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Background: Given the increasing interest in dietary interventions to improve cardiovascular health, this trial assessed the impact of fortified eggs (FE) versus nonegg supplemented diet and time-restricted eating (TRE) versus usual care diet on cardiovascular biomarkers., Methods: The study was a unblinded, 2-by-2 factorial design, which randomized patients, with either a prior cardiovascular event or 2 cardiovascular risk factors, to FE or a nonegg supplemented diet and TRE or usual care diet. Patients randomized to FE were instructed to consume at least 12 FE/week (with eggs provided); those on a nonegg supplemented diet restricted egg consumption to <2 eggs/week. TRE participants were instructed to consume all calories within an 8-hour window daily and fasted for the remaining 16 hours. Patients randomized to usual diet were advised to maintain current dietary habits. Follow-up was performed in-person at 1 and 4 months, and telephone calls at 2 and 3 months. Co-primary endpoints were 4-month LDL- and HDL-cholesterol. Secondary endpoints included additional lipids, cardiometabolic- and inflammatory biomarkers and micronutrient levels at 4-months., Results: Overall, 140 patients were randomized with median (25th, 75th percentiles) age 66 (58, 73) years; 72 (51%) women, 38 (27%) Black, and 33 (24%) with diabetes mellitus. The difference in least squares (LS) means from baseline to 4-months for HDL and LDL levels revealed no significant clinical difference between FE vs nonegg supplemented diet (HDL: -0.64 mg/dL [95% CI: -3.86, 2.58]; LDL: -3.14 mg/dL [-10.81, 4.52]) and TRE vs usual care diet (HDL: 1.51 mg/dL [-1.65, 4.68]; LDL 1.17 mg/dL [-6.36, 8.70]). Prespecified subgroups revealed a nonsignificant HDL increase and LDL decrease with FE in patients ≥65 years., Conclusions: These data did not demonstrate clinically relevant differences in changes in LDL and HDL levels over 4 months with FE and TRE compared with nonegg supplemented diet and usual care diet, respectively, providing evidence that adverse short-term lipid and biomarker changes did not occur with FE consumption., Trial Registration: ClinicalTrials.gov Identifier: NCT04673721., Competing Interests: Declaration of competing interest NN received speaker fees from AstraZeneca and Bayer. RJM received research support from Eggland's Best to his institution to support the trial. NJP received research support from Alnylam, Amgen, Bayer, Boehringer Ingelheim, Eggland's Best, Eli Lilly, Novartis, Novo Nordisk, Merck. Consultation/Advisory Panels for Bayer, Boehringer Ingelheim, CRISPR Therapeutics, Eli Lilly, Esperion, AstraZeneca, Merck, Novartis, and Novo Nordisk. Executive Committee member for trials sponsored by Novo Nordisk and by Amgen. DSMB for trials sponsored by J+J and Novartis. Medical advisory board for Miga Health. DH, KM, BTS and MW are employees of Eggland's Best, LLC, Malvern, PA, USA. JH has no disclosures., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Porous metallic prosthesis components can now be manufactured using additive manufacturing techniques, and may prove beneficial for promoting bony ingrowth, for accommodating drug delivery systems, and for reducing stress shielding. Using finite element modeling techniques, 36 scenarios (three porous stems, three bone densities, and four held arm positions) were analysed to assess the viability of porous humeral stems for use in total shoulder arthroplasty, and their resulting mechanobiological impact on the surrounding humerus bone. All three porous stems were predicted to experience stresses below the yield strength of Ti6Al4V (880 MPa) and to be capable of withstanding more than 10 million cycles of each loading scenario before failure. There was an indication that within an 80 mm region of the proximal humerus, there would be a reduction in bone resorption as stem porosity increased. Overall, this study shows promise that these porous structures are mechanically viable for incorporation into permanent shoulder prostheses to combat orthopedic infections., (© 2024 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Porous additively-manufactured structures could have a niche in orthopaedic implants, due to their potential to reduce stiffness (stress-shielding), improve bony ingrowth, and potential to house reservoirs of drug-eluting non-structural biomaterials. Computer aided design and finite element (FE) modelling plays an important role in the design of porous structured biomedical implants; however it is important to validate both their static and fatigue behaviours using experimental testing. This study compared the mechanical behaviors of titanium cylindrical gyroid structures of varying porosities using physical testing of additively manufactured prototypes and FE models. There was agreement in the measured and predicted relationships between porosity and apparent modulus of elasticity. As porosity increased (and wall thickness decreased), the structures failed at a lower number of cycles when loaded at the same percentage of their yield strengths. Calibration of the fatigue strength coefficient from a previously published value of 1586.5 MPa-1225 MPa greatly improved the fatigue life prediction accuracy for all the gyroid structures. Nevertheless, differences of up to 54% in the predicted versus experimental fatigue lives remained, which could be attributed to difficulties with how the precise time and location of failure is defined in the simulations, and/or minor differences in nominal and actual porosities. Although further calibration and validation should be explored, this study demonstrates that static and fatigue FE-modelling techniques could be used to aid in the design of porous prosthetics., 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.The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Sydney Hitchon reports financial support was provided by Government of Canada., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The number of animals used in a nonhuman primate (NHP) in vivo QTc assessment conducted as part of the safety pharmacology (SP) studies on a potential new drug is relatively small (4-8 subjects). The number is much smaller than the number of healthy volunteers in a conventional thorough QT (TQT) study (40-60 volunteers). How is it possible that such small studies could offer an equivalent sensitivity in an integrated nonclinical and clinical cardiac repolarization risk assessment? This study provided the opportunity to empirically demonstrate in a large number of NHPs the performance of a nonclinical evaluation at a similar size to a TQT study. By contrasting an analysis mimicking the sampling and aggregation of QTc interval data in a manner which is TQT-like with a more conventional SP-like analysis it was demonstrated that the SP-like analysis was more sensitive. In prospective power calculations 80% power at p = 0.05 can be achieved for a 5 ms QTc change with only n = 8 NHPs using the SP-like analysis and in a group of only 4 NHPs 80% power to detect 10 ms could be achieved. By contrast groups of 24 NHPs would be required to achieve 80% power to detect 5 ms using the TQT-like sampling and aggregation approach. Overall, this study has demonstrated that smaller safety pharmacology in vivo QTc assessments using all the available data in larger data aggregates can achieve sensitivity comparable to a human TQT study., Competing Interests: Declaration of Competing Interest “A definitive nonhuman primate evaluation of moxifloxacin sized as a clinical thorough QT (TQT) study to define the operating characteristics of more conventionally sized nonclinical regulatory in vivo QTc studies”. None of the authors of this manuscript have any conflict of interest to declare. Their affiliations and employers are as indicated., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Competing Interests: Conflict of interest: None declared.

This article provides an overview of the recommendations of the Aviation and Occupational Cardiology Task Force of the European Association of Preventive Cardiology on returning individuals to work in high-hazard occupations (such as flying, diving, and workplaces that are remote from healthcare facilities) following symptomatic Coronavirus Disease 2019 (COVID-19) infection. This process requires exclusion of significant underlying cardiopulmonary disease and this consensus statement (from experts across the field) outlines the appropriate screening and investigative processes that should be undertaken. The recommended response is based on simple screening in primary healthcare to determine those at risk, followed by first line investigations, including an exercise capacity assessment, to identify the small proportion of individuals who may have circulatory, pulmonary, or mixed disease. These individuals can then receive more advanced, targeted investigations. This statement provides a pragmatic, evidence-based approach for those (in all occupations) to assess employee health and capacity prior to a return to work following severe disease, or while continuing to experience significant post-COVID-19 symptoms (so-called 'long-COVID' or post-COVID-19 syndrome)., Competing Interests: Conflict of interest: none declared., (© Crown copyright 2022.)

Background: Existing pathways for investigating coronary artery disease (CAD) in individuals undertaking high-hazard employment are currently guided by coronary artery calcium scoring (CACS) or coronary CT angiography (CTA). The optimal pathway has not been established., Aim: To compare the diagnostic outcome and occupational recommendations from two differing investigative pathways for the investigation of CAD in a cohort of high-hazard employees., Methods: We collected CACS and coronary CTA data from three clinics across two Hospitals on 200 consecutive individuals employed in high-hazard occupations to confirm/exclude occupationally significant CAD. High-hazard occupations were grouped into civil/military pilots and aircraft controllers (n ​= ​106); non-pilot aircrew (NPA) (n ​= ​26); and ground-based (military) personnel (GBP) (n ​= ​52). Demographics, referral indications and recommended occupational outcomes between pathways were compared between groups., Results: The CACS pathway led to more than double the number of individuals being returned to partial or full employment, compared with the coronary CTA pathway (OR 2.10, [95%CI 1.54-2.85], P ​< ​0.001). This effect was seen in all sub-groups. Of the 177 subjects that would have been returned to full employment using CACS, 21 (11.9%) would have been occupationally restricted on the basis of significant non-calcified plaque disease using coronary CTA (11.4% pilots/controllers; 19.2% non-pilot aircrew, and 7.7% ground-based personnel)., Conclusion: Using CACS to determine the presence of occupational CAD risks returning individuals to roles with occupationally significant CAD that may lead to an unacceptably high likelihood of an incapacitating/distracting acute coronary event. Coronary CTA appears to be a more reliable, non-invasive imaging modality for confirming or excluding occupationally significant CAD in high-hazard employees., Competing Interests: Declaration of competing interest The following authors declare that there is no conflict of interest for the following article: Coronary Artery Calcium Scoring vs. coronary CT Angiography for the assessment of occupationally significant coronary artery disease., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

Objective: When reporting coronary CT angiography (CCTA), extracardiac structures are routinely assessed, usually on a wide field-of-view (FOV) reconstruction. We performed a retrospective observational cross-sectional study to investigate the impact of incidental extracardiac abnormalities on resource utilisation and treatment, and cost-effectiveness., Methods: All patients undergoing CCTA at a single institution between January 2012 and March 2020 were identified. The indication for CCTA was chest pain or dyspnoea in >90%. Patients with ≥1 significant extracardiac findings were selected. Clinical follow-up, investigations and treatment were documented, and costs were calculated., Results: 4340 patients underwent CCTA; 717 extracardiac abnormalities were identified in 687 individuals (15.8%; age 62±12 years; male 336, 49%). The abnormality was already known in 162 (23.6%). Lung nodules and cysts were the most common abnormalities (296, 43.1%). Clinical and/or imaging follow-up was pursued in 292 patients (42.5%). Treatment was required by 14 patients (0.3% of the entire population), including lung resection for adenocarcinoma in six (0.1%). All but two abnormalities (both adenocarcinomas) were identifiable on the limited cardiac FOV. The cost of reporting (£20) and follow-up (£33) of extracardiac abnormalities was £53 per patient. The cost per discounted quality-adjusted life year was £23 930, increasing to £46 674 for reporting the wide FOV rather than the cardiac FOV alone., Conclusions: Extracardiac abnormalities are common on CCTA, but identification and follow-up are costly. The few requiring treatment are usually identifiable without review of the wide FOV. The way in which CCTAs are scrutinised for extracardiac abnormalities in a resource-limited healthcare system should be questioned., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Work is beneficial for health, but many individuals develop cardiovascular disease (CVD) during their working lives. Occupational cardiology is an emerging field that combines traditional cardiology sub-specialisms with prevention and risk management unique to specific employment characteristics and conditions. In some occupational settings incapacitation through CVD has the potential to be catastrophic due to the nature of work and/or the working environment. These are often termed 'hazardous' or 'high-hazard' occupations. Consequently, many organizations that employ individuals in high-hazard roles undertake pre-employment medicals and periodic medical examinations to screen for CVD. The identification of CVD that exceeds predefined employer (or regulatory body) risk thresholds can result in occupational restriction, or disqualification, which may be temporary or permanent. This article will review the evidence related to occupational cardiology for several high-hazard occupations related to aviation and space, diving, high altitude, emergency workers, commercial transportation, and the military. The article will focus on environmental risk, screening, surveillance, and risk management for the prevention of events precipitated by CVD. Occupational cardiology is a challenging field that requires a broad understanding of general cardiology, environmental, and occupational medicine principles. There is a current lack of consensus and contemporary evidence which requires further research. Provision of evidence-based, but individualized, risk stratification and treatment plans is required from specialists that understand the complex interaction between work and the cardiovascular system. There is a current lack of consensus and contemporary evidence in occupational cardiology and further research is required., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Purpose: In this study, we determined ketone oxidation rates in athletes under metabolic conditions of high and low carbohydrate (CHO) and fat availability. Methods: Six healthy male athletes completed 1 h of bicycle ergometer exercise at 75% maximal power (WMax) on three occasions. Prior to exercise, participants consumed 573 mg·kg bw -1 of a ketone ester (KE) containing a 13 C label. To manipulate CHO availability, athletes undertook glycogen depleting exercise followed by isocaloric high-CHO or very-low-CHO diets. To manipulate fat availability, participants were given a continuous infusion of lipid during two visits. Using stable isotope methodology, β-hydroxybutyrate (βHB) oxidation rates were therefore investigated under the following metabolic conditions: (i) high CHO + normal fat (KE+CHO); (ii) high CHO + high fat KE+CHO+FAT); and (iii) low CHO + high fat (KE+FAT). Results: Pre-exercise intramuscular glycogen (IMGLY) was approximately halved in the KE+FAT vs. KE+CHO and KE+CHO+FAT conditions (both p < 0.05). Blood free fatty acids (FFA) and intramuscular long-chain acylcarnitines were significantly greater in the KE+FAT vs. other conditions and in the KE+CHO+FAT vs. KE+CHO conditions before exercise. Following ingestion of the 13 C labeled KE, blood βHB levels increased to ≈4.5 mM before exercise in all conditions. βHB oxidation was modestly greater in the KE+CHO vs. KE+FAT conditions (mean diff. = 0.09 g·min -1 , p = 0.03; d = 0.3), tended to be greater in the KE+CHO+FAT vs. KE+FAT conditions (mean diff. = 0.07 g·min -1 ; p = 0.1; d = 0.3) and were the same in the KE+CHO vs. KE+CHO+FAT conditions ( p < 0.05; d < 0.1). A moderate positive correlation between pre-exercise IMGLY and βHB oxidation rates during exercise was present ( p = 0.04; r = 0.5). Post-exercise intramuscular βHB abundance was markedly elevated in the KE+FAT vs. KE+CHO and KE+CHO+FAT conditions (both, p < 0.001; d = 2.3). Conclusion: βHB oxidation rates during exercise are modestly impaired by low CHO availability, independent of circulating βHB levels., Competing Interests: KC is the director of TΔS Ltd., a spin-out company of the University of Oxford, established to develop and commercialise products based on the BHB monoester used in this study. DD is a current employee of TΔS Ltd and TK and BS are former employees. AB was employed by the company Sterling Pharma Solutions Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dearlove, Holdsworth, Kirk, Hodson, Charidemou, Kvalheim, Stubbs, Beevers, Griffin, Evans, Robertson, Clarke and Cox.)

Background: The longitudinal trajectories of cardiopulmonary abnormalities and symptoms following infection with coronavirus disease (COVID-19) are unclear. We sought to describe their natural history in previously hospitalised patients, compare this with controls, and assess the relationship between symptoms and cardiopulmonary impairment at 6 months post-COVID-19., Methods: Fifty-eight patients and thirty matched controls (single visit), recruited between 14 th March - 25 th May 2020, underwent symptom-questionnaires, cardiac and lung magnetic resonance imaging (CMR), cardiopulmonary exercise test (CPET), and spirometry at 3 months following COVID-19. Of them, forty-six patients returned for follow-up assessments at 6 months., Findings: At 2-3 months, 83% of patients had at least one cardiopulmonary symptom versus 33% of controls. Patients and controls had comparable biventricular volumes and function. Native cardiac T 1 (marker of fibroinflammation) and late gadolinium enhancement (LGE, marker of focal fibrosis) were increased in patients at 2-3 months. Sixty percent of patients had lung parenchymal abnormalities on CMR and 55% had reduced peak oxygen consumption (pV̇O 2 ) on CPET. By 6 months, 52% of patients remained symptomatic. On CMR, indexed right ventricular (RV) end-diastolic volume (-4·3 mls/m 2 , P =0·005) decreased and RV ejection fraction (+3·2%, P =0·0003) increased. Native T 1 and LGE improved and was comparable to controls. Lung parenchymal abnormalities and peak V̇O 2 , although better, were abnormal in patients versus controls. 31% had reduced pV̇O 2 secondary to symptomatic limitation and muscular impairment. Cardiopulmonary symptoms in patients did not associate with CMR, lung function, or CPET measures., Interpretation: In patients, cardiopulmonary abnormalities improve over time, though some measures remain abnormal relative to controls. Persistent symptoms at 6 months post-COVID-19 did not associate with objective measures of cardiopulmonary health., Funding: The authors' work was supported by the NIHR Oxford Biomedical Research Centre, Oxford British Heart Foundation (BHF) Centre of Research Excellence (RE/18/3/34214), United Kingdom Research Innovation and Wellcome Trust. This project is part of a tier 3 study (C-MORE) within the collaborative research programme entitled PHOSP-COVID Post-hospitalization COVID-19 study: a national consortium to understand and improve long-term health outcomes, funded by the Medical Research Council and Department of Health and Social Care/National Institute for Health Research Grant (MR/V027859/1) ISRCTN number 10980107., Competing Interests: MC reports a grant from the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. EMT reports a grant from the NIHR Oxford Biomedical Research Centre and is a shareholder in Perspectum. AL is a shareholder in Perspectum. SKP acknowledges support from the British Heart Foundation (BHF) Centre of Research Excellence and the NIHR Oxford Biomedical Research Centre at the Oxford University Hospitals, University of Oxford, UK. SKP has a US patent 61/387,591 licensed to Siemens and US patents 61/630,508 and 61-630,510 licensed to Perspectum. RAE reports a grant from the NIHR/Medical Research Council (MRC) for the PHOSP-COVID study. VMF reports grants from the BHF and the NIHR Oxford Biomedical Research Centre. SN reports grants from the NIHR Oxford Biomedical Research Centre, UK Research and Innovation, BHF and is a shareholder in Perspectum. SN was a board member and consultant to Perspectum until 2019. SN has patents ‘Multi-parametric magnetic resonance diagnosis & staging of liver disease’ and ‘System and methods for gated mapping of T1 values in abdominal visceral organs’ licensed to Perspectum. BR reports grants from the Oxford BHF Centre for Research Excellence (RE/18/3/34214), the NIHR Oxford Biomedical Research Centre and the United Kingdom Research Innovation Award. All other authors do not have relationships with industry or funding sources to declare., (© 2021 The Authors.)

The purpose of this research was to investigate the use of a standardized model of data collection, storage, and interpretation to evaluate the organized response to emergencies. The Standardized Emergency Response Incident Evaluation System (SERIES) model was employed to support practitioner evaluation of a fire service response to a simulated high-rise building fire. A comprehensive dataset representing quantitative and qualitative characteristics of the emergency response is established through content analysis of documents produced during the response and interviews with responders post-incident. Data are encoded within a standardized framework employing network the-ory. This dataset is then evaluated by fire service subject matter experts to identify learning outcomes relevant to emergency response effectiveness and organizational development. The results demonstrate that emergency response management system data can be collected and stored within a standardized framework. The results also demonstrate that not only can the resultant dataset support the identification of a range of learning outcomes by fire service practitioners, but that this approach can lead to a more comprehensive understanding of the response and deeper learning than that provided by existing evaluation methods.

Background: The medium-term effects of Coronavirus disease (COVID-19) on organ health, exercise capacity, cognition, quality of life and mental health are poorly understood., Methods: Fifty-eight COVID-19 patients post-hospital discharge and 30 age, sex, body mass index comorbidity-matched controls were enrolled for multiorgan (brain, lungs, heart, liver and kidneys) magnetic resonance imaging (MRI), spirometry, six-minute walk test, cardiopulmonary exercise test (CPET), quality of life, cognitive and mental health assessments., Findings: At 2-3 months from disease-onset, 64% of patients experienced breathlessness and 55% reported fatigue. On MRI, abnormalities were seen in lungs (60%), heart (26%), liver (10%) and kidneys (29%). Patients exhibited changes in the thalamus, posterior thalamic radiations and sagittal stratum on brain MRI and demonstrated impaired cognitive performance, specifically in the executive and visuospatial domains. Exercise tolerance (maximal oxygen consumption and ventilatory efficiency on CPET) and six-minute walk distance were significantly reduced. The extent of extra-pulmonary MRI abnormalities and exercise intolerance correlated with serum markers of inflammation and acute illness severity. Patients had a higher burden of self-reported symptoms of depression and experienced significant impairment in all domains of quality of life compared to controls ( p <0.0001 to 0.044)., Interpretation: A significant proportion of patients discharged from hospital reported symptoms of breathlessness, fatigue, depression and had limited exercise capacity. Persistent lung and extra-pulmonary organ MRI findings are common in patients and linked to inflammation and severity of acute illness., Funding: NIHR Oxford and Oxford Health Biomedical Research Centres, British Heart Foundation Centre for Research Excellence, UKRI, Wellcome Trust, British Heart Foundation., Competing Interests: Dr. Raman reports grants from NIHR Oxford Biomedical Research Centre, grants from United Kingdom Research Innovation Award, during the conduct of the study. Dr. Cassar reports grants from NIHR Oxford Biomedical Research Centre, during the conduct of the study. Dr. Tunnicliffe reports grants from NIHR Oxford Biomedical Research Centre, during the conduct of the study; shareholding in Perspectum, outside the submitted work; In addition, Dr. Tunnicliffe has a patent Systems and methods for gated mapping of T1 values in abdominal visceral organs GB2497668B licensed to Perspectum, a patent Multi-parametric magnetic resonance diagnosis and staging of liver disease GB2498254B licensed to Perspectum, and a patent Processing MR relaxometry data of visceral tissue to obtain a corrected value of relaxometry data based on a normal iron content for the visceral tissue GB2513474B licensed to Perspectum. Dr. Okell reports grants from Wellcome Trust/Royal Society, during the conduct of the study; personal fees from SBGNeuro, personal fees from Oxford University Press, personal fees from Siemens Healthineers, outside the submitted work; In addition, Dr. Okell has a patent Combined angiography and perfusion using radial imaging and arterial spin labeling pending, a patent Off-resonance Correction for Pseudo-continuous Arterial Spin Labeling pending, a patent Estimation of blood flow rates issued, a patent Fast analysis method for non-invasive imaging of blood flow using vessel-encoded arterial spin labelling with royalties paid to Siemens Healthineers, and a patent Quantification of blood volume flow rates from dynamic angiography data with royalties paid to Siemens Healthineers. Dr. Lewandowski reports non-financial support from Perspectum as a minority share-holder. Dr. Jenkinson reports personal fees from Oxford University Innovations, outside the submitted work. Dr. Channon reports grants funding from the British Heart Foundation and the National Institute for Health Research. Dr. Ferreira reports grants from British Heart Foundation, grants from National Institute Health Research Oxford Biomedical Research Centre, during the conduct of the study. Dr. Piechnik has a patent US patent 61/387,591 licensed to Siemens, a patent US patent 61/630,508 licensed to Perspectum, and a patent US patent 61-630,510 licensed to Perspectum. Dr. Pavlides reports other from Perspectum, outside the submitted work. Dr. Neubauer reports grants from Oxford NIHR Biomedical Research Centre, grants from UKRI, during the conduct of the study; personal fees and other from Perspectum Diagnostics, outside the submitted work; In addition, Dr. Neubauer has a patent Multi-parametric magnetic resonance diagnosis & staging of liver disease licensed to Perspectum., (Crown Copyright © 2020 Published by Elsevier Ltd.)

In 2006 the National Toxicology Program (NTP) of the FDA shifted to the preferred use of Wistar-Han rats from the more commonly used Sprague-Dawley (SD) strain - and industry followed. While European laboratories preferred the Wistar-Han line, there was a paucity of relevant historical control data in many US research institutions for the new "industry standard" rat strain. In 2010 the NTP reversed its decision and shifted back to SD rats because of reproductive issues with the Wistar strain. For post hoc comparative analyses, we report minimal practical differences in Functional Observational Battery (FOB) data from a large sample of male and female Wistar-Han and SD rats. In summarizing data from the preclinical safety evaluations of the CNS effects of new drugs using the FOB, it is crucial to understand the value of not only how the functional expression of drug effects in the rat are predictive of the human response, but also how and why they differ. What we can predict from the behavioral and physiological response of the designated test system to drug administration is the foundation of "generalizability" to the human's response. Here, we conclude that the use of either SD or WH rat strains in standard CNS safety studies provide equivalent supportive data for CNS safety assessment required for IND approval under the harmonized guidelines., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Previous research demonstrated that the attachment of the anterolateral ligament (ALL) to the lateral meniscus is stiffer and stronger in its tibial attachment than its femoral attachment. How this relates to anterolateral knee stability and lateral meniscal function is unknown., Hypothesis/purpose: The hypothesis was that the ALL acts as a peripheral anchor to the lateral meniscus, aiding in anterolateral rotatory stability, and that the inframeniscal fibers of the ALL will provide greater anterolateral rotatory stability because of their greater tensile properties. The purpose was therefore to compare the difference in kinematics of the anterior cruciate ligament (ACL)-deficient knee between the infra- and suprameniscal ALL-sectioned states., Study Design: Controlled laboratory study., Methods: Eight paired fresh-frozen cadaveric knees were tested in a 5-degree of freedom loading jig under the following loading conditions: 5-N·m internal rotation at 15° incremental angles of flexion and combined 5-N·m internal rotation moment, 10-N·m valgus moment, and 88-N anterior translation force representing a pivot shift test at 0°, 15°, and 30° of flexion. The knees were tested under intact, ACL-deficient, and ACL-/ALL-deficient conditions, with the pairs of knees being randomized to either supra- or inframeniscal ALL sectioning. Resultant joint kinematics and tibiofemoral translations were measured and compared with a 2-way mixed repeated measures analysis of variance., Results: Internal rotation increased by 3° after sectioning of the ACL at 0° of knee flexion ( P = .035). At 45° of knee flexion, internal rotation increased significantly by 2° between the ACL-deficient and the ACL-/ALL-deficient conditions ( P = .049). Secondary kinematics of valgus and anterior translation were observed in response to the 5-N·m load after ACL and ALL sectioning. Analysis of the pivot shift showed increases in tibiofemoral translation after sectioning of the ACL, with further translations after sectioning of the ALL. No differences were observed between supra- and inframeniscal ALL sectioning under any of the loading conditions., Conclusion: An injury to the ALL, coexisting with ACL deficiency, results in only minor increases in knee joint patholaxity. No differences in pivot-shift kinematics or tibiofemoral rotations were observed between the supra- and inframeniscal sectioning of the ALL in the ACL-deficient knee., Clinical Relevance: Tears of the midbody and/or posterior root attachment of the lateral meniscus are often observed at the time of ACL reconstruction. Increased anterolateral rotatory laxity has been observed in both lateral meniscus- and ALL-deficient states in combination with an ACL injury. While no significant functional relationship was found between the ALL and lateral meniscus, ALL sectioning did result in increased knee joint patholaxity, as demonstrated by composite tibiofemoral rotations.

Three significant contributions to the field of safety pharmacology were recently published detailing the use of electroencephalography (EEG) by telemetry in a critical role in the successful evaluation of a compound during drug development (1] Authier, Delatte, Kallman, Stevens & Markgraf; JPTM 2016; 81:274-285; 2] Accardi, Pugsley, Forster, Troncy, Huang & Authier; JPTM; 81: 47-59; 3] Bassett, Troncy, Pouliot, Paquette, Ascaha, & Authier; JPTM 2016; 70: 230-240). These authors present a convincing case for monitoring neocortical biopotential waveforms (EEG, ECoG, etc) during preclinical toxicology studies as an opportunity for early identification of a central nervous system (CNS) risk during Investigational New Drug (IND) Enabling Studies. This review is about "ictogenesis" not "epileptogenesis". It is intended to characterize overt behavioral and physiological changes suggestive of drug-induced neurotoxicity/ictogenesis in experimental animals during Tier 1 safety pharmacology testing, prior to first dose administration in man. It is the presence of these predictive or comorbid biomarkers expressed during the requisite conduct of daily clinical or cage side observations, and in early ICH S7A Tier I CNS, pulmonary and cardiovascular safety study designs that should initiate an early conversation regarding Tier II inclusion of EEG monitoring. We conclude that there is no single definitive clinical marker for seizure liability but plasma exposures might add to set proper safety margins when clinical convulsions are observed. Even the observation of a study-related full tonic-clonic convulsion does not establish solid ground to require the financial and temporal investment of a full EEG study under the current regulatory standards., Prefatory Note: For purposes of this review, we have adopted the FDA term "sponsor" as it refers to any person who takes the responsibility for and initiates a nonclinical investigations of new molecular entities; FDA uses the term "sponsor" primarily in relation to investigational new drug application submissions., (Copyright © 2018. Published by Elsevier Inc.)

Background: Countries with population-based colorectal cancer screening using faecal occult blood test kits performed in the home and posted to the laboratory struggle to achieve higher than 60% uptake. We measured the impact on participation of offering a community laboratory drop-off (CLD) alternative to postal return in New Zealand's Bowel Screening Pilot., Methods: From May to September, 2015, a flyer added to the bowel screening test kit offered CLD as an alternative to returning the kit by post. Participation rates for equal-length periods before and after were measured. Interrupted time series and logistic regression models measured CLD-attributable the changes in screening participation., Results: Overall, 26% of invitees used the CLD option. The effect of the CLD option on participation varied significantly by age, gender and ethnicity. There was a significant increase in participation among males (+1.75%; P = 0.002); patients under 60 (+1.65%; P = 0.006); Māori and Pacific (+2.88%; P = 0.029); and in the European/other ethnic group (+1.04%; P = 0.045) but not in Asians., Conclusions: Both analyses showed that at little or no additional cost, the CLD option produced small but significant increases in participation for non-Asian men and younger invitees. A CLD kit return option may have benefits for other bowel screening programmes.

Introduction: High-altitude environments lead to a significant physiological challenge and disease processes which can be life threatening; operational effectiveness at high altitude can be severely compromised. The UK military research is investigating ways of mitigating the physiological effects of high altitude., Methods: The British Service Dhaulagiri Research Expedition took place from March to May 2016, and the military personnel were invited to consent to a variety of study protocols investigating adaptation to high altitudes and diagnosis of high-altitude illness. The studies took place in remote and austere environments at altitudes of up to 7500 m., Results: This paper gives an overview of the individual research protocols investigated, the execution of the expedition and the challenges involved. 129 servicemen and women were involved at altitudes of up to 7500 m; 8 research protocols were investigated., Conclusions: The outputs from these studies will help to individualise the acclimatisation process and inform strategies for pre-acclimatisation should troops ever need to deploy at high altitude at short notice., Competing Interests: Competing interests: AM has received an honorarium for talking at a Medtronic meeting. The Reveal LINQ devices used in one study described were provided free of charge by Medtronic., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Purpose: Circulating acylated ghrelin concentrations are associated with altitude-induced anorexia in laboratory environments, but have never been measured at terrestrial altitude. This study examined time course changes in appetite, energy intake, body composition, and ghrelin constituents during a high-altitude trek., Methods: Twelve participants [age: 28(4) years, BMI 23.0(2.1) kg m -2 ] completed a 14-day trek in the Himalayas. Energy intake, appetite perceptions, body composition, and circulating acylated, des-acylated, and total ghrelin concentrations were assessed at baseline (113 m, 12 days prior to departure) and at three fixed research camps during the trek (3619 m, day 7; 4600 m, day 10; 5140 m, day 12)., Results: Relative to baseline, energy intake was lower at 3619 m (P = 0.038) and 5140 m (P = 0.016) and tended to be lower at 4600 m (P = 0.056). Appetite perceptions were lower at 5140 m (P = 0.027) compared with baseline. Acylated ghrelin concentrations were lower at 3619 m (P = 0.046) and 4600 m (P = 0.038), and tended to be lower at 5140 m (P = 0.070), compared with baseline. Des-acylated ghrelin concentrations did not significantly change during the trek (P = 0.177). Total ghrelin concentrations decreased from baseline to 4600 m (P = 0.045). Skinfold thickness was lower at all points during the trek compared with baseline (P ≤ 0.001) and calf girth decreased incrementally during the trek (P = 0.010)., Conclusions: Changes in plasma acylated and total ghrelin concentrations may contribute to the suppression of appetite and energy intake at altitude, but differences in the time course of these responses suggest that additional factors are also involved. Interventions are required to maintain appetite and energy balance during trekking at terrestrial altitudes.

Background: HIV-1-infected, virologically suppressed adults wanting to simplify or change their non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens may benefit from switching to the single-tablet regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (E/C/F/TDF)., Objective: We examined differences in the proportion of participants with HIV-1 RNA < 50 copies/mL (Snapshot analysis), change in CD4 cell count, safety, and patient-reported outcomes in participants switching to E/C/F/TDF from an NNRTI + FTC/TDF (TVD) regimen., Methods: STRATEGY-NNRTI was a 96-week, phase 3b, randomized, open-label, study examining the efficacy, safety, and tolerability of switching to E/C/F/TDF in virologically suppressed individuals (HIV-1 RNA < 50 copies/mL) on an NNRTI + TVD regimen. Participants were randomized to switch or remain on their NNRTI-based regimen (no-switch)., Results: At Week 96, 87% (251/290) of switch and 80% (115/143) of no-switch participants maintained HIV-1 RNA < 50 copies/mL (difference 6.1%; 95% CI -1.3 to 14.2%; p = 0.12) according to the FDA-defined snapshot algorithm. Both groups had similar proportions of subjects with virologic failure (2.8% switch, 1.4% no-switch). Discontinuations resulting from adverse events were infrequent (3% [9/291] switch, 2% [3/143] no-switch). Three switch participants (1%) discontinued due to renal adverse events (2 of the 3 before Week 48). Switch participants reported significant improvements in neuropsychiatric symptoms by as early as Week 4, and which were maintained through Week 96., Conclusions: E/C/F/TDF is safe and effective and reduces NNRTI-associated neuropsychiatric symptoms for virologically suppressed HIV-positive adults switching from an NNRTI plus FTC/TDF-based regimen.

Purpose: To investigate whether there is a differential response at rest and following exercise to conditions of genuine high altitude (GHA), normobaric hypoxia (NH), hypobaric hypoxia (HH), and normobaric normoxia (NN)., Method: Markers of sympathoadrenal and adrenocortical function [plasma normetanephrine (PNORMET), metanephrine (PMET), cortisol], myocardial injury [highly sensitive cardiac troponin T (hscTnT)], and function [N-terminal brain natriuretic peptide (NT-proBNP)] were evaluated at rest and with exercise under NN, at 3375 m in the Alps (GHA) and at equivalent simulated altitude under NH and HH. Participants cycled for 2 h [15-min warm-up, 105 min at 55% Wmax (maximal workload)] with venous blood samples taken prior (T0), immediately following (T120) and 2-h post-exercise (T240)., Results: Exercise in the three hypoxic environments produced a similar pattern of response with the only difference between environments being in relation to PNORMET. Exercise in NN only induced a rise in PNORMET and PMET., Conclusion: Biochemical markers that reflect sympathoadrenal, adrenocortical, and myocardial responses to physiological stress demonstrate significant differences in the response to exercise under conditions of normoxia versus hypoxia, while NH and HH appear to induce broadly similar responses to GHA and may, therefore, be reasonable surrogates.

Objectives: The electrocardiogram (ECG) is the most commonly used tool to screen for left ventricular hypertrophy (LVH), and yet current diagnostic criteria are insensitive in modern increasingly overweight society. We propose a simple adjustment to improve diagnostic accuracy in different body weights and improve the sensitivity of this universally available technique., Methods: Overall, 1295 participants were included-821 with a wide range of body mass index (BMI 17.1-53.3 kg/m(2)) initially underwent cardiac magnetic resonance evaluation of anatomical left ventricular (LV) axis, LV mass and 12-lead surface ECG in order to generate an adjustment factor applied to the Sokolow-Lyon criteria. This factor was then validated in a second cohort (n=520, BMI 15.9-63.2 kg/m(2))., Results: When matched for LV mass, the combination of leftward anatomical axis deviation and increased BMI resulted in a reduction of the Sokolow-Lyon index, by 4 mm in overweight and 8 mm in obesity. After adjusting for this in the initial cohort, the sensitivity of the Sokolow-Lyon index increased (overweight: 12.8% to 30.8%, obese: 3.1% to 27.2%) approaching that seen in normal weight (37.8%). Similar results were achieved in the validation cohort (specificity increased in overweight: 8.3% to 39.1%, obese: 9.4% to 25.0%) again approaching normal weight (39.0%). Importantly, specificity remained excellent (>93.1%)., Conclusions: Adjusting the Sokolow-Lyon index for BMI (overweight +4 mm, obesity +8 mm) improves the diagnostic accuracy for detecting LVH. As the ECG, worldwide, remains the most widely used screening tool for LVH, implementing these findings should translate into significant clinical benefit., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background. Chronic or persistent pain and disability following noncatastrophic "musculoskeletal" (MSK) trauma is a pervasive public health problem. Recent intervention trials have provided little evidence of benefit from several specific treatments for preventing chronic problems. Such findings may appear to argue against formal targeted intervention for MSK traumas. However, these negative findings may reflect a lack of understanding of the causal mechanisms underlying the transition from acute to chronic pain, rendering informed and objective treatment decisions difficult. The Canadian Institutes of Health Research (CIHR) Institute of Musculoskeletal Health and Arthritis (IMHA) has recently identified better understanding of causal mechanisms as one of three priority foci of their most recent strategic plan. Objectives. A 2-day invitation-only active participation workshop was held in March 2015 that included 30 academics, clinicians, and consumers with the purpose of identifying consensus research priorities in the field of trauma-related MSK pain and disability, prediction, and prevention. Methods. Conversations were recorded, explored thematically, and member-checked for accuracy. Results. From the discussions, 13 themes were generated that ranged from a focus on identifying causal mechanisms and models to challenges with funding and patient engagement. Discussion. Novel priorities included the inclusion of consumer groups in research from the early conceptualization and design stages and interdisciplinary longitudinal studies that include evaluation of integrated phenotypes and mechanisms.

Background: Classically, biomarkers such as the natriuretic peptides (NPs) BNP/NT-proBNP are associated with the diagnosis of heart failure and hs-cTnT with acute coronary syndromes. NPs are also elevated in pulmonary hypertension. High pulmonary artery systolic pressure (PASP) is a key feature of high altitude pulmonary edema (HAPE), which may be difficult to diagnose in the field. We have previously demonstrated that NPs are associated with high PASP and the presence of acute mountain sickness (AMS) in a small cohort at HA. We aimed to investigate the utility of several common cardiac biomarkers in diagnosing high PASP and AMS., Methods: 48 participants were assessed post-trekking and at rest at three altitudes: 3833 m, 4450 m, and 5129 m. NPs, hs-cTnT and hsCRP, were quantified using immunoassays, PASP was measured by echocardiography, and AMS scores were recorded., Results: Significant changes occurred with ascent in NPs, hs-cTnT, hsCRP (all p<0.001) and PASP (p=0.006). A high PASP (≥40 mm Hg) was associated with higher NPs, NT-proBNP: 137±195 vs. 71.8±68 (p=0.001); BNP 15.3±18.1 vs. 8.7±6.6 (p=0.001). NPs were significantly higher in those with AMS or severe AMS vs. those without (severe AMS: NT-proBNP: 161.2±264 vs. 76.4±82.5 (p=0.008)). The NPs correlated with hsCRP. cTnT increased with exercise at HA and was also higher in those with a high PASP (13.8±21 vs. 7.8±6.5, p=0.018)., Conclusion: The NPs and hs-cTnT are associated with high PASP at HA and the NPs with AMS.

Training in core echocardiography skills within the UK has been the focus of considerable discussion following recent national surveys. This article reports the proceedings of a joint meeting held by the British Society of Echocardiography and British Junior Cardiologists' Association. It considers the current issues impacting on high-quality training and presents potential solutions for the future.

The British Junior Cardiologists' Association surveyed members to analyse their perception and experience of training. Cardiology trainees perceive significant limitations with the current training structure. This article gives suggestions which could lead to improvements in training and patient care.

Several new porous ingrowth surfaces for acetabular component fixation have recently been developed. The purpose of this study was to compare the in vivo fixation achieved by two different porosity ingrowth surfaces using radiostereometric analysis (RSA). Sixty-two patients undergoing primary total hip arthroplasty (THA) were randomized to receive a cementless acetabular component with either a 61% high porosity asymmetric titanium porous surface (StikTite, Smith and Nephew, TN, USA) or a 45% low porosity sintered bead porous surface (Roughcoat, Smith and Nephew, TN, USA). RSA and clinical follow-up examinations were done post-operatively, 6-weeks, 3-months, 6-months, 1-year and 2-years. Both the high porosity StikTite and lower porosity Roughcoat surfaces provided excellent biologic fixation., (© 2013.)

Purpose: To design, construct and commission a set of computer-controlled motorized jaws for a micro-CT to perform conformal image-guided small animal radiotherapy., Methods: We report on the design and evaluation of our custom-built motorized orthogonal jaws, which allows the delivery of off-axis rectangular fields, installed on a GE eXplore CT 120 preclinical imaging system. The jaws in the x direction are independently driven, while the y direction jaws are symmetric. All motors have backup encoders, verifying their positions. Measurements were performed using the large focal spot (1.0 mm) at 140 kVp, 50 mA, 25 ms pulse duration, with 220 ms between pulses. Additionally, a Monte Carlo beam model of the micro-CT and jaws has been created in BEAMnrc. Square beam profiles (2 × 2, 5 × 5, 10 × 10, 20 × 20 and 30 × 30 mm) were measured using EBT2 film in the center of a 40 × 40 × 40 mm solid water block. A calibrated Farmer ion chamber in a 50 × 20 × 70 mm solid water block was used to measure the output of three field sizes: 50 × 50, 40 × 40 and 30 × 30 mm. Both setups were simulated in DOSXYZnrc. Films were scanned on a flatbed scanner (Epson 1000XL) and converted to dose using a fitted calibration curve., Results: Relative output factors measured with the ion chamber agree with Monte Carlo simulations within 2%. Penumbra widths from film agree well with simulations. The averaged random error of positioning both jaws is estimated at less than 0.1 mm. Finer calibration points will improve the absolute jaw positioning errors., Conclusion: The computer-controlled motorized jaws can be positioned reliably down to sub-millimeter resolutions. Upon completion of small field dosimetry (< 1 cm), this will be ready for conformal radiotherapy for small animals., (© 2012 American Association of Physicists in Medicine.)

Purpose: To investigate the profiles of chromosome damage induced in vitro by exposure to alpha-particles and gamma-rays., Materials and Methods: Human peripheral blood lymphocytes were exposed to three dose regimes: alpha-particle doses of 0.2 and 0.5 Gy and a gamma-ray dose of 1.5 Gy. After culturing for 47 hours, chromosome aberrations involving the number 5 chromosomes were identified using a multi-coloured banding (mBAND) technique., Results: Analysis of the frequencies of chromosome 5 breaks within aberrant cells and within aberrant number 5 chromosomes demonstrated that alpha-particle irradiation is more likely to result in multiple breaks in a chromosome than gamma-irradiation. Additionally, overdispersion was observed for all doses for the distribution of breaks amongst all cells analysed and breaks amongst total number 5 chromosomes, with this being greatest for the 0.2 Gy alpha-particle dose. The ratio of interchanges to intrachanges (F ratio) was 1.4 and 2.4 for 0.2 and 0.5 Gy alpha-particles respectively and 5.5 for 1.5 Gy gamma-rays. Evaluation of simple versus complex exchanges indicated ratios of 1.9 and 2.7 for 0.2 and 0.5 Gy alpha-particles respectively and 10.6 for 1.5 Gy gamma-rays. The majority of the intrachanges involving chromosomes 5 induced by alpha-particle radiation were associated with more complex exchanges., Conclusions: This study has confirmed that exchanges induced by exposure to high linear energy transfer (LET) alpha-particle radiation comprise a greater proportion of intrachanges than those induced by exposure to low LET gamma-rays. However, since the majority of these are associated with complex rearrangements and likely to be non-transmissible, this limits their applicability as a marker of past in vivo exposure.

We present a completely automated 2D-3D registration technique that accurately maps a patient-specific heart model, created from preoperative images, to the patient's orientation in the operating room. This mapping is based on the registration of preoperatively acquired 3D vascular data with intraoperatively acquired angiograms. Registration using both single and dual-plane angiograms is explored using simulated but realistic datasets that were created from clinical images. Heart deformations and cardiac phase mismatches are taken into account in our validation using a digital 4D human heart model. In an ideal situation where the pre- and intraoperative images were acquired at identical time points within the cardiac cycle, the single-plane and the dual-plane registrations resulted in 3D root-mean-square (rms) errors of 1.60 +/- 0.21 and 0.53 +/- 0.08 mm, respectively. When a 10% timing offset was added between the pre- and the intraoperative acquisitions, the single-plane registration approach resulted in inaccurate registrations in the out-of-plane axis, whereas the dual-plane registration exhibited a 98% success rate with a 3D rms error of 1.33 +/- 0.28 mm. When all potential sources of error were included, namely, the anatomical background, timing offset, and typical errors in the vascular tree reconstruction, the dual-plane registration performed at 94% with an accuracy of 2.19 +/- 0.77 mm.

Purpose: To investigate the relationship between stable chromosome aberration frequency in peripheral blood lymphocytes and occupational cumulative radiation exposure., Materials and Methods: Cytogenetic analysis using G-banding was performed on peripheral blood lymphocyte cultures from 104 workers from the British Nuclear Fuels PLC facility at Sellafield, UK. The study group comprised 61 men with lifetime cumulative doses > 500 mSv, 39 men with minimal exposure (i.e. < 50 mSv) who formed a control group and 4 men with intermediate doses., Results: The slope of the dose-response, adjusted for smoking status, for translocations and insertions was 0.55+/-0.31 x 10(-2)/cell/Sv. Consideration of chromosome breakpoints for all aberrations combined in the radiation workers revealed an excess in the C group chromosomes and a deficit in the F group chromosomes with breakpoints being concentrated in the terminal regions whereas the distribution in the control group did not deviate from expectation., Conclusions: The dose-response was not significantly different from the parallel FISH analysis (Tucker et al. 1997) and confirms that chronic radiation exposure appears to be substantially less effective at inducing stable chromosome aberrations in comparison with acute exposure.

To test the hypothesis that an antiresorptive agent might reduce the dosing requirement for an anabolic drug during reversal of osteopenia due to estrogen deficiency, the following experiment was conducted in 6-month-old female rats. Ovariectomy or sham surgery was performed and the following six experimental groups were studied. Untreated (SHAM) or ovariectomized (OVX) animals served as control groups. Four weeks post-OVX, osteopenic rats (now 7 months old), were treated in one of four experimental protocols: human parathyroid hormone (hPTH(1-34)), 80 microg/kg/day, given by subcutaneous injection 5 days/week; a selective estrogen receptor modulator (SERM), raloxifene analog LY117018 (RA), 3 mg/kg/day, given by gavage 5 days/week; and two combinations of LY117018 at the same dose and frequency with hPTH(1-34) (same dose, 5 times/week) and a reduced dosing interval of hPTH(1-34) (same dose, 2 times/week). After 12 weeks of treatment, the four experimental groups were sacrificed at age 10 months. SHAM and OVX controls were also studied at 7 and 10 months of age. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry at four skeletal sites: two mixed cortical/trabecular sites (femur and tibia) and two predominantly trabecular sites (lumbar spine and pelvis). The differences in BMD were consistent at all four sites. RA alone maintained BMD at all skeletal sites, but the results were not significantly improved over OVX controls, at age 10 months. hPTH(1-34) injections given 5 days/week resulted in BMD increments significantly higher than in either OVX or SHAM controls (p < 0.001). While the RA did not enhance the anabolic effects of full doses of hPTH(1-34), the addition of RA treatment to twice-weekly hPTH(1-34) dosing resulted in BMD increments at all four skeletal sites that were similar to the more intensive anabolic regimen of hPTH(1-34) therapy given 5 times/week. Therefore, an antiresorptive agent such as SERMs may potentially reduce the pharmacologic doses of PTH needed to reverse estrogen deficiency-induced osteopenia.

This experiment was designed to evaluate the ability of a raloxifene analogue (RA), LY117018, with or without reduced dosing of human parathyroid hormone (hPTH)(1-34) to maintain gains in bone mass after a fully anabolic treatment regimen given to aging osteopenic rats. Six-month-old rats were ovariectomized (ovx) or sham-operated (sham). After 1 month, ovx rats were treated with an anabolic regimen consisting of subcutaneous hPTH(1-34) 80 microg/kg/day and oral raloxifene 3 mg/kg/day, each given 5 days/week for 3 months. Thereafter, the treated ovx rats went on to an 8 week maintenance phase of treatment with either RA alone at the same dose, hPTH(1-34) at a reduced dosing interval (twice a week), or a combination of the two. Bone mineral density (BMD) was measured ex vivo at four skeletal sites, lumbar spine (L2-4), proximal hemipelvis, whole femur, and tibia, by dual-energy X-ray densitometry. All four sites showed a similar pattern of response. After the 3 month anabolic phase, the sham group had significantly higher BMD values than ovx rats at all skeletal sites (p < or = 0.002). The ovx rats treated with PTH + RA during the anabolic phase of the protocol had significantly higher BMD than the sham group in the femur, tibia, and spine (p < or = 0.02) and higher but not significantly different values in the pelvis. Following the 2 month maintenance phase, comparisons were made with the PTH-RA group at the end of the anabolic phase. Decrements in BMD were seen in all three maintenance therapy groups, but they were not statistically significant in the RA plus reduced PTH dose group. However, reduced hPTH(1-34) dosing and RA alone resulted in significant reductions of bone mass measurements at several skeletal sites during the maintenance phase. We conclude that the raloxifene analogue LY117018 may be useful in maintaining bone mass in aging ovx rats following anabolic therapy with hPTH(1-34) and raloxifene analogue, but that this strategy only allows for dose reduction of hPTH(1-34) rather than its discontinuation.

The British Nuclear Fuels plc facility at Sellafield performs a range of nuclear-related activities. The site has been in operation since 1950 and has, in general, employed a stable work force, many of whom have accumulated relatively high occupational exposures to ionizing radiation. This paper compares the physical dosimetry with two biological end points for evaluating radiation exposure: fluorescence in situ hybridization with whole-chromosome painting probes to quantify stable chromosome aberrations (translocations and insertions), and glycophorin A (GPA) analysis of variant erythrocytes. For the cytogenetic analyses, 81 workers were evaluated in five dose categories, including 23 with minimal radiation exposure (< or = 50 mSv) and 58 with exposures ranging from 173 to 1108 mSv, all but 3 being > 500 mSv. In a univariate analysis, the mean stable chromosome aberration frequencies showed a significant increase with dose category (P = 0.032), and with cumulative dose when dose is treated as a continuous variable (P = 0.015). The slope of the dose response for stable aberrations is 0.79 +/- 0.22 aberrations per 100 cells per sievert (adjusted for smoking status), which is less than that observed among atomic bomb survivors, and suggests a dose and dose-rate effectiveness factor for chronic exposure of about 6. Analyses of the data for GPA N/O and N/N variants from 36 workers revealed no correlation with dose. Neither was there a correlation between the frequencies of N/O GPA variants and stable aberrations, although a weak negative association was observed between N/N variant frequency and stable aberrations (r = -0.38, P = 0.05). These results provide clear evidence for the accumulation of stable aberrations under conditions of chronic occupational exposure to ionizing radiation and show that stable chromosome aberrations are a more sensitive indicator for chronic radiation exposure than GPA variants. In comparison with human studies of brief exposure, chronic low-dose exposures appear substantially less effective for producing somatic effects as reflected by stable chromosome aberrations.

Objective: This study was designed to evaluate the role of technetium-99m (99mTc) hexamethyl propylene amine oxime (HMPAO)-labelled leucocyte imaging as an initial screening test in patients suspected of having inflammatory bowel disease (IBD)., Patients and Methods: Thirty-one patients in whom a final diagnosis of irritable bowel syndrome (IBS) was made (group 1) and another 33 patients with established Crohn's disease (group 2) were studied. All patients had 99mTc HMPAO-labelled leucocyte scan with imaging at 40 and 120 min. Scans with abnormal bowel uptake were considered positive and this uptake was quantified by visual grading and computer-based methods (scan score). Group 1 patients with positive 99mTc HMPAO scan underwent an indium-111 (111In)-labelled leucocyte scan (imaging at 180 min) followed by endoscopy and barium radiology as deemed necessary in order to verify the 99m Tc HMPAO result., Results: Three scan patterns were seen: well localized and unequivocally positive scans at both 40 min and 2 h were obtained from 28 patients. All but one had established Crohn's disease. Diffuse bowel uptake was seen in 14 scans. Ten of these (false positive) were obtained from symptomatic patients with IBS and four (false negative) from patients with asymptomatic Crohn's disease. No bowel uptake at 40 min and 2 h was seen in 22 scans. All but two of these (who had quiescent Crohn's disease) were obtained from patients with IBS. Active Crohn's disease is associated with significantly higher scan score (mean +/- SEM, 82.1 +/- 13.6) than the false positive scans (12.5 +/- 3.1, P > or = 0.001). Patients with false positive 99mTc HMPAO scans had negative 111In scans, endoscopy and barium radiology., Conclusion: Bowel scanning using either 111In or 99mTc HMPAO is useful in excluding active IBD. Because of radiation dose, image quality and availability 99mTc may be preferred to 111In.

The frequency of hypoxanthine-guanine phosphoribosyltransferase (hprt) mutations has been determined in the peripheral T-lymphocytes of 18 workers at the Sellafield nuclear reprocessing installation with cumulative recorded radiation doses of about 500 mSv or more in comparison with a matched control group of 18 workers with doses less than 50 mSv. The mean dose of the exposed group was 663 mSv (range 449.3-880.8), and of the unexposed group 10.9 mSv (range 0-46.5). During the most recent 6 y the mean doses were 40.1 mSv (range 1.9-93.9) and 2.3 mSv (range 0-8.7), respectively. The logarithmic mean mutant frequency of the exposed group (9.3 x 10(-6)) was lower than that of the unexposed group (12.4 x 10(-6)). The apparent inverse association of mutant frequency and exposure varied in statistical significance tests from borderline to p < 0.01 depending on how the analysis was performed and whether recent or total exposure was considered.

This study reports some biological studies on the alkaloid virosecurinine isolated from the plant Securinega Virosa. Virosecurinine is an isomer of the securinine group of alkaloids present in plants used in traditional medicines in many areas, including the Central District of Papua New Guinea. Virosecurinine is mildly toxic to mice with an LD50 of 73 milligrams per kilogram body weight. Death results from violent tonic convulsions and paralysis similar to those observed with strychnine poisoning. Virosecurinine had no effect on the growth of the following bacteria, E. coli, S. aureus, and B. subtilis, or the fungi, F. monoliforme, P. viridicatum, A. niger, R. solani, R. stolonifer and C. lunata.

Plants have been used as traditional medicine in many areas of Papua New Guinea. Over thrity different plants used to treat malaria and fevers have been collected and their uses recorded. Many of the plants taken internally, but few others, are found to contain alkaloids.

In 46 patients with rheumatoid arthritis (RA) the allele C4B*3 occurred in 6 patients, while among 350 normal controls, it occurred 6 times (P less than 0.00002). Among 9 white and 1 black families, each of which had 2 or more members with RA, there were 36 haplotypes associated with RA. An extended haplotype (specific HLA-B, DR, complotype haplotypes in significant linkage disequilibrium) containing C4B*3: HLA-B15, DR4, BF*S, C2*C, C4A*3, C4B*3, was found twice (P less than 0.001) among whites with the disease-associated chromosomes.

A recent paper discussed plants used in traditional medicine for fevers and malaria throughout Papua New Guinea (Holdsworth, 1975 a). This paper summarises information now available on plants used to treat gastric ailments, especially diarrhea and dysentery.

Thrombocytopenia developed in 23 patients with rheumatoid arthritis treated with gold salts over 25 years. All patients recovered, and there were no episodes of life-threatening hemorrhage; four patients eventually needed splenectomy. The clinical presentation of gold-induced thrombocytopenia and its treatment and outcome are reviewed. Because gold-induced thrombocytopenia is believed to have an immunologic basis, we sought an association between this complication and antigens of the human leukocyte antigen (HLA) region. The most significant finding was the association of the HLA-DR3 alloantigen in 12 of 15 of these patients compared with 26 of 84 in a control population (x2 12.9, p less than 0.001). This study provides further evidence that gold-induced thrombocytopenia is immunologically mediated and that genes of the major histocompatibility complex are involved.