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Abstract Purpose First-pass perfusion cardiovascular magnetic resonance (CMR) is increasingly being utilized in both clinical practice and research. However, the reproducibility of this technique remains incompletely evaluated, particularly in patients with severe coronary artery disease (CAD). The purpose of this study was to determine the inter-study reproducibility of adenosine stress CMR in patients with symptomatic multi-vessel CAD and those at low risk for CAD. Methods Twenty patients (10 with CAD, 10 low risk CAD) underwent two CMR scans 8 ± 2 days apart. Basal, mid and apical left ventricular short axis slices were acquired using gadolinium 0.05 mmol/kg at peak stress (adenosine, 140 μ/kg/min, 4 min) and rest. Myocardial perfusion was evaluated qualitatively by assessing the number of ischemic segments, and semi-quantitatively by determining the myocardial perfusion reserve index (MPRi) using a normalized upslope method. Inter-study and observer reproducibility were assessed--the latter being defined by the coefficient of variation (CoV), which was calculated from the standard deviation of the differences of the measurements, divided by the mean. Additionally, the percentage of myocardial segments with perfect agreement and inter- and intra-observer MPRi correlation between studies, were also determined. Results The CoV for the number of ischemic segments was 31% with a mean difference of -0.15 ± 0.88 segments and 91% perfect agreement between studies. MPRi was lower in patients with CAD (1.13 ± 0.21) compared to those with low risk CAD (1.59 ± 0.58), p = 0.02. The reproducibility of MPRi was 19% with no significant difference between patients with CAD and those with low risk CAD (p = 0.850). Observer reproducibility for MPRi was high: inter-observer CoV 9%, r = 0.93 and intra-observer CoV 5%, r = 0.94. For trials using perfusion CMR as an endpoint, an estimated sample size of 12 subjects would be required to detect a two-segment change in the number of ischemic segments (power 0.9, α 0.05). Conclusions Adenosine stress CMR, by qualitative and semi-quantitative normalized upslope analyses are reproducible techniques in both patients with multi-vessel CAD and those without known CAD. The robust inter-study reproducibility of perfusion CMR supports its clinical and research application.

Objective: This study aimed to better understand the mental health experiences of students as they prepared to transition out of university., Participants: Participants included 18 recently graduated students from a Canadian university., Methods: Virtual one-on-one semi-structured qualitative interviews were conducted and analyzed following the protocol for content analysis and using QSR NVivo., Results: Four main themes were identified, including: distress and feelings of doubt, the importance of connections, the impact of the COVID-19 pandemic, and experiences with mental health service use. Participants discussed feeling pressured to succeed and a fear of failure, uncertainty and unpreparedness for next steps, the importance of connections to peers and professors, a lack of motivation and feeling 'unfinished' due to the COVID-19 pandemic response, and the need for flexible and accessible mental health services to address immediate and longer-term needs., Conclusion: Results have implications for better support of students as they prepare for graduation., (© 2024 The Author(s). Journal of Adolescence published by John Wiley & Sons Ltd on behalf of Foundation for Professionals in Services to Adolescents.)

Background and Objectives: There are many potential etiologies of impaired cardiovascular control, from chronic stress to neurodegenerative conditions or central nervous system lesions. Since 1959, spinal cord stimulation (SCS) has been reported to modulate blood pressure (BP), heart rate (HR), and HR variability (HRV), yet the specific stimulation sites and parameters to induce a targeted cardiovascular (CV) change for mitigating abnormal hemodynamics remain unclear. To investigate the ability and parameters of SCS to modulate the CV, we reviewed clinical studies using SCS with reported HR, BP, or HRV findings., Materials and Methods: A keyword-based electronic search was conducted through MEDLINE, Embase, and PubMed data bases, last searched on February 3, 2023. Inclusion criteria were studies with human participants receiving SCS with comparison with SCS turned off, with reporting of either HR, HRV, or BP findings. Non-English studies, conference abstracts, and studies not reporting standalone effects of SCS when comparing SCS with non-SCS interventions were excluded. Results were plotted for visual analysis. When available, participant-specific stimulation parameters and effects were extracted and quantitatively analyzed using ordinary least squares regression., Results: A total of 59 studies were included in this review; 51 studies delivered SCS invasively through implanted/percutaneous leads. Eight studies used noninvasive, transcutaneous electrodes. We found numerous reports of cervical, high thoracic, and mid-to-low thoracolumbar SCS increasing resting BP, and cervical/mid-to-low thoracolumbar SCS decreasing BP. The effect of SCS location on HR and HRV was equivocal. We were unable to analyze stimulation parameters owing to inadequate parameter reporting in many publications., Conclusions: Our findings suggest CV neuromodulation, particularly BP modulation, with SCS to be a promising frontier. Further research with larger randomized controlled trials and detailed reporting of SCS parameters will be necessary for appropriate evaluation of SCS as a CV therapy., Competing Interests: Conflict of interest The authors reported no conflict of interest., (Copyright © 2023 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Background & Aims: An optimal HCV vaccine requires the induction of antibodies that neutralise the infectivity of many heterogenous viral isolates. In this study, we have focused on determining the optimal recombinant envelope glycoprotein component to elicit cross-neutralising antibodies against global HCV genotypes. We compared the immunoreactivity and antigenicity of the HCV genotype 1a strain H77C-derived envelope glycoprotein heterodimer gpE1/gpE2 with that of recombinant gpE2 alone., Methods: Characterisation of the envelope glycoproteins was accomplished by determining their ability to bind to a panel of broadly cross-neutralising monoclonal antibodies. Immunogenicity was determined by testing the ability of vaccine antisera to neutralise the infectivity in vitro of a panel of pseudotyped HCV particles in which gpE1/gpE2 derived from representative isolates of the major global HCV genotypes were displayed., Results: gpE1/gpE2 binds to more diverse broadly cross-neutralising antibodies than gpE2 alone and elicits a broader profile of cross-neutralising antibodies in animals, especially against more heterologous, non-1a genotypes. While not all heterologous HCV strains can be potently inhibited in vitro by gpE1/gpE2 antisera derived from a single HCV strain, the breadth of heterologous cross-neutralisation is shown to be substantial., Conclusions: Our work supports the inclusion of gpE1/gpE2 in an HCV vaccine in order to maximise the cross-neutralisation of heterogenous HCV isolates. Our data also offers future directions in formulating a cocktail of gpE1/gpE2 antigens from a small selection of HCV genotypes to further enhance cross-neutralisation of global HCV strains and hopefully advance the development of a globally effective HCV vaccine., Impact and Implications: An HCV vaccine is urgently required to prevent the high global incidence of HCV infection and disease. Since HCV is a highly heterogeneous virus, it is desirable for a vaccine to elicit antibodies that neutralise the infectivity of most global strains. To this end, we have compared the immunoreactivity and antigenicity of recombinant H77C E1E2 heterodimer with that of H77C E2 alone and show that the former exhibits more cross-neutralising epitopes and demonstrates a broader cross-neutralisation profile in vitro. In addition, our data suggests a way to further broaden cross-neutralisation using a combination of E1E2 antigens derived from a few different HCV clades. Our work is relevant for the development of an effective global HCV vaccine., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Dexmedetomidine improves intrapulmonary shunt in thoracic surgery and minimizes inflammatory response during one-lung ventilation (OLV). However, it is unclear whether such benefits translate into less postoperative pulmonary complications (PPCs). Our objective was to determine the impact of dexmedetomidine on the incidence of PPCs after thoracic surgery., Methods: Major databases were used to identify randomized trials that compared dexmedetomidine versus placebo during thoracic surgery in terms of PPCs. Our primary outcome was atelectasis within 7 days after surgery. Other specific PPCs included hypoxemia, pneumonia, and acute respiratory distress syndrome (ARDS). Secondary outcome included intraoperative respiratory mechanics (respiratory compliance [Cdyn]) and postoperative lung function (forced expiratory volume [FEV1]). Random effects models were used to estimate odds ratios (OR)., Results: Twelve randomized trials, including 365 patients in the dexmedetomidine group and 359 in the placebo group, were analyzed in this meta-analysis. Patients in the dexmedetomidine group were less likely to develop postoperative atelectasis (2.3% vs 6.8%, OR 0.42, 95%CI 0.18-0.95, P = 0.04; low certainty) and hypoxemia (3.4% vs 11.7%, OR 0.26, 95%CI 0.10-0.68, P = 0.01; moderate certainty) compared to the placebo group. The incidence of postoperative pneumonia (3.2% vs 5.8%, OR 0.57, 95%CI 0.25-1.26, P = 0.17; moderate certainty) or ARDS (0.9% vs 3.5%, OR 0.39, 95%CI 0.07-2.08, P = 0.27; moderate certainty) was comparable between groups. Both intraoperative Cdyn and postoperative FEV1 were higher among patients that received dexmedetomidine with a mean difference of 4.42 mL/cmH 2 O (95%CI 3.13-5.72) and 0.27 L (95%CI 0.12-0.41), respectively., Conclusion: Dexmedetomidine administration during thoracic surgery may potentially reduce the risk of postoperative atelectasis and hypoxemia. However, current evidence is insufficient to demonstrate an effect on pneumonia or ARDS., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: The objectives were to (1) identify themes related to competitive peer-to-peer interactions elicited from the lived experiences of undergraduate medical students, and (2) understand how these experiences influenced medical students' choices related to surgical residency programs., Design: A qualitative descriptive methodology, with purposive and maximal variation sampling (e.g., selection based on medical school location; gender), was adopted for this study., Setting: Temerty Faculty of Medicine, University of Toronto., Participants: Participants were 15 undergraduate medical students from 4 medical schools in Ontario, Canada, who agreed to an individual semi-structured interview by Zoom or telephone., Results: Peer-to-peer interactions influence students' perception of self and identity formation related to surgical specialty decision-making and interest. These interactions were shown to hold greater value, specifically for information gathering. Identity formation, related to pursuing a surgical residency, was influenced by the attitudes and perceptions of competition with peers throughout medical school. Cultures of competition were seen to dictate peer-to-peer interactions and their associated value, with their perception and experience differing between medical schools., Conclusions: Peer-to-peer interactions and a culture of competition have inherent roles in the residency decision-making process. We observed that student background and pre-formed relationships influenced how students perceived and responded to competition. Addressing the culture of competitiveness associated with peer-to-peer interactions along with considering student background and pre-existing relationships may provide insight into how medical educators can tailor learning experiences that limit the detrimental effects of hidden curriculum influences., (Copyright © 2023 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Background: We investigated the value of automated enlarged perivascular spaces (ePVS) quantification to distinguish chronic traumatic brain injury (TBI) patients with post-traumatic epilepsy (PTE + ) from chronic TBI patients without PTE (PTE - ) in a feasibility study., Methods: Patients with and without PTE were recruited and underwent an MRI post-TBI. Multimodal auto identification of ePVS algorithm was applied to T1-weighted MRIs to segment ePVS. The total number of ePVS was calculated and corrected for white matter volume, and an asymmetry index (AI) derived., Results: PTE was diagnosed in 7 out of the 99 participants (male=69) after a median time of less than one year since injury (range 10-22). Brain lesions were observed in all 7 PTE + cases (unilateral=4, 57%; bilateral=3, 43%) as compared to 40 PTE - cases (total 44%; unilateral=17, 42%; bilateral=23, 58%). There was a significant difference between PTE + (M=1.21e -4 , IQR [8.89e -5 ]) and PTE - cases (M=2.79e -4 , IQR [6.25e -5 ]) in total corrected numbers of ePVS in patients with unilateral lesions (p=0.024). No differences in AI, trauma severity and lesion volume were seen between groups., Conclusion: This study has shown that automated quantification of ePVS is feasible and provided initial evidence that individuals with PTE with unilateral lesions may have fewer ePVS compared to TBI patients without epilepsy. Further studies with larger sample sizes should be conducted to determine the value of ePVS quantification as a PTE-biomarker., Competing Interests: Declaration of Competing Interest Author Gernot Hlauschek has served as a lecturer for Eisai, unrelated to this study. Author Morten Ingvar Lossius has served as a paid consultant and lecturer for Eisai, UCB and Arvelle Therapeutics, unrelated to this study. None of the other authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

T2 relaxation times (T2 times) are different between resting and exercised muscles and between muscles of healthy subjects and subjects with muscle pathology. However, studies specifically focusing on neck muscles are lacking. Furthermore, normative neck muscle T2 times are not well defined and methodology used to analyse T2 times in neck muscles is not robust. We analysed T2 times in key neck muscles and explored factors affecting variability between muscles. 20 healthy subjects were recruited. Two circular regions of interest (ROIs) were drawn in two mutually exclusive regions within neck muscles on T2 weighted images and values averaged. ROI measurements were performed by a co-investigator, supervised by a neuro-radiologist. For the first ten subjects, measurements were done from C1-T1. For the remaining subjects, ROIs were drawn at two pre-determined levels. Two MRIs were repeated at 31 degrees acquisition to evaluate the effect of muscle fibre orientation. ROI values were translated into T2 times. Results showed semispinalis capitis had the longest T2 times (range 46.88-51.42 ms), followed by splenius capitis (range 47.37-48.33 ms), trapezius (range 45.27-47.46 ms), levator scapulae (range 43.17-45.63 ms) and sternocleidomastoid (range 38.45-42.91 ms). T2 times did not vary along length of muscles and were unaffected by muscle fibre orientation (P > 0.05). T2 times of splenius capitis correlated significantly with age at C2/C3 and C5/C6 levels and trapezius at C7/T1 level. Gender did not influence relaxation times (P > 0.05). In conclusion, results of normative neck muscle T2 time values and factors influencing the T2 times could serve as a reference for future MR analysis of neck muscles. The methodology used may also be useful for related studies of neck muscles., Competing Interests: Declaration of Competing Interest All authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess the degree of pathologic complete response (pCR), postoperative surgical complication rates, and oncological outcomes in women with locally advanced breast cancer or high-risk breast cancers treated with neoadjuvant radiation therapy (NART)., Methods and Materials: This retrospective, multi-institutional review involved 138 clinically staged patients with 140 breast cancers treated with NART between January 2014 and February 2021. Treatments involved sequential neoadjuvant chemotherapy and NART, followed by mastectomy with or without axillary surgery and immediate autologous breast reconstruction. Descriptive statistics were used to assess patient and disease features, treatment regimens, pathologic response, and factors affecting postoperative complications. Kaplan-Meier curves were performed to assess locoregional recurrence-free, distant metastasis-free, and overall survival outcomes., Results: Median age was 47 years (interquartile range, 42-52). The median follow-up was 35.2 months (interquartile range, 17.1-46.5). pCR was achieved in 36.4% (as defined by Chevallier classification) or 42.1% (as defined by Miller-Payne scores) of patients. Greater pCR rates were achieved for HER2+ (73.8%-85.7%) and triple-negative phenotypes (47.6%-57.1%). There were 21 grade 3 surgical complications including 10 grade 3B breast events and 8 grade 3B donor-site events, where surgical reintervention was required. At 3-years' follow-up, the locoregional recurrence-free survival was 98.1%, distant metastasis-free survival was 83.6%, and overall survival was 95.3%%., Conclusions: NART is feasible to facilitate a single-stage mastectomy and immediate autologous breast reconstruction. This study demonstrated comparable rates of postoperative complication to standard of care, and high rates of pCR, which translates to high rates of locoregional control, distant metastasis-free survival, and overall survival., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: The study aimed to determine the diagnostic yield, optimal timing, and methodology of next generation sequencing data reanalysis in suspected Mendelian disorders., Methods: We conducted a systematic review and meta-analysis of studies that conducted data reanalysis in patients with suspected Mendelian disorders. Random effects model was used to pool the estimated outcome with subgroup analysis stratified by timing, sequencing methodology, sample size, segregation, use of research validation, and artificial intelligence (AI) variant curation tools., Results: A search of PubMed, Embase, Scopus, and Web of Science between 2007 and 2021 yielded 9327 articles, of which 29 were selected. Significant heterogeneity was noted between studies. Reanalysis had an overall diagnostic yield of 0.10 (95% CI = 0.06-0.13). Literature updates accounted for most new diagnoses. Diagnostic yield was higher after 24 months, although this was not statistically significant. Increased diagnoses were obtained with research validation and data sharing. AI-based tools did not adversely affect reanalysis diagnostic rate., Conclusion: Next generation sequencing data reanalysis can improve diagnostic yield. Owing to the heterogeneity of the studies, the optimal time to reanalysis and the impact of AI-based tools could not be determined with confidence. We propose standardized guidelines for future studies to reduce heterogeneity and improve the quality of the conclusions., Competing Interests: Conflict of Interest The authors declare no conflicts of interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: A prophylactic vaccine is required to eliminate HCV as a global public health threat. We developed whole virus inactivated HCV vaccine candidates employing a licensed adjuvant. Further, we investigated the effects of HCV envelope protein modifications (to increase neutralization epitope exposure) on immunogenicity., Methods: Whole virus vaccine antigen was produced in Huh7.5 hepatoma cells, processed using a multistep protocol and formulated with adjuvant (MF-59 analogue AddaVax or aluminium hydroxide). We investigated the capacity of IgG purified from the serum of immunized BALB/c mice to neutralize genotype 1-6 HCV (by virus neutralization assays) and to bind homologous envelope proteins (by ELISA). Viruses used for immunizations were (i) HCV5aHi with strain SA13 envelope proteins and modification of an O-linked glycosylation site in E2 (T385P), (ii) HCV5aHi(T385) with reversion of T385P to T385, featuring the original E2 sequence determined in vivo and (iii) HCV5aHi(ΔHVR1) with deletion of HVR1. For these viruses, epitope exposure was investigated using human monoclonal (AR3A and AR4A) and polyclonal (C211 and H06) antibodies in neutralization assays., Results: Processed HCV5aHi formulated with AddaVax induced antibodies that efficiently bound homologous envelope proteins and broadly neutralized cultured genotype 1-6 HCV, with half maximal inhibitory concentrations of between 14 and 192 μg/ml (mean of 36 μg/ml against the homologous virus). Vaccination with aluminium hydroxide was less immunogenic. Compared to HCV5aHi(T385) with the original E2 sequence, HCV5aHi with a modified glycosylation site and HCV5aHi(ΔHVR1) without HVR1 showed increased neutralization epitope exposure but similar immunogenicity., Conclusion: Using an adjuvant suitable for human use, we developed inactivated whole HCV vaccine candidates that induced broadly neutralizing antibodies, which warrant investigation in further pre-clinical studies., Lay Summary: A vaccine against hepatitis C virus (HCV) is needed to prevent the estimated 2 million new infections and 400,000 deaths caused by this virus each year. We developed inactivated whole HCV vaccine candidates using adjuvants licensed for human use, which, following immunization of mice, induced antibodies that efficiently neutralized all HCV genotypes with recognized epidemiological importance. HCV variants with modified envelope proteins exhibited similar immunogenicity as the virus with the original envelope proteins., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Deep inspiration breath hold (DIBH) is an innovative technique routinely used for left-sided breast radiotherapy to significantly reduce harmful dose to the heart and ipsilateral lung. Currently, there is scant literature exploring DIBH for right-sided whole breast and regional nodal irradiation (WB & RNI). The purpose of this study is to examine if DIBH produces a clinically significant reduction in organ at risk (OAR) dose for right-sided WB + RNI, whilst comparatively analysing the use of volumetric arc therapy (VMAT) versus tangential inverse modulated radiotherapy (t-IMRT)., Methods and Materials: Ten patients, previously treated for left sided breast cancer (with a FB and DIBH CT scan), were selected from our database to be retrospectively replanned to the right breast and nodal regions. Planning target volumes (PTV) were marked to include the whole right breast and regional nodes, encompassing the supraclavicular fossa (SCF) and internal mammary nodes (IMN). PTVs and OARs were contoured on the Pinnacle workstation according to the Radiation Therapy Oncology Group (RTOG) guidelines. VMAT and t-IMRT plans were generated to a prescribed dose of 50 Gy in 25 fractions on both the DIBH and FB data sets for dosimetric analysis., Results: Coverage of the right breast (mean, D95%) and SCF (D95%) were significantly improved with VMAT in comparison to t-IMRT, with no statistically significant variation on the IMN PTV (D95%). The use of DIBH did not impact PTV coverage compared with FB. VMAT reduced dose to the ipsilateral lung (mean, V20Gy), combined lungs (mean, V20Gy) and liver (D2cc); conversely dose to the heart (mean), left lung (mean, V5Gy) and contralateral breast (mean) were increased. For both techniques DIBH significantly improved dose to OARs including the ipsilateral lung (mean, V20Gy, V5Gy), total lung (mean, V20Gy), heart (mean, V25Gy) and liver (D2cc) when compared to FB., Conclusion: DIBH could be considered for patients treated with right-sided WB and RNI due to a significant decrease in heart, ipsilateral lung, total lung and liver doses. VMAT significantly improves PTV coverage over t-IMRT whilst reducing dose to the ipsilateral lung and liver, albeit to the detriment of the left lung, contralateral breast and heart. The increase in heart dose can be mitigated by the use of DIBH. We recommend if VMAT is utilised for superior target volume coverage, DIBH should also be implemented to reduce OAR toxicity. RÉSUMÉ:   BUT: La retenue respiratoire profonde (DIBH) est une technique innovante couramment utilisée pour la radiothérapie du cÔté gauche du sein afin de réduire de manière significative la dose nocive pour le cŒur et le poumon ipsilatéral (13-15). Actuellement, il existe peu d'ouvrages sur la DIBH pour l'irradiation du sein entier du cÔté droit et des nodules régionaux (WB+RNI). L'objectif de cette étude est d'examiner si la DIBH produit une réduction cliniquement significative de la dose d'organe à risque (OAR) pour la WB+RNI du cÔté droit, tout en analysant comparativement l'utilisation de l'arcthérapie volumétrique (VMAT) par rapport à la radiothérapie par modulation d'intensité tangentielle (t-IMRT). MéTHODOLOGIE ET MATéRIEL: Dix scans tomodensitométriques avec un ensemble de données DIBH et de respiration libre (FB) ont été sélectionnés de manière rétrospective. Les volumes cibles de planification (PTV) ont été marqués pour inclure le sein droit entier et les ganglions régionaux, englobant la fosse supraclaviculaire (SCF) et les ganglions mammaires internes (IMN). Les PTV et les OAR ont été définis sur la station de travail Pinnacle conformément aux directives du groupe de radiothérapie oncologique (RTOG) (17). Les plans t-IMRT et VMAT ont été générés pour une dose prescrite de 50Gy en 25 fractions sur les ensembles de données DIBH et FB pour l'analyse dosimétrique. RéSULTATS: La couverture du sein droit (moyenne, D95%) et du SCF (D95%) a été significativement améliorée avec la VMAT par rapport à la t-IMRT, sans variation statistiquement significative sur la PTV IMN (D95%). L'utilisation de la DIBH n'a pas eu d'impact sur la couverture du PTV par rapport à la FB. La VMAT a réduit la dose dans le poumon ipsilatéral (moyenne, V20Gy), les poumons combinés (moyenne, V20Gy) et le foie (D2cc) ; à l'inverse, la dose dans le cŒur (moyenne), le poumon gauche (moyenne, V5Gy) et le sein controlatéral (moyenne) a été augmentée. Pour les deux techniques, la DIBH a amélioré de manière significative la dose aux OAR, y compris le poumon ipsilatéral (moyenne, V20Gy, V5Gy), le poumon total (moyenne, V20Gy), le cŒur (moyenne, V25Gy) et le foie (D2cc), par rapport à la respiration libre., Conclusion: La DIBH pourrait être envisagé pour les patients traités par WB+RNI du cÔté droit en raison d'une diminution significative des doses dans le cŒur, le poumon ipsilatéral, le poumon total et le foie. La VMAT améliore considérablement la couverture de la PTV par rapport à la t-IMRT tout en réduisant la dose dans le poumon ipsilatéral et le foie, mais au détriment du poumon gauche, du sein controlatéral et du cŒur. L'augmentation de la dose au cŒur peut être atténuée par l'utilisation de la DIBH. Nous recommandons, si la VMAT est utilisée pour une couverture supérieure du volume cible, de mettre également en Œuvre la DIBH pour réduire la toxicité aux OAR., (Copyright © 2021. Published by Elsevier Inc.)

Objectives: To determine the comparative prognostic utility of commonly used disease prediction scores in adults with presumed community-acquired sepsis in a resource-limited tropical setting., Methods: This prospective, observational study was performed on the medical ward of a tertiary-referral hospital in Yangon, Myanmar. The ability of the National Early Warning Score 2 (NEWS2), quick NEWS (qNEWS), quick Sequential Organ Failure Assessment (qSOFA) score, Universal Vital Assessment (UVA) and Sequential Organ Failure Assessment (SOFA) scores to predict a complicated inpatient course (death or requirement for intensive care unit (ICU) support) in patients with two or more systemic inflammatory response syndrome criteria was determined., Results: Among the 509 patients, 30 (6%) were HIV-seropositive. The most commonly confirmed diagnoses were tuberculosis (30/509, 5.9%) and measles (26/509, 5.1%). Overall, 75/509 (14.7%) died or required ICU support. All the scores except the qSOFA score, which was inferior, had a similar ability to predict a complicated inpatient course., Conclusions: In this resource-limited tropical setting, disease severity scores calculated at presentation using only vital signs-such as the NEWS2 score-identified high-risk sepsis patient as well as the SOFA score, which is calculated at 24 h and which also requires laboratory data. Use of these simple clinical scores can be used to facilitate recognition of the high-risk patient and to optimise the use of finite resources., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Routine staging investigations are not recommended for early breast cancer (EBC). Staging scans and further confirmatory tests add to the cost of breast cancer treatment. Despite recommendations from international guidelines, whole body bone scan (BS) is commonly used for staging EBC. We examined our experience with BS as a staging investigation when selectively used in EBC., Patients and Methods: All EBC patients who underwent treatment through the Eastern Health breast unit during a 50-month period from January 2012 were included in this study. All staging BS results were reviewed to evaluate yield and false-positive rate. The causes of false-positive results were analyzed. The role of BS when performed along with computed tomographic scans of chest, abdomen, and pelvis (CTCAP) was evaluated., Results: Even with the selective use of BS, we could only achieve a yield of 1% (95% confidence interval, -0.6, 2.7) in EBC. When combined with CTCAP, only one additional metastasis was detected in 194 BSs., Conclusion: BS plays only a limited role in staging EBC. Patients who have undergone CTCAP will experience minimal benefit by undergoing additional BS., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background & Aims: High HCV treatment uptake among people at most risk of transmission is essential to achieve elimination. We aimed to characterise subpopulations of people with HCV based on drug dependence, to estimate direct-acting antiviral (DAA) uptake in an unrestricted treatment era, and to evaluate factors associated with treatment uptake among people with recent drug dependence., Methods: HCV notifications in New South Wales, Australia (1995-2017) were linked to opioid agonist therapy (OAT), hospitalisations, incarcerations, HIV notifications, deaths, and prescription databases. Drug dependence was defined as hospitalisation due to injectable drugs or receipt of OAT, with indicators in 2016-2018 considered recent. Records were weighted to account for spontaneous clearance. Logistic regression was used to analyse factors associated with treatment uptake among those with recent drug dependence., Results: 57,467 people were estimated to have chronic HCV throughout the DAA era. Treatment uptake was highest among those with recent (47%), compared to those with distant (38%), and no (33%) drug dependence. Among those with recent drug dependence, treatment was more likely among those with HIV (adjusted odds ratio [aOR] 1.71; 95% CI 1.24-2.36), recent incarceration (aOR 1.10; 95% CI 1.01-1.19), and history of alcohol use disorder (aOR 1.22; 95% CI 1.13-1.31). Treatment was less likely among women (aOR 0.78; 95% CI 0.72-0.84), patients of Indigenous ethnicity (aOR 0.75; 95% CI 0.69-0.81), foreign-born individuals (aOR 0.86; 95% CI 0.78-0.96), those with outer-metropolitan notifications (aOR 0.90; 95% CI 0.82-0.98), HBV coinfection (aOR 0.69; 95% CI 0.59-0.80), and >1 recent hospitalisation (aOR: 0.91; 95% CI 0.84-0.98)., Conclusions: These data provide evidence of high DAA uptake among people with recent drug dependence, including those who are incarcerated. Enhancing this encouraging initial uptake among high-risk populations will be essential to achieve HCV elimination., Lay Summary: To facilitate HCV elimination, those at highest risk of infection and transmission are a treatment priority. This study shows the successes of Australia's universal provision of DAA therapy in reducing the barriers to treatment which have historically persisted among people who inject drugs. Despite higher DAA therapy uptake among those with recent drug dependence, gaps remain. Strategies which aim to reduce marginalisation and increase treatment uptake to ensure equitable HCV elimination must be advanced., Competing Interests: Conflict of interest GD reports grants from Gilead, Abbvie, Merck, and Bristol-Myers Squibb, personal fees from Gilead, Abbvie, and Merck, and non-financial support from Gilead, Abbvie, and Merck, outside the submitted work. JGrebely reports grants from Merck, grants from Cepheid, during the conduct of the study; grants and personal fees from Abbvie, grants and personal fees from Gilead Sciences, grants and personal fees from Merck, grants and personal fees from Cepheid, grants from Hologic, grants from Indivior, outside the submitted work. ML reports grants from Gilead, ViiV Healthcare and Janssen outside the submitted work. MK reports receiving grants from Boehringer Ingelheim, Hologic, Merck, Roche Molecular Systems, and Siemens Healthcare Diagnostics outside of the submitted work. JGeorge reports funding from MSD, Abbvie, BMS, Pharmaxis, Norvartis, Cincera, and Bayer outside the submitted work. BH reports grants from NSW Health and Cancer Council NSW. LD has received investigator-initiated untied educational grants for studies of opioid medications in Australia from Indivior, Mundipharma and Seqirus. All remaining authors have no potential conflicts to declare. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

With the growth of global pharmacy partnerships and collaborative research, particularly between high-income countries and low- or middle-income countries, it is necessary to establish best practices for fair and ethical collaboration and research. There is a gap in the pharmacy literature in this regard. Through this commentary, authors will present a pathway for future global health researchers including generating ideas based on mutual needs of the partnership and the community; exploring the importance of regulations including the need to conduct research and partnership projects within the confines of each participant's professional scope of practice, expertise, and licensure; describing the need to develop agreements and the components that should be included in such an agreement; discussing ethical guidelines for research planning, obtaining ethical approval, and planning for adverse events; and illustrating ethical considerations for research implementation with considerations around consent, data collection, linking patients to care after the completion of the study, and dissemination. Global examples, with a pharmacy-specific approach where applicable, within each section highlight the importance of discussion and action around ethics and equity when pursuing collaborative research, recognizing that many of these situations involve difficult decisions., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background & Aims: HCV reinfection following successful treatment can compromise treatment outcomes. This systematic review assessed the rate of HCV reinfection following treatment among people with recent drug use and those receiving opioid agonist therapy (OAT)., Methods: We searched bibliographic databases and conference abstracts for studies assessing post-treatment HCV reinfection rates among people with recent drug use (injecting or non-injecting) or those receiving OAT. Meta-analysis was used to cumulate reinfection rates and meta-regression was used to explore heterogeneity across studies., Results: Thirty-six studies were included (6,311 person-years of follow-up). The overall rate of HCV reinfection was 5.9/100 person-years (95% CI 4.1-8.5) among people with recent drug use (injecting or non-injecting), 6.2/100 person-years (95% CI 4.3-9.0) among people recently injecting drugs, and 3.8/100 person-years (95% CI 2.5-5.8) among those receiving OAT. Reinfection rates were comparable following interferon-based (5.4/100 person-years; 95% CI 3.1-9.5) and direct-acting antiviral (3.9/100 person-years; 95% CI 2.5-5.9) therapy. In stratified analysis, reinfection rates were 1.4/100 person-years (95% CI 0.8-2.6) among people receiving OAT with no recent drug use, 5.9/100 person-years (95% CI 4.0-8.6) among people receiving OAT with recent drug use, and 6.6/100 person-years (95% CI 3.4-12.7) among people with recent drug use not receiving OAT. In meta-regression analysis, longer follow-up was associated with lower reinfection rate (adjusted rate ratio [aRR] per year increase in mean/median follow-up 0.77; 95% CI 0.69-0.86). Compared with people receiving OAT with no recent drug use, those with recent drug use receiving OAT (aRR 3.50; 95% CI 1.62-7.53), and those with recent drug use not receiving OAT (aRR 3.96; 95% CI 1.82-8.59) had higher reinfection rates., Conclusion: HCV reinfection risk following treatment was higher among people with recent drug use and lower among those receiving OAT. The lower rates of reinfection observed in studies with longer follow-up suggested higher reinfection risk early post-treatment., Lay Summary: Our findings demonstrate that although reinfection by hepatitis C virus occurs following successful treatment in people with recent drug use, the rate of hepatitis C reinfection is lower than the rates of primary infection reported in the literature for this population - reinfection should not be used as a reason to withhold therapy from people with ongoing injecting drug use. The rate of hepatitis C reinfection was lowest among people receiving opioid agonist therapy with no recent drug use. These data illustrate that harm reduction services are required to reduce the reinfection risk, while regular post-treatment hepatitis C assessment is required for early detection and retreatment., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

The quality assurance of pharmacy education is a global goal and indicator of transformative pharmacy workforce development. FIP has published a number of tools, guidelines and resources to support individuals, institutions, nations and regions advance pharmacy education - especially as the state of pharmacy education varies widely in countries around the world. The Nanjing Statements offer a potential additional tool aimed primarily at institutions to evaluate, monitor and advance their educational standards. The upcoming assessment tool being developed by FIP in partnership with Howard University will facilitate its utilization by educators and institutions worldwide and provides a global, practical mechanism of advancing the education of the pharmacy workforce worldwide., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Extent of resection of glioblastoma is an important predictor for overall survival, and 5-aminolevulinic acid fluorescence-guided surgery can improve outcomes. However, the technique requires the installation of a blue light module on operative microscopes and may be cost prohibitive. A novel and economical blue light-emitting headlamp was designed, and its clinical utility was explored., Methods: A remote-controlled dual light emitting diode headlamp system was constructed with 1 diode emitting white light and the other blue. Spectrographic analysis of the blue light emitted from a commercial operative microscope and the headlamp was performed. A comparative evaluation of the 2 illumination systems was conducted for 3 patients who underwent craniotomy for glioblastoma resection. Histologic examination of the fluorescing tissue detected by the headlamp was performed, and the extent of resection was assessed by postoperative day 1 magnetic resonance imaging., Results: Spectrography of blue light emitted from the headlamp system was wavelength specific with a single emission peak at 416 nm and a linewidth of 35 nm. In contrast, blue light from the microscope (peak: 426 nm) had a wider linewidth of 54 nm and was not wavelength specific with additional infrared radiation detected. Gross or near-total resection of contrast-enhancing glioblastoma was performed for all 3 patients. Intraoperatively, comparable tumor fluorescence was observed under microscope and headlamp blue light illumination. Histologic examination of tissue fluorescing under headlamp blue light confirmed the presence of glioblastoma., Conclusions: This novel proof-of-concept blue light-emitting headlamp device may offer an opportunity for institutions with limited resources to implement 5-aminolevulinic acid fluorescence-guided glioblastoma resections., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Recently, the first 7-Tesla MR system was approved for clinical use in Europe and the United States. Unfortunately, few metallic objects have undergone testing in association with this high-field-strength scanner, including essential equipment such as patient support devices and other items. Therefore, the objective of this investigation was to assess metallic patient support devices and other items for translational attraction at 7-Tesla., Methods: Thirteen different metallic items (e.g., gurney, Mayo stand, step stool, utility table, wheelchair, etc.) underwent testing for translational attraction using a previously described methodology in association with a clinical 7-T MR system. The findings were categorized as pass (no translational attraction) or fail (the item was attracted by the scanner)., Results: Every metallic item tested exhibited a lack of magnetism while in a worst-case use position and, thus, passed the test for translational attraction in associated with the 7-Tesla MR system., Conclusions: The different thirteen different metallic patient support devices and other items can be designated as MR Conditional at 7-T or less. Furthermore, because each item represented a worst-case with respect to its mass and the type of metallic material used for its fabrication, the results can be applied to 46 additional smaller items made from the same material or material with a lower magnetic susceptibility. This expanded list of essential patient support devices and other items will facilitate the clinical use of a comparable 7-Tesla scanner, or another UHF scanner with similar fringe field characteristics., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Recently, the first 7-T MR system was approved for clinical use in the United States. Unfortunately, relatively few metallic implants have undergone testing to determine if they are acceptable or pose hazards to research subjects and patients at this ultra-high-field strength. Therefore, in lieu of not performing a research or clinical MRI exam at 7-T, the supervising physician may make a decision to scan the individual with an untested metallic implant based on an analysis of the risks vs. the benefits. We present a case report of a research subject with bilateral, total knee replacement implants that safely underwent MRI of the brain at 7-T and provide guidelines for healthcare professionals to follow in order to ensure safety in research subjects or patients with metallic implants referred for 7-T scans., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Effective targeting of harm reduction programs for people who inject drugs (PWID) requires timely and robust estimates of the size of this population. This study estimated the number of people who inject drugs on a regular basis in Australia, calculated syringe coverage per person and the proportion of their injections covered by a sterile needle and syringe., Methods: We used trends in indicators of injection drug use to extend the 2005 estimate of the population of people who regularly inject drugs from 2005 to 2016. Included indicators were lifetime/recent injection of illicit drugs, drug-related arrests, drug-related seizures, accidental deaths due to opioids, opioid-related hospital admissions/separations and new diagnoses of hepatitis C virus infection among those aged 15-24 years. Syringe distribution and frequency of injection data were used to assess syringe coverage per PWID and the proportion of their injections covered by a sterile syringe., Results: The estimated number of people who regularly inject drugs in Australia increased by 7%, from 72,000 in 2005 to 77,270 in 2016. The annual number of syringes distributed per person increased 34%, from 470 syringes in 2005 to 640 syringes in 2016. Syringe coverage per injection first exceeded 100% in Australia in 2013., Conclusions: Despite Australia's high syringe coverage by international standards, the number of syringes distributed is likely to be only narrowly meeting demand. It is critical that needle syringe programs be provided with sufficient resources to continue their role as the key intervention required to prevent HIV and HCV transmission among PWID., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Broadly neutralizing antibodies (bnAbs) are potential therapeutic molecules and valuable tools for studying conserved viral targets for vaccine and drug design. Interestingly, antibody responses to conserved epitopes can be highly convergent at the molecular level. Human antibodies targeting a number of viral antigens have often been found to utilize a restricted set of immunoglobulin germline genes in different individuals. Here we review recent knowledge on V H 1-69-encoded antibodies in antiviral responses to influenza virus, HCV, and HIV-1. These antibodies share common genetic and structural features, and often develop neutralizing activity against a broad spectrum of viral strains. Understanding the genetic and structural characteristics of such antibodies and the target epitopes should help advance novel strategies to elicit bnAbs through vaccination., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Screening young adults who are sexually active for genital Chlamydia trachomatis infection is promoted in several high-income countries, but its effectiveness at the population level is highly debated. We aimed to investigate the effects of opportunistic chlamydia testing in primary care on the estimated chlamydia prevalence in the population aged 16-29 years in Australia., Methods: We did a cluster-randomised controlled trial. Clusters were rural towns with a minimum of 500 women and men aged 16-29 years and no more than six primary care clinics. We randomly allocated each cluster using a computer-generated minimisation algorithm to receive a multifaceted, clinic-based chlamydia testing intervention or to continue usual care. The intervention included computerised reminders to test patients, an education package, payments for chlamydia testing, and feedback on testing rates. The primary outcome was chlamydia prevalence, estimated before randomisation (survey 1) and at the end of the trial (survey 2) in patients aged 16-29 years who attended the clinics. Analyses were done by intention to treat. General practitioners and clinic staff were aware of group allocation, whereas patients and laboratory staff who performed the chlamydia tests were not. This trial was completed on Dec 31, 2015, and is registered (ACTRN12610000297022)., Findings: Between Dec 14, 2010, and Sept 14, 2015, 26 clusters (63 clinics) received the chlamydia testing intervention and 26 (67 clinics) continued usual care. Over a mean duration of 3·1 years (SD 0·3), 93 828 young adults attended intervention clinics and 86 527 attended control clinics. The estimated chlamydia prevalence decreased from 5·0% (95% CI 3·8 to 6·2) at survey 1 to 3·4% (2·7 to 4·1) at survey 2 in the intervention clusters (difference -1·6%, 95% CI -2·9 to -0·3) and from 4·6% (95% CI 3·5 to 5·7) at survey 1 to 3·4% (2·4 to 4·5) at survey 2 in the control clusters (difference -1·1%, -2·7 to 0·5). The unadjusted odds ratio for the difference between intervention and control clusters was 0·9 (95% CI 0·5 to 1·5)., Interpretation: These findings, in conjunction with evidence about the feasibility of sustained uptake of opportunistic testing in primary care, indicate that sizeable reductions in chlamydia prevalence might not be achievable., Funding: Australian Government Department of Health, National Health and Medical Research Council, Victorian Department of Health and Human Services, and New South Wales Ministry of Health., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective/background: Increasingly, reports show that compliance rates with endovascular aneurysm repair (EVAR) surveillance are often suboptimal. The aim of this study was to determine the safety implications of non-compliance with surveillance., Methods: The study was carried out according to the Preferred Items for Reporting of Systematic Reviews and Meta-Analyses (PRISMA) guidelines. An electronic search was undertaken by two independent authors using Embase, MEDLINE, Cochrane, and Web of Science databases from 1990 to July 2017. Only studies that analysed infrarenal EVAR and had a definition of non-compliance described as weeks or months without imaging surveillance were analysed. Meta-analysis was carried out using the random-effects model and restricted maximum likelihood estimation., Results: Thirteen articles (40,730 patients) were eligible for systematic review; of these, seven studies (14,311 patients) were appropriate for comparative meta-analyses of mortality rates. Three studies (8316 patients) were eligible for the comparative meta-analyses of re-intervention rates after EVAR and four studies (12,995 patients) eligible for meta-analysis for abdominal aortic aneurysm related mortality (ARM). The estimated average non-compliance rate was 42.0% (95% confidence interval [CI] 28-56%). Although there is some evidence that non-compliant patients have better survival rates, there was no statistically significant difference in all cause mortality rates (year 1: odds ratio [OR] 5.77, 95% CI 0.74-45.14; year 3: OR 2.28, 95% CI 0.92-5.66; year 5: OR 1.81, 95% CI 0.88-3.74) and ARM (OR 1.47, 95% CI 0.99-2.19) between compliant and non-compliant patients in the first 5 years after EVAR. The re-intervention rate was statistically significantly higher in compliant patients from 3 to 5 years after EVAR (year 1: OR 6.36, 95% CI 0.23-172.73; year 3: OR 3.94, 85% CI 1.46-10.69; year 5: OR 5.34, 95% CI 1.87-15.29)., Conclusion: This systematic review and meta-analysis suggests that patients compliant with EVAR surveillance programmes may have an increased re-intervention rate but do not appear to have better survival rates than non-compliant patients., (Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background & Aims: The risk of hepatocellular carcinoma (HCC) occurrence or recurrence following direct-acting antiviral (DAA) hepatitis C virus (HCV) therapy remains unclear. The aims of this study were to compare the rate of HCC occurrence in patients with HCV-related cirrhosis, following DAA vs. interferon (IFN)-based cure, and to compare the rate of HCC recurrence in patients who received curative HCC treatment, following DAA vs. IFN-based cure., Methods: A search was conducted for reports published between January 2000 and February 2017. Studies were included if they assessed HCC outcomes by type and response to HCV therapy. Random-effects meta-analyses were undertaken to determine a combined estimate of HCC incidence rate per 100/person-years (py) among patients with a sustained virological response (SVR)., Results: A total of 41 studies (n=13,875 patients), including 26 on HCC occurrence (IFN=17, DAA=9; prospective=19, retrospective=5, retrospective-prospective=2), and 17 on HCC recurrence (IFN=7, DAA=10; prospective=11, retrospective=5 and retrospective-prospective=1) were included. In studies assessing HCC occurrence, average follow-up was shorter (1.0 vs. 5.5years), and average age older (60 vs. 52years) in DAA studies. In studies assessing HCC recurrence, average follow-up was shorter (1.3 vs. 5.0years), but average age similar (64 vs. 66years) in DAA studies. HCC occurrence was 1.14/100 py (95% CI 0.86-1.52) and 2.96/100 py (95% CI 1.76-4.96) in IFN and DAA studies respectively. HCC recurrence was 9.21/100 py (95% CI 7.18-11.81) and 12.16/100 py (95% CI 5.00-29.58) in IFN and DAA studies respectively. In meta-regression adjusting for study follow-up and age, DAA therapy was not associated with higher HCC occurrence (RR 0.68; 95% CI 0.18-2.55; p=0.55) or recurrence (RR 0.62, 95% CI 0.11-3.45, p=0.56)., Conclusion: There is no evidence for differential HCC occurrence or recurrence risk following SVR from DAA and IFN-based therapy., Lay Summary: The risk of hepatocellular carcinoma (HCC) occurrence or recurrence following direct-acting antiviral (DAA) hepatitis C virus (HCV) therapy remains unclear. We conducted a meta-analysis to compare occurrence and recurrence of HCC in patients receiving either DAA or interferon (IFN) therapy. There is no evidence that HCC occurrence or recurrence is different between patients receiving DAA or IFN therapy., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Understanding the extent to which vascular disease and its risk factors are associated with prodromal dementia, notably Alzheimer's disease (AD), may enhance predictive accuracy as well as guide early interventions. One promising avenue to determine this relationship consists of looking for reliable and sensitive in-vivo imaging methods capable of characterizing the subtle brain alterations before the clinical manifestations. However, little is known from the imaging perspective about how risk factors such as vascular disease influence AD progression. Here, for the first time, we apply an innovative T1 and DTI fusion analysis of 3D corpus callosum (CC) on mild cognitive impairment (MCI) populations with different levels of vascular profile, aiming to de-couple the vascular factor in the prodromal AD stage. Our new fusion method successfully increases the detection power for differentiating MCI subjects with high from low vascular risk profiles, as well as from healthy controls. MCI subjects with high and low vascular risk profiles showed differed alteration patterns in the anterior CC, which may help to elucidate the inter-wired relationship between MCI and vascular risk factors.

A shared genetic susceptibility between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) has been suggested. We investigated this by assessing the contribution of rare variants in genes involved in CMM to PD risk. We studied rare variation across 29 CMM risk genes using high-quality genotype data in 6875 PD cases and 6065 controls and sought to replicate findings using whole-exome sequencing data from a second independent cohort totaling 1255 PD cases and 473 controls. No statistically significant enrichment of rare variants across all genes, per gene, or for any individual variant was detected in either cohort. There were nonsignificant trends toward different carrier frequencies between PD cases and controls, under different inheritance models, in the following CMM risk genes: BAP1, DCC, ERBB4, KIT, MAPK2, MITF, PTEN, and TP53. The very rare TYR p.V275F variant, which is a pathogenic allele for recessive albinism, was more common in PD cases than controls in 3 independent cohorts. Tyrosinase, encoded by TYR, is the rate-limiting enzyme for the production of neuromelanin, and has a role in the production of dopamine. These results suggest a possible role for another gene in the dopamine-biosynthetic pathway in susceptibility to neurodegenerative Parkinsonism, but further studies in larger PD cohorts are needed to accurately determine the role of these genes/variants in disease pathogenesis., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background & Aims: This study evaluates trends in hepatocellular carcinoma (HCC) among people with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection in New South Wales (NSW), Australia between 2000 and 2014., Methods: Data on HBV and HCV notifications between January 1993 and December 2012 were linked to the NSW Admitted Patients Data Collection database between July 2000 and June 2014 and NSW Registry of Births Deaths and Marriages. The burden, crude and age-standardised incidence of HCC based on first hospitalization were calculated., Results: In NSW between 2000-2014, there were 54,399, 93,099 and 3,809 individuals notified with HBV, HCV and HBV/HCV coinfection respectively. There were 725 (1.3%) with HCC among those with HBV notification as compared to 1,309 with HCC (1.4%) in those with HCV notification. The population-level burden of new HCC cases per year has stabilised in the HBV cohort (53 in 2001 and 44 in 2013), but increased markedly in the HCV cohort (49 in 2001 to 151 in 2013). The age-standardised incidence rates of HCC (per 1,000 person-years) declined from 2.3 (95% confidence interval (CI) 1.4, 3.1) in 2001 to 0.9 (95% CI 0.6, 1.2) in 2012 among those with HBV and remained stable between 2001 (1.4; 95% CI 0.8, 1.9) and 2012 (1.5; 95% CI 1.2, 1.7) in those with HCV. Main factors associated with HCC in those with HBV included later study period (2005-2009; 2010-2014) (hazard ratio (HR)=0.54, 95% CI 0.42, 0.70), male gender (HR=4.50, 95% CI 3.6, 5.6), Asia-Pacific country of birth (HR=3.84, 95% CI 2.58, 5.71) and alcohol dependency (HR=2.84, 95% CI 1.95, 4.13). Main factors associated with HCC in those with HCV included male gender (HR=2.56, 95% CI 2.20, 2.98), rural place of residence (HR=0.73, 95% CI 0.62, 0.86), Asia-Pacific country of birth (HR=2.37, 95% CI 1.99, 2.82) and alcohol dependency (HR=3.90, 95% CI 3.39, 4.49)., Conclusions: Individual-level risk of HBV-related HCC has declined, suggesting an impact of more effective antiviral therapy from mid-2000s. In contrast, the interferon-containing HCV treatment era had no impact on individual-level HCV-related HCC risk and has seen escalating population-level HCC burden., Lay Summary: Individual-level risk of HBV-related HCC has declined, suggesting an impact of more effective antiviral therapy from mid-2000s. In contrast, the interferon-containing HCV treatment era had no impact on individual-level HCV-related HCC risk and has seen escalating population-level HCC burden., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

This Review is intended to help clinicians, patients, and the public make informed decisions about statin therapy for the prevention of heart attacks and strokes. It explains how the evidence that is available from randomised controlled trials yields reliable information about both the efficacy and safety of statin therapy. In addition, it discusses how claims that statins commonly cause adverse effects reflect a failure to recognise the limitations of other sources of evidence about the effects of treatment. Large-scale evidence from randomised trials shows that statin therapy reduces the risk of major vascular events (ie, coronary deaths or myocardial infarctions, strokes, and coronary revascularisation procedures) by about one-quarter for each mmol/L reduction in LDL cholesterol during each year (after the first) that it continues to be taken. The absolute benefits of statin therapy depend on an individual's absolute risk of occlusive vascular events and the absolute reduction in LDL cholesterol that is achieved. For example, lowering LDL cholesterol by 2 mmol/L (77 mg/dL) with an effective low-cost statin regimen (eg, atorvastatin 40 mg daily, costing about £2 per month) for 5 years in 10 000 patients would typically prevent major vascular events from occurring in about 1000 patients (ie, 10% absolute benefit) with pre-existing occlusive vascular disease (secondary prevention) and in 500 patients (ie, 5% absolute benefit) who are at increased risk but have not yet had a vascular event (primary prevention). Statin therapy has been shown to reduce vascular disease risk during each year it continues to be taken, so larger absolute benefits would accrue with more prolonged therapy, and these benefits persist long term. The only serious adverse events that have been shown to be caused by long-term statin therapy-ie, adverse effects of the statin-are myopathy (defined as muscle pain or weakness combined with large increases in blood concentrations of creatine kinase), new-onset diabetes mellitus, and, probably, haemorrhagic stroke. Typically, treatment of 10 000 patients for 5 years with an effective regimen (eg, atorvastatin 40 mg daily) would cause about 5 cases of myopathy (one of which might progress, if the statin therapy is not stopped, to the more severe condition of rhabdomyolysis), 50-100 new cases of diabetes, and 5-10 haemorrhagic strokes. However, any adverse impact of these side-effects on major vascular events has already been taken into account in the estimates of the absolute benefits. Statin therapy may cause symptomatic adverse events (eg, muscle pain or weakness) in up to about 50-100 patients (ie, 0·5-1·0% absolute harm) per 10 000 treated for 5 years. However, placebo-controlled randomised trials have shown definitively that almost all of the symptomatic adverse events that are attributed to statin therapy in routine practice are not actually caused by it (ie, they represent misattribution). The large-scale evidence available from randomised trials also indicates that it is unlikely that large absolute excesses in other serious adverse events still await discovery. Consequently, any further findings that emerge about the effects of statin therapy would not be expected to alter materially the balance of benefits and harms. It is, therefore, of concern that exaggerated claims about side-effect rates with statin therapy may be responsible for its under-use among individuals at increased risk of cardiovascular events. For, whereas the rare cases of myopathy and any muscle-related symptoms that are attributed to statin therapy generally resolve rapidly when treatment is stopped, the heart attacks or strokes that may occur if statin therapy is stopped unnecessarily can be devastating., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Central neurocytomas comprise nearly half of adult intraventricular neoplasms. The median age of onset is 34 years. It is typically a low-grade neoplasm (World Health Organization grade II), although some cases of malignant neurocytomas have been described. We present a rare case of an atypical central neurocytoma with craniospinal dissemination, including both imaging and pathologic findings., (Published by Elsevier Inc.)

Purpose: To develop and evaluate a novel 3D Cartesian sampling scheme which is well suited for time-resolved 3D MRI using parallel imaging and compressed sensing., Methods: The proposed sampling scheme, termed GOlden-angle CArtesian Randomized Time-resolved (GOCART) 3D MRI, is based on golden angle (GA) Cartesian sampling, with random sampling of the ky-kz phase encode locations along each Cartesian radial spoke. This method was evaluated in conjunction with constrained reconstruction of retrospectively and prospectively undersampled in-vivo dynamic contrast enhanced (DCE) MRI data and simulated phantom data., Results: In in-vivo retrospective studies and phantom simulations, images reconstructed from phase encodes defined by GOCART were equal to or superior to those with Poisson disc or GA sampling schemes. Typical GOCART sampling tables were generated in <100ms. GOCART has also been successfully utilized prospectively to produce clinically valuable whole-brain DCE-MRI images., Conclusion: GOCART is a practical and efficient sampling scheme for time-resolved 3D MRI. It shows great potential for highly accelerated DCE-MRI and is well suited to modern reconstruction methods such as parallel imaging and compressed sensing., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: In multisite human immunodeficiency virus (HIV) observational cohorts, clustering of observations often occurs within sites. Ignoring clustering may lead to "Simpson's paradox" (SP) where the trend observed in the aggregated data is reversed when the groups are separated. This study aimed to investigate the SP in an Asian HIV cohort and the effects of site-level adjustment through various Cox regression models., Study Design and Setting: Survival time from combination antiretroviral therapy (cART) initiation was analyzed using four Cox models: (1) no site adjustment; (2) site as a fixed effect; (3) stratification through site; and (4) shared frailty on site., Results: A total of 6,454 patients were included from 23 sites in Asia. SP was evident in the year of cART initiation variable. Model (1) shows the hazard ratio (HR) for years 2010-2014 was higher than the HR for 2006-2009, compared to 2003-2005 (HR = 0.68 vs. 0.61). Models (2)-(4) consistently implied greater improvement in survival for those who initiated in 2010-2014 than 2006-2009 contrasting findings from model (1). The effects of other significant covariates on survival were similar across four models., Conclusions: Ignoring site can lead to SP causing reversal of treatment effects. Greater emphasis should be made to include site in survival models when possible., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Hepatitis C virus (HCV) is a positive-strand RNA virus within the Flaviviridae family. The viral "spike" of HCV is formed by two envelope glycoproteins, E1 and E2, which together mediate viral entry by engaging host receptors and undergoing conformational changes to facilitate membrane fusion. While E2 can be readily produced in the absence of E1, E1 cannot be expressed without E2 and few reagents, including monoclonal antibodies (mAbs), are available for study of this essential HCV glycoprotein. A human mAb to E1, IGH526, was previously reported to cross-neutralize different HCV isolates, and therefore, we sought to further characterize the IGH526 neutralizing epitope to obtain information for vaccine design. We found that mAb IGH526 bound to a discontinuous epitope, but with a major component corresponding to E1 residues 314-324. The crystal structure of IGH526 Fab with this E1 glycopeptide at 1.75Å resolution revealed that the antibody binds to one face of an α-helical peptide. Single mutations on the helix substantially lowered IGH526 binding but did not affect neutralization, indicating either that multiple mutations are required or that additional regions are recognized by the antibody in the context of the membrane-associated envelope oligomer. Molecular dynamics simulations indicate that the free peptide is flexible in solution, suggesting that it requires stabilization for use as a candidate vaccine immunogen., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Hepatitis C virus infects nearly 3% of the world's population and is often referred as a silent epidemic. It is a leading cause of liver cirrhosis and hepatocellular carcinoma in endemic countries. Although antiviral drugs are now available, they are not readily accessible to marginalized social groups and developing nations that are disproportionally impacted by HCV. To stop the HCV pandemic, a vaccine is needed. Recent advances in HCV research have provided new opportunities for studying HCV neutralizing antibodies and their subsequent use for rational vaccine design. It is now recognized that neutralizing antibodies to conserved antigenic sites of the virus can cross-neutralize diverse HCV genotypes and protect against infection in vivo. Structural characterization of the neutralizing epitopes has provided valuable information for design of candidate immunogens., (Copyright © 2015 Elsevier B.V. All rights reserved.)