Tacrolimus versus mycophenolate for AutoImmune hepatitis patients with incompLete response On first-line therapy (TAILOR study): a study protocol for a phase III, open-label, multicentre, randomised controlled trial.

BACKGROUND: Autoimmune hepatitis (AIH) is a rare, chronic inflammatory disease of the liver. The treatment goal is reaching complete biochemical response (CR), defined as the normalisation of aspartate and alanine aminotransferases and immunoglobulin gamma. Ongoing AIH activity can lead to fibrosis and (decompensated) cirrhosis. Incomplete biochemical response is the most important risk factor for liver transplantation or liver-related mortality. First-line treatment consists of a combination of azathioprine and prednisolone. If CR is not reached, tacrolimus (TAC) or mycophenolate mofetil (MMF) can be used as second-line therapy. Both products are registered for the prevention of graft rejection in solid organ transplant recipients. The aim of this study is to compare the effectiveness and safety of TAC and MMF as second-line treatment for AIH. METHODS: The TAILOR study is a phase IIIB, multicentre, open-label, parallel-group, randomised (1:1) controlled trial performed in large teaching and university hospitals in the Netherlands. We will enrol 86 patients with AIH who have not reached CR after at least 6 months of treatment with first-line therapy. Patients are randomised to TAC (0.07 mg/kg/day initially and adjusted by trough levels) or MMF (max 2000 mg/day), stratified by the presence of cirrhosis at inclusion. The primary endpoint is the difference in the proportion of patients reaching CR after 12 months. Secondary endpoints include the difference in the proportion of patients reaching CR after 6 months, adverse effects, difference in fibrogenesis, quality of life and cost-effectiveness. DISCUSSION: This is the first randomised controlled trial comparing two second-line therapies for AIH. Currently, second-line treatment is based on retrospective cohort studies. The rarity of AIH is the main issue in clinical research for alternative treatment options. The results of this trial can be implemented in existing international clinical guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT05221411 . Retrospectively registered on 3 February 2022; EudraCT number 2021-003420-33. Prospectively registered on 16 June 2021.

A multi-framework analysis of stakeholders' perceptions in developing a localized blue carbon ecosystems strategy in Eastern Samar, Philippines.

Blue carbon ecosystems (BCEs) are vital for global climate change mitigation and offer diverse local ecosystem co-benefits. Despite existing literatures on integrating national and international BCE agendas at the local level, the development and implementation of localized BCE strategies often lag behind. To provide insights on this knowledge gap, we present a case study conducted in Eastern Samar, Philippines. Employing a multi-framework analysis- encompassing DPSIR (drivers, pressures, state, impact, responses), SOAR (strengths, opportunities, aspirations, results), and PESTLE (political, economic, social, technological, legal, environmental) frameworks, stakeholder perceptions collected from focus group discussions highlight issues and challenges in developing and implementing a BCE strategy. Findings reveal that the aftermath of Typhoon Haiyan in 2013 in the study sites stimulated conservation efforts and raised awareness, but governance structures and policy enforcement influence the success and longevity of management and conservation efforts. Through the integration of multiple frameworks, this study outlined a potential localized BCE strategy, emphasizing both internal priorities such as stakeholder engagement and alternative livelihoods and external priorities related to policy and technological supports. While developed based on a specific case study in the Philippines, the proposed strategy is presented in a general manner, enabling its potential replication in other provinces in the Philippines or in countries with similar geographic settings.

Critical factors influencing visitor emotions: analysis of "restorativeness" in urban park visits in Fuzhou, China.

Objective: To date, a comprehensive analysis of urban green space (UGS) visitors' emotional remains largely unexplored. In this study, we focus on how UGS environmental preferences, restorativeness, other physical factors (sound, air, and thermal environments), and individual characteristics affecting visitor emotions. Such a comprehensive analysis would allow relevant practitioners to check the environmental quality of UGSs and improve certain conditions to promote visitor emotions. Methods: A total of 904 questionnaire responses with concurrently monitored physical factors were analyzed by independent sample t-tests, one-way ANOVA and path analysis. Results: The thermal evaluation had the largest impact on positive emotions (ß = 0.474), followed by perceived restorativeness (ß = 0.297), which had ß values of -0.120 and -0.158, respectively, on negative emotions. Air evaluation was more effective for increasing positive emotions (ß = 0.293) than reducing negative emotions (ß = -0.115). Sound evaluation also had similar results (ß = 0.330 vs. ß = -0.080). Environmental preference significantly influenced only positive emotions (ß = 0.181) but could still indirectly impact negative emotions. Moreover, objective physical factors can indirectly affect visitors' emotions by enhancing their evaluations.. Conclusion: The influence of different UGS environmental factors on visitors' emotions vary, as does their impacts on positive versus negative emotions. Positive emotions were generally more affected than negative emotions by UGS. Visitor emotions were mainly influenced by physical and psychological factors. Corresponding suggestions are proposed for UGS design and management in this study.

Structured alcohol cessation support program versus current practice in acute alcoholic pancreatitis (PANDA): Study protocol for a multicentre cluster randomised controlled trial.

BACKGROUND/OBJECTIVES: The most important risk factor for recurrent pancreatitis after an episode of acute alcoholic pancreatitis is continuation of alcohol use. Current guidelines do not recommend any specific treatment strategy regarding alcohol cessation. The PANDA trial investigates whether implementation of a structured alcohol cessation support program prevents pancreatitis recurrence after a first episode of acute alcoholic pancreatitis. METHODS: PANDA is a nationwide cluster randomised superiority trial. Participating hospitals are randomised for the investigational management, consisting of a structured alcohol cessation support program, or current practice. Patients with a first episode of acute pancreatitis caused by harmful drinking (AUDIT score >7 and < 16 for men and >6 and < 14 for women) will be included. The primary endpoint is recurrence of acute pancreatitis. Secondary endpoints include cessation or reduction of alcohol use, other alcohol-related diseases, mortality, quality of life, quality-adjusted life years (QALYs) and costs. The follow-up period comprises one year after inclusion. DISCUSSION: This is the first multicentre trial with a cluster randomised trial design to investigate whether a structured alcohol cessation support program reduces recurrent acute pancreatitis in patients after a first episode of acute alcoholic pancreatitis, as compared with current practice. TRIAL REGISTRATION: Netherlands Trial Registry (NL8852). Prospectively registered.

Frailty screening associates with hospitalization and decline in quality of life and functional status in older patients with inflammatory bowel disease.

BACKGROUND AND AIMS: To study frailty screening in association with hospitalization and decline in quality of life (QoL) and functional status in older patients with Inflammatory Bowel Diseases (IBD). METHODS: A prospective multicentre cohort study in IBD patients ≥65 years using frailty screening (G8 Questionnaire). Outcomes were all-cause, acute and IBD-related hospitalization, any infection, any malignancy, QoL (EQ5D-3L) and functional decline (Instrumental Activities of Daily Living, (IADL)) during 18 months follow-up. Confounders: age, IBD type, biochemical disease activity (C-reactive protein ≥10 mg/L and/or fecal calprotectin ≥250 µg/g), comorbidity (Charlson Comorbidity Index). RESULTS: Out of 405 patients, median age 70 years, 196 (48%) screened at risk for frailty. All-cause hospitalizations occurred 136 times in 96 patients (23.7%), acute hospitalizations 103 times in 74 (18.3%). Risk of frailty did not associate with all-cause (aHR 1.5, 95% CI 0.9-2.4), but did associate with acute hospitalizations (aHR 2.2, 95% CI 1.3-3.8). Infections occurred in 86 patients (21.2%) and were not associated with frailty. Decline in QoL was experienced by 108 (30.6%) patients, decline in functional status by 46 (13.3%). Frailty screening associated with decline in QoL (aOR 2.1, 95% CI 1.3-3.6) and functional status (aOR 3.7, 95% CI 1.7-8.1). CONCLUSIONS: Frailty screening associates with worse health outcomes in older patients with IBD. Further studies are needed to assess feasibility and effectiveness of implementation in routine care.

Potential of seagrass habitat restorations as nature-based solutions: Practical and scientific implications in Indonesia.

Seagrasses offer diverse ecosystem services, yet, they are among the most threatened ecosystems. When degraded or destroyed, their services are lost or reduced in the process, affecting, for instance, local communities directly dependent on their livelihood provision. The Intergovernmental Panel on Climate Change (IPCC) reported that climate change is projected to worsen over time; thus, there is an urgent need for mitigation strategies in practice and also in the longer term. This work aims to provide an alternative perspective of seagrass restoration as a nature based solution (NbS) on a global scale, yet, giving an emphasis on tropical regions such as Indonesia. We focused on seagrass restorations which are not yet well established in comparison with other restoration programs (e.g., mangroves) despite their critical roles. We present in this work how restoring seagrass meadows fits the global standard of NbS published by the International Union for Conservation of Nature (IUCN). The results of this study can serve as a basis for promoting seagrass restorations as NbS against climate change particularly in countries with a wide extent of seagrass coverage.

Clinical applicability of the Polygenic Risk Score for breast cancer risk prediction in familial cases.

BACKGROUND: Common low-risk variants are presently not used to guide clinical management of familial breast cancer (BC). We explored the additive impact of a 313-variant-based Polygenic Risk Score (PRS313) relative to standard gene testing in non-BRCA1/2 Dutch BC families. METHODS: We included 3918 BC cases from 3492 Dutch non-BRCA1/2 BC families and 3474 Dutch population controls. The association of the standardised PRS313 with BC was estimated using a logistic regression model, adjusted for pedigree-based family history. Family history of the controls was imputed for this analysis. SEs were corrected to account for relatedness of individuals. Using the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) V.5 model, lifetime risks were retrospectively calculated with and without individual PRS313. For 2586 cases and 2584 controls, the carrier status of pathogenic variants (PVs) in ATM, CHEK2 and PALB2 was known. RESULTS: The family history-adjusted PRS313 was significantly associated with BC (per SD OR=1.97, 95% CI 1.84 to 2.11). Including the PRS313 in BOADICEA family-based risk prediction would have changed screening recommendations in up to 27%, 36% and 34% of cases according to BC screening guidelines from the USA, UK and the Netherlands (National Comprehensive Cancer Network, National Institute for Health and Care Excellence, and Netherlands Comprehensive Cancer Organisation), respectively. For the population controls, without information on family history, this was up to 39%, 44% and 58%, respectively. Among carriers of PVs in known moderate BC susceptibility genes, the PRS313 had the largest impact for CHEK2 and ATM. CONCLUSIONS: Our results support the application of the PRS313 in risk prediction for genetically uninformative BC families and families with a PV in moderate BC risk genes.

Tourism impacts on small island ecosystems: public perceptions from Karimunjawa Island, Indonesia.

In Indonesia, tourism has become a promising major economic sector, particularly because of its contributions toward developing the economy and creating employment opportunities for local communities with rich coastal ecosystems. However, the balance between the environmental, social, and economic realms has come into question, as unsustainable tourism practices continue to be promoted in Indonesia. To address such challenges, it is important to identify tourism impacts and provide sustainable policies and plans. Communities often record tourism impacts through their perceptions and act as important stakeholders in the process of sustainable tourism development. We examined tourism impacts on coastal ecosystems in Karimunjawa from the perspective of local communities. More comprehensively, we investigated their perceptions from three perspectives: socio-cultural, economic, and environmental. The study results revealed that the respondents held positive perceptions about tourism's impact on socio-cultural and economic sectors and negative perceptions about its impact in the environmental domain. A chi-square test and Spearman's correlation analysis indicated that the respondents' educational attainment and tourism involvement influenced their perceptions on these issues. The current study results could be used as a baseline reference for contextualizing sustainable tourism plans regarding small island ecosystems in Indonesia. Supplementary Information: The online version contains supplementary material available at 10.1007/s11852-022-00852-9.

Community perceptions of long-term mangrove cover changes and its drivers from a typhoon-prone province in the Philippines.

Mangrove forests are among the most productive ecosystems with important services such as food and livelihood provisions, recreations, and regulations (e.g., coastal protection) in local scales. At global scale, they are gaining salience for their carbon sequestration capacities, currently conceptualized as "blue carbon." However, their essential benefits are reduced or lost when degraded. There is, therefore, a need to explore long-term mangrove cover change (MCC) and its underpinning drivers to develop sustainable management strategies. MCC has been analyzed extensively, including satellite images and field surveys, with drivers of changes frequently embedded in local contexts. Thus, in this study, MCC and the causal factors are evaluated at the local scale by gathering community perceptions in Eastern Samar, a typhoon-prone province in the Philippines, with a timeframe since the 1970s until the present. Results show that mangrove cover loss was observed following the occurrence of Typhoon Agnes in 1984 and Typhoon Haiyan in 2013 while conversion of mangrove areas to residential spaces was identified as a recurring driver of mangrove depletion from the early 1970s to 1990s. Study participants perceived that natural threats and lack of law enforcement were the leading proximate and underlying drivers of degradation, respectively. Respondents perceived that mangrove cover is increasing mainly due to successive reforestation programs coupled with stricter implementation of local ordinances in the sites. The results indicate the increased role of mangrove forests in disaster risk reduction and climate change mitigation strategies, while the perceptions of drivers change in long terms.

Does improved radiographic alignment truly enhance dynamic functional balance?

Prospective, concurrent-cohort study. To establish the relationship between radiographic alignment parameters and functional CoE measurements at one week before and at three months after realignment surgery in ADS patients. Adult degenerative scoliosis (ADS) represents a significant healthcare burden with exceedingly high and increasing prevalence, particularly among the elderly. Radiographic alignment measures and patient-reported outcomes currently serve as the standard means to assess spinal alignment, deformity, and stability. Neurological examinations have served as qualitative measures for indicating muscle strength, motor deficits, and gait abnormalities. Three-Dimensional motion analysis is increasingly being used to identify and measure gait and balance instability. Recently, techniques have been established to quantify balance characteristics described by Dubousset as the "cone of economy" (CoE). The relationship between radiographic alignment parameters and CoE balance measures of ADS patients before and after realignment surgery is currently unknown. 29 ADS patients treated with realignment surgery. Patients were evaluated at one week before realignment surgery and at their three-month follow-up examination. During each evaluation, patients completed self-reported outcomes (visual analog scales for pain, Oswestry Disability Index, SRS22r) and a functional balance test. Mean changes in dependent measures from before to after surgery were compared using paired t-tests. Pearson correlations were used to test for significant correlations between changes in radiographic and CoE measures. Significant improvements were found for all patient-reported outcomes, in several radiographic measures, and in CoE measures. Improvements of scoliosis Cobb angle, coronal pelvic tilt, lumbar lordosis, and thoracic kyphosis showed significant correlations with CoE sway and total distance measures at both the center of mass and center of the head. Improved radiographic alignment measures significantly correlated with improved CoE balance measures among ADS patients treated with realignment surgery at their three-month follow-up. These findings indicate that functional balance evaluations when used in conjunction with radiographic measurements, may provide a more robust and improved patient-specific sensitivity for postoperative assessments. CoE balance may represent a new measure of added value for surgical intervention of ADS.

The effect of scoliosis support orthosis bracing on adult spinal deformity patients: evaluation of gait and dynamic balance.

Non-operative treatment is regarded as the first-line therapy for patients with adult spinal deformity (ASD) without neurologic deficits or significant impairment. While there is high-level evidence supporting the use of rigid bracing in adolescent idiopathic scoliosis, there is a paucity of literature pertaining to the use of scoliosis support orthosis (SSO) in ASD patients. To investigate the impact of an SSO on pain, gait parameters, and functional balance measures in symptomatic ASD patients. Thirty ASD patients (26 Females, Age: 72.7, Cobb Angle: 47.1°) were evaluated on 3 different occasions: first day of bracing: baseline (Pre), and 45-min post fitting (Post45m), and after 8-weeks of bracing for 4 hours a day (Post8w). Each patient performed a 6-minute walk (over-ground gait), a dynamic balance test, and completed VAS, ODI, and SRS22r. Significant short- and long-term improvements using SSO were found in the 6-minute walk (Pre: 278.6; Post45m: 322.2; Post8w: 338.8 m, p<0.001), walking speed (Pre: 0.88; Post45m: 0.97; Post8w: 0.97 m/s, p<0.001), head total sway distance during the balance test (Pre: 81.33; Post45m: 68.63; Post8w: 60.72 cm, p=0.048), low-back pain (VAS: Pre: 5.5; Post45m: 3.5; Post8w: 3.3, p<0.001), and for the ODI (Pre: 41.9; Post45m: 32.9; Post8w: 30.1, p=0.005).This study demonstrated clinically significant improvements in PROMs, spatiotemporal gait measures, and functional balance measures after continuous use of a SSO. These improvements were observed immediately following brace-fitting and maintained at an 8-week follow-up. Given these results, it is reasonable to consider a SSO for conservative management of patients with mild symptoms of pain and deformity, and who have not yet progressed to meet surgical indications.

Systematic review with meta-analysis: risk factors for recurrent primary sclerosing cholangitis after liver transplantation.

BACKGROUND: After liver transplantation primary sclerosing cholangitis (PSC), the condition returns in the transplanted liver in a subset of patients (recurrent primary sclerosing cholangitis, rPSC). AIM: To define risk factors for rPSC. METHODS: We searched Pubmed, Embase, Web of Science, and Cochrane library for articles published until March 2018. Studies addressing risk factors for developing rPSC were eligible for inclusion. A random effects meta-analysis was conducted using hazard ratios (HR) as effect measure. Study quality was evaluated with the Newcastle Ottawa scale. Statistical analysis was performed using Cochrane Review Manager. RESULTS: The electronic database search yielded 449 results. Twenty-one retrospective cohort studies met the inclusion criteria for the review; 14 were included in the meta-analysis. The final cohort included 2159 patients (age range 31-49 years, 68.8% male), of whom 17.7% developed rPSC. Colectomy before liver transplantation, HR 0.65 (95% CI: 0.42-0.99), cholangiocarcinoma before liver transplantation, HR 2.42 (95% CI: 1.20-4.86), inflammatory bowel disease, HR 1.73 (95% CI: 1.17-2.54), donor age, HR 1.24 (95% CI 1.0-1.45) per ten years, MELD score, HR 1.05 (95% CI: 1.02-1.08) per point and acute cellular rejection, HR of 1.94 (95% CI: 1.32-2.83) were associated with the risk of rPSC. CONCLUSIONS: Multiple risk factors for rPSC were identified. Colectomy before liver transplantation reduced the risk of rPSC.

Combination of modified mixing technique and low frequency ultrasound to control the elution profile of vancomycin-loaded acrylic bone cement.

OBJECTIVES: The objective of this study was to determine if combining variations in mixing technique of antibiotic-impregnated polymethylmethacrylate (PMMA) cement with low frequency ultrasound (LFUS) improves antibiotic elution during the initial high phase (Phase I) and subsequent low phase (Phase II) while not diminishing mechanical strength. METHODS: Three batches of vancomycin-loaded PMMA were prepared with different mixing techniques: a standard technique; a delayed technique; and a control without antibiotic. Daily elution samples were analysed using flow injection analysis (FIA). Beginning in Phase II, samples from each mix group were selected randomly to undergo either five, 15, 45, or 0 minutes of LFUS treatment. Elution amounts between LFUS treatments were analysed. Following Phase II, compression testing was done to quantify strength. A-priori t-tests and univariate ANOVAs were used to compare elution and mechanical test results between the two mix groups and the control group. RESULTS: The delayed technique showed a significant increase in elution on day one compared with the standard mix technique (p < 0.001). The transition point from Phase I to Phase II occurred on day ten. LFUS treatments significantly increased elution amounts for all groups above control. Delayed technique resulted in significantly higher elution amounts for the five-minute- (p = 0.004) and 45-minute- (p < 0.001) duration groups compared with standard technique. Additionally, the correlations between LFUS duration and total elution amount for both mix techniques were significant (p = 0.03). Both antibiotic-impregnated groups exhibited a significant decrease in offset yield stress compared with the control group (p < 0.001), however, their lower 95% confidence intervals were all above the 70 MPa limit defined by International Standards Organization (ISO) 5833-2 reference standard for acrylic bone cement. CONCLUSION: The combination of a delayed mix technique with LFUS treatments provides a reasonable means for increasing both short- and long-term antibiotic elution without affecting mechanical strength.Cite this article: Dr. T. McIff. Combination of modified mixing technique and low frequency ultrasound to control the elution profile of vancomycin-loaded acrylic bone cement. Bone Joint Res 2016;5:26-32. doi: 10.1302/2046-3758.52.2000412.

Production and evaluation of silicon immersion gratings for infrared astronomy.

Immersion gratings, diffraction gratings where the incident radiation strikes the grooves while immersed in a dielectric medium, offer significant compactness and performance advantages over front-surface gratings. These advantages become particularly large for high-resolution spectroscopy in the near-IR. The production and evaluation of immersion gratings produced by fabricating grooves in silicon substrates using photolithographic patterning and anisotropic etching is described. The gratings produced under this program accommodate beams up to 25 mm in diameter (grating areas to 55 mm x 75 mm). Several devices are complete with appropriate reflective and antireflection coatings. All gratings were tested as front-surface devices as well as immersed gratings. The results of the testing show that the echelles behave according to the predictions of the scalar efficiency model and that tests done on front surfaces are in good agreement with tests done in immersion. The relative efficiencies range from 59% to 75% at 632.8 nm. Tests of fully completed devices in immersion show that the gratings have reached the level where they compete with and, in some cases, exceed the performance of commercially available conventional diffraction gratings (relative efficiencies up to 71%). Several diffraction gratings on silicon substrates up to 75 mm in diameter having been produced, the current state of the silicon grating technology is evaluated.

IMIM - Institut Hospital del Mar d'Investigacions Mèdiques

Organismo público dedicado a la investigación científica en el campo de la Biomedicina y las Ciencias de la Salud que se estructura en cinco programas de carácter multidisplinar: cáncer, epidemiología y salud pública, procesos inflamatorios y cardiovasculares, informática biomédica y neurociencias. La página contiene información corporativa, información de los programas y proyectos de investigación, publicaciones científicas, servicios científicotécnicos, etc.

Phase synchronization of chaotic systems with small phase diffusion.

The geometric theory of phase locking between periodic oscillators is extended to phase coherent chaotic systems. This approach explains the qualitative features of phase locked chaotic systems and provides an analytical tool for a quantitative description of the phase locked states. Moreover, this geometric viewpoint allows us to identify obstructions to phase locking even in systems with negligible phase diffusion, and to provide sufficient conditions for phase locking to occur. We apply these techniques to the Rössler system and a phase coherent electronic circuit and find that numerical results and experiments agree well with theoretical predictions.

Three coupled oscillators as a universal probe of synchronization stability in coupled oscillator arrays

We show that the stability surface that governs the synchronization of a large class of arrays of identical oscillators can be probed with a simple array of just three identical oscillators. Experimentally this implies that it may be possible to probe the synchronization conditions of many arrays all at the same time. In the process of developing a theory of the three-oscillator probe, we also show that several regimes of asymptotic coupling can be derived for the array classes, including the case of large imaginary coupling, which apparently has not been explored.