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No Difference in Clinical Effects When Comparing Alfredson Eccentric and Silbernagel Combined Concentric-Eccentric Loading in Achilles Tendinopathy: A Randomized Controlled Trial
No full textBackground:Alfredson isolated eccentric loading and Silbernagel concentric–eccentric loading have both shown beneficial effects on clinical symptoms in midportion Achilles tendinopathy (AT), but they have never been compared directly.Purpose:To test for differences in clinical effects at 1-year follow-up between Alfredson and Silbernagel loading in midportion AT.Study Design:Randomized controlled trial; Level of evidence, 2.Methods:A total of 40 recreational athletes were allocated to the Alfredson group (AG) or the Silbernagel group (SG). The primary outcome was the difference in the Victorian Institute of Sports Assessment–Achilles (VISA-A) at 1-year follow-up. Secondary outcomes were the visual analog scale for pain during activities of daily living (VAS-ADL) and sports activities (VAS–sports), the EuroQol 5 Dimensions instrument (EQ-5D), and global perceived effect score. Measurements were performed at baseline and 12-week, 26-week, and 1-year follow-up. Analysis was performed using a linear mixed-regression model with intervention (AG vs SG), time (12 weeks, 26 weeks, and 1 year postoperatively), and intervention-by-time interaction.Results:The VISA-A score improved for both AG and SG, from 60.7 ± 17.1 at baseline to 89.4 ± 13.0 at 1-year follow-up and from 59.8 ± 22.2 to 83.2 ± 22.4, respectively (P < .001 for both). Because the interaction term did not significantly improve the model, we reported a treatment effect without interaction term, indicating a constant difference at each follow-up. The linear mixed model with correction for baseline VISA-A and confounders revealed a nonsignificant treatment effect (2.4 [95% CI, –8.5 to 13.3]; P = .656). In addition, after adjustment for the respective baseline values and confounders, nonsignificant treatment effects were found for the VAS-ADL (–2.0 [95% CI, –11.3 to 7.3]; P = .665) and VAS-sports (1.3 [95% CI, –12.8 to 15.3], P = .858). The EQ-5D subscales improved in both groups. After 1 year, significantly more SG participants considered themselves improved (77.3% [SG] vs 50.0% [AG]; P = .04).Conclusion:No differences in clinical effects were found between Alfredson and Silbernagel loading at up to 1-year follow-up. Both programs significantly improved clinical symptoms, and given their high adherence rates, offering either of them as a home-based program with limited supervision appears to be an effective treatment strategy for midportion AT.Registration:NTR5638 (Netherlands Trial Register number)
Human leishmaniasis vaccines
No full textThe development of vaccines against one or all forms of human leishmaniasis remains ham-pered by a paucity of investment, at least in part resulting from the lack of well-evidenced and agreed estimates of vaccine demand. Starting from the definition of 4 main use cases (prevention of visceral leishmaniasis, prevention of cutaneous leishmaniasis, prevention of post-kala-azar dermal leishmaniasis and treatment of post-kala-azar dermal leishmaniasis), we have estimated the size of each target population, focusing on those endemic countries where incidence levels are sufficiently high to justify decisions to adopt a vaccine. We assumed a dual vaccine delivery strategy, including a wide age-range catch-up campaign before the start of routine immunisation. Vaccine characteristics and delivery parameters reflective of a target product profile and the likely duration of the clinical development effort were considered in forecasting the demand for each of the four indications. Over a period of 10 years, this demand is forecasted to range from 300–830 million doses for a vaccine preventing visceral leishmaniasis and 557–1400 million doses for a vaccine preventing cutaneous leishmaniasis under the different scenarios we simulated. In a scenario with an effective prophylactic visceral leishmaniasis vaccine, demand for use to prevent or treat post-kala-azar dermal leishmaniasis would be more limited (over the 10 years ~160,000 doses for prevention and ~7,000 doses for treatment). Demand would rise to exceed 330,000 doses, however, in the absence of an effective vaccine for visceral leishmaniasis. Because of the sizeable demand and potential for public health impact, a single-indication prophylactic vaccine for visceral or cutaneous leishmaniasis, and even more so a cross-protective prophylactic vaccine could attract the interest of commercial developers. Continuous refinement of these first-of-their kind estimates and confirmation of country willingness and ability to pay will be paramount to inform the decisions of policy makers and developers in relation to a leishmaniasis vaccine. Positive decisions can provide a much-needed contribution towards the achievement of global leishmaniasis control.</p
Associations of changes in late-life blood pressure with cognitive impairment among older population in China
No full textBackground: The cognitive impact of changes in late-life blood pressure is less clear. We aimed to investigate the association between late-life blood pressure changing pattern and risk of cognitive impairment. Methods: Using data from the community-based Chinese Longitudinal Healthy Longevity Survey, change in systolic (SBP) or diastolic (DBP) blood pressure was calculated as the difference between follow-up and baseline, cognitive impairment was defined based on both the Mini-Mental State Examination and education level. The generalized additive model with penalized spline and multivariate logistic regression model were used, respectively, to examine the associations between continuous and categorized blood pressure changes with cognitive impairment at the follow-up wave. Results: A total of 8493 Chinese elderly without cognitive impairment were included, with mean (standard deviation) age 80.6 (10.7) years. U-shaped associations between late-life blood pressure changes and risk of cognitive impairment were found, with only stable optimal blood pressure related to the lowest risk. For participants with baseline SBP around 130–150 mmHg, the adjusted odds ratio was 1.48 (1.13–1.93) for increasing follow-up SBP (> 150 mmHg), 1.28 (1.02–1.61) for decreasing follow-up SBP (< 130 mmHg), compared to stable follow-up SBP (130–150 mmHg). For participants with relative lower baseline DBP (< 80 mmHg), increasing their DBP to 80–90 mmHg during follow-up was associated with lower cognitive impairment risk (0.73 (0.58–0.93)), compared to steady low follow-up DBP (< 80 mmHg). Sex-specific analysis suggested that men were more vulnerable in term of SBP change. Conclusions: Adhering to a stable optimal level of blood pressure in late-life is related to lower risk of cognitive impairment in Chinese elderly.</p
The netherlands is on track to meet the world health organization hepatitis C elimination targets by 2030
No full textBackground: The Netherlands strives for hepatitis C virus (HCV) elimination, in accordance with the World Health Organization targets. An accurate estimate when HCV elimination will be reached is elusive. We have embarked on a nationwide HCV elimination project (CELINE) that allowed us to harvest detailed data on the Dutch HCV epidemic. This study aims to provide a well‐supported timeline towards HCV elimination in The Netherlands. Methods: A previously published Markov model was used, adopting published data and unpublished CELINE project data. Two main scenarios were devised. In the Status Quo scenario, 2020 diagnosis and treatment levels remained constant in subsequent years. In the Gradual Decline scenario, an annual decrease of 10% in both diagnoses and treatments was implemented, starting in 2020. WHO incidence target was disregarded, due to low HCV incidence in The Netherlands (≤5 per 100,000). Results: Following the Status Quo and Gradual Decline scenarios, The Netherlands would meet WHO’s elimination targets by 2027 and 2032, respectively. From 2015 to 2030, liver‐related mortality would be reduced by 97% in the Status Quo and 93% in the Gradual Decline scenario. Compared to the Status Quo scenario, the Gradual Decline scenario would result in 12 excess cases of decompensated cirrhosis, 18 excess cases of hepatocellular carcinoma, and 20 excess cases of liverrelated death from 2020-2030. Conclusions: The Netherlands is on track to reach HCV elimination by 2030. However, it is vital that HCV elimination remains high on the agenda to ensure adequate numbers of patients are being diagnosed and treated.</p
Efficacy of Sertraline Plus Placebo or Add-On Celecoxib in Major Depressive Disorder
No full textIntroduction: Previous research delivers strong indications that inflammatory activation leads to treatment resistance in a subgroup of patients with Major Depressive Disorder (MDD). Thus, tailored interventions are needed. The present study aimed to find potential biomarkers that may enable patients to be stratified according to immune activation. Methods: A phase IIa randomized placebo-controlled trial was performed to assess levels of inflammatory compounds in responders/remitters and non-responders/non-remitters to sertraline plus celecoxib (n = 20) and sertraline plus placebo (n = 23). Levels of macrophage migration inhibitory factor, neopterin, and tumor necrosis factor alpha were determined by enzyme-linked immunosorbent assay; response and remission were measured by reduction of the Montgomery Åsberg Depression Rating Scale score. Results: Both treatment groups showed a significant decline in depression symptoms, but no difference was found between groups. A clear pattern emerged only for macrophage migration inhibitory factor: placebo remitters showed significantly lower baseline levels than non-remitters (a similar trend was seen in responders and non-responders) while celecoxib responders showed a trend for higher baseline levels than non-responders. Conclusion: Small subsample sizes are a notable limitation, wherefore results are preliminary. However, the present study provides novel insights by suggesting macrophage migration inhibitory factor as a promising biomarker for treatment choice. The trial was registered in EU Clinical Trials Register (EU-CTR): https://www.clinicaltrialsregister.eu/ctr-search/trial/2009-011990-34/DE, EudraCT-No.: 2009-011990-34.</p
Cervical intraepithelial neoplasia and the risk of spontaneous preterm birth
No full textBackground Excisional procedures of cervical intraepithelial neoplasia (CIN) may increase the risk of preterm birth. It is unknown whether this increased risk is due to the excision procedure itself, to the underlying CIN, or to secondary risk factors that are associated with both preterm birth and CIN. The aim of this study is to assess the risk of spontaneous preterm birth in women with treated and untreated CIN and examine possible associations by making a distinction between the excised volume of cervical tissue and having cervical disease. Methods and findings This Dutch population-based observational cohort study identified women aged 29 to 41 years with CIN between 2005 and 2015 from the Dutch pathology registry (PALGA) and frequency matched them with a control group without any cervical abnormality based on age at and year of pathology outcome (i.e., CIN or normal cytology) and urbanization (<100,000 inhabitants or ≥100,000 inhabitants). All their 45,259 subsequent singleton pregnancies with a gestational age ≥16 weeks between 2010 and 2017 were identified from the Dutch perinatal database (Perined). Nineteen potential confounders for preterm birth were identified. Adjusted odds ratios (ORs) were calculated for preterm birth comparing the 3 different groups of women: (1) women without CIN diagnosis; (2) women with untreated CIN; and (3) women with treated CIN prior to each childbirth. In total, 29,907, 5,940, and 9,412 pregnancies were included in the control, untreated CIN, and treated CIN group, respectively. The control group showed a 4.8% (1,002/20,969) proportion of spontaneous preterm birth, which increased to 6.9% (271/3,940) in the untreated CIN group, 9.5% (600/6,315) in the treated CIN group, and 15.6% (50/321) in the group with multiple treatments. Women with untreated CIN had a 1.38 times greater odds of preterm birth compared to women without CIN (95% confidence interval (CI) 1.19 to 1.60; P < 0.001). For women with treated CIN, these odds 2.07 times increased compared to the control group (95% CI 1.85 to 2.33; P < 0.001). Treated women had a 1.51 times increased odds of preterm birth compared to women with untreated CIN (95% CI 1.29 to 1.76; P < 0.001). Independent from cervical disease, a volume excised from the cervix of 0.5 to 0.9 cc increased the odds of preterm birth 2.20 times (37/379 versus 1,002/20,969; 95% CI 1.52 to 3.20; P < 0.001). These odds further increased 3.13 times and 5.93 times for women with an excised volume of 4 to 8.9 cc (90/724 versus 1,002/20,969; 95% CI 2.44 to 4.01; P < 0.001) and ≥9 cc (30/139 versus 1,002/20,969; 95% CI 3.86 to 9.13; P < 0.001), respectively. Limitations of the study include the retrospective nature, lack of sufficient information to calculate odds of preterm birth <24 weeks, and that the excised volume could only be calculated for a select group of women. Conclusions In this study, we observed a strong correlation between preterm birth and a volume of ≥0.5 cc excised cervical tissue, regardless of the severity of CIN. Caution should be taken when performing excisional treatment in women of reproductive age as well as prudence in case of multiple biopsies. Fertile women with a history of performing multiple biopsies or excisional treatment for CIN may benefit from close surveillance during pregnancy.</p
Diversity and reassortment rate of influenza a viruses in wild ducks and gulls
No full textInfluenza A viruses (IAVs) evolve via point mutations and reassortment of viral gene segments. The patterns of reassortment in different host species differ considerably. We investigated the genetic diversity of IAVs in wild ducks and compared it with the viral diversity in gulls. The complete genomes of 38 IAVs of H1N1, H1N2, H3N1, H3N2, H3N6, H3N8, H4N6, H5N3, H6N2, H11N6, and H11N9 subtypes isolated from wild mallard ducks and gulls resting in a city pond in Moscow, Russia were sequenced. The analysis of phylogenetic trees showed that stable viral genotypes do not persist from year to year in ducks owing to frequent gene reassortment. For comparison, similar analyses were carried out using sequences of IAVs isolated in the same period from ducks and gulls in The Netherlands. Our results revealed a significant difference in diversity and rates of reassortment of IAVs in ducks and gulls.</p
Predictive performance of newer Asian hepatocellular carcinoma risk scores in treated Caucasians with chronic hepatitis B
No full textBackground & Aims: Recently, several risk scores for prediction of hepatocellular carcinoma (HCC) were developed in cohorts of treated Asian patients with chronic hepatitis B (CHB), but they have not been assessed in non-Asian patients. We evaluated the predictability and comparative utility of our PAGE-B and recent Asian HCC risk scores in nucleos(t)ide analogue (NA)-treated adult Caucasian patients with CHB, with or without well-documented compensated cirrhosis but not previous diagnosis of HCC. Methods: We included 1,951 patients treated with entecavir/tenofovir and followed up for a median of 7.6 years. The c-statistic was used to estimate the predictability of PAGE-B, HCC-Rescue, CAMD, mPAGE-B, and AASL score for HCC development within 5 or 10 years. The low- and high-risk group cut-offs were used for estimation of negative (NPV) and positive predictive values (PPV), respectively. Results: HCC developed in 103/1,951 (5.3%) patients during the first 5 years and in another 39/1,428 (2.7%) patients between years 5 and 10. The 3-, 5-, and 10-year cumulative HCC rates were 3.3%, 5.9%, and 9.6%, respectively. All scores offered good 5- and 10-year HCC prediction (c-statistic: 0.78–0.82). NPVs were always >99% (99.3–100%), whereas PPV ranged between 13% and 24%. Conclusions: In NA-treated Caucasian patients with CHB including compensated cirrhosis, HCC risk scores developed in NA-treated Asian patients offer good 5- and 10-year HCC predictability, similar to that of PAGE-B. PAGE-B and mPAGE-B scores are simpler in clinical practice, as they do not require an accurate diagnosis of cirrhosis, but the addition of albumin in mPAGE-B score does not seem to offer an advantage in patients with well compensated liver disease. Lay summary: Several risk scores for prediction of hepatocellular carcinoma (HCC) were recently developed in cohorts of treated Asian patients with chronic hepatitis B (CHB). In Caucasian patients with CHB treated with oral antivirals, newer Asian HCC risk scores offer good 5- and 10-year HCC predictability, similar to that of PAGE-B. For clinical practice, PAGE-B and mPAGE-B scores are simpler, as they do not require an accurate diagnosis of cirrhosis.</p
Multicomponent Mechanical Characterization of Atherosclerotic Human Coronary Arteries
No full textAtherosclerotic plaque rupture in coronary arteries, an important trigger of myocardial infarction, is shown to correlate with high levels of pressure-induced mechanical stresses in plaques. Finite element (FE) analyses are commonly used for plaque stress assessment. However, the required information of heterogenous material properties of atherosclerotic coronaries remains to be scarce. In this work, we characterized the component-wise mechanical properties of atherosclerotic human coronary arteries. To achieve this, we performed ex vivo inflation tests on post-mortem human coronary arteries and developed an inverse FE modeling (iFEM) pipeline, which combined high-frequency ultrasound deformation measurements, a high-field magnetic resonance-based artery composition characterization, and a machine learning-based Bayesian optimization (BO) with uniqueness assessment. By using the developed pipeline, 10 cross-sections from five atherosclerotic human coronary arteries were analyzed, and the Yeoh material model constants of the fibrous intima and arterial wall components were determined. This work outlines the developed pipeline and provides the knowledge of non-linear, multicomponent mechanical properties of atherosclerotic human coronary arteries.</p
