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Mitochondrial and thus cellular energetics are highly regulated both thermodynamically and kinetically. Cellular energetics is of prime importance in the regulation of cellular functions since it provides ATP for their accomplishment. However, cellular energetics is not only about ATP production but also about the ability to re-oxidize reduced coenzymes at a proper rate, such that the cellular redox potential remains at a level compatible with enzymatic reactions. However, this parameter is not only difficult to assess due to its dual compartmentation (mitochondrial and cytosolic) but also because it is well known that most NADH in the cells is bound to the enzymes. In this paper, we investigated the potential relevance of mitochondrial quinones redox state as a marker of mitochondrial metabolism and more particularly mitochondrial redox state. We were able to show that Q 2 is an appropriate redox mediator to assess the mitochondrial quinone redox states. On isolated mitochondria, the mitochondrial quinone redox states depend on the mitochondrial substrate and the mitochondrial energetic state (phosphorylating or not phosphorylating). Last but not least, we show that the quinones redox state response allows to better understand the Krebs cycle functioning and respiratory substrates oxidation. Taken together, our results suggest that the quinones redox state is an excellent marker of mitochondrial metabolism., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objective: We examined the frequency and categories of end-of-life care transitions among assisted living community decedents and their associations with state staffing and training regulations., Design: Cohort study., Setting and Participants: Medicare beneficiaries who resided in assisted living facilities and had validated death dates in 2018-2019 (N = 113,662)., Methods: We used Medicare claims and assessment data for a cohort of assisted living decedents. Generalized linear models were used to examine the associations between state staffing and training requirements and end-of-life care transitions. The frequency of end-of-life care transitions was the outcome of interest. State staffing and training regulations were the key covariates. We controlled for individual, assisted living, and area-level characteristics., Results: End-of-life care transitions were observed among 34.89% of our study sample in the last 30 days before death, and among 17.25% in the last 7 days. Higher frequency of care transitions in the last 7 days of life was associated with higher regulatory specificity of licensed [incidence risk ratio (IRR) = 1.08; P = .002] and direct care worker staffing (IRR = 1.22; P < .0001). Greater regulatory specificity of direct care worker training (IRR = 0.75; P < .0001) was associated with fewer transitions. Similar associations were found for direct care worker staffing (IRR = 1.15; P < .0001) and training (IRR = 0.79; P < .001) and transitions within 30 days of death., Conclusions and Implications: There were significant variations in the number of care transitions across states. The frequency of end-of-life care transitions among assisted living decedents during the last 7 or 30 days of life was associated with state regulatory specificity for staffing and staff training. State governments and assisted living administrators may wish to set more explicit guidelines for assisted living staffing and training to help improve end-of-life quality of care., (Copyright © 2023 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: To facilitate the development of new therapies for Prader-Willi syndrome (PWS), we sought to develop a reliable and valid assessment of anxiousness and distress, common characteristics that have a significant negative impact on individuals with PWS and their families., Methods: The PWS Anxiousness and Distress Behaviors Questionnaire (PADQ) was developed with extensive input from clinical experts, as well as caregivers of individuals with PWS, who participated in iterative sets of qualitative interviews. The psychometric properties of the PADQ were subsequently demonstrated in a cross-sectional evaluation using data from the Global PWS Registry provided by > 400 caregivers and confirmed using data from a phase 3 clinical trial of an oxytocin analogue (intranasal carbetocin, LV-101)., Results: Qualitative interview participants consistently endorsed the content of the PADQ and were confident they could accurately respond to each item based on their observations of their child's behavior. Analysis of cross-sectional data supported the computation of a total PADQ score, as well as the reliability and validity of the measure. The results of analyses using longitudinal clinical trial data confirmed these properties and provided evidence for the responsiveness of the PADQ, further supporting its appropriateness for the evaluation of new treatments targeting anxiousness and distress in PWS., Conclusions: The current body of evidence supports the conclusion that the PADQ measures observable behaviors that are meaningful to patients and their families and provides a valid and reliable method to assess beneficial treatment effects for some of the most challenging behaviors associated with PWS., (Copyright © 2022 International Society for Pharmacoeconomics and Outcomes Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Accurate prognostication of stroke may help in appropriate therapy and rehabilitation planning. In the past few years, several machine learning (ML) algorithms were applied for prediction of stroke outcomes. We aimed to examine the performance of machine learning-based models for the prediction of mortality after stroke, as well as to identify the most prominent factors for mortality., Materials and Methods: We searched MEDLINE/PubMed and Web of Science databases for original publications on machine learning applications in stroke mortality prediction, published between January 1, 2011, and October 27, 2022. Risk of bias and applicability were evaluated using the tailored QUADAS-2 tool., Results: Of the 1015 studies retrieved, 28 studies were included. Twenty-Five studies were retrospective. The ML models demonstrated a favorable range of AUC for mortality prediction (0.67-0.98). In most of the articles, the models were applied for short-term post stroke mortality. The number of explanatory features used in the models to predict mortality ranged from 5 to 200, with substantial overlap in the variables included. Age, high BMI and high NIHSS score were identified as important predictors for mortality. Almost all studies had a high risk of bias in at least one category and concerns regarding applicability., Conclusion: Using machine learning, data available at the time of admission may aid in stroke mortality prediction. Notwithstanding, current research is based on few preliminary works with high risk of bias and high heterogeneity. Thus, future prospective, multicenter studies with standardized reports are crucial to firmly establish the usefulness of the algorithms in stroke prognostication., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The number of patients with primary cutaneous lymphoma (PCL) relative to other non-Hodgkin lymphomas (NHLs) is small and the number of subtypes large. Although clinical trial guidelines have been published for mycosis fungoides/Sézary syndrome, the most common type of PCL, none exist for the other PCLs. In addition, staging of the PCLs has been evolving based on new data on potential prognostic factors, diagnosis, and assessment methods of both skin and extracutaneous disease and a desire to align the latter with the Lugano guidelines for all NHLs. The International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous LymphomaConsortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organization for the Research and Treatment of Cancer (EORTC) now propose updated staging and guidelines for the study design, assessment, endpoints, and response criteria in clinical trials for all the PCLs in alignment with that of the Lugano guidelines. These recommendations provide standardized methodology that should facilitate planning and regulatory approval of new treatments for these lymphomas worldwide, encourage cooperative investigator-initiated trials, and help to assess the comparative efficacy of therapeutic agents tested across sites and studies., (© 2022 by The American Society of Hematology.)

Objective: The relation between respiratory symptoms and the range of tobacco product use among US adolescents/young adults is not yet clear. This cross-sectional analysis examines tobacco product use and respiratory symptoms in a nationally representative sample of 21,057 adolescents/young adults aged 12-24 years from Wave 4 (2016-17) of the Population Assessment of Tobacco and Health Study., Methods: Presence of functionally important respiratory symptoms was defined by questions regarding wheezing and nighttime cough at a cutoff score associated with poorer functional health status. Past-30-day tobacco use was analyzed 2 ways: never-tobacco users (reference) versus combustible users, noncombustible-only users, and former users; or frequency of use of cigarettes and/or e-cigarettes. Weighted Poisson regression adjusted for past-30-day marijuana use, secondhand smoke exposure, and asthma., Results: Functionally important respiratory symptoms were present in 10.0% overall: 13.8% of combustible users, 9.0% of noncombustible users, 8.2% of noncurrent users and 9.7% of never users. Functionally important respiratory symptoms were associated with combustible tobacco use (relative risk [RR] = 1.52[95% CI 1.29, 1.80]), marijuana use (RR = 1.54[1.34, 1.77]) and secondhand smoke exposure (RR = 1.04[1.03, 1.05]). Higher cigarette smoking frequency was also associated with functionally important respiratory symptoms for frequency categories >14 days/month (eg, RR = 1.93[1.50, 2.49] for 15-29 days/month). Frequency of e-cigarette use was not associated with functionally important respiratory symptoms., Conclusions: During 2016-17, smoking cigarettes, marijuana use, and secondhand smoke exposure were cross-sectionally associated with functionally important respiratory symptoms in adolescents/young adults. Risk increased with increased frequency of cigarette use but not e-cigarette use. Given changes to contemporary e-cigarettes and use, findings may not generalize to newer products., (Copyright © 2022 Academic Pediatric Association. All rights reserved.)

Assisted living (AL) has existed in the United States for decades, evolving in response to older adults' need for supportive care and distaste for nursing homes and older models of congregate care. AL is state-regulated, provides at least 2 meals a day, around-the-clock supervision, and help with personal care, but is not licensed as a nursing home. The key constructs of AL as originally conceived were to provide person-centered care and promote quality of life through supportive and responsive services to meet scheduled and unscheduled needs for assistance, an operating philosophy emphasizing resident choice, and a residential environment with homelike features. As AL has expanded to constitute half of all long-term care beds, the increasing involvement of the real estate, hospitality, and health care sectors has raised concerns about the variability of AL, the quality of AL, and standards for AL. Although the intent to promote person-centered care and quality of life has remained, those key constructs have become mired under tensions related to models of AL, regulation, financing, resident acuity, and the workforce. These tensions have resulted in a model of care that is not as intended, and which must be reimagined if it is to be an affordable care option truly providing quality, person-centered care in a suitable environment. Toward that end, 25 stakeholders representing diverse perspectives conferred during 2 half-day retreats to identify the key tensions in AL and discuss potential solutions. This article presents the background regarding those tensions, as well as potential solutions that have been borne out, paving the path to a better future of assisted living., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: In nursing homes (NHs), psychoactive medication use has received notable attention, but less is known about prescribing in assisted living (AL). This study examined how antipsychotic and antianxiety medication prescribing in AL compares with NHs., Design: Observational, cross-sectional AL data linked to publicly reported NH measures., Setting and Participants: Random sample of 250 AL communities and the full sample of 3371 NHs in 7 states., Methods: We calculated the percentage of residents receiving antipsychotics and antianxiety medications. For each AL community, we calculated the distance to NHs in the state. Linear models estimated the relationship between AL prescribing and that of the closest and farthest 5 NHs, adjusting for AL characteristics and state fixed effects., Results: The prescribing rate of potentially inappropriate antipsychotics (i.e., excluding for persons with recorded schizophrenia and Tourette syndrome) and of antianxiety medications (excluding for those on hospice) in AL was 15% and 21%, respectively. Unadjusted mean antipsychotic prescribing rates were nominally higher in AL than NHs (14.8% vs 14.6%; P = .056), whereas mean antianxiety prescribing was nominally lower in AL (21.2% vs 22.6%; P = .032). In adjusted analyses, AL rates of antipsychotic use were not associated with NH rates. However, being affiliated with an NH was associated with a lower rate of antipsychotic use [b = -0.03; 95% confidence interval (CI) -0.50 to -0.001; P = .043], whereas antianxiety rates were associated with neighboring NHs' prescribing rates (b = 0.43; 95% CI 0.16-0.70; P = .002)., Conclusions and Implications: This study suggests reducing antipsychotic medication use in NHs may influence AL practices in a way not accounted for by local NH patterns. And, because antianxiety medications have not been the focus of national campaigns, they may be more subject to local prescribing behaviors. It seems advantageous to consider prescribing in AL when efforts are implemented to change NH prescribing, as there seems to be related influence whether by affiliation or region., (Published by Elsevier Inc.)

Introduction: Squamous cell carcinoma (SCC) and extramammary Paget's Disease (EMPD) of the scrotum are exceedingly rare. Given their propensity for local invasion and treatment with wide local excision, they can be highly morbid conditions. Outcomes of Mohs Micrographic Surgery (MMS) for scrotal cutaneous malignancy is not well described in current literature. We hypothesized that MMS for scrotal cutaneous malignancy would provide equivalent or improved oncologic outcomes while limiting the morbidity associated with wide excision., Materials/methods: This is a retrospective review and analysis of a prospectively maintained database spanning entries from 2005 to 2019. Collected data included general patient characteristics and surgical characteristics reported on a per lesion basis. MMS was performed by our institution's department of dermatology using their standard technique., Results: Overall, a total of 26 consecutive patients with 28 lesions (SCC or EMPD) were analyzed. Out of our cohort of 15 patients with 16 scrotal SCC lesions, 10 (66%) patients were current or former smokers, 4 (26%) were immunosuppressed, and 2 (13%) had HPV infections. The median preoperative and postoperative size of SCC lesions were 5.7cm [2] and 20.2cm [2] respectively. There was one (6%) oncologic recurrence of SCC of the scrotum and one (6%) local wound complication. Our cohort also included 11 patients with 12 scrotal EMPD lesions. One patient (9%) had an underlying associated malignancy (prostate cancer). The preoperative and postoperative area of lesions were 50.6cm [2] and 96.4cm [2] respectively. One (9%) EMPD lesion had a positive final margin at resection requiring reoperation. After achieving negative surgical margins, no patients in this cohort had an oncologic recurrence. 3 (26%) scrotal EMPD cases had local wound postoperative complications, only one required reoperation., Conclusion: To our knowledge, this is the first case series focused on MMS for both SCC and EMPD with scrotal involvement. Our data suggests that MMS for scrotal cutaneous malignancy may improve oncologic outcomes and may decreases local post-operative reconstructive issues when compared to reported outcomes of treatment with wide local excision. When able, scrotal cutaneous malignancy patients should be referred to urologists at centers with MMS capabilities as it likely will improve their outcomes. The urologist should maintain active involvement with these patients to coordinate this complex and advanced pattern of care., Competing Interests: Conflicts of Interest No relevant conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: The objective of the study is to present the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) conceptual approach to the assessment of certainty of evidence from modeling studies (i.e., certainty associated with model outputs)., Study Design and Setting: Expert consultations and an international multidisciplinary workshop informed development of a conceptual approach to assessing the certainty of evidence from models within the context of systematic reviews, health technology assessments, and health care decisions. The discussions also clarified selected concepts and terminology used in the GRADE approach and by the modeling community. Feedback from experts in a broad range of modeling and health care disciplines addressed the content validity of the approach., Results: Workshop participants agreed that the domains determining the certainty of evidence previously identified in the GRADE approach (risk of bias, indirectness, inconsistency, imprecision, reporting bias, magnitude of an effect, dose-response relation, and the direction of residual confounding) also apply when assessing the certainty of evidence from models. The assessment depends on the nature of model inputs and the model itself and on whether one is evaluating evidence from a single model or multiple models. We propose a framework for selecting the best available evidence from models: 1) developing de novo, a model specific to the situation of interest, 2) identifying an existing model, the outputs of which provide the highest certainty evidence for the situation of interest, either "off-the-shelf" or after adaptation, and 3) using outputs from multiple models. We also present a summary of preferred terminology to facilitate communication among modeling and health care disciplines., Conclusion: This conceptual GRADE approach provides a framework for using evidence from models in health decision-making and the assessment of certainty of evidence from a model or models. The GRADE Working Group and the modeling community are currently developing the detailed methods and related guidance for assessing specific domains determining the certainty of evidence from models across health care-related disciplines (e.g., therapeutic decision-making, toxicology, environmental health, and health economics)., (Copyright © 2020. Published by Elsevier Inc.)

Sleep loss is a widespread phenomenon and a public health threat. Sleep disorders, medical conditions, lifestyles, and occupational factors all contribute to insufficient sleep. Regardless of the underlying cause, insufficient sleep has well-defined consequences and the severity of said consequences partially influenced by individual characteristics. It is here where precision medicine needs to understand and define sleep insufficiency in hopes for personalizing medical approach to improve patient outcomes. Following a discussion on causes and consequences of sleep loss, this article discusses tools for assessing sleep sufficiency, mitigating strategies to sleep loss, and sleep loss in the context of fatigue management., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Anatomic assessment of the medial upper arm to identify potential sites for insertion of the etonogestrel (ENG) implant., Study Design: Forty female cadaveric arms were dissected. Two rows of 1×2-cm dissection windows were created in the inner arm overlying the triceps approximately 2-3 and 4-5 cm posterior to the bicipital sulcus (sulcus). The primary window was 8-10 cm proximal to the medial epicondyle and approximately 2-3 cm posterior to the sulcus. Neurovascular structures within each window were identified. The entire medial upper arm was dissected to visualize underlying structures., Results: Mean age (± SD) of cadavers at death was 72.0±11.0 years. Arm measurements at the primary window were circumference 28.2±4.8 cm [range: 21-41], skin thickness 0.6±0.2 mm [0.3-1.0] and subcutaneous tissue thickness: 12.3±4.9 mm [4.7-21]. The basilic vein and the medial brachial cutaneous, ulnar and medial antebrachial cutaneous nerves were located in 40%, 58%, 40% and 18% of the primary windows, respectively. No major neurovascular structures were located 3-5 cm posterior to the sulcus. More neurovascular structures were identified overlying the biceps than triceps. Elbow flexion with the hand underneath the head displaced the ulnar nerve anteriorly towards the sulcus., Conclusion: As no major neurovascular structures were identified overlying the triceps 8-10 cm proximal to the medial epicondyle and 3-5 cm posterior to the sulcus, ENG implant insertion at this location may minimize risk of injury associated with improper deep insertion. Elbow flexion deflects the ulnar nerve away from this area and may further decrease risk of injury secondary to inadvertent deep insertion., Implications: Although a limited cadaver study, this anatomic assessment provides rationale for insertion of the ENG implant overlying the triceps 8-10 cm proximal to the medial epicondyle and 3-5 cm posterior to the sulcus. This area is theoretically safer for insertion of the ENG implant than areas of the inner arm where major neurovascular structures are commonly located., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Population-based estimates on the prevalence of atopic dermatitis in adults vary widely. The objectives of this study were to determine the prevalence of atopic dermatitis in the population of the United States, the distribution of disease severity, and its impact on health-related quality of life. Among 1,278 participating adults, the prevalence (95% confidence interval) of atopic dermatitis was 7.3% (5.9-8.8). Overall, 60.1% (56.1-64.1) of participants were classified as having mild, 28.9% (25.3-32.7) as having moderate, and 11% as having severe (8.6-13.7) disease. Patients with atopic dermatitis and those with more severe disease had higher scores in the dermatology life quality index (mean [standard deviation] for AD patients = 4.71 [6.44] vs. control individuals = 0.97 [2.12]) (P < 0.001) and the hospital anxiety (mean [standard deviation] for AD patients = 7.03 [4.80] vs. control individuals = 4.73 [4.8]) and depression (mean, [standard deviation] for AD patients = 5.83 [4.54] vs. control individuals = 3.62 [3.61]) scales, indicating a worse impact on quality of life and an increased likelihood of anxiety or depression. Based on our prevalence estimates, 16.5 million adults would have a diagnosis of atopic dermatitis, with 6.6 million meeting criteria for moderate to severe disease. Our study confirms the high prevalence and disease burden of atopic dermatitis in this population., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Faces convey rich perceptual and social information. The contribution of perceptual and social information to face recognition has been typically examined in separate experiments. Here, we take a comprehensive approach by studying the contributions of both perceptual experience and social-conceptual information to face learning within the same experimental design. The effect of perceptual experience was examined by systematically varying the similarity between the learned and test face views. Social information was manipulated by asking participants to make social, perceptual, or no evaluations on faces during learning. Results show better recognition for the learned views, which declines as a function of the dissimilarity between the learned and unlearned views. Additionally, processing faces as social concepts produced a general gain in performance of a similar magnitude for both the learned and unlearned views. We concluded that both social-conceptual and perceptual information contribute to face recognition but through complementary, independent mechanisms. These findings highlight the importance of considering both cognition and perception to obtain comprehensive understanding of face recognition., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Peripheral T-cell lymphomas (PTCL) are a group of rare malignancies characterized by chemotherapy resistance and poor prognosis. Romidepsin and pralatrexate were approved by the US Food and Drug Administration for patients with relapsed/refractory PTCL, exhibiting response rates of 25% and 29% respectively. Based on synergy in preclinical models of PTCL, we initiated a phase 1 study of pralatrexate plus romidepsin in patients with relapsed/refractory lymphoma. This was a single institution dose-escalation study of pralatrexate plus romidepsin designed to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, pharmacokinetic profile, and response rates. Patients were treated with pralatrexate (10 to 25 mg/m 2 ) and romidepsin (12 to 14 mg/m 2 ) on 1 of 3 schedules: every week × 3 every 28 days, every week × 2 every 21 days, and every other week every 28 days. Treatment continued until progression, withdrawal of consent, or medical necessity. Twenty-nine patients were enrolled and evaluable for toxicity. Coadministration of pralatrexate and romidepsin was safe, well tolerated, with 3 DLTs across all schedules (grade 3 oral mucositis × 2; grade 4 sepsis × 1). The recommended phase 2 dose was defined as pralatrexate 25 mg/m 2 and romidepsin 12 mg/m 2 every other week. Twenty-three patients were evaluable for response. The overall response rate was 57% (13/23) across all patients and 71% (10/14) in PTCL. The phase 1 study of pralatrexate plus romidepsin resulted in a high response rate in patients with previously treated PTCL. A phase 2 study in PTCL will determine the efficacy of the combination. This trial was registered at www.clinicaltrials.gov as #NCT01947140., (© 2018 by The American Society of Hematology.)

In recent years, the number of approved and investigational agents that can be safely administered for the treatment of lymphoma patients for a prolonged period of time has substantially increased. Many of these novel agents are evaluated in early-phase clinical trials in patients with a wide range of malignancies, including solid tumors and lymphoma. Furthermore, with the advances in genome sequencing, new "basket" clinical trial designs have emerged that select patients based on the presence of specific genetic alterations across different types of solid tumors and lymphoma. The standard response criteria currently in use for lymphoma are the Lugano Criteria which are based on [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography or bidimensional tumor measurements on computerized tomography scans. These differ from the RECIST criteria used in solid tumors, which use unidimensional measurements. The RECIL group hypothesized that single-dimension measurement could be used to assess response to therapy in lymphoma patients, producing results similar to the standard criteria. We tested this hypothesis by analyzing 47 828 imaging measurements from 2983 individual adult and pediatric lymphoma patients enrolled on 10 multicenter clinical trials and developed new lymphoma response criteria (RECIL 2017). We demonstrate that assessment of tumor burden in lymphoma clinical trials can use the sum of longest diameters of a maximum of three target lesions. Furthermore, we introduced a new provisional category of a minor response. We also clarified response assessment in patients receiving novel immune therapy and targeted agents that generate unique imaging situations., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Objectives: To develop key messages for methadone and buprenorphine safety education material based on an analysis of calls to the NYC Poison Control Center (NYC PCC) and designed for distribution to caregivers of young children., Methods: Retrospective review of all calls for children 5 years of age and younger involving methadone or buprenorphine from January 1, 2000, to June 15, 2014. A data abstraction form was completed for each case to capture patient demographics, exposure and caller sites, caller relation to patient, qualitative information regarding the exposure scenario, the product information, if naloxone was given, and the medical outcome of the case., Results: A total of 123 cases were identified. The ages of the children ranged from 4 days to 5 years; 55% were boys. All exposures occurred in a home environment. The majority of the calls were made to the NYC PCC by the doctor (74%) or nurse (2%) at a health care facility. Approximately one-fourth of the calls came from the home and were made by the parent (22%) or grandparent (2%). More than one-half of the exposures involved methadone (64%). Naloxone was administered in 28% of cases. Approximately one-fourth of the children did not experience any effect after the reported exposure, one-half (51%) experienced some effect (minor, moderate, or major), and there was 1 death (1%). More than one-half of the children were admitted to the hospital, with 40% admitted to critical care and 13% to noncritical care. Approximately 23% were treated and released from the hospital, and 20% were lost to follow-up or never arrived to the hospital. The remaining 4% were managed on site without a visit to the hospital., Conclusion: Exposures to methadone and buprenorphine are dangerous with some leading to serious health effects. Safe storage and disposal instructions are needed for homes where children may be present., (Published by Elsevier Inc.)

Objective: The objective was to monitor the effectiveness of the etonogestrel implant clinical training program through a voluntary active monitoring program (AMP)., Study Design: US health care providers underwent mandatory training by the manufacturer on etonogestrel implant insertion, localization and removal. After training, health care providers could enroll in a voluntary AMP to provide outcome data to meet a postmarketing commitment of the manufacturer with the US Food and Drug Administration (FDA). Those who volunteered completed and faxed forms to the manufacturer after implant insertion and removal detailing the procedure and device-related outcomes, including insertion-, localization- or removal-associated events. Experts reviewed outcome data quarterly, which the Sponsor then reported to the FDA., Results: Among 42,337 health care providers completing the training program, 4294 (10.1%) volunteered to participate in the AMP. The 26,198 forms submitted over 6.4 years included more insertion (n=20,497) forms than removal forms (n=5701). The volunteers reported 646 events on 566 (2.2%) forms related to insertion (n=197), localization (n=34), removal (n=357) and "other" (n=58). Clinically important events included noninsertion (n=4), serum etonogestrel positive but implant not found (n=1), and possible nerve (n=66) or vascular (n=5) injury. The reports did not include any insertion-, localization- or removal-associated hospitalizations. Eight (0.14%) removal reports described referral for surgical implant removal., Conclusion: Events related to insertion, localization or removal of the etonogestrel implant are uncommon among US providers who received mandatory training in the use of the implant., Implications: This report presents results from the first mandatory US contraceptive training program. Health care providers volunteered to report information about etonogestrel implant insertion, localization and removal. Although the data do not demonstrate whether a mandatory program improves outcomes, they elucidate the utility and real-life experience that clinical training programs can provide., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Electromagnetic interference (EMI) can affect the function of implantable cardioverter defibrillators (ICD). Hybrid electric vehicles (HEV) have increased popularity and are a potential source of EMI. Little is known about the in vivo effects of EMI generated by HEV on ICD., Objective: This study evaluated the in vivo interaction between EMI generated by HEV with ICD., Methods and Results: Thirty patients (73±9 y/o; 80% male) with stable ICD function were exposed to EMI generated by a Toyota Prius Hybrid®. The vehicle was lifted above the ground, allowing safe changes in engine rotation and consequent variations in electromagnetic emission. EMI was measured (NARDA STS® model EHP-50C) and expressed in A/m (magnetic), Volts/m (electrical), and Hertz (frequency). Six positions were evaluated: driver, front passenger, right and left back seats, outside, at the back and front of the car. Each position was evaluated at idle, 30 mph, 60 mph and variable speeds (acceleration-deceleration-brake). All ICD devices were continuously monitored during the study. The levels of EMI generated were low (highest mean levels: 2.09A/m at right back seat at 30 mph; and 3.5V/m at driver seat at variable speeds). No episode of oversensing or inadvertent change in ICD programming was observed., Conclusion: It is safe for patients with ICD to interact with HEV. This is the first study to address this issue using an in vivo model. Further studies are necessary to evaluate the interaction of different models of HEV or electric engine with ICD or unipolar pacemakers., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Uniformly adopted response criteria are essential for assessment of therapies incorporating conventional chemotherapy and chemoimmunotherapy regimens. Recently, immunomodulatory agents, such as immune checkpoint inhibitors, have demonstrated impressive activity in a broad range of lymphoma histologies. However, these agents may be associated with clinical and imaging findings during treatment suggestive of progressive disease (PD) despite evidence of clinical benefit (eg, tumor flare or pseudo-progression). Considering this finding as PD could lead to patients being prematurely removed from a treatment from which they actually stand to benefit. This phenomenon has been well described with checkpoint blockade therapy in solid tumors and anecdotally seen in lymphoma as well. To address this issue in the context of lymphoma immunomodulatory therapy, a workshop was convened to provide provisional recommendations to modify current response criteria in patients receiving these and future agents in clinical trials. The term "indeterminate response" was introduced to identify such lesions until confirmed as flare/pseudo-progression or true PD by either biopsy or subsequent imaging., (© 2016 by The American Society of Hematology.)

Background: Graft stenosis may be associated with future graft failure. The purpose of this investigation was to compare graft stenosis between radial artery (RA) grafts and saphenous vein grafts (SVGs) at least 5 years postoperatively using the multicenter Radial Artery Patency Study (RAPS) data., Methods: Two hundred thirty-four patients underwent late invasive angiography after coronary artery bypass operations. The study population consists of 163 patients with thrombolysis in myocardial infarction (TIMI) 3 flow of both the RA graft and study SVGs. Angiograms were reviewed centrally and in a blinded fashion. Graft stenosis was recorded for the proximal anastomosis, graft body, and distal anastomosis; significant stenosis was defined as greater than or equal to 50%. Major adverse cardiac events (MACE) were reported in patients with and those without significant graft stenosis., Results: There was no difference in significant graft stenosis of the patent RA grafts and SVGs (14 of 163 [8.6%] versus 19 of 163 [11.7%]) or in the proximal anastomosis (5 of 163 [3.1%] versus 5 of 163 [3.1%]), graft body (6 of 163 [3.7%] versus 13 of 163 [8.0%]), or distal anastomosis (4 of 163 [2.5%] versus 5 of 163 [3.1%]) considered separately. However, the overall burden of graft body disease was higher in SVGs (p = 0.03). MACE was higher in patients with significant graft stenosis than in patients without stenosis (10 of 28 [35.7%] versus 7 of 135 [5.2%]; p < 0.0001)., Conclusions: There was no significant difference in the rates of significant stenosis of patent RA grafts and SVGs more than 5 years postoperatively. However, the burden of graft body stenosis was less in RA grafts compared with SVGs, suggesting that the RA grafts will continue to outperform the SVGs late after operation., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: The link between ethics and epidemiology can go unnoticed in contemporary gatherings of professional epidemiologists or trainees at conferences and workshops, as well as in teaching. Our goal is to provide readers with information about the activities of the College and to provide a broad perspective on a recent major issue in epidemiology., Methods: The Ethics Committee of the American College of Epidemiology (ACE) presented a plenary session at the 2015 Annual Meeting in Atlanta, GA, on the complexities of ethics and epidemiology in the context of the 2014-2015 Ebola virus disease outbreak and response in West Africa. This article presents a summary and further discussion of that plenary session., Results: Three main topic areas were presented: clinical trials and ethics in public health emergencies, public health practice, and collaborative work. A number of key ethical concepts were highlighted and discussed in relation to Ebola and the ACE Ethics Guidelines., Conclusions: The Ebola virus disease outbreak is an example of a public health humanitarian crisis from which we hope to better understand the role of professional epidemiologists in public health practice and research and recognize ethical challenges epidemiologists faced., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: To determine what is known from the existing literature about empirical relationships between numeracy and the three stages of the treatment decision making process (information exchange, deliberation, and deciding on the treatment to implement). We also examined if, and how, numeracy was mentioned in relation to health literacy., Methods: A search of four databases returned 2772 records. After de-duplication and three levels of relevance screening, 38 primary studies were included in this review., Results: Relationships between numeracy and the information exchange stage have received greater attention than relationships between numeracy and the deliberation and deciding on the treatment to implement stages. The lack of overlap in the empirical relationships examined in studies, the measure(s) of numeracy used, and the characteristics of study populations, made findings difficult to compare. Multiple knowledge gaps and measurement-related problems were identified. Numeracy and health literacy have largely been treated as separate concepts., Conclusion: More research is needed to better understand the importance of numeracy and health literacy to treatment decision making., Practice Implications: Decision aids designed for patients with different levels of health literacy may not meet the needs of patients with different levels of numeracy. The numeracy skills of health professionals require attention., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

A new technology recently appeared for the treatment of endo-uterine pathologies: hysteroscopic morcellators. It seemed to us useful to review this new technology. The morcellator we mostly experiment is the Myosure®, in 14 patients, with a median age of 40.5 years (28-58). The time of procedure went from 5 to 75 min with a median time at 26 min. The median of the total fluid deficit was 300 mL (0-1500 mL). A conversion in traditional resectoscopy happened in 4 cases (29%). This results are not so good as in literature. This is probably bound to one the learning curve but also the type of pathology. For the operative time, all the studies agree that hysteroscopic morcellation is faster than hysteroscopic resection. The quantity of fluid used is also lesser, as the deficit of fluid when the morcellator is used. The percentage of success to remove the pathology is high, close to 100% for the polyps and 92% for the submucous myomas. The indications are the polyps and the submucous myomas type 0 or 1. The morcellation of remnant trophoblastic tissues is also described and seems effective. Others indications, as the removal of uterine septum or cure of uterine synechias, are criticisable. In conclusion, hysteroscopic morcellators are probably a great progress for the cure of the endo-uterine pathologies. They cannot yet concurrence the hysterosopic resectoscopes for the treatment of big submucous myoma or those with a large intramyometrial involvement., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Purpose: Researchers must monitor the safety of research participants, particularly in studies involving children and adolescents. Yet, there is limited guidance for the development and implementation of oversight committees for psychosocial, behavioral intervention, and observational studies., Methods: We implemented a model for an Event Monitoring Committee (EMC) in three related studies recruiting 6- to 19-year-old girls from families with and without breast cancer., Results: The EMC model can be valuable for investigators and local institutional review boards when additional oversight is desired. Recommendations are provided and intended to be broadly applicable to a wide range of research activities designed to improve the health of children, adolescents, and families. EMC goals, membership, and procedures for monitoring and assessing risks and benefits should be defined but should also be flexible and tailored to the study design and population. The EMC model also provides an independent comprehensive, study-wide oversight mechanism for multicenter psychosocial, behavioral intervention, and observational studies., Conclusions: An EMC provides an alternative oversight approach where additional independent assessment and oversight of study-related risks are desired, particularly in the setting of vulnerable populations, children and adolescents, or where risks nontraditional to the medical field (i.e., social, emotional, or cultural) are possible., (Copyright © 2014 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Mast cell leukemia (MCL), the leukemic manifestation of systemic mastocytosis (SM), is characterized by leukemic expansion of immature mast cells (MCs) in the bone marrow (BM) and other internal organs; and a poor prognosis. In a subset of patients, circulating MCs are detectable. A major differential diagnosis to MCL is myelomastocytic leukemia (MML). Although criteria for both MCL and MML have been published, several questions remain concerning terminologies and subvariants. To discuss open issues, the EU/US-consensus group and the European Competence Network on Mastocytosis (ECNM) launched a series of meetings and workshops in 2011-2013. Resulting discussions and outcomes are provided in this article. The group recommends that MML be recognized as a distinct condition defined by mastocytic differentiation in advanced myeloid neoplasms without evidence of SM. The group also proposes that MCL be divided into acute MCL and chronic MCL, based on the presence or absence of C-Findings. In addition, a primary (de novo) form of MCL should be separated from secondary MCL that typically develops in the presence of a known antecedent MC neoplasm, usually aggressive SM (ASM) or MC sarcoma. For MCL, an imminent prephase is also proposed. This prephase represents ASM with rapid progression and 5%-19% MCs in BM smears, which is generally accepted to be of prognostic significance. We recommend that this condition be termed ASM in transformation to MCL (ASM-t). The refined classification of MCL fits within and extends the current WHO classification; and should improve prognostication and patient selection in practice as well as in clinical trials., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Myocardial contrast echocardiography during angiography is critical in identifying appropriate septal perforator(s) for alcohol septal ablation (ASA) in patients with hypertrophic obstructive cardiomyopathy. We evaluated whether there were other angiographic and/or echocardiographic markers that might identify patients who are anatomically suitable for ASA., Methods: We performed quantitative coronary angiographic analysis and echocardiographic assessment on 74 patients referred for ASA from January 2004 to July 2012 at the Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada. Patients who proceeded to ASA were compared with those in whom ASA was aborted., Results: Of the 74 patients referred for ASA, 63 proceeded to ASA and in 11 patients ASA was aborted because of various anatomic and technical reasons. There were no clinically significant differences observed in quantitative angiographic and echocardiographic measurements between the 2 groups. The ratio of ostial left main (LM) to ablated septal distance on angiography vs the basal septum to the septum area where the mitral valve contacted the septum because of systolic anterior motion (SAM) was 1.53. In the whole cohort, a significant correlation was observed between the ostial LM to the target septal distance and the distance from basal septum to SAM-septal contact point on echocardiography (r = 0.39; P = 0.008). A stronger correlation was evident when analysis was restricted to patients undergoing ASA only (r = 0.44; P = 0.006)., Conclusions: Echocardiographic and angiographic assessments of the distance between the basal septum to SAM-septal contact point and ostial LM to the target septal distance might be useful in preprocedural selection of the appropriate septal perforator for ASA., (Copyright © 2014. Published by Elsevier Inc.)

Traumatic brain injury and posttraumatic stress disorder are the signature injuries of the Iraq and Afghanistan wars. Holistic medicine (comprising multispecialty care integration, patient/family-centered care, wellness interventions, and the construction of architectural "healing environments") has much to offer these patients. In this work we describe the architecture and holistic medicine programming of the National Intrepid Center of Excellence (NICoE), a new clinical research center for traumatic brain injury and posttraumatic stress disorder in the Military Health System. Architecture and clinical process are united in a "design/care continuum" for optimal healing. A groundbreaking institution, the NICoE foreshadows many trends in national healthcare for the 21st century., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to investigate whether a relationship exists between an acute reduction in resting left ventricular outflow tract (LVOT) gradient with balloon occlusion and the final invasive gradient response following alcohol septal ablation (ASA)., Background: ASA is an alternative therapy to myectomy surgery to reduce the basal septal thickness and decrease the resting and/or provocable LVOT gradient in patients with hypertrophic cardiomyopathy. Patients have a variable gradient response to occlusion of the septal perforator artery before ethanol infusion for ASA., Methods: From November 1998 to November 2008, 120 patients (mean age 60 years [range 16 to 87 years], 50% women) with hypertrophic cardiomyopathy underwent ASA at our institution. The resting LVOT gradient (peak systolic left ventricle [LV] pressure - peak systolic aortic pressure) was measured continuously during the ASA procedure. The time to significant LVOT gradient decrease (defined as >50% decrease from baseline) was recorded following balloon occlusion of the dominant septal perforator coronary artery, which was found to perfuse the basal septum based on contrast echocardiographic studies., Results: The mean baseline resting LVOT gradient was 86 ± 43 mm Hg, and it decreased to 17 ± 11 mm Hg following ASA (-80.2%). The mean time to significant gradient reduction was 3.6 ± 2 min (range 25 s to 11 min). The time to significant LVOT gradient reduction strongly correlated with the final magnitude of gradient reduction following ASA (r = -0.81, p < 0.001)., Conclusions: This study demonstrates a correlation between the time to significant LVOT gradient reduction following septal perforator balloon occlusion and the magnitude of final gradient response after ASA., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Specific Aim: To review the evidence indicating that volumetric image analysis of computed tomography scans meets specifications for qualification as a biomarker in clinical trials or the management of individual patients with lung cancer., Methods: Claims of value were broken down into questions about technical feasibility, accuracy, the precision of measurement, sensitivity, the correlations with health outcomes, and the risks of producing misleading information. For each claim, the pertinent literature was reviewed., Results: Technical feasibility has now been shown, but only in limited contexts. Accuracy has been demonstrated, but only for tumors with favorable anatomical features. Measurement error still makes the assessment of change in small nodules precarious in diagnostic settings unless rigorous image acquisition and analysis procedures are followed. Precision is sufficient in some larger masses to make volumetrics a sensitive biomarker. In a few trials, correlations with clinical outcomes have been higher for volumetric-based measures than for unidimensional or bidimensional diameters. Value in clinical practice settings and clinical trials has been suggested, but not proven., Conclusion: The weight of the evidence indicates there are circumstances in which volumetric image analysis adds value to clinical trial science and the practice of medicine.

Background: Hemarthroses in severe hemophilia precipitate physical, psychosocial and financial difficulties., Objective: To compare the effects of secondary prophylaxis with on-demand sucrose-formulated recombinant factor VIII (rFVIII-FS) therapy in severe hemophilia A., Patients and Methods: This open-label study included patients aged 30-45 years with factor VIII (FVIII) coagulant activity < 1 IU dL(-1) who were using on-demand FVIII treatment. Patients were treated with rFVIII-FS on demand for 6 months, followed by 7 months prophylaxis (20-40 IU kg(-1), three times per week, with the first month considered a run-in). The primary endpoint was the number of hemarthroses., Results: Twenty patients were enrolled (n = 19 completed); the mean age was 36.4 years, and 16 had target joints. The median (25-75%) number of joint bleeds decreased significantly with prophylaxis [0 (0-3)] vs. on-demand [15 (11-26); P < 0.001] therapy. The number of all bleeds was 0 (0-3) vs. 20.5 (14-37; P < 0.001), respectively. Median (range) total Gilbert scores improved after prophylaxis [18 (3-39)] compared with on-demand [25 (4-46)] therapy, predominantly reflecting the improved bleeding score. Median time from last prophylactic infusion to bleed was 2 days; 82.5% of bleeds occurred 2-3 days after the last infusion. Median 48-h and 72-h FVIII trough levels measured during months 10 and 13 were consistently > 6 and > 4 IU dL(-1), respectively. Treatment was well tolerated, and no inhibitor formation was observed., Conclusion: Secondary prophylaxis with rFVIII-FS significantly reduced the frequency of hemarthroses compared with on-demand therapy in adult patients with severe hemophilia A.

Background: This study reports the results of hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone (dex) in patients with unresectable intrahepatic cholangiocarcinoma (ICC) or hepatocellular carcinoma (HCC) and investigates dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) assessment of tumor vascularity as a biomarker of outcome., Patients and Methods: Thirty-four unresectable patients (26 ICC and eight HCC) were treated with HAI FUDR/dex. Radiologic dynamic and pharmacokinetic parameters related to tumor perfusion were analyzed and correlated with response and survival., Results: Partial responses were seen in 16 patients (47.1%); time to progression and response duration were 7.4 and 11.9 months, respectively. Median follow-up and median survival were 35 and 29.5 months, respectively; 2-year survival was 67%. DCE-MRI data showed that patients with pretreatment integrated area under the concentration curve of gadolinium contrast over 180 s (AUC 180) >34.2 mM.s had a longer median survival than those with AUC 180 <34 mM.s (35.1 versus 19.1 months, P = 0.002). Decreased volume transfer exchange between the vascular space and extracellular extravascular space (-DeltaK(trans)) and the corresponding rate constant (-Deltak(ep)) on the first post-treatment scan both predicted survival., Conclusions: In patients with unresectable primary liver cancer, HAI therapy can be effective and safe. Pretreatment and early post-treatment changes in tumor perfusion characteristics may predict treatment outcome.

There are three options for the treatment of patients with coronary artery disease: coronary artery bypass graft surgery (CABG), percutaneous coronary intervention (PCI) and optimal medical treatment alone. While there has been an active interface between CABG and PCI, medical treatment has not been as vociferously advocated. However, it performs well in randomized trials and is still a treatment arm in studies such as the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. The present review compares these options in acute and chronic coronary syndromes, including the indications for each as summarized by recent American College of Cardiology and American Heart Association guidelines. While the landscape in Canada is changing for CABG and PCI, with an increase in the latter procedure for patients with multivessel disease, optimal medical treatment alone is very effective. There are few subsets, particularly in chronic syndromes, in which revascularization is indicated for prognosis alone.

Background: Pegylated interferon (IFN) has a longer serum half-life compared with standard IFN, and this allows for weekly dosing. In this study, the efficacy and toxicity of pegylated IFN was assessed in patients with metastatic renal cell carcinoma (mRCC)., Patients and Methods: Thirty-two patients with previously untreated mRCC were treated with pegylated IFN-alpha 2b in a prospective, single-arm phase II trial. Pegylated IFN was given by subcutaneous administration on a weekly schedule at a dose of 4.5 microg/kg., Results: Of the 32 assessable patients, 29 (91%) had a nephrectomy previously, and none had been treated previously with systemic therapy. Forty-one percent had good-risk, 53% had intermediate-risk, and 6% had poor-risk features per Memorial Sloan-Kettering Cancer Center risk criteria. The best response was a complete response (CR) in 1 patient (3%). Nine patients (28%) had a partial response. Fifteen patients (47%) had stable disease. The median progression-free survival (PFS) was 5 months (95% CI, 3-7 months), and median overall survival was 31 months (95% CI, 18 months to not reached). Five patients had a prolonged PFS of > or = 17 months, 1 of whom achieved a CR. There were no grade 4 toxicities; primary grade 3 toxicities were hematologic (11 of 32 patients; 34%) and fatigue (4 of 32 patients; 13%)., Conclusion: Pegylated IFN administered weekly has antitumor activity in patients with mRCC with predominantly good- and intermediate-risk features. This study suggests comparable efficacy and safety compared with standard IFN-alpha.

Seventy-five percent of the myoblasts transplanted in the mouse muscle die during the first 4 days following transplantation. The purpose of this study was to determine if anoikis plays a role in this phenomenon. Survival and proliferation of myoblasts in vitro were determined by Hoescht-PI labeling and cell counts respectively. In vivo cell survival and proliferation were quantified by injecting human male myoblasts labeled with (14)C-thymidine in SCID mouse muscles. Survival and proliferation of the transplanted myoblasts were evaluated by scintigraphy and quantitative PCR of human Y chromosomal DNA. Inclusion of the extracellular matrix protein fibronectin enhanced transplanted myoblast survival by 1.7-fold while vitronectin improved their proliferation by 1.8-fold. Reductions in FADD and Bit1 expression reduced anoikis in vitro and improved the injected myoblast survival in vivo. Ectopic expression of the anti-apoptotic protein Bcl-2 completely abolished myoblast anoikis in vitro and enhanced cell survival by 3.1-fold in vivo. Cell death following transplantation appears to me mediated in part by anoikis. Inclusion of extracellular matrix proteins enhanced both survival and proliferation. Reduced expression of the proapoptotic proteins Bit1 and FADD or overexpression of Bcl-2 improved myoblast survival.

Background: Accurate response assessment is essential for evaluating new cancer treatments. We evaluated the impact of Response Evaluation Criteria in Solid Tumors (RECIST), World Health Organization (WHO) criteria and tumor shape on response assessment in patients with metastatic esophageal cancer., Patients and Methods: In 19 patients with metastatic esophageal cancer in a phase II trial of bryostatin-1 and paclitaxel, response was retrospectively assessed for 89 lesions with RECIST and WHO criteria on baseline and serial follow-up CT scans. The eccentricity factor (EF) was introduced for measuring the degree to which tumor shape diverges from a perfect sphere [EF = radical1-(LPD/MD)(2), where LPD is the largest perpendicular diameter and MD is the maximal diameter]., Results: The disagreement rate in best overall response categorization between RECIST (unidimensional) and WHO (bidimensional) criteria was 26.3%. Change in eccentricity was significantly greater (P < 0.01) for patients with disagreement (mean 0.31, range 0-0.91). When the short axis was used for unidimensional lymph node measurement, disagreement between WHO and RECIST lessened., Conclusions: Response assessment by WHO and RECIST differs substantially. Greater change in eccentricity is associated with greater discordance between WHO and RECIST. The discordance between WHO and RECIST may impact on how effective a therapy is judged to be.

Background: Histone deacetylase inhibitors are a novel class of therapeutic agents that inhibit deacetylate histones and other proteins involved in the regulation of gene expression and cell cycle progression. Phase I trials of intravenous and oral formulations of one such agent, vorinostat (suberoylanilide hydroxamic acid [SAHA]), have shown that it is safe and tolerable, that it inhibits histone deacetylation in peripheral blood mononuclear cells, and that it has a broad range of antitumor activity., Patients and Methods: Thirteen patients with mesothelioma were included in a phase I trial of oral SAHA. All but one had previously been treated with chemotherapy., Results: Four patients completed > or = 6 cycles of therapy; 2 patients demonstrated a partial response. The toxicities in this cohort of patients were similar to those observed in the entire phase I trial: primarily fatigue, dehydration, nausea, and vomiting., Conclusion: Given the dearth of treatment options for patients with advanced mesothelioma who have progressed after first-line chemotherapy, these results are encouraging. A placebo-controlled, randomized phase III study of oral SAHA is now open for patients with mesothelioma in whom treatment with pemetrexed has failed.

Background: Self-management (SM) of warfarin by patients is an attractive strategy, particularly if it improves anticoagulation control and can be done safely under minimal physician supervision., Objective: To compare the effect of SM with physician-management (PM) on the maintenance of therapeutic anticoagulation., Methods: A randomized, open-label eight-month trial was performed. Patients 18 years of age and older were eligible if they were receiving warfarin for at least one month before enrolment and required anticoagulation for at least one year to a target international normalized ratio (INR) of 2.0 to 3.0 or 2.5 to 3.5. Exclusion criteria were a known hypercoaguable disorder, mental incompetence, a language barrier or an inability to attend training sessions. Patients randomly assigned to SM tested their INR using a point-of-care device (Pro Time Microcogulation System, International Technidyne Corporation, USA) and adjusted their warfarin doses using a nomogram. Patients randomly assigned to PM received usual care from their general practitioner. The primary outcome was to demonstrate 20% improvement in anticoagulation control by SM., Results: One hundred forty patients were randomly assigned (70 per group). Thirteen patients dropped out of SM early due to an inability to self-manage. Based on intention-to-treat analysis, there was no difference in the proportion of INR in range (SM 64.8% versus PM 58.7%, P=0.23) or time in target range (SM 71.8% versus PM 63.2%, P=0.14). Patients managing their own therapy spent less time below the therapeutic range (15.0% versus 27.3%, P=0.04). There were three major complications of thrombosis or bleeding, all occurring in the PM arm. All patients who completed SM preferred to continue with that strategy., Conclusions: SM was not significantly better than PM in maintaining therapeutic anticoagulation. SM was feasible and appeared safe in the present study population.

Background: Development of recombinant factor VIII (rFVIII) replacement therapy represents a milestone in the treatment of hemophilia A., Objective: The objective of this long-term, multicenter study was to assess the safety, efficacy and rate of inhibitor formation of rFVIII (Kogenate) in the treatment of hemophilia A in a group of previously untreated patients (PUPs)., Patients and Methods: Between January 1989 and October 1997, 102 evaluable patients (mean age 3.9 years) were treated with rFVIII as sole therapy for prophylaxis against bleeding or for hemorrhage. Patients with mild hemophilia were treated for > or =2 years, while those with moderate or severe hemophilia were treated for > or =5 years or 100 exposure days., Results: All patients responded well to therapy, so that 82% of bleeding episodes required a single infusion for treatment. Only four mild drug-related adverse events were recorded during the study for an overall rate of 0.03% (4/13 464 infusions). No viral seroconversions were observed. The inhibitor incidence in PUPs with severe hemophilia was 29% (19/65). Overall, inhibitory antibodies developed in 21 patients (20.6%). Inhibitor titers were low (<10 Bethesda Units) in nine of the 21 patients despite continued episodic treatment with rFVIII and transient in eight patients receiving episodic treatment (seven low titer, one high titer). Eight high-titer inhibitor patients were treated with immune-tolerance induction therapy; five had successful outcomes., Conclusions: The observed incidence of inhibitor formation is similar to studies of PUPs receiving plasma-derived FVIII. These results demonstrate the safety and efficacy of rFVIII in long-term treatment of hemophilia A.

Background: Several trials have demonstrated that the response proportions to microtubule agents in patients with prostate cancer are increased by the addition of estramustine phosphate (EMP). The epothilone B analog BMS-247550 is a novel microtubule agent that has shown activity in taxane-resistant tumors. We conducted a dose-escalation study to determine a safe dose of BMS-247550 to combine with EMP in patients with metastatic prostate cancer., Patients and Methods: Chemotherapy-naive patients with castrate-metastatic prostate cancer were treated with intravenous BMS-247550 and oral EMP (280 mg three times daily for 5 days) every 3 weeks., Results: Thirteen patients were treated at two dose levels (35 and 40 mg/m(2)). Three of six patients treated at 40 mg/m(2) developed grade 4 neutropenia, establishing 35 mg/m(2) as the maximum-tolerated dose. Significant peripheral neuropathy (grade >/= 2) was related to dose level and infusion rate. A decline in prostate-specific antigen (PSA) of >/= 50% was seen in 11 of 12 evaluable patients (92%) (95% confidence interval 76% to 100%). There were objective responses in soft tissue (57%) and bone metastasis (40%)., Conclusions: The phase II dose of BMS-247550 combined with EMP is 35 mg/m(2) over 3 h every 3 weeks. This combination is safe and >/= 50% post-therapy declines in PSA were seen in 11 of 12 patients (92%).

Background: Septal ethanol ablation (SEA) is a relatively new interventional nonsurgical treatment for patients with hypertrophic obstructive cardiomyopathy (HOCM). This procedure involves targeted infarction of the basal interventricular septum to reduce left ventricular outflow tract (LVOT) obstruction., Objectives: To describe the experience with this technique in a large tertiary care centre., Methods and Results: Since 1998, 40 HOCM patients with disabling symptoms refractory to medical treatment have undergone SEA. Procedural success was 88% (35 of 40 patients). The LVOT gradient decreased from 86+/-38 mmHg to 16+/-16 mmHg. There were two major complications: one patient died of respiratory failure at 30 days following SEA, and one patient developed a major coronary dissection during the procedure and required emergency myectomy and coronary bypass surgery. There were two late failures (6% of initially successful cases). In both patients, the LVOT gradient and symptoms reappeared some months after the procedure and further interventions were required. In the remaining patients, the gradient continued to decrease to one year; 86% were asymptomatic or have mild symptoms compared with 94% with severe symptoms before SEA. Septal thickness decreased from 20.8+/-2.9 mm to 13.2+/-3.3 mm (P<0.001) at the site of the targeted septal infarct., Conclusion: SEA is a feasible option for suitable patients with HOCM.

The majority of patients undergoing coronary bypass surgery have at least one internal thoracic artery used as a conduit. Internal thoracic artery atherosclerosis is a rare but distal anastamotic stenosis or occlusion can occur often early after surgery. Percutaneous coronary intervention is a management option. A patient with a left internal thoracic artery-left anterior descending coronary artery occlusion eight days after implantation, in whom balloon angioplasty resulted in avulsion of the left internal thoracic artery, is presented. Emergency coronary rebypass surgery was life-saving. A review of the pathology and clinical literature suggests that percutaneous coronary intervention may be a risky strategy in this scenario. Other options should be sought or percutaneous coronary intervention should be delayed until full surgical healing of the distal anastomosis surgery, which usually takes at least two months.

Background: Pharmaceutical companies spent US$1.8 billion on direct-to-consumer advertisements for prescription drugs in 1999. Our aim was to establish what messages are being communicated to the public by these advertisements., Methods: We investigated the content of advertisements, which appeared in ten magazines in the USA. We examined seven issues of each of these published between July, 1998, and July, 1999., Findings: 67 advertisements appeared a total of 211 times during our study. Of these, 133 (63%) were for drugs to ameliorate symptoms, 54 (26%) to treat disease, and 23 (11%) to prevent illness. In the 67 unique advertisements, promotional techniques used included emotional appeals (45, 67%) and encouragement of consumers to consider medical causes for their experiences (26, 39%). More advertisements described the benefit of medication with vague, qualitative terms (58, 87%), than with data (9, 13%). However, half the advertisements used data to describe side-effects, typically with lists of side-effects that generally occurred infrequently. None mentioned cost., Interpretation: Provision of complete information about the benefit of prescription drugs in advertisements would serve the interests of physicians and the public.

alpha- and beta-tryptase genes encode serine proteases that are abundantly expressed by mast cells. Under physiologic conditions other myeloid cells are virtually tryptase negative. However, tryptases are also expressed in several myeloid leukemia cell lines. In this study, serum total tryptase levels were determined in 150 patients with acute leukemias (de novo acute myeloid leukemia [AML], n = 108; secondary AML, n = 25; acute lymphoid leukemia [ALL], n = 17) by fluoroenzyme immunoassay. In healthy subjects (n = 30), tryptase levels ranged between 2.0 and 12.6 ng/mL. Elevated tryptase levels (> 15) were detected in 42 (39%) of 108 patients with de novo AML and in 11 (44%) of 25 patients with secondary AML. No elevated tryptase levels were found in patients with ALL. In de novo AML, elevated tryptase levels were frequently detected in patients with French-American-British classification M0 (6 of 9), M2 (9 of 14), M3 (4 of 6), and M4eo (7 of 7), and less frequently in M1 (7 of 20), M4 (6 of 26), M5 (2 of 18), M6 (0 of 5), or M7 (1 of 3). The highest tryptase levels were found in M4eo. Immunohistochemical staining of bone marrow sections with anti-tryptase antibody as well as immunoelectron microscopy revealed tryptase expression in the cytoplasm of myeloblasts. As assessed by Northern blotting and reverse transcriptase-polymerase chain reaction, AML cells expressed alpha-tryptase messenger RNA (mRNA) but little or no beta-tryptase mRNA. In AML patients with elevated serum tryptase before chemotherapy, who entered complete remission, tryptase levels returned to normal or near normal values. Blast cell persistence or regrowth was associated with a persistently elevated level or recurrent increase of tryptase. Together, tryptase is expressed in myeloblasts in a group of AML and may serve as a useful disease-related marker.