-0.92; P=0.003), although this was not independent of the concurrent improvement in left ventricular function. Baseline tricuspid regurgitant velocity, a measure of pulmonary systolic pressure, was predictive of events in a multivariate analysis (hazard ratio, 1.86; 95% confidence interval, 1.24-2.8; P=0.003)., Conclusions: In this population with mild heart failure symptoms, CRT was associated with improvement in RVF, which improved in parallel with improvement in left ventricular function. Patients with the best RVF at 1 year demonstrated the lowest subsequent event rates., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01294449.

Importance: Randomized clinical trials have shown that implantable cardioverter-defibrillator (ICD) therapy saves lives. Whether the survival of patients who received an ICD in primary prevention clinical trials differs from that of trial-eligible patients receiving a primary prevention ICD in clinical practice is unknown., Objective: To determine whether trial-eligible patients who received a primary prevention ICD as documented in a large national registry have a survival rate that differs from the survival rate of similar patients who received an ICD in the 2 largest primary prevention clinical trials, MADIT-II (n = 742) and SCD-HeFT (n = 829)., Design, Setting, and Patients: Retrospective analysis of data for patients enrolled in the National Cardiovascular Data Registry ICD Registry between January 1, 2006, and December 31, 2007, meeting the MADIT-II criteria (2464 propensity score-matched patients) or the SCD-HeFT criteria (3352 propensity score-matched patients). Mortality data for the registry patients were collected through December 31, 2009., Main Outcome Measures: Cox proportional hazards models were used to compare mortality from any cause., Results: The median follow-up time in MADIT-II, SCD-HeFT, and the ICD Registry was 19.5, 46.1, and 35.2 months, respectively. Compared with patients enrolled in the clinical trials, patients in the ICD Registry were significantly older and had a higher burden of comorbidities. In the matched cohorts, there was no significant difference in survival between MADIT-II-like patients in the registry and MADIT-II patients randomized to receive an ICD (2-year mortality rates: 13.9% and 15.6%, respectively; adjusted ICD Registry vs trial hazard ratio, 1.06; 95% CI, 0.85-1.31; P = .62). Likewise, the survival among SCD-HeFT-like patients in the registry was not significantly different from survival among patients randomized to receive ICD therapy in SCD-HeFT (3-year mortality rates: 17.3% and 17.4%, respectively; adjusted registry vs trial hazard ratio, 1.16; 95% CI, 0.97-1.38; P = .11)., Conclusions and Relevance: There was no significant difference in survival between clinical trial patients randomized to receive an ICD and a similar group of clinical registry patients who received a primary prevention ICD. Our findings support the continued use of primary prevention ICDs in similar patients seen in clinical practice., Trial Registration: clinicaltrials.gov Identifier: NCT00000609.

Background: The Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) trial demonstrated that cardiac resynchronization therapy (CRT) when added to the implantable cardiac defibrillator (ICD) reduces risk of heart failure or death in minimally symptomatic patients with reduced cardiac ejection fraction and wide QRS complex., Objectives: To evaluate 4-year cost-effectiveness of CRT-ICD compared to ICD alone using MADIT-CRT data., Research Design: Patients enrolled in the trial were randomized to implantation of either ICD or CRT-ICD in a 2:3 ratio, with up to 4-year follow-up period. Cost-effectiveness analyses were conducted, and sensitivity analyses by age, gender, and left bundle branch block (LBBB) conduction pattern were performed., Subjects: A total of 1,271 patients with ICD or CRT-ICD (US centers only) who reported healthcare utilization and health-related quality of life data., Measures: We used the EQ-5D (US weights) to assess patient HRQOL and translated utilization data to costs using national Medicare reimbursement rates., Results: Average 4-year healthcare expenditures in CRT-ICD patients were higher than costs of ICD patients ($62,600 vs 57,050, P = 0.015), mainly due to the device and implant-related costs. The incremental cost-effectiveness ratio of CRT-ICD compared to ICD was $58,330/quality-adjusted life years (QALY) saved. The cost effectiveness improved with longer time horizon and for the LBBB subgroup ($7,320/QALY), with no cost-effectiveness benefit being evident in the non-LBBB group., Conclusions: In minimally symptomatic patients with low ejection fraction and LBBB, CRT-ICD is cost effective within 4-year horizon when compared to ICD-only., (© 2012 Wiley Periodicals, Inc.)

Aims: We aimed to evaluate the influence of left ventricular (LV) lead position on the risk of ventricular tachyarrhythmias in cardiac resynchronization therapy (CRT) patients., Methods and Results: Left ventricular (LV) lead position was evaluated by biplane coronary venograms and anterior/posterior, lateral chest X-rays in patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial - Cardiac Resynchronization Therapy (MADIT-CRT). The LV lead location could be defined in 797 of 1089 patients (73%). The LV lead was placed at the LV apex in 110 (14%) patients, in the anterior position in 146 (18%), in the lateral position in 448 (56%), and in the posterior position in 93 (12%) patients. After adjustment for clinical covariates, lateral or posterior lead location was associated with significantly lower risk of ventricular tachycardia (VT)/ventricular fibrillation (VF) [hazard ratio (HR) = 0.57, 95% confidence interval (CI): 0.38-0.85; P = 0.006] when compared with an anterior lead location. Patients with anterior lead position had similar risk of VT/VF as patients with implantable cardioverter defibrillator (ICD)-only (HR = 1.04, 95% CI: 0.72-1.81; P = 0.837). There was no difference in the risk of mortality between posterior or lateral and anterior LV lead locations., Conclusion: Cardiac resynchronization therapy with posterior or lateral LV lead position is associated with decreased risk of arrhythmic events in comparison with anterior lead location and ICD-only patients. There is no evidence for increased risk of VT/VF episodes associated with CRT.

Background: The implantable cardioverter-defibrillator (ICD) is highly effective in reducing mortality among patients at risk for fatal arrhythmias, but inappropriate ICD activations are frequent, with potential adverse effects., Methods: We randomly assigned 1500 patients with a primary-prevention indication to receive an ICD with one of three programming configurations. The primary objective was to determine whether programmed high-rate therapy (with a 2.5-second delay before the initiation of therapy at a heart rate of ≥200 beats per minute) or delayed therapy (with a 60-second delay at 170 to 199 beats per minute, a 12-second delay at 200 to 249 beats per minute, and a 2.5-second delay at ≥250 beats per minute) was associated with a decrease in the number of patients with a first occurrence of inappropriate antitachycardia pacing or shocks, as compared with conventional programming (with a 2.5-second delay at 170 to 199 beats per minute and a 1.0-second delay at ≥200 beats per minute)., Results: During an average follow-up of 1.4 years, high-rate therapy and delayed ICD therapy, as compared with conventional device programming, were associated with reductions in a first occurrence of inappropriate therapy (hazard ratio with high-rate therapy vs. conventional therapy, 0.21; 95% confidence interval [CI], 0.13 to 0.34; P<0.001; hazard ratio with delayed therapy vs. conventional therapy, 0.24; 95% CI, 0.15 to 0.40; P<0.001) and reductions in all-cause mortality (hazard ratio with high-rate therapy vs. conventional therapy, 0.45; 95% CI, 0.24 to 0.85; P=0.01; hazard ratio with delayed therapy vs. conventional therapy, 0.56; 95% CI, 0.30 to 1.02; P=0.06). There were no significant differences in procedure-related adverse events among the three treatment groups., Conclusions: Programming of ICD therapies for tachyarrhythmias of 200 beats per minute or higher or with a prolonged delay in therapy at 170 beats per minute or higher, as compared with conventional programming, was associated with reductions in inappropriate therapy and all-cause mortality during long-term follow-up. (Funded by Boston Scientific; MADIT-RIT ClinicalTrials.gov number, NCT00947310.).

Objectives: This study compared the quality of life (QOL) of patients with cardiac resynchronization therapy (CRT) and an implantable cardioverter-defibrillator (ICD) to patients with an ICD only., Background: CRT with ICD is associated with a reduction in heart failure risk among minimally symptomatic patients. It is unknown whether this improves QOL., Methods: This study uses the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) data. The MADIT-CRT enrolled 1,820 patients at 110 centers across 14 countries. Patients had ischemic cardiomyopathy (New York Heart Association [NYHA] functional class I or II) or nonischemic cardiomyopathy (NYHA functional class II only), sinus rhythm, an ejection fraction of 30% or less, and prolonged intraventricular conduction with a QRS duration of 130 ms or more. QOL was evaluated on the 1,699 patients with baseline and follow-up measures using the Kansas City Cardiomyopathy Questionnaire (KCCQ). Six dimensions (Physical Limitation, Symptom Stability, Symptom Frequency, Symptom Burden, Quality of Life, and Social Limitations) and 3 summary scores (Total Symptom, Clinical Summary, and Overall Summary) were analyzed., Results: During an average follow-up of 2.4 years, the CRT-ICD group had greater improvement than the ICD-only group on all KCCQ measures (p < 0.05 on each scale). These differences were significant among patients with left bundle branch block conduction disturbance (n = 1,204, p < 0.01 on each scale), but not among patients without left bundle branch block (n = 494)., Conclusions: Compared with patients with ICD only, CRT-ICD is associated with greater improvement in QOL among relatively asymptomatic patients, specifically among those with left bundle branch conduction disturbance., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to evaluate the effect of cardiac resynchronization therapy with a defibrillator (CRT-D) on the risks of first and recurrent ventricular tachyarrhythmic events (VTEs) in the MADIT-CRT., Background: Reverse remodeling associated with CRT-D therapy was suggested to reduce arrhythmic risk. However, the effect of the device on the risk of recurrent VTEs among patients who experience a first arrhythmic event has not been investigated., Methods: The CRT-D versus defibrillator-only risks for first and subsequent fast VTEs (>180 beats/min) were assessed by Cox proportional hazards and Andersen-Gill proportional intensity regression modeling, respectively, in efficacy analyses recognizing active device-type during follow-up., Results: Multivariate analysis showed that CRT-D was associated with a significant 29% (p = 0.003) reduction in the risk of a first VTE, with a pronounced effect among patients with left bundle branch block (LBBB) (hazard ratio [HR]: 0.58; p < 0.001) and no significant effect among non-LBBB patients (HR: 1.05; p = 0.82, p for the difference = 0.02). Patients with LBBB who experienced a first VTE had no change in the risk of subsequent VTEs with CRT-D (HR: 0.98; p = 0.85). In contrast, the risk of recurrent VTEs with CRT-D was significantly increased among non-LBBB patients (HR: 3.62; p = 0.002, p for the difference = 0.009). Recurrent VTEs increased the risk of subsequent heart failure or death., Conclusions: In MADIT-CRT, active treatment with CRT-D was associated with a significant reduction in the risk of life-threatening VTEs. However, our findings suggest that CRT-D does not reduce the risk of subsequent VTEs in patients who experience a first arrhythmic event and may increase subsequent arrhythmic risk in non-LBBB patients. (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271)., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study hypothesized that time-dependent statin therapy will reduce the risk of life-threatening ventricular tachyarrhythmias among patients with nonischemic cardiomyopathy (NICM) enrolled in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy)., Background: Prior studies suggested that statin therapy exerts antiarrhythmic properties among patients with coronary artery disease. However, data regarding the effect of statins on arrhythmic risk among patients with NICM are limited., Methods: Multivariate Cox proportional hazards regression modeling was used to assess the effect of statin therapy, evaluated as a time-dependent covariate, on the risk of appropriate defibrillator therapy for fast ventricular tachycardia (VT) (defined as a rate faster than 180 beats/min)/ventricular fibrillation (VF) or death (primary endpoint) and appropriate defibrillator shocks (secondary endpoint) among 821 patients with NICM enrolled in the MADIT-CRT trial., Results: Statin users (n = 499) were older and had a higher prevalence of diabetes and hypertension yet were less frequently smokers. Multivariate analysis showed that time-dependent statin therapy was independently associated with a significant 77% reduction in the risk of fast VT/VF or death (p < 0.001) and with a significant 46% reduction in the risk of appropriate implantable cardioverter defibrillator shocks (p = 0.01). Consistent with these findings, the cumulative probability of fast VT/VF or death at 4 years of follow-up was significantly lower among patients who were treated with statins (11%) as compared with study patients who were not treated with statins (19%; p = 0.006 for the overall difference during follow-up)., Conclusions: Statin use was associated with a significant reduction in the risk of life-threatening ventricular tachyarrhythmias among patients with NICM., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The implantable cardioverter defibrillator (ICD) is highly effective in reducing mortality due to cardiac arrhythmias in high-risk cardiac patients. However, inappropriate therapies caused predominantly by supraventricular tachyarrhythmias (SVTs) remain a significant side effect of ICD therapy despite medical treatment, affecting 8-40% of patients. The MADIT-RIT is a global, prospective, randomized, nonblinded, three-arm, multicenter clinical investigation to be performed in the Unites States, Europe, Canada, Israel and Japan, and will utilize approximately 90 centers with plan to enroll 1500 patients programmed to three treatment arms. The objective of the MADIT-RIT trial is to determine if dual-chamber ICD or CRT-D devices with high rate cutoff (MADIT-RIT-Arm B) and/or long delay in combination with detection enhancements (MADIT-RIT-Arm C) are associated with fewer patients experiencing inappropriate therapies than standard programming (MADIT-RIT-Arm A) during postimplant follow-up of patients with indication for primary prevention device therapy. This paper describes design and analytic plan for the MADIT-RIT trial., (©2012, Wiley Periodicals, Inc.)

Background: We hypothesized that combined assessment of factors that are associated with favorable reverse remodeling after cardiac resynchronization-defibrillator therapy (CRT-D) can be used to predict clinical response to the device., Methods and Results: The study population comprised 1761 patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT). Best-subset regression analysis was performed to identify factors associated with echocardiographic response (defined as percent reduction in left ventricular end-diastolic volume 1 year after CRT-D implantation) and to create a response score. Cox proportional hazards regression analysis was used to evaluate the CRT-D versus defibrillator-only reduction in the risk of heart failure or death by the response score. Seven factors were identified as associated with echocardiographic response to CRT-D and made up the response score (female sex, nonischemic origin, left bundle-branch block, QRS ≥150 milliseconds, prior hospitalization for heart failure, left ventricular end-diastolic volume ≥125 mL/m(2), and left atrial volume <40 mL/m(2)). Multivariate analysis showed a 13% (P<0.001) increase in the clinical benefit of CRT-D per 1-point increment in the response score (range, 0-14) and a significant direct correlation between risk reduction associated with CRT-D and response score quartiles: Patients in the first quartile did not derive a significant reduction in the risk of heart failure or death with CRT-D (hazard ratio=0.87; P=0.52); patients in the second and third quartiles derived 33% (P=0.04) and 36% (P=0.03) risk reductions, respectively; and patients in the upper quartile experienced a 69% (P<0.001) risk reduction (P for trend=0.005)., Conclusion: Combined assessment of factors associated with reverse remodeling can be used for improved selection of patients for cardiac resynchronization therapy. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.

Objectives: The evaluation of the risk of recurring heart failure events (HFEs) was a pre-specified substudy of MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy)., Background: There are limited data regarding the effect of cardiac resynchronization therapy with a defibrillator (CRT-D) on the occurrence of recurring heart failure episodes after a first post-implantation HFE., Methods: Data with regard to recurring HFEs were prospectively collected for all 1,820 MADIT-CRT participants. The CRT-D versus defibrillator-only risk for nonfatal first- and subsequent-HFEs was assessed by Cox proportional hazards and Andersen-Gill proportional intensity regression modeling, respectively, in efficacy analyses recognizing active device-type during follow-up., Results: Multivariate analysis showed that CRT-D was associated with a significant reduction in the risk of a first HFE (hazard ratio [HR]: 0.54, 95% confidence interval [CI]: 0.44 to 0.67, p < 0.001) and with a similar magnitude of reduction in the risk of HFEs subsequent to a first post-enrollment event (HR: 0.62, 95% CI: 0.45 to 0.85, p = 0.003). The benefit of CRT-D for the prevention of first and subsequent HFEs was pronounced among patients with left bundle branch block (HR: 0.38, 95% CI: 0.29 to 0.49, p < 0.001; and HR: 0.50, 95% CI: 0.33 to 0.76, p = 0.001, respectively) and nonsignificant in non-left bundle branch block patients (HR: 1.12, 95% CI: 0.77 to 1.64, p = 0.55; and HR: 0.99, 95% CI: 0.58 to 1.69, p = 0.96, respectively; p values for interaction: p < 0.001 and p = 0.06, respectively). The occurrences of first and second HFEs were associated with 7- and nearly 19-fold respective increases in the risk of subsequent mortality., Conclusions: In the MADIT-CRT trial, the benefit of cardiac resynchronization therapy for the reduction in recurring HFEs was maintained after the occurrence of a first post-enrollment event. The occurrence of HFEs greatly increased the risk of death. (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy; NCT00180271)., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Despite benefits of cardiac resynchronization therapy (CRT) in patients with severe but less symptomatic heart failure, approximately 30% of patients do not fully respond to treatment. We hypothesized that a combined assessment of left ventricular (LV) dyssynchrony and contractile function by strain-based imaging would identify patients who would most benefit from CRT., Methods and Results: We studied 1077 patients with New York Heart Association class I/II, LV ejection fraction ≤30% and QRS width ≥130 ms enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy trial with sufficient echocardiographic image quality for cardiac deformation analysis (implantable cardioverter-defibrillator [ICD], n=416; CRT, n=661). Patients were assigned to CRT plus an ICD or to ICD alone in 3:2 random assignment. We assessed the degree to which baseline echocardiographic assessments of dyssynchrony, measured as the standard deviation of time-to-peak transverse strain over 12 segments, contractile function, measured as global longitudinal strain, or both predicted the effect of treatment on the primary outcome of death or heart failure. With 213 primary events occurring over a mean of 2.4 years, the benefit of CRT plus an ICD relative to ICD alone was greatest in patients with mild to moderate dyssynchrony (time-to-peak transverse strain standard deviation, 142 to 230 ms) and greater baseline contractile function (global longitudinal strain ≤-8.7%). Overall, those patients with mild to moderate dyssynchrony and those with best contractile function at baseline demonstrated the greatest benefit from CRT (adjusted hazards ratio, 0.20; 95% confidence interval, 0.09 to 0.44). Dyssynchrony and global longitudinal strain predicted response to CRT independent of each other, QRS width, LV ejection fraction, and presence versus absence of left bundle-branch block, although the observed benefit remained greatest in patients with left bundle-branch block., Conclusions: Both mechanical dyssynchrony and contractile function are important independent correlates of benefit from CRT., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.

Aims: To assess long-term effects of cardiac resynchronization therapy (CRT) on left ventricular (LV) dyssynchrony and contractile function, by two-dimensional speckle-tracking echocardiography, compared with implantable cardioverter defibrillator (ICD) only in MADIT-CRT., Methods and Results: We studied 761 patients in New York Heart Association I/II, ejection fraction ≤30%, and QRS ≥130 ms [n = 434, CRT-defibrillator (CRT-D), n = 327, ICD] with echocardiographic studies available at baseline and 12 months. Dyssynchrony was determined as the standard deviation of time to peak transverse strain between 12 segments of apical four- and two-chamber views, and contractile function as global longitudinal strain (GLS) by averaging longitudinal strain over these 12 segments. We compared changes in LV dyssynchrony and contractile function between treatment groups and assessed relationships between these changes over the first year and subsequent outcomes (median post 1-year follow-up = 14.9 months). Mean changes in LV dyssynchrony and contractile function measured by GLS in the overall population were, respectively, -29 ± 83 ms and -1 ± 2.9%. However, both LV dyssynchrony (CRT-D: -47 ± 83 ms vs. ICD: -6 ± 76 ms, P < 0.001) and contractile function (CRT-D: -1.4 ± 3.1% vs. ICD: -0.4 ± 2.5%, P < 0.001) improved to a greater extent in the CRT-D group compared with the ICD-only group. A greater improvement in dyssynchrony and contractile function at 1 year was associated with lower rates of the subsequent primary outcome of death or heart failure, adjusting for baseline dyssynchrony and contractile function, treatment arm, ischaemic status, and change in LV end-systolic volume. Each 20 ms decrease in LV dyssynchrony was associated with a 7% reduction in the primary outcome (P = 0.047); each 1% improvement in GLS over the 12-month period was associated with a 24% reduction in the primary outcome (P < 0.001)., Conclusion: Cardiac resynchronization therapy resulted in a significant improvement in both LV dyssynchrony and contractile function measured by GLS compared with ICD only and these improvements were associated with better subsequent outcomes.

Aims: Cardiac remodelling is a progressive process after myocardial infarction (MI). However, currently there are no data regarding the effect of s:elapsed time from MI on the benefit of cardiac resynchronization therapy with defibrillator (CRT-D). The present study was designed to evaluate the relationship between elapsed time from MI and the benefit of preventive CRT-D therapy in patients with ischaemic cardiomyopathy (ICM)., Methods and Results: The risk of heart failure (HF) or death as a function of elapsed time from MI to enrolment, by treatment with CRT-D vs. implantable cardioverter defibrillator (ICD)-only therapy, was assessed among 704 ICM patients with a documented MI enrolled in MADIT-CRT, and separately in a subset of ICM patients without a documented prior MI (n = 237). In ICD patients, the adjusted risk of HF or death increased by 4% (P = 0.01) for each year elapsed from MI. Multivariate analysis demonstrated that patients with remote MI [categorized at the median value (≥8 years)] derived a significantly greater benefit from CRT-D [HR = 0.42 (P < 0.001)] than those with a more recent MI [HR = 1.26 (P = 0.35); P-value for interaction <0.001]. Consistently, the benefit of CRT-D was directly related to increasing quartiles of elapsed time from MI [Q(1) (<3 years): HR = 1.67; P = 0.20, Q(2) (3-8 years): HR = 1.12; P = 0.71, Q(3) (8-15 years): HR = 0.47; P = 0.02, and Q(4) (≥15 years): HR = 0.38; P = 0.001]. The ICM subgroup with no documented MI also derived enhanced benefit from CRT-D (HR = 0.43; P = 0.003)., Conclusion: In patients with ischaemic cardiomyopathy, the risk of HF or death and the magnitude of CRT-D benefit are directly related to elapsed time from MI.

Aims: There are no data regarding the differential response to cardiac resynchronization therapy with defibrillator (CRT-D) by the aetiology of cardiomyopathy in mildly symptomatic patients. We evaluated the outcome of patients enrolled in MADIT-CRT by ischaemic and non-ischaemic aetiology of cardiomyopathy (ICM and non-ICM, respectively)., Methods and Results: The clinical response to CRT-D was assessed among ICM (n = 1046) and non-ICM (n = 774) patients enrolled in MADIT-CRT during an average follow-up of 2.4 years, and echocardiographic response was assessed at 1 year. Cardiac resynchronization therapy with defibrillator vs. ICD therapy was associated with respective 34% (P = 0.001) and 44% (P = 0.002) reductions in the risk of heart failure or death among ICM and non-ICM patients (P for interaction = 0.455). In the ICM group, CRT-D was associated with mean (±SD) 29 ± 14% and 18 ± 10% reductions in left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV), respectively. In the non-ICM group, CRT-D was associated with significantly greater volume reductions compared with the ICM group [37 ± 16% and 24 ± 12% reductions in LVESV and LVEDV, respectively (P < 0.001 for all)]. Risk subsets in the ICM group that showed a favourable clinical response to CRT-D included patients with QRS ≥150 ms, systolic blood pressure <115 mmHg, and left bundle branch block (LBBB), whereas in the non-ICM group females, patients with diabetes mellitus, and LBBB, displayed a favourable clinical response., Conclusion: Mildly symptomatic ICM and non-ICM patients show significant differences in the echocardiographic response to CRT-D and in the clinical benefit within risk subsets suggesting that risk assessment for CRT-D in this population should be aetiology-specific.

Background: Women with congenital long-QT syndrome experience an increased risk for cardiac events after the onset of adolescence that is more pronounced among carriers of the LQT2 genotype. We hypothesized that the hormonal changes associated with menopause may affect clinical risk in this population., Methods and Results: We used a repeated-events analysis to evaluate the risk for recurrent syncope during the menopause transition and postmenopausal periods (5 years before and after the age at onset of menopause, respectively) among 282 LQT1 (n=151) and LQT2 (n=131) women enrolled in the Long-QT Syndrome Registry. Multivariate analysis showed that the risk for recurrent syncope (n=150) among LQT2 women was significantly increased during both menopause transition (hazard ratio, 3.38; P=0.005) and the postmenopausal period (hazard ratio, 8.10; P<0.001) compared with the reproductive period. The risk increase was evident among women who did or did not receive estrogen therapy. In contrast, among LQT1 women, the onset of menopause was associated with a reduction in the risk for recurrent syncope (hazard ratio, 0.19; P=0.05; P=0.02 for genotype-by-menopause interaction). Only 22 women (8%) experienced aborted cardiac arrest or sudden cardiac death during follow-up. The frequency of aborted cardiac arrest/sudden cardiac death showed a similar genotype-specific association with the onset of menopause., Conclusions: The onset of menopause is associated with a significant increase in the risk of cardiac events (dominated by recurrent episodes of syncope) in LQT2 women, suggesting that careful follow-up and continued long-term therapy are warranted in this population.

Although rare, osteosarcoma is an aggressive cancer that often metastasizes to the lungs. Toward the goal of developing new treatment options for osteosarcoma, we show that the cyclin-dependent kinase (CDK) inhibitor SCH 727965 (SCH) induces the apoptosis of several osteosarcoma cell lines including those resistant to doxorubicin and dasatinib. Cell lines prepared in our laboratory from patients who had received adjuvant chemotherapy and explants derived from a human osteosarcoma xenograft in mice were also responsive to SCH. Apoptosis occurred at low nanomolar concentrations of SCH, as did CDK inhibition, and was p53-independent. SCH activated the mitochondrial pathway of apoptosis as evidenced by caspase-9 cleavage and accumulation of cytoplasmic cytochrome c. Amounts of the apoptotic proteins Bax and Bim increased in mitochondria, whereas amounts of the antiapoptotic proteins Mcl-1 and Bcl-x(L) declined. Osteosarcoma cells apoptosed when codepleted of CDK1 and CDK2 but not when depleted of other CDK combinations. We suggest that SCH triggers the apoptosis of osteosarcoma cells by inactivating CDK1 and CDK2 and that SCH may be useful for treatment of drug-resistant osteosarcomas. SCH also induced the apoptosis of other sarcoma types but not of normal quiescent osteoblasts or fibroblasts.

Background: This study aimed to determine whether QRS morphology identifies patients who benefit from cardiac resynchronization therapy with a defibrillator (CRT-D) and whether it influences the risk of primary and secondary end points in patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) trial., Methods and Results: Baseline 12-lead ECGs were evaluated with regard to QRS morphology. Heart failure event or death was the primary end point of the trial. Death, heart failure event, ventricular tachycardia, and ventricular fibrillation were secondary end points. Among 1817 patients with available sinus rhythm ECGs at baseline, there were 1281 (70%) with left bundle-branch block (LBBB), 228 (13%) with right bundle-branch block, and 308 (17%) with nonspecific intraventricular conduction disturbances. The latter 2 groups were defined as non-LBBB groups. Hazard ratios for the primary end point for comparisons of CRT-D patients versus patients who only received an implantable cardioverter defibrillator (ICD) were significantly (P < 0.001) lower in LBBB patients (0.47; P < 0.001) than in non-LBBB patients (1.24; P = 0.257). The risk of ventricular tachycardia, ventricular fibrillation, or death was decreased significantly in CRT-D patients with LBBB but not in non-LBBB patients. Echocardiographic parameters showed significantly (P < 0.001) greater reduction in left ventricular volumes and increase in ejection fraction with CRT-D in LBBB than in non-LBBB patients., Conclusions: Heart failure patients with New York Heart Association class I or II and ejection fraction ≤ 30% and LBBB derive substantial clinical benefit from CRT-D: a reduction in heart failure progression and a reduction in the risk of ventricular tachyarrhythmias. No clinical benefit was observed in patients with a non-LBBB QRS pattern (right bundle-branch block or intraventricular conduction disturbances)., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.

Objectives: The purpose of this study was to investigate the factors related to sex-specific outcomes for death and heart failure events in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) trial., Background: In the MADIT-CRT trial, women seemed to achieve a better result from resynchronization therapy than men., Methods: All 1,820 patients (453 female and 1,367 male) enrolled in the MADIT-CRT trial were included in this sex-specific outcome analysis that compared the effect of cardiac resynchronization therapy with defibrillator (CRT-D) relative to implanted cardioverter-defibrillator (ICD) on death or heart failure (whichever came first), heart failure only, and death at any time., Results: Female patients were more likely to have nonischemic cardiomyopathy and left bundle branch block and less likely to have renal dysfunction than male patients. Overall, female patients had a better result from CRT-D therapy than male patients, with a significant 69% reduction in death or heart failure (hazard ratio: 0.31, p < 0.001) and 70% reduction in heart failure alone (hazard ratio: 0.30, p < 0.001). Women had a significant 72% reduction in all-cause mortality in the total population (hazard ratio: 0.28, p = 0.02) and significant 82% and 78% reductions in mortality in those with QRS ≥ 150 ms and with left bundle branch block conduction disturbance, respectively, with sex-by-treatment interactions for mortality reduction significant at p < 0.05 in each of these 3 patient groups. These beneficial CRT-D effects among women were associated with consistently greater echocardiographic evidence of reverse cardiac remodeling in women than in men., Conclusions: Women in the MADIT-CRT trial obtained significantly greater reductions in death or heart failure (whichever came first), heart failure alone, and all-cause mortality with CRT-D therapy than men, with consistently greater echocardiographic evidence of reverse cardiac remodeling in women than in men. (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271)., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Coronary revascularization (CR) may confer electrical stability in patients with ischemic cardiomyopathy. However, data regarding the effect of CR on the development of ventricular tachyarrhythmias in this population are limited., Objective: The purpose of this study was to evaluate the association between CR and arrhythmic risk in postmyocardial infarction (post-MI) patients with left ventricular dysfunction., Methods: The risk for life-threatening ventricular tachyarrhythmias (defined as a first appropriate defibrillator therapy for ventricular tachycardia [VT]/ventricular fibrillation [VF] or death) was compared between post-MI patients with and those without prior CR (n = 612 and 147, respectively) enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT)., Results: The 3-year cumulative rate of VT/VF or death was significantly higher among patients without prior CR (42%) than in patients who underwent prior CR (32%, P = .02). Multivariate analysis demonstrated that patients without prior CR had 48% increased risk (P = .01) for VT/VF or death. Risk reduction associated with CR was related to elapsed time from CR, assessed both as a categorical variable (tertiles for time from CR: ≥7 years, hazard ratio [HR] = 1.93, P = .001; 1.5-7 years, HR = 1.70, P = .01 vs <1.5 years) and as a continuous measure (4%, P = .002, increased risk for VT/VF or death per 1-year increment of elapsed time from CR). The effect of CR on arrhythmic risk was similar in patients treated with a defibrillator alone or when combined with cardiac resynchronization therapy., Conclusion: Post-MI patients with left ventricular dysfunction who undergo CR experience a time-dependent reduction in the risk for subsequent life-threatening ventricular tachyarrhythmias., (Copyright © 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: The Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) showed a significant 31 reduction in the risk of death with primary implantable cardioverter-defibrillator (ICD) therapy during a median follow-up of 1.5 years. However, currently there are no data on the long-term efficacy of primary defibrillator therapy., Methods and Results: MADIT-II enrolled 1232 patients with ischemic left ventricular dysfunction who were randomized to ICD and non-ICD medical therapy and were followed up through November 2001. For the present long-term study, we acquired posttrial mortality data through March 2009 for all study participants (median follow-up, 7.6 years). Multivariate Cox proportional hazards regression modeling was performed to calculate the hazard ratio for ICD versus non-ICD therapy during long-term follow-up. At 8 years of follow-up, the cumulative probability of all-cause mortality was 49 among patients treated with an ICD compared with 62 among non-ICD patients (P<0.001). Multivariate analysis demonstrated that ICD therapy was associated with a significant long-term survival benefit (hazard ratio for 0- through 8-year mortality=0.66 [95 confidence interval, 0.56 to 0.78]; P<0.001). Treatment with an ICD was shown to be associated with a significant reduction in the risk of death during the early phase of the extended follow-up period (0 through 4 years: hazard ratio=0.61 [95 confidence interval, 0.50 to 0.76]; P<0.001) and with continued life-saving benefit during the late phase of follow-up (5 through 8 years: hazard ratio=0.74 [95 confidence interval, 0.57 to 0.96]; P=0.02)., Conclusions: Our findings demonstrate a sustained 8-year survival benefit with primary ICD therapy in the MADIT-II population.

Rationale: Despite the importance of bronchiolitis obliterans syndrome (BOS) in lung transplantation, little is known regarding the factors that influence survival after the onset of this condition, particularly among bilateral transplant recipients., Objectives: To identify factors that influence survival after the onset of BOS among bilateral lung transplant recipients., Methods: The effect of demographic or clinical factors, occurring before BOS, upon survival after the onset of BOS was studied in 95 bilateral lung transplant recipient using Cox proportional hazards models., Measurements and Main Results: Although many factors, including prior acute rejection or rejection treatments, were not associated with survival after BOS, BOS onset within 2 years of transplantation (early-onset BOS), or BOS onset grade of 2 or 3 (high-grade onset) were predictive of significantly worse survival (early onset P = 0.04; hazard ratio, 1.84; 95% confidence interval, 1.03-3.29; high-grade onset P = 0.003; hazard ratio, 2.40; 95% confidence interval, 1.34-4.32). The effects of both early onset and high-grade onset on survival persisted in multivariable analysis and after adjustment for concurrent treatments. Results suggested an interaction might exist between early onset and high-grade onset. In particular, high-grade onset of BOS, regardless of its timing after transplant, is associated with a very poor prognosis., Conclusions: The course of BOS after bilateral lung transplantation is variable. Distinct patterns of survival after BOS are evident and related to timing or severity of onset. Further characterization of these subgroups should provide a more rational basis from which to design, stratify, and assess response in future BOS treatment trials.

Background: Cardiac resynchronization therapy (CRT) plus implantation of an implantable cardioverter defibrillator (ICD) reduced the risk of death or heart failure event in patients with mildly symptomatic heart failure, left ventricular dysfunction, and wide QRS complex compared with an ICD only. We assessed echocardiographic changes in patients enrolled in the MADIT-CRT trial (Multicenter Automatic Defibrillator Implantation Trial: Cardiac Resynchronization Therapy) to evaluate whether the improvement in outcomes with CRT plus an ICD was associated with favorable alterations in cardiac size and function., Methods and Results: A total of 1,820 patients were randomly assigned to CRT plus an ICD or to an ICD only in a 3:2 ratio. Echocardiographic studies were obtained at baseline and 12 months later in 1,372 patients. We compared changes in cardiac size and performance between treatment groups and assessed the relationship between these changes over the first year, as well as subsequent outcomes. Compared with the ICD-only group, the CRT-plus-ICD group had greater improvement in left ventricular end-diastolic volume index (-26.2 versus -7.4 mL/m(2)), left ventricular end-systolic volume index (-28.7 versus -9.1 mL/m(2)), left ventricular ejection fraction (11% versus 3%), left atrial volume index (-11.9 versus -4.7 mL/m(2)), and right ventricular fractional area change (8% versus 5%; P<0.001 for all). Improvement in end-diastolic volume at 1 year was predictive of subsequent death or heart failure, with adjustment for baseline covariates and treatment group; each 10% decrease in end-diastolic volume was associated with a 40% reduction in risk (P<0.001)., Conclusions: CRT resulted in significant improvement in cardiac size and performance compared with an ICD-only strategy in patients with mildly symptomatic heart failure. Improvement in these measures accounted for the outcomes benefit. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.

Rationale: Cytomegalovirus pneumonitis is one of the most prevalent opportunistic infections after lung transplantation. Early studies reported that cytomegalovirus pneumonitis was a risk factor for chronic allograft dysfunction. More recently, in the era of routine prophylaxis and ganciclovir treatment, the adverse impact of treated cytomegalovirus pneumonitis on bronchiolitis obliterans syndrome has been challenged., Objectives: We hypothesized that cytomegalovirus pneumonitis contributes to adverse outcomes in the current antiviral era. We sought to define the impact of treated cytomegalovirus pneumonitis on bronchiolitis obliterans syndrome and survival in a large single-center cohort (n = 231) of consecutive patients undergoing lung transplantation from 2000 to 2004, all receiving short-course ganciclovir prophylaxis., Methods: Transbronchial biopsies were performed at defined intervals with prospective cytomegalovirus immunostaining on every biopsy (n = 1,887). Cox proportional hazards models were used to assess the relationship between treated cytomegalovirus pneumonitis and clinical outcomes., Measurements and Main Results: Forty-nine (21%) recipients developed cytomegalovirus pneumonitis a median of 106 days after transplantation. Treated cytomegalovirus pneumonitis within the first 6 months after transplantation significantly increased the risk for bronchiolitis obliterans syndrome (P = 0.001; hazard ratio, 2.19; 95% confidence interval, 1.36-3.51) and post-transplantation death (P = 0.02; hazard ratio, 1.89; 95% confidence interval, 1.11-3.23). This risk persisted when cytomegalovirus pneumonitis was considered as a time-dependent predictor as well as in multivariable models controlling for other risk factors., Conclusions: Cytomegalovirus pneumonitis affects more than 20% of lung transplant recipients. Despite treatment, it increases the risk for bronchiolitis obliterans syndrome and death. More effective preventive strategies for cytomegalovirus pneumonitis are needed to improve long-term outcomes after lung transplantation.

No vaccine exists for the prevention of infection with the ubiquitous gastric pathogen Helicobacter pylori, and drug therapy for the infection is complicated by poor patient compliance, the high cost of treatment, and ineffectiveness against drug-resistant strains. A new medical advancement is required to reduce the incidence of peptic ulcer disease and stomach cancer, two conditions caused by infection with H. pylori. Clinical trials have been performed with a formalin-inactivated H. pylori whole cell (HWC) vaccine, given orally in combination with the mucosal adjuvant mLT(R192G), a mutant of Escherichia coli heat-labile toxin. Following the initial dose of this vaccine, some subjects experienced gastrointestinal side effects. To reduce side effects and potentially further increase the amount of adjuvant that can safely be administered with the HWC vaccine, experiments were performed with a form of LT that carried two mutations in the A subunit, a substitution of G for R at position 192, and A for L at position 211. The double mutant LT (dmLT) adjuvant stimulated immune responses as effectively as the single mutant LT in mice. Additionally, following a challenge infection, the dmLT-adjuvanted vaccine was as effective as single mutant LT in reducing gastric urease levels (diagnostic for H. pylori infection), and H. pylori colonization in the stomach as assessed by quantitative analysis of stomach homogenates. A lyophilized formulation of HWC was developed to improve stability and to potentially reduce reliance on cold chain maintenance. It was observed that a dmLT-adjuvanted lyophilized vaccine was equally as protective in the mouse model as the liquid formulation as assessed by gastric urease analysis and analysis of stomach homogenates for viable H. pylori. No readily detectable effect of tonicity or moisture content was observed for the lyophilized vaccine within the formulation limits evaluated. In an accelerated stability study performed at 37 degrees C the lyophilized vaccine remained equally as protective as vaccine stored at 2-8 degrees C. The formulation selected for clinical development consisted of 2.5 x 10(10) formalin-inactivated cells per ml in 6.5% trehalose, 0.5% mannitol, and 10mM citrate buffer at pH 6.8., ((c) 2009 Elsevier Ltd. All rights reserved.)