Mediterranean springs: Keystone ecosystems and biodiversity refugia threatened by global change.

Mediterranean spring ecosystems are unique habitats at the interface between surface water and groundwater. These ecosystems support a remarkable array of biodiversity and provide important ecological functions and ecosystem services. Spring ecosystems are influenced by abiotic, biotic, and anthropogenic factors such as the lithology of their draining aquifers, their climate, and the land use of their recharge area, all of which affect the water chemistry of the aquifer and the spring discharges. One of the most relevant characteristics of spring ecosystems is the temporal stability of environmental conditions, including physicochemical features of the spring water, across seasons and years. This stability allows a wide range of species to benefit from these ecosystems (particularly during dry periods), fostering an unusually high number of endemic species. However, global change poses important threats to these freshwater ecosystems. Changes in temperature, evapotranspiration, and precipitation patterns can alter the water balance and chemistry of spring water. Eutrophication due to agricultural practices and emergent pollutants, such as pharmaceuticals, personal care products, and pesticides, is also a growing concern for the preservation of spring biodiversity. Here, we provide a synthesis of the main characteristics and functioning of Mediterranean spring ecosystems. We then describe their ecological value and biodiversity patterns and highlight the main risks these ecosystems face. Moreover, we identify existing knowledge gaps to guide future research in order to fully uncover the hidden biodiversity within these habitats and understand the main drivers that govern them. Finally, we provide a brief summary of recommended actions that should be taken to effectively manage and preserve Mediterranean spring ecosystems for future generations. Even though studies on Mediterranean spring ecosystems are still scarce, our review shows there are sufficient data to conclude that their future viability as functional ecosystems is under severe threat.

Effect of FeCl3 concentration in chemically enhanced primary treatment on the performance of a conventional wastewater treatment plant. A case study.

The effect of coagulant dosage in a chemically enhanced primary treatment (CEPT) on the performance of a conventional wastewater treatment plant (WWTP) has been investigated. Lab-scale experiments simulations were carried out in order to evaluate the effect of coagulant addition on the primary settling performance. In these experiments, FeCl3 was used as coagulant. Later, the WWTP was theoretically simulated using a commercial software (WEST®) to evaluate the effect of coagulation/flocculation on the global system, based on the results obtained at lab-scale. According to these results, the CEPT modifies the organic matter balance in the WWTP, decreasing the contribution of readily (SS) and slowly (XS) biodegradable fractions of COD to the aerobic biological process up to 27.3% and 80.8%, respectively, for a dosage of FeCl3 of 24 mg L-1. Consequently, total suspended solids in the aerobic reactor and the secondary purged sludge decreased up to 33% and 13%, respectively. However, the influence on effluent quality was negligible. On the contrary, suspended solids concentration in the sludge to be treated by anaerobic digestion increased, mainly regarding the Ss and Xs fractions, which caused an 8.1% increase in biogas production potential, with approximately 60% of CH4 concentration.

Effect of positive pressure ventilation and bariatric surgery on extracellular vesicle microRNAs in patients with severe obesity and obstructive sleep apnea.

INTRODUCTION: Obstructive sleep apnea (OSA) and severe obesity share a common pathophysiological phenomenon, systemic and tissue hypoxia. Hypoxaemia modifies microRNA expression, particularly, extracellular vesicles microRNAs which are involved in the progression of cardiovascular diseases, metabolic syndrome and cancer. We aim to evaluate extracellular vesicle miRNAs among patients with severe obesity with and without OSA and the effect of OSA and severe obesity treatment: continuous positive airway pressure (CPAP) and bariatric surgery. METHODS: Patients were selected from the Epigenetics Modification in Morbid Obesity and Obstructive Sleep Apnea (EPIMOOSA) study (NCT03995836), a prospective observational study of patients undergoing bariatric surgery. Patients were divided into OSA (Apnea-hyponea index (AHI) > 10) and non-OSA (AHI < 10). Patients with OSA were treated with CPAP for 6 months. Then, all patients had bariatric surgery and re-evaluated 12 months later. At each visit, blood samples were obtained for biobanking. Subsequently, extracellular vesicles were extracted, and then, miRNA expression was analysed. RESULTS: 15 patients with OSA and 9 without OSA completed the protocol. At baseline, patients with OSA showed higher miR16, miR126 and miR320 (p < 0.05) and lower miR223 expression (p < 0.05) than those without OSA. In patients with severe obesity and OSA, after 6 months with CPAP, we observed a significant decrease in miR21 (p < 0.01), miR126 (p < 0.001) and miR320 (p < 0.001), with no changes in any miRNA in patients without OSA. No changes were detected in any miRNA after 6 months of bariatric surgery in patients with or without OSA. CONCLUSION: Co-existance of OSA and severe obesity alters the profile of extracellular vesicle miRNAs. Bariatric surgery and weight loss did not reverse this effect meanwhile the treatment with CPAP in patients with severe obesity and OSA showed a recovery outcome in those extracellular vesicle miRNAs. Those facts remark the need for OSA screening in patients with severe obesity. CLINICAL TRIAL REGISTRATION: The study has also been registered at ClinicalTrials.gov identifier: NCT03995836.

Mutation and SARS-CoV-2 strain competition under vaccination in a modified SIR model.

The crisis caused by the COVID-19 outbreak around the globe raised an increasing concern about the ongoing emergence of variants of the virus that may evade the immune response provided by vaccines. New variants appear due to mutation, and as the cases accumulate, the probability of the emergence of a variant of concern increases. In this article, we propose a modified susceptible, infected, and recovered (SIR) model with waning immunity that captures the competition of two strain classes of an infectious disease under the effect of vaccination with a highly contagious and deadlier strain class emerging from a prior strain due to mutation. When these strains compete for a limited supply of susceptible individuals, changes in the efficiency of vaccines may affect the behaviour of the disease in a non-trivial way, resulting in complex outcomes. We characterise the parameter space including intrinsic parameters of the disease, and using the vaccine efficiencies as control variables. We find different types of transcritical bifurcations between endemic fixed points and a disease-free equilibrium and identify a region of strain competition where the two strain classes coexist during a transient period. We show that a strain can be extinguished either due to strain competition or vaccination, and we obtain the critical values of the efficiency of vaccines to eradicate the disease. Numerical studies using parameters estimated from publicly reported data agree with our theoretical results. Our mathematical model could be a tool to assess quantitatively the vaccination policies of competing and emerging strains using the dynamics in epidemics of infectious diseases.

A randomised controlled trial in patients undergoing arthroscopic shoulder surgery comparing interscalene block with either 10 ml or 20 ml levobupivacaine 0.25.

The interscalene brachial plexus block is recommended for analgesia after shoulder surgery but it may cause hemidiaphragmatic dysfunction. We tested whether ipsilateral hemidiaphragmatic contraction was better after a smaller dose of local anaesthetic without impairing analgesic effect. We randomly allocated 48 adults to 10 ml or 20 ml levobupivacaine 0.25% before arthroscopic shoulder surgery. The primary outcome was hemidiaphragmatic paralysis, defined as inspiratory thickness < 1.2 times expiratory thickness, measured by ultrasound 4 h after block. Hemidiaphragmatic paralysis was recorded for 6/24 vs. 23/24 supine participants after 10 ml vs. 20 ml levobupivacaine 0.25%, respectively, and for 4/24 vs. 23/24 sitting participants, respectively, p < 0.001 for both. Pain scores after 10 ml injectate were not worse than after 20 ml injectate. Median (IQR [range]) morphine doses in the first 24 postoperative hours after 10 ml and 20 ml levobupivacaine 0.25% were 2 (0-6 [0-23]) mg vs. 1 (0-2 [0-11]) mg, respectively, p = 0.12. No participant had a complication after 10 ml interscalene levobupivacaine, whereas seven had complications after 20 ml levobupivacaine, p = 0.009. Hemidiaphragmatic function was better after 10 ml vs. 20 ml interscalene levobupivacaine 0.25% without impairing analgesia for 24 postoperative hours.

Could pulmonary low-dose radiation therapy be an alternative treatment for patients with COVID-19 pneumonia? Preliminary results of a multicenter SEOR-GICOR nonrandomized prospective trial (IPACOVID trial).

PURPOSE: To evaluate the efficacy and safety of lung low-dose radiation therapy (LD-RT) for pneumonia in patients with coronavirus disease 2019 (COVID-19). MATERIALS AND METHODS: Inclusion criteria comprised patients with COVID-19-related moderate-severe pneumonia warranting hospitalization with supplemental O2 and not candidates for admission to the intensive care unit because of comorbidities or general status. All patients received single lung dose of 0.5 Gy. Respiratory and systemic inflammatory parameters were evaluated before irradiation, at 24 h and 1 week after LD-RT. Primary endpoint was increased in the ratio of arterial oxygen partial pressure (PaO2) or the pulse oximetry saturation (SpO2) to fractional inspired oxygen (FiO2) ratio of at least 20% at 24 h with respect to the preirradiation value. RESULTS: Between June and November 2020, 36 patients with COVID-19 pneumonia and a mean age of 84 years were enrolled. Seventeen were women and 19 were men and all of them had comorbidities. All patients had bilateral pulmonary infiltrates on chest X­ray. All patients received dexamethasone treatment. Mean SpO2 pretreatment value was 94.28% and the SpO2/FiO2 ratio varied from 255 mm Hg to 283 mm Hg at 24 h and to 381 mm Hg at 1 week, respectively. In those who survived (23/36, 64%), a significant improvement was observed in the percentage of lung involvement in the CT scan at 1 week after LD-RT. No adverse effects related to radiation treatment have been reported. CONCLUSIONS: LD-RT appears to be a feasible and safe option in a population with COVID-19 bilateral interstitial pneumonia in the presence of significant comorbidities.

The global prevalence of apical periodontitis: a systematic review and meta-analysis.

BACKGROUND: Apical periodontitis (AP) frequently presents as a chronic asymptomatic disease. To arrive at a true diagnosis, in addition to the clinical examination, it is mandatory to undertake radiographic examinations such as periapical or panoramic radiographs, or cone-beam computed tomography (CBCT). Thus, the worldwide burden of AP is probably underestimated or unknown. Previous systematic reviews attempted to estimate the prevalence of AP, but none have investigated which factors may influence its prevalence worldwide. OBJECTIVES: To assess: (i) the prevalence of AP in the population worldwide, as well as the frequency of AP in all teeth, nontreated teeth and root filled teeth; (ii) which factors can modify the prevalence of AP. METHODS: A search was conducted in the PubMed-MEDLINE, EMBASE, Cochrane-CENTRAL, LILACS, Google scholar and OpenGrey databases, followed by hand searches, until September 2019. Cross-sectional, case-control and cohort studies reporting the prevalence of AP in humans, using panoramic or periapical radiograph or CBCT as image methods were included. No language restriction was applied. An adaptation of the Newcastle-Ottawa Scale was used to evaluate the quality of the studies. A meta-analysis was performed to determine the pooled prevalence of AP at the individual level. Secondary outcomes were the frequency of AP in all teeth, nontreated teeth and rootfilled teeth. Subgroup analyses using random-effect models were carried out to analyse the influence of explanatory covariables on the outcome. RESULTS: The search strategy identified 6670 articles, and 114 studies were included in the meta-analysis, providing data from 34 668 individuals and 639 357 teeth. The prevalence of AP was 52% at the individual level (95% CI 42%-56%, I2  = 97.8%) and 5% at the tooth level (95% CI 4%-6%; I2  = 99.5%). The frequency of AP in root-filled teeth and nontreated teeth was 39% (95% CI 36%-43%; I2  = 98.5%) and 3% (95% CI 2%-3%; I2  = 99.3%), respectively. The prevalence of AP was greater in samples from dental care services (DCS; 57%; 95% CI 52%-62%; I2  = 97.8%) and hospitals (51%; 95% CI 40%-63%; I2  = 95.9%) than in those from the general population (GP; 40%; 95% CI 33%-46%; I2  = 96.5%); it was also greater in people with a systemic condition (63%; 95% CI 56%-69%, I2  = 89.7%) compared to healthy individuals (48%; 95% CI 43%-53%; I2  = 98.3%). DISCUSSION: The subgroup analyses identified explanatory factors related to the variability in the prevalence of AP. However, the high clinical heterogeneity and high risk of bias across the primary studies indicate that the findings must be interpreted with caution. CONCLUSIONS: Half of the adult population worldwide have at least one tooth with apical periodontitis. The prevalence of AP is greater in samples from the dental care services, but it is also high amongst community representative samples from the general population. The present findings should bring the attention of health policymakers, medical and dental communities to the hidden burden of endodontic disease in the population worldwide.

Incubation period of COVID-19: A systematic review and meta-analysis. / Período de incubación de la COVID-19: revisión sistemática y metaanálisis.

BACKGROUND AND OBJECTIVE: The incubation period of COVID-19 helps to determine the optimal duration of the quarantine and inform predictive models of incidence curves. Several emerging studies have produced varying results; this systematic review aims to provide a more accurate estimate of the incubation period of COVID-19. METHODS: For this systematic review, a literature search was conducted using Pubmed, Scopus/EMBASE, and the Cochrane Library databases, covering all observational and experimental studies reporting the incubation period and published from 1 January 2020 to 21 March 2020.We estimated the mean and 95th percentile of the incubation period using meta-analysis, taking into account between-study heterogeneity, and the analysis with moderator variables. RESULTS: We included seven studies (n = 792) in the meta-analysis. The heterogeneity (I2 83.0%, p < 0.001) was significantly decreased when we included the study quality and the statistical model used as moderator variables (I2 15%). The mean incubation period ranged from 5.6 (95% CI: 5.2 to 6.0) to 6.7 days (95% CI: 6.0 to 7.4) according to the statistical model. The 95th percentile was 12.5 days when the mean age of patients was 60 years, increasing 1 day for every 10 years. CONCLUSION: Based on the published data reporting the incubation period of COVID-19, the mean time between exposure and onset of clinical symptoms depended on the statistical model used, and the 95th percentile depended on the mean age of the patients. It is advisable to record sex and age when collecting data in order to analyze possible differential patterns.

Clinical Predictive Model of Multidrug Resistance in Neutropenic Cancer Patients with Bloodstream Infection Due to Pseudomonas aeruginosa.

We aimed to assess the rate and predictive factors of bloodstream infection (BSI) due to multidrug-resistant (MDR) Pseudomonas aeruginosa in neutropenic cancer patients. We performed a multicenter, retrospective cohort study including oncohematological neutropenic patients with BSI due to P. aeruginosa conducted across 34 centers in 12 countries from January 2006 to May 2018. A mixed logistic regression model was used to estimate a model to predict the multidrug resistance of the causative pathogens. Of a total of 1,217 episodes of BSI due to P. aeruginosa, 309 episodes (25.4%) were caused by MDR strains. The rate of multidrug resistance increased significantly over the study period (P = 0.033). Predictors of MDR P. aeruginosa BSI were prior therapy with piperacillin-tazobactam (odds ratio [OR], 3.48; 95% confidence interval [CI], 2.29 to 5.30), prior antipseudomonal carbapenem use (OR, 2.53; 95% CI, 1.65 to 3.87), fluoroquinolone prophylaxis (OR, 2.99; 95% CI, 1.92 to 4.64), underlying hematological disease (OR, 2.09; 95% CI, 1.26 to 3.44), and the presence of a urinary catheter (OR, 2.54; 95% CI, 1.65 to 3.91), whereas older age (OR, 0.98; 95% CI, 0.97 to 0.99) was found to be protective. Our prediction model achieves good discrimination and calibration, thereby identifying neutropenic patients at higher risk of BSI due to MDR P. aeruginosa The application of this model using a web-based calculator may be a simple strategy to identify high-risk patients who may benefit from the early administration of broad-spectrum antibiotic coverage against MDR strains according to the local susceptibility patterns, thus avoiding the use of broad-spectrum antibiotics in patients at a low risk of resistance development.

Cost-effectiveness of Telemedicine-directed Specialized vs Standard Care for Patients With Inflammatory Bowel Diseases in a Randomized Trial.

BACKGROUND & AIMS: Telemedicine can be used to monitor determinants and outcomes of patients with chronic diseases, possibly increasing the quality and value of care. Telemedicine was found to reduce outpatient visits and hospital admissions for patients with inflammatory bowel diseases (IBD). We performed a full economic evaluation of telemedicine interventions in patients with IBD, comparing the cost-utility of telemedicine vs standard care. METHODS: We performed a randomized trial of 909 patients with IBD at 2 academic and 2 non-academic hospitals in The Netherlands. Patients were randomly assigned to groups that received telemedicine (myIBDcoach; n = 465) or standard outpatient care (n = 444) and followed for 12 months. Costs were measured from a societal perspective. Direct healthcare costs were based on actual resource use. Indirect costs comprised self-reported hours sick leave from work, intervention costs (annual license fee of €40 per patient [$45]), and utility costs (assessed using EQ5D). Cost-utility and uncertainty were estimated using the non-parametric bootstrapping method. RESULTS: Telemedicine resulted in lower mean annual costs of €547/patient [$612] (95% CI, €1029-2143 [$1150-2393]; mean costs of €9481 [$10,587] for standard care and €8924 [$9965] for telemedicine) without changing quality adjusted life years. At the Dutch threshold of €80,000 [$89,335] per quality adjusted life year, the intervention had increased incremental cost-effectiveness over standard care in 83% of replications and an incremental net monetary benefit of €707/patient [$790] (95% CI, €1241-2544 [$1386-2841]). CONCLUSIONS: Telemedicine with myIBDcoach is cost saving and has a high probability of being cost effective for patients with IBD. This self-management tool enables continuous registration of quality indicators and (patient-reported) outcomes and might help reorganize IBD care toward value-based healthcare. ClinicalTrials.gov no: NCT02173002.

Internalizing and externalizing symptoms and suicidal behaviour in young people: a systematic review and meta-analysis of longitudinal studies.

OBJECTIVE: To assess internalizing and externalizing symptoms as risk factors for suicidal behaviour and suicide among adolescents and young adults. METHOD: We conducted a systematic review of articles published until January 2017. We identified 26 883 potential papers; 1701 full-text articles were assessed for eligibility, of which 1479 were excluded because of methodological reasons. Diverse meta-analyses were performed for each group of symptoms. Odds ratios (ORs) and 95% confidence intervals (95% CI) or beta coefficients for categorical variables, and effect size (ES) were calculated for continuous variables. RESULTS: Finally, 41 studies were included, involving participants aged 12-26 years for a systematic review, and 24 articles were included for meta-analysis. The meta-analysis showed that youths with any internalizing (ES = 0.93) or externalizing symptoms (ES = 0.76 and OR = 2.59) were more likely to attempt suicide in future. This effect was also seen in depression symptoms (OR = 6.58 and ES = 1.00), legal problems (OR = 3.36), and anxiety (ES = 0.65). CONCLUSION: Reported internalizing and externalizing symptoms are predictors of suicide behaviour in young people; therefore, the detection and management of these symptoms in young populations could be a crucial strategy for preventing suicidality in this group.

Characterization of minimal lesions related to the presence of visna/maedi virus in the mammary gland and milk of dairy sheep.

BACKGROUND: In order to characterize the complete range of lesions, especially minimal, affecting mammary gland and viral antigen distribution and target cells using immunohistochemistry in naturally Visna/maedi (VM) 84 infected sheep were studied, forty-four from flocks with clinical cases (A) and 35 randomly sampled from two abattoirs (B) together with five negative controls (C). An immunocytochemistry technique was developed and further milk samples (n = 39) were used to study viral excretion, carrier cells and the role of milk and colostrum in the transmission of the disease. RESULTS: All sheep from group C and three sheep from group B were negative to VM in tissue sections by histopathology, immunohistochemistry and PCR, and also in serum using ELISA. Several degrees of CD3 + lymphocytic interstitial mastitis were observed in groups A and B: minimal (+) n = 26 sheep; moderate (++), n = 32 and severe (+++), n = 12. No differences in lesion distribution were observed between groups A and B. Viral presence was confirmed by immunohistochemistry using two different antibodies and/or PCR in every tissue with lesions while serology was negative in six sheep with lesions. Two milk samples taken from milk tanks from two flocks from group A and fourteen milk samples from 29 infected sheep from group B were positive to VM (most of them from animals with moderate and severe lesions). Positivity was only found in macrophages, even in focal and minimal lesions, while no positivity was observed in epithelial or any other cells in either tissue and milk samples. CONCLUSIONS: This new observation of the minimal lesions described in this work increased the prevalence of VM lesions in mammary gland up to 90.9% and VM should be considered as a differential diagnosis when minimal interstitial lesions are detected. A high prevalence of VM was observed in intensive milk-producing sheep, ELISA serology did not detect as positivity all infected animals, while histology, IHC or PCR showed higher sensitivity. The cytological technique developed was very useful in milk-cell studies using hematoxylin and eosin and immunocytochemistry. Viral detection in milk samples (16/39) confirms a potential but limited role of milk/colostrum in viral transmission.

Genetic Polymorphisms in Cytokine Genes in Colombian Patients with Ocular Toxoplasmosis.

Toxoplasmosis is caused by infection with the protozoan parasite Toxoplasma gondii, which has the capacity to infect all warm-blooded animals worldwide. Toxoplasmosis is a major cause of visual defects in the Colombian population; however, the association between genetic polymorphisms in cytokine genes and susceptibility to ocular toxoplasmosis has not been studied in this population. This work evaluates the associations between polymorphisms in genes coding for the cytokines tumor necrosis factor alpha (TNF-α) (rs1799964, rs1800629, rs1799724, rs1800630, and rs361525), interleukin 1ß (IL-1ß) (rs16944, rs1143634, and rs1143627), IL-1α (rs1800587), gamma interferon (IFN-γ) (rs2430561), and IL-10 (rs1800896 and rs1800871) and the presence of ocular toxoplasmosis (OT) in a sample of a Colombian population (61 patients with OT and 116 healthy controls). Genotyping was performed with the "dideoxynucleotide (ddNTP) primer extension" technique. Functional-effect predictions of single nucleotide polymorphisms (SNPs) were done by using FuncPred. A polymorphism in the IL-10 gene promoter (-1082G/A) was significantly more prevalent in OT patients than in controls (P = 1.93e-08; odds ratio [OR] = 5.27e+03; 95% confidence interval [CI] = 3.18 to 8.739; Bonferroni correction [BONF] = 3.48e-07). In contrast, haplotype "AG" of the IL-10 gene promoter polymorphisms (rs1800896 and rs1800871) was present at a lower frequency in OT patients (P = 7e-04; OR = 0.10; 95% CI = 0.03 to 0.35). The +874A/T polymorphism of IFN-γ was associated with OT (P = 3.37e-05; OR = 4.2; 95% CI = 2.478 to 7.12; BONF = 6.07e-04). Haplotype "GAG" of the IL-1ß gene promoter polymorphisms (rs1143634, rs1143627, and rs16944) appeared to be significantly associated with OT (P = 0.0494). The IL-10, IFN-γ, and IL-1ß polymorphisms influence the development of OT in the Colombian population.

Telemedicine for management of inflammatory bowel disease (myIBDcoach): a pragmatic, multicentre, randomised controlled trial.

BACKGROUND: Tight and personalised control of inflammatory bowel disease in a traditional setting is challenging because of the disease complexity, high pressure on outpatient clinics, and rising incidence. We compared the effects of self-management with a telemedicine system, which was developed for all subtypes of inflammatory bowel disease, on health-care utilisation and patient-reported quality of care versus standard care. METHODS: We did this pragmatic, randomised trial in two academic and two non-academic hospitals in the Netherlands. Outpatients aged 18-75 years with inflammatory bowel disease and without an ileoanal or ileorectal pouch anastomosis, who had internet access and Dutch proficiency, were randomly assigned (1:1) to care via a telemedicine system (myIBDcoach) that monitors and registers disease activity or standard care and followed up for 12 months. Randomisation was done with a computer-generated sequence and used the minimisation method. Participants, health-care providers, and staff who assessed outcome measures were not masked to treatment allocation. Primary outcomes were the number of outpatient visits and patient-reported quality of care (assessed by visual analogue scale score 0-10). Safety endpoints were the numbers of flares, corticosteroid courses, hospital admissions, emergency visits, and surgeries. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02173002. FINDINGS: Between Sept 9, 2014, and May 18, 2015, 909 patients were randomly assigned to telemedicine (n=465) or standard care (n=444). At 12 months, the mean number of outpatient visits to the gastroenterologist or nurse was significantly lower in the telemedicine group (1·55 [SD 1·50]) than in the standard care group (2·34 [1·64]; difference -0·79 [95% CI -0·98 to -0·59]; p<0·0001), as was the mean number of hospital admissions (0·05 [0·28] vs 0·10 [0·43]; difference -0·05 [-0·10 to 0·00]; p=0·046). At 12 months, both groups reported high mean patient-reported quality of care scores (8·16 [1·37] in the telemedicine group vs 8·27 [1·28] in the standard care group; difference 0·10 [-0·13 to 0·32]; p=0·411). The mean numbers of flares, corticosteroid courses, emergency visits, and surgeries did not differ between groups. INTERPRETATION: Telemedicine was safe and reduced outpatient visits and hospital admissions compared with standard care. This self-management tool might be useful for reorganising care of inflammatory bowel disease towards personalised and value-based health care. FUNDING: Maastricht University Medical Centre and Ferring.

Patient-Reported Outcome Measures for Use in Clinical Trials and Clinical Practice in Inflammatory Bowel Diseases: A Systematic Review.

BACKGROUND & AIMS: Mucosal inflammation must be carefully monitored to improve the long-term outcomes of patients with inflammatory bowel diseases (IBD). Patient-reported outcome measures (PROMs) are used increasingly to monitor disease activity in clinical practice and as endpoints in clinical trials. We performed a systematic review to provide an overview of the available PROMs on IBD activity and to evaluate their diagnostic value. METHODS: A systematic search of the PubMed, Medline, Cochrane library, and Embase databases using defined keywords, identified 973 articles. These were screened by 2 independent reviewers, and 37 articles on development or validation of PROMs to assess IBD activity were identified for further analysis. Based on the recommendations of the Food and Drug Administration (FDA), the following measurement properties were evaluated: content, construct, and criterion validity; reliability; and responsiveness to change. In addition, data on ease of use in clinical practice were collected. RESULTS: Seventeen articles presenting 20 different PROMs were included the final analysis, although none met all the FDA-recommended criteria. Only 2 PROMs (patient-reported Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores) reported patient involvement during its development. Only 6 PROMs (patient-reported global assessment, patient assessment of disease activity, mobile health index for Crohn's disease, mobile health index for ulcerative colitis, patient-reported outcome derived from the Mayo score, and the 6-point Mayo score) were validated as markers of IBD activity, using findings from endoscopy as the reference standard; these PROMs identified patients with mucosal inflammation with area under the curve values of 0.63-0.82. The mobile health index for CD and UC scores had the best measurement properties for use in clinical practice and in clinical trials. CONCLUSIONS: In a systematic review, we identified more than 20 PROMS that have been developed and tested for their ability to determine IBD activity. Further studies are needed to determine their accuracy and whether they can be used effectively in routine practice, clinical trials, telemedicine systems, and value-based healthcare programs.

Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression.

BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is an aggressive tumor type affecting cholangiocytes. CCAs frequently arise under certain cholestatic liver conditions. Intrahepatic accumulation of bile acids may facilitate cocarcinogenic effects by triggering an inflammatory response and cholangiocyte proliferation. Here, the role of bile acid receptors FXR and TGR5 in CCA progression was evaluated. METHODS: FXR and TGR5 expression was determined in human CCA tissues and cell lines. An orthotopic model of CCA was established in immunodeficient mice and tumor volume was monitored by magnetic resonance imaging under chronic administration of the specific FXR or TGR5 agonists, obeticholic acid (OCA) or INT-777 (0,03% in chow; Intercept Pharmaceuticals), respectively. Functional effects of FXR or TGR5 activation were evaluated on CCA cells in vitro. RESULTS: FXR was downregulated whereas TGR5 was upregulated in human CCA tissues compared to surrounding normal liver tissue. FXR expression correlated with tumor differentiation and TGR5 correlated with perineural invasion. TGR5 expression was higher in perihilar than in intrahepatic CCAs. In vitro, FXR was downregulated and TGR5 was upregulated in human CCA cells compared to normal human cholangiocytes. OCA halted CCA growth in vivo, whereas INT-777 showed no effect. In vitro, OCA inhibited CCA cell proliferation and migration which was associated with decreased mitochondrial energy metabolism. INT-777, by contrast, stimulated CCA cell proliferation and migration, linked to increased mitochondrial energy metabolism. CONCLUSION: Activation of FXR inhibits, whereas TGR5 activation may promote, CCA progression by regulating proliferation, migration and mitochondrial energy metabolism. Modulation of FXR or TGR5 activities may represent potential therapeutic strategies for CCA.

Comparing genetic diversity and demographic history in co-distributed wild South American camelids.

Vicuñas and guanacos are two species of wild South American camelids that are key ruminants in the ecosystems where they occur. Although closely related, these species feature differing ecologies and life history characters, which are expected to influence both their genetic diversity and population differentiation at different spatial scales. Here, using mitochondrial and microsatellite genetic markers, we show that vicuña display lower genetic diversity within populations than guanaco but exhibit more structure across their Peruvian range, which may reflect a combination of natural genetic differentiation linked to geographic isolation and recent anthropogenic population declines. Coalescent-based demographic analyses indicate that both species have passed through a strong bottleneck, reducing their effective population sizes from over 20,000 to less than 1000 individuals. For vicuña, this bottleneck is inferred to have taken place ~3300 years ago, but to have occurred more recently for guanaco at ~2000 years ago. These inferred dates are considerably later than the onset of domestication (when the alpaca was domesticated from the vicuña while the llama was domesticated from the guanaco), coinciding instead with a major human population expansion following the mid-Holocene cold period. As importantly, they imply earlier declines than the well-documented Spanish conquest, where major mass mortality events were recorded for Andean human and camelid populations. We argue that underlying species' differences and recent demographic perturbations have influenced genetic diversity in modern vicuña and guanaco populations, and these processes should be carefully evaluated in the development and implementation of management strategies for these important genetic resources.

Multicenter study to assess presenteeism in systemic lupus erythematosus and its relationship with clinical and sociodemographic features.

Objective The aim of this study was to measure presenteeism (productivity impairment while the patient is at work) and the related risk factors in patients with systemic lupus erythematosus (SLE) from Argentina. Methods A total of 130 consecutive (1997 American College of Rheumatology (ACR) criteria) working patients with SLE were assessed using a standardized data collection form. Sociodemographic, disease and work-related variables were collected. The Work Productivity and Activity Impairment (WPAI) questionnaire was performed. Results Overall, 130 patients were included in the analysis; 91% were women, and the mean age was 39 years (range 19-77). A total of 43% were White, 43% Mestizo and 13% Amerindian. Overall, 38% were single and 38% were married. A total of 75% had more than 12 years of formal education. The median disease duration was 7 years (interquartile range 25-75 (IQR) 4-13). Median Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score was 0 (IQR 0-2), and median Systemic Lupus International Collaborating Clinics/ACR Damage Index (SLICC-SDI) score was 0 (IQR 0-1). Lupus quality of life (LupusQoL) domains scores were: physical health 87 (IQR 70-96), emotional health 78 (IQR 54-91), burden to others 75 (IQR 50-92), intimate relationships 87 (IQR 50-100), and body image 85 (IQR 70-100). Absenteeism was 8%, presenteeism was 19%, and overall work impairment (absenteeism + presenteeism) was 26%. In the multiple regression analysis, considering presenteeism as dependent variable, (adjusting by age, disease duration, >12 years of education, Non-white race, Visual Analogue Scale (VAS) pain, VAS fatigue, SLICC-SDI, LupusQoL, physical and emotional domains), we found that SLICC-SDI (odds ratio (OR) 1.68, confidence interval (CI) 1-2.7) and Non-white race (OR 3.27, CI 1.04-10) were related to presenteeism and >12 years of education (OR 0.30, CI 0.09-0.98) and higher scores of LupusQoL emotional health domain (OR 0.95, CI 0.92-0.98) were protective. Conclusions organ damage and Non-white race were significantly associated with presenteeism while >12 years of education and higher scores of LupusQoL emotional health domain were protective.

Flunarizine in migraine-related headache prevention: results from 200 patients treated in the UK.

BACKGROUND AND PURPOSE: For over 20 years, as a group we have been using flunarizine in primary headache disorders. Flunarizine is widely used in Europe, but not licensed in the UK. In September 2014, the National Institute for Clinical Excellence published supportive guidelines for flunarizine use in migraine, based on randomized controlled evidence that it is as effective as propranolol and topiramate in adults. METHODS: We reviewed a cohort of adult patients (n = 200) treated with flunarizine from our practice. The clinical information of these patients, i.e. diagnosis, dose, efficacy, side effects and duration of treatment, was collected. RESULTS: The most common indication for flunarizine use was chronic migraine, followed by migraine with aura, sporadic hemiplegic migraine, familial hemiplegic migraine and new daily persistent headache with migrainous features. Flunarizine was generally effective, with only 24% (n = 47) of patients reporting no clinical effect. The most common dose used was 10 mg per day. Duration of treatment information was available for 39% (n = 78) of patients. Of these patients, 64% (n = 50) continued treatment for more than 1 year. Doses up to 15 mg were generally well tolerated, with only 10.5% (n = 21) of patients stopping treatment due to adverse effects. The most common adverse events were tiredness, mood change and weight gain. CONCLUSION: The data provide supportive evidence from tertiary headache practice in the UK for the use of flunarizine in migraine. The data encourages development of future guidance regarding flunarizine use in headache centres in countries where its use is not routine.

Exploring conditions for redistribution of anti-tumor necrosis factors to reduce spillage: A study on the quality of anti-tumor necrosis factor home storage.

BACKGROUND AND AIM: Biologicals are potent drugs for immune-mediated inflammatory diseases. After discontinuation or switch of therapy, many patients have unused biological injectors left. This study aimed to evaluate potential redistribution of unused injectors to prevent spillage of these costly drugs by assessing (i) the quality of transport and home storage through the proportion of injectors stored within the recommended temperature range (2-8 °C) and (ii) acceptance of redistribution by patients. METHODS: All golimumab users, irrespective of the indication, at Maastricht University Medical Center were eligible for inclusion. Patients received golimumab in a sealed bag containing a validated temperature sensor, measuring temperature every 5 min. Patients were asked to store their medication as usual. Deviations from the recommended range were defined as any duration below 0 °C and > 30 min below 2 °C or above 8 °C. After 3 months, patients completed a questionnaire on their opinion towards potential redistribution of unused biologicals. RESULTS: Fifty patients (42.0% male, mean age 53.2 ± 14.3 years) received 276 injectors. The mean storage time was 30.9 ± 33.1 days. Only 11.6% of the injectors were stored within the recommended temperature range. In addition, 11.2% were stored > 30 min below 0 °C and 33.2% were stored > 1 week above 8 °C. Of all patients, 95% would accept redistributed medication when product quality is ensured. CONCLUSIONS: During transport and home storage, only one in eight biological injectors was stored within the recommended temperature range. This hinders redistribution of unused injectors but also raises concern regarding drug effectiveness in immune-mediated inflammatory disease patients.