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Background: The emotional health of adolescent and young adult (AYA) cancer survivors is compromised both during and after cancer treatment. Targeted programs designed to support AYAs' ability to cope with stress in the years following treatment completion are lacking. Mind-body programs may ameliorate the negative psychological and emotional effects of stress and assist AYAs with managing the psychosocial challenges of early survivorship., Objective: Our randomized waitlist-control trial aims to assess the feasibility, acceptability, and preliminary efficacy of a virtual group program (Bounce Back) to promote stress management and resiliency among posttreatment AYAs., Methods: Bounce Back is a stress management and resiliency program delivered via videoconference by a trained mental health clinician. Sessions were adapted from an evidence-based mind-body program (Stress Management and Resiliency Training - Relaxation Response Resiliency Program [SMART-3RP]) grounded in relaxation response elicitation, mindfulness, cognitive behavioral therapy, and positive psychology. Seventy-two AYAs (diagnosed with cancer between ages 14 years and 29 years and had completed cancer treatment within the last 5 years) were randomly assigned to the Bounce Back program or waitlist-control group and completed assessments at baseline, 3 months postbaseline, and 6 months postbaseline. The primary aim of the study is to determine the feasibility and acceptability of the Bounce Back program. Descriptive statistics, including means, frequencies, and ranges supplemented by qualitative exit interview feedback will be used to characterize the sample and to summarize feasibility and acceptability. The exploratory aims are to evaluate the preliminary effects of the program on stress coping and psychosocial outcome measures (ie, anxiety, depression) collected across the 3 time points., Results: This study was funded by the National Cancer Institute in July 2017. Study procedures were approved by the Dana-Farber Harvard Cancer Center Institutional Review Board in October 2018 (Protocol 18-428). The randomized trial was conducted from July 2019 to March 2021. Quantitative data collection is complete, and qualitative exit interview data collection is ongoing. Results are expected to be published in peer-reviewed journals and presented at local, national, or international meetings in the coming years., Conclusions: Few evidence-based programs exist that tackle the key transitional issues faced by AYA cancer survivors. Future analyses will help us determine the feasibility and acceptability of the Bounce Back program and its impact on AYA stress coping and psychological well-being., Trial Registration: ClinicalTrials.gov NCT03768336; https://clinicaltrials.gov/ct2/show/NCT03768336., International Registered Report Identifier (irrid): DERR1-10.2196/34033., (©Helen Mizrach, Brett Goshe, Elyse R Park, Christopher Recklitis, Joseph A Greer, Yuchiao Chang, Natasha Frederick, Annah Abrams, Mary D Tower, Emily A Walsh, Mary Huang, Lisa Kenney, Alan Homans, Karen Miller, John Denninger, Ghazala Naheed Usmani, Jeffrey Peppercorn, Giselle K Perez. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 26.01.2022.)

The study was conducted to improve knowledge and provide guidance on reducing uncertainty with impact predictions when drilling near sensitive environments. Near/Far-field hindcast modelling of cuttings/drilling fluid (mud) discharges from a floating platform was conducted, based on measured discharge amounts and durations and validated by ROV-based plume and seabed sampling. The high volume, concentration, and discharge rate water-based drilling mud discharges (mud pit dumps) were identified as the most significant dispersal risk, but longer-range movement was limited by the generation of jet-like plumes on release, which rapidly delivered muds to the seabed (80 m). Effects to the sparse benthic filter feeder communities close to the wells were observed, but no effects were seen on the epibenthic or demersal fish assemblages across the nearby mesophotic reef. For future drilling near sensitive environments, the study emphasized the need to better characterise drilling fluid discharges (volumes/discharge rates) to reduce uncertainty in modelling outputs., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: We conducted a secondary analysis of changes in the Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 over 30 days in a randomized trial of self-care coaching versus structured usual care in patients with acute heart failure who were discharged from the emergency department., Methods: Patients in 15 emergency departments completed the KCCQ-12 at emergency department discharge and at 30 days. We compared change in KCCQ-12 scores between the intervention and usual care arms, adjusted for enrollment KCCQ-12 and demographic characteristics. We used linear regression to describe changes in KCCQ-12 summary scores and logistic regression to characterize clinically meaningful KCCQ-12 subdomain changes at 30 days., Results: There were 350 patients with both enrollment and 30-day KCCQ summary scores available; 166 allocated to usual care and 184 to the intervention arm. Median age was 64 years (interquartile range, 55-70), 37% were female participants, 63% were Black, median KCCQ-12 summary score at enrollment was 47 (interquartile range, 33-64). Self-care coaching resulted in significantly greater improvement in health status compared with structured usual care (5.4-point greater improvement, 95% CI, 1.12-9.68; P =0.01). Improvements in health status in the intervention arm were driven by improvements within the symptom frequency (adjusted odds ratio, 1.62 [95% CI, 1.01-2.59]) and quality of life (adjusted odds ratio, 2.39 [95% CI, 1.46-3.90]) subdomains., Conclusions: In this secondary analysis, patients with acute heart failure who received a tailored, self-care intervention after emergency department discharge had clinically significant improvements in health status at 30 days compared with structured usual care largely due to improvements within the symptom frequency and quality of life subdomains of the KCCQ-12. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02519283.

Children learn to extract number information from utterances using a variety of language-specific cues, but in some languages this information is encoded in features that display high variability in their realization. How does this affect their acquisition process? In this paper, we present an eye tracking study comparing 3.5- to 7.5-year-old children and adults' use of number information on the verb and the determiner of the subject noun phrase in Chilean Spanish, a dialect of Spanish with variable realization of plural morphology in the noun phrase (due to phonological weakening) and categorical realization of number on the verb. Our results suggest that, while adults can determine whether the subject refers to a plurality or a singleton set based on the morphology of the verb alone, even 5- to 7.5-year-old children do not and, instead, require information from the noun phrase determiner to make a decision. Children younger than 5 years, instead, cannot use number information on the verb and on the determiner to make a decision. This supports Miller and Schmitt's (2010, 2012) hypothesis that number morphology is not always mapped into syntactic and semantic features by younger children in varieties of Spanish where number is subject to variation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Because of inconsistent findings regarding the relationship between sleep quality and cognitive function in people with age-related memory complaints, we examined how self-reports of sleep quality were related to multiple domains of both objective and subjective cognitive function in middle-aged and older adults., Design: A cross-sectional study involving analysis of baseline data, collected as part of a clinical trial., Measurements: Two hundred and three participants (mean age = 60.4 [6.5] years, 69.0% female) with mild memory complaints were asked to rate their sleep quality using the Pittsburgh Sleep Quality Index (PSQI) and their memory performance using the Memory Functioning Questionnaire (MFQ), which measures self-awareness of memory ability. Neurocognitive performance was evaluated using the Continuous Performance Test (CPT), Trail Making Test, Buschke Selective Reminding Test, and the Brief Visuospatial Test - Revised (BVMT-R)., Results: Total PSQI scores were significantly associated with objective measures of sustained attention (CPT hit reaction time by block and standard error by block) and subjective memory loss (MFQ frequency and seriousness of forgetting). The PSQI components of (poorer) sleep quality and (greater) sleep disturbance were related to (worse) sustained attention scores while increased sleep latency and daytime sleepiness were associated with greater frequency and seriousness of forgetting., Conclusions: Sleep quality is related to both objective measures of sustained attention and self-awareness of memory decline. These findings suggest that interventions for improving sleep quality may contribute not only to improving the ability to focus on a particular task but also in reducing memory complaints in middle-aged and older adults.

In 2011, the enigma of "mystery circles," small but complex underwater structures first observed by divers from southern Japan in 1995, was solved when a new species of pufferfish, white-spotted pufferfish (Torquigener albomaculosus Matsuura 2014), was identified as the responsible agent. To date these circles have been described only from Japan, where they are formed on a sandy seafloor in water depths less than 30 m. A survey of oil field infrastructure on the North West Shelf of Western Australia in 2018 using a remotely operated vehicle and hybrid autonomous underwater vehicle (HAUV) recorded a high-resolution video and bathymetric data of 21 circular formations with similar features to those described in Japan. The circles display dimensions and morphology like those described from Japan, but were observed in water depths between 129 and 137 m. The HAUV also recorded high-resolution photographs which captured a Torquigener sp. fish in the immediate vicinity of the circles. An additional circle and Torquigener sp. were observed in images collected by baited remote underwater stereo-video in a nearby location in 129 m depth. These circles are the first to be found in Australia. The pufferfish species responsible cannot be identified from images collected. Such a discovery not only generates intrigue and wonder among scientists and the general public but also provides an insight into the reproductive behaviour and evolution of pufferfish globally., (© 2020 Fisheries Society of the British Isles.)

Objectives: The goal of this study was to evaluate the ability of semantic (animal naming) and phonemic (FAS) fluency in their ability to discriminate between normal aging, amnestic-Mild Cognitive Impairment (a-MCI), and Alzheimer's disease (AD)., Design: We used binary logistic regressions, multinomial regressions, and discriminant analysis to evaluate the predictive value of semantic and phonemic fluency in regards to specific diagnostic classifications., Setting: Outpatient geriatric neuropsychology clinic., Participants: 232 participants (normal aging = 99, a-MCI = 90, AD = 43; mean age = 65.75 years)., Measurements: Mini-mental State Examination (MMSE), Controlled Oral Word Association Test., Results: Results indicate that semantic and phonemic fluency were significant predictors of diagnostic classification, and semantic fluency explained a greater amount of the discriminant ability of the model., Conclusions: These results suggest that verbal fluency, particularly semantic fluency, may be an accurate and efficient tool in screening for early dementia in time-limited medical settings.

Background: A WW (formerly Weight Watchers) program adapted for persons with type 2 diabetes mellitus (T2DM) previously was found to be more effective than standard care (SC) intervention for weight loss, improved glycemic control, and weight- and diabetes-related quality of life measures. With data from the same national trial, this study examined whether WW adapted for persons with T2DM also increased engagement in weight control behaviors and decreased hedonic hunger, each of which could contribute to improved diabetes management., Intervention and Methods: Individuals with T2DM (n = 563) and overweight or obesity participated in a 12-month, 16-site, randomized trial of WW with diabetes counseling or SC. Hierarchical linear modeling (HLM) evaluated whether 12-month changes in weight control behaviors (Eating Behavior Inventory; EBI) and hedonic hunger (Power of Food Scale; PFS) differed by treatment condition. If a significant treatment effect was found, 12-month changes in EBI/PFS were regressed on 12-month changes in HbA 1c and percent weight loss to explore potential treatment differences in these associations., Results: EBI scores increased significantly over the 12-months (p < 0.001), with greater improvements in WW than SC (p < 0.001). PFS decreased significantly in the 12-months (p < 0.001), with no differences between treatment groups (p = 0.15). HLM analyses that followed up on the significant treatment effect for 12-month change in EBI revealed no significant differences by treatment condition for the relationship between change in EBI scores and change in HbA 1c (p = 0.14) or percent weight loss (p = 0.32). Across all participants, 12-month improvements in EBI and PFS were related to improved HbA 1c (r = 0.22; -0.13, respectively) and greater percent weight loss (r = 0.41; -0.18, respectively) (ps < 0.01)., Conclusions: WW with diabetes counseling produced greater engagement in weight control behaviors in those with T2DM than did SC. Across both groups, improved weight control behaviors and hedonic hunger were related to improved glycemic control and weight loss.

Malaria eradication is critically dependent on new therapeutics that target resistant Plasmodium parasites and block transmission of the disease. Here, we report that pantothenamide bioisosteres were active against blood-stage Plasmodium falciparum parasites and also blocked transmission of sexual stages to the mosquito vector. These compounds were resistant to degradation by serum pantetheinases, showed favorable pharmacokinetic properties, and cleared parasites in a humanized mouse model of P. falciparum infection. Metabolomics revealed that coenzyme A biosynthetic enzymes converted pantothenamides into coenzyme A analogs that interfered with parasite acetyl-coenzyme A anabolism. Resistant parasites generated in vitro showed mutations in acetyl-coenzyme A synthetase and acyl-coenzyme A synthetase 11. Introduction and reversion of these mutations in P. falciparum using CRISPR-Cas9 gene editing confirmed the roles of these enzymes in the sensitivity of the malaria parasites to pantothenamides. These pantothenamide compounds with a new mode of action may have potential as drugs against malaria parasites., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

There is concern internationally that many older people are using an inappropriate number of medicines, and that complex combinations of medicines may cause more harm than good. This article discusses how person-centred medicines optimisation for older people can be conducted in clinical practice, including the process of deprescribing. The evidence supports that if clinicians actively include people in decision making, it leads to better outcomes. We share techniques, frameworks, and tools that can be used to deprescribe safely whilst placing the person's views, values, and beliefs about their medicines at the heart of any deprescribing discussions. This includes the person-centred approach to deprescribing (seven steps), which incorporates the identification of the person's priorities and the clinician's priorities in relation to treatment with medication and promotes shared decision making, agreed goals, good communication, and follow up. The authors believe that delivering deprescribing consultations in this manner is effective, as the person is integral to the deprescribing decision-making process, and we illustrate how this approach can be applied in real-life case studies.

Public health programs may be seriously affected in periods of federal retrenchment. During these times, state-based strategies provide an alternate pathway for advancing public health.A 12-year campaign to secure state support for a network of Centers of Excellence in Children's Environmental Health (CEH) promoting health of children across New York State is described. It was driven by rising rates of asthma, birth defects, developmental disorders, and other noncommunicable diseases in children; growing evidence associating hazardous environmental exposures with these conditions; and recognition that federal resources in CEH are insufficient.Critical campaign elements were (1) formation of a statewide coalition of academic health centers, health care providers, public health officials, community advocates, and other stakeholders; (2) bipartisan collaborations with legislative champions and government leaders; (3) assessment of the burden of developmental disorders and noncommunicable diseases associated with environmental exposures among children; (4) maps documenting the presence of environmental hazards in every county statewide; (5) iterative charting of a changing political landscape; and (6) persistence. The 2017 award of a 5-year, $10 million contract to establish Centers of Excellence in CEH demonstrates the value of this statewide strategy.

In January 2017, the Colorado Department of Public Health and Environment (CDPHE) identified four epidemiologically linked cases of mumps among persons from a Marshallese community who were members of the same church in the Denver metropolitan area. During 2016-2017, sizable outbreaks of mumps reported in Arkansas, Hawaii, and Washington also affected the Marshallese population (1). CDPHE, the Tri-County Health Department (TCHD), and Denver Public Health collaborated to conduct an outbreak investigation during January-March 2017 using active and passive surveillance that identified 17 confirmed and 30 probable cases. Public health actions included conducting measles-mumps-rubella (MMR) vaccination clinics at local Marshallese churches; these resulted in the vaccination of 126 persons with ≥1 doses of MMR vaccine. Implementation of active surveillance and support from local Marshallese church leaders in promoting vaccination programs likely contributed to interruption of the outbreak., Competing Interests: All authors have completed and submitted the ICMJE form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Scleractinian corals, primarily plate corals in families Agaricidae and Acroporidae, were monitored in situ before, during and after a 3D marine seismic survey. An initial four day seismic run, resulting in a maximum 24 h received sound exposure level (SEL 24 ) of 204 dB re 1 μPa 2 ·s and received 0-to-peak pressure (PK Pressure) of 226 dB re 1 μPa, had no detectable effect on soft tissues or skeletal integrity. Subsequently, a full marine seismic survey (Maxima 3D MSS), proceeded over two months and included seismic acquisition lines at 240 m spacing over the broader reef lagoon (South Scott Reef), generating maximum received SEL 24 of 197 dB re 1 μPa 2 ·s and received PK Pressure of 220 dB re 1 μPa at the coral monitoring sites. The analysis detected no effect of seismic activity measured as coral mortality, skeletal damage or visible signs of stress immediately after and up to four months following the 3D marine seismic survey., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: To test the effects of employer subsidies on employee enrollment, attendance, and weight loss in a nationally available weight management program., Design: A randomized trial tested the impact of employer subsidy: 100%; 80%, 50%, and a hybrid 50% subsidy that could become a 100% subsidy by attaining attendance targets., Trial Registration: NCT01756066., Setting and Participants: Twenty three thousand twenty-three employees of 2 US companies., Measures: The primary outcome was the percentage of employees who enrolled in the weight management program. We also tested whether the subsidies were associated with differential attendance and weight loss over 12 months, as might be predicted by the expectation that they attract employees with differing degrees of motivation. Analysis and Results: Enrollment differed significantly by subsidy level ( P < .0001). The 100% subsidy produced the highest enrollment (7.7%), significantly higher than each of the lower subsidies (vs 80% subsidy: 6.2%, P = .002; vs 50% subsidy: 3.9%, P < .0001; vs hybrid: 3.7%, P < .0001). Enrollment in the 80% subsidy group was significantly higher than both lower subsidy groups (vs 50% subsidy: 3.9%, P < .0001; vs hybrid: 3.7%, P < .0001). Among enrollees, there were no differences among the 4 groups in attendance or weight loss., Conclusion: This pragmatic trial, conducted in a real-world workplace setting, suggests that higher rates of employer subsidization help individuals to enroll in weight loss programs, without a decrement in program effectiveness. Future research could explore the cost-effectiveness of such subsidies or alternative designs.

Aims: Type 2 diabetes mellitus (T2DM) can substantially decrease quality of life (QOL). This study examined the effects on QOL-relevant psychosocial measures of a widely available commercial weight loss program enhanced for individuals with T2DM., Methods: A year-long multi-site randomized clinical trial compared the Weight Watchers (WW) approach, supplemented with phone and email counseling with a certified diabetes educator (CDE), to brief standard diabetes nutrition counseling and education (Standard Care; SC). Participants were 400 women and 163 men (N=279 WW; 284 SC) with T2DM [mean (±SD) HbA 1c 8.32±1%; BMI=37.1±5.7kg/m 2 ; age=55.1 ± 9.1years]. Psychosocial outcomes were assessed at baseline, month 6, and month 12 using a diabetes specific psychosocial measure (Diabetes Distress Scale [DDS]), Impact of Weight on Quality of Life-Lite scale (IWQOL), a generic QOL measure (SF-36), and a depression screen (PHQ-9)., Results: WW participants showed significantly greater improvements than did SC participants on all DDS subscales and total score and on IWQOL total score and physical function, sex life and work domains (all ps<.05). There was no significant treatment effect on SF-36 scores or PHQ-9., Conclusions: WW enhanced for individuals with T2DM was superior to SC in improving psychosocial outcomes most specific to T2DM and obesity. Available commercial WL programs, combined with scalable complementary program-specific diabetes counseling, may have benefits that extend to diabetes-related distress and weight-relevant QOL., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Residential aged care environments can provide valuable learning opportunities for health professional education. An aged care community-university partnership developed the Beyond the Teaching Nursing Home: Community Partnership of Learning and Care (BTTNH: CPLC) programme, where older adults volunteer in learning activities with health professional students. This article describes medical students' experience of participating in a clinical learning activity as part of the broader programme., Method: Fourth-year medical students (enrolled in a 6-year medical degree) on geriatric medicine rotation participated in a half-day clinical visit as part of the BTTNH: CPLC programme. Medical students participated in an interview activity with an older adult from the aged care facility. A survey was administered to evaluate medical students' experience of the structured clinical visit to a residential aged care facility. Residential aged care environments can provide valuable learning opportunities for health professional education RESULTS: Medical students valued the learning experience of interacting with older adults, observation of the residential aged care environment and learning about the needs of older adults living in residential aged care., Conclusions: Providing meaningful learning opportunities for medical students in residential aged care environments may contribute to a better understanding of residents, aged care environments, development of communication skills, professional role and clinical decision-making skills that are relevant for the care of older adults not only in aged care but also in other care settings., (© 2016 John Wiley & Sons Ltd.)

GUIDED-HF (Get With the Guidelines in Emergency Department Patients With Heart Failure) is a multicenter randomized trial of a patient-centered transitional care intervention in patients with acute heart failure (AHF) who are discharged either directly from the emergency department (ED) or after a brief period of ED-based observation. To optimize care and reduce ED and hospital revisits, there has been significant emphasis on improving transitions at the time of hospital discharge for patients with HF. Such efforts have been almost exclusively directed at hospitalized patients; individuals with AHF who are discharged from the ED or ED-based observation are not included in these transitional care initiatives. Patients with AHF discharged directly from the ED or after a brief period of ED-based observation are randomly assigned to our transition GUIDED-HF strategy or standard ED discharge. Patients in the GUIDED arm receive a tailored discharge plan via the study team, based on their identified barriers to outpatient management and associated guideline-based interventions. This plan includes conducting a home visit soon after ED discharge combined with close outpatient follow-up and subsequent coaching calls to improve postdischarge care and avoid subsequent ED revisits and inpatient admissions. Up to 700 patients at 11 sites will be enrolled over 3 years of the study. GUIDED-HF will test a novel approach to AHF management strategy that includes tailored transitional care for patients discharged from the ED or ED-based observation. If successful, this program may significantly alter the current paradigm of AHF patient care., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02519283., (© 2017 American Heart Association, Inc.)

Objective: Modest weight loss from clinical interventions improves glycemic control in type 2 diabetes (T2DM). Data are sparse on the effects of weight loss via commercial weight loss programs. This study examined the effects on glycemic control and weight loss of the standard Weight Watchers program, combined with telephone and email consultations with a certified diabetes educator (WW), compared with standard diabetes nutrition counseling and education (standard care, SC)., Methods: In a 12-month randomized controlled trial at 16 U.S. research centers, 563 adults with T2DM (HbA 1c 7-11%; BMI 27-50 kg/m 2 ) were assigned to either the commercially available WW program (regular community meetings, online tools), plus telephone and email counseling from a certified diabetes educator, or to SC (initial in-person diabetes nutrition counseling/education, with follow-up informational materials)., Results: Follow-up rate was 86%. Twelve-month HbA 1c changes for WW and SC were -0.32 and +0.16, respectively; 24% of WW versus 14% of SC achieved HbA 1c <7.0% (P = 0.004). Weight losses were -4.0% for WW and -1.9% for SC (Ps < 0.001). 26% of WW versus 12% of SC reduced diabetes medications (P < 0.001). WW participants had greater reductions in waist circumference (P < 0.001) and C-reactive protein (P = 0.02) but did not differ on other cardiovascular risk factors., Conclusions: Widely available commercial weight loss programs with community and online components, combined with scalable complementary diabetes education, may represent accessible and effective components of management plans for adults with overweight/obesity and T2DM., (© 2016 The Obesity Society.)

Clinical interest in the measurement of Cereblon (CRBN), the primary target of the IMiDs immunomodulatory drugs lenalidomide and pomalidomide, has been fueled by its essential requirement for antitumor or immunomodulatory activity of both drugs in multiple myeloma (MM). However, limited analyses of clinical samples for CRBN gene expression or protein levels have utilized unvalidated reagents and assays, raising uncertainty about the interpretation of these results. We previously described a highly specific rabbit monoclonal antibody CRBN65 against 65-76 AA of human Cereblon. Here we describe a validated dual color bright-field Cereblon/CD138 immunohistochemical (IHC) assay utilizing CRBN65 and a commercial mouse monoclonal CD138 antibody. Sensitivity and specificity of the assay was determined and assay precision was shown for both cytoplasmic and nuclear Cereblon in MM bone marrow samples with coefficient of variation values of 5% and 2%, respectively. The dual IHC assay was effective for detecting a continuous range of Cereblon levels in 22 MM patient bone marrow core biopsies and aspirate clots, as shown by average cytoplasmic H-scores ranging from 63 to 267 and nuclear H-scores ranging from 17 to 250. Interpathologist comparison of MM sample H-scores by 3 pathologists demonstrated good concordance (R=0.73). This dual assay demonstrated superior Cereblon IHC measurement in MM samples compared with the single IHC assay using a published commercial rabbit polyclonal Cereblon antibody and could be used to explore the potential utility of Cereblon as a biomarker in the clinic., Competing Interests: All authors except D.E.H. are employees of Celgene and all Celgene employees have equity ownership in Celgene Corporation. D.E.H. is a Celgene consultant.

Immunomodulatory drugs bind to cereblon (CRBN) to confer differentiated substrate specificity on the CRL4(CRBN) E3 ubiquitin ligase. Here we report the identification of a new cereblon modulator, CC-885, with potent anti-tumour activity. The anti-tumour activity of CC-885 is mediated through the cereblon-dependent ubiquitination and degradation of the translation termination factor GSPT1. Patient-derived acute myeloid leukaemia tumour cells exhibit high sensitivity to CC-885, indicating the clinical potential of this mechanism. Crystallographic studies of the CRBN-DDB1-CC-885-GSPT1 complex reveal that GSPT1 binds to cereblon through a surface turn containing a glycine residue at a key position, interacting with both CC-885 and a 'hotspot' on the cereblon surface. Although GSPT1 possesses no obvious structural, sequence or functional homology to previously known cereblon substrates, mutational analysis and modelling indicate that the cereblon substrate Ikaros uses a similar structural feature to bind cereblon, suggesting a common motif for substrate recruitment. These findings define a structural degron underlying cereblon 'neosubstrate' selectivity, and identify an anti-tumour target rendered druggable by cereblon modulation.

Objective: Weight losses between a group of participants assigned to a weight loss program based in the community [i.e., specifically the methodology used by Weight Watchers (WW)] and a Nutrition Education (NE) control group were compared in this study., Methods: In this 6-month trial, 300 participants with overweight or obesity were recruited from Beijing city, China, and randomly assigned to the WW or NE group. Weight, waist circumference, and biochemical parameters were assessed at baseline and 6 months., Results: At 6 months, the majority of participants (79% for WW; 89% for NE) completed the study. WW participants lost significantly more weight than the NE group (-4.2 ± 5.6 kg vs. -0.6 ± 3.6 kg). More WW participants lost 5% or 10% of their starting weight [≥5%: 52.0% of WW participants vs. 11.3% of NE participants (odds ratio 8.15, 95% CI: 4.43-14.97)]; [≥10%: 26.0% of WW vs. 3.3% of NE participants (odds ratio 9.39, 95% CI: 3.55-24.83)]. In addition, WW participants reduced waist circumference by 3.9 ± 6.3 cm, while the NE group increased waist circumference by 0.6 ± 5.5 cm., Conclusions: The WW program was associated with clinically significant weight loss, demonstrating its potential value as an intervention strategy, based in the community, for the treatment of obesity in China., (© 2016 The Obesity Society.)

Objectives: To determine if a widely available weight-management program (Weight Watchers) could achieve sufficient weight loss in persons with prediabetes compared with a Diabetes Prevention Program-based individual counseling program supported by National Diabetes Education Program materials., Methods: We conducted an individual, randomized intervention trial in Indianapolis, Indiana, in 2013 to 2014, in 225 persons with prediabetes. We compared the Weight Watchers weight-management program (n = 112) with Your Game Plan to Prevent Type 2 Diabetes, a program developed by the National Diabetes Education Program. Outcomes were weight and metabolic markers measured at baseline, 6 months, and 12 months., Results: Intervention participants lost significantly more weight than controls at 6 months (5.5% vs 0.8%) and 12 months (5.5% vs 0.2%; both P < .001). The intervention group also had significantly greater improvements in hemoglobin A1c and high-density lipoprotein cholesterol level than did controls., Conclusions: A large weight-management program is effective for achieving lifestyle changes associated with diabetes prevention. Such programs could significantly increase the availability of diabetes prevention programs worldwide making an immediate and significant public health impact.

In changing higher education environments, health profession's educators have been increasingly challenged to prepare future health professionals to care for aging populations. This article reports on an exploratory, mixed-method research study that used an innovative photo-elicitation technique and interprofessional small-group work in the classroom to enhance the reflective learning experience of medical and nursing students. Data were collected from pre- and postquestionnaires and focus groups to explore shifts in perceptions toward older persons following the reflective learning session. The qualitative data revealed how using visual images of older persons provides a valuable learning space for reflection. Students found meaning in their own learning by creating shared storylines that challenged their perceptions of older people and themselves as future health professionals. These data support the use of visual methodologies to enhance engagement, reflection, and challenge students to explore and deepen their understanding in gerontology.

Pomalidomide is an IMiD(®) immunomodulatory agent, which has shown clinically significant benefits in relapsed and/or refractory multiple myeloma (rrMM) patients when combined with dexamethasone, regardless of refractory status to lenalidomide or bortezomib. (Schey et al, ; San Miguel et al, 2013; Richardson et al, 2014; Scott, ) In this work, we present preclinical data showing that the combination of pomalidomide with dexamethasone (PomDex) demonstrates potent anti-proliferative and pro-apoptotic activity in both lenalidomide-sensitive and lenalidomide-resistant MM cell lines. PomDex also synergistically inhibited tumour growth compared with single-agent treatment in xenografts of lenalidomide-resistant H929 R10-1 cells. Typical hallmarks of IMiD compound activity, including IKZF3 (Aiolos) degradation, and the downregulation of interferon regulatory factor (IRF) 4 and MYC, seen in lenalidomide-sensitive H929 MM cell lines, were also observed in PomDex-treated lenalidomide-resistant H929 MM cells. Remarkably, this resulted in strong, synergistic effects on the induction of apoptosis in both lenalidomide-sensitive and resistant MM cells. Furthermore, gene expression profiling revealed a unique differential gene expression pattern in PomDex-treated samples, highlighted by the modulation of pro-apoptotic pathways in lenalidomide-resistant cells. These results provide key insights into molecular mechanisms of PomDex in the lenalidomide-resistant setting., (© 2016 John Wiley & Sons Ltd.)

A complete taxonomic revision of the genus Primnoisis (Isididae) is presented herein, based on original type material of all nominal species and additional specimens from deep-water surveys in sub-temperate and Antarctic waters. A multi-disciplinary approach was used combining morphological characteristics such as colonial branching patterns, polyp structure, sclerite form and arrangement, together with phylogenetic reconstructions using two mitochondrial gene regions (mtMutS and igr1-cox1). The genus Primnoisis is retained with 7 of the 8 nominal species validated (P. antarctica Wright & Studer, 1889, P. rigida Wright & Studer, 1889, P. ambigua Wright & Studer, 1889, P. delicatula Hickson, 1907, P. fragilis Kükenthal, 1912, P. formosa Gravier, 1913 and P. mimas Bayer & Stefani, 1987), with the eighth (P. sparsa Wright & Studer, 1889), synonymised with P. antarctica. In addition, the species Mopsea gracilis Gravier, 1913 is reassigned to Primnoisis and an additional five new species are described (P. chatham n. sp., P. erymna n. sp., P. millerae n. sp., P. niwa n. sp. and P. tasmani n. sp). Most of the species fell into two clear groups, defined both by morphology and genetic grouping, for which two new sub-genera are proposed (P. (Primnoisis) n. subg. and P. (Delicatisis) n. subg.). Three species, P. ambigua, P. mimas and P. tasmani, could not be placed reliably in either sub-genus due to distinctive morphological features or genetic dissimilarity. It was not possible to confirm the monophyly of the genus due to unresolved relationships with the closely related genus Notisis Gravier, 1913 and an undescribed genus of Mopseinae.

Background: Major, long-term environmental changes are projected in the Southern Ocean and these are likely to have impacts for marine predators such as the Adélie penguin (Pygoscelis adeliae). Decadal monitoring studies have provided insight into the short-term environmental sensitivities of Adélie penguin populations, particularly to sea ice changes. However, given the long-term nature of projected climate change, it is also prudent to consider the responses of populations to environmental change over longer time scales. We investigated the population trajectory of Adélie penguins during the last glacial-interglacial transition to determine how the species was affected by climate warming over millennia. We focussed our study on East Antarctica, which is home to 30 % of the global population of Adélie penguins., Methods: Using mitochondrial DNA from extant colonies, we reconstructed the population trend of Adélie penguins in East Antarctica over the past 22,000 years using an extended Bayesian skyline plot method. To determine the relationship of East Antarctic Adélie penguins with populations elsewhere in Antarctica we constructed a phylogeny using mitochondrial DNA sequences., Results: We found that the Adélie penguin population expanded 135-fold from approximately 14,000 years ago. The population growth was coincident with deglaciation in East Antarctica and, therefore, an increase in ice-free ground suitable for Adélie penguin nesting. Our phylogenetic analysis indicated that East Antarctic Adélie penguins share a common ancestor with Adélie penguins from the Antarctic Peninsula and Scotia Arc, with an estimated age of 29,000 years ago, in the midst of the last glacial period. This finding suggests that extant colonies in East Antarctica, the Scotia Arc and the Antarctic Peninsula were founded from a single glacial refuge., Conclusions: While changes in sea ice conditions are a critical driver of Adélie penguin population success over decadal and yearly timescales, deglaciation appears to have been the key driver of population change over millennia. This suggests that environmental drivers of population trends over thousands of years may differ to drivers over years or decades, highlighting the need to consider millennial-scale trends alongside contemporary data for the forecasting of species' abundance and distribution changes under future climate change scenarios.

Purpose: To quantify the impact of a commercial weight management program on weight change in obese patients with coronary heart disease., Methods: An observational, single-center pilot study in the Netherlands. Forty-five patients diagnosed with a recent acute coronary syndrome and a body mass index of >30 kg/m2 were recruited. The commercial weight management intervention (Weight Watchers) promotes a hypoenergetic and balanced diet, increased physical activity, and group support. The program included weekly 30-minute in-hospital meetings with an experienced coach. The program was offered in parallel with a cardiac rehabilitation program., Results: Thirty-five patients completed the program. Of these patients, 32 patients (91%) decreased body weight. Mean weight change was -5.8 kg (range: +0.6 kg to -15.4 kg), and 20 patients (57%) achieved the target of 5% weight loss of their initial weight. Twenty-seven patients continued the commercial weight loss program after 14 weeks, the mean followup of these patients was 34 weeks and their mean weight change was -9.1 kg (range: 0.0-23.0 kg)., Conclusions: Obese patients, discharged after an acute coronary syndrome, who were referred to a commercial weight management program, achieved significant weight loss. Although this is a nonrandomized pilot study with patients who were selected by motivation and by the ability to participate in the program, the proportion of weight loss is significant and promising.

Unlabelled: The purpose of this article is to recommend a risk-based strategy for determining clearance testing requirements of the process reagents used in manufacturing biopharmaceutical products. The strategy takes account of four risk factors. Firstly, the process reagents are classified into two categories according to their safety profile and history of use: generally recognized as safe (GRAS) and potential safety concern (PSC) reagents. The clearance testing of GRAS reagents can be eliminated because of their safe use historically and process capability to remove these reagents. An estimated safety margin (Se) value, a ratio of the exposure limit to the estimated maximum reagent amount, is then used to evaluate the necessity for testing the PSC reagents at an early development stage. The Se value is calculated from two risk factors, the starting PSC reagent amount per maximum product dose (Me), and the exposure limit (Le). A worst-case scenario is assumed to estimate the Me value, that is common. The PSC reagent of interest is co-purified with the product and no clearance occurs throughout the entire purification process. No clearance testing is required for this PSC reagent if its Se value is ≥1; otherwise clearance testing is needed. Finally, the point of the process reagent introduction to the process is also considered in determining the necessity of the clearance testing for process reagents. How to use the measured safety margin as a criterion for determining PSC reagent testing at process characterization, process validation, and commercial production stages are also described., Lay Abstract: A large number of process reagents are used in the biopharmaceutical manufacturing to control the process performance. Clearance testing for all of the process reagents will be an enormous analytical task. In this article, a risk-based strategy is described to eliminate unnecessary clearance testing for majority of the process reagents using four risk factors. The risk factors included in the strategy are (i) safety profile of the reagents, (ii) the starting amount of the process reagents used in the manufacturing process, (iii) the maximum dose of the product, and (iv) the point of introduction of the process reagents in the process. The implementation of the risk-based strategy can eliminate clearance testing for approximately 90% of the process reagents used in the manufacturing processes. This science-based strategy allows us to ensure patient safety and meet regulatory agency expectations throughout the product development life cycle., (© PDA, Inc. 2015.)

The Cul4-Rbx1-DDB1-Cereblon E3 ubiquitin ligase complex is the target of thalidomide, lenalidomide and pomalidomide, therapeutically important drugs for multiple myeloma and other B-cell malignancies. These drugs directly bind Cereblon (CRBN) and promote the recruitment of substrates Ikaros (IKZF1) and Aiolos (IKZF3) to the E3 complex, thus leading to substrate ubiquitination and degradation. Here we present the crystal structure of human CRBN bound to DDB1 and the drug lenalidomide. A hydrophobic pocket in the thalidomide-binding domain (TBD) of CRBN accommodates the glutarimide moiety of lenalidomide, whereas the isoindolinone ring is exposed to solvent. We also solved the structures of the mouse TBD in the apo state and with thalidomide or pomalidomide. Site-directed mutagenesis in lentiviral-expression myeloma models showed that key drug-binding residues are critical for antiproliferative effects.

CoA (coenzyme A) is an essential cofactor that is involved in many metabolic processes. CoA is derived from pantothenate in five biosynthetic reactions. The CoA biosynthetic pathway is regulated by PanKs (pantothenate kinases) and four active isoforms are expressed in mammals. The critical physiological functions of the PanKs are revealed by systematic deletion of the Pank genes in mice.

Purpose: To examine the production of plural morphology in children acquiring a dialect of Spanish with syllable-final /s/ lenition with the goal of comparing how plural marker omissions in the speech of these children compare with plural marker omissions in children with language impairment acquiring other varieties of Spanish., Method: Three production tasks were administered to children. A repetition task was used to examine children's production of the plural marker in plural noun phrases, and 2 Berko-style tasks evaluated children's production of the plural marker in bare nouns. Behavior on these tasks was compared with plural marker comprehension for each individual child., Results: There was a correlation between children's comprehension of the plural marker and their production of the plural marker on plural noun phrases in the repetition task but not between comprehension and production of the plural marker on bare nouns in the Berko-style tasks., Conclusions: Assessments of plural morphology as a clinical marker of language impairment in Spanish-speaking children may be problematic, especially in children acquiring dialects of Spanish with /s/ lenition, such as those originating in Chile, the Dominican Republic, Cuba, Puerto Rico, and Central America. Instead, for children acquiring /s/-leniting dialects of Spanish, assessments of the plural marker in noun phrases produced within a sentence frame may be a better indicator of acquisition than traditional Berko-style tasks that elicit bare nouns.

The hedgehog (Hh) pathway is aberrantly activated in a number of tumors. In medulloblastoma, basal cell carcinoma, and rhabdomyosarcoma, mutations in Hh pathway genes lead to ligand-independent pathway activation. In many other tumor types, ligand-dependent activation of Hh signaling is potentiated through crosstalk with other critical molecular signaling pathways. Among such pathways, RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, EGFR, and Notch are of particular interest because agents that selectively inhibit these pathways are available and can be readily combined with agents such as vismodegib, sonidegib (LDE225), and BMS-833923, which target smoothened-a key Hh pathway regulator. Numerous preclinical studies have revealed the ways in which Hh intersects with each of these pathways, and combination therapies have resulted in improved antitumor efficacy and survival in animal models. Hh also plays an important role in hematopoiesis and in the maintenance of BCR-ABL-driven leukemic stem cells. Thus, combined inhibition of the Hh pathway and BCR-ABL has emerged as a promising potential therapeutic strategy in chronic myeloid leukemia (CML). A number of clinical trials evaluating combinations of Hh inhibitors with other targeted agents are now underway in CML and a variety of solid tumors. This review highlights these trials and summarizes preclinical evidence of crosstalk between Hh and four other actionable pathways-RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, EGFR, and Notch-as well as the role of Hh in the maintenance of BCR-ABL-driven leukemic stem cells., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Aspirin (ASA) is recommended for the prevention of cardiovascular disease; however, the compliance is low. Reported use may not reflect actual use. Serum thromboxane B2 (STxB2) measurement was evaluated to validate reported ASA use. Males aged 45 to 79 years and females aged 55 to 79 years completed a survey and STxB2 measurement (Thromboxane B2 EIA Kit; Cayman Chemical, Ann Arbor, Michigan). The 107 patients were grouped by use of ASA (56 ASA+ and 51 ASA-) and possible interfering medications (INT) such as nonsteroidal anti-inflammatory drugs. The STxB2 levels (ng/mL) were significantly lower in ASA users: ASA+ INT- 3.0 (0.7, 8.4), ASA+ INT+ 2.0 (0.8, 4.9), ASA- INT+ 176 (75, 390), and ASA- INT- 271 (199, 366). The INT use did not cause a significant difference in STxB2 levels. A STxB2 cut point of 25 ng/mL had high sensitivity (94.1%) and specificity (91.1%) for ASA use. The STxB2 was a reliable marker of ASA use and could be used to confirm ASA exposure in population-based health studies.

Cereblon, a member of the cullin 4 ring ligase complex (CRL4), is the molecular target of the immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide and is required for the antiproliferative activity of these agents in multiple myeloma (MM) and immunomodulatory activity in T cells. Cereblon's central role as a target of lenalidomide and pomalidomide suggests potential utility as a predictive biomarker of response or resistance to IMiD therapy. Our studies characterized a cereblon monoclonal antibody CRBN65, with high sensitivity and specificity in Western analysis and immunohistochemistry that is superior to commercially available antibodies. We identified multiple cereblon splice variants in both MM cell lines and primary cells, highlighting challenges with conventional gene expression assays given this gene complexity. Using CRBN65 antibody and TaqMan quantitative reverse transcription polymerase chain reaction assays, we showed lack of correlation between cereblon protein and mRNA levels. Furthermore, lack of correlation between cereblon expression in MM cell lines and sensitivity to lenalidomide was shown. In cell lines made resistant to lenalidomide and pomalidomide, cereblon protein is greatly reduced. These studies show limitations to the current approaches of cereblon measurement that rely on commercial reagents and assays. Standardized reagents and validated assays are needed to accurately assess the role of cereblon as a predictive biomarker., (© 2013 Celgene Corporation. British Journal of Haematology published by John Wiley & Sons Ltd.)

Objective: This study assessed changes in cardiovascular disease risk factors among participants in a 12-week behavioral weight loss intervention featuring a commercial format., Method: 132 participants were enrolled in a randomized controlled trial of a 12-week group-based lifestyle intervention that involved two structured food plan conditions. Of them, 112 (100 women and 12 men, mean BMI=31.44 ± 2.18 kg/m(2)) completed the program with post-treatment assessments. Weight and changes in risk factors (cholesterol, triglycerides, fasting blood glucose, and blood pressure) were assessed at pre- and posttreatment. Additionally, changes for each risk factor were examined among participants with baseline values of risk factors beyond recommended cut points., Results: With no weight loss differences between conditions, analyses used the combined sample. Participants lost 3.74 ± 3.16 kg (4.37 ± 3.71% of baseline weight), and exhibited significant decreases in triglyceride, total cholesterol and LDL-cholesterol levels. There were trends toward reductions in fasting glucose, systolic blood pressure, and HDL cholesterol. Among participants with elevated baseline values, significant reductions were seen on all risk factors, with the exception of HDL cholesterol., Discussion: Modest weight loss achieved via a relatively brief, non-intensive intervention using a commercial format can yield significant improvements in cardiovascular disease risk factors, particularly among individuals with initially higher-risk values., (© 2013.)

Case: Julie is a 4-year-old girl with autism spectrum disorder (ASD) who presented to the emergency room with severe unilateral hip pain and limping. Initial evaluation indicated increased inflammatory markers and blasts on a blood smear. A bone marrow biopsy revealed acute lymphoblastic leukemia (ALL), and Julie was admitted for induction chemotherapy. Julie was diagnosed with ASD 1 year before this presentation. Her parents, who had immigrated to the United States from China before her birth, indicated that it took them some time to accept the diagnosis of ASD but they were feeling more confident in addressing her behavior challenges and comfortable with the progress she had been making. They now expressed concerns about the possible loss of services in the setting of her hospitalization. At the time of diagnosis, Julie had been receiving in-home behavioral therapy (applied behavioral analysis), speech therapy, and occupational therapy at a hospital-based center. In addition, she had an individualized education plan and was enrolled in a specialized preschool classroom for children with ASD.As Julie's hospital stay became more prolonged, her medical care team started reporting more challenges communicating with Julie without the presence of 1 of her parents, difficulty conducting routine care (e.g., obtaining vitals), sleep disruption, and safety concerns (e.g., Julie would frequently climb on the window sill increasing her fall risk). As her primary care clinician, you are called by the hospital team to help bridge the communication and behavioral divide that has widened--what would you do next?

Background: The US Preventive Services Task Force (USPSTF) recommends that clinicians refer obese adults for intensive, multicomponent behavioral counseling, yet most obese Americans choose a self-help approach to lose weight. The current study examined weight loss between a community-based, intensive behavioral counseling program (Weight Watchers program) and a self-help condition., Methods: A total of 292 participants were randomized to either a Weight Watchers condition (WW) (n = 147) or a self-help condition (n = 145). Participants in the WW condition were provided with 3 ways to access the treatment: weekly meetings; WW mobile application; and WW online tools. Weights were measured at baseline and at 3 and 6 months. Additionally, self-report use of access modes was collected at 3 and 6 months., Results: Participants in the WW condition significantly decreased their body mass index at 6 months (F = 36.7, P <.001) and were 8.0 and 8.8 times more likely to achieve a 5% and 10% reduction in weight, respectively, compared with those in the self-help condition. In a secondary analysis, high usage of all 3 access modes resulted in the greatest weight loss (P <.001)., Conclusion: Use of the WW program yielded significantly greater weight loss than a self-help approach, suggesting it is a viable community-based provider of weight loss treatment, as recommended by the USPSTF. Further, high usage of 3 access modes was associated with greater weight loss results., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Overexpression of the antiapoptotic members of the Bcl-2 family of proteins is commonly associated with cancer cell survival and resistance to chemotherapeutics. Here, we describe the structure-based optimization of a series of N-heteroaryl sulfonamides that demonstrate potent mechanism-based cell death. The role of the acidic nature of the sulfonamide moiety as it relates to potency, solubility, and clearance is examined. This has led to the discovery of novel heterocyclic replacements for the acylsulfonamide core of ABT-737 and ABT-263.

Background: More than 25% of Medicare patients hospitalized for heart failure are readmitted within 30 days. The contributions of numeracy and health literacy to recidivism for patients with acute heart failure (AHF) are not known., Methods and Results: A cohort of patients with acute heart failure who presented to 4 emergency departments between January 2008 and September 2011. Research assistants administered subjective measures of numeracy and health literacy; 30-day follow-up was performed by phone interview. Recidivism was defined as any unplanned return to the emergency department or hospital within 30 days of the index emergency department visit for AHF. Multivariable logistic regression adjusting for patient age, sex, race, insurance status, hospital site, days eligible for recidivism, chronic kidney disease, abnormal hemoglobin, and low ejection fraction evaluated the relation between numeracy and health literacy with 30-day recidivism. Of the 709 patients included in the analysis, 390 (55%) had low numeracy skills and 258 (37%) had low literacy skills. Low numeracy was associated with increased odds of recidivism within 30 days (adjusted odds ratio, 1.41; 95% confidence interval, 1.00-1.98; P=0.048). For low health literacy, adjusted odds ratio of recidivism was 1.17 (95% confidence interval, 0.83-1.65; P=0.37)., Conclusions: Low numeracy was associated with greater odds of 30-day recidivism. Further investigation is warranted to determine whether addressing numeracy and health literacy may reduce 30-day recidivism for patients with acute heart failure.

This work is aimed at correlating pre-mortem [18F]FDDNP positron emission tomography (PET) scan results in a patient with dementia with Lewy bodies (DLB), with cortical neuropathology distribution determined postmortem in three physical dimensions in whole brain coronal sections. Analysis of total amyloid-β (Aβ) distribution in frontal cortex and posterior cingulate gyrus confirmed its statistically significant correlation with cortical [18F]FDDNP PET binding values (distribution volume ratios, DVR) (p < 0.001, R = 0.97, R2 = 0.94). Neurofibrillary tangle (NFT) distribution correlated significantly with cortical [18F]FDDNP PET DVR in the temporal lobe (p < 0.001, R = 0.87, R2 = 0.76). Linear combination of Aβ and NFT densities was highly predictive of [18F]FDDNP PET DVR through all analyzed regions of interest (p < 0.0001, R = 0.92, R2 = 0.85), and both densities contributed significantly to the model. Lewy bodies were present at a much lower level than either Aβ or NFTs and did not significantly contribute to the in vivo signal. [18F]FDG PET scan results in this patient were consistent with the distinctive DLB pattern of hypometabolism. This work offers a mapping brain model applicable to all imaging probes for verification of imaging results with Aβ and/or tau neuropathology brain distribution using immunohistochemistry, fluorescence microscopy, and autoradiography.

Greater use of key self-regulatory behaviors (e.g., self-monitoring of food intake and weight) is associated with greater weight loss within behavioral weight loss treatments, although this association is less established within widely-available commercial weight loss programs. Further, high hedonic hunger (i.e., susceptibility to environmental food cues) may present a barrier to successful behavior change and weight loss, although this has not yet been examined. Adult men and women (N=111, body mass index M±SD=31.5±2.7kg/m(2)) were assessed before and after participating in a 12-week commercial weight loss program. From pre- to post-treatment, reported usage of weight control behaviors improved and hedonic hunger decreased, and these changes were inversely associated. A decrease in hedonic hunger was associated with better weight loss. An improvement in reported weight control behaviors (e.g., self-regulatory behaviors) was associated with better weight loss, and this association was even stronger among individuals with high baseline hedonic hunger. Findings highlight the importance of specific self-regulatory behaviors within weight loss treatment, including a commercial weight loss program developed for widespread community implementation. Assessment of weight control behavioral skills usage and hedonic hunger may be useful to further identify mediators of weight loss within commercial weight loss programs. Future interventions might specifically target high hedonic hunger and prospectively examine changes in hedonic hunger during other types of weight loss treatment to inform its potential impact on sustained behavior change and weight control., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Aims: Lacosamide (LCM; SPM 927, Vimpat®) is an antiepileptic drug (AED) used as adjunctive treatment for adults with partial-onset seizures. LCM has a different mode of action from traditional sodium channel blocking AEDs in that it selectively enhances slow inactivation of sodium channels without affecting fast inactivation. Initial investigations suggested that LCM might have an additional mode of action by binding to the collapsin response mediator protein 2 (CRMP-2), which is further investigated here., Methods: LCM binding to native and cloned human CRMP-2 was determined using radioligand binding experiments and surface plasmon resonance measurements., Results: No specific binding of [(3) H]LCM (free concentration 100-1450 nM) to isolated or membrane bound human CRMP-2 expressed in mammalian cell systems and bacteria was observed. Surface plasmon resonance analysis also showed that LCM, over a concentration range of 0.39-100 μM, does not specifically bind to human CRMP-2., Conclusion: The diverse drug binding methods employed here are well suited to detect specific binding of LCM to CRMP-2 in the micromolar range, yet the results obtained were all negative. Results of this study suggest that LCM does not specifically bind to CRMP-2., (© 2012 Blackwell Publishing Ltd.)

Breast cancer remained a hidden disease among women in the United States until the 20th century. It was initially brought into the open with public revelations from individual women, which was followed by the development of support groups and ultimately the formation of political activist groups with various priorities. Those concerned with toxic environmental exposures as a potential cause of breast cancer organized, demonstrated, and lobbied for research funding and eventually became partners in the research that arose from their efforts. One representative example was the Breast Cancer and Environment Research Centers (BCERC) Project (2003-2010), supported by the National Institute of Environmental Health Sciences (NIEHS) and the National Cancer Institute (NCI). The BCERC embedded a Community Outreach and Translational Core into its formal organizational infrastructure to ensure advocate involvement in the standing scientific subcommittees of BCERC, the first project funded by NIEHS and NCI to do so. The formal integration of advocates as partners in scientific studies focused on breast cancer is embedded in a rich history of action on the part of many courageous women. This article describes the historical evolution of breast cancer activism in the United States, which provided a critical foundation for the formation of BCERC. This description is followed by a discussion of BCERC as an example of the transdisciplinary research model, a paradigm that strives for inclusion of multiple stakeholders and increased interaction between scientists from a wide spectrum of disciplines, advocates, and lay audiences in order to more effectively conduct critical research and to translate and disseminate its findings.

The present study investigated the effects of a Neurologic Music Therapy (NMT) sensory-motor rehabilitation technique, Therapeutic Instrumental Music Performance (TIMP) as compared to Traditional Occupational Therapy (TOT), on endurance, self-perceived fatigue, and self-perceived exertion of 35 hospitalized patients in physical rehabilitation. The present study attempted to examine whether an active musical experience such as TIMP with musical cueing (i.e., rhythmic auditory cueing) during physical exercises influences one's perception of pain, fatigue, and exertion. All participants were diagnosed with a neurologic disorder or had recently undergone orthopedic surgery. Investigators measured the effects of TOT and TIMP during upper extremity exercise of the less affected or stronger upper extremity. Results showed no significant difference on endurance measures between the 2 treatment conditions (TIMP and TOT). Statistically significant differences were found between TIMP and TOT when measuring their effects on perceived exertion and perceived fatigue. TIMP resulted in significantly less perception of fatigue and exertion levels than TOT. TIMP can be used foran effective sensory-motor rehabilitation technique to decrease perceived exertion and fatigue level of inpatients in physical rehabilitation.

Inhibitors of the Hedgehog (Hh) molecular signaling pathway have emerged in recent years as a promising new class of potential therapeutics for cancer treatment. Numerous drug discovery efforts have resulted in the identification of a wide variety of small molecules that target different members of this pathway, including Smoothened (Smo), Sonic hedgehog protein (Shh), and Gli1. Several Smo inhibitors have now entered human clinical trials, and successful proof-of-concept studies have been carried out in patients with defined genetic mutations in the Hh pathway. This review provides a general overview of three main topics in this rapidly expanding area: 1) the various types of biological assays and in vivo models that have been employed for the identification and optimization of Hh pathway inhibitors; 2) Smo inhibitors reported to date, including recent clinical results where available; and 3) efforts toward the identification and characterization of inhibitors of other members of the Hh pathway.

CASE 1: At 3 years of age, Billy was seen by his pediatrician for a well child visit. Spontaneous speech was limited during the visit. He did not interact with the pediatrician and attempts to play with Billy resulted in oppositional behavior. About 3 months after the visit, Billy's parents requested a developmental evaluation; he was diagnosed with autism by means of an observational measure and a parent interview. Billy was born full term after an uncomplicated labor, delivery and postnatal period. Motor milestones were normal. His parents recalled that he used his finger to point to an object prior to using words. He spoke several single words by his first birthday and used phrases before age 2 years. Billy was described as often having difficulty with transitions, but he is happy and outgoing in familiar situations. At 3 years old, when he started preschool, Billy did not speak to either the teacher or other children. This pattern of refusal to speak persists. His parents report that he talks to them and one uncle using complete sentences with clear speech. Billy prefers to repeat activities and is reluctant to try activities. He frequently plays with the same toy cars placing them in a neat line and becomes upset if things are not done in the same way. An uncle has Asperger syndrome. CASE 2: Juan, a 3 year old Mexican-American boy, was referred by his preschool teacher because "he does not interact with other children or use language at an age-appropriate level." He prefers to play alone, resists participation in group activities at preschool, and does not share as well as other students according to his teacher. Expressive language with speech is rarely seen in preschool. In contrast, at home he plays interactively, shares toys with his older brother and speaks in short, clear sentences. In preschool, English is spoken exclusively. At home, Spanish is the primary language. Prenatal and birth histories were uneventful. Motor and social milestones were achieved art the expected times. He spoke his first word at 18 months and 2-word phrases at 2 years. Currently, he speaks in full sentences with pleurals and pronouns. He follows commands and recently had a normal audiogram. His parents, who speak English with ease, are concerned about the teacher's observations at school. The physical examination was normal; the developmental and behavioral assessments were conducted by an English speaking clinician. Juan played interactively with toys while demonstrating curiosity, showing and joint attention. There was no speech production during a 30 minute period although he did follow directions. When a Spanish speaking clinician assumed responsibility for the assessment, Juan's speech production increased significantly. He told a story about his drawing and talked about the family dog and his brother. He had good eye contact and appropriate pragmatic speech when the dialogue was in Spanish.