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PLOS ONE 16(1), e0246182 (2021). doi:10.1371/journal.pone.0246182, Published by PLOS, San Francisco, California, US

For functional MRI with a multi-channel receiver RF coil, images are often reconstructed channel by channel, resulting into multiple images per time frame. The final image to analyze usually is the result of the covariance Sum-of-Squares (covSoS) combination across these channels. Although this reconstruction is quasi-optimal in SNR, it is not necessarily the case in terms of temporal SNR (tSNR) of the time series, which is yet a more relevant metric for fMRI data quality. In this work, we investigated tSNR optimality through voxel-wise RF coil combination and its effects on BOLD sensitivity. An analytical solution for an optimal RF coil combination is described, which is somewhat tied to the extended Krueger-Glover model involving both thermal and physiological noise covariance matrices. Compared experimentally to covSOS on four volunteers at 7T, the method yielded great improvement of tSNR but, surprisingly, did not result into higher BOLD sensitivity. Solutions to improve the method such as for example the t-score for the mean recently proposed are also explored, but result into similar observations once the statistics are corrected properly. Overall, the work shows that data-driven RF coil combinations based on tSNR considerations alone should be avoided unless additional and unbiased assumptions can be made.

Background Prediction models should be externally validated to assess their performance before implementation. Several prediction models for coronavirus disease-19 (COVID-19) have been published. This observational cohort study aimed to validate published models of severity for hospitalized patients with COVID-19 using clinical and laboratory predictors. Methods Prediction models fitting relevant inclusion criteria were chosen for validation. The outcome was either mortality or a composite outcome of mortality and ICU admission (severe disease). 1295 patients admitted with symptoms of COVID-19 at Kings Cross Hospital (KCH) in London, United Kingdom, and 307 patients at Oslo University Hospital (OUH) in Oslo, Norway were included. The performance of the models was assessed in terms of discrimination and calibration. Results We identified two models for prediction of mortality (referred to as Xie and Zhang1) and two models for prediction of severe disease (Allenbach and Zhang2). The performance of the models was variable. For prediction of mortality Xie had good discrimination at OUH with an area under the receiver-operating characteristic (AUROC) 0.87 [95% confidence interval (CI) 0.79–0.95] and acceptable discrimination at KCH, AUROC 0.79 [0.76–0.82]. In prediction of severe disease, Allenbach had acceptable discrimination (OUH AUROC 0.81 [0.74–0.88] and KCH AUROC 0.72 [0.68–0.75]). The Zhang models had moderate to poor discrimination. Initial calibration was poor for all models but improved with recalibration. Conclusions The performance of the four prediction models was variable. The Xie model had the best discrimination for mortality, while the Allenbach model had acceptable results for prediction of severe disease.

Background Early diagnosis and treatment are one of the key strategies of tuberculosis control globally, and there are strong efforts in detecting and treating tuberculosis cases in Ethiopia. Smear microscopy examination has been a routine diagnostic test for pulmonary tuberculosis diagnosis in resource-constrained settings for decades. Recently, many countries, including Ethiopia, are scaling up the use of Gene Xpert without the evaluation of the cost and cost-effectiveness implications of this strategy. Therefore, this study evaluated the cost and cost-effectiveness of Gene Xpert (MTB/RIF) and smear microscopy tests to diagnosis tuberculosis patients in Ethiopia. Methods We compared the costs and cost-effectiveness of tuberculosis diagnosis using smear microscopy and Gene Xpert among 1332 patients per intervention in the Arsi zone. We applied combinations of top-down and bottom-up costing approaches. The costs were estimated from the health providers’ perspective within one year (2017–2018). We employed “cases detected” as an effectiveness measure, and the incremental cost-effectiveness ratio was calculated by dividing the changes in cost and change in effectiveness. All costs and incremental cost-effectiveness ratio were reported in 2018 US$. Results The unit cost per test for Gene Xpert was $12.9 whereas it is $3.1 for AFB smear microscopy testing. The cost per TB case detected was $77.9 for Gene Xpert while it was $55.8 for the smear microscopy method. The cartridge kit cost accounted for 42% of the overall Gene Xpert’s costs and the cost of the reagents and consumables accounted for 41.3% ($1.3) of the unit cost for the smear microscopy method. The ICER for the Gene Xpert strategy was $20.0 per tuberculosis case detected. Conclusion Using Gene Xpert as a routine test instead of standard care (smear microscopy) can be potentially cost-effective. In the cost scenario analysis, the price of the cartridge, the number of tests performed per day, and the life span of the capital equipment were the drivers of the unit cost of the Gene Xpert method. Therefore, Gene Xpert can be a part of the routine TB diagnostic testing strategy in Ethiopia.

Extensive non-pharmaceutical and physical distancing measures are currently the primary interventions against coronavirus disease 2019 (COVID-19) worldwide. It is therefore urgent to estimate the impact such measures are having. We introduce a Bayesian epidemiological model in which a proportion of individuals are willing and able to participate in distancing, with the timing of distancing measures informed by survey data on attitudes to distancing and COVID-19. We fit our model to reported COVID-19 cases in British Columbia (BC), Canada, and five other jurisdictions, using an observation model that accounts for both underestimation and the delay between symptom onset and reporting. We estimated the impact that physical distancing (social distancing) has had on the contact rate and examined the projected impact of relaxing distancing measures. We found that, as of April 11 2020, distancing had a strong impact in BC, consistent with declines in reported cases and in hospitalization and intensive care unit numbers; individuals practising physical distancing experienced approximately 0.22 (0.11–0.34 90% CI [credible interval]) of their normal contact rate. The threshold above which prevalence was expected to grow was 0.55. We define the “contact ratio” to be the ratio of the estimated contact rate to the threshold rate at which cases are expected to grow; we estimated this contact ratio to be 0.40 (0.19–0.60) in BC. We developed an R package ‘covidseir’ to make our model available, and used it to quantify the impact of distancing in five additional jurisdictions. As of May 7, 2020, we estimated that New Zealand was well below its threshold value (contact ratio of 0.22 [0.11–0.34]), New York (0.60 [0.43–0.74]), Washington (0.84 [0.79–0.90]) and Florida (0.86 [0.76–0.96]) were progressively closer to theirs yet still below, but California (1.15 [1.07–1.23]) was above its threshold overall, with cases still rising. Accordingly, we found that BC, New Zealand, and New York may have had more room to relax distancing measures than the other jurisdictions, though this would need to be done cautiously and with total case volumes in mind. Our projections indicate that intermittent distancing measures—if sufficiently strong and robustly followed—could control COVID-19 transmission. This approach provides a useful tool for jurisdictions to monitor and assess current levels of distancing relative to their threshold, which will continue to be essential through subsequent waves of this pandemic.

IntroductionSince their emergence, SARS-CoV-2 variants of concern (VOC) B.1.1.7 and B.1.351 have spread worldwide. We estimated the risk of hospitalisation and admission to an intensive care unit (ICU) for infections with B.1.1.7 and B.1.351 in Norway, compared to infections with non-VOC.Materials and methodsUsing linked individual-level data from national registries, we conducted a cohort study on laboratory-confirmed cases of SARS-CoV-2 in Norway diagnosed between 28 December 2020 and 2 May 2021. Variants were identified based on whole genome sequencing, partial sequencing by Sanger sequencing or PCR screening for selected targets. The outcome was hospitalisation or ICU admission. We calculated adjusted risk ratios (aRR) with 95% confidence intervals (CIs) using multivariable binomial regression to examine the association between SARS-CoV-2 variants B.1.1.7 and B.1.351 with i) hospital admission and ii) ICU admission compared to non-VOC.ResultsWe included 23,169 cases of B.1.1.7, 548 B.1.351 and 4,584 non-VOC. Overall, 1,017 cases were hospitalised (3.6%) and 206 admitted to ICU (0.7%). B.1.1.7 was associated with a 1.9-fold increased risk of hospitalisation (aRR 95%CI 1.6–2.3) and a 1.8-fold increased risk of ICU admission (aRR 95%CI 1.2–2.8) compared to non-VOC. Among hospitalised cases, no difference was found in the risk of ICU admission between B.1.1.7 and non-VOC. B.1.351 was associated with a 2.4-fold increased risk of hospitalisation (aRR 95%CI 1.7–3.3) and a 2.7-fold increased risk of ICU admission (aRR 95%CI 1.2–6.5) compared to non-VOC.DiscussionOur findings add to the growing evidence of a higher risk of severe disease among persons infected with B.1.1.7 or B.1.351. This highlights the importance of prevention and control measures to reduce transmission of these VOC in society, particularly ongoing vaccination programmes, and preparedness plans for hospital surge capacity.

Introduction The use of patient-reported outcomes (PROs) to systematically quantify adverse events (AE) will assist in the improvement of medical care and the QoL of patients living with HIV (PLWH). The aim of this study was to investigate the associations between self-reported side effects and other PROs, demographics and laboratory data, and further evaluate the Health Questionnaire (HQ) as a tool for following trends in patient-reported side effects over time in relation to trends in prescribed third agent in ART. Materials and methods The Swedish National Registry InfCareHiv includes an annual self-reported nine-item HQwhich is used in patient-centered HIV care in all Swedish HIV units. In this study, the experience of side effects was addressed. We analyzed 9,476 HQs completed by 4,186 PLWH together with details about their prescribed ART and relevant biomarkers collected during 2011–2017. Data were analyzed using descriptive statistics, Pearson’s correlation coefficient and mixed logistic regression. Results The cross-sectional analysis of the HQs showed that the frequency of reported side effects decreased from 32% (2011) to 15% (2017). During the same period, there was a shift in ART prescription from efavirenz (EFV) to dolutegravir (DTG) (positive correlation coefficient r = 0.94, p = 0.0016). Further, PLWH who reported being satisfied with their physical health (OR: 0.47, p = Conclusions Self-reported side effects were found to have a close relationship with the patient’s ratings of their overall health situation and demonstrated a strong correlation with the sharp decline in use of EFV and rise in use of DTG, with reported side effects being halved. This study supports the feasibility of using the HQ as a tool for longitudinal follow up of trends in PROs.

BackgroundThe viral load and tissue distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain important questions. The current study investigated SARS-CoV-2 viral load, biodistribution and anti-SARS-CoV-2 antibody formation in patients suffering from severe corona virus disease 2019 (COVID-19) induced acute respiratory distress syndrome (ARDS).MethodsThis is a retrospective single-center study in 23 patients with COVID-19-induced ARDS. Data were collected within routine intensive care. SARS-CoV-2 viral load was assessed via reverse transcription quantitative polymerase chain reaction (RT-qPCR). Overall, 478 virology samples were taken. Anti-SARS-CoV-2-Spike-receptor binding domain (RBD) antibody detection of blood samples was performed with an enzyme-linked immunosorbent assay.ResultsMost patients (91%) suffered from severe ARDS during ICU treatment with a 30-day mortality of 30%. None of the patients received antiviral treatment. Tracheal aspirates tested positive for SARS-CoV-2 in 100% of the cases, oropharyngeal swabs only in 77%. Blood samples were positive in 26% of the patients. No difference of viral load was found in tracheal or blood samples with regard to 30-day survival or disease severity. SARS-CoV-2 was never found in dialysate. Serologic testing revealed significantly lower concentrations of SARS-CoV-2 neutralizing IgM and IgA antibodies in survivors compared to non-survivors (p = 0.009).ConclusionsCOVID-19 induced ARDS is accompanied by a high viral load of SARS-CoV-2 in tracheal aspirates, which remained detectable in the majority throughout intensive care treatment. Remarkably, SARS-CoV-2 RNA was never detected in dialysate even in patients with RNAemia. Viral load or the buildup of neutralizing antibodies was not associated with 30-day survival or disease severity.

The paper deals with the impact of chosen geometric and material factors on maximal stresses in carotid atherosclerotic plaque calculated using patient-specific finite element models. These stresses are believed to be decisive for the plaque vulnerability but all applied models suffer from inaccuracy of input data, especially when obtained in vivo only. One hundred computational models based on ex vivo MRI are used to investigate the impact of wall thickness, MRI slice thickness, lipid core and fibrous tissue stiffness, and media anisotropy on the calculated peak plaque and peak cap stresses. The investigated factors are taken as continuous in the range based on published experimental results, only the impact of anisotropy is evaluated by comparison with a corresponding isotropic model. Design of Experiment concept is applied to assess the statistical significance of these investigated factors representing uncertainties in the input data of the model. The results show that consideration of realistic properties of arterial wall in the model is decisive for the stress evaluation; assignment of properties of fibrous tissue even to media and adventitia layers as done in some studies may induce up to eightfold overestimation of peak stress. The impact of MRI slice thickness may play a key role when local thin fibrous cap is present. Anisotropy of media layer is insignificant, and the stiffness of fibrous tissue and lipid core may become significant in some combinations.

IntroductionSexual and reproductive health are significant aspects of quality of life. Healthcare often fails to provide adequate support for young cancer survivors in this area, hence the need to develop more effective interventions. The present study aimed to describe experiences of participating in a web-based psycho-educational intervention focusing on sexual dysfunction and fertility distress after cancer, and to explore these experiences within the theoretical frame of the basic psychological needs for competence, relatedness and autonomy according to self-determination theory.MethodsIndividual semi-structured interviews with 24 women and 4 men, age 19-40, were abductively analyzed using the Framework approach for qualitative content analysis.ResultsParticipant experiences corresponded well with the three main deductive themes competence, relatedness and autonomy, divided into a total of nine subthemes illustrating varying degrees of basic need satisfaction with considerable nuance but not without ambiguity. While satisfaction of the need for competence could be linked to the amount of information in relation to participants' cognitive capacity, satisfaction of the need for relatedness seemed to be of special importance for these young adults with cancer experience. Invitation to the program meant a chance at alleviating loneliness and normalizing problems, symptoms and concerns. Participants' descriptions of perceived autonomy support were more challenging and ambiguous, because of the many contradictions in participants' responses to their variable situations.ConclusionBasic psychological needs were confirmed as flexible positions along a continuum rather than discrete and mutually exclusive qualities. Understanding the variety of basic need satisfaction may enhance the design of future web-based interventions to be even more inclusive, tailorable and autonomy-supportive. Further research is warranted to determine the role of basic need satisfaction as a possible mediator for web-based psychoeducational interventions in cancer survivorship care.

An innovative approach to a non-destructive lock mechanism examination by means of X-ray computed tomography (CT) was involved in a careful opening of a locked 19(th)century chest missing the key, as an interdisciplinary cooperation with the restorers. In regard of the exploration and conservation of such locked objects, their opening is important to the restorers. However, the opening may be complicated, if not impossible, without damaging the object when the key is missing. Moreover, the historical locks might be equipped with protective mechanisms. Despite the exceeding dimensions and the weight of the steel chest, a CT analysis was performed, which enabled a detailed exploration of the lock based on a system of levers and bolts handled by a single key, located in a case on the inside of the chest lid, including the dimensions essential for manufacturing of a new key copy. Moreover, two secret protective mechanisms were revealed, as well as all the damages of the object.

In vivo measurements of muscle architecture (i.e. the spatial arrangement of muscle fascicles) are routinely included in research and clinical settings to monitor muscle structure, function and plasticity. However, in most cases such measurements are performed manually, and more reliable and time-efficient automated methods are either lacking completely, or are inaccessible to those without expertise in image analysis. In this work, we propose an ImageJ script to automate the entire analysis process of muscle architecture in ultrasound images: Simple Muscle Architecture Analysis (SMA). Images are filtered in the spatial and frequency domains with built-in commands and external plugins to highlight aponeuroses and fascicles. Fascicle dominant orientation is then computed in regions of interest using the OrientationJ plugin. Bland-Altman plots of analyses performed manually or with SMA indicates that the automated analysis does not induce any systematic bias and that both methods agree equally through the range of measurements. Our test results illustrate the suitability of SMA to analyse images from superficial muscles acquired with a broad range of ultrasound settings., Comment: 8 pages, 7 figures, 1 appendix

In intraoperative electron radiation therapy (IOERT) the energy of the electron beam is selected under the conventional assumption of water-equivalent tissues at the applicator end. However, the treatment field can deviate from the theoretic flat irradiation surface, thus altering dose profiles. This patient-based study explored the feasibility of acquiring intraoperative computed tomography (CT) studies for calculating three-dimensional dose distributions with two factors not included in the conventional assumption, namely the air gap from the applicator end to the irradiation surface and tissue heterogeneity. In addition, dose distributions under the conventional assumption and from preoperative CT studies (both also updated with intraoperative data) were calculated to explore whether there are other alternatives to intraoperative CT studies that can provide similar dose distributions. The IOERT protocol was modified to incorporate the acquisition of intraoperative CT studies before radiation delivery in six patients. Three studies were not valid to calculate dose distributions due to the presence of metal artefacts. For the remaining three cases, the average gamma pass rates between the doses calculated from intraoperative CT studies and those obtained assuming water-equivalent tissues or from preoperative CT studies were 73.4% and 74.0% respectively. The agreement increased when the air gap was included in the conventional assumption (98.1%) or in the preoperative CT images (98.4%). Therefore, this factor was the one mostly influencing the dose distributions of this study. Our experience has shown that intraoperative CT studies are not recommended when the procedure includes the use of shielding discs or surgical retractors unless metal artefacts are removed. IOERT dose distributions calculated under the conventional assumption or from preoperative CT studies may be inaccurate unless the air gap (which depends on the surface irregularities of the irradiated volume and on the applicator pose) is included in the calculations. This study was supported by Ministerio de Ciencia, Innovacion y Universidades (http://www.ciencia.gob.es) [grant number TEC2013–48251-C2 to JP, VG-V and MJL-C], co-funded by European Regional Development Fund (ERDF), “A way of making Europe” (https://ec.europa.eu/regional_policy/en/funding/erdf); by Ministerio de Ciencia, Innovacion y Universidades (http://www.ciencia.gob.es), Instituto de Salud Carlos III (https://www.isciii.es) [grant numbers DTS14/00192 to JP, VG-V and FAC; PI15/02121 to FAC and JC-H; PI18/01625 to JP], co-funded by European Regional Development Fund (ERDF), “A way of making Europe” (https://ec.europa.eu/regional_policy/en/funding/erdf); and by Comunidad de Madrid (http://www.comunidad.madrid) [grant number TOPUS-CM S2013/ MIT3024 to JP], co-funded by European Structural and Investment Fund (https://ec.europa.eu/info/funding-tenders/funding-opportunities/fundingprogrammes/overview-funding-programmes_en). The CNIC is supported by the Ministerio de Ciencia, Innovacion y Universidades (http://www.ciencia.gob.es) and the Pro CNIC Foundation (https://www.fundacionprocnic.es) [to MD], and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Sí

Previous unimodal PET and fMRI studies in humans revealed a reproducible vestibular brain activation pattern, but with variations in its weighting and expansiveness. Hybrid studies minimizing methodological variations at baseline conditions are rare and still lacking for task-based designs. Thus, we applied for the first time hybrid 3T PET-MRI scanning (Siemens mMR) in healthy volunteers using galvanic vestibular stimulation (GVS) in healthy volunteers in order to directly compare H215O-PET and BOLD MRI responses. List mode PET acquisition started with the injection of 750 MBq H215O simultaneously to MRI EPI sequences. Group-level statistical parametric maps were generated for GVS vs. rest contrasts of PET, MR-onset (event-related), and MR-block. All contrasts showed a similar bilateral vestibular activation pattern with remarkable proximity of activation foci. Both BOLD contrasts gave more bilateral wide-spread activation clusters than PET; no area showed contradictory signal responses. PET still confirmed the right-hemispheric lateralization of the vestibular system, whereas BOLD-onset revealed only a tendency. The reciprocal inhibitory visual-vestibular interaction concept was confirmed by PET signal decreases in primary and secondary visual cortices, and BOLD-block decreases in secondary visual areas. In conclusion, MRI activation maps contained a mixture of CBF measured using H215O-PET and additional non-CBF effects, and the activation-deactivation pattern of the BOLD-block appears to be more similar to the H215O-PET than the BOLD-onset.

Background COVID-19 rapidly escalated into a pandemic, threatening 213 countries, areas, and territories the world over. We aimed to identify potential province-level socioeconomic determinants of the virus’s dissemination, and explain between-province differences in the speed of its spread, based on data from 36 provinces of Northern Italy. Methods This is an ecological study. We included all confirmed cases of SARS-CoV-2 reported between February 24th and March 30th, 2020. For each province, we calculated the trend of contagion as the relative increase in the number of individuals infected between two time endpoints, assuming an exponential growth. Pearson’s test was used to correlate the trend of contagion with a set of healthcare-associated, economic, and demographic parameters by province. The virus’s spread was input as a dependent variable in a stepwise OLS regression model to test the association between rate of spread and province-level indicators. Results Multivariate analysis showed that the spread of COVID-19 was correlated negatively with aging index (p-value = 0.003), and positively with public transportation per capita (p-value = 0.012), the % of private long-term care hospital beds and, to a lesser extent (p-value = 0.070), the % of private acute care hospital beds (p-value = 0.006). Conclusion Demographic and socioeconomic factors, and healthcare organization variables were found associated with a significant difference in the rate of COVID-19 spread in 36 provinces of Northern Italy. An aging population seemed to naturally contain social contacts. The availability of healthcare resources and their coordination could play an important part in spreading infection.

White matter abnormalities are well-established in adult patients with psychosis. Less is known about abnormalities in the rarely occurring adolescent early onset psychosis (EOP). In particular, whether antipsychotic medication might impact white matter microstructure is not known. Using 3T diffusion weighted imaging, we investigated differences in white matter microstructure and the impact of antipsychotic medication status in medicated (n = 11) and unmedicated (n = 11) EOP patients relative to healthy controls (n = 33), aged between 12-18 years. Using Tract-based Spatial Statistics, we calculate case-control differences in scalar diffusion measures, i.e. fractional anisotropy (FA), axial diffusion (AD) and radial diffusion (RD), and investigated their association with antipsychotic medication in patients. We found significantly lower FA in the left genu of the corpus callosum, the left anterior corona radiata (ACR) and the right superior longitudinal fasciculus in EOP patients relative to healthy controls. AD values were also lower in the left ACR, largely overlapping with the FA findings. Mean FA in the left ACR was significantly associated with antipsychotic medication status (Cohen's d = 1.37, 95% CI [0.01, 2.68], p = 0.008), showing higher FA values in medicated compared to unmedicated EOP patients. The present study is the first to link antipsychotic medication status to altered regional FA in the left ACR, a region hypothesized to contribute to the etiology of psychosis. Replications are warranted to draw firm conclusions about putatively enhancing effects of antipsychotic medication on white matter microstructure in adolescent-onset psychosis.

PLOS ONE 15(3), e0229636 (2020). doi:10.1371/journal.pone.0229636, Published by PLOS, San Francisco, California, US

Access to efficient laboratory services is critical to patient care. Turnaround Time (TAT) is one of the most important measures when judging the efficiency of any laboratory and care system. Few studies on TAT exist for inpatient care settings within low- and middle-income countries (LMICs). Methods We evaluated therapeutic TAT for a tertiary hospital in Western Kenya, using a time-motion study focusing specifically on common hematology and biochemistry orders. The aim was to determine significant bottlenecks in diagnostic testing processes at the institution. Results A total of 356 (155 hematology and 201 biochemistry) laboratory tests were fully tracked from the time of ordering to availability of results to care providers. The total therapeutic TAT for all tests was 21.5 ± 0.249 hours (95% CI). The therapeutic TAT for hematology was 20.3 ± 0.331 hours (95% CI) while that for biochemistry tests was 22.2 ± 0.346 hours (95% CI). Printing, sorting and dispatch of the printed results emerged as the most significant bottlenecks, accounting for up to 8 hours of delay (Hematology—8.3 ± 1.29 hours (95% CI), Biochemistry—8.5 ± 1.18 hours (95% CI)). Time of test orders affected TAT, with orders made early in the morning and those in the afternoon experiencing the most delays in TAT. Conclusion Significant inefficiencies exist at multiple steps in the turnaround times for routine laboratory tests at a large referral hospital within an LMIC setting. Multiple opportunities exist to improve TAT and streamline processes around diagnostic testing in this and other similar settings. publishedVersion

Chronic cancer-related fatigue (CF) is a common and distressing condition in a subset of cancer survivors and common also after successful treatment of malignant lymphoma. The etiology and pathogenesis of CF is unknown, and lack of biomarkers hampers development of diagnostic tests and successful therapy. Recent studies on the changes of amino acid levels and other metabolites in patients with chronic fatigue syndrome/myalgic encephalopathy (CFS/ME) have pointed to possible central defects in energy metabolism. Here we report a comprehensive analysis of serum concentrations of amino acids, including metabolites of tryptophan, the kynurenine pathway and vitamin B6 in a well characterized national Norwegian cohort of lymphoma survivors after high-dose therapy and autologous stem cell transplantation. Among the 20 standard amino acids in humans, only tryptophan levels were significantly lower in both males and females with CF compared to non-fatigued survivors, a strikingly different pattern than seen in CFS/ME. Markers of tryptophan degradation by the kynurenine pathway (kynurenine/tryptophan ratio) and activation of vitamin B6 catabolism (pyridoxic acid/(pyridoxal + pyridoxal 5'-phosphate), PAr index) differed in survivors with or without CF and correlated with known markers of immune activation and inflammation, such as neopterin, C-reactive protein and Interleukin-6. Among personal traits and clinical findings assessed simultaneously in participating survivors, higher neuroticism score, obesity and higher PAr index were significantly associated with increased risk of CF. Collectively, these data point to low grade immune activation and inflammation as a basis for CF in lymphoma survivors. publishedVersion

The novel coronavirus (SARS-CoV-2), identified in China at the end of December 2019 and causing the disease COVID-19, has meanwhile led to outbreaks all over the globe with about 2.2 million confirmed cases and more than 150,000 deaths as of April 17, 2020. In this work, mathematical models are used to reproduce data of the early evolution of the COVID-19 outbreak in Germany, taking into account the effect of actual and hypothetical non-pharmaceutical interventions. Systems of differential equations of SEIR type are extended to account for undetected infections, stages of infection, and age groups. The models are calibrated on data until April 5. Data from April 6 to 14 are used for model validation. We simulate different possible strategies for the mitigation of the current outbreak, slowing down the spread of the virus and thus reducing the peak in daily diagnosed cases, the demand for hospitalization or intensive care units admissions, and eventually the number of fatalities. Our results suggest that a partial (and gradual) lifting of introduced control measures could soon be possible if accompanied by further increased testing activity, strict isolation of detected cases, and reduced contact to risk groups.

BackgroundSub-optimal adherence to infant prophylaxis has been associated with mother-to-child-transmission of HIV. However, the factors associated have not been well characterised in different settings. This study describes barriers and enablers of adherence to infant prophylaxis among 6-week-old HIV exposed infants in Lira district, Northern Uganda.MethodsThis prospective cohort study was conducted from 2018-2020 at the PMTCT clinic at Lira Regional Referral Hospital and included 472 mother-infant pairs. HIV-infected pregnant women were recruited, followed up at delivery and 6 weeks postpartum. We used a structured questionnaire to obtain data on socio-demographic, reproductive-related, HIV-related characteristics and adherence. Data were analysed using Stata to estimate adjusted risk ratios using Poisson regression models to ascertain barriers and enablers of adherence to infant nevirapine prophylaxis.ResultsBarriers to infant adherence are maternal characteristics including: younger age (≤20 years adjusted risk ratio (ARR) = 1.55; 95% CI: 1.1-2.2), missing a viral load test during pregnancy (ARR: 1.4; 95% CI: 1.1-1.7) and not receiving nevirapine syrup for the baby after childbirth (ARR = 6.2; 95% CI: 5.1-7.6). Enablers were: having attained ≥14 years of schooling (ARR = 0.7; 95% CI: 0.5-0.9), taking a nevirapine-based regimen (ARR = 0.6; 95% CI: 0.4-0.9), long-term ART (≥ 60 months ARR = 0.75; 95% CI: 0.6-0.9), accompanied by a husband to hospital during labour and childbirth (ARR = 0.5; 95% CI: 0.4-0.7) and labour starting at night (ARR = 0.7; 95% CI: 0.6-0.8).Conclusion and recommendationsDespite mothers receiving nevirapine syrup from the health workers for the infant, non-adherence rates still prevail at 14.8%. The health system needs to consider giving HIV infected pregnant women the nevirapine syrup before birth to avoid delays and non-adherence. There is need to pay particular attention to younger women and those who recently started ART.

Inhibition of the key glycolytic activator 6-phosphofructokinase 2/fructose-2,6-bisphosphatase-3 (PFKFB3) by 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) strongly attenuates pathological angiogenesis in cancer and inflammation. In addition to modulating endothelial proliferation and migration, 3PO also dampens proinflammatory activation of endothelial cells and experimental inflammation in vivo, suggesting a potential for 3PO in the treatment of chronic inflammation. The aim of our study was to explore if the anti-inflammatory action of 3PO in human endothelial cells was mediated by inhibition of PFKFB3 and glycolysis and assess if other means of PFKFB3 inhibition reduced inflammatory activation in a similar manner. We found that 3PO caused a rapid and transient reduction in IL-1β- and TNF-induced phosphorylation of both IKKα/β and JNK, thus inhibiting signaling through the NFκB and the stress-activated kinase pathways. However, in contrast to 3PO-treatment, neither shRNA-mediated silencing of PFKFB3 nor treatment with the alternative PFKFB3 inhibitor 7,8-dihydroxy-3-(4-hydroxy-phenyl)-chromen-4-one (YN1) prevented cytokine-induced NFκB signaling and upregulation of the adhesion molecules VCAM-1 and E-selectin, implying off target effects of 3PO. Collectively, our results suggest that the anti-inflammatory action of 3PO in human endothelial cells is not limited to inhibition of PFKFB3 and cellular glycolysis.

PLOS ONE 15(8), e0237494 (2020). doi:10.1371/journal.pone.0237494, Published by PLOS, San Francisco, California, US

For better management of patients with febrile neutropenia, our study investigated the epidemiologic, microbiologic, and clinical characteristics of adult inpatients with febrile neutropenia and their mortality-associated factors. To this end, we carried out a prospective, observational, multicenter study in 28 Argentinian hospitals between 2007 and 2012. We included 515 episodes of febrile neutropenia from 346 patients, median age 49 years. Neutropenia followed chemotherapy in 77% of cases, half of the cases due to hematological malignancies. Most episodes were classified as high-risk according to MASCC criteria, and 53.6% of patients were already hospitalized at the onset of febrile neutropenia. Bloodstream infections were detected in 14% episodes; whereas an infectious source of fever was identified in 80% of cases. Mortality rate achieved to 14.95%. The binary regression analysis showed that persistence of fever at day 7, or neutropenia at day 14, dehydration and tachycardia at the onset of febrile neutropenia as well as prior infections were significantly associated with mortality. In addition to expanding our current knowledge on the features of adult patients with febrile neutropenia, present findings provide useful information for better management of them in Argentina, given the appropriate representativeness of centers participating in the study. Fil: Parodi, Roberto Leandro. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina Fil: Lagrutta, Mariana. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina Fil: Tortolo, Mauro. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina Fil: Navall, Estefanía. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina Fil: Rodríguez, María S.. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina Fil: Sasia, Gervasio F.. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina Fil: De Candia, Lucas F.. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina Fil: Gruvman, Matias A.. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina Fil: Bottasso, Oscar Adelmo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; Argentina Fil: Greca, Alcides Alejandro. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina

Lung disease is regularly reported in human filarial infections but the molecular pathogenesis of pulmonary filariasis is poorly understood. We used Litomosoides sigmodontis, a rodent filaria residing in the pleural cavity responsible for pleural inflammation, to model responses to human filarial infections and probe the mechanisms. Wild-type and Th2-deficient mice (ΔdblGata1 and Il-4receptor(r)a-/-/IL-5-/-) were infected with L. sigmodontis. Survival and growth of adult filariae and prevalence and density of microfilariae were evaluated. Cells and cytokines in the pleural cavity and bronchoalveolar space were characterized by imaging, flow cytometry and ELISA. Inflammatory pathways were evaluated by transcriptomic microarrays and lungs were isolated and analyzed for histopathological signatures. 40% of WT mice were amicrofilaremic whereas almost all mutant mice display blood microfilaremia. Microfilariae induced pleural, bronchoalveolar and lung-tissue inflammation associated with an increase in bronchoalveolar eosinophils and perivascular macrophages, production of mucus, visceral pleura alterations and fibrosis. Inflammation and pathology were decreased in Th2-deficient mice. An IL-4R-dependent increase of CD169 was observed on pleural and bronchoalveolar macrophages in microfilaremic mice. CD169+ tissue-resident macrophages were identified in the lungs with specific localizations. Strikingly, CD169+ macrophages increased significantly in the perivascular area in microfilaremic mice. These data describe lung inflammation and pathology in chronic filariasis and emphasize the role of Th2 responses according to the presence of microfilariae. It is also the first report implicating CD169+ lung macrophages in response to a Nematode infection., Author summary Filarial infections are tropical diseases caused by nematodes of the Onchocercidae family. Infections due to filariae regularly induce pulmonary manifestations, however lung pathogenesis of human filarial infections is poorly understood. Litomosoides sigmodontis is a rodent filaria living in the pleural cavity and responsible for pleural inflammation which is used to model responses in human filarial infections. Here, we analyse lung inflammation during the chronic phase of the infection, when female parasites release their offspring (microfilariae). 40% of mice do not present circulating microfilariae. We show that microfilariae enhance pleural cavity responses and induce pulmonary pathology (bronchoalveolar eosinophilia, perivascular cell infiltrates, mucus production and fibrosis of the visceral pleura). Numerous groups of tissue-resident macrophages are identified at homeostasis in the lungs which increase upon infection. Th2-deficient mice present higher parasite burden but lower inflammation and pathology. Our study provides new insight in filarial lung inflammation which may help to understand pathogenesis of human infections.

This study aims at assessing the validity and reliability of the Spanish version of the Lysholm score, a widely used instrument for assessing knee function and activity level after ligament injuries. Ninety-five participants (67.4% male, 22±5 years) completed the questionnaire twice within 7 days and a subsample of 42 participants completed a test-retest reliability. Reliability, validity and feasibility psychometric properties were studied. The validity of the questionnaire was analysed using ceiling and floor effects. Factor structure and construct validity were analysed with the SF-36, the Hip and Knee Questionnaire (HKQ) and one leg jump test (OLJT). Criterion validity with the SF-36 Physical State was moderate (r = 0.50 and p, This study takes place thanks to the additional funding from the University of Granada, Plan Propio de Investigación 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES).

Cytomegalovirus (CMV) is a ubiquitous herpesvirus infecting most of the world’s population. CMV has been rigorously investigated for its impact on lifelong immunity and potential complications arising from lifelong infection. A rigorous adaptive immune response mounts during progression of CMV infection from acute to latent states. CD8 T cells, in large part, drive this response and have very clearly been demonstrated to take up residence in the salivary gland and lungs of infected mice during latency. However, the role of tissue resident CD8 T cells as an ongoing defense mechanism against CMV has not been studied in other anatomical locations. Therefore, we sought to identify additional locations of anti-CMV T cell residency and the physiological consequences of such a response. Through RT-qPCR we found that mouse CMV (mCMV) infected the visceral adipose tissue and that this resulted in an expansion of leukocytes in situ. We further found, through flow cytometry, that adipose tissue became enriched in cytotoxic CD8 T cells that are specific for mCMV antigens from day 7 post infection through the lifespan of an infected animal (> 450 days post infection) and that carry markers of tissue residence. Furthermore, we found that inflammatory cytokines are elevated alongside the expansion of CD8 T cells. Finally, we show a correlation between the inflammatory state of adipose tissue in response to mCMV infection and the development of hyperglycemia in mice. Overall, this study identifies adipose tissue as a location of viral infection leading to a sustained and lifelong adaptive immune response mediated by CD8 T cells that correlates with hyperglycemia. These data potentially provide a mechanistic link between metabolic syndrome and chronic infection., Author summary Mouse cytomegalovirus (mCMV) infection results in initial systemic viremia that is thereafter controlled by the adaptive immune system. Control is mediated in part by T cells that render the virus undetectable systemically, and latent in specific organs, including the lungs and salivary glands. It remains unclear how latent virus is controlled across tissues given the large pool of systemic mCMV-specific T cells. We explored mCMV control in the adipose tissue, whose cellular constituents are potentially susceptible to infection. We found that mCMV infects the adipose tissue during the acute phase, causing local inflammation and a lifelong mCMV-specific CD8 T cell immune response. The response consisted largely from non-recirculating, tissue-resident T cells. The infected adipose tissue showed signs of metabolic changes, that may potentially predispose the infected host to metabolic dysregulation as evidenced by hyperglycemia. Accumulation and persistence of mCMV specific non-circulating resident CD8 T cells (Trm) in adipose tissue reveal a likely generalized mechanism of mCMV tissue reservoir control by Trm cells and identify the adipose tissue as a persistent mCMV reservoir, with potential implications for metabolic health.

The neuroscientific study of love has been boosted by an extended corpus of research on face-identity recognition. However, few studies have compared the emotional mechanisms activated by loved faces and names and none have simultaneously examined fMRI and autonomic measures. The present study combined fMRI with the heart rate response when 21 participants (10 males) passively viewed the face or the written name of 4 loved people and 4 unknown people. The results showed accelerative patterns in heart rate, together with brain activations, which were significantly higher for loved people than for unknown people. Significant correlations were found between heart rate and brain activation in frontal areas, for faces, and in temporal areas, for names. The results are discussed in the context of previous studies using the same passive viewing procedure, highlighting the relevance of integrating peripheral and central measures in the scientific study of positive emotion and love., This work was supported by a grant to JV from the Spanish Ministry of Science and Innovation (Grant PSI2011-28530)

Background and aimsEustachian tube dysfunction (ETD) is a commonly diagnosed disorder of Eustachian tube opening and closure, which may be associated with severe symptoms and middle ear disease. Currently the diagnosis of obstructive and patulous forms of ETD is primarily based on non-specific symptoms or examination findings, rather than measurement of the underlying function of the Eustachian tube. This has proved problematic when selecting patients for treatment, and when designing trial inclusion criteria and outcomes. This study aims to determine the correlation and diagnostic value of various tests of ET opening and patient reported outcome measures (PROMs), in order to generate a recommended diagnostic pathway for ETD.MethodsIndex tests included two PROMs and 14 tests of ET opening (nine for obstructive, five for patulous ETD). In the absence of an accepted reference standard two methods were adopted to establish index test accuracy: expert panel diagnosis and latent class analysis. Index test results were assessed with Pearson correlation and principle component analysis, and test accuracy was determined. Logistic regression models assessed the predictive value of grouped test results.ResultsThe expert panel diagnosis and PROMs results correlated with each other, but not with ET function measured by tests of ET opening. All index tests were found to be feasible in clinic, and acceptable to patients. PROMs had very poor specificity, and no diagnostic value. Combining the results of tests of ET function appeared beneficial. The latent class model suggested tympanometry, sonotubometry and tubomanometry have the best diagnostic performance for obstructive ETD, and these are included in a proposed diagnostic pathway.ConclusionsETD should be diagnosed on the basis of clinical assessment and tests of ET opening, as PROMs have no diagnostic value. Currently diagnostic uncertainty exists for some patients who appear to have intermittent ETD clinically, but have negative index test results.

Doxorubicin (DOX) is a widely used chemotherapeutic anticancer drug. Its intrinsic fluorescence properties enable investigation of tumor response, drug distribution and metabolism. First phantom studies in vitro showed optoacoustic property of DOX. We therefore aimed to further investigate the optoacoustic properties of DOX in biological tissue in order to explore its potential as theranostic agent. We analysed doxorubicin hydrochloride (Dox·HCl) and liposomal encapsulated doxorubicin hydrochloride (Dox·Lipo), two common drugs for anti-cancer treatment in clinical medicine. Optoacoustic measurements revealed a strong signal of both doxorubicin substrates at 488 nm excitation wavelength. Post mortem analysis of intra-tumoral injections of DOX revealed a detectable optoacoustic signal even at three days after the injection. We thereby demonstrate the general feasibility of doxorubicin detection in biological tissue by means of optoacoustic tomography, which could be applied for high resolution imaging at mesoscopic depths dictated by effective penetration of visible light into the biological tissues., PLoS ONE, 14 (5), ISSN:1932-6203

Dual Energy X-Ray Absorptiometry (DXA) is currently the most widely adopted non-invasive clinical technique to assess bone mineral density and bone mineral content in human research and represents the primary tool for the diagnosis of osteoporosis. DXA measures areal bone mineral density, BMD, which does not account for the three-dimensional structure of the vertebrae and for the distribution of bone mass. The result is that longitudinal DXA can only predict about 70% of vertebral fractures. This study proposes a complementary tool, based on Finite Element (FE) models, to improve the DXA accuracy. Bone is simulated as elastic and inhomogeneous material, with stiffness distribution derived from DXA greyscale images of density. The numerical procedure simulates a compressive load on each vertebra to evaluate the local minimum principal strain values. From these values, both the local average and the maximum strains are computed over the cross sections and along the height of the analysed bone region, to provide a parameter, named Strain Index of Bone (SIB), which could be considered as a bone fragility index. The procedure is initially validated on 33 cylindrical trabecular bone samples obtained from porcine lumbar vertebrae, experimentally tested under static compressive loading. Comparing the experimental mechanical parameters with the SIB, we could find a higher correlation of the ultimate stress, σULT, with the SIB values (R2adj = 0.63) than that observed with the conventional DXA-based clinical parameters, i.e. Bone Mineral Density, BMD (R2adj = 0.34) and Trabecular Bone Score, TBS (R2adj = -0.03). The paper finally presents a few case studies of numerical simulations carried out on human lumbar vertebrae. If our results are confirmed in prospective studies, SIB could be used-together with BMD and TBS-to improve the fracture risk assessment and support the clinical decision to assume specific drugs for metabolic bone diseases.

Background Recent studies are suggesting a U-shaped relationship between antenatal iron exposure and birth outcomes. Little is known about the iron status and associated birth outcomes of pregnant women in South Africa. Our aim was to assess iron status at early, mid- and late pregnancy, and to determine associations with gestational age and birth weight in women in Johannesburg, South Africa. Methods In this prospective study of 250 pregnant women, we measured haemoglobin, biomarkers of iron status and inflammation at, PLoS ONE, 14 (9), ISSN:1932-6203

Background: Alzheimer’s disease (AD) remains a clinical diagnosis but biomarkers from cerebrospinal fluid (CSF) and more lately amyloid imaging with positron emission tomography (PET), are important to support a diagnosis of AD. Objective: To compare amyloid-β (Aβ) PET imaging with biomarkers in CSF and evaluate the prediction of Aβ PET on diagnosis in a memory clinic setting. Methods: We included 64 patients who had lumbar puncture and Aβ PET with 18F-Flutemetamol performed within 190 days. PET was binary classified (Flut+ or Flut-) and logistic regression analyses for correlation to each CSF biomarker; Aβ 42 (Aβ42), total tau (T-tau) and phosphorylated tau (P-tau), were performed. Cut-off values were assessed by receiver operating characteristic (ROC) curves. Logistic regression was performed for prediction of clinical AD diagnosis. We assessed the interrater agreement of PET classification as well as for diagnoses, which were made both with and without knowledge of PET results. Results: Thirty-two of the 34 patients (94%) in the Flut+ group and nine of the 30 patients (30%) in the Flut- group had a clinical AD diagnosis. There were significant differences in all CSF biomarkers in the Flut+ and Flut- groups. Aβ42 showed the highest correlation with 18F-Flutemetamol PET with a cut-off value of 706.5 pg/mL, corresponding to sensitivity of 88% and specificity of 87%. 18F-Flutemetamol PET was the best predictor of a clinical AD diagnosis. We found a very high interrater agreement for both PET classification and diagnosis. Conclusions: The present study showed an excellent correlation of Aβ42 in CSF and 18F-Flutemetamol PET and the presented cut-off value for Aβ42 yields high sensitivity and specificity for 18F-Flutemetamol PET. 18F-Flutemetamol PET was the best predictor of clinical AD diagnosis. EGM (Ebba Gløersen Müller) received grants from Civitan Norway Research Foundation for Alzheimer´s disease.

Copyright: © 2019 Weis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited., Acute pancreatitis is a severe systemic disease triggered by a sterile inflammation and initial local tissue damage of the pancreas. Immune cells infiltrating into the pancreas are main mediators of acute pancreatitis pathogenesis. In addition to their antimicrobial potency, macrolides possess anti-inflammatory and immunomodulatory properties which are routinely used in patients with chronic airway infections and might also beneficial in the treatment of acute lung injury. We here tested the hypothesis that the macrolide antibiotic azithromycin can improve the course of acute experimental pancreatitis via ameliorating the damage imposed by sterile inflammation, and could be used as a disease specific therapy. However, our data show that azithromycin does not have influence on caerulein induced acute pancreatitis in terms of reduction of organ damage, and disease severity. Furthermore Infiltration of immune cells into the pancreas or the lungs was not attenuated by azithromycin as compared to controls or ampicillin treated animals with acute experimental pancreatitis. We conclude that in the chosen model, azithromycin does not have any beneficial effects and that its immunomodulatory properties cannot be used to decrease disease severity in the model of caerulein-induced pancreatitis in mice., MH was supported by the Formel1 Grant from University of Leipzig. SW and EJ are currently supported by the German Ministry of Education and Research (BMBF; grant 01 EO 1502) via the Jena Center of Sepsis Control and Care.

To test the hypothesis that cognitive load (low vs. high load) during a 20 min self-paced cycling exercise affects physical performance. Bayes analyses revealed extreme evidence for the 2-back task being more demanding than the 1-back task, both in terms of accuracy (BF10 = 4490) and reaction time (BF = 1316). The data only showed anecdotal evidence for the alternative hypothesis for the power output (BF10 = 1.52), moderate evidence for the null hypothesis for the heart rate (BF10 = 0.172), anecdotal evidence for RPE (BF10 = 0.72) and anecdotal evidence for mental fatigue (BF10 = 0.588). Our data seem to challenge the idea that self-paced exercise is regulated by top-down processing, given that we did not show clear evidence of exercise impairment (at the physical, physiological and subjective levels) in the high cognitive load condition task with respect to the low working memory load condition. The involvement of top-down processing in selfpacing the physical effort, however, cannot be totally discarded. Factors like the duration of the physical and cognitive tasks, the potential influence of dual-tasking, and the participants’ level of expertise, should be taken into account in future attempts to investigate the role of top-down processing in self-paced exercise., This project was supported by grant PSI2016-75956-P from Ministerio de Economía, Industria y Competitividad, awarded to DS and MZ, and grant FPU14/06229 from Ministerio de Educación, Cultura y Deporte, awarded to DH.

ObjectivesTo apply the MB (multiband) excitation and blipped-CAIPI (blipped-controlled aliasing in parallel imaging) techniques in a spin and gradient-echo (SAGE) EPI sequence to improve the slice coverage for vessel architecture imaging (VAI).Materials and methodsBoth MB excitation and blipped-CAIPI with in-plane parallel imaging were incorporated into a gradient-echo (GE)/spin-echo (SE) EPI sequence for simultaneous tracking of the dynamic MR signal changes in both GE and SE contrasts after the injection of contrast agent. MB and singleband (SB) excitation were compared using a 20-channel head coil at 3 Tesla, and high-resolution MB VAI could be performed in 32 glioma patients.ResultsWhole-brain covered high resolution VAI can be achieved after applying multiband excitation with a factor of 2 and in-plane parallel imaging with a factor of 3. The quality of the images resulting from MB acceleration was comparable to those from the SB method: images were reconstructed without any loss of spatial resolution or severe distortions. In addition, MB and SB signal-to-noise ratios (SNR) were similar. A relative low g-factor induced from the MB acceleration method was achieved after using a blipped-CAIPI technique (1.35 for GE and 1.33 for SE imaging). Performing quantitative VAI, we found that, among all VAI parametric maps, microvessel type indicator (MTI), distance map (I) and vascular-induced bolus peak-time shift (VIPS) were highly correlated. Likewise, VAI parametric maps of slope, slope length and short axis were highly correlated.ConclusionsMultiband accelerated SAGE successfully doubles the number of readout slices in the same measurement time when compared to conventional readout sequences. The corresponding VAI parametric maps provide insights into the complexity and heterogeneity of vascular changes in glioma.

Acute kidney injury (AKI) corrupts the outcome of about 50% of all critically ill patients. We investigated the possible contribution of the pathology acidemia on the development of AKI. Pigs were exposed to acidemia, acidemia plus hypoxemia or a normal acid-base balance in an experimental setup, which included mechanical ventilation and renal replacement therapy to facilitate biotrauma caused by extracorporeal therapies. Interestingly, extensive histomorphological changes like a tubular loss of cell barriers occurred in the kidneys after just 5 hours exposure to acidemia. The additional exposure to hypoxemia aggravated these findings. These 'early' microscopic pathologies opposed intra vitam data of kidney function. They did not mirror cellular or systemic patterns of proinflammatory molecules (like TNF-α or IL 18) nor were they detectable by new, sensitive markers of AKI like Neutrophil gelatinase-associated lipocalin. Instead, the data suggest that the increased renal proton excretion during acidemia could be an 'early' first hit in the multifactorial pathogenesis of AKI.

A physiologically relevant in vitro human-based model could be the ‘gold standard’ to clarify the pathological steps involved in glaucoma onset. In this regard, human 3D cultures may represent an excellent starting point to achieve this goal. Indeed, the 3D matrix allows to re-create the in vivo-like tissue architecture, maintaining its functionality and cellular behaviour, compared to the 2D model. Thus, we propose a comparison between the 2D and 3D in vitro models of human trabecular meshwork cells in terms of cellular responses after chronic stress exposure. Our results showed that 3D-cells are more sensitive to intracellular reactive oxidative specie production induced by hydrogen peroxide treatment, compared to 2D cultures. Additionally, in 3D cultures a more accurate regulation of the apoptosis trigger and cell adaptation mechanisms was detected than in 2D models. In line with these findings, the 3D-HTMC model shows the ability to better mimic the in vivo cell behaviour in adaptive responses to chronic oxidative stress than 2D.

ObjectiveBetter biomarkers are needed in order to identify patients with endometrial carcinoma at risk of recurrence and who may profit from a more aggressive treatment regimen. Our objective was to explore the applicability of plasma growth differentiation factor 15 (GDF-15) as a marker for recurrent disease, as well as a marker for poor prognosis and lymph node metastases.MethodsEDTA-blood samples were obtained from 235 patients with endometrial cancer before primary surgery. For 36 of these patients, matching blood samples were collected at time of recurrence. Blood samples were also collected from 78 patients with endometrial hyperplasia. Plasma GDF-15 was measured by an enzyme-linked immunosorbent assay (ELISA). Preoperative pelvic MRI scans for 141 patients were investigated in parallel for imaging variables.ResultsPreoperative plasma level of GDF-15 was significantly higher for patients who experienced recurrence (1780 ng/L; 95% CI; 518-9475 ng/L) than for patients who did not develop recurrent disease (1236 ng/L; 95% CI; 307-7030 ng/L) (pConclusionElevated plasma level of GDF-15 is associated with aggressive disease and lymph node metastasis in endometrial carcinoma. GDF-15 may be helpful in indicating recurrent disease.

Integrated exercises that mimic daily tasks are generally preferred for improving performance and the later stages of rehabilitation, but it is unknown whether integrated core exercises are better than isolated core exercises at improving muscle activation for hypertrophy. The aim of the study was to compare the electromyographic (EMG) activity in rectus abdominis, oblique externus, and erector spinae while performing three conditions of integrated core exercises (lunges) with three isolated core exercises (prone bridge, side bridge and back extension). The three conditions of lunges were: on a stable surface, unstable surface and with external resistance to the trunk using an elastic band. The external resistance was measured with a force cell and peaked at 75N. After one familiarization session, all exercises were performed in one experimental session in randomized order. The isolated core exercises were performed in 20 seconds and the time performing the five repetitions with lunges was matched (20 seconds). Significantly greater peak normalized EMG activity were observed in the isolated core exercises compared to the three integrated core exercises (P

Various feature selection algorithms have been proposed to identify cancer prognostic biomarkers. In recent years, however, their reproducibility is criticized. The performance of feature selection algorithms is shown to be affected by the datasets, underlying networks and evaluation metrics. One of the causes is the curse of dimensionality, which makes it hard to select the features that generalize well on independent data. Even the integration of biological networks does not mitigate this issue because the networks are large and many of their components are not relevant for the phenotype of interest. With the availability of multi-omics data, integrative approaches are being developed to build more robust predictive models. In this scenario, the higher data dimensions create greater challenges.We proposed a phenotype relevant network-based feature selection (PRNFS) framework and demonstrated its advantages in lung cancer prognosis prediction. We constructed cancer prognosis relevant networks based on epithelial mesenchymal transition (EMT) and integrated them with different types of omics data for feature selection. With less than 2.5% of the total dimensionality, we obtained EMT prognostic signatures that achieved remarkable prediction performance (average AUC values >0.8), very significant sample stratifications, and meaningful biological interpretations. In addition to finding EMT signatures from different omics data levels, we combined these single-omics signatures into multi-omics signatures, which improved sample stratifications significantly. Both single- and multi-omics EMT signatures were tested on independent multi-omics lung cancer datasets and significant sample stratifications were obtained.

Albeit differences in climbing-specific strength of the forearms have been demonstrated between lead and boulder climbers, little is known about the potential differences in force and power output of the upper body pulling-apparatus between disciplines. The aim of this study was to compare the climbing-specific upper-body strength and finger flexor endurance between lead and boulder climbers, as well as to examine the relative utilization of force when testing on a ledge hold compared to a jug hold. Sixteen boulder climbers (red-point climbing grade 17.9 ± 3.3) and fifteen lead climbers (red-point climbing grade 20.5 ± 3.5) performing on an advanced level volunteered for the study. Peak force, average force and rate of force development (RFD) were measured during an isometric pull-up, average velocity in dynamic pull-up, and finger flexor endurance in an intermittent test to fatigue. The isometric pull-up was performed on a ledge hold (high finger strength requirements) and on a jug hold (very low finger strength requirements). Boulder climbers demonstrated a higher maximal and explosive strength in all strength and power measurements (26.2–52.9%, ES = 0.90–1.12, p = 0.006–0.023), whereas the finger flexor endurance test showed no significant difference between the groups (p = 0.088). Both groups were able to utilize 57–69% of peak force, average force and RFD in the ledge condition compared to the jug condition, but the relative utilization was not different between the groups (p = 0.290–0.996). In conclusion, boulder climbers were stronger and more explosive compared to lead climbers, whereas no differences in finger flexor endurance were observed. Performing climbing-specific tests on a smaller hold appears to limit the force and power output equally between the two groups.

A major tenet in theoretical neuroscience is that cognitive and behavioral processes are ultimately implemented in terms of the neural system dynamics. Accordingly, a major aim for the analysis of neurophysiological measurements should lie in the identification of the computational dynamics underlying task processing. Here we advance a state space model (SSM) based on generative piecewise-linear recurrent neural networks (PLRNN) to assess dynamics from neuroimaging data. In contrast to many other nonlinear time series models which have been proposed for reconstructing latent dynamics, our model is easily interpretable in neural terms, amenable to systematic dynamical systems analysis of the resulting set of equations, and can straightforwardly be transformed into an equivalent continuous-time dynamical system. The major contributions of this paper are the introduction of a new observation model suitable for functional magnetic resonance imaging (fMRI) coupled to the latent PLRNN, an efficient stepwise training procedure that forces the latent model to capture the ‘true’ underlying dynamics rather than just fitting (or predicting) the observations, and of an empirical measure based on the Kullback-Leibler divergence to evaluate from empirical time series how well this goal of approximating the underlying dynamics has been achieved. We validate and illustrate the power of our approach on simulated ‘ground-truth’ dynamical systems as well as on experimental fMRI time series, and demonstrate that the learnt dynamics harbors task-related nonlinear structure that a linear dynamical model fails to capture. Given that fMRI is one of the most common techniques for measuring brain activity non-invasively in human subjects, this approach may provide a novel step toward analyzing aberrant (nonlinear) dynamics for clinical assessment or neuroscientific research., PLoS Computational Biology, 15 (8), ISSN:1553-734X, ISSN:1553-7358

PLOS ONE 14(2), e0211876 (2019). doi:10.1371/journal.pone.0211876, Published by PLOS, San Francisco, California, US

Copyright: © 2019 Rocha et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited., Purpose: To demonstrate the production of inflammatory mediators by cells located in bone marrow spaces inside rodent menisci. Methods: Mice subjected to transection of the medial collateral and anterior cruciate ligaments and meniscotomy (osteoarthritis model) or to a sham procedure, as well as non-operated (naive) mice and rats, had knee joints excised. Tissues were stained with hematoxylin-eosin and tartrate-resistant acid phosphatase (TRAP). CD68+ cells, inducible nitric oxide synthase (iNOS), interleukin (IL)-1β, and tumor necrosis factor (TNF) expression were detected using immunohistochemistry. Results: Lamellar ossified areas, bone-entrapped osteocytes and bone marrow spaces were found inside menisci of one week up to 6 months-old naïve mice, regardless of gender. Menisci from naive rats also showed the same pattern with bone marrow areas. CD68+ cells were identified in bone marrow areas inside the meniscus of mice. TRAP+ osteoclasts, and hematogenous precursors expressing IL-1β, TNF, and iNOS were identified inside bone marrow areas in meniscal samples from both naïve and sham operated mice. Quantitative immunoexpression of IL-1 β, TNF and iNOS was more intense, P = 0.0194, 0.0293, 0.0124, respectively, in mouse knees from mice sacrificed 49 days after being subjected to an osteoarthritis (OA) model as compared to sham operated animals. Conclusion: We provide novel data showing that rodent menisci display bone marrow areas with cells able to produce inflammatory mediators. Immunoexpression of inflammatory mediators in those bone marrow areas is significantly more pronounced in mice subjected to experimental OA., The study was funded by: UID/BIM/50005/2019, project funded by Fundação para a Ciência e a Tecnologia (FCT)/ Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through Fundos do Orçamento de Estado.

PLOS ONE 14(11), e0225218 (2019). doi:10.1371/journal.pone.0225218, Published by PLOS, San Francisco, California, US

Producción Científica, Metronomic chemotherapy using the 5-FU prodrug uracil-tegafur (UFT) and cyclophosphamide (CTX) was previously shown to only modestly delay primary tumor growth, but nevertheless markedly suppressed the development of micro-metastasis in an orthotopic breast cancer xenograft model, using the metastatic variant of the MDA-MB-231 cell line, 231/LM2-4. Furthermore, a remarkable prolongation of survival, with no toxicity, was observed in a model of postsurgical advanced metastatic disease. A question that has remained unanswered is the seemingly selective anti-metastatic mechanisms of action responsible for this treatment. We assessed the in vivo effect of metronomic UFT, CTX or their combination, on vascular density, collagen deposition and c-Met (cell mediators or modulators of tumor cell invasion or dissemination) via histochemistry/immunohistochemistry of primary tumor sections. We also assessed the effect of continuous exposure to low and non-toxic doses of active drug metabolites 5-fluorouracil (5-FU), 4-hydroperoxycyclophosphamide (4-HC) or their combination, on 231/LM2-4 cell invasiveness in vitro. In the in vivo studies, a significant reduction in vascular density and p-Met[Y1003] levels was associated with UFT+CTX treatment. All treatments reduced intratumoral collagen deposition. In the in vitro studies, a significant reduction of collagen IV invasion by all treatments was observed. The 3D structures formed by 231/LM2-4 on Matrigel showed a predominantly Mass phenotype under treated conditions and Stellate phenotype in untreated cultures. Taken together, the results suggest the low-dose metronomic chemotherapy regimens tested can suppress several mediators of tumor invasiveness highlighting a new perspective for the anti-metastatic efficacy of metronomic chemotherapy., Canadian Institutes of Health Research (grant 364411)

ObjectivesThe aim of this study was to examine the natural history of brain involvement in adult-onset myotonic dystrophies type 1 and 2 (DM1, DM2).MethodsWe conducted a longitudinal observational study to examine functional and structural cerebral changes in myotonic dystrophies. We enrolled 16 adult-onset DM1 patients, 16 DM2 patients, and 17 controls. At baseline and after 5.5 ± 0.4 years participants underwent neurological, neuropsychological, and 3T-brain MRI examinations using identical study protocols that included voxel-based morphometry and diffusion tensor imaging. Data were analyzed by (i) group comparisons between patients and controls at baseline and follow-up, and (ii) group comparisons using difference maps (baseline-follow-up in each participant) to focus on disease-related effects over time.ResultsWe found minor neuropsychological deficits with mild progression in DM1 more than DM2. Daytime sleepiness was restricted to DM1, whereas fatigue was present in both disease entities and stable over time. Comparing results of cross-sectional neuroimaging analyses at baseline and follow-up revealed an unchanged pattern of pronounced white matter alterations in DM1. There was mild additional gray matter reduction in DM1 at follow-up. In DM2, white matter reduction was of lesser extent, but there were some additional alterations at follow-up. Gray matter seemed unaffected in DM2. Intriguingly, longitudinal analyses using difference maps and comparing them between patients and controls did not reveal any significant differences of cerebral changes over time between patients and controls.ConclusionThe lack of significant disease-related progression of gray and white matter involvement over a period of five years in our cohort of DM1 and DM2 patients suggests either a rather slowly progressive process or even a stable course of cerebral changes in middle-aged adult-onset patients. Being the first longitudinal neuroimaging trial in DM1 and DM2, this study provides useful additional information regarding the natural history of brain involvement.

Protein expression of Myristoylated alanine-rich C kinase substrate like-1 (MARCKSL1) has been identified as a prognostic factor in lymph-node negative (LN-) breast cancer patients. We aim to validate MARCKSL1 protein expression as a prognostic marker for distant metastasis-free survival (DMFS) in a new cohort of LN- breast cancer patients. MARCKSL1 expression was evaluated in 151 operable T1,2N0M0 LN- breast cancer patients by immunohistochemistry. Median follow-up time was 152 months, range 11–189 months. Results were compared with classical prognosticators (age, tumor diameter, grade, estrogen receptor, and proliferation) using single (Kaplan-Meier) and multivariate (Cox model) survival analysis. Thirteen patients (9%) developed distant metastases. With both single and multiple analysis of all features, MARCKSL1 did not show a significant prognostic value for DMFS (p = 0.498). Of the assessed classical prognosticators, only tumor diameter showed prognostic value (hazard ratio 9.3, 95% confidence interval 2.8–31.0, p