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This work proposes a modelling framework to analyse flow and pressure distributions throughout the lung of mechanically ventilated COVID-19 patients. The methodology involves: segmentation of the lungs and major airways from patient CT images; a volume filling algorithm that creates a dichotomous airway network in the remaining volume of the lung; an estimate of resistance and compliance within the lung based on Hounsfield unit values from the CT scan; and a computational fluid dynamics model to analyse flow, lung inflation, and pressure throughout the airway network. Mechanically ventilated patients with differing progression and severity of the disease were simulated. The results indicate that the flow distribution within the lung can be significantly affected when there are competing types of lung damage. These competing types are primarily fibrosis-like lung damage that creates higher resistance and lower compliance in that region; and emphysema, which causes a decrease in resistance and increase in compliance. In a patient with severe disease, the model predicted an increase in inflation by 33% in an area affected by emphysema-like conditions. This could increase the risk of alveolar rupture. The framework could readily be adapted to study other respiratory diseases. Early interventions in critical respiratory care could be facilitated through such efficient patient-specific modelling approaches., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Computational models can be at the basis of new powerful technologies for studying and classifying disorders like pre-eclampsia, where it is difficult to distinguish pre-eclamptic patients from non-pre-eclamptic based on pressure when patients have a track record of hypertension. Computational models now enable a detailed analysis of how pregnancy affects the cardiovascular system. Therefore, new non-invasive biomarkers were developed that can aid the classification of pre-eclampsia through the integration of six different measured non-invasive cardiovascular signals. Datasets of 21 pregnant women (no early onset pre-eclampsia, n = 12; early onset pre-eclampsia, n = 9) were used to create personalised cardiovascular models through computational modelling resulting in predictions of blood pressure and flow waveforms in all major and minor vessels of the utero-ovarian system. The analysis performed revealed that the new predictors PPI (pressure pulsatility index) and RI (resistance index) calculated in arcuate and radial/spiral arteries are able to differentiate between the 2 groups of women (t-test scores of p < .001) better than PI (pulsatility index) and RI (Doppler calculated in the uterine artery) for both supervised and unsupervised classification. In conclusion, two novel high-performing biomarkers for the classification of pre-eclampsia have been identified based on blood velocity and pressure predictions in the smaller placental vasculatures where non-invasive measurements are not feasible., (© 2024. The Author(s).)

Background: Historically, hepatitis C virus (HCV) was difficult to treat among people with HIV. However, treatment with direct-acting antivirals (DAAs) results in 90%-95% of people being cured. There is a need to understand why a proportion of people are not cured. We aimed to examine characteristics that may indicate an increased probability of unsuccessful DAA HCV treatment., Methods: Data were from the International Collaboration on Hepatitis C Elimination in HIV Cohorts. People who commenced DAA HCV treatment between 2014 and 2019 were included. Unsuccessful treatment was defined as a positive HCV RNA test at a person's first RNA test at least 4 weeks (SVR4+) following the end of treatment. Multivariable mixed-effects logistic regression was used to examine characteristics associated with unsuccessful treatment., Results: Of 4468 people who commenced DAA treatment, 4098 (91.7%) had an SVR test 4+ weeks following the end of treatment, 207 (5%) of whom were unsuccessfully treated. Compared to a CD4+ cell count > 500 cells/mm 3 , cell counts < 200 (aOR 1.81, 95%CI 1.00-3.29) and between 200 and 349 (aOR 1.95, 95%CI 1.30-2.93) were associated with increased odds of unsuccessful treatment. Among 1921 people with data on injection drug use in the 12 months prior to treatment, there was some evidence that recent injection drug use was associated with increased odds of unsuccessful treatment; however, this was not statistically significant (aOR 1.67, 95%CI 0.99-2.82)., Conclusions: The overwhelming majority of people were successfully treated for HCV. Overall, 5% of those with an SVR4+ test were unsuccessfully treated; this was more likely among people with evidence of immunodeficiency and those who reported recently injecting drugs., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

People in prison are at high risk of HCV given high injecting drug use prevalence. This study evaluated HCV incidence and associated injecting drug use characteristics in prison. The SToP-C study enrolled people incarcerated in four Australian prisons. Participants were tested for HCV at enrolment and then every 3-6 months (October-2014 to November-2019). Participants eligible for this analysis included those at-risk of HCV primary infection (anti-HCV negative) or re-infection (anti-HCV positive, HCV RNA negative) with follow-up assessment. A total of 1643 eligible participants were included in analyses (82% male; median age 33 years; 30% injected drugs in prison; 1818 person-years of follow-up). Overall HCV incidence was 6.11/100 person-years (95%CI: 5.07-7.35), with higher rate of re-infection (9.34/100 person-years; 95%CI: 7.15-12.19) than primary infection (4.60/100 person-years; 95%CI: 3.56-5.96). In total population (n = 1643), HCV risk was significantly higher among participants injecting drugs in prison [vs. no injecting; adjusted hazard ratio (aHR): 10.55, 95%CI: 5.88-18.92), and those who were released and re-incarcerated during follow-up (vs. remained incarcerated; aHR: 1.60, 95%CI: 1.03-2.49). Among participants who injected recently (during past month, n = 321), HCV risk was reduced among those receiving high-dosage opioid agonist therapy (OAT), i.e. methadone ≥60 mg/day or buprenorphine ≥16 mg/day, (vs. no OAT, aHR: 0.11, 95%CI: 0.02-0.80) and increased among those sharing needles/syringes without consistent use of disinfectant to clean injecting equipment (vs. no sharing, HR: 4.60, 95%CI: 1.35-15.66). This study demonstrated high HCV transmission risk in prison, particularly among people injecting drugs. High-dosage OAT was protective, but improved OAT coverage and needle/syringe programmes to reduce sharing injecting equipment are required., (© 2023 The Authors. Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

We assessed the predictive capacity of the HCV-MOSAIC risk score, originally developed for primary early HCV infection, as a screening tool for HCV reinfection in 103 men who have sex with men (MSM) with HIV using data from the MOSAIC cohort, including MSM with HIV/HCV-coinfection who became reinfected (cases, n = 27) or not (controls, n = 76) during follow-up. The overall predictive capacity of the score was assessed using the area under the receiver operating characteristic (AUROC) curve. The effects of covariates on the receiver operating characteristic (ROC) curve were assessed using parametric ROC regression. The score cut-off validated for primary early infection (≥2.0) was used, from which the sensitivity and specificity were calculated. The AUROC was 0.74 (95% confidence interval (CI) = 0.63-0.84). Group sex significantly increased the predictive capacity. Using the validated cut-off, sensitivity was 70.4% (95%CI = 49.8-86.2%) and specificity was 59.2% (95%CI: 47.3-70.4%). External validation from a cohort of 25 cases and 111 controls, all MSM with HIV, resulted in a sensitivity of 44.0% (95%CI = 24.4-65.1) and specificity of 71.2% (95%CI = 61.8-79.4). The HCV-MOSAIC risk score may be useful for identifying individuals at risk of HCV reinfection. In sexual health or HIV-care settings, this score could help guide HCV-RNA testing in MSM with a prior HCV infection.

Introduction: Supine sleep position is associated with stillbirth, likely secondary to inferior vena cava compression, and a reduction in cardiac output (CO) and uteroplacental perfusion. Evidence for the effects of prone position in pregnancy is less clear. This study aimed to determine the effect maternal prone position on maternal haemodynamics and fetal heart rate, compared with left lateral position., Methods: Twenty-one women >28 weeks' gestation underwent non-invasive CO monitoring (Cheetah) every 5 minutes and continuous fetal heart rate monitoring (MONICA) in left lateral (20 minutes), prone (30 minutes), followed by left lateral (20 minutes). Anxiety and comfort were assessed by questionnaires. Regression analyses (adjusted for time) compared variables between positions. The information derived from the primary study was used in an existing mathematical model of maternal circulation in pregnancy, to determine whether occlusion of the inferior vena cava could account for the observed effects. In addition, a scoping review was performed to identify reported clinical, haemodynamic and fetal effects of maternal prone position; studies were included if they reported clinical outcomes or effects or maternal prone position in pregnancy. Study records were grouped by publication type for ease of data synthesis and critical analysis. Meta-analysis was performed where there were sufficient studies., Results: Maternal blood pressure (BP) and total vascular resistance (TVR) were increased in prone (sBP 109 vs 104 mmHg, p = 0.03; dBP 74 vs 67 mmHg, p = 0.003; TVR 1302 vs 1075 dyne.s-1cm-5, p = 0.03). CO was reduced in prone (5.7 vs 7.1 mL/minute, p = 0.003). Fetal heart rate, variability and decelerations were unaltered. However, fetal accelerations were less common in prone position (86% vs 95%, p = 0.03). Anxiety was reduced after the procedure, compared to beforehand (p = 0.002), despite a marginal decline in comfort (p = 0.04).The model predicted that if occlusion of the inferior vena cava occurred, the sBP, dBP and CO would generally decrease. However, the TVR remained relatively consistent, which implies that the MAP and CO decrease at a similar rate when occlusion occurs. The scoping review found that maternal and fetal outcomes from 47 included case reports of prone positioning during pregnancy were generally favourable. Meta-analysis of three prospective studies investigating maternal haemodynamic effects of prone position found an increase in sBP and maternal heart rate, but no effect on respiratory rate, oxygen saturation or baseline fetal heart rate (though there was significant heterogeneity between studies)., Conclusion: Prone position was associated with a reduction in CO but an uncertain effect on fetal wellbeing. The decline in CO may be due to caval compression, as supported by the computational model. Further work is needed to optimise the safety of prone positioning in pregnancy., Trial Registration: This trial was registered at clinicaltrials.gov (NCT04586283)., Competing Interests: Karli Buchling is the inventor of the Anna Cushion and is the Founder of Natal Comfort who market the cushion. She applied for the research funding with Professor Heazell, but had no part in the conduct of the experiments or analysis of the data. This does not alter our adherence to PLoS One policies on sharing data and materials., (Copyright: © 2023 Ormesher et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Reinfection poses a challenge to hepatitis C virus (HCV) elimination. This analysis assessed incidence of, and factors associated with reinfection among people treated for recent HCV (duration of infection <12 months)., Methods: Participants treated for recent HCV (primary infection or reinfection) in an international randomized trial were followed at 3-monthly intervals for up to 2 years to assess for reinfection. Reinfection incidence was calculated using person-time of observation. Factors associated with HCV reinfection were assessed using Cox proportional hazards regression analysis., Results: Of 222 participants treated for recent HCV, 196 (62% primary infection, 38% reinfection) were included in the cohort at risk for reinfection, of whom 87% identified as gay or bisexual men, 71% had HIV and 20% injected drugs in the month prior to enrolment. During 198 person-years of follow-up, 28 cases of HCV reinfection were identified among 27 participants, for an incidence of 14.2 per 100 person-years [95% confidence interval (CI) 9.8-20.5]. Reinfection was associated with prior HCV reinfection [adjusted hazards ratio (aHR) 2.42; 95% CI 1.08-5.38], injection drug use posttreatment (aHR 2.53; 95% CI 1.14-5.59), condomless anal intercourse with casual male partners (aHR 3.32; 95% CI 1.14-9.65) and geographic region (United Kingdom, aHR 0.21; 95% CI 0.06-0.75). Among gay and bisexual men (GBM), reinfection was also associated with sexualized drug use involving injecting posttreatment (aHR 2.97; 95% CI 1.10-8.02)., Conclusion: High reinfection incidence following treatment for recent HCV among people with ongoing sexual and drug use risk behaviour highlights the need for posttreatment surveillance, rapid retreatment of reinfection and targeted harm reduction strategies., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Exploration of sexual and drug use behaviours following treatment for recent hepatitis C virus (HCV) is limited. This analysis modelled behavioural trajectories following treatment for recent HCV and assessed reinfection., Methods: Participants treated for recent HCV in an international trial (enrolled 2017-2019) were followed at 3-monthly intervals for up to 2 years to assess longitudinal behaviours. Population-averaged changes were assessed using generalized estimating equations. Distinct behavioural trajectories were identified using group-based trajectory modelling. HCV reinfection incidence was calculated using person-years (PY) of observation., Results: During the follow-up of 212 participants (84% gay and bisexual men [GBM]; 69% HIV; 26% current injecting drug use [IDU]), behavioural trajectories for IDU and stimulant use (past month) did not change. However, population-averaged decreases in the likelihood of daily IDU (adjusted odds ratio [AOR] 0.83; 95% CI 0.72, 0.95) and opioid use (AOR 0.84; 95% CI 0.75, 0.93) were observed. Among GBM, behavioural trajectories for chemsex did not change. Population-averaged decreases in condomless anal intercourse with casual male partners (CAI-CMP) (AOR 0.95; 95% CI 0.90, 0.99) and group-sex (AOR 0.86; 95% CI 0.80, 0.93) were observed, but masked distinct trajectories. While a proportion had a decreased probability of CAI-CMP (23%) and group-sex (59%) post-treatment, a substantial proportion retained a high probability of these behaviours. High HCV reinfection incidence was observed for the sustained high probability IDU (33.0/100 PY; 95% CI 17.7, 61.3) and chemsex (23.3/100 PY; 95% CI 14.5, 37.5) trajectories., Conclusions: Limited sexual and drug use behavioural change was observed following treatment for recent HCV, supporting access to surveillance and (re)treatment., (© 2023 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Background: People experiencing homelessness are disproportionately affected by hepatitis C virus (HCV) infection compared with housed populations. Surveillance for HCV reinfection after successful treatment is a critical step in the care cascade, but limited data on reinfection are available among this highly marginalized group. This study assessed posttreatment reinfection risk in a real-world cohort of homeless-experienced individuals in Boston., Methods: Individuals receiving HCV direct-acting antiviral treatment through Boston Health Care for the Homeless Program during 2014-2020 with posttreatment follow-up assessment were included. Reinfection was identified based on recurrent HCV RNA at 12 weeks posttreatment with HCV genotype switch or any recurrent HCV RNA following sustain virologic response., Results: A total of 535 individuals were included (81% male, median age 49 years, 70% unstably housed or homeless at treatment initiation). Seventy-four HCV reinfections were detected, including 5 second reinfections. HCV reinfection rate was 12.0/100 person-years (95% confidence interval [CI]: 9.5-15.1) overall, 18.9/100 person-years (95% CI: 13.3-26.7) among individuals with unstable housing and 14.6/100 person-years (95% CI: 10.0-21.3) among those experiencing homelessness. In adjusted analysis, experiencing homelessness (vs stable housing, adjusted hazard ratio, 2.14; 95% CI: 1.09-4.20; P = .026) and drug use within 6 months before treatment (adjusted hazard ratio, 5.23; 95% CI: 2.25-12.13; P < .001) were associated with increased reinfection risk., Conclusions: We found high HCV reinfection rates in a homeless-experienced population, with increased risk among those homeless at treatment. Tailored strategies to address the individual and systems factors impacting marginalized populations are required to prevent HCV reinfection and to enhance engagement in posttreatment HCV care., Competing Interests: Potential conflicts of interest . M. E. B., S. K. S., and L. C. S. report payment or honoraria received from New England AIDS Education and Training Center. M. E. B. also reports an unpaid position on the Steering Committee for EndHepCMA. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background & Aims: Population-level uptake of direct-acting antiviral (DAA) treatment for hepatitis C virus (HCV) infection, including retreatment, can be estimated through administrative pharmaceutical dispensation data. However, the reasons for retreatment are not captured in these data. We developed a machine learning model to classify retreatments as reinfection or treatment failure at a national level., Methods: Retreatment data from the REACH-C cohort (n = 10,843 treated with DAAs; n = 320 retreatments with known reason), were used to train a random forest model. Nested cross validation was undertaken to assess model performance and to optimise hyperparameters. The model was applied to data on DAA retreatment dispensed during 2016-2021 in Australia, to identify the reason for retreatment (treatment failure or reinfection)., Results: Average predictive accuracy, precision, sensitivity, specificity and F 1 -score for the model were 96.3%, 96.5%, 96.3%, 96.3% and 96.3%, respectively. Nationally, 95,272 individuals initiated DAAs, with treatment uptake declining from 32,454 in 2016 to 6,566 in 2021. Of those treated, 6,980 (7%) were retreated. Our model classified 51.8% (95% CI 46.7-53.6%; n = 3,614) of cases as reinfection and 48.2% (95% CI 46.4-53.3%; n = 3,366) as treatment failure. Retreatment for reinfection increased steadily over the study period from 14 in 2016 to 1,092 in 2020, stabilising in 2021. Retreatment for treatment failure increased from 73 in 2016 to 1,077 in 2019, then declined to 515 in 2021. Among individuals retreated for treatment failure, 50% had discontinued initial treatment., Conclusions: We used a novel methodology with high classification accuracy to evaluate DAA retreatment patterns at a national level. Increases in retreatment uptake for treatment failure corresponded to the availability of pangenotypic and salvage regimens. Increasing retreatment uptake for reinfection likely reflects increasing reinfection incidence., Impact and Implications: This study used machine learning methodologies to analyse national administrative data and characterise trends in HCV retreatment due to reinfection and treatment failure. Retreatment for reinfection increased over time, reflecting increasing numbers of people at risk for reinfection following HCV cure. Increased retreatment for treatment failure corresponded to the availability of pangenotypic and salvage DAA regimens. The findings of this study can be used by public health agencies and policy makers to guide and assess HCV elimination strategies, while the novel methodology for monitoring trends in HCV retreatment has the potential to be used in other settings, and health conditions., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Injection drug use (IDU) following treatment for hepatitis C virus (HCV) infection may lead to reinfection, particularly if access to harm reduction services is suboptimal. This study assessed HCV reinfection risk following direct-acting antiviral therapy within Australian prisons that had opioid agonist therapy (OAT) programs but did not have needle and syringe programs (NSPs)., Methods: The Surveillance and Treatment of Prisoners With Hepatitis C (SToP-C) study enrolled people incarcerated in 4 prisons between 2014 and 2019. Participants treated for HCV were followed every 3-6 months to identify reinfection (confirmed by sequencing). Reinfection incidence and associated factors were evaluated., Results: Among 388 participants receiving treatment, 161 had available posttreatment follow-up and were included in analysis (92% male; median age, 33 years; 67% IDU in prison; median follow-up 9 months). Among those with recent (in the past month) IDU (n = 71), 90% had receptive needle/syringe sharing. During 145 person-years (PY) of follow-up, 18 cases of reinfection were identified. Reinfection incidence was 12.5/100 PY (95% confidence interval [CI]: 7.9-19.8) overall, increasing to 28.7/100 PY (95% CI: 16.3-50.6) among those with recent IDU and needle/syringe sharing. In adjusted analysis, recent IDU with needle/syringe sharing was associated with increased reinfection risk (adjusted hazard ratio [aHR], 4.74 [95% CI: 1.33-16.80]; P = .016) and longer HCV testing interval with decreased risk (ie, chance of detection; aHR, 0.41 per each month increase [95% CI: .26-.64]; P < .001)., Conclusions: A high rate of HCV reinfection was observed within prison. Posttreatment surveillance and retreatment are -essential to limit the impact of reinfection. High-coverage OAT and NSPs should be considered within prisons., Clinical Trials Registration: NCT02064049., Competing Interests: Potential conflicts of interest. A. R. L. and G. J. D. were supported by NHMRC Practitioner Fellowships. J. G. was supported by an NHMRC Investigator Grant. E. C. is supported by a postdoctoral fellowship from the Canadian Network on Hepatitis C. P. V. acknowledges support from the US National Institute on Drug Abuse (NIDA; grant numbers R01AI147490, R01DA033679, R01DA037773, R21DA046809, and R01DA047952); the National Institute for Health Research (NIHR) Health Protection Research Unit in Evaluation of Interventions and Behavioral Science at the University of Bristol; and the NIHR-funded EPIToPe project. N. K. M. acknowledges support from the US National Institute of Allergy and Infectious Diseases and NIDA (grant number R01AI147490), and the University of California, San Diego Center for AIDS Research, a program funded by the US National Institutes of Health (grant number P30 AI036214). C. T. reports research funds, unrelated to this project, paid to the institution from Merck, and speaker’s fees from AbbVie and Gilead. G. J. D. reports research grants outside the submitted work from AbbVie, Gilead Sciences, and Merck. G. V. M. reports research grants from AbbVie and Gilead, outside the submitted work, and payment or honoraria from Janssen (speaker’s bureau) and AstraZeneca (advisory board). J. G. reports grants or contracts outside the submitted work from AbbVie, Camurus, Cepheid, Hologic, Indivior, and Merck and payment or honoraria from AbbVie, Cepheid, Gilead Sciences, and Merck. N. K. M. reports unrestricted research grants to the university unrelated to this research from Gilead and Merck. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Virological failure occurs in a small proportion of people treated for hepatitis C virus (HCV) with direct-acting antiviral (DAA) therapies. This study assessed retreatment for virological failure in a large real-world cohort. REACH-C is an Australian observational study (n=10843) evaluating treatment outcomes of sequential DAA initiations across 33 health services between March 2016 to June 2019. Virological failure retreatment data were collected until October 2020. Of 408 people with virological failure (81% male; median age 53; 38% cirrhosis; 56% genotype 3), 213 (54%) were retreated once; 15 were retreated twice. A range of genotype specific and pangenotypic DAAs were used to retreat virological failure in primary (n=56) and tertiary (n=157) settings. Following sofosbuvir/velpatasvir/voxilaprevir availability in 2019, the proportion retreated in primary care increased from 21% to 40% and median time to retreatment initiation declined from 294 to 152 days. Per-protocol (PP) sustained virological response (SVR12) was similar for people retreated in primary and tertiary settings (80% vs 81%; p=1.000). In regression analysis, sofosbuvir/velpatasvir/voxilaprevir (vs. other regimens) significantly decreased likelihood of second virological failure (PP SVR12 88% vs. 77%; adjusted odds ratio [AOR] 0.29; 95%CI 0.11-0.81); cirrhosis increased likelihood (PP SVR12 69% vs. 91%; AOR 4.26; 95%CI 1.64-11.09). Indigenous Australians had lower likelihood of retreatment initiation (AOR 0.36; 95%CI 0.15-0.81). Treatment setting and prescriber type were not associated with retreatment initiation or outcome. Virological failure can be effectively retreated in primary care. Expanded access to simplified retreatment regimens through decentralised models may increase retreatment uptake and reduce HCV-related mortality., (This article is protected by copyright. All rights reserved.)

Australia was one of the first countries with unrestricted access to government subsidized direct-acting antiviral (DAA) therapy for adults with chronic hepatitis C virus. This study assessed real-world DAA treatment outcomes across a diverse range of Australian clinical services and evaluated factors associated with successful treatment and loss to follow-up. Real-world Effectiveness of Antiviral therapy in Chronic Hepatitis C (REACH-C) consisted a national observational cohort of 96 clinical services including specialist clinics and less traditional settings such as general practice. Data were obtained on consecutive individuals who commenced DAAs from March 2016 to June 2019. Effectiveness was assessed by sustained virological response ≥12 weeks following treatment (SVR) using intention-to-treat (ITT) and per-protocol (PP) analyses. Within REACH-C, 10,843 individuals initiated DAAs (male 69%; ≥50 years 52%; cirrhosis 22%). SVR data were available in 85% (9,174 of 10,843). SVR was 81% (8,750 of 10,843) by ITT and 95% (8,750 of 9,174) by PP. High SVR (≥92%) was observed across all service types and participant characteristics. Male gender (adjusted odds ratio [aOR] 0.56, 95% confidence interval [CI] 0.43-0.72), cirrhosis (aOR 0.52, 95% CI 0.41-0.64), recent injecting drug use (IDU; aOR 0.64, 95% CI 0.46-0.91) and previous DAA treatment (aOR 0.50, 95% CI 0.28-0.90) decreased the likelihood of achieving SVR. Multiple factors modified the likelihood of loss to follow-up including IDU ± opioid agonist therapy (OAT; IDU only: aOR 1.75, 95% CI 1.44-2.11; IDU + OAT: aOR 1.39, 95% CI 1.11-1.74; OAT only, aOR 1.36; 95% CI 1.13-1.68) and age (aOR 0.97, 95% CI 0.97-0.98). Conclusion: Treatment response was high in a diverse population and through a broad range of services following universal access to DAA therapy. Loss to follow-up presents a real-world challenge. Younger people who inject drugs were more likely to disengage from care, requiring innovative strategies to retain them in follow-up., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Fractional flow reserve (FFR) provides the functional relevance of coronary atheroma. The FFR-guided strategy has been shown to reduce unnecessary stenting, improve overall health outcome, and to be cost-saving. The non-invasive, coronary computerised tomography (CT) angiography-derived FFR (cFFR) is an emerging method in reducing invasive catheter based measurements. This computational fluid dynamics-based method is laborious as it requires expertise in multidisciplinary analysis of combining image analysis and computational mechanics. In this work, we present a rapid method, powered by unsupervised learning, to automatically calculate cFFR from CT scans without manual intervention., (© 2021 The Authors. International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd.)

Background: Direct acting antiviral (DAA) therapy is highly effective for hepatitis C virus (HCV) infection, but reinfection following treatment may compromise benefits of cure. This study assessed the real-world effectiveness of treatment for reinfection., Methods: Real-world effectiveness of antiviral therapy in chronic hepatitis C (REACH-C) is an observational study evaluating treatment outcomes following sequential DAA initiations across 33 health services in Australia between March 2016-June 2019. Reinfection was defined by post-treatment genotype switch or HCV viraemia after sustained virologic response (SVR12)., Results: Of the 10,843 individuals initiating DAA therapy post-treatment viraemia was reported in 526 of whom 99 were reinfections. Treatment for reinfection occurred in 88 individuals. In those with available treatment outcomes, SVR12 was similar to initial treatment in the overall REACH-C cohort (95% vs 95%; p = 0.745) and comparable across primary, tertiary, and prison settings. Classifying unknown treatment outcomes as failures, SVR12 for treatment of reinfection was lower than initial treatment in REACH-C (67% vs 81%; p = 0.002), due to higher lost to follow-up., Conclusions: Treatment of reinfection is highly effective and can be delivered in non-specialist settings. Access to treatment for reinfection in high-risk populations is crucial to HCV elimination., Competing Interests: Declarations of Interest GVM reports grants from Gilead Sciences and grants from AbbVie. GJD reports grants, personal fees, and nonfinancial support from AbbVie, Gilead, Merck, Bristol-Myers Squibb, and Roche; grants and personal fees from Janssen; personal fees and nonfinancial support from Gilead Sciences; and personal fees from GlaxoSmithKline and Abbott Diagnostics. DI reports fees from Gilead, Merck, BMS, and AbbVie. PR reports fees for educational talks from Gilead Sciences, Merck Sharp & Dohme, and AbbVie and is on the advisory board for Merck Sharp & Dohme. AB reports sponsorship from Gilead to participate in online HCV medical educational modules. JDo reports grants to his institution for investigator initiated research and consulting fees from Gilead Sciences, Merck/MSD, AbbVie and Bristol-Myers Squibb. JO reports speaker fees from Gilead and BMS. MM reports grants from Gilead Sciences. JC/JY/BH/JH/JDa/PM report none., (Copyright © 2021. Published by Elsevier B.V.)

We present a novel framework for investigating the role of vascular structure on arterial haemodynamics in large vessels, with a special focus on the human common carotid artery (CCA). The analysis is carried out by adopting a three-dimensional (3D) derived, fibre-reinforced, hyperelastic structural model, which is coupled with an axisymmetric, reduced order model describing blood flow. The vessel transmural pressure and lumen area are related via a Holzapfel-Ogden type of law, and the residual stresses along the thickness and length of the vessel are also accounted for. After a structural characterization of the adopted hyperelastic model, we investigate the link underlying the vascular wall response and blood-flow dynamics by comparing the proposed framework results against a popular tube law. The comparison shows that the behaviour of the model can be captured by the simpler linear surrogate only if a representative value of compliance is applied. Sobol's multi-variable sensitivity analysis is then carried out in order to identify the extent to which the structural parameters have an impact on the CCA haemodynamics. In this case, the local pulse wave velocity (PWV) is used as index for representing the arterial transmission capacity of blood pressure waveforms. The sensitivity analysis suggests that some geometrical factors, such as the stress-free inner radius and opening angle, play a major role on the system's haemodynamics. Subsequently, we quantified the differences in haemodynamic variables obtained from different virtual CCAs, tube laws and flow conditions. Although each artery presents a distinct vascular response, the differences obtained across different flow regimes are not significant. As expected, the linear tube law is unable to accurately capture all the haemodynamic features characterizing the current model. The findings from the sensitivity analysis are further confirmed by investigating the axial stretching effect on the CCA fluid dynamics. This factor does not seem to alter the pressure and flow waveforms. On the contrary, it is shown that, for an axially stretched vessel, the vascular wall exhibits an attenuation in absolute distension and an increase in circumferential stress, corroborating the findings of previous studies. This analysis shows that the new model offers a good balance between computational complexity and physics captured, making it an ideal framework for studies aiming to investigate the profound link between vascular mechanobiology and blood flow., (© 2021. The Author(s).)

Comprehensive and spatially mapped molecular atlases of organs at a cellular level are a critical resource to gain insights into pathogenic mechanisms and personalized therapies for diseases. The Kidney Precision Medicine Project (KPMP) is an endeavor to generate three-dimensional (3-D) molecular atlases of healthy and diseased kidney biopsies by using multiple state-of-the-art omics and imaging technologies across several institutions. Obtaining rigorous and reproducible results from disparate methods and at different sites to interrogate biomolecules at a single-cell level or in 3-D space is a significant challenge that can be a futile exercise if not well controlled. We describe a "follow the tissue" pipeline for generating a reliable and authentic single-cell/region 3-D molecular atlas of human adult kidney. Our approach emphasizes quality assurance, quality control, validation, and harmonization across different omics and imaging technologies from sample procurement, processing, storage, shipping to data generation, analysis, and sharing. We established benchmarks for quality control, rigor, reproducibility, and feasibility across multiple technologies through a pilot experiment using common source tissue that was processed and analyzed at different institutions and different technologies. A peer review system was established to critically review quality control measures and the reproducibility of data generated by each technology before their being approved to interrogate clinical biopsy specimens. The process established economizes the use of valuable biopsy tissue for multiomics and imaging analysis with stringent quality control to ensure rigor and reproducibility of results and serves as a model for precision medicine projects across laboratories, institutions and consortia.

Fractional flow reserve is the current reference standard in the assessment of the functional impact of a stenosis in coronary heart disease. In this study, three models of artificial intelligence of varying degrees of complexity were compared to fractional flow reserve measurements. The three models are the multivariate polynomial regression, which is a statistical method used primarily for correlation; the feed-forward neural network; and the long short-term memory, which is a type of recurrent neural network that is suited to modelling sequences. The models were initially trained using a virtual patient database that was generated from a validated one-dimensional physics-based model. The feed-forward neural network performed the best for all test cases considered, which were a single vessel case from a virtual patient database, a multi-vessel network from a virtual patient database, and 25 clinically invasive fractional flow reserve measurements from real patients. The feed-forward neural network model achieved around 99% diagnostic accuracy in both tests involving virtual patients, and a respectable 72% diagnostic accuracy when compared to the invasive fractional flow reserve measurements. The multivariate polynomial regression model performed well in the single vessel case, but struggled on network cases as the variation of input features was much larger. The long short-term memory performed well for the single vessel cases, but tended to have a bias towards a positive fractional flow reserve prediction for the virtual multi-vessel case, and for the patient cases. Overall, the feed-forward neural network shows promise in successfully predicting fractional flow reserve in real patients, and could be a viable option if trained using a large enough data set of real patients.

In this work, we estimate the diagnostic threshold of the instantaneous wave-free ratio (iFR) through the use of a one-dimensional haemodynamic framework. To this end, we first compared the computed fractional flow reserve (cFFR) predicted from a 1D computational framework with invasive clinical measurements. The framework shows excellent promise and utilises minimal patient data from a cohort of 52 patients with a total of 66 stenoses. The diagnostic accuracy of the cFFR model was 75.76%, with a sensitivity of 71.43%, a specificity of 77.78%, a positive predictive value of 60%, and a negative predictive value of 85.37%. The validated model was then used to estimate the diagnostic threshold of iFR. The model determined a quadratic relationship between cFFR and the ciFR. The iFR diagnostic threshold was determined to be 0.8910 from a receiver operating characteristic curve that is in the range of 0.89 to 0.9 that is normally reported in clinical studies., (© 2019 The Authors. International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd.)

Non-invasive coronary computed tomography (CT) angiography-derived fractional flow reserve (cFFR) is an emergent approach to determine the functional relevance of obstructive coronary lesions. Its feasibility and diagnostic performance has been reported in several studies. It is unclear if differences in sensitivity and specificity between these studies are due to study design, population, or "computational methodology." We evaluate the diagnostic performance of four different computational workflows for the prediction of cFFR using a limited data set of 10 patients, three based on reduced-order modelling and one based on a 3D rigid-wall model. The results for three of these methodologies yield similar accuracy of 6.5% to 10.5% mean absolute difference between computed and measured FFR. The main aspects of modelling which affected cFFR estimation were choice of inlet and outlet boundary conditions and estimation of flow distribution in the coronary network. One of the reduced-order models showed the lowest overall deviation from the clinical FFR measurements, indicating that reduced-order models are capable of a similar level of accuracy to a 3D model. In addition, this reduced-order model did not include a lumped pressure-drop model for a stenosis, which implies that the additional effort of isolating a stenosis and inserting a pressure-drop element in the spatial mesh may not be required for FFR estimation. The present benchmark study is the first of this kind, in which we attempt to homogenize the data required to compute FFR using mathematical models. The clinical data utilised in the cFFR workflows are made publicly available online., (© 2019 The Authors International Journal for Numerical Methods in Biomedical Engineering Published by John Wiley & Sons Ltd.)

The most common renal disease associated with human immunodeficiency virus infection (HIV) is HIV-associated nephropathy (HIVAN), especially in the African American patient population. However, various patterns of glomerulonephritis (GN) are not uncommon, collectively accounting for nearly half of the renal biopsies performed in HIV patients. Most GNs that occur in HIV patients are immune complex mediated, often with concurrent infections such as hepatitis B or C. Fibrillary glomerulonephritis (FGN), a rare primary glomerular disease, has only been reported in 2 HIV patients, and both patients had concurrent hepatitis C (HCV) infection. Here we report a unique case of FGN with unusual ultrastructural morphology in an HIV-positive African American patient without concurrent HCV infection. The patient presented with nephrotic range proteinuria and renal insufficiency. A percutaneous kidney biopsy showed mesangial and segmental endocapillary proliferative GN with crescent formation. Immunofluorescence studies revealed IgG-, κ-, and C3-positive deposits in the mesangium and capillary loops. Electron microscopy demonstrated diagnostic features of FGN: randomly-arranged fibrillary deposits with a diameter of 15 - 30 nm. The deposits had an unusual distribution pattern of hump-like large deposits on the subepithelial aspect. Additionally, smaller deposits were also present in the mesangium. To our knowledge, this is the first reported case of FGN in an HIV patient without concurrent HCV infection.
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The influence of an aortic aneurysm on blood flow waveforms is well established, but how to exploit this link for diagnostic purposes still remains challenging. This work uses a combination of experimental and computational modelling to study how aneurysms of various size affect the waveforms. Experimental studies are carried out on fusiform-type aneurysm models, and a comparison of results with those from a one-dimensional fluid-structure interaction model shows close agreement. Further mathematical analysis of these results allows the definition of several indicators that characterize the impact of an aneurysm on waveforms. These indicators are then further studied in a computational model of a systemic blood flow network. This demonstrates the methods' ability to detect the location and severity of an aortic aneurysm through the analysis of flow waveforms in clinically accessible locations. Therefore, the proposed methodology shows a high potential for non-invasive aneurysm detectors/monitors.

Situations encountered on-call often bring some of the most unique and educationally rich questions to a pathology resident's attention which can be difficult to incorporate into institutional memory. A searchable online site (wiki) provides an easily accessible platform by which to do this and could serve as a valuable after-hour resident resource. Therefore, we evaluated a wiki's usefulness by creating a wiki using Campuspack for residents to catalog uncommon questions/situations encountered on call or rotations. After 41 months in use, analytic software embedded in the site was queried for usage statistics and one year's cohort of residents was surveyed to assess the wiki's value. Since the sites inception, over 7200 individual interactions with the site were recorded, with June through August being the most active period each year. Of the 15 residents surveyed, 60% utilized the site to answer a clinical question at least monthly and the majority (93%) considered the wiki a valuable on call resource. These findings suggest that an on-call wiki is a convenient tool for capturing the unique situations that pathology residents encounter. The majority of residents find the site a valuable resource and utilize it to answer clinical questions., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Albuminuria is a strong, independent predictor of chronic kidney disease progression. We hypothesize that podocyte processing of albumin via the lysosome may be an important determinant of podocyte injury and loss. A human urine derived podocyte-like epithelial cell (HUPEC) line was used for in vitro experiments. Albumin uptake was quantified by Western blot after loading HUPECs with fluorescein-labeled (FITC) albumin. Co-localization of albumin with lysosomes was determined by confocal microscopy. Albumin degradation was measured by quantifying FITC-albumin abundance in HUPEC lysates by Western blot. Degradation experiments were repeated using HUPECs treated with chloroquine, a lysosome inhibitor, or MG-132, a proteasome inhibitor. Lysosome activity was measured by fluorescence recovery after photo bleaching (FRAP). Cytokine production was measured by ELISA. Cell death was determined by trypan blue staining. In vivo, staining with lysosome-associated membrane protein-1 (LAMP-1) was performed on tissue from a Denys-Drash trangenic mouse model of nephrotic syndrome. HUPECs endocytosed albumin, which co-localized with lysosomes. Choloroquine, but not MG-132, inhibited albumin degradation, indicating that degradation occurs in lysosomes. Cathepsin B activity, measured by FRAP, significantly decreased in HUPECs exposed to albumin (12.5% of activity in controls) and chloroquine (12.8%), and declined further with exposure to albumin plus chloroquine (8.2%, p<0.05). Cytokine production and cell death were significantly increased in HUPECs exposed to albumin and chloroquine alone, and these effects were potentiated by exposure to albumin plus chloroquine. Compared to wild-type mice, glomerular staining of LAMP-1 was significantly increased in Denys-Drash mice and appeared to be most prominent in podocytes. These data suggest lysosomes are involved in the processing of endocytosed albumin in podocytes, and lysosomal dysfunction may contribute to podocyte injury and glomerulosclerosis in albuminuric diseases. Modifiers of lysosomal activity may have therapeutic potential in slowing the progression of glomerulosclerosis by enhancing the ability of podocytes to process and degrade albumin.

Calcineurin inhibitors (CNI) have been clearly associated with posttransplant thrombotic microangiopathy (PTTMA). We report a case of de novo PT-TMA involving predominantly small arteries and arterioles of a renal allograft in a patient receiving tacrolimus. Serial biopsies demonstrate the natural history of this lesion through the chronic nonspecific phase. The case is discussed in the context of a literature review of PT-TMA in general and CNI use in particular.

In response to the Fukushima nuclear reactor accident, on March 20th, 2011, Natural Resources Canada conducted aerial radiation surveys over water just off the west coast of Vancouver Island. Dose-rate levels were found to be consistent with background radiation, however a clear signal due to (133)Xe was observed. Methods to extract (133)Xe count rates from the measured spectra, and to determine the corresponding (133)Xe activity concentration, were developed. The measurements indicate that (133)Xe concentrations on average lie in the range of 30-70 Bq/m(3)., (Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.)

The proliferation signal inhibitors (PSIs)-sirolimus, everolimus, and temsirolimus-have been associated with a noninfectious pneumonitis characterized by lymphocytic alveolitis and bronciolitis obliterans with organizing pneumonia (BOOP). This condition usually occurs within the first year. Herein we presented a case of a deceased donor renal transplant with interstitial pneumonitis developing 6 years after a switch from tacrolimus to sirolimus due to chronic graft dysfunction. After the addition of intravenous pentamidine due to the suspicion of Pneumocystis pneumonia, there was marked clinical deterioration requiring intubation. Open lung biopsy revealed sirolimus-induced pulmonary toxicity (BOOP) with the additional finding of a drug-induced phospholipidosis (DIPL) that we ascribe to pentamidine treatment. After cessation of both drugs and application of corticosteroid therapy, there was only partial improvement. Eight months later the residual interstitial fibrosis demands supplemental home oxygen. We review the literature on PSI-induced pneumonitis and discuss the pathophysiology of a potential interaction with pentamidine. We caution against its use in the setting of PSI-induced pneumonitis. It is currently unknown whether these concerns also apply to prescription of other more commonly used medications associated with DIPL, eg, amiodarone and aminoglycosides., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Unlabelled: The most accurate way to estimate the glucose metabolic rate (or its influx constant) from (18)F-FDG PET is to perform a full kinetic analysis (or its simplified Patlak version), requiring dynamic imaging and the knowledge of arterial activity as a function of time. To avoid invasive arterial blood sampling, a simplified kinetic analysis (SKA) has been proposed, based on blood curves measured from a control group. Here, we extend the SKA by allowing for a greater variety of arterial input function (A(t)) curves among patients than in the original SKA and by accounting for unmetabolized (18)F-FDG in the tumor., Methods: Ten A(t)s measured in patients were analyzed using a principal-component analysis to derive 2 principal components describing most of the variability of the A(t). The mean distribution volume of (18)F-FDG in tumors for these patients was used to estimate the corresponding quantity in other patients. In subsequent patient studies, the A(t) was described as a linear combination of the 2 principal components, for which the 2 scaling factors were obtained from an early and a late venous sample drawn for the patient. The original and extended SKA (ESKA) were assessed using fifty-seven (18)F-FDG PET scans with various tumor types and locations and using different injection and acquisition protocols, with the K(i) derived from Patlak analysis as a reference., Results: ESKA improved the accuracy or precision of the input function (area under the blood curve) for all protocols examined. The mean errors (±SD) in K(i) estimates were -12% ± 33% for SKA and -7% ± 22% for ESKA for a 20-s injection protocol with a 55-min postinjection PET scan, 20% ± 42% for SKA and 1% ± 29% for ESKA (P < 0.05) for a 120-s injection protocol with a 55-min postinjection PET scan, and -37% ± 19% for SKA and -4% ± 6% for ESKA (P < 0.05) for a 20-s injection protocol with a 120-min postinjection PET scan. Changes in K(i) between the 2 PET scans in the same patients also tended to be estimated more accurately and more precisely with ESKA than with SKA., Conclusion: ESKA, compared with SKA, significantly improved the accuracy and precision of K(i) estimates in (18)F-FDG PET. ESKA is more robust than SKA with respect to various injection and acquisition protocols.

Purpose: This study examined the effects of gender on graded exercise stress test (GXT) response in moderate-altitude (MA)-acclimatized cyclists during sea-level (SL) simulation. It was hypothesized that alterations in arterial saturation would relate to changes in VO2peak., Methods: Twenty competitive cyclists (12 males, 8 females) who were residents of MA locations underwent two randomized bicycle GXTs: one under local normoxic hypobaria, and the other under simulated SL conditions., Results: Under the SL condition, the cyclists demonstrated a significant increase (2-3%) in absolute and relative VO2peak, improved (4%) economy at lactate threshold (LT), and time-adjusted peak power (7%); the range of improvement between individuals varied from -6% to +25%. Simulated SL also resulted in a greater arterial saturation (S(a)O2) at rest and VO2peak, and significantly less desaturation (4 vs 8%) from rest to VO2peak. The individual variability in the change (Delta) in VO2peak was not significantly correlated to SL S(a)O2 or any other S(a)O2 variable analyzed, regardless of whether we examined each gender individually or combined. Significant correlations were found between Delta-peak power and Delta-economy as well as Delta-VO2peak and Delta-GXT time. These correlations as well as degree of improvement varied by gender., Conclusions: These data suggest that chronic residence at MA may attenuate the occurrence of exercise-induced arterial hypoxemia and eliminate the relationship between S(a)O2 and Delta-VO2peak that has been reported among SL residents acutely exposed to altitude. Additionally, the improvements that occur in predictors of aerobic performance when MA residents are exposed acutely to SL conditions have a large degree of individual variability, and the mechanism(s) for improvement may vary by gender.

Maximal aerobic capacity (Vo(2max)) decreases progressively with age, primarily because of a reduction in maximal cardiac output (Q(max)). This age-associated decline in Vo(2max) may be partially mediated by the development of oxidative stress that can suppress beta-adrenergic-receptor responsiveness and, consequently, reduce Q(max). To test this hypothesis, Vo(2max) (indirect calorimetry) and Q(max) (open-circuit acetylene breathing) were determined in 12 young (23 +/- 1 yr, mean +/- SE) and 10 older (61 +/- 1 yr) adults following systemic infusion of either saline (control) and/or the powerful antioxidant ascorbic acid (acute: bolus 0.06; drip 0.02 g/kg fat-free mass) and following chronic 30-day oral administration of ascorbic acid (500 mg/day). Plasma ascorbic acid concentration was not different between young and older adults and was increased similarly, independent of age [change (Delta) acute = 1,055 +/- 117%; Delta chronic = 62 +/- 19%]. Oxidized low-density lipoprotein concentration was greater (P < 0.001) in older (57 +/- 5 U/l) compared with young (34 +/- 3 U/l) adults and was reduced in both groups (P < 0.02) following acute (Delta = -6 +/- 2%) but not chronic (P = 0.18) ascorbic acid administration. Control (baseline) Vo(2max) and Q(max) were positively related (r = 0.76, P < 0.001) and were lower (P < 0.05) in older (34 +/- 2 ml.kg(-1).min(-1); 16.1 +/- 1.1 l/min) compared with young (43 +/- 3 ml.kg(-1).min(-1); 20.2 +/- 0.9 l/min) adults. Following ascorbic acid administration, neither Vo(2max) (young acute = 41 +/- 2; young chronic = 42 +/- 2; older acute = 34 +/- 2; older chronic = 34 +/- 2 ml.kg(-1).min(-1)) nor Q(max) (young acute = 20.1 +/- 0.9; young chronic = 19.1 +/- 0.8; older acute = 16.2 +/- 1.1; older chronic = 16.6 +/- 1.4 l/min) was changed. These data suggest that ascorbic acid administration does not affect the age-associated reduction in Q(max) and Vo(2max).

Unlabelled: Standardized uptake value (SUV) is often used to quantify (18)F-FDG tumor use. Although useful, SUV suffers from known quantitative inaccuracies. Simplified kinetic analysis (SKA) methods have been proposed to overcome the shortcomings of SUV. Most SKA methods rely on a single time point (SKA-S), not on tumor uptake rate. We describe a hybrid between Patlak analysis and existing SKA-S methods, using multiple time points (SKA-M) but reduced imaging time and without measurement of an input function. We compared SKA-M with a published SKA-S method and with Patlak analysis., Methods: Twenty-seven dynamic (18)F-FDG scans were performed on 11 cancer patients. A population-based (18)F-FDG input function was generated from an independent patient population. SKA-M was calculated using this population input function and either a short, late, dynamic acquisition over the tumor (starting 25-35 min after injection and ending approximately 55 min after injection) or dynamic imaging 10 or 25 min to approximately 55 min after injection but using only every second or third time point, to permit a 2- or 3-field-of-view study. SKA-S was also calculated. Both SKA-M and SKA-S were compared with the gold standard, Patlak analysis., Results: Both SKA-M (1 field of view) and SKA-S correlated well with Patlak slope (r > 0.99, P < 0.001, and r = 0.96, P < 0.001, respectively), as did multilevel SKA-M (r > 0.99 and P < 0.001 for both). Mean values of SKA-M (25-min start time) and SKA-S were statistically different from Patlak analysis (P < 0.001 and P < 0.04, respectively). One-level SKA-M differed from the Patlak influx constant by only -1.0% +/- 1.4%, whereas SKA-S differed by 15.1% +/- 3.9%. With 1-level SKA-M, only 2 of 27 studies differed from K(i) by more than 20%, whereas with SKA-S, 10 of 27 studies differed by more than 20% from K(i)., Conclusion: Both SKA-M and SKA-S compared well with Patlak analysis. SKA-M (1 or multiple levels) had lower variability and bias than did SKA-S, compared with Patlak analysis. SKA-M may be preferred over SUV or SKA-S when a large unmetabolized (18)F-FDG fraction is expected and 1-3 fields of view are sufficient.

The standardized uptake value (SUV) and the slope of the Patlak plot ( K) have both been proposed as indices to monitor the progress of disease during cancer therapy. Although a good correlation has been reported between SUV and K, they are not equivalent, and may not be equally affected by metabolic changes occurring during disease progression or therapy. We wished to compare changes in tumor SUV with changes in K during serial positron emission tomography (PET) scans for monitoring therapy. Thirteen patients enrolled in a protocol to treat renal cell carcinoma metastases were studied. Serial dynamic fluorodeoxyglucose (FDG) PET scans and computed tomography (CT) and magnetic resonance (MR) scans were performed once prior to treatment, once at 36+/-2 days after the start of treatment, and (in 7/13 subjects, 16/27 lesions) a third time at 92+/-9 days after the start of treatment. This resulted in a total of 33 scans, and 70 tumor Patlak and SUV values (one value for each lesion at each time point). SUV and K were measured over one to four predefined tumors/patient at each time point. The input function was obtained from regions of interest over the heart, combined, if necessary, with late blood samples. Over all tumors and scans, SUV and K correlated well ( r=0.97, P<0.0001). However, change in SUV with treatment over all tumor scan pairs was much less well correlated with the corresponding change in K ( r=0.73, P<0.0001). The absolute difference in % change was outside the 95% confidence limits expected from previous variability studies in 6 of 43 pairs of tumor scans, and greater than 50% in 2 of 43 tumor scan pairs. In four of the six cases, the two indices predicted opposing therapeutic outcomes. Similar results were obtained for SUV normalized by body weight or body surface area and for SUVs using mean or maximum count. Changes in CT and MR tumor cross-product dimensions correlated poorly with each other ( r=0.47, P=NS), and so could not be used to determine the "correct" PET index. Absolute values of SUV and K correlated well over the patient population. However, when monitoring individual patient therapy serially, large differences in the % changes in the two indices were occasionally found, sometimes sufficient to produce opposing conclusions regarding the progression of disease.

Three isolates of a previously undescribed Dermatophilus sp. obtained from chelonids (two strains obtained from turtles and one strain obtained from a tortoise) were compared with 30 Dermatophilus congolensis isolates obtained from Australian mammals. The microscopic appearance, the colony morphology, and most biochemical test results for the chelonid isolates were characteristic of the genus Dermatophilus. Our isolates differed from the mammalian D. congolensis isolates in a number of cultural characteristics, including faster growth at 27 degrees C than at 37 degrees C, formation of two hemolysis zones around colonies on blood agar at 37 degrees C in the presence of 10% CO2, poor motility, and production of a distinctive odor. The DNA restriction enzyme digestion and protein electrophoresis patterns of our strains were distinct. The electrophoretic mobilities of 11 enzymes differed from the mobilities observed with D. congolensis strains. A monoclonal antibody to a surface antigen of an ovine isolate did not react with zoospores or filaments of the chelonid isolates. Biochemical differences between our isolates and D. congolensis included the ability of the chelonid isolates to reduce nitrate to nitrate and the fact that the chelonid isolates exhibit collagenase activity in vitro. We propose that the chelonid isolates should be placed in a new species, Dermatophilus chelonae. Strain W16, which was isolated from a nose scab on a snapping turtle, is the type strain; a culture of this strain has been deposited in the American Type Culture Collection as strain ATCC 51576.

Multilocus enzyme electrophoresis was used to examine a collection of 41 mainly Australian isolates of Dermatophilus congolensis that had been cultured from sheep, cattle, horses, a goat, a marsupial and Chelonids. Allelic variation was examined at 16 enzyme loci. The isolates were divided into eight distinct electrophoretic types (ETs) with a mean genetic diversity per locus of 0.41. The three isolates from Chelonids represented a distinct clone in ET 1 which was separated from the remaining cluster of isolates of D. congolensis by a genetic distance of 0.852. These findings supported a previous proposal that the isolates from Chelonids represent a new species of Dermatophilus. The other 38 D. congolensis isolates were separated into two divisions (I and II) by a genetic distance of 0.560. The divisions were both subdivided into groups that either only contained alpha-hemolytic or beta-hemolytic isolates, but all isolates in each ET had only one hemolytic pattern. Isolates originating from the same animal species, or from the same geographic location, were not all closely related genetically. The allocation of isolates into ETs correlated well with their distribution into DNA restriction endonuclease analysis patterns previously established for the collection. Although relatively few distinct strains of D. congolensis were identified amongst the collection, significant genetic diversity existed within this population.

Recent vaccination studies with Dermatophilus congolensis showed that variation of challenge strains had a considerable influence on protection afforded by the vaccines. In this study cultural, morphological and biochemical properties of 30 D. congolensis isolates from throughout Australian were investigated. The infective dose required to produce lesions of equivalent severity by these isolates for sheep, rabbits and guinea pigs was also examined and the isolates were grouped into four clusters of similar infectivity ranking. Analysis of the relationship between cultural, morphological and biochemical characteristics and infectivity rankings of clusters was undertaken to determine if certain properties were linked to infectivity. Considerable variability was found in haemolytic activity on blood agar, mucoid nature of colonies, motility, flagella density and polarity, capsule width, restriction enzyme profiles of bacterial DNA, protein electropherotype, carbohydrate content, and enzymic activity against proteins, maltose, chondroitin-4-sulphate, phospholipids and lipids. Of these properties haemolytic activity and enzyme activity against casein, chondroitin-4-sulphate and lipids showed some link with infectivity ranking for these isolates.

A careful individual and family history is of utmost importance in evaluating MH susceptibility. Patients having myopathy with or without a significant family history of MH must be suspected of having the condition. The initial evaluation should include routine blood studies and CPK determinations in addition to an electrocardiogram. Full evaluation differentiating rigid from nonrigid types must include a muscle biopsy for microscopic and contraction studies. Platelet ATP depletion with exposure to halothane shows promise as a prescreening test. Susceptible patients can be given both general and local anesthetics if the surgeon and support personnel have a thorough understanding of MH and if proper precautions have been taken and preparation of facilities has been made.

Nineteen patients who have undergone surgical resection of low grade soft tissue sarcomas were retrospectively reviewed. Four patients received additional radiation therapy, and 15 did not. Of the 15 patients treated by surgery alone, 4 had positive margins in the original specimen; all 4 had local recurrence within a mean of 42 months. Eleven patients had negative margins. Ten have had no recurrence in a mean of 40 months. One patient had local recurrence at 36 months. Two of the four patients with positive margins were reoperated on and in achieving negative margins have remained disease-free a mean of 84 months. Three patients receiving additional postoperative radiation therapy had positive margins, and all had recurrence in a mean of 36 months. One patient with negative margins who also received radiation therapy is disease-free at 144 months. It appears that tumor-positive margins are associated with a high likelihood of local recurrence, whereas negative margins appear associated with a long disease-free interval and possible cure. Radiation therapy to positive margins did not prevent local recurrence.

The discovery of captopril as a potent, orally active inhibitor of angiotensin-converting enzyme (ACE) led to the recent development of many series of novel structures with similar biological activity. To date, however, all of these inhibitors are flexible or semiflexible molecules, and there is therefore no clear definition of the conformational requirements for ACE inhibition. In an effort to solve this problem, we have carried out conformational energy calculations on a series of eight structurally diverse ACE inhibitors. Comparison of the low-energy conformations available to these molecules leads to the conclusion that there is a common low-energy conformation throughout the series. The calculations thus define the structural and conformational requirements for ACE inhibition. Expansion of this model to the receptor level has been achieved by considering possible alternative receptor sites for each of the molecules in its proposed biologically active conformation and leads to an active-site model for ACE which may be useful for the design of further inhibitors.