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Background: Hereditary hemorrhagic telangiectasia (HHT) is characterized by extensive telangiectasias and arteriovenous malformations. The primary clinical manifestation is epistaxis that results in iron-deficiency anemia and reduced health-related quality of life., Methods: We conducted a randomized, placebo-controlled trial to evaluate the safety and efficacy of pomalidomide for the treatment of HHT. We randomly assigned patients, in a 2:1 ratio, to receive pomalidomide at a dose of 4 mg daily or matching placebo for 24 weeks. The primary outcome was the change from baseline through week 24 in the Epistaxis Severity Score (a validated bleeding score in HHT; range, 0 to 10, with higher scores indicating worse bleeding). A reduction of 0.71 points or more is considered clinically significant. A key secondary outcome was the HHT-specific quality-of-life score (range, 0 to 16, with higher scores indicating more limitations)., Results: The trial was closed to enrollment in June 2023 after a planned interim analysis met a prespecified threshold for efficacy. A total of 144 patients underwent randomization; 95 patients were assigned to receive pomalidomide and 49 to receive placebo. The baseline mean (±SD) Epistaxis Severity Score was 5.0±1.5, a finding consistent with moderate-to-severe epistaxis. At 24 weeks, the mean difference between the pomalidomide group and the placebo group in the change from baseline in the Epistaxis Severity Score was -0.94 points (95% confidence interval [CI], -1.57 to -0.31; P = 0.004). The mean difference in the changes in the HHT-specific quality-of-life score between the groups was -1.4 points (95% CI, -2.6 to -0.3). Adverse events that were more common in the pomalidomide group than in the placebo group included neutropenia, constipation, and rash., Conclusions: Among patients with HHT, pomalidomide treatment resulted in a significant, clinically relevant reduction in epistaxis severity. No unexpected safety signals were identified. (Funded by the National Heart, Lung, and Blood Institute; PATH-HHT Clinicaltrials.gov number, NCT03910244)., (Copyright © 2024 Massachusetts Medical Society.)

Self-injurious thoughts and behaviors (SITBs), including suicidal thoughts, suicide attempts, and nonsuicidal self-injury, are highly prevalent among adolescents. Identifying adolescents at risk for SITBs relies on their disclosure, and these disclosures commonly occur in therapy context. Moreover, therapists often breach confidentiality to inform adolescents' parent or guardian when they disclose SITBs. Research has explored rates of and barriers to disclosure among adolescents, yet no studies have examined adolescents' experiences of disclosure in the therapy context. Further, no studies have examined adolescents' experiences when their parents are then informed. In this study, we examined qualitative responses from 1495 adolescents who had experienced a SITB disclosure in the therapy context. Qualitative questions included asking adolescents to describe how the SITB disclosure occurred, how their parents were informed, and their parents' reactions. Using open and axial coding, several themes emerged. Adolescents described therapist breaches of confidentiality as collaborative, noncollaborative, or unclear. Adolescents described their parents' affective responses, communication about SITBs, validating and invalidating responses, treatment-oriented responses, and ways that parents restricted their access to people, places, and activities. Findings have implications for the development of clinical guidelines when adolescents disclose SITBs in therapy and highlight areas for future research in adolescent SITB disclosure., (© 2023 Wiley Periodicals LLC.)

Purpose: The Canadian Addiction Treatment Centre (CATC) cohort was established during a period of increased provision of opioid agonist treatment (OAT), to study patient outcomes and trends related to the treatment of opioid use disorder (OUD) in Canada. The CATC cohort's strengths lie in its unique physician network, shared care model and event-level data, making it valuable for validation and integration studies. The CATC cohort is a valuable resource for examining OAT outcomes, providing insights into substance use trends and the impact of service-level factors., Participants: The CATC cohort comprises 32 246 people who received OAT prescriptions between April 2014 and February 2021, with ongoing tri-annual updates planned until 2027. The cohort includes data from all CATC clinics' electronic medical records and includes demographic information and OAT clinical indicators., Findings to Date: This cohort profile describes the demographic and clinical characteristics of patients being treated in a large OAT physician network. As well, we report the longitudinal OAT retention by treatment type during a time of increasing exposure to a contaminated dangerous drug supply. Notable findings also include retention differences between methadone (32% of patients at 1 year) and buprenorphine (20% at 1 year). Previously published research from this cohort indicated that patient-level factors associated with retention include geographic location, concurrent substance use and prior treatment attempts. Service-level factors such as telemedicine delivery and frequency of urine drug screenings also influence retention. Additionally, the cohort identified rising OAT participation and a substantial increase in fentanyl use during the COVID-19 pandemic., Future Plans: Future research objectives are the longitudinal evaluation of retention and flexible modelling techniques that account for the changes as patients are treated with OAT. Furthermore, future research aims are the use of conditional models, and linkage with provincial-level administrative datasets., Competing Interests: Competing interests: DM previously held the position of Chief Medical Director at CATC ending in June 2022, and maintains the role of OAT provider. DM had no ownership stake in the CATC as a stipendiary employee. We do not foresee any conflict of interest as findings will be made freely available to the public and the CATC, and neither the Universities nor CATC can prevent publication and dissemination of knowledge. The authors have no conflicts declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Lipoabdominoplasty is an established technique, however outcomes for high lipoaspirate volumes in large series are lacking. We present the UK experience of high-volume, drainless lipoabdominoplasty using progressive deep tension sutures., Methods: 286 consecutive patients at a single centre underwent drainless lipoabdominoplasty with a lipoaspirate volume of 500 ml or greater between 2017 and 2023. Surgery was performed under total intravenous anaesthesia with SAFELipo©, MicroAire® and a superwet technique. Abdominoplasty was commenced via a low convex abdominal incision with multilayer rectus plication, and abdominal closure undertaken with progressive tension sutures. Logistic regression was used to determine the relationship between lipoaspirate volume and four primary outcomes - all complications, delayed healing, seroma, and need for revision., Results: The mean lipoaspirate volume was 2392.4 ml (500-5900), and abdominal tissue resection weight 1392.0 g (346-3802). One third of patients had local complications - minor irregularities (14.0%), abdominal scar problems (12.9%), umbilical shape/scar (4.5%), localised infection (4.2%) and delayed healing (3.8%). One (0.3%) had a small area of localised necrosis successfully managed by further tissue advancement. There was one abdominal haematoma, and two systemic complications- venous thromboembolism (0.3%) and drug-induced hepatitis. Seroma rate was 3.1%. 16.0% of patients required revision under general anaesthesia, and 6.6% under local anaesthetic. There was no significant relationship between the lipoaspirate volume and any of the four primary outcome measures., Conclusions: High-volume liposuction can safely be performed simultaneously with abdominoplasty. Our complication rates are equivalent to, or lower than other published data on lipoabdominoplasy, challenging current concepts in body sculpting., Competing Interests: Financial disclosures, conflicts of interest, and products: The authors have nothing to disclose., (Copyright © 2024 by the American Society of Plastic Surgeons.)

Saturation-recovery (SR)-EPR can determine electron spin-lattice relaxation rates in liquids over a wide range of effective viscosity, making it especially useful for biophysical and biomedical applications. Here, I develop exact solutions for the SR-EPR and SR-ELDOR rate constants of 14 N-nitroxyl spin labels as a function of rotational correlation time and spectrometer operating frequency. Explicit mechanisms for electron spin-lattice relaxation are: rotational modulation of the N-hyperfine and electron-Zeeman anisotropies (specifically including cross terms), spin-rotation interaction, and residual frequency-independent vibrational contributions from Raman processes and local modes. Cross relaxation from mutual electron and nuclear spin flips, and direct nitrogen nuclear spin-lattice relaxation, also must be included. Both the latter are further contributions from rotational modulation of the electron-nuclear dipolar interaction (END). All the conventional liquid-state mechanisms are defined fully by the spin-Hamiltonian parameters; only the vibrational contributions contain fitting parameters. This analysis gives a firm basis for interpreting SR (and inversion recovery) results in terms of additional, less standard mechanisms., 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 © 2023 Elsevier Inc. All rights reserved.)

In this study, 129 exposure situations (ESs) with six or more measured inhalation exposures to dust from solids or vapour from liquids in occupational settings were compared with modelled European Centre of Ecotoxicology and Toxicology of Chemicals (ECETOC) targeted risk assessment tool, version 3 (TRAv3) estimates. The measurement data were extracted from previously published studies examining TRAv3 performance and pooled into a curated database. The comparison exercise focussed on the vapour exposure scenarios, as there were too few dust scenarios for a meaningful analysis of any required model corrections. A group of experts in the exposure modelling field retrieved and reviewed the input parameters used in these ESs. Where considered appropriate, modifications were applied to better match the input parameter definitions and the scope of applicability of the TRAv3. Differences and mean absolute error (MAE) were calculated between the log-transformed modelled exposure value and the 75th percentile of each measured data set and regression analysis was performed. The results indicated that the TRAv3 overestimated 80% of the measured data sets. Both over- and underestimations were mostly by factors 1-5. The calculated MAE for liquids was 0.7, indicating that on average the difference between the 75th percentile and the TRAv3 estimate was less than one order of magnitude. A multiple linear regression showed that some input parameters such as medium volatility, certain process categories (PROC), industrial setting, and the presence of local exhaust ventilation are associated with underestimations. The results of the regression analysis can be used by TRAv3 users to review the degree of over- or underestimation in their current exposure assessments, compared to the curated database. Although multiple linear regression is an appropriate methodology to characterize the TRAv3's performance, more data sets are still needed in view of some remaining data gaps. Nevertheless, the results of the current analysis are being used by ECETOC to further develop the tool as a suitably conservative screening tool for use in REACH chemical safety assessment of occupational exposure to chemicals., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.)

Background: There are limited randomized controlled trials with long-term outcomes comparing autologous chondrocyte implantation (ACI) versus alternative forms of surgical cartilage management within the knee., Purpose: To determine at 5 years after surgery whether ACI was superior to alternative forms of cartilage management in patients after a failed previous treatment for chondral or osteochondral defects in the knee., Study Design: Randomized controlled trial; Level of evidence, 1., Methods: In total, 390 participants were randomly assigned to receive either ACI or alternative management. Patients aged 18 to 55 years with one or two symptomatic cartilage defects who had failed 1 previous therapeutic surgical procedure in excess of 6 months prior were included. Dual primary outcome measures were used: (1) patient-completed Lysholm knee score and (2) time from surgery to cessation of treatment benefit. Secondary outcome measures included International Knee Documentation Committee and Cincinnati Knee Rating System scores, as well as number of serious adverse events. Analysis was performed on an intention-to-treat basis., Results: Lysholm scores were improved by 1 year in both groups (15.4 points [95% CI, 11.9 to 18.8] and 15.2 points [95% CI, 11.6 to 18.9]) for ACI and alternative, with this improvement sustained over the duration of the trial. However, no evidence of a difference was found between the groups at 5 years (2.9 points; 95% CI, -1.8 to 7.5; P = .46). Approximately half of the participants (55%; 95% CI, 47% to 64% with ACI) were still experiencing benefit at 5 years, with time to cessation of treatment benefit similar in both groups (hazard ratio, 0.97; 95% CI, 0.72 to 1.32; P > .99). There was a differential effect on Lysholm scores in patients without previous marrow stimulation compared with those with marrow stimulation ( P = .03; 6.4 points in favor of ACI; 95% CI, -0.4 to 13.1). More participants experienced a serious adverse event with ACI ( P = .02)., Conclusion: Over 5 years, there was no evidence of a difference in Lysholm scores between ACI and alternative management in patients who had previously failed treatment. Previous marrow stimulation had a detrimental effect on the outcome of ACI., Registration: International Standard Randomised Controlled Trial Number: 48911177.

Coronavirus Disease 2019 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has become a worldwide pandemic. Since 2019, the virus has mutated into multiple variants that have made it harder to eradicate and have increased the rate of infection. This virus can affect the structure and the function of the heart and can lead to cardiovascular symptoms that can have long-lasting effects despite recovery from COVID-19. These symptoms include chest pain, palpitations, fatigue, shortness of breath, rapid heartbeat, arrhythmias, cough and hypotension. These symptoms may persist due to myocardial injury, cardiac inflammation or systemic damage that may have been caused during infection. If these symptoms persist, the patient should visit their cardiologist for diagnosis and treatment plan for any type of cardiovascular disease that may have developed Post-COVID 19., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Hypertrophic cardiomyopathy (HCM) is a genetic autosomal dominant disorder of the heart muscle that is characterized by left ventricular hypertrophy and sudden cardiac death. It is the most common inherited cardiac disease. HCM is defined by sarcomeric mutations that result in fibrosis of the heart, affecting contraction. In most cases, clinical presentations can range from asymptomatic to systolic and diastolic ventricular dysfunction, arrhythmias, and sudden cardiac death. Some histopathologic features typical of the disease are changes in myocyte disarray and myocardial fibrosis. Mutations in the β-myosin heavy chain and myosin-binding protein C have been identified as the cause of the disease. The goals of pharmacological therapy as well as nonpharmacological therapy are to alleviate the symptoms and to prevent sudden cardiac death. Anatomical defects are treated primarily by surgical intervention, whereas other issues such as hypercontractility are treated with pharmacotherapy. In this article, we review the pathophysiology and treatment options for HCM.

Objective: The objective of this study was to evaluate how urine drug screening (UDS) frequency is associated with retention in opioid agonist treatment (OAT)., Methods: Data for this retrospective cohort study of 55 921 adults in OAT in Ontario, Canada, were derived from administrative sources between 1 January 2011 and 31 December 2015. All patient information was linked anonymously across databases using encrypted health card numbers. Descriptive statistics were calculated for comparing UDS frequency groups using standardised differences (d) where d less than 10% indicated a statistically significant difference. A logistic regression model was then used to calculate ORs adjusting for baseline covariates, including sex, age, location of residence, income quintile, mental disorders, HIV status and deep tissue infections., Results: Over 70% of the cohort had four or more UDS tests per month (weekly or more UDS). Significant associations were observed between UDS frequency and 1-year treatment retention in OAT biweekly (adjusted OR (aOR)=3.20, 95% CI 2.75 to 3.75); weekly UDS (aOR=6.86, 95% CI 5.88 to 8.00) and more than weekly (aOR=8.03, 95% CI 6.87 to 9.38) using the monthly or less groups as the reference., Conclusion: This study identified an association between weekly UDS and 1-year treatment retention in OAT. There is an active discussion within Canada about the utility of UDS. The lack of evidence for the impact of UDS on retention has left it open to some to argue they simply provide a barrier to patient engagement. Therefore, it is timely of this study to demonstrate that more frequent urine testing is not associated with a reduction in treatment retention., Competing Interests: Competing interests: DM maintains the following roles: chief medical director at CATC (Canadian Addiction Treatment Center) and opioid agonist therapy provider. DM has no ownership stake in the CATC as a stipendiary employee. We do not foresee any conflict of interest as data will be made freely available to the public and the CATC, and the universities have no ability to prevent publication and dissemination of knowledge. The authors have no conflicts declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Complex parenting has been proposed to contribute to the evolutionary success of vertebrates. However, the evolutionary routes to complex parenting and the role of parenting in vertebrate diversity are still contentious. Although basal vertebrates provide clues to complex reproduction, these are often understudied. Using 181 species that represent all major lineages of an early vertebrate group, the salamanders and newts (Caudata, salamanders henceforth) here we show that fertilisation mode is tied to parental care: male-only care occurs in external fertilisers, whereas female-only care exclusively occurs in internal fertilisers. Importantly, internal fertilisation opens the way to terrestrial reproduction, because fertilised females are able to deposit their eggs on land, and with maternal care provision, the eggs could potentially develop outside the aquatic environment. Taken together, our results of a semi-aquatic early vertebrate group propose that the diversity and follow-up radiation of terrestrial vertebrates are inherently associated with a complex social behaviour, parenting., (© 2022. The Author(s).)

Background: falls and fall-related injuries are common in older adults, have negative effects on functional independence and quality of life and are associated with increased morbidity, mortality and health related costs. Current guidelines are inconsistent, with no up-to-date, globally applicable ones present., Objectives: to create a set of evidence- and expert consensus-based falls prevention and management recommendations applicable to older adults for use by healthcare and other professionals that consider: (i) a person-centred approach that includes the perspectives of older adults with lived experience, caregivers and other stakeholders; (ii) gaps in previous guidelines; (iii) recent developments in e-health and (iv) implementation across locations with limited access to resources such as low- and middle-income countries., Methods: a steering committee and a worldwide multidisciplinary group of experts and stakeholders, including older adults, were assembled. Geriatrics and gerontological societies were represented. Using a modified Delphi process, recommendations from 11 topic-specific working groups (WGs), 10 ad-hoc WGs and a WG dealing with the perspectives of older adults were reviewed and refined. The final recommendations were determined by voting., Recommendations: all older adults should be advised on falls prevention and physical activity. Opportunistic case finding for falls risk is recommended for community-dwelling older adults. Those considered at high risk should be offered a comprehensive multifactorial falls risk assessment with a view to co-design and implement personalised multidomain interventions. Other recommendations cover details of assessment and intervention components and combinations, and recommendations for specific settings and populations., Conclusions: the core set of recommendations provided will require flexible implementation strategies that consider both local context and resources., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Anion-exchange-membrane water electrolyzers (AEMWEs) in principle operate without soluble electrolyte using earth-abundant catalysts and cell materials and thus lower the cost of green H 2 . Current systems lack competitive performance and the durability needed for commercialization. One critical issue is a poor understanding of catalyst-specific degradation processes in the electrolyzer. While non-platinum-group-metal (non-PGM) oxygen-evolution catalysts show excellent performance and durability in strongly alkaline electrolyte, this has not transferred directly to pure-water AEMWEs. Here, AEMWEs with five non-PGM anode catalysts are built and the catalysts' structural stability and interactions with the alkaline ionomer are characterized during electrolyzer operation and post-mortem. The results show catalyst electrical conductivity is one key to obtaining high-performing systems and that many non-PGM catalysts restructure during operation. Dynamic Fe sites correlate with enhanced degradation rates, as does the addition of soluble Fe impurities. In contrast, electronically conductive Co 3 O 4 nanoparticles (without Fe in the crystal structure) yield AEMWEs from simple, standard preparation methods, with performance and stability comparable to IrO 2 . These results reveal the fundamental dynamic catalytic processes resulting in AEMWE device failure under relevant conditions, demonstrate a viable non-PGM catalyst for AEMWE operation, and illustrate underlying design rules for engineering anode catalyst/ionomer layers with higher performance and durability., (© 2022 Wiley-VCH GmbH.)

This narrative review describes efforts to improve the care and prevention of fragility fractures in New Zealand from 2012 to 2022. This includes development of clinical standards and registries to benchmark provision of care, and public awareness campaigns to promote a life-course approach to bone health., Purpose: This review describes the development and implementation of a systematic approach to care and prevention for New Zealanders with fragility fractures, and those at high risk of first fracture. Progression of existing initiatives and introduction of new initiatives are proposed for the period 2022 to 2030., Methods: In 2012, Osteoporosis New Zealand developed and published a strategy with objectives relating to people who sustain hip and other fragility fractures, those at high risk of first fragility fracture or falls and all older people. The strategy also advocated formation of a national fragility fracture alliance to expedite change., Results: In 2017, a previously informal national alliance was formalised under the Live Stronger for Longer programme, which includes stakeholder organisations from relevant sectors, including government, healthcare professionals, charities and the health system. Outputs of this alliance include development of Australian and New Zealand clinical guidelines, clinical standards and quality indicators and a bi-national registry that underpins efforts to improve hip fracture care. All 22 hospitals in New Zealand that operate on hip fracture patients currently submit data to the registry. An analogous approach is ongoing to improve secondary fracture prevention for people who sustain fragility fractures at other sites through nationwide access to Fracture Liaison Services., Conclusion: Widespread participation in national registries is enabling benchmarking against clinical standards as a means to improve the care of hip and other fragility fractures in New Zealand. An ongoing quality improvement programme is focused on eliminating unwarranted variation in delivery of secondary fracture prevention., (© 2022. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Peptide-based analogues of the gut-derived incretin hormone, glucagon-like peptide 1 (GLP1), stimulate insulin secretion in a glucose-dependent manner. Currently marketed GLP1 receptor (GLP1R) agonists are safe and effective in the management of Type 2 diabetes but often offer only modest weight loss. This has prompted the search for safe and effective alternatives to enhance the weight loss component of these treatments. We have demonstrated that concomitant activation GLP1R and the glucagon receptor (GCGR) can improve glucose metabolism and provide superior weight loss when compared to selective GLP1R agonism in preclinical species. This paper will highlight chemistry structure-activity relationship optimization and summarize in vivo efficacy studies toward the discovery of a once daily balanced dual agonist 12 (MK-1462), which was advanced into clinical trials., Competing Interests: The authors declare no competing financial interest., (© 2022 American Chemical Society.)

Introduction: Splenic injury is common in blunt trauma. We sought to evaluate the injury characteristics and outcomes of BSI admitted over a 10-y period to an academic trauma center., Methods: A retrospective review of adult blunt splenic injury patients admitted between January 2009 and September 2018., Results: The 423 patients meeting inclusion criteria were divided by management: Observational (OBS, n = 261), splenic surgery (n = 114 including 4 splenorrhaphy patients), SAE (n = 43), and multiple treatment modalities (3 had SAE followed by surgery and 2 OBS patients underwent splenic surgery at readmission). The most common mechanism of injury was motor vehicle collision (47.8%). The median ISS (OBS 17, SAE 22, Surgery 34) and spleen AIS (OBS 2, SAE 3, Surgery 4) were significantly different.  Complication rates (OBS 21.8%, SAE 9.3%, Surgery 45.6%) rates were significantly different, but mortality (OBS 7.3%, SAE 2.3%, Surgery 13.2%), discharge to home and readmission rates were not. Additional abdominal injuries were identified in 26.3% of the surgery group and 2.7% of OBS group. SAE rate increased from 3.0% to 28%; median spleen AIS remained 2-3. Thirty-five patients expired; 28 had severe head, chest, and/or extremity injuries (AIS ≥4)., Conclusion: SAE rates increased over time. Splenorrhaphy rates were low. SAE was associated with relatively low rates of mortality and complications in appropriately selected patients., (Copyright © 2021. Published by Elsevier Inc.)

Spin labels based on cinobufagin, a specific inhibitor of the Na,K-ATPase, have proved valuable tools to characterize the binding site of cardiotonic steroids (CTSs), which also constitutes the extracellular cation pathway. Because existing literature suggests variations in the physiological responses caused by binding of different CTSs, we extended the original set of spin-labeled inhibitors to the more potent bufalin derivatives. Positioning of the spin labels within the Na,K-ATPase site was defined and visualized by molecular docking. Although the original cinobufagin labels exhibited lower affinity, continuous-wave electron paramagnetic resonance spectra of spin-labeled bufalins and cinobufagins revealed a high degree of pairwise similarity, implying that these two types of CTS bind in the same way. Further analysis of the spectral lineshapes of bound spin labels was performed with emphasis on their structure (PROXYL vs. TEMPO), as well as length and rigidity of the linkers. For comparable structures, the dynamic flexibility increased in parallel with linker length, with the longest linker placing the spin label at the entrance to the binding site. Temperature-related changes in spectral lineshapes indicate that six-membered nitroxide rings undergo boat-chair transitions, showing that the binding-site cross section can accommodate the accompanying changes in methyl-group orientation. D 2 O-electron spin echo envelope modulation in pulse-electron paramagnetic resonance measurements revealed high water accessibilities and similar polarity profiles for all bound spin labels, implying that the vestibule leading to steroid-binding site and cation-binding sites is relatively wide and water-filled., (Copyright © 2021 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Background: Humans are exposed to tens of thousands of chemical substances that need to be assessed for their potential toxicity. Acute systemic toxicity testing serves as the basis for regulatory hazard classification, labeling, and risk management. However, it is cost- and time-prohibitive to evaluate all new and existing chemicals using traditional rodent acute toxicity tests. In silico models built using existing data facilitate rapid acute toxicity predictions without using animals., Objectives: The U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) Acute Toxicity Workgroup organized an international collaboration to develop in silico models for predicting acute oral toxicity based on five different end points: Lethal Dose 50 ( LD 50 value, U.S. Environmental Protection Agency hazard (four) categories, Globally Harmonized System for Classification and Labeling hazard (five) categories, very toxic chemicals [ LD 50 ( LD 50 ≤ 50 mg / kg )], and nontoxic chemicals ( L D 50 > 2,000 mg / kg )., Methods: An acute oral toxicity data inventory for 11,992 chemicals was compiled, split into training and evaluation sets, and made available to 35 participating international research groups that submitted a total of 139 predictive models. Predictions that fell within the applicability domains of the submitted models were evaluated using external validation sets. These were then combined into consensus models to leverage strengths of individual approaches., Results: The resulting consensus predictions, which leverage the collective strengths of each individual model, form the Collaborative Acute Toxicity Modeling Suite (CATMoS). CATMoS demonstrated high performance in terms of accuracy and robustness when compared with in vivo results., Discussion: CATMoS is being evaluated by regulatory agencies for its utility and applicability as a potential replacement for in vivo rat acute oral toxicity studies. CATMoS predictions for more than 800,000 chemicals have been made available via the National Toxicology Program's Integrated Chemical Environment tools and data sets (ice.ntp.niehs.nih.gov). The models are also implemented in a free, standalone, open-source tool, OPERA, which allows predictions of new and untested chemicals to be made. https://doi.org/10.1289/EHP8495.

(1) Background: The ECETOC Targeted Risk Assessment (TRA) tool is widely used for estimation of worker exposure levels in the development of dossiers for REACH registration of manufactured or imported chemical substances in Europe. A number of studies have been published since 2010 in which the exposure estimates of the tool are compared with workplace exposure measurement results and in some instances an underestimation of exposure was reported. The quality and results of these studies are being reviewed by ECETOC. (2) Methods: Original exposure measurement data from published comparison studies for which six or more data points were available for each workplace scenario and a TRA estimate had been developed to create a curated database to examine under what conditions and for which applications the tool is valid or may need adaptation. (3) Results: The published studies have been reviewed for completeness and clarity and TRA estimates have been constructed based on the available information, following a set of rules. The full review findings are expected to be available in the course of 2021. (4) Conclusions: The ECETOC TRA tool developers periodically review the validity and limitations of their tool, in line with international recommendations.

Purpose: This study investigated whether muscle cooling and its associated effects on skeletal muscle oxidative responses, blood gases, and hormonal concentrations influenced energy metabolism during cycling., Methods: Twelve healthy participants (Males: seven; Females: five) performed two steady-state exercise sessions at 70% of ventilatory threshold on a cycle ergometer. Participants completed one session with pre-exercise leg cooling until muscle temperature (T m ) decreased by 6 °C (LCO), and a separate session without cooling (CON). They exercised until T m returned to baseline and for an additional 30 min. Cardiovascular, respiratory, metabolic, hemodynamic variables, and skeletal muscle tissue oxidative responses were assessed continuously. Venous blood samples were collected to assess blood gases, and hormones., Results: Heart rate, stroke volume, and cardiac output all increased across time but were not different between conditions. V̇O 2 was greater in LCO when muscle temperature was restored until the end of exercise (p < 0.05). Cycling in the LCO condition induced lower oxygen availability, tissue oxygenation, blood pH, sO 2 %, and pO 2 (p < 0.05). Insulin concentrations were also higher in LCO vs. CON (p < 0.05). Importantly, stoichiometric equations from respiratory gases indicated no differences in fat and CHO oxidation between conditions., Conclusion: The present study demonstrated that despite muscle cooling and the associated oxidative and biochemical changes, energy metabolism remained unaltered during cycling. Whether lower local and systemic oxygen availability is counteracted via a cold-induced activation of lipid metabolism pathways needs to be further investigated.

Objectives: South African Africans have been reported to have experienced negative or null secular trends in stature and other measures of skeletal structure across the 19th and 20th centuries, presumably due to poor living conditions during a time of intensifying racial discrimination. Here, we investigate whether any secular trend is apparent in limb bone strength during the same period., Materials and Methods: Cadaver-derived skeletons (n = 221) were analyzed from female and male South African Africans who were born between 1839 and 1970, lived in and around Johannesburg, and died between 1925 and 1991 when they were 17-90 years of age. For each skeleton, a humerus and femur were scanned using computed tomography, and mid-diaphyseal cross-sectional geometric properties were calculated and scaled according to body size., Results: In general linear mixed models accounting for sex, age at death, and skeletal element, year of birth was a significant (p < .05) negative predictor of size-standardized mid-diaphyseal cortical area (a proxy for resistance to axial loading) and polar moment of area (a proxy for resistance to bending and torsion), indicating a temporal trend toward diminishing limb bone strength. No significant interactions were detected between year of birth and age at death, suggesting that the decline in limb bone strength was mainly due to changes in skeletal maturation rather than severity of age-related bone loss., Discussion: Limb bone strength is thus potentially another feature of the skeletal biology of South African Africans that was compromised by poor living conditions during the 19th and 20th centuries., (© 2020 Wiley Periodicals, Inc.)

Concentrations of the air pollutants (NO 2 and particulate matter) were measured for several months and at multiple locations inside and outside two enclosed railway stations in the United Kingdom - Edinburgh Waverly (EDB) and London King's Cross (KGX) - which, respectively, had at the time 59% and 18% of their train services powered by diesel engines. Average concentrations of NO 2 were above the 40 μg m -3 annual limit value outside the stations and were further elevated inside, especially at EDB. Concentrations of PM 2.5 inside the stations were 30-40% higher at EDB than outside and up to 20% higher at KGX. Concentrations of both NO 2 and PM 2.5 were highest closer to the platforms, especially those with a higher frequency of diesel services. A random-forest regression model was used to quantify the impact of numbers of different types of diesel trains on measured concentrations allowing prediction of the impact of individual diesel-powered rolling stock., 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 © 2020 Elsevier Ltd. All rights reserved.)

Many derived aspects of modern human axial skeletal morphology reflect our reliance on obligate bipedal locomotion. Insight into the adaptive significance of features, particularly in the spine, has been gained through experimental studies that induce bipedal standing or walking in quadrupedal mammals. Using an experimental animal model (Rattus norvegicus), the present study builds on earlier work by incorporating additional metrics of the cranium, employing quantitative methods established in the paleoanthropological literature, and exploring how variation in mechanical loading regimes impacts axial anatomy. Rats were assigned to one of five experimental groups, including "fully loaded bipedal walking," "partially loaded bipedal walking," "standing bipedally," "quadrupedal walking," and "no exercise control," and engaged in the behavior over 12-weeks. From μCT data obtained at the beginning and end of the experiment, we measured foramen magnum position and orientation, lumbar vertebral body wedging, cranial surface area of the lumbar and first sacral vertebral bodies, and sacral mediolateral width. Results demonstrate that bipedal rodents generally have more anteriorly positioned foramina magna, more dorsally wedged lumbar vertebrae, greater articular surface areas of lumbar and first sacral vertebral bodies, and sacra that exhibit greater mediolateral widths, compared to quadrupedal rodents. We further document variation among bipedal loading behavior groups (e.g., bipedal standing vs. walking). Our experimental animal model reveals how loading behaviors and adaptations may be specifically linked, and implicates a potential role for developmental plasticity in the evolutionary acquisition of bipedal adaptations in the hominin lineage. Anat Rec, 2018. © 2018 American Association for Anatomy., (© 2018 American Association for Anatomy.)

Introduction: Primary care practitioners (PCPs) are concerned about adverse effects and poor outcomes of opioid use but may find opioid tapering difficult because of a lack of pain management training or time constraints limiting patient counseling. In 2010, Kaiser Permanente Northwest implemented a pharmacist-led opioid tapering program-Support Team Onsite Resource for Management of Pain (STORM)-to address high rates of opioid use, alleviate PCPs' workload demands, and improve patient outcomes., Objective: To describe the rationale, structure, and delivery of this unique pharmacist-led program, which partners with PCPs and provides individualized care to help patients reduce opioid use, and the Facilitating Lower Opioid Amounts through Tapering study, which examines the program's effectiveness, cost-effectiveness, and implementation., Results: The STORM program includes a pain medicine physician, a social worker or nurse, and pharmacists who have received specialized clinical and communications training. The program has a 2-fold role: 1) to provide PCP education about pain management and opioid use and 2) to offer clinician and patient support with opioid tapering and pain management. After program training, PCPs are equipped to discuss the need for tapering with a patient and to refer to the program. Program pharmacists provide a range of services, including opioid taper plans, nonopioid pain management recommendations, and taper-support outreach to patients., Discussion: The STORM program provides individualized care to assist patients with opioid tapering while reducing the burden on PCPs., Conclusion: The STORM program may be a valuable addition to health care systems and settings seeking options to address their patients' opioid tapering needs.

Introduction: Early identification and appropriate treatment of child and adolescent mental health disorders can often be hampered by patchwork services with poorly planned or unclear pathways. The Choice and Partnership Approach (CAPA) is an evidence-based transformational model of community (community-based or outpatient) mental health and addictions services for children and adolescents that aims to better match services to needs and to improve timely access to care. CAPA has been variably implemented across jurisdictions but has not been comprehensively evaluated for its impact on system and client outcomes. Our research question is, 'To what degree does CAPA work, for whom and under what circumstances?'. The purpose of this review is twofold: (1) to gain an understanding of the extent and outcomes of the implementation of CAPA in community mental health and addictions services; and (2) to identify the role of context as it influences the implementation of CAPA and resulting client and system outcomes., Methods and Analysis: We will conduct a realist-informed scoping review of the literature related to CAPA in either child and adolescent or adult community mental health and addictions services. Relevant studies, reports and documentation will be identified by searching the following online databases: MEDLINE, Embase, CINAHL, PsycINFO, Academic Search Premier, ERIC, Web of Science, Cochrane, Dissertations Abstracts, NCBI Bookshelf, PubMed Central and the Canadian Health Research Collection. The search strategy was developed by a health sciences library scientist and informed by a multidisciplinary team comprising methodological and content knowledge experts. The search will gather evidence from multiple online databases of peer-reviewed literature and grey literature repositories. All articles will be independently assessed for inclusion by pairs of reviewers. The key themes derived from a thematic analysis of extracted data will be presented in a narrative overview., Ethics and Dissemination: Research ethics review is not required for this scoping review. The results will be disseminated through meetings with stakeholders (including clients and families, clinicians and decision-makers), conference presentations and peer-reviewed publication. The results of this review will inform an overarching programme of research, policy and quality indicator development to ultimately improve mental health and addictions care and subsequent mental health outcomes for children and adolescents., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cannabis is the most commonly used substance among patients in methadone maintenance treatment (MMT) for opioid use disorder. Current treatment programmes neither screen nor manage cannabis use. The recent legalisation of cannabis in Canada incites consideration into how this may affect the current opioid crisis., Aims: Investigate the health status of cannabis users in MMT., Method: Patients were recruited from addiction clinics in Ontario, Canada. Regression analyses were used to assess the association between adverse health conditions and cannabis use. Further analyses were used to assess sex differences and heaviness of cannabis use., Results: We included 672 patients (49.9% cannabis users). Cannabis users were more likely to consume alcohol (odds ratio 1.46, 95% CI 1.04-2.06, P = 0.029) and have anxiety disorders (odds ratio 1.75, 95% CI 1.02-3.02, P = 0.043), but were less likely to use heroin (odds ratio 0.45, 95% CI 0.24-0.86, P = 0.016). There was no association between cannabis use and pain (odds ratio 0.98, 95% CI 0.94-1.03, P = 0.463). A significant association was seen between alcohol and cannabis use in women (odds ratio 1.79, 95% CI 1.06-3.02, P = 0.028), and anxiety disorders and cannabis use in men (odds ratio 2.59, 95% CI 1.21-5.53, P = 0.014). Heaviness of cannabis use was not associated with health outcomes., Conclusions: Our results suggest that cannabis use is common and associated with psychiatric comorbidities and substance use among patients in MMT, advocating for screening of cannabis use in this population., Declaration of Interest: None.

Background: Clostridium difficile is a major pathogen responsible for nosocomial infectious diarrhea. After a spike in Clostridium difficile infection (CDI) cases, the focus team identified several cases of inappropriate sampling, i.e., asymptomatic patients being tested. We hypothesized that the inappropriate samples were leading to a high number of false-positive cases. We explored appropriate patient stool sampling as a strategy for reducing the number of asymptomatic cases in a 275-bed rural community hospital., Methods: We conducted a prospective cohort study of inpatients to determine if appropriate stool sampling would result in a reduction in false positive Clostridium difficile cultures and decrease incidence of Clostridium difficile. We developed a checklist that would guide the nurse to improve the sampling process., Results: The study implementation period ran from July through December 2016, with comparison to a control cohort in the prior six months. From Jan. 16 to May 15, the control group consisted of 461 inpatients, of which 89 tested positive for CDI 32.3 per 10,000 patient days. Of those 89 positive cases, 74 were identified as healthcare acquired infection (HAI) 26.8 per 10,000 patient days. Of these HAIs, 25 (33.8 percent) were inappropriate samples. In comparison, among the study period cohort of 277 inpatients, 46 inpatients tested positive for CDI 16.9 per 10,000 patient days, of which 26 were HAIs 9.5 per 10,000 patient days. During the study period, three samples (11.5 percent) were determined to be inappropriate. After the checklist implementation, the proportion of incorrect samples decreased from 33.8 percent to 11.5 percent. The number of HAI/patient days decreased form 0.024 percent to 0.08 percent. Similarly, the number of CDI/patient days also decreased from 0.295 percent to 0.15 percent., Conclusion: Implementation of a simple checklist prior to collection of stool sample proved to be effective in reducing the number of inappropriate samples sent for CDI testing, with a subsequent decrease in hospital acquired Clostridium difficile infections reported., (Copyright© South Dakota State Medical Association.)

Here we explore the neurodevelopmental aspects of macroautophagy (henceforth known as autophagy), the process by which cells remove and remodel their structure in a regulated and spatially restricted manner. Autophagy is a catabolic pathway in which cytosolic substances, such as protein complexes, lipids, and organelles, are engulfed by an autophagic vesicle. Degradation occurs once an autophagosome fuses with a lysosome, allowing the macromolecular cargo sequestered within the autophagic vesicle to be recycled. It is firmly established that autophagy plays a pivotal role in maintaining cellular homeostasis. Nevertheless, new evidence has emerged that the molecular mechanisms which regulate brain growth and neuronal connectivity involve autophagic processes. Our aim, as we endeavor to review data from model systems, is to show that autophagy performs a fundamental role in the development of the central nervous system (CNS). Moreover, we discuss human genetic data to underscore that mutations in autophagy-related genes are a contributing factor in childhood neurological disorders. To emphasize the importance of regulated vesicle transport pathways during the formation of the CNS, we discuss autophagy in relation to endosomal sorting to the lysosome, and explore how these mechanisms might intersect to regulate developmental events. We maintain that a deeper understanding of the function of autophagy in the CNS can shed new light on the biological basis of neurodevelopmental disorders., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A major goal of proteomics research is the accurate and sensitive identification and quantification of a broad range of proteins within a sample. Data-independent acquisition (DIA) approaches that acquire MS/MS spectra independently of precursor information have been developed to overcome the reproducibility challenges of data-dependent acquisition and the limited breadth of targeted proteomics strategies. Typical DIA implementations use wide MS/MS isolation windows to acquire comprehensive fragment ion data. However, wide isolation windows produce highly chimeric spectra, limiting the achievable sensitivity and accuracy of quantification and identification. Here, we present a DIA strategy in which spectra are collected with overlapping (rather than adjacent or random) windows and then computationally demultiplexed. This approach improves precursor selectivity by nearly a factor of 2, without incurring any loss in mass range, mass resolution, chromatographic resolution, scan speed, or other key acquisition parameters. We demonstrate a 64% improvement in sensitivity and a 17% improvement in peptides detected in a 6-protein bovine mix spiked into a yeast background. To confirm the method's applicability to a realistic biological experiment, we also analyze the regulation of the proteasome in yeast grown in rapamycin and show that DIA experiments with overlapping windows can help elucidate its adaptation toward the degradation of oxidatively damaged proteins. Our integrated computational and experimental DIA strategy is compatible with any DIA-capable instrument. The computational demultiplexing algorithm required to analyze the data has been made available as part of the open-source proteomics software tools Skyline and msconvert (Proteowizard), making it easy to apply as part of standard proteomics workflows. Graphical Abstract.

Background: With the growing number of total hip arthroplasty (THA) procedures performed, revision surgery is also proportionately increasing, resulting in greater health care expenditures. The purpose of this study was to assess clinical outcomes and cost when using a collared, fully hydroxyapatite-coated primary femoral stem for revision THA compared to commonly used revision femoral stems., Methods: We retrospectively identified patients who underwent revision THA with a primary stem between 2011 and 2016 and matched them on demographic variables and reason for revision to a similar cohort who underwent revision THA. We extracted operative data and information on in-hospital resource use from the patients’ charts to calculate average cost per procedure. Patient-reported outcomes were recorded preoperatively and 1 year postoperatively., Results: We included 20 patients in our analysis, of whom 10 received a primary stem and 10, a typical revision stem. There were no significant between-group differences in mean Western Ontario and McMaster Universities Osteoarthritis Index score, Harris Hip Score, 12-Item Short Form Health Survey (SF-12) Mental Composite Scale score or Physical Composite Scale score at 1 year. Operative time was significantly shorter and total cost was significantly lower (mean difference –3707.64, 95% confidence interval –5532.85 to –1882.43) with a primary stem than with other revision femoral stems., Conclusion: We found similar clinical outcomes and significant institutional cost savings with a primary femoral stem in revision THA. This suggests a role for a primary femoral stem such as a collared, fully hydroxyapatite-coated stem for revision THA., Competing Interests: E. Vasarhelyi and B. Lanting have received consulting fees and research support from Smith & Nephew, DePuy Synthes and Stryker. No other competing interests declared., (© 2019 Joule Inc. or its licensors)

Introduction: Illicit opioid use has become a national crisis in Canada, with over 65 000 people seeking treatment for opioid use disorder (OUD) in Ontario and British Columbia alone. Medication-assisted treatment (MAT) is a common treatment for OUD. There is substantial variability in treatment outcomes used to evaluate effectiveness of MAT, making it difficult to establish clinically and scientifically relevant treatment effect. Furthermore, patients are often excluded from the process of determining these outcomes. The primary objective of this review is to examine outcomes currently used to measure MAT effectiveness and to identify patient-relevant outcomes to enhance effectiveness of treatment options. This review refers to patient-important outcomes as those outcomes patients consider important to or markers of treatment success., Methods and Analysis: MEDLINE, EMBASE, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Cochrane Library, Cochrane Clinical Trials Registry, National Institutes for Health Clinical Trials Registry and WHO International Clinical Trials Registry Platform databases will be searched. We will search databases from inception to the date the search is ran. Studies of interest include those evaluating the effectiveness of MAT for patients with OUD, with or without consultation with patients regarding what they consider to be important as an indicator of treatment success. Results will be analysed using thematic analysis and qualitative analysis where possible. This will result in comprehensive synthesis of all outcomes and measures found related to OUD treatment effectiveness., Ethics and Dissemination: We are collaborating with Canadian Addiction Treatment Centres which provide MAT to patients with OUD who will participate in disseminating study results. Dissemination strategies will involve sharing study results through workshops, presentations, peer-reviewed publications, study reports, community presentations and resources in primary care settings., Prospero Registration Number: CRD42018095553., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Earlier we created a chemical hazard database via natural language processing of dossiers submitted to the European Chemical Agency with approximately 10 000 chemicals. We identified repeat OECD guideline tests to establish reproducibility of acute oral and dermal toxicity, eye and skin irritation, mutagenicity and skin sensitization. Based on 350-700+ chemicals each, the probability that an OECD guideline animal test would output the same result in a repeat test was 78%-96% (sensitivity 50%-87%). An expanded database with more than 866 000 chemical properties/hazards was used as training data and to model health hazards and chemical properties. The constructed models automate and extend the read-across method of chemical classification. The novel models called RASARs (read-across structure activity relationship) use binary fingerprints and Jaccard distance to define chemical similarity. A large chemical similarity adjacency matrix is constructed from this similarity metric and is used to derive feature vectors for supervised learning. We show results on 9 health hazards from 2 kinds of RASARs-"Simple" and "Data Fusion". The "Simple" RASAR seeks to duplicate the traditional read-across method, predicting hazard from chemical analogs with known hazard data. The "Data Fusion" RASAR extends this concept by creating large feature vectors from all available property data rather than only the modeled hazard. Simple RASAR models tested in cross-validation achieve 70%-80% balanced accuracies with constraints on tested compounds. Cross validation of data fusion RASARs show balanced accuracies in the 80%-95% range across 9 health hazards with no constraints on tested compounds.

The ageing of society is driving an enormous increase in fragility fracture incidence and imposing a massive burden on patients, their families, health systems and societies globally. Disrupting the status quo has therefore become an obligation and a necessity. Initiated by the Fragility Fracture Network (FFN) at a "Presidents' Roundtable" during the 5 th FFN Global Congress in 2016 several leading organisations agreed that a global multidisciplinary and multiprofessional collaboration, resulting in a Global Call to Action (CtA), would be the right step forward to improve the care of people presenting with fragility fractures. So far global and regional organisations in geriatrics/internal medicine, orthopaedics, osteoporosis/metabolic bone disease, rehabilitation and rheumatology were contacted as well as national organisations in five highly populated countries (Brazil, China, India, Japan and the United States), resulting in 81societies endorsing the CtA. We call for implementation of a systematic approach to fragility fracture care with the goal of restoring function and preventing subsequent fractures without further delay. There is an urgent need to improve: To address this fragility fracture crisis, the undersigned organisations pledge to intensify their efforts to improve the current management of all fragility fractures, prevent subsequent fractures, and strive to restore functional abilities and quality of life., (Copyright © 2018. Published by Elsevier Ltd.)

A high proportion of patients with fragility fracture, mainly hip fracture, have a variable degree of comorbidity and show some degree of dependence in basic or more complex activities of daily living. Evaluating these patents following the geriatric concept of frailty, about one third of hip fracture patients may be categorised as frail with high risk of poor outcomes and prolonged length of stay, one third as not frail, and about one third with an intermediate condition. Due to the high vulnerability, combined with the hip fracture event and surgical repair procedures, a multidisciplinary approach that includes geriatric competencies becomes essential to improve short and long-term outcomes after hip fracture. A key element of an effective process of care is a true co-managed approach that applies quality standards and provides a fast-track pathway of care, minimises the time the patient spends in bed, and reduces postoperative complications by means of standardised procedures. The occurrence of a fragility fracture is the strongest risk factor for a subsequent fracture. Moreover, frail subjects have a further risk of fracture due to high risk of falls - related to loss of muscle mass, multiple illnesses, impaired balance and weakness. Thus, effective secondary prevention strategies are essential to reduce morbidity and mortality after hip fracture, and they are currently a standard task of orthogeriatric care. Fracture liaison services (FLS) are probably the most efficient way of addressing secondary prevention including the assessment of both bone health and falls risk. Therefore, the optimal management of frail patients with fragility fracture includes both orthogeriatric care and FLS, which are complementary to each other. Orthogeriatric collaboration is also powerful in influencing healthcare policy. British experience as well as that in Ireland, Australia and New Zealand, have shown that when two widely disparate specialisms say the same thing, they may achieve a fundamental shift in attitudes and behaviour of both managers and clinicians. Furthermore, a continuous real-time audit, at national level, is a powerful driver for change and better standards of care., (Copyright © 2018. Published by Elsevier Ltd.)

Two-component nitroxide spin-label electron paramagnetic presonance (EPR) spectra are important to the analysis of lipid-protein interactions, phase separation in lipid membranes, and conformational changes in proteins. A paper published in this journal offers an interpretation of such spectra based on simulations with single-site models. It is not possible to reproduce those simulations published in Meirovitch , E. ; [ Analysis of Protein Lipid Interactions Based on Model Simulations of Electron Spin Resonance Spectra . J. Phys. Chem. 1984 , 88 , 3454 - 3465 ] that might conceivably be taken to resemble two-component line shapes, when using the motional model and parameters given in that paper. Instead of the apparent two components, the spectra resemble single-component powder patterns expected from axially anisotropic, partial motional-averaging (a situation familiar for chain-labeled lipids in nonaligned fluid membranes). This is because: (i) the nitroxide z-axis is inclined at a fixed angle to the principal diffusion axis, and (ii) motion perpendicular to the principal diffusion axis is so slow as to approximate a powder distribution. The line shapes are compatible with simulations that use the same model for a complete range of nitroxide order parameters [ Schorn , K. ; Extracting Order Parameters from Powder EPR Lineshapes for Spin-Labelled Lipids in Membranes . Spectrochim. Acta, Part A 1997 , 53 , 2235 - 2240 ], which are able to describe single-component experimental spectra from lipids spin-labeled at different chain positions in fluid-bilayer membranes [ Schorn , K. ; Lipid Chain Dynamics in Diacylglycerol-Phosphatidylcholine Mixtures Studied by Slow-Motional Simulations of Spin Label ESR Spectra . Chem. Phys. Lipids 1996 , 82 , 7 - 14 ]. Neither from simulation nor from experiment is there any basis to assert that single-component nitroxyl EPR spectra resemble those containing two components.

Glioblastoma is an aggressive brain tumor that carries a poor prognosis. The tumor's molecular and cellular landscapes are complex, and their relationships to histologic features routinely used for diagnosis are unclear. We present the Ivy Glioblastoma Atlas, an anatomically based transcriptional atlas of human glioblastoma that aligns individual histologic features with genomic alterations and gene expression patterns, thus assigning molecular information to the most important morphologic hallmarks of the tumor. The atlas and its clinical and genomic database are freely accessible online data resources that will serve as a valuable platform for future investigations of glioblastoma pathogenesis, diagnosis, and treatment., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Electron spin echo envelope modulation (ESEEM) and conventional electron paramagnetic resonance (EPR) of site-specifically spin-labelled phospholipids are used to investigate the effect of ether-linked chains on the water-penetration and polarity profiles, as well as the phase behaviour and chain flexibility profiles, of phospholipid membranes. D 2 O-ESEEM reveals that water exposure of the terminal methyl groups in the interdigitated phase of dihexadecyl phosphatidylcholine (DHPC) is comparable to that of the methylene groups at the polar head-group end of the chains. Similarly, an uniform transmembrane polarity profile is obtained from the dependence of the outer 14 N-hyperfine splitting on the spin-label position along the chain in frozen interdigitated DHPC dispersions. Two-component conventional EPR spectra of spin labels at the terminal methyl end of the chain reveal that the intermediate gel phase above the pretransition of DHPC contains components in which the lipid chains are interdigitated. The polarity and chain-flexibility profiles in the fluid L α -phase of DHPC with ether-linked chains are shifted outwards, towards the polar-apolar interface, as compared with that of dihexadecanoyl phosphatidylcholine (DPPC) with ester-linked chains. Also, the polarity profile of DHPC is shifted upwards, to higher polarities. These differences reflect those in hydrocarbon thickness and area/lipid molecule reported by x-ray diffraction for the L α -phases of the two lipids., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Interpretation of saturation-recovery EPR experiments on nitroxide spin labels whose angular rotation is restricted by the orienting potential of the environment (e.g., membranes) currently concentrates on the influence of rotational rates and not of molecular order. Here, I consider the dependence on molecular ordering of contributions to the rates of electron spin-lattice relaxation and cross relaxation from modulation of N-hyperfine and Zeeman anisotropies. These are determined by the averages 〈cos 2 θ〉 and 〈cos 4 θ〉, where θ is the angle between the nitroxide z-axis and the static magnetic field, which in turn depends on the angles that these two directions make with the director of uniaxial ordering. For saturation-recovery EPR at 9 GHz, the recovery rate constant is predicted to decrease with increasing order for the magnetic field oriented parallel to the director, and to increase slightly for the perpendicular field orientation. The latter situation corresponds to the usual experimental protocol and is consistent with the dependence on chain-labelling position in lipid bilayer membranes. An altered dependence on order parameter is predicted for saturation-recovery EPR at high field (94 GHz) that is not entirely consistent with observation. Comparisons with experiment are complicated by contributions from slow-motional components, and an unexplained background recovery rate that most probably is independent of order parameter. In general, this analysis supports the interpretation that recovery rates are determined principally by rotational diffusion rates, but experiments at other spectral positions/field orientations could increase the sensitivity to order parameter., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The extent to which current force fields faithfully reproduce conformational properties of lipids in bilayer membranes, and whether these reflect the structural principles established for phospholipids in bilayer crystals, are central to biomembrane simulations. We determine the distribution of dihedral angles in palmitoyl-oleoyl phosphatidylcholine from molecular dynamics simulations of hydrated fluid bilayer membranes. We compare results from the widely used lipid force field of Berger et al. with those from the most recent C36 release of the CHARMM force field for lipids. Only the CHARMM force field produces the chain inequivalence with sn-1 as leading chain that is characteristic of glycerolipid packing in fluid bilayers. The exposure and high partial charge of the backbone carbonyls in Berger lipids leads to artifactual binding of Na + ions reported in the literature. Both force fields predict coupled, near-symmetrical distributions of headgroup dihedral angles, which is compatible with models of interconverting mirror-image conformations used originally to interpret NMR order parameters. The Berger force field produces rotamer populations that correspond to the headgroup conformation found in a phosphatidylcholine lipid bilayer crystal, whereas CHARMM36 rotamer populations are closer to the more relaxed crystal conformations of phosphatidylethanolamine and glycerophosphocholine. CHARMM36 alone predicts the correct relative signs of the time-average headgroup order parameters, and reasonably reproduces the full range of NMR data from the phosphate diester to the choline methyls. There is strong motivation to seek further experimental criteria for verifying predicted conformational distributions in the choline headgroup, including the 31 P chemical shift anisotropy and 14 N and CD 3 NMR quadrupole splittings., (Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Calibrations are given to extract orientation order parameters from pseudo-powder electron paramagnetic resonance line shapes of 14 N-nitroxide spin labels undergoing slow rotational diffusion. The nitroxide z -axis is assumed parallel to the long molecular axis. Stochastic-Liouville simulations of slow-motion 9.4-GHz spectra for molecular ordering with a Maier-Saupe orientation potential reveal a linear dependence of the splittings, [Formula: see text] and [Formula: see text], of the outer and inner peaks on order parameter [Formula: see text] that depends on the diffusion coefficient [Formula: see text] which characterizes fluctuations of the long molecular axis. This results in empirical expressions for order parameter and isotropic hyperfine coupling: [Formula: see text] and [Formula: see text], respectively. Values of the calibration constants [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text] are given for different values of [Formula: see text] in fast and slow motional regimes. The calibrations are relatively insensitive to anisotropy of rotational diffusion [Formula: see text], and corrections are less significant for the isotropic hyperfine coupling than for the order parameter.