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Background & Aims: HBV coinfection is common among people living with HIV (PLWH) and is the most important cause of hepatocellular carcinoma (HCC). While risk prediction tools for HCC have been validated in patients with HBV monoinfection, they have not been evaluated in PLWH. Thus, we performed an external validation of PAGE-B in people with HIV/HBV coinfection.Methods: We included data on PLWH from four European cohorts who were positive for HBsAg and did not have HCC before starting tenofovir. We estimated the predictive performance of PAGE-B for HCC occurrence over 15 years in patients receiving tenofovir-containing antiretroviral therapy. Model discrimination was assessed after multiple imputation using Cox regression with the prognostic index as a covariate, and by calculating Harrell's c-index. Calibration was assessed by comparing our cumulative incidence with the PAGE-B derivation study using Kaplan-Meier curves.Results: In total, 2,963 individuals with HIV/HBV coinfection on tenofovir-containing antiretroviral therapy were included. PAGE-B was Conclusions: For individuals with HIV/HBV coinfection, PAGE-B is a valid tool to determine the need for HCC screening. Impact and implications: Chronic HBV infection is the most important cause of hepatocellular carcinoma (HCC) among people living with HIV. Valid risk prediction may enable better targeting of HCC screening efforts to high-risk individuals. We aimed to validate PAGE-B, a risk prediction tool that is based on age, sex, and platelets, in 2,963 individuals with HIV/HBV coinfection who received tenofovir-containing antiretroviral therapy. In the present study, PAGE-B showed good discrimination, adequate calibration, and a cut-off of

BACKGROUND: The prevalence of atrial fibrillation(AF) and diabetes mellitus is rising to epidemic proportions. We aimed to assess the impact of diabetes on the management and outcomes of patients with AF.METHODS: The EORP-AF General Long-Term Registry is a prospective, observational registry from 250 centres across 27 European countries. Outcomes of interest were as follows: i)rhythm control interventions; ii)quality of life; iii)healthcare resource utilisation; and iv)major adverse events.RESULTS: Of 11,028 patients with AF, the median age was 71 (63-77) years and 2537 (23.0%) had diabetes. Median follow-up was 24 months. Diabetes was related to increased use of anticoagulation but less rhythm control interventions. Using multivariable analysis, at 2-year follow-up, patients with diabetes were associated with greater levels of anxiety (p = 0.038) compared to those without diabetes. Overall, diabetes was associated with worse health during follow-up, as indicated by Health Utility Score and Visual Analogue Scale. Healthcare resource utilisation was greater with diabetes in terms of length of hospital stay (8.1 (±8.2) vs. 6.1 (±6.7) days); cardiology and internal medicine/general practitioner visits; and emergency room admissions. Diabetes was an independent risk factor of major adverse cardiovascular event (MACE; HR 1.26 [95% CI, 1.04-1.52]), all-cause mortality (HR 1.28 [95% CI, 1.08-1.52]), and cardiovascular mortality (HR 1.41 [95% CI, 1.09-1.83]).CONCLUSION: In this contemporary AF cohort, diabetes was present in 1 in 4 patients and it served as an independent risk factor for reduced quality of life, greater healthcare resource utilisation and excess MACE, all-cause mortality and cardiovascular mortality. There was increased use of anticoagulation therapy in diabetes but with less rhythm control interventions.

The Amargosa niterwort is a narrow endemic restricted to alkali wetlands of the northern Mojave Desert in Inyo County, California and Nye County, Nevada. Groundwater pumping and subsequent hydrological alteration within the Amargosa groundwater basin has been identified as the most significant threat to the long-term persistence of the species. Parallel monitoring programs were established in California (2010) and Nevada (2014) to establish baseline trends in abundance, measured as ramet (stem) number, and to aid in determining management actions that are needed to ensure the long-term viability of populations. Monitoring in California shows significant variation in abundance between years; however, there are consistent trends, indicating that factors influencing increase or decrease in abundance is similar across the population. However, this pattern is not shared in Nevada, where following a sharp decline between 2014 and 2015 the population has remained relatively stable. Two of the three Nevada macroplots are downstream from Crystal Reservoir and are likely influenced by discharge from the reservoir including periodic water releases and leakage from the earthen dam. Significant increases and decreases in abundance within macroplots are not correlated with climate variables including precipitation, thus it is important to understand how groundwater flow and spring discharge impacts abundance of plants within and between populations.

BackgroundPediatric obesity is a multifactorial disease which can be caused by underlying medical disorders arising from disruptions in the hypothalamic leptin-melanocortin pathway, which regulates satiety and energy expenditure.AimTo investigate and compare resting energy expenditure (REE) and body composition characteristics of children and adolescents with severe obesity with or without underlying medical causes.MethodsThis prospective observational study included pediatric patients who underwent an extensive diagnostic workup in our academic centre that evaluated endocrine, non-syndromic and syndromic genetic, hypothalamic, and medication-induced causes of obesity. REE was assessed by indirect calorimetry; body composition by air displacement plethysmography. The ratio between measured REE (mREE) and predicted REE (Schofield equations), REE%, was calculated, with decreased mREE defined as REE% ≤90% and elevated mREE ≥110%. Additionally, the influence of fat-free-mass (FFM) on mREE was evaluated using multiple linear regression.ResultsWe included 292 patients (146 [50%] with body composition measurements), of which 218 (75%) patients had multifactorial obesity and 74 (25%) an underlying medical cause: non-syndromic and syndromic genetic (n= 29 and 28, respectively), hypothalamic (n= 10), and medication-induced (n= 7) obesity. Mean age was 10.8 ± 4.3 years, 59% were female, mean BMI SDS was 3.8 ± 1.1, indicating severe obesity. Mean REE% was higher in children with non-syndromic genetic obesity (107.4% ± 12.7) and lower in children with hypothalamic obesity (87.6% ± 14.2) compared to multifactorial obesity (100.5% ± 12.6, both p0.05).ConclusionsIn this cohort of children with severe obesity due to various etiologies, large inter-individual differences in mREE were found. Consistent with previous studies, almost half of patients had decreased or elevated mREE. This knowledge is important for patient-tailored treatment, e.g. personalized dietary and physical activity interventions and consideration of pharmacotherapy affecting central energy expenditure regulation in children with decreased mREE.

Many viruses achieve reversible attachment to sialic acid (Sia) by encoding envelope glycoproteins with receptor-binding and receptor-destroying activities. Toroviruses and group 2 coronaviruses bind to O-acetylated Sias, presumably via their spike proteins (S), whereas other glycoproteins, the hemagglutinin-esterases (HE), destroy Sia receptors by de-O-acetylation. Here, we present a comprehensive study of these enzymes. Sialate-9-O-acetylesterases specific for 5-N-acetyl-9-O-acetylneuraminic acid, described for bovine and human coronaviruses, also occur in equine coronaviruses and in porcine toroviruses. Bovine toroviruses, however, express novel sialate-9-O-acetylesterases, which prefer the di-O-acetylated substrate 5-N-acetyl-7(8),9-di-O-acetylneuraminic acid. Whereas most rodent coronaviruses express sialate-4-O-acetylesterases, the HE of murine coronavirus DVIM cleaves 9-O-acetylated Sias. Under the premise that HE specificity reflects receptor usage, we propose that two types of Sias serve as initial attachment factors for coronaviruses in mice. There are striking parallels between orthomyxo- and nidovirus biology. Reminiscent of antigenic shifts in orthomyxoviruses, rodent coronaviruses exchanged S and HE sequences through recombination to extents not appreciated before. As for orthomyxovirus reassortants, the fitness of nidovirus recombinant offspring probably depends both on antigenic properties and on compatibility of receptor-binding and receptor-destroying activities.

Carbon (C) emissions from wildfires are a key terrestrial–atmosphere interaction that influences global atmospheric composition and climate. Positive feedbacks between climate warming and boreal wildfires are predicted based on top-down controls of fire weather and climate, but C emissions from boreal fires may also depend on bottom-up controls of fuel availability related to edaphic controls and overstory tree composition. Here we synthesized data from 417 field sites spanning six ecoregions in the northwestern North American boreal forest and assessed the network of interactions among potential bottom-up and top-down drivers of C emissions. Our results indicate that C emissions are more strongly driven by fuel availability than by fire weather, highlighting the importance of fine-scale drainage conditions, overstory tree species composition and fuel accumulation rates for predicting total C emissions. By implication, climate change-induced modification of fuels needs to be considered for accurately predicting future C emissions from boreal wildfires.

IntroductionHypothalamic obesity (HO) in children has severe health consequences. Lifestyle interventions are mostly insufficient and currently no drug treatment is approved for children with HO. Amphetamines are known for their stimulant side-effect on resting energy expenditure (REE) and suppressing of appetite. Earlier case series have shown positive effects of amphetamines on weight in children with acquired HO. We present our experiences with dextroamphetamine treatment in the, up to now, largest cohort of children with HO.MethodsA retrospective cohort evaluation was performed of children with HO treated with dextroamphetamine at two academic endocrine pediatric clinics. Off-label use of dextroamphetamine was initiated in patients with progressive, therapy-resistant acquired or congenital HO. Anthropometrics, REE, self-reported (hyperphagic) behavior and energy level, and side effects were assessed at start and during treatment.ResultsNineteen patients with a mean age of 12.3 ± 4.0 years had been treated with dextroamphetamine. In two patients, ΔBMI SDS could not be evaluated due to short treatment duration or the simultaneous start of extensive lifestyle treatment. Mean treatment duration of the 17 evaluated patients was 23.7 ± 12.7 months. Fourteen patients (n = 10 with acquired HO, n = 4 with congenital HO) responded by BMI decline or BMI stabilization (mean ΔBMI SDS of -0.6 ± 0.8, after a mean period of 22.4 ± 10.5 months). In three patients, BMI SDS increased (mean ΔBMI SDS of +0.5 ± 0.1, after a mean period of 29.7 ± 22.6 months). In 11 responders, measured REE divided by predicted REE increased with +8.9%. Thirteen patients (68.4%) reported decreased hyperphagia, improvement of energy level and/or behavior during treatment. Two patients developed hypertension during treatment, which resulted in dosage adjustment or discontinuation of treatment. Twelve children continued treatment at last moment of follow-up.ConclusionIn addition to supportive lifestyle interventions, dextroamphetamine treatment may improve BMI in children with HO. Furthermore, dextroamphetamines have the potential to decrease hyperphagia and improve resting energy expenditure, behavior, and energy level. In patients with acquired HO, these effects seem to be more pronounced when compared to patients with congenital HO. Future studies are needed to support these results.

Purpose: The purpose of this study was to observe the impact of oral oncological treatment, including the recovery of several tongue functions (force, mobility, and sensory functions), and to determine the influence of these functions on masticatory performance. Materials and methods: Masticatory performance and tongue force, mobility, and sensory functions were determined in 123 patients with oral cavity cancer. The assessments were performed 4 weeks before treatment and 4 to 6 weeks, 6 months, 1 year, and 5 years after treatment. Generalized estimation equations and mixed model analyses were performed, correcting for previously identified factors in the same population. Results: A significant deterioration in tongue mobility and sensory function was observed in patients with mandible and tongue and/or floor-of-mouth tumors. Better tongue force and sensory function (thermal and tactile) positively influenced masticatory performance, and this effect was stronger where fewer occlusal units were present. The effect of both the tongue force and maximum bite force was weaker in dentate patients in comparison with patients with full dentures. A web-based application was developed to enable readers to explore our results and provide insight into the coherence between the found factors in the mixed model. Conclusions: Tongue function deteriorates after oral oncological treatment, without statistically significant recovery. Adequate bite and tongue forces are especially important for patients with a poor prosthetic state. Patients with sensory tongue function deficits especially benefit from the presence of more occluding pairs.

Objective Old or frail acutely hospitalised patients can benefit from geriatric rehabilitation but criteria concerning referral decisions are unclear. This review presents an overview of clinical factors associated with referral to geriatric rehabilitation that may further consensus between hospital and rehabilitation professionals on triage. Design Scoping review. Methods A review was conducted following Arksey and O’Malley’s framework. The search included literature concerning a broad spectrum of acutely hospitalised patients and factors associated with their referral to geriatric rehabilitation. Results Selected abstracts were categorised into distinct geriatric rehabilitation care pathways such as stroke, hip fracture, amputation of lower limb, cardiac and oncologic rehabilitation. Abstracts on internal medical patients were further reviewed and 29 studies were included. A total of 13 studies focused on factors identifying rehabilitation needs and 16 on factors associated with outcome of geriatric rehabilitation. Triage factors were diverse and included frailty status, functional decline, cognitive symptoms and multimorbidity. Mood symptoms and living situation further specified post-acute care needs. In overview, triage factors could be characterised as demographic (n = 4), diagnosis-related (n = 8), mental (n = 6), functional (n = 10) or multi-domain (n = 12) and mapped in a transitional care pathway. Conclusions and implications Frailty and functional decline are characteristics frequently associated with referral to geriatric rehabilitation of acutely hospitalised internal medical patients. A comprehensive geriatric assessment or a simpler multi-domain set of tests reveals rehabilitation needs and approximates a functional prognosis. Professional consensus on factors and timing of triage in hospital is within reach.

BACKGROUND: Cardiac troponins (cTn) have been reported to be predictors for adverse outcomes in atrial fibrillation (AF), patients, but their actual use is still unclear.AIM: To assess the factors associated with cTn testing in routine practice and evaluate the association with outcomes.METHODS: Patients enrolled in the ESC-EHRA EORP-AF General Long-Term Registry were stratified into 3 groups according to cTn levels as (i) cTn not tested, (ii) cTn in range (≤99th percentile), (iii) cTn elevated (>99th percentile). The composite outcome of any thromboembolism /any acute coronary syndrome/cardiovascular (CV) death, defined as Major Adverse Cardiovascular Events (MACE) and all-cause death were the main endpoints.RESULTS: Among 10 445 AF patients (median age 71 years, 40.3% females) cTn were tested in 2834 (27.1%). cTn was elevated in 904/2834 (31.9%) and in-range in 1930/2834 (68.1%) patients. Female sex, in-hospital enrollment, first-detected AF, CV risk factors, history of coronary artery disease, and atypical AF symptoms were independently associated with cTn testing. Elevated cTn were independently associated with a higher risk for MACE (Model 1, hazard ratio [HR] 1.74, 95% confidence interval [CI] 1.40-2.16, Model 2, HR 1.62, 95% CI 1.28-2.05; Model 3 HR 1.76, 95% CI 1.37-2.26) and all-cause death (Model 1, HR 1.45, 95% CI 1.21-1.74; Model 2, HR 1.36, 95% CI 1.12-1.66; Model 3, HR 1.38, 95% CI 1.12-1.71).CONCLUSIONS: Elevated cTn levels were associated with an increased risk of all-cause mortality and adverse CV events. Clinical factors that might enhance the need to rule out CAD were associated with cTn testing.

Candida glabrata is among the most prevalent causes of candidiasis. Unlike Candida albicans, it is not capable of changing morphology between yeast and hyphal forms but instead has developed other virulence factors. An important feature is its unprecedented large repertoire of predicted cell wall adhesins, which are thought to enable adherence to a variety of surfaces under different conditions. Here, we analyzed the wall proteome of PEU1221, a high biofilm-forming clinical strain isolated from an infected central venous catheter, under biofilm-forming conditions. This isolate shows increased incorporation of putative adhesins, including eight proteins that were not detected in walls of reference strain ATCC 2001, and of which Epa22, Awp14, and Awp2e were identified for the first time. The proteomics data suggest that cluster III adhesin Awp14 is relatively abundant in PEU1221. Phenotypic studies with awp14Δ deletion mutants showed that Awp14 is not responsible for the high biofilm formation of PEU1221 onto polystyrene. However, awp14Δ mutant cells in PEU1221 background showed a slightly diminished binding to chitin and seemed to sediment slightly slower than the parental strain suggesting implication in fungal cell-cell interactions. By structural modeling, we further demonstrate similarity between the ligand-binding domains of cluster III adhesin Awp14 and those of cluster V and VI adhesins. In conclusion, our work confirms the increased incorporation of putative adhesins, such as Awp14, in high biofilm-forming isolates, and contributes to decipher the precise role of these proteins in the establishment of C. glabrata infections.

Background Shoulder injections for conditions such as adhesive capsulitis are commonly performed and can be administered through image-based or landmark-based injection approaches. Ultrasound-guided injections are widely used and accurate because ultrasound allows real-time visualization of the needle and injected contrast. Landmark-based injections would be advantageous, if they were accurate, because they would save the time and expense associated with ultrasound. However, few prospective studies have compared well-described landmark-based shoulder injection techniques without ultrasound. Question/purpose Using anatomic landmarks, and without using ultrasound, is the accuracy of glenohumeral injection for adhesive capsulitis greater via the posterior approach or via a new anterior approach? Methods Between 2018 and 2020, we treated 108 patients potentially eligible for adhesive capsulitis treatment. These patients had clinical symptoms of aggravating shoulder pain with a duration of less than 4 months and passively impaired, painful glenohumeral ROM. Due to the exclusion of patients with other shoulder conditions (full-thickness rotator cuff ruptures and posttraumatic stiffness), 95 patients received an injection in this sequential, prospective, comparative study. Between 2018 and 2019, 41 patients (17 males and 24 females; mean age 52 ± 5 years; mean BMI 24 ± 3 kg/m2) were injected through the posterior approach, with the acromion as the anatomical landmark, during the first part of the study period. After that, between 2019 and 2020, 54 patients (20 males and 34 females; mean age 54 ± 4 years; mean BMI 23 ± 3 kg/m2) received an injection through a new anterior approach, with the acromioclavicular joint as the anatomic landmark, during the second part of the study period. Injections via both approaches were administered by two experienced shoulder specialists (both with more than 10 years of experience). Both specialists had experience with the posterior approach before this study, and neither had previous training with the new anterior approach. Injections contained a corticosteroid, local anaesthetic, and contrast medium. Radiographs were taken within 20 minutes after the injection, and a radiologist blinded to the technique determined accuracy. Accurate injections were defined as having contrast fluid limited to the glenohumeral joint, while inaccurate injections displayed leakage of contrast fluid into the soft tissue or subacromial space. All of the enrolled patients were analyzed. Results In the group with the posterior approach, the accuracy was 78% (32 of 41) in contrast to 94% (51 of 54, odds ratio 0.21 [95% CI 0.05 to 0.83]; p = 0.03) in patients with the new anterior approach. Conclusion The new anterior approach without the use of ultrasound was more accurate than the posterior approach. In fact, it was nearly as accurate as previously published ultrasound-guided approaches. We recommend using the new anterior approach for intraarticular glenohumeral injections instead of ultrasound-guided injections because it will save time and costs associated with ultrasound. Still, the clinical effects (anxiety, pain, functional outcome, and adverse events) of the new anterior approach should be compared with ultrasound-guided injections in a randomized study. Level of evidence Level II, therapeutic study.

Preliminary data suggest that allogeneic stem cell transplantation (allo-SCT) may be effective in T-prolymphocytic leukemia (T-PLL). The purpose of the present observational study was to assess the outcome of allo-SCT in patients aged 65 years or younger with a centrally confirmed diagnosis of T-PLL. Patients were consecutively registered with the EBMT at the time of transplantation and followed by routine EBMT monitoring but with an extended dataset. Between 2007 and 2012, 37 evaluable patients (median age 56 years) were accrued. Pre-treatment contained alemtuzumab in 95% of patients. Sixty-two percent were in complete remission (CR) at the time of allo-SCT. Conditioning contained total body irradiation with 6 Gy or more (TBI6) in 30% of patients. With a median follow-up of 50 months, the 4-year non-relapse mortality, relapse incidence, progression-free (PFS) and overall survival were 32, 38, 30 and 42%, respectively. By univariate analysis, TBI6 in the conditioning was the only significant predictor for a low relapse risk, and an interval between diagnosis and allo-SCT of more than 12 months was associated with a lower NRM. This study confirms for the first time prospectively that allo-SCT can provide long-term disease control in a sizable albeit limited proportion of patients with T-PLL.

Rationale: Strontium isotope analysis can be applied to the calcined human otic capsule in the petrous part (pars petrosa ossis temporalis; PP) to gain information on childhood mobility in archaeological and forensic contexts. However, only a thin layer of the otic capsule, the inner cortex, demonstrates virtually no remodelling. This paper proposes an improved sampling method for the accurate sampling of the inner cortex of the otic capsule to ensure that 87Sr/86Sr ratios related to early childhood are obtained. Methods: Calcined rib and diaphyseal fragments and PP from ten cremation deposits are sampled for strontium isotope analysis, whereby our improved sampling strategy is applied to sample the inner cortex of the otic capsule. This allows inter- and intraskeletal 87Sr/86Sr comparison within an Iron Age collection from Oss, The Netherlands. Results: Forty percent (4/10) of the calcined PP that were evaluated for this study show marked differences in 87Sr/86Sr (0.00035–0.00065) between the inner cortex and the bone sample surrounding this layer, the external cortex that has higher remodelling rates. Differences in 87Sr/86Sr between various skeletal elements also aided in the identification of the minimum number of individuals. Conclusions: Our study demonstrates the problematic nature of the external cortex and stresses the need for a precise sampling method of the correct areas of the otic capsule. This can only be obtained by cutting the calcined PP midmodiolarly to enable adequate combustion degree assessment, and the correct identification and sampling of the inner cortex of the otic capsule.

Contains fulltext : 232443.pdf (Publisher’s version ) (Closed access) BACKGROUND: In the Netherlands, access to direct-acting antivirals (DAAs) against hepatitis C virus (HCV) has been unrestricted for chronic infection since 2015. We evaluated whether the nationwide incidence of HCV infections in individuals with HIV has changed since 2015. METHODS: In this retrospective cohort study, data from the ATHENA cohort of people with HIV aged 18 years or older attending any of the 24 HIV treatment centres in the Netherlands between 2000 and 2019 were assessed. We used parametric proportional hazards models with a piecewise exponential survival function to model HCV primary infection and reinfection incidence per 1000 person-years. FINDINGS: Of the 23 590 individuals without previous HCV infection, 1269 cases of HCV primary infection were documented (incidence 5·2 per 1000 person-years [95% CI 5·0-5·5]). The highest incidence was observed in men who have sex with men (MSM; 7·7 per 1000 person-years [7·3-8·2]) and was lower in people who inject drugs (PWID; 1·7 per 1000 person-years [0·7-4·1]) and other key populations (1·0 per 1000 person-years [0·8-1·2]). In MSM, incidence increased in 2007 to 14·3 per 1000 person-years and fluctuated between 8·7 and 13·0 per 1000 person-years from 2008 to 2015. In 2016, incidence declined to 6·1 cases per 1000 person-years and remained steady between 4·1 and 4·9 per 1000 person-years from 2017 to 2019. Of the 1866 individuals with a previous HCV infection, 274 reinfections were documented (incidence 26·9 per 1000 person-years [95% CI 23·9-30·3]). The highest incidence rate was observed in MSM (38·5 per 1000 person-years [33·9-43·7]) and was lower in PWID (10·9 per 1000 person-years [3·5-33·8]) and other key populations (8·9 per 1000 person-years [6·3-12·5]). In MSM, reinfection incidence fluctuated between 38·0 and 88·9 per 1000 person-years from 2006 to 2015, reaching 55·6 per 1000 person-years in 2015. In 2016, reinfection incidence declined to 41·4 per 1000 person-years, followed by further decreases to 24·4 per 1000 person-years in 2017 and 11·4 per 1000 person-years in 2019. INTERPRETATION: The sharp decline in HCV incidence in MSM with HIV shortly after restrictions on DAAs were lifted suggests a treatment-as-prevention effect. HCV incidence was already low in PWID and other groups before unrestricted access. Ongoing HCV transmission is occurring in MSM, as illustrated by a declining but high rate of reinfection, stressing the need for additional preventive measures. FUNDING: Dutch Ministry of Health, Welfare, and Sport.

Candida auris is an emerging multidrug-resistant fungal pathogen responsible for nosocomial outbreaks of invasive candidiasis. Although several studies on the pathogenicity of this species have been reported, the knowledge on C. auris virulence is still limited. This study aims to analyze the pathogenicity of C. auris, using one aggregating isolate and eleven non-aggregating isolates from different clinical origins (blood, urine and oropharyngeal specimens) in two alternative host models of candidiasis: Caenorhabditis elegans and Galleria mellonella. Furthermore, possible associations between virulence, aggregation, biofilm-forming capacity, and clinical origin were assessed. The aggregating phenotype isolate was less virulent in both in vivo invertebrate infection models than non-aggregating isolates but showed higher capacity to form biofilms. Blood isolates were significantly more virulent than those isolated from urine and respiratory specimens in the G. mellonella model of candidiasis. We conclude that both models of candidiasis present pros and cons but prove useful to evaluate the virulence of C. auris in vivo. Both models also evidence the heterogeneity in virulence that this species can develop, which may be influenced by the aggregative phenotype and clinical origin. This work was supported by the Euskal Herriko Unibertsitatea [PIF 16/39]; Euskal Herriko Unibertsitatea [PIF17/167]; Eusko Jaurlaritza [GIC15/78 IT-990-16]; Ministerio de Economia y Competitividad [SAF2017-86188-P].

Candida parapsilosis is a frequent cause of fungal bloodstream infections, especially in critically ill neonates or immunocompromised patients. Due to the formation of biofilms, the use of indwelling catheters and other medical devices increases the risk of infection and complicates treatment, as cells embedded in biofilms display reduced drug susceptibility. Therefore, biofilm formation may be a significant clinical parameter, guiding downstream therapeutic choices. Here, we phenotypically characterized 120 selected isolates out of a prospective collection of 215 clinical C. parapsilosis isolates, determining biofilm formation, major emerging colony morphotype, and antifungal drug susceptibility of the isolates and their biofilms. In our isolate set, increased biofilm formation capacity was independent of body site of isolation and not predictable using standard or modified European Committee on Antimicrobial Susceptibility Testing (EUCAST) drug susceptibility testing protocols. In contrast, biofilm formation was strongly correlated with the appearance of non-smooth colony morphotypes and invasiveness into agar plates. Our data suggest that the observation of non-smooth colony morphotypes in cultures of C. parapsilosis may help as an indicator to consider the initiation of anti-biofilm-active therapy, such as the switch from azole- to echinocandin- or polyene-based strategies, especially in case of infections by potent biofilm-forming strains. This work was funded in part by grants or scholarships from the ZabaldUz program (Universidad del País Vasco/Euskal Herriko Unibertsitatea) to IDlP, the Consejería de Educación, Universidades e Investigación (GIC15/78 IT-990-16) of Gobierno Vasco-Eusko Jaurlaritza to GQ, the Ministerio de Economía y Competitividad (grants SAF2013-47570-P and SAF2017-86188-P, the latter co-financed by FEDER) of the Spanish government to P.G. and G.Q., and the FP7-PEOPLE-2013-ITN—Marie-Curie Action: “Initial Training Networks”: Molecular Mechanisms of Human Fungal Pathogen Host Interaction, ImResFun, MC-ITN-606786, to O.B. and U.G.

Tiny Earth (TE) is a popular international citizen science program aimed at improving public awareness on the growing antimicrobial resistance problem of which MicroMundo Albacete is a Spanish node. With a protocol that is focused on the isolation of antibiotics-producing actinomycetes from soil, 70% of the high school students in MicroMundo Albacete 2020 isolated colonies with antagonistic activity against Gram-positive tester bacteria. However, no activity was found against Gram-negative bacteria. Here, we further adapted the protocol toward a more targeted screening that also enables isolation of antagonistic bacteria against Gram negatives using two different reverse-antibiosis approaches involving a spraying technique or flipping soil sample disks upside down. Exploiting the soil samples from MicroMundo Albacete 2020, the new approaches yielded isolation of actinomycete bacteria with antagonistic activity against Gram-negative as well as Gram-positive tester bacteria. We propose that (educational) science programs which aim to search for antibiotic-producing bacteria may implement these approaches in their protocol to promote a successful and stimulating outcome of the experiment for the participating students.

Slow dissolution of the borosilicate container of triple-point-of-water (TPW) cell is widely recognized as the main cause of long-term drift in observed triple point temperature. We add to the available experimental data a comparison of two large batches of TPW cells (67 cells in total) of various ages (from 1 year to 64 years), manufacturers (NRC, VSL, Fluke, Isotech, etc.), and materials (borosilicate glass and fused-silica) which was undertaken in 2018. After measuring the TPW temperatures realized by all 67 cells, 12 borosilicate cells were opened and their water was analyzed by Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) in order to correlate their impurity content with their respective age and their realized TPW temperature. No direct correlation was observed between the TPW cells age/impurity content and their measured triple-point temperature for neither borosilicate cells nor fused silica cells (Pearson's correlation coefficient rxy is within the range -0.60≤ rxy≤+0.40 for all the pairs considered). For fused-silica cells, the results indicate that after the isotopic variation in the water source is taken into account, the long-term drift due to the dissolution of glass envelope, if any, is negligibly small: (+0.4(±0.6) μK.yr-1 reported herein). Given that all the fused-silica cells realize the TPW temperature within 100 μK of NRC and VSL national reference cells and since the analyzed time period of 15 years is equal to the average lifespan of a TPW cell, we conclude that fused-silica TPW cells are superior to those made from borosilicate glass.

Background: Positioning and fit of the knee prostheses in patients determines functional outcome. For that matter anthropometric differences between knee joints of patients, will affect function. Since most total knees implant systems are designed for caucasians, discrepancies in matching to Asian patients might exist, with consequently less optimal fit of the implant. The aim of this study was to evaluate differences in anthropometric dimensions between Caucasian and Asian knees of patients eligible for total knee arthroplasty. Materials and Methods: 134 patients were included for radiographic anthropometric measurements on distal femurs, proximal tibia and patellar dimension were measured of 67 Caucasian and 67 Asian patients. Patient groups were age and gender matched. All radiographs were obtained preoperatively prior to total knee arthroplasty at two different centers, Jakarta and Leiden. The radiographic measurements were widest anteroposterior (AP) and widest mediolateral (ML) dimensions, aspect ratio (ML/AP), patellar length and patellar tendon length, patellar tendon/patella ratio. Sizes of eight knee implant designs (Vanguard, Genesis II, Persona -standard and narrow-, GK Sphere, Gemini, Attune and Sigma PFC) were collected from manufactures brochures and compared to the anthropometric measurements. Chi-Square test, student t-test and Bayesian statistics were used to compare differences between the two populations. Results: The mean age of the Caucasian group was 68 ± 7.1 years and the Asian patients were 67 ± 7.8 years. Both groups included 14.9% males and 85.1% females. The Dutch patients had a height of 166cm (sd 8.1 cm) the Indonesian patients 156 cm (sd 8.0 cm), the Dutch being 6.4% taller. Preoperative deformities in the Asians was predominantly into varus, while the Dutch patients had a slight valgus alignment; 90% of the KL scores were grade 3 and 4, comparable in both groups. In AP and ML the Caucasian femur is larger than the Asian femur (male-AP 12%, female-AP 15%, male-ML 6%, female-ML 9%). The Caucasian tibia is larger in AP and ML dimensions compared to the Asian patient’s tibia. The ML/AP aspect ratios were significantly different (pConclusion: Absolute and relative differences of knee dimensions exist between Caucasian and Asian knees. Caucasian has larger AP and ML for both tibial and femoral but smaller in aspect ratio for both tibia and femur compared to Asian patients. With respect to the fit of the implant to the natural knee, total knee arthroplasty remains a compromise to nature

Purpose The aim of this study was to evaluate the anthropometric differences between knees of Indonesian Asians and Dutch Caucasians and the fit of nine different knee implant systems. Methods A total of 268 anteroposterior (AP) and lateral knee preoperative radiographs from 134 consecutive patients scheduled for total knee arthroplasty at two different centres in Jakarta and Leiden were included. Both patient groups were matched according to age and sex and included 67 Asians and 67 Caucasians. We assessed the radiographic differences between the Asian and Caucasian anthropometric data. The dimensions of the nine knee implant designs (Vanguard, Genesis II, Persona Standard, Persona Narrow, GK Sphere, Gemini, Attune Standard, Attune Narrow, and Sigma PFC) were compared with the patients' anthropometric (distal femur and proximal tibia) measurements. Results The Dutch Caucasian patients had larger mediolateral (ML) and AP femoral and tibial dimensions than the Indonesian Asians. The aspect ratios of the distal femur and tibia were larger in Asians than in Caucasians. The AP and ML dimensions were mismatched between the tibial components of the nine knee systems and the Asian anthropometric data. Both groups had larger ML distal femoral dimensions than the knee systems. Conclusion Absolute and relative differences in knee dimensions exist not only between Asian and Caucasian knees but also within both groups. Not all TKA systems had a good fit with the Asian and Caucasian knee phenotypes. An increase in the range of available knee component sizes would be beneficial, although TKA remains an adequate compromise.

Publicado en Nature Microbiology (doi: 10.1038/s41564-020-0695-z) http://hdl.handle.net/10261/213002, The present outbreak of lower respiratory tract infections, including respiratory distress syndrome, is the third spillover, in only two decades, of an animal coronavirus to humans resulting in a major epidemic. Here, the Coronavirus Study Group (CSG) of the International Committee on Taxonomy of Viruses, which is responsible for developing the official classification of viruses and taxa naming (taxonomy) of the Coronaviridae family, assessed the novelty of the human pathogen tentatively named 2019-nCoV. Based on phylogeny, taxonomy and established practice, the CSG formally recognizes this virus as a sister to severe acute respiratory syndrome coronaviruses (SARS-CoVs) of the species Severe acute respiratory syndrome-related coronavirus and designates it as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To facilitate communication, the CSG further proposes to use the following naming convention for individual isolates: SARS-CoV-2/Isolate/Host/Date/Location. The spectrum of clinical manifestations associated with SARS-CoV-2 infections in humans remains to be determined. The independent zoonotic transmission of SARS-CoV and SARS-CoV-2 highlights the need for studying the entire (virus) species to complement research focused on individual pathogenic viruses of immediate significance. This research will improve our understanding of virus-host interactions in an ever-changing environment and enhance our preparedness for future outbreaks., Work on DEmARC advancement and coronavirus and nidovirus taxonomies was supported by the EU Horizon2020 EVAg 653316 project, the LUMC MoBiLe program and a Mercator Fellowship by the Deutsche Forschungsgemeinschaft (to AEG) in the context of the SFB1021 (A01 to JZ)

The type I interferon response is an important innate antiviral pathway. Recognition of viral RNA by RIG-I-like receptors (RLRs) activates a signaling cascade that leads to type I interferon (IFN-α/β) gene transcription. Multiple proteins in this signaling pathway (e.g. RIG-I, MDA5, MAVS, TBK1, IRF3) are regulated by (de)ubiquitination events. Most viruses have evolved mechanisms to counter this antiviral response. The leader protease (Lpro) of foot-and-mouth-disease virus (FMDV) has been recognized to reduce IFN-α/β gene transcription; however, the exact mechanism is unknown. The proteolytic activity of Lpro is vital for releasing itself from the viral polyprotein and for cleaving and degrading specific host cell proteins, such as eIF4G and NF-κB. In addition, Lpro has been demonstrated to have deubiquitination/deISGylation activity. Lpro’s deubiquitination/deISGylation activity and the cleavage/degradation of signaling proteins have both been postulated to be important for reduced IFN-α/β gene transcription. Here, we demonstrate that TBK1, the kinase that phosphorylates and activates the transcription factor IRF3, is cleaved by Lpro in FMDV-infected cells as well as in cells infected with a recombinant EMCV expressing Lpro. In vitro cleavage experiments revealed that Lpro cleaves TBK1 at residues 692–694. We also observed cleavage of MAVS in HeLa cells infected with EMCV-Lpro, but only observed decreasing levels of MAVS in FMDV-infected porcine LFPK αVβ6 cells. We set out to dissect Lpro’s ability to cleave RLR signaling proteins from its deubiquitination/deISGylation activity to determine their relative contributions to the reduction of IFN-α/β gene transcription. The introduction of specific mutations, of which several were based on the recently published structure of Lpro in complex with ISG15, allowed us to identify specific amino acid substitutions that separate the different proteolytic activities of Lpro. Characterization of the effects of these mutations revealed that Lpro’s ability to cleave RLR signaling proteins but not its deubiquitination/deISGylation activity correlates with the reduced IFN-β gene transcription., Author summary Outbreaks of the picornavirus foot-and-mouth disease virus (FMDV) have significant consequences for animal health and product safety and place a major economic burden on the global livestock industry. Understanding how this notorious animal pathogen suppresses the antiviral type I interferon (IFN-α/β) response may help to develop countermeasures to control FMDV infections. FMDV suppresses the IFN-α/β response through the activity of its Leader protein (Lpro), a protease that can cleave host cell proteins. Lpro was also shown to have deubiquitinase and deISGylase activity, raising the possibility that Lpro suppresses IFN-α/β by removing ubiquitin and/or ISG15, two posttranslational modifications that can regulate the activation, interactions and localization of (signaling) proteins. Here, we show that TBK1 and MAVS, two signaling proteins that are important for activation of IFN-α/β gene transcription, are cleaved by Lpro. By generating Lpro mutants lacking either of these two activities, we demonstrate that Lpro’s ability to cleave signaling proteins, but not its deubiquitination/deISGylase activity, correlates with suppression of IFN-β gene transcription.

Introduction: Obesity is highly prevalent, comes with serious health burden and is difficult to treat. In a minority, there is a genetic cause for the obesity. In these patients, therapy-resistant obesity is often observed despite intensive lifestyle treatment. Moreover, it is still unclear whether bariatric surgery is less successful in genetic obesity. Liraglutide is a Glucagon-Like-Peptide-1 (GLP-1) receptor agonist or GLP-1 analogue, showing positive effects on metabolic parameters, satiety and weight loss in lifestyle-induced obesity. We present our experiences of GLP-1 analogue treatment in patients with genetic obesity disorders. Methods: Adults with overweight or severe obesity and a molecularly proven genetic cause were treated with liraglutide 3,0 mg daily, in addition to ongoing intensive supportive lifestyle treatment. Anthropometrics, metabolic parameters, resting energy expenditure (REE), side effects, and subjectively reported satiety and quality of life were assessed. Results: Two patients with a heterozygous pathogenic melanocortin 4 recepter variant and two patients with 16p11.2 deletion syndrome, ranging in age between 21 and 32 years and in BMI between 28.1 and 55.7 kg/m2 at baseline, were treated. At end of follow-up, ranging between 33 weeks and 12 years, a mean change in BMI and waist circumference was observed of -5.7 ± 3.8 kg/m2 and -15.2 ± 21.1 cm, respectively. All patients reported better quality of life, three of them also reported improved satiety. Moreover, improvement of metabolic parameters was seen. No clear effect on REE was observed. Two patients experienced mild side effects, e.g. nausea and stomach pain, for a brief period. Conclusion: We here show beneficial effects of GLP-1 analogues on weight, metabolic parameters, and quality of life in four patients with genetic obesity. Satiety improved in three of the four patients. All patient achieved at least the clinically relevant 5–10% weight loss. Our findings suggest that GLP-1 analogue treatment might be an effective treatment option, in addition to a healthy lifestyle, for patients with genetic obesity.

Background Airway epithelial cells have a well-accepted role in the regulation of local inflammatory processes in allergic and innate defence responses. However, their role the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP) is unclear. The objective was to investigate whether potential differences in the mRNA expression profile of nasal epithelia from healthy individuals and from CRSwNP patients would shed new light on disease mechanisms. Methods Primary epithelial cells from nasal polyps of 24 affected individuals and from middle turbinates of 9 healthy controls were obtained using magnetic beat assisted isolation and were used for expression profiling using the Human Genome U133 Plus 2.0 Genechip Array. Results Multiple gene probes corresponding to 27 genes showed an aberrant expression profile in polyp epithelial cells compared to healthy controls. Most of these genes are linked to pathogenic mechanisms seen in neoplasm formation, including changes in cell-cell adhesion, metabolic processes, cell cycle control, and differentiation. Remarkably, our data additionally suggest a role for maternally expressed genes in the pathogenesis of CRSwNP and reveal two distinct states of polyp epithelium that could not be linked to the presence or absence of atopy in patients or to the level of eosinophilia or neutrophilia of the polyp. Conclusions Our data suggest new roles for nasal epithelium in the pathogenesis of CRSwNP.

The street food sector in Sub-Saharan Africa is a source of affordable and nutritious meals for the urban poor, while also being an important source of income for the women who dominate this sector. Despite the importance of this sector, many micro- and informal enterprises are labelled as 'survivalist', beyond the reach of common development policies, which give priority to so-called growth-oriented enterprises. When given the chance to speak for themselves, do enterprises express any aspirations to grow? Contrary to the literature, our findings show that necessity-driven enterprises do aspire to grow and that this is true for both those owned by men and women. Using contextual interaction theory, this paper explains why it is possible for previous authors to come to such a different conclusion.

The nasal cavity displays immune tolerance to commensal bacteria under homeostatic conditions, which is rapidly converted to a pro-inflammatory response upon infection. Yet, the factors that control this conversion are still largely unknown. Here, we provide evidence that Fc gamma receptor III (FcγRIII) stimulation breaks immune tolerance to bacteria in the human nasal cavity through activation of nasal epithelial cells, which are the first line of defense against invading microbes. While under steady-state conditions human nasal epithelial cells were completely non-responsive to Gram-negative bacteria P. aeruginosa or TLR4 ligand LPS, IgG opsonization of bacteria, as occurs upon infection, strongly induced production of pro-inflammatory agents such as IL-6 and IL-8. This breaking of tolerance to bacteria was completely dependent on FcγRIII, which amplified cytokine gene transcription through cross-talk with TLR4. In addition, we identified that epithelial cells from patients suffering from chronic rhinosinusitis with nasal polyps do not display LPS tolerance, thereby providing an explanation for the disturbed host defense responses of these patients. Taken together, these data are the first to identify FcγR expression on nasal epithelial cells, as well as to identify its important role in controlling the balance between tolerance and inflammation in the nasal cavity.