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Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. Methods: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Results: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56–0.87]; P =0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50–0.81]; P =0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%–10.2%) in first events, with a number needed to treat of 16 (95% CI, 10–44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P =0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

BACKGROUND CONTEXT Nonphysiological mechanical loading and inflammation are both critically involved in intervertebral disc (IVD) degeneration, which is characterized by an increase in cytokines and matrix metalloproteases (MMPs) in the nucleus pulposus (NP). This process is known to be mediated by the NF-κB pathway. CLINICAL SIGNIFICANCE Current clinical treatments for IVD degeneration focus on the alleviation of symptoms rather than targeting the underlying mechanism. Injection of an NF-κB inhibitor may attenuate the progression of IVD degeneration. PURPOSE To investigate the ability of the NF-κB inhibitor, NEMO binding domain peptide (NBD), to alter IVD degeneration processes by reducing IL-1β- and mechanically-induced cytokine and MMP levels in human nucleus pulposus cells in vitro, and by attenuating IVD degeneration in an in vivo rat model for disc degeneration. STUDY DESIGN Experimental in vitro and animal model. PATIENT SAMPLE Discarded specimens of lumbar disc from 21 patients, and 12 Sprague Dawley rats. OUTCOME MEASURES Gene and protein expression, cell viability, µMRI and histology. METHODS IL-1β-prestimulated human nucleus pulposus cells embedded into fibrin constructs were loaded in the Flexcell FX-5000 compression system at 5 kPa and 1 Hz for 48 hours in the presence and absence of NBD. Unloaded hNPC/fibrin constructs served as controls. Cell viability in loaded and unloaded constructs was quantified, and gene and protein expression levels determined. For in vivo testing, a rat needle disc puncture model was employed. Experimental groups included injured discs with and without NBD injection and uninjured controls. Levels of disc degeneration were determined via µMRI, qPCR and histology. Funding sources include $48,874 NASS Young Investigator Research Grant and $119,174 NIH 5K01AR071512-02. There were no applicable financial relationships or conflicts of interest. RESULTS Mechanical compression of hNPC/fibrin constructs resulted in upregulation of MMP-3 and IL-8. Supplementation of media with 10 μM NBD during loading increased cell viability, and decreased MMP-3 gene and protein levels. IVD injury in rat resulted in an increase in MMP-3, IL-1β and IL-6 gene expression. Injections of 250 µg of NBD during disc injury resulted in decreased IL-6 gene expression. µMRI analysis demonstrated a reduction of disc hydration in response to disc needle injury, which was attenuated in NBD-treated IVDs. Histological evaluation showed NP and AF lesion in injured discs, which was attenuated by NBD injection. CONCLUSIONS The results of this study show NBD peptide's capacity to reduce IL-1β- and loading-induced MMP-3 levels in hNPC/fibrin constructs while increasing the cells’ viability, and to attenuate IVD degeneration in rat, involving downregulation of IL-6. Therefore, NBD may be a potential therapeutic agent to treat IVD degeneration.

Surgical care is an integral part of any healthcare system, yet there is a paucity of data on the burden of surgical disease, surgical capacity and access to surgical services in the Pacific region. This study aimed to evaluate access to surgical care through a pilot household survey in the Vanuatu island of Efate and five of its surrounding islands. The 2009 Vanuatu census’ GPS coordinates were used to randomly select 150 rural and 150 urban households from Efate and its surrounding islands. A total of 143 urban households and 142 rural households were available for inclusion in this study. A household questionnaire was developed to evaluate access to surgical care and included information regarding household demographics, socio-economic indicators and perceived and realised barriers to accessing care. The questionnaire was administered by local health workers, and data were collected electronically. Questionnaires were completed by 285 households. Two hundred and forty-one out of 254 (94.8%) households reported being able to access Port Vila Hospital, if required. The most commonly cited potential barriers to accessing surgical care were financial constraints (42.4%) and transport (26.4%). Our results provide important insights into the geographic, sociocultural and economic barriers to seeking, reaching and receiving surgical care in this region of Vanuatu. Identifying specific areas and communities with poor access to care, alongside the determinants of access, will help in designing both clinical and policy interventions to improve access to surgical care.

BACKGROUND Patients who survive traumatic atlanto-occipital dissociation (AOD) may present with normal neurological examinations and near-normal-appearing diagnostic images, such as cervical radiographs and computed tomography (CT) scans. OBSERVATIONS The authors described a neurologically intact 64-year-old female patient with a degenerative autofusion of her right C4–5 facet joints who presented to their center after a motor vehicle collision. Prevertebral soft tissue swelling and craniocervical subarachnoid hemorrhage prompted awareness and consideration for traumatic AOD. An abnormal occipital condyle–C1 interval (4.67 mm) on CT and craniocervical junction ligamentous injury on magnetic resonance imaging (MRI) confirmed the diagnosis of AOD. Her autofused right C4–5 facet joints were incorporated into the occipitocervical fusion construct. LESSONS Traumatic AOD can be easily overlooked in patients with a normal neurological examination and no associated upper cervical spine fractures. A high index of suspicion is needed when evaluating CT scans because normal values for craniocervical parameters are significantly different from the accepted ranges of normal on radiographs in the adult population. MRI of the cervical spine is helpful to evaluate for atlanto-occipital ligamentous injury and confirm the diagnosis. Occipitocervical fusion construct may need to be extended to incorporate spinal levels with degenerative autofusion to prevent adjacent level degeneration.

NEW FINDINGS What is the central question of this study? Does habitual resistance and endurance exercise modify dynamic cerebral autoregulation? What is the main finding and its importance? To the authors' knowledge, this is the first study to directly assess dynamic cerebral autoregulation in resistance-trained individuals, and potential differences between exercise training modalities. Forced oscillations in blood pressure were induced by repeated squat-stands, from which dynamic cerebral autoregulation was assessed using transfer function analysis. These data indicate that dynamic cerebral autoregulatory function is largely unaffected by habitual exercise type, and further document the systemic circulatory effects of regular exercise. ABSTRACT Regular endurance and resistance exercise produce differential but desirable physiological adaptations in both healthy and clinical populations. The chronic effect of these different exercise modalities on cerebral vessels' ability to respond to rapid changes in blood pressure (BP) had not been examined. We examined dynamic cerebral autoregulation (dCA) in 12 resistance-trained (mean ± SD, 25 ± 6 years), 12 endurance-trained (28 ± 9 years) and 12 sedentary (26 ± 6 years) volunteers. The dCA was assessed using transfer function analysis of forced oscillations in BP vs. middle cerebral artery blood velocity (MCAv), induced via repeated squat-stands at 0.05 and 0.10 Hz. Resting BP and MCAv were similar between groups (interaction: both P ≥ 0.544). The partial pressure of end-tidal carbon dioxide ( PETCO2 ) was unchanged (P = 0.561) across squat-stand manoeuvres (grouped mean for absolute change +0.6 ± 2.3 mmHg). Gain and normalized gain were similar between groups across all frequencies (both P ≥ 0.261). Phase showed a frequency-specific effect between groups (P = 0.043), tending to be lower in resistance-trained (0.63 ± 0.21 radians) than in endurance-trained (0.90 ± 0.41, P = 0.052) and -untrained (0.85 ± 0.38, P = 0.081) groups at slower frequency (0.05 Hz) oscillations. Squat-stands induced mean arterial pressure perturbations differed between groups (interaction: P = 0.031), with greater changes in the resistance (P

Background Subependymomas are rare in the spinal cord. They are typically expansile, intramedullary spinal cord masses, eccentrically located with minimal gadolinium enhancement. Case Description We present a case of subependymoma originating from the cervical cord with an unusual exophytic appearance. Hallmarks of subependymoma and treatment are reviewed. Conclusions This is the first case, to our knowledge, where imaging revealed a mass appearing to be completely extramedullary with a primary exophytic component. Therefore, subependymomas should remain on the differential for masses in the spinal cord that appear extramedullary and exophytic.

Objective (a) To establish baseline lateral craniofacial morphology and soft tissue profile outcomes for New Zealand children with complete unilateral and complete bilateral cleft lip and palate (CUCLP/CBCLP) and determine differences in relation to demographic characteristics including cleft type, sex and ethnicity and (b) To compare these outcomes to similar international studies. Settings and sample population Nation-wide prospective and retrospective cephalometric analysis of 76 patients with CUCLP and 23 patients with CBCLP pre-secondary alveolar bone graft. Materials and methods Assessment was undertaken by three experienced orthodontists blinded to patient identity. A total of 13 hard tissue and 8 soft tissue landmarks were identified allowing for an assessment of 16 angular, three linear and one ratio variables. Inter-assessor reliability was determined by pre-defined measurement error thresholds. Results Inter-assessor reliability of cephalometric landmarks restricted reporting to 10 hard tissue, four soft tissue and one ratio variables. CUCLP had greater midface and mandibular retrusion than CBCLP. Females had greater midface and mandibular prominence and smaller nasal projections. The Pacific and Māori groups had more retrusive midfacial profiles, and the Pacific group had more prominent mandibles. A sub-analysis of New Zealand European CUCLP results found they were closely aligned to Eurocleft and Americleft study centres with less favourable outcomes. Conclusions The reliability of a number of cephalometric measurements was poor. Lateral craniofacial morphology and soft tissue profile outcomes varied between CUCLP/CBCLP, sex and ethnicity. The New Zealand European outcomes are similar to or less favourable to other studies.

Resistance exercise (RE) is a popular modality for the general population and athletes alike, due to the numerous benefits of regular participation. The acute response to dynamic RE is characterised by temporary and bidirectional physiological extremes, not typically seen in continuous aerobic exercise (e.g. cycling) and headlined by phasic perturbations in blood pressure that challenge cerebral blood flow (CBF) regulation. Cerebral autoregulation has been heavily scrutinised over the last decade with new data challenging the effectiveness of this intrinsic flow regulating mechanism, particularly to abrupt changes in blood pressure over the course of seconds (i.e. dynamic cerebral autoregulation), like those observed during RE. Acutely, RE can challenge CBF regulation, resulting in adverse responses (e.g. syncope). Compared with aerobic exercise, RE is relatively understudied, particularly high-intensity dynamic RE with a concurrent Valsalva manoeuvre (VM). However, the VM alone challenges CBF regulation and generates additional complexity when trying to dissociate the mechanisms underpinning the circulatory response to RE. Given the disparate circulatory response between aerobic and RE, primarily the blood pressure profiles, regulation of CBF is ostensibly different. In this review, we summarise current literature and highlight the acute physiological responses to RE, with a focus on the cerebral circulation.

BACKGROUND Cervical spine surgery sometimes necessitates complex ventral/dorsal approaches or osteotomies that place the vertebral artery (VA) at risk of inadvertent injury. Tortuosity of the VA poses increased risk of vessel injury during anterior decompression or placement of posterior instrumentation. OBSERVATIONS In this report, the authors describe a patient with degenerative cervical spondylotic myelopathy and focal kyphotic deformity requiring corrective surgery via a combined ventral/dorsal approach. Computed tomography (CT) and CT angiography (CTA) of the spine identified a left medially enlarged C4 transverse foramen and tortuous VA V2 segment forming a potentially dangerous medial loop into the vertebral body, respectively. The patient’s presentation and management are described. LESSONS The course of the VA is variable, and a tortuous VA with significant medial or lateral displacement may be dangerous during ventral and dorsal approaches to the cervical spine. CTA of the cervical spine is warranted in cases in which atlantoaxial fixation is needed or suspicious transverse foramen morphology is identified to understand the course of the VA and identify anatomical variations that would put the VA at risk during cervical spine surgery.

International audience; Background & Aims: Increased de novo lipogenesis creates excess intrahepatic fat and lipotoxins, propagating liver damage in nonalcoholic steatohepatitis. TVB-2640, a fatty acid synthase inhibitor, was designed to reduce excess liver fat and directly inhibit inflammatory and fibrogenic pathways. We assessed the safety and efficacy of TVB-2640 in patients with nonalcoholic steatohepatitis in the United States.Methods: 3V2640-CLIN-005 (FASCINATE-1) was a randomized, placebo-controlled, single-blind study at 10 US sites. Adults with ≥8% liver fat, assessed by magnetic resonance imaging proton density fat fraction, and evidence of liver fibrosis by magnetic resonance elastography ≥2.5 kPa or liver biopsy were eligible. Ninety-nine patients were randomized to receive placebo or 25 mg or 50 mg of TVB-2640 (orally, once-daily for 12 weeks). The primary end points of this study were safety and relative change in liver fat after treatment.Results: Liver fat increased in the placebo cohort by 4.5% relative to baseline; in contrast TVB-2640 reduced liver fat by 9.6% in the 25-mg cohort (n = 30; least squares mean: –15.5%; 95% confidence interval, –31.3 to –0.23; P = .053), and 28.1% in the 50-mg cohort (n = 28; least squares mean: –28.0%; 95% confidence interval, –44.5 to –11.6; P = .001). Eleven percent of patients in the placebo group achieved a ≥30% relative reduction of liver fat compared to 23% in the 25-mg group, and 61% in the 50-mg group (P < .001). Secondary analyses showed improvements of metabolic, pro-inflammatory and fibrotic markers. TVB-2640 was well tolerated; adverse events were mostly mild and balanced among the groups.Conclusions: TVB-2640 significantly reduced liver fat and improved biochemical, inflammatory, and fibrotic biomarkers after 12 weeks, in a dose-dependent manner in patients with nonalcoholic steatohepatitis. ClinicalTrials.gov, Number NCT03938246.

We describe non-operative management a rare traumatic clival fracture extending through the bilateral occipital condyles. Clinical History: A 26-year-old female who was involved in a high-speed motor vehicle crash presented to an outside facility with difficulty speaking. Subsequent CT of the cervical spine demonstrated a fracture of the clivus with extension through the bilateral occipital condyles. She was then transferred to our hospital for further management where complete trauma survey noted multiple other injuries including traumatic subarachnoid hemorrhage, spinal epidural hematoma, bilateral pneumothoraces, liver laceration, bilateral upper extremity injuries, and lumbosacral fractures. Additional spinal imaging was negative for any associated vascular or spinal cord injury. Given her young age, there was a strong interest to preserve craniocervical motion and the decision was made to treat her with non-operatively with halo placement. After 18 weeks of rigid fixation, follow up imaging demonstrated completely healed fractures and at twenty-one weeks post fixation she demonstrated preserved motion of the craniocervical junction. This is a review of the literature and case report regarding this rare entity and its management.

Hyperthermia produces profound redistribution of blood and circulatory reflex function. We investigated the potential for lower body positive pressure (LBPP) to maintain or restore haemodynamics during graded hyperthermia. Eight healthy adults rested supine in a custom-made LBPP box, sealed distal to the iliac crest. Following 5 min of normothermic rest, 20 mmHg of LBPP was applied and repeated when core temperature (Tcore ) had increased passively by +0.5 and +1°C. Primary dependent variables included mean middle cerebral artery blood velocity (MCAvmean , transcranial Doppler), mean arterial blood pressure (MAP, finger photoplethysmography), heart rate (HR) and partial pressure of end-tidal carbon dioxide (PET CO2 ). The absolute increase in MAP during LBPP was lower at Tcore +1°C (2 ± 3 mmHg), compared with normothermia (7 ± 3 p = .01). The modest increase in MCAvmean was unchanged by Tcore (normothermia, 2 ± 3 cm/s; +0.5°C, 3 ± 3 cm/s and +1°C, 3 ± 4 cm/s, p = .74). By design, PET CO2 was unchanged in all conditions from normothermic baseline (42 ± 1, p = .81). LBPP-induced changes in HR were greater at +0.5°C (-13 ± 4 b/min) and +1°C (-12 ± 6 b/min) compared with normothermia (-3 ± 3 b/min, p = .01 and p = .01, respectively). These data indicate that despite a significant attenuation in MAP to LBPP with moderate hyperthermia, MCAvmean dynamics were unchanged among the thermal manipulations.

Objectives: We examined the acute effects of anthocyanin-rich New Zealand blackcurrant extract and a placebo on hemodynamics during 120 min of sedentary sitting in healthy males. Additionally, we investigated whether changes in resting hemodynamics altered repeated isometric hand-grip exercise performance and post exercise forearm blood flow (FBF).Methods: Ten healthy males completed two trials during which they ingested either blackcurrant extract (1.87 mg total anthocyanins/kg bodyweight) or placebo powder. Heart rate, blood pressure and forearm blood flow were measured, and venous blood was sampled, prior to and 30, 60, 90 and 120 min-post ingestion. Participants remained seated for the duration of each trial. At 120 min post-ingestion participants completed as many repetitions of isometric hand-grip contractions as possible.Results: Heart rate, blood pressure and mean arterial pressure changed over time (all p < 0.001) but did not differ between treatments. A treatment x time interaction for FBF (p = 0.025) and forearm vascular resistance (FVR) (p = 0.002) was found. No difference in the number of isometric hand-grip contractions was observed between treatments (p = 0.68) nor was there any treatment x time interaction in post-exercise FBF (p = 0.997). Plasma endothelin-1 (p = 0.023) and nitrate (p = 0.047) changed over time but did not differ between treatments (both p > 0.1). Plasma nitrite did not change over time (p = 0.732) or differ between treatments (p = 0.373).Conclusion: This study demonstrated that acute ingestion of a single dose of blackcurrant extract maintained FBF and FVR during an extended period of sitting; however, this did not influence exercise performance during hand-grip exercise.

Background Missed hospital outpatient appointments is a commonly reported problem in healthcare services around the world; for example, they cost the National Health Service (NHS) in the UK millions of pounds every year and can cause operation and scheduling difficulties worldwide. In 2002, the World Health Organization (WHO) published a report highlighting the need for a model of care that more readily meets the needs of people with chronic conditions. Patient-initiated appointment systems may be able to meet this need at the same time as improving the efficiency of hospital appointments. Objectives To assess the effects of patient-initiated appointment systems compared with consultant-led appointment systems for people with chronic or recurrent conditions managed in secondary care. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and six other databases. We contacted authors of identified studies and conducted backwards and forwards citation searching. We searched for current/ongoing research in two trial registers. Searches were run on 13 March 2019. Selection criteria We included randomised trials, published and unpublished in any language that compared the use of patient-initiated appointment systems to consultant-led appointment systems for adults with chronic or recurrent conditions managed in secondary care if they reported one or more of the following outcomes: physical measures of health status or disease activity (including harms), quality of life, service utilisation or cost, adverse effects, patient or clinician satisfaction, or failures of the 'system'. Data collection and analysis Two review authors independently screened all references at title/abstract stage and full-text stage using prespecified inclusion criteria. We resolved disagreements though discussion. Two review authors independently completed data extraction for all included studies. We discussed and resolved discrepancies with a third review author. Where needed, we contacted authors of included papers to provide more information. Two review authors independently assessed the risk of bias using the Cochrane Effective Practice and Organisation of Care 'Risk of bias' tool, resolving any discrepancies with a third review author. Two review authors independently assessed the certainty of the evidence using GRADE. Main results The 17 included randomised trials (3854 participants; mean age 41 to 76 years; follow-up 12 to 72 months) covered six broad health conditions: cancer, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis and inflammatory bowel disease. The certainty of the evidence using GRADE ratings was mainly low to very low. The results suggest that patient-initiated clinics may make little or no difference to anxiety (odds ratio (OR) 0.87, 95% confidence interval (CI) 0.68 to 1.12; 5 studies, 1019 participants; low-certainty evidence) or depression (OR 0.79 95% CI 0.51 to 1.23; 6 studies, 1835 participants; low-certainty evidence) compared to the consultant-led appointment system. The results also suggest that patient-initiated clinics may make little or no difference to quality of life (standardised mean difference (SMD) 0.12, 95% CI 0.00 to 0.25; 7 studies, 1486 participants; low-certainty evidence) compared to the consultant-led appointment system. Results for service utilisation (contacts) suggest there may be little or no difference in service utilisation in terms of contacts between the patient-initiated and consultant-led appointment groups; however, the effect is not certain as the rate ratio ranged from 0.68 to 3.83 across the studies (median rate ratio 1.11, interquartile (IQR) 0.93 to 1.37; 15 studies, 3348 participants; low-certainty evidence). It is uncertain if service utilisation (costs) are reduced in the patient-initiated compared to the consultant-led appointment groups (8 studies, 2235 participants; very low-certainty evidence). The results suggest that adverse events such as relapses in some conditions (inflammatory bowel disease and cancer) may have little or no reduction in the patient-initiated appointment group in comparison with the consultant-led appointment group (MD -0.20, 95% CI -0.54 to 0.14; 3 studies, 888 participants; low-certainty evidence). The results are unclear about any differences the intervention may make to patient satisfaction (SMD 0.05, 95% CI -0.41 to 0.52; 2 studies, 375 participants) because the certainty of the evidence is low, as each study used different questions to collect their data at different time points and across different health conditions. Some areas of risk of bias across all the included studies was consistently high (i.e. for blinding of participants and personnel and blinding of outcome assessment, other areas were largely of low risk of bias or were affected by poor reporting making the assessment unclear). Authors' conclusions Patient-initiated appointment systems may have little or no effect on patient anxiety, depression and quality of life compared to consultant-led appointment systems. Other aspects of disease status and experience also appear to show little or no difference between patient-initiated and consultant-led appointment systems. Patient-initiated appointment systems may have little or no effect on service utilisation in terms of service contact and there is uncertainty about costs compared to consultant-led appointment systems. Patient-initiated appointment systems may have little or no effect on adverse events such as relapse or patient satisfaction compared to consultant-led appointment systems.

Importance: The potential benefit of novel skeletal muscle anabolic agents to improve physical function in people with sarcopenia and other muscle wasting diseases is unknown. Objective: To confirm the safety and efficacy of bimagrumab plus the new standard of care on skeletal muscle mass, strength, and physical function compared with standard of care alone in community-dwelling older adults with sarcopenia. Design, Setting, and Participants: This double-blind, placebo-controlled, randomized clinical trial was conducted at 38 sites in 13 countries among community-dwelling men and women aged 70 years and older meeting gait speed and skeletal muscle criteria for sarcopenia. The study was conducted from December 2014 to June 2018, and analyses were conducted from August to November 2018. Interventions: Bimagrumab 700 mg or placebo monthly for 6 months with adequate diet and home-based exercise. Main Outcomes and Measures: The primary outcome was the change in Short Physical Performance Battery (SPPB) score after 24 weeks of treatment. Secondary outcomes included 6-minute walk distance, usual gait speed, handgrip strength, lean body mass, fat body mass, and standard safety parameters. Results: A total of 180 participants were recruited, with 113 randomized to bimagrumab and 67 randomized to placebo. Among these, 159 participants (88.3%; mean [SD] age, 79.1 [5.3] years; 109 [60.6%] women) completed the study. The mean SPPB score increased by a mean of 1.34 (95% CI, 0.90 to 1.77) with bimagrumab vs 1.03 (95% CI, 0.53 to 1.52) with placebo (P = .13); 6-minute walk distance increased by a mean of 24.60 (95% CI, 7.65 to 41.56) m with bimagrumab vs 14.30 (95% CI, -4.64 to 33.23) m with placebo (P = .16); and gait speed increased by a mean of 0.14 (95% CI, 0.09 to 0.18) m/s with bimagrumab vs 0.11 (95% CI, 0.05 to 0.16) m/s with placebo (P = .16). Bimagrumab was safe and well-tolerated and increased lean body mass by 7% (95% CI, 6% to 8%) vs 1% (95% CI, 0% to 2%) with placebo, resulting in difference of 6% (95% CI, 4% to 7%) (P

High fidelity, scale-resolving numerical simulations of flow and pollutant dispersion around several elongated isolated buildings are presented in this paper. The embedded large eddy simulation (ELES) is used to model flow and concentration fields for six test cases with various source-building geometries. Specifically, the influence of building aspect ratio, wind direction, and source location is examined with these cases. Results obtained from the present ELES model are evaluated using available wind tunnel measurements, including those of streamwise and spanwise velocities, turbulent kinetic energy, and streamwise, lateral, and spanwise pollutant concentrations. Comparisons indicate that the ELES provides realistic representations of the flow and concentration fields observed in wind tunnel experiments, and captures several complex phenomena including the lateral shift and enhanced descent of the plume for rotated/elongated buildings. Furthermore, the ELES provides a means to study the advective and turbulent concentration fluxes, plume shapes, and geometry of vortical structures that is used to examine turbulent transport of pollutants around buildings. We investigate the enhancement of vertical and lateral plume spread as the building aspect ratio is increased. In addition, through the study of advective and turbulent concentration fluxes, we shed light on the physics behind higher ground-level concentrations observed for rotated buildings.

PURPOSE: Assess systemic vascular endothelial growth factor-A (VEGF) levels after treatment with intravitreous aflibercept, bevacizumab or ranibizumab. DESIGN: Comparative-effectiveness trial with participants randomly assigned to 2-mg aflibercept, 1.25-mg bevacizumab, or 0.3-mg ranibizumab following a retreatment algorithm. PARTICIPANTS: Participants with available plasma samples (N=436) METHODS: Plasma samples were collected before injections at baseline, 4-week, 52-week and 104-week visits. In a pre-planned secondary analysis, systemic free-VEGF levels from an ELISA immunoassay were compared across anti-VEGF agents and correlated with systemic side effects. MAIN OUTCOME MEASURES: Changes in the natural log (ln) of plasma VEGF levels. RESULTS: Baseline free-VEGF levels were similar across all 3 groups. At 4 weeks, mean ln(VEGF) changes were −0.30±0.61, −0.31±0.54, −0.02±0.44 pg/ml for the aflibercept, bevacizumab, and ranibizumab groups, respectively. The adjusted differences between treatment groups (adjusted CI; P-value) were −0.01 (−0.12, +0.10; P=0.89), −0.31 (−0.44, −0.18; P

Objectives To assess the effects of bimagrumab on skeletal muscle mass and function in older adults with sarcopenia and mobility limitations. Design A 24-week, randomized, double-blind, placebo-controlled, parallel-arm, proof-of-concept study. Setting Five centers in the United States. Participants Community-dwelling adults (N = 40) aged 65 and older with gait speed between 0.4 and 1.0 m/s over 4 m and an appendicular skeletal muscle index of 7.25 kg/m2 or less for men and 5.67 kg/m2 or less for women. Intervention Intravenous bimagrumab 30 mg/kg (n = 19) or placebo (n = 21). Measurements Change from baseline in thigh muscle volume (TMV), subcutaneous and intermuscular fat, appendicular and total lean body mass, grip strength, gait speed, and 6-minute walk distance (6MWD). Results Thirty-two (80%) participants completed the study. TMV increased by Week 2, was sustained throughout the treatment period, and remained above baseline at the end of study in bimagrumab-treated participants, whereas there was no change with placebo treatment (Week 2: 5.15 ± 2.19% vs −0.34 ± 2.59%, P

Key points Despite an attenuated fluctuation in ovarian hormone concentrations in well-trained women, one in two of such women believe their menstrual cycle negatively impacts training and performance. Forthcoming large international events will expose female athletes to hot environments, and studies evaluating aerobic exercise performance in such environments across the menstrual cycle are sparse, with mixed findings. We have identified that autonomic heat loss responses at rest and during fixed-intensity exercise in well-trained women are not affected by menstrual cycle phase, but differ between dry and humid heat. Furthermore, exercise performance is not different across the menstrual cycle, yet is lower in humid heat, in conjunction with reduced evaporative cooling. Menstrual cycle phase does not appear to affect exercise performance in the heat in well-trained women, but humidity impairs performance, probably due to reduced evaporative power. Abstract We studied thermoregulatory responses of ten well-trained [VO2 max , 57 (7) ml min−1 kg−1] eumenorrheic women exercising in dry and humid heat, across their menstrual cycle. They completed four trials, each of resting and cycling at fixed intensities (125 and 150 W), to assess autonomic regulation, then self-paced intensity (30 min work trial), to assess behavioural regulation. Trials were in early-follicular (EF) and mid-luteal (ML) phases in dry (DRY) and humid (HUM) heat matched for wet bulb globe temperature (WBGT, 27°C). During rest and fixed-intensity exercise, rectal temperature was ∼0.2°C higher in ML than EF (P

Anterior lumbar approaches have historically been regarded as maximally invasive. However, with the advent of well-trained vascular surgeons to do the approaches through smaller incisions and with decreased operative time, anterior lumbar approaches are becoming more widely utilized. Stand-alone lumbar interbody fusions and artificial disc replacements are two of the mainstay procedures for this approach. This chapter will give an overview of the procedure and nuances to consider along the way.

The Lancet Commission on Global Surgery proposed that population access to essential surgical care within 2 h is a core indicator of health system preparedness. Little evidence exists to characterise access to surgical care for island nations, including Vanuatu, a lower middle-income country in the Western Pacific. A descriptive, facility-based, survey of surgical inpatients was undertaken over a 6-month period at Northern Provincial Hospital (NPH), Espiritu Santo, Vanuatu. This evaluated demographics, access to surgical care using the ‘three delays’ framework and clinical outcomes. A total of 121 participants were surveyed (60% of all surgical admissions), of which 31% required emergency surgery. Only 20% of emergency surgical cases accessed care within 2 h. There were no emergency cases from Torba or Malekula. The first delay (delay in seeking care) had the biggest impact on timely access. There was a geographic gradient to access, gender preponderance (males), and a delay in seeking surgical care due to a preference for traditional healers. There is urgent need to improve access to surgical care in Vanuatu, particularly for Torba and Malekula catchments. Demographic, geographic, sociocultural, and economic factors impact on timely access to surgical care within the northern regions of Vanuatu and support the notion that addressing access barriers is more complex than ensuring the availability of surgical resources. Future priorities should include efforts to reduce the first delay, address the role of traditional medicine, and review the geographic disparities in access.

To examine the interactive effects of VM and isometric resistance exercise on cerebral haemodynamics. Eleven healthy participants (mean ± SD 28 ± 9 years; 2 females) completed 20-s bilateral isometric leg extension at 50% of maximal voluntary contraction with continued ventilation (RE), a 20-s VM at mouth pressure of 40 mmHg (VM), and a combination (RE + VM), in randomised order. Mean beat-to-beat blood velocity in the posterior (PCAvmean) and middle cerebral arteries (MCAvmean), vertebral artery blood flow, end-tidal partial pressure of CO2 and mean arterial pressure (MAP) were measured. RE data were time aligned to RE + VM and analysed according to standard VM phases. Interaction effects (VM phase × condition) were observed for MCAvmean, PCAvmean, vertebral artery blood flow and MAP (all ≤ 0.010). Phase I MCAvmean was greatest for RE [88 ± 19, vs. 71 ± 11 and 78 ± 12 cm s−1 for VM (P = 0.008) and RE + VM (P = 0.021), respectively]. Greater increases in MCAvmean than PCAvmean occurred in phase I of RE only (24 ± 15% vs. 16 ± 16%, post hoc P = 0.044). In phase IIb, MAP was lower in RE than RE + VM (115 ± 15 vs. 138 ± 21 mmHg, P = 0.004), but did not reduce MCAvmean (78 ± 8 vs. 79 ± 9 cm s−1, P = 0.579) or PCAvmean (45 ± 11 vs .46 ± 11 cm s−1, P = 0.617). Phase IIb MCAvmean and PCAvmean was lowest in VM (66 ± 6 and 39 ± 8 cm s−1, respectively, all P

Introduction: Radiation oncology (ro) is one of several specialties identified by the Royal College of Physicians and Surgeons of Canada with employment difficulties for graduating trainees. The purpose of the present study was to determine the employment status and location of recent Canadian ro trainees within 2 years after graduation, to monitor workforce recruitment trends over time, and to capture the opinions of program directors about employment difficulty for graduates and resident morale. Methods: Visa trainee graduates were excluded. Results of the survey administered to ro program directors in 2016 and again in 2018, both with 100% response rates, are presented here. Results: In both surveys, approximately 57% of ro graduates had attained staff or locum employment in Canada or abroad within 2 years from graduation (p = 0.92). However, graduates with Canadian staff employment increased by 46% to 32 in 2018 from 22 in 2016, while the proportion of graduates with staff positions abroad decreased to 6% from 27% (p = 0.04). Most trainees without staff positions were employed as fellows. The proportion of program directors reporting employment difficulties for graduates in the Canadian labour market declined to 38% from 85% (p = 0.04), and the morale of residents in training programs remained high. Conclusions: Employment challenges for newly certified Canadian-trained radiation oncologists continue. However, compared with the situation 2 years ago, trends in the Canadian ro job market suggest a modest improvement, with more staff employment in Canada and lower emigration rates for jobs abroad.

Purpose Permanent implant prostate brachytherapy plays an important role in prostate cancer treatment, but dose evaluations typically follow the water-based TG-43 formalism, ignoring patient anatomy and interseed attenuation. The purpose of this study is to investigate advanced TG-186 model-based dose calculations via retrospective dosimetric and radiobiological analysis for a new patient cohort. Methods and Materials A cohort of 155 patients treated with permanent implant prostate brachytherapy from The Ottawa Hospital Cancer Centre is considered. Monte Carlo (MC) dose calculations are performed using tissue-based virtual patient models. Dose–volume histogram (DVH) metrics (target, organs at risk) are extracted from 3D dose distributions and compared with those from calculations under TG-43 assumptions (TG43). Equivalent uniform biologically effective dose and tumor control probability are calculated. Results For the target, D90 (V100) is 136.7 ± 20.6 Gy (85.8% ± 7.8%) for TG43 and 132.8 ± 20.1 Gy (84.1% ± 8.2%) for MC; D90 is 3.0% ± 1.1% lower for MC than TG43. For organs at risk, MC D1cc = 104.4 ± 27.4 Gy (TG43: 106.3 ± 28.3 Gy) for rectum and 80.8 ± 29.7 Gy (TG43: 78.4 ± 28.4 Gy) for bladder; D1cc = 185.9 ± 30.2 Gy (TG43: 191.1 ± 32.0 Gy) for urethra. Equivalent uniform biologically effective dose and tumor control probability are generally lower when evaluated using MC doses. The largest dosimetric and radiobiological discrepancies between TG43 and MC are for patients with intraprostatic calcifications, for whom there are low doses (cold spots) in the vicinity of calcifications within the target, identified with MC but not TG43. Conclusions DVH metrics and radiobiological indices evaluated with TG43 are systematically inaccurate by upward of several percent compared with MC patient-specific models. Mean cohort DVH metrics and their MC:TG43 variances are sensitive to patient cohort and clinical practice, underlining the importance of further retrospective MC studies toward widespread clinical adoption of advanced model-based dose calculations.

Background The Pacific Island nation of Samoa faces a number of challenges in delivering surgical care. Our group aimed to identify the barriers and opportunities to improving the delivery of safe, affordable, timely surgical care in Samoa. Methods A mixed-methods approach was undertaken. The quantitative analysis used a modified version of the World Health Organization Emergency and Essential Surgical Checklist while the qualitative methodology used semi-structured interviews. Respondents were asked to share their views on the capacity, quality, accessibility and future directions of surgery in Samoa. Interviews were transcribed and analysed using open and axial coding techniques. Results Stakeholders had a positive outlook on the delivery of surgical care, but it was suggested that existing services were not meeting needs. Respondents cited limited access to equipment and resources, compounded by insufficient organizational and logistical infrastructure. Shortage of medical staff and retention was identified as a key issue. Shortcomings in primary care and poor health literacy were seen as significant barriers to accessing care. Conclusion Documenting locally identified barriers and solutions to surgical care in Samoa is an important first step towards the development of formal strategies for improving surgical services nationally.

Antibody blockade of activin type II receptor (ActRII) signaling stimulates skeletal muscle growth. Previous clinical studies suggest that ActRII inhibition with the monoclonal antibody bimagrumab also promotes excess adipose tissue loss and improves insulin resistance.To evaluate the efficacy and safety of bimagrumab on body composition and glycemic control in adults with type 2 diabetes and overweight and obesity.This double-masked, placebo-controlled, 48-week, phase 2 randomized clinical trial was conducted among adults with type 2 diabetes, body mass index between 28 and 40, and glycated hemoglobin (HbA1c) levels between 6.5% and 10.0% at 9 US and UK sites. The trial was conducted from February 2017 to May 2019. Only participants who completed a full treatment regimen were included in analysis.Patients were randomized to intravenous infusion of bimagrumab (10 mg/kg up to 1200 mg in 5% dextrose solution) or placebo (5% dextrose solution) treatment every 4 weeks for 48 weeks; both groups received diet and exercise counseling.The primary end point was least square mean change from baseline to week 48 in total body fat mass (FM); secondary and exploratory end points were lean mass (LM), waist circumference (WC), HbA1c level, and body weight (BW) changes from baseline to week 48.A total of 75 patients were randomized to bimagrumab (n = 37; 23 [62.2%] women) or placebo (n = 38; 12 [31.6%] women); 58 (77.3%) completed the 48-week study. Patients at baseline had a mean (SD) age of 60.4 (7.7) years; mean (SD) BMI of 32.9 (3.4); mean (SD) BW of 93.6 (14.9) kg; mean (SD) FM of 35.4 (7.5) kg; and mean (SD) HbA1c level of 7.8% (1.0%). Changes at week 48 for bimagrumab vs placebo were as follows: FM, -20.5% (-7.5 kg [80% CI, -8.3 to -6.6 kg]) vs -0.5% (-0.18 kg [80% CI, -0.99 to 0.63 kg]) (P .001); LM, 3.6% (1.70 kg [80% CI, 1.1 to 2.3 kg]) vs -0.8% (-0.4 kg [80% CI, -1.0 to 0.1 kg]) (P .001); WC, -9.0 cm (80% CI, -10.3 to -7.7 cm) vs 0.5 cm (80% CI, -0.8 to 1.7 cm) (P .001); HbA1c level, -0.76 percentage points (80% CI, -1.05 to -0.48 percentage points) vs -0.04 percentage points (80% CI, -0.23 to 0.31 percentage points) (P = .005); and BW, -6.5% (-5.9 kg [80% CI, -7.1 to -4.7 kg]) vs -0.8% (-0.8 kg [80% CI, -1.9 to 0.3 kg]) (P .001). Bimagrumab's safety and tolerability profile was consistent with prior studies.In this phase 2 randomized clinical trial, ActRII blockade with bimagrumab led to significant loss of FM, gain in LM, and metabolic improvements during 48 weeks in patients with overweight or obesity who had type 2 diabetes. ActRII pathway inhibition may provide a novel approach for the pharmacologic management of excess adiposity and accompanying metabolic disturbances.ClinicalTrials.gov number: NCT03005288.

This paper presents a wind tunnel study of the effects of elongated rectangular buildings on the dispersion of pollutants from nearby stacks. The study examines the influence of source location, building aspect ratio, and wind direction on pollutant dispersion with the goal of developing improved algorithms within dispersion models. The paper also examines the current AERMOD/PRIME modeling capabilities compared to wind tunnel observations. Differences in the amount of plume material entrained in the wake region downwind of a building for various source locations and source heights are illustrated with vertical and lateral concentration profiles. These profiles were parameterized using the Gaussian equation and show the influence of building/source configurations on those parameters. When the building is oriented at 45° to the approach flow, for example, the effective plume height descends more rapidly than it does for a perpendicular building, enhancing the resulting surface concentrations in the wake region. Buildings at angles to the wind cause a cross-wind shift in the location of the plume resulting from a lateral mean flow established in the building wake. These and other effects that are not well represented in many dispersion models are important considerations when developing improved algorithms to estimate the location and magnitude of concentrations downwind of elongated buildings.

Managing the efficiency and costs of residents' drug regimens outside the acute-care hospital and through transitions of care requires a toolbox filled with cost-control tools and careful collaboration among the pharmacy provider(s), facility staff, and the consultant/senior care pharmacist. This article will provide the reader with key long-term care business strategies that affect the profitability of the pharmacy provider in various care settings while, at the same time, ensuring optimal therapy for residents as they transition across levels of care. Readers can take away ideas on how to access critical information, what they can do with this information, and how they can improve the overall care process. Four experts in various aspects of pharmacy management share their insights on pharmacy practice issues including formulary management, performance metrics, short-cycle dispensing challenges/solutions, cost-control measures, facility surveys, billing practices, medication reconciliation, prospective medication reviews, and transitions of care.

Rationale, aims and objectives: The management of rheumatoid arthritis (RA) usually entails regular hospital reviews with a specialist often when the patient is well rather than during a period of exacerbation. An alternative approach where patients initiate appointments when they need them can improve patient satisfaction and resource use whilst being safe. This service evaluation reports a system-wide implementation of a patient-initiated review appointment system called Direct Access (DA) for people with RA. The aim was to establish the impact on patient satisfaction of the new system versus usual care as well as evaluate the implementation processes. Methods: As all patients could not start on the new system at once, in order to manage the implementation, patients were randomly allocated to DA or to usual care. Instead of regular follow-up appointments, DA comprised an education session and access to a nurse-led telephone advice line where appointments could be accessed within two weeks. Usual care comprised routine follow-ups with the specialist. Data were collected on patient satisfaction, service use and outcomes of any contact to the advice line. Results: Three hundred and eleven patients with RA were assessed as being suitable for DA. In terms of patient satisfaction, between-group differences were found in favour of DA for accessibility and convenience, ease of contacting the nurse and overall satisfaction with the service. Self-reported visits to the general practitioner were also significantly lower. DA resulted in a greater number of telephone contacts (incidence rate ratio = 1.69; 95% confidence interval 1.07 to 2.68). Hospital costs of the two different service models were similar. Mean waiting time for an appointment was 10.8 days. Conclusion: This service evaluation found that DA could be implemented and it demonstrated patient benefit in a real-world setting. Further research establishing the broader cost–consequences across the whole patient pathway would add to our findings.

Consensus guidelines from the Growth Hormone Research Society Workshop recommend growth hormone therapy in all children with genetically confirmed Prader-Willi syndrome (PWS) in combination with dietary, lifestyle and environmental interventions. As yet, however, there are limited published data regarding the use of growth hormone therapy in adolescents and young adults with PWS. This review focuses on the advantages and disadvantages of growth hormone therapy in this particular group. The risk of complications, challenges with consent for therapy, the need for contraception in females with PWS and the appropriate monitoring required are all factors which must be carefully considered in this challenging patient group. Transition from paediatric to adult services can be difficult for most adolescents, but especially so for PWS adolescents and should be undertaken under the care of experienced paediatric and adult endocrinologists and a multidisciplinary team approach. Further research is, however, still required in the management of PWS patients during adolescence.

The purpose of this study was to identify whether post-resistance exercise (REx) blood flow restriction (BFR) can elicit a similar acute training stimulus to that offered by either heavy REx or traditional low-load BFR REx.Ten men completed trials with 30% one-repetition maximum (1RM) for 5 sets of 15 repetitions without BFR (30%), with BFR during exercise (30% RD), and with postexercise BFR (30% RP) and at 75% 1RM for 3 sets of 10 repetitions. Lactate and cortisol were measured before and up to 60 min after exercise. Thigh circumference, ratings of perceived exertion (RPE), and pain were measured before and after exercise. Surface electromyography was measured during exercise.All conditions had a large effect (effect size [ES] 0.8) on lactate, with the largest effects observed with the 75% condition; no differences were observed between the 30% conditions. All conditions had a moderate effect (ES 0.25 ≤ 0.4) on increasing thigh circumference. This effect was maintained (ES = 0.35) with the application of BFR after REx (30% RP). Change in RPE, from the first to last set, was significantly greater with 30% RD compared with other conditions (all p .05). Electromyography amplitude was higher and percentage change was greater for the 75% condition compared with the other conditions (both p .05).The application of BFR immediately post-REx altered several of the responses associated with REx that is aimed at inducing muscular hypertrophy. Additionally, these changes occurred with less pain and perceived exertion suggesting that this form of REx may offer an alternative, tolerable method of REx.

KEY POINTS: One in two female athletes chronically take a combined, monophasic oral contraceptive pill (OCP). Previous thermoregulatory investigations proposed that an endogenous rhythm of the menstrual cycle still occurs with OCP usage. Forthcoming large international sporting events will expose female athletes to hot environments differing in their thermal profile, yet few data exist on how trained women will respond from both a thermoregulatory and performance stand‐point. In the present study, we have demonstrated that a small endogenous rhythm of the menstrual cycle still affects T (core) and also that chronic OCP use attenuates the sweating response, whereas behavioural thermoregulation is maintained. Furthermore, humid heat affects both performance and thermoregulatory responses to a greater extent than OCP usage and the menstrual cycle does. ABSTRACT: We studied thermoregulatory responses of ten well‐trained ([Formula: see text] , 57 ± 7 mL min(−1) kg(−1)) women taking a combined, monophasic oral contraceptive pill (OCP) (≥12 months) during exercise in dry and humid heat, across their active OCP cycle. They completed four trials, each of resting and cycling at fixed intensities (125 and 150 W), aiming to assess autonomic regulation, and then a self‐paced intensity (30‐min work trial) to assess behavioural regulation. Trials were conducted in quasi‐follicular (qF) and quasi‐luteal (qL) phases in dry (DRY) and humid (HUM) heat matched for wet bulb globe temperature (WBGT) (27°C). During rest and exercise at 125 W, rectal temperature was 0.15°C higher in qL than qF (P = 0.05) independent of environment (P = 0.17). The onset threshold and thermosensitivity of local sweat rate and forearm blood flow relative to mean body temperature was unaffected by the OCP cycle (both P > 0.30). Exercise performance did not differ between quasi‐phases (qF: 268 ± 31 kJ, qL: 263 ± 26 kJ, P = 0.31) but was 5 ± 7% higher during DRY than during HUM (273 ± 29 kJ, 258 ± 28 kJ; P = 0.03). Compared to matched eumenorrhoeic athletes, chronic OCP use impaired the sweating onset threshold and thermosensitivity (both P < 0.01). In well‐trained, OCP‐using women exercising in the heat: (i) a performance‐thermoregulatory trade‐off occurred that required behavioural adjustment; (ii) humidity impaired performance as a result of reduced evaporative power despite matched WBGT; and (iii) the sudomotor but not behavioural thermoregulatory responses were impaired compared to matched eumenorrhoeic athletes.

The cold pressor test (CPT) is widely used in clinical practice and physiological research. It is characterized by a robust autonomic response, with associated increases in heart rate (HR), mean arterial pressure (MAP) and mean middle cerebral artery blood flow velocity (MCAv(mean)). Hydration status is not commonly reported when conducting this test, yet blood viscosity alone can modulate MCAv(mean), potentially modifying the MCAv(mean) response to the CPT. We investigated the effect of mild dehydration on the physiological response to the CPT in 10 healthy men (mean ± SD: age 28 ± 5 years; body mass 83 ± 5 kg). All participants completed two CPTs, cold water (0°C) immersion of both feet for 90 s, with the order of the euhydration and dehydration trials counterbalanced. Beat-to-beat MCAv, MAP, HR and breath-by-breath partial pressure of end-tidal CO2 (P(ET,CO2)) were measured continuously. Participants' pain perception was measured 1 min into the CPT using a visual analog scale (no pain = 0; maximal pain = 10). Dehydration significantly elevated plasma osmolality and urine specific gravity and reduced body mass (all P 0.05). After 90 s of immersion, the change in MCAv(mean) from baseline was less in the dehydration compared with the euhydration trial (change 0 ± 5 versus 7 ± 7 cm s(-1), P = 0.01), as was P(ET,CO2) (change -3 ± 2 versus 0 ± 3 mmHg, P = 0.02). Dehydration was associated with greater relative pain sensation during the CPT (7.0 ± 1.3 vs 5.8 ± 1.8, P = 0.02). Our results demonstrate that mild dehydration can modify the cerebrovascular response to the CPT, with dehydration increasing perceived pain, lowering P ET ,CO2 and, ultimately, blunting the MCAv(mean) response.

New Findings What is the central question of this study? Following exercise, hypotension is often reported and syncope is more likely. It is unresolved whether the postexercise hypotension associated with different exercise intensities contributes to the rate at which syncope develops. What is the main finding and its importance? The physiological events that induce presyncope are the same both before and after exercise; however, more intense exercise accelerated the development of hypocapnia, hypotension and, ultimately, syncope. These data indicate that higher intensity exercise induces a postexercise hypotension that reduces cardiovascular reserve, an earlier development of hypocapnia and, ultimately, cerebral hypoperfusion. After exercise, a reduction in mean arterial pressure is often experienced and is referred to as postexercise hypotension. Whilst syncope is more likely following exercise, it is unknown whether orthostatic tolerance is impacted by any exercise intensity-mediated effect on postexercise hypotension. We examined the effect of exercise intensity on time to presyncope, induced via combined head-up tilt and lower body negative pressure following 1 h of cycling at 30 and 70% of heart rate range. Healthy participants (n = 8; mean ± SD, 28 ± 5 years old) completed orthostatic testing to presyncope before and after exercise. Beat-to-beat middle cerebral artery blood flow velocity (MCAv), mean arterial pressure and cerebral oxygenation (measured by near-infrared spectroscopy) were recorded continuously throughout orthostatic testing. During exercise, heart rates were 95 ± 6 and 147 ± 5 beats min−1 for 30 and 70% heart rate range, respectively, with average power outputs of 103 ± 22 and 221 ± 45 W, respectively. Time to presyncope occurred 32% sooner after the 70% heart rate range trial (952 ± 484 versus 1418 ± 435 s; P = 0.004). Both before and after exercise, presyncope occurred at the same reduction in MCAv (grouped mean, −30 ± 11 cm s−1), mean arterial pressure (−18 ± 13 mmHg), total oxygenation index (−6 ± 2%) and partial pressure of end-tidal CO2 (−16 ± 8 mmHg; all P > 0.1). At presyncope following exercise, the MCAv response was related more to the change in partial pressure of end-tidal CO2 from the baseline preceding orthostatic testing (r2 = 0.50, P = 0.01) than to the hypotension (r2 = 0.12, P = 0.17). Presyncope both before and after exercise occurred as a result of the same physiological perturbations, albeit greatly accelerated following more intense exercise.

Climate change and associated changes in streamflow may alter riparian habitats substantially in coming decades. Riparian restoration provides opportunities to respond proactively to projected climate change effects, increase riparian ecosystem resilience to climate change, and simultaneously address effects of both climate change and other human disturbances. However, climate change may alter which restoration methods are most effective and which restoration goals can be achieved. Incorporating climate change into riparian restoration planning and design is critical to long-term restoration of desired community composition and ecosystem services. In this review, we discuss and provide examples of how climate change might be incorporated into restoration planning at the key stages of assessing the project context, establishing restoration goals and design criteria, evaluating design alternatives, and monitoring restoration outcomes. Restoration planners have access to numerous tools to predict future climate, streamflow, and riparian ecology at restoration sites. Planners can use those predictions to assess which species or ecosystem services will be most vulnerable under future conditions, and which sites will be most suitable for restoration. To accommodate future climate and streamflow change, planners may need to adjust methods for planting, invasive species control, channel and floodplain reconstruction, and water management. Given the considerable uncertainty in future climate and streamflow projections, riparian ecological responses, and effects on restoration outcomes, planners will need to consider multiple potential future scenarios, implement a variety of restoration methods, design projects with flexibility to adjust to future conditions, and plan to respond adaptively to unexpected change. Copyright © 2015 John Wiley & Sons, Ltd.

In 2015, the Lancet Commission on Global Surgery (LCoGS) recommended six surgical metrics to enable countries to measure their surgical and anaesthesia care delivery. These indicators have subsequently been accepted by the World Bank for inclusion in the World Development Indicators. With support from the Royal Australasian College of Surgeons and the Pacific Islands Surgical Association, 14 South Pacific countries collaborated to collect the first four of six LCoGS indicators. Thirteen countries collected all four indicators over a 6-month period from October 2015 to April 2016. Australia and New Zealand exceeded the recommended LCoGS target for all four indicators. Only 5 of 13 countries (38%) achieved 2-hour access for at least 80% of their population, with a range of 20% (Papua New Guinea and Solomon Islands) to over 65% (Fiji and Samoa). Five of 13 (38%) countries met the target surgical volume of 5000 procedures per 100 000 population, with six performing less than 1600. Four of 14 (29%) countries had at least 20 surgical, anaesthesia and obstetric providers in their workforce per 100 000 population, with a range of 0.9 (Timor Leste) to 18.5 (Tuvalu). Perioperative mortality rate was reported by 13 of 14 countries, and ranged from 0.11% to 1.0%. We believe it is feasible to collect global surgery indicators across the South Pacific, a diverse geographical region encompassing high-income and low-income countries. Such metrics will allow direct comparison between similar nations, but more importantly provide baseline data that providers and politicians can use in advocacy national health planning.

Background: Multiple radiation-induced cavernous malformations of the cauda equina are extremely rare. A review of the literature suggested that the post-irradiation lumbosacral radiculopathy in our patient was most likely associated with a diagnosis of multiple radiation-induced cavernous malformations of the cauda equina. Case Description: A 76-year-old man with a remote history of abdominal radiation therapy presented with a 6-month history of progressively worsening right foot drop and balance impairment. Magnetic resonance imaging (MRI) revealed multiple enhancing areas of the cauda equina concerning for carcinomatous meningitis, however, cerebrospinal fluid (CSF) analysis was unrevealing. Intraoperative findings were consistent with multiple radiation-induced cavernous malformations of the cauda equina. Conclusions: Multiple radiation-induced cavernous malformations of the cauda equina may mimic carcinomatous or infectious meningitis. Clinicians should be suspicious of this diagnosis when CSF and MRI findings are inconsistent with metastatic disease or infectious meningitis in patients who present with radiculopathy and a history of radiation therapy.

Alzheimer’s disease (AD) is classically defined by the accumulation of abnormal aggregates mainly comprised of two proteins: phosphorylated tau (ptau) and amyloid beta (Aβ). It has been proposed that those aggregates lead to several cellular changes that are translated into neuronal loss and the impoverishment of cognitive functions. Although there is a strong correlation between these protein aggregates and dementia, the exact mechanisms connecting their pathological effects remain poorly understood. Indeed, the role of Aβ deposition as the event that causes the AD pathology is currently under heated debate. In contrast, tau deposits are far more related to clinical dementia. However, during AD development, the dynamic cellular and molecular relationship between tau and Aβ remains under extensive study. Clearly, both proteins are well related to the disease progression and not surprisingly both are currently the main therapeutic targets for new AD treatments. Unfortunately, nothing but moderate success has emerged from a variety of therapeutic strategies targeting either tau or Aβ. One potential explanation for the current failure is that therapeutic interventions are provided at late stages of the disease instead of being administrated at early stages. Taking this hypothesis into account, we will discuss the role of abnormally ptau protein as an early AD marker and discuss the molecular relationships between Aβ and ptau during synaptic activity. Finally, as a proposal that aims to restore normal brain activity, we will briefly discuss a therapeutic strategy that would be based on modifying several tau protein targets by cocktail therapies.

Object Classic biomechanical models have used thoracic spines disarticulated from the rib cage, but the biomechanical influence of the rib cage on fracture biomechanics has not been investigated. The well-accepted construct for stabilizing midthoracic fractures is posterior instrumentation 3 levels above and 2 levels below the injury. Short-segment fixation failure in thoracolumbar burst fractures has led to kyphosis and implant failure when anterior column support is lacking. Whether shorter constructs are viable in the midthoracic spine is a point of controversy. The objective of this study was the biomechanical evaluation of a burst fracture at T-9 with an intact rib cage using different fixation constructs for stabilizing the spine. Methods A total of 8 human cadaveric spines (C7–L1) with intact rib cages were used in this study. The range of motion (ROM) between T-8 and T-10 was the outcome measure. A robotic spine testing system was programmed to apply pure moment loads (± 5 Nm) in lateral bending, flexion-extension, and axial rotation to whole thoracic specimens. Intersegmental rotations were measured using an optoelectronic system. Flexibility tests were conducted on intact specimens, then sequentially after surgically induced fracture at T-9, and after each of 4 fixation construct patterns. The 4 construct patterns were sequentially tested in a nondestructive protocol, as follows: 1) 3 above/2 below (3A/2B); 2) 1 above/1 below (1A/1B); 3) 1 above/1 below with vertebral body augmentation (1A/1B w/VA); and 4) vertebral body augmentation with no posterior instrumentation (VA). A repeated-measures ANOVA was used to compare the segmental motion between T-8 and T-10 vertebrae. Results Mean ROM increased by 86%, 151%, and 31% after fracture in lateral bending, flexion-extension, and axial rotation, respectively. In lateral bending, there was significant reduction compared with intact controls for all 3 instrumented constructs: 3A/2B (−92%, p = 0.0004), 1A/1B (−63%, p = 0.0132), and 1A/1B w/VA (−66%, p = 0.0150). In flexion-extension, only the 3A/2B pattern showed a significant reduction (−90%, p = 0.011). In axial rotation, motion was significantly reduced for the 3 instrumented constructs: 3A/2B (−66%, p = 0.0001), 1A/1B (−53%, p = 0.0001), and 1A/1B w/VA (−51%, p = 0.0002). Between the 4 construct patterns, the 3 instrumented constructs (3A/2B, 1A/1B, and 1A/1B w/VA) showed comparable stability in all 3 motion planes. Conclusions This study showed no significant difference in the stability of the 3 instrumented constructs tested when the rib cage is intact. Fractures that might appear more grossly unstable when tested in the disarticulated spine may be bolstered by the ribs. This may affect the extent of segmental spinal instrumentation needed to restore stability in some spine injuries. While these initial findings suggest that shorter constructs may adequately stabilize the spine in this fracture model, further study is needed before these results can be extrapolated to clinical application.

This paper presents an analysis of wind tunnel experiments of twelve different roadway configurations and modeling of these configurations using a Large-Eddy Simulation (LES) model, aiming at investigating how flow structures affect the impact of roadway features on near-road and on-road air quality. The presence of roadside barriers, elevated fill and depressed roadways, and combinations of these configurations all reduce ground-level air pollutant concentrations immediately downwind of roadways. However, all of these cases, except the elevated fill configuration, increase pollutant concentrations on the roadway itself. For a roadside barrier with finite length, higher concentrations than those without a barrier are present in a small region near the edge of the barrier, influenced by complex flow in that region which we term “Edge Effects”. The inclusion of multiple roadway features often result in lower downwind pollutant concentrations than those with single roadway features; however, adding features typically offers diminishing returns in concentration reduction. Generally, the effects on concentration, both beneficial and adverse will damp out within 15 multiples of the characteristic height, be it the barrier height or the elevation/depression height of the roadway. Thus, evaluating the trade-off between the air pollutant reductions near the ground and the air pollutant increases on the roadway and elevated above the ground will be important in designing a sustainable transportation system.

Purpose The in vivo dosimetry tool, RADPOS, has been modified to include a metal oxide–silicon semiconductor field effect transistor (MOSFET) array with an electromagnetic positioning sensor. This allows dose monitoring at five points rather than just at single dose point as in the other versions of the device. The detector has been used in a clinical trial, which is the first to measure both urethral dose and internal motion concurrently during permanent seed implantation for prostate brachytherapy using a single probe. Methods and Materials The RADPOS detector was secured inside a Foley catheter inside the patient's urethra. Spatial coordinates of the RADPOS detector were read every 0.5 s, and the timing of events such as needle insertion was noted. The MOSFET readings were taken over two 10-min periods; once all seeds had been implanted both before and after the transrectal ultrasound (TRUS), the probe was removed. Measurements were completed for 16 patients. Results Maximum integral dose in the prostatic urethral ranged from 89 to 195 Gy, and dose varied from −66% to 36% depending on the rectal probe position. The change in position of the RADPOS sensor owing to the removal of the TRUS probe ranged from 1.4 to 9.7 mm. Conclusions The modified RADPOS detector with MOSFET array is able to provide real-time dose information, which can be used to monitor dose rates while implantation is performed and to estimate the total integrated dose. Changes in position including those owing to the TRUS probe can be significant and should be quantified to evaluate the influence on dose distributions.

Upright resistance exercise causes large transient fluctuations in blood pressure during and immediately after the performance. We examined the effect of resistance load and the number of repetitions on the middle cerebral artery blood flow velocity (MCAv) response during and after upright squatting exercise.Healthy males (n = 12; mean ± SD: 26 ± 5 yr) completed 30%, 60%, and 90% of their six-repetition maximum load, completing two and six repetitions of these loads during two visits (order randomized). Beat-to-beat MCAv, blood pressure, and continuous end-tidal PCO2 during exercise, at nadir, and during recovery are reported as the change from preexercise standing baseline.During exercise, MCAvmean increased 31% ± 16% (P0.001) across all loads (P = 0.74) and repetitions (P = 0.89), whereas mean arterial pressure (MAP) increased (all P0.05) as load and repetitions increased (e.g., 122 ± 9 (two repetitions) vs 135 ± 11 mm Hg (six repetitions) and 128 ± 13 vs 143 ± 14 mm Hg, at 30% and 60%, respectively). Within the six-repetition sets, peak MCAvmean remained unchanged across the set (P = 0.61), whereas MAP increased (P = 0.003). The 90% load produced the lowest MCAvmean nadir (pooled means, -18 ± 6 vs -10 ± 7 cm·s, P0.001 vs 30%) and MAP nadir (-34 ± 7 and -43 ± 5 mm Hg, for two and six repetitions, respectively; P0.001) after exercise. Postexercise MCAvmean reductions occurred via a selective, load-dependent (P0.001) decrease in diastolic MCAv. MCAvmean remained below baseline for the longest period after the 90% six-repetition set (10 s postexercise, P0.01) and took the longest to recover (14.8 ± 6.9 s, P = 0.002).These data indicate that higher relative loads produce a greater postexercise hypotension and result in a proportionate reduction in MCAvmean.

There is a growing need for developing mitigation strategies for near-road air pollution. Roadway design is being considered as one of the potential options. Particularly, it has been suggested that sound barriers, erected to reduce noise, may prove effective at decreasing pollutant concentrations. However, there is still a lack of mechanistic understanding of how solid barriers affect pollutant transport, especially under a variety of meteorological conditions. In this study, we utilized the Comprehensive Turbulent Aerosol Dynamics and Gas Chemistry (CTAG) model to simulate the spatial gradients of SF6 concentrations behind a solid barrier under a variety of atmospheric stability conditions collected during the Near Road Tracer Study (NRTS08). We employed two different CFD models, RANS and LES. A recirculation zone, characterized by strong mixing, forms in the wake of a barrier. It is found that this region is important for accurately predicting pollutant dispersion, but is often insufficiently resolved by the less complex RANS model. The RANS model was found to perform adequately away from the leading edge of the barrier. The LES model, however, performs consistently well at all flow locations. Therefore, the LES model will make a significant improvement compared to the RANS model in regions of strong recirculating flow or edge effects. Our study suggests that advanced simulation tools can potentially provide a variety of numerical experiments that may prove useful for roadway design communities to intelligently design roadways, making effective use of roadside barriers.