Search

BackgroundSoft-robotic gloves with an assist-as-needed control have the ability to assist daily activities where needed, while stimulating active and highly functional movements within the user's possibilities. Employment of hand activities with glove support might act as training for unsupported hand function.ObjectiveTo evaluate the therapeutic effect of a grip-supporting soft-robotic glove as an assistive device at home during daily activities.MethodsThis multicentre intervention trial consisted of 3 pre-assessments (averaged if steady state = PRE), one post-assessment (POST), and one follow-up assessment (FU). Participants with chronic hand function limitations were included. Participants used the Carbonhand glove during six weeks in their home environment on their most affected hand. They were free to choose which activities to use the glove with and for how long. The primary outcome measure was grip strength, secondary outcome measures were pinch strength, hand function and glove use time.Results63 patients with limitations in hand function resulting from various disorders were included. Significant improvements (difference PRE-POST) were found for grip strength (+1.9 kg, CI 0.8 to 3.1; p = 0.002) and hand function, as measured by Jebson-Taylor Hand Function Test (-7.7 s, CI -13.4 to -1.9; p = 0.002) and Action Research Arm Test (+1.0 point, IQR 2.0; p≤0.001). Improvements persisted at FU. Pinch strength improved slightly in all fingers over six-week glove use, however these differences didn't achieve significance. Participants used the soft-robotic glove for a total average of 33.0 hours (SD 35.3), equivalent to 330 min/week (SD 354) or 47 min/day (SD 51). No serious adverse events occurred.ConclusionThe present findings showed that six weeks use of a grip-supporting soft-robotic glove as an assistive device at home resulted in a therapeutic effect on unsupported grip strength and hand function. The glove use time also showed that this wearable, lightweight glove was able to assist participants with the performance of daily tasks for prolonged periods.

Background Mountain biking and hiking continue to grow in popularity. With new participants to these sports, it is likely the number of injuries will increase. To assist medical personnel in the management of these patients we attempted to quantify the types and locations of injuries sustained by mountain bikers and hikers. Objective The objective of this systematic review is to identify the type and anatomical location of injuries for both mountain bikers and hikers. Methods A systematic search was undertaken using CINAHL, Cochrane, ProQuest, PubMed and Scopus databases. Reviewers assessed the eligibility of articles by a title/abstract review and final full-text review. Studies were included if the types of injuries were reported by medical personnel and contained anatomical locations. Studies were excluded if it did not take place on a trail or if the injuries were self-reported. Risk of bias was assessed utilising the Joanna Briggs Institute (JBI) checklists for study quality. No meta-analysis or comparison between mountain bikers and hikers was possible due to the high heterogeneity of the definition of injury. Results A total of 24 studies met the inclusion criteria, 17 covering mountain biking and 7 hiking. This represented 220,935 injured mountain bikers and 17,757 injured hikers. The most common type of injuries sustained by mountain bikers included contusions, abrasions and minor lacerations, which made up between 45–74% of reported injuries in studies on competitive racing and 8–67% in non-competitive studies. Fractures represented between 1.5–43% of all reported injuries. The most injured region was the upper limbs reported in 10 of 17 studies. For hikers the most common injuries included blisters and ankle sprains with blisters representing 8–33% of all reported injuries. The most common body location to be injured by hikers was a lower limb in all 7 studies. Conclusions This is the first systematic review to report on the injury epidemiology of the two most common trail users; mountain bikers and hikers. For participants in both activities the majority of injuries were of minor severity. Despite this, the high proportions of upper limb fractures in mountain bikers and ankle sprains in hikers cannot be ignored. Trial registration Registration: This systematic review was prospectively registered with the University of York PROSPERO database on the 12/4/2021 (CRD42021229623) https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021229623.

Iceland border the Arctic with cold maritime climate and a large proportion of the land placed at highland plateaus. About 1100 years of human disturbance, such as grazing and wood harvesting, has left much of the island's ecosystems in a poor state, ranging from barren deserts to areas with altered vegetative composition and degraded soils. We constructed a novel resilience-based model (RBC-model) for current land condition in Iceland to test which and how factors, including elevation, slope characteristics, drainage, and proximity to volcanic activity, influence the resilience and stability of ecosystems to human disturbances. We tested the model by randomly placing 500 sample areas (250 x 250 m) all over the country and obtaining values for each factor and current land conditions for each area from existing databases and satellite images. Elevation and drainage explained the largest portions of variability in land condition in Iceland, while both proximity to volcanic activity and the presence of scree slopes also yielded significant relationships. Overall, the model explained about 65% of the variability. The model was improved (R2 from 0.65 to 0.68) when the country was divided into four broadly defined regions. Land condition at the colder northern peninsulas was poorer at lower elevations compared to inland positions. This novel RBC model was successful in explaining differences in present land condition in Iceland. The results have implication for current land use management, especially grazing, suggesting that management should consider elevation, drainage, slopes and location within the country in addition to current land condition.

Intragenic CpG dinucleotides are tightly conserved in evolution yet are also vulnerable to methylation-dependent mutation, raising the question as to why these functionally critical sites have not been deselected by more stable coding sequences. We previously showed in cell lines that altered exonic CpG methylation can modify promoter start sites, and hence protein isoform expression, for the human TP53 tumor suppressor gene. Here we extend this work to the in vivo setting by testing whether synonymous germline modifications of exonic CpG sites affect murine development, fertility, longevity, or cancer incidence. We substituted the DNA-binding exons 5-8 of Trp53, the mouse ortholog of human TP53, with variant-CpG (either CpG-depleted or -enriched) sequences predicted to encode the normal p53 amino acid sequence; a control construct was also created in which all non-CpG sites were synonymously substituted. Homozygous Trp53-null mice were the only genotype to develop tumors. Mice with variant-CpG Trp53 sequences remained tumor-free, but were uniquely prone to dental anomalies causing jaw malocclusion (p < .0001). Since the latter phenotype also characterises murine Rett syndrome due to dysfunction of the trans-repressive MeCP2 methyl-CpG-binding protein, we hypothesise that CpG sites may exert non-coding phenotypic effects via pre-translational cis-interactions of 5-methylcytosine with methyl-binding proteins which regulate mRNA transcript initiation, expression or splicing, although direct effects on mRNA structure or translation are also possible.

Not all fossil sites preserve microfossils that can be extracted using acid digestion, which may leave knowledge gaps regarding a site's age or environmental characteristics. Here we report on a citizen science approach that was developed to identify microfossils in situ on the surface of sedimentary rocks. Samples were collected from McGraths Flat, a recently discovered Miocene rainforest lake deposit located in central New South Wales, Australia. Composed entirely of iron-oxyhydroxide, McGraths Flat rocks cannot be processed using typical microfossil extraction protocols e.g., acid digestion. Instead, scanning electron microscopy (SEM) was used to automatically acquire 25,200 high-resolution images from the surface of three McGraths Flat samples, covering a total area of 1.85 cm2. The images were published on the citizen science portal DigiVol, through which 271 citizen scientists helped to identify 300 pollen and spores. The microfossil information gained in this study is biostratigraphically relevant and can be used to constrain the environmental characteristics of McGraths Flat. Our findings suggest that automated image acquisition coupled with an evaluation by citizen scientists is an effective method of determining the age and environmental characteristics of fossiliferous rocks that cannot be investigated using traditional methods such as acid digestion.

BackgroundQuality indicators are used to quantify the quality of care. A large number of quality indicators makes assessment of overall quality difficult, time consuming and impractical. There is consequently an increasing interest for composite measures based on a combination of multiple indicators.ObjectiveTo examine the use of different approaches to construct composite measures of quality of care and to assess the use of methodological considerations and justifications.MethodsWe conducted a literature search on PubMed and EMBASE databases (latest update 1 December 2020). For each publication, we extracted information on the weighting and aggregation methodology that had been used to construct composite indicator(s).ResultsA total of 2711 publications were identified of which 145 were included after a screening process. Opportunity scoring with equal weights was the most used approach (86/145, 59%) followed by all-or-none scoring (48/145, 33%). Other approaches regarding aggregation or weighting of individual indicators were used in 32 publications (22%). The rationale for selecting a specific type of composite measure was reported in 36 publications (25%), whereas 22 papers (15%) addressed limitations regarding the composite measure.ConclusionOpportunity scoring and all-or-none scoring are the most frequently used approaches when constructing composite measures of quality of care. The attention towards the rationale and limitations of the composite measures appears low.DiscussionConsidering the widespread use and the potential implications for decision-making of composite measures, a high level of transparency regarding the construction process of the composite and the functionality of the measures is crucial.

Introduction The COVID-19 pandemic triggered a rapid shift towards telephone consultations (TC) in the out-patient clinic setting with little knowledge of the consequences. The aims of this study were to evaluate patient-centred experiences with TC, to describe patterns in clinical outcomes from TC and to pinpoint benefits and drawbacks associated with this type of consultations. Methods This mixed methods study combined an analysis of quantitative and qualitative data. A quantitative, retrospective observational study was conducted employing data from all 248 patients who received TC at an out-patient cardiology clinic during April 2020 with a one-month follow-up. Semi-structured interviews were conducted; Ten eligible patients were recruited from the outpatient clinic by purposive sampling. Results Within the follow-up period, no patients died or were acutely hospitalised. Approximately one in every four patients was transferred to their general practitioner, while the remaining three-quarter of the patients had a new examination or a new consultation planned. The cardiologist failed to establish contact with more than a fifth of the patients, often due to missing phone numbers. Ten patients were interviewed. Five themes emerged from the interviews: 1) Knowing an estimated time of the consultation is essential for patient satisfaction, 2) TC are well perceived when individually adapted, 3) TC can be a barrier to patient questions, 4) Video consultations should only be offered to patients who request it, and 5) Prescriptions or instructions made via TC do not cause uncertainty in patients. Conclusions The TC program was overall safe and the patients felt comfortable. Crucial issues include precise time planning, the patient’s availability on the phone and a correct phone number. Patients stressed that TC are unsuitable when addressing sensitive topics. A proposed visitation tool is presented.

BackgroundUrban renewal traditionally involves policy sectors such as housing, transport, and employment, which potentially can enhance the health of residents living in deprived areas. Additional involvement of the public health sector might increase the health impact of these urban renewal activities. This study evaluates the health impact of an additional focus on health, under the heading of Healthy District Experiments (HDE), within districts where an urban renewal programme was carried out.MethodsWe evaluated changes in health outcomes before the start of the HDE and after implementation, and compared these changes with health changes in control areas, e.g. districts from the urban renewal programme where no additional HDE was implemented. Additionally, we gathered information on the content of the experiments to determine what types of activities have been implemented.ResultsThe additional activities from the HDE were mostly aimed at strengthening the health care in the districts and at promoting physical activity. When we compared the prevalence in general health, mental health, overweight, obesity, smoking, and physical activity during the study period between the HDE districts and control districts, we found no significant differences in the rate of change. The study is limited by a small sample size and the cross-sectional nature of the data. These and other limitations are discussed.ConclusionWe found no evidence for a beneficial health impact of the activities that were initiated with a specific focus on health, within a Dutch urban renewal programme. Specific attention for network management and the integration of such activities in the wider programme, as well as an allocated budget might be needed in order to sort a health impact.

Objective Trophoblast inclusions—cross sections of abnormal trophoblast bilayer infoldings—have previously been associated with aneuploidy, placenta accreta, and prematurity. This study was conducted to establish the relationship between trophoblast inclusions and a range of placental, pregnancy, and birth outcomes in a patient population with high smoking and alcohol exposure. Specifically, we sought to evaluate the association between the presence of trophoblast inclusions and 1) three primary birth outcomes: full-term birth, preterm birth, and stillbirth; 2) gestational age at delivery; and 3) specific placental pathologies. Methods Two slides containing chorionic villi were evaluated from 589 placentas that were collected from Stellenbosch University in Cape Town, South Africa as part of the prospective, multicenter cohort Safe Passage Study of the Prenatal Alcohol and SIDS and Stillbirth Network. The subsample included 307 full-term live births, 212 preterm live births, and 70 stillbirths. Results We found that the odds of identifying at least one trophoblast inclusion across two slides of chorionic villi was significantly higher for placentas from preterm compared to term liveborn deliveries (OR = 1.74; 95% CI: 1.22, 2.49, p = 0.002), with an even greater odds ratio for placentas from stillborn compared to term liveborn deliveries (OR = 4.95; 95% CI: 2.78, 8.80, p < 0.001). Gestational age at delivery was inversely associated with trophoblast inclusion frequency. Trophoblast inclusions were significantly associated with small for gestational age birthweight, induction of labor, villous edema, placental infarction, and inflammation of the chorionic plate. Conclusions The novel associations that we report warrant further investigation in order to understand the complex network of biological mechanisms through which the factors that lead to trophoblast inclusions may influence or reflect the trajectory and health of a pregnancy. Ultimately, this line of research may provide critical insights that could inform both clinical and research applications.

IntroductionIn order to study the role of the microbiome in hematopoietic stem cell transplantation (HCT), researchers collect stool samples from patients at various time points throughout HCT. However, stool collection requires active subject participation and may be limited by patient reluctance to handling stool.MethodsWe performed a prospective study on the impact of financial incentives on stool collection rates. The intervention group consisted of allogeneic HCT patients from 05/2017-05/2018 who were compensated with a $10 gas gift card for each stool sample. The intervention group was compared to a historical control group of allogeneic HCT patients from 11/2016-05/2017 who provided stool samples before the incentive was implemented. To control for possible changes in collections over time, we also compared a contemporaneous control group of autologous HCT patients from 05/2017-05/2018 with a historical control group of autologous HCT patients from 11/2016-05/2017; neither autologous HCT group was compensated. The collection rate was defined as the number of samples provided divided by the number of time points we attempted to obtain stool.ResultsThere were 35 allogeneic HCT patients in the intervention group, 19 allogeneic HCT patients in the historical control group, 142 autologous HCT patients in the contemporaneous control group (that did not receive a financial incentive), and 75 autologous HCT patients in the historical control group. Allogeneic HCT patients in the intervention group had significantly higher average overall collection rates when compared to the historical control group allogeneic HCT patients (80% vs 37%, pConclusionOur results demonstrate that a modest incentive can significantly increase collection rates. These results may help to inform the design of future studies involving stool collection.

BackgroundIn 2016, WHO launched the Global Health Sector Strategy on STIs, 2016-2021 (GHSS) to provide guidance and benchmarks for country achievement by 2020 and four global targets for achievement by 2030.MethodsA country survey jointly developed by experienced technical personnel at WHO Headquarters (HQ) and WHO regional offices was reviewed and distributed by WHO regional advisors to 194 WHO Member States in September-March 2020. The survey sought to assess implementation and prioritization of STI policy, surveillance, service delivery, commodity availability, and surveillance based on targets of the GHSS.ResultsA majority (58%, 112/194) of countries returned a completed survey reflecting current (2019) STI activities. The regions with the highest survey completion rates were South-East Asia Region (91%, 10/11), Region of the Americas (71%, 25/35) and Western Pacific Region (67%, 18/27). Having a national STI strategy was reported by 64% (72/112) and performing STI surveillance activities by 88% (97/110) of reporting countries. Availability of STI services within primary health clinics was reported by 88% of countries (99/112); within HIV clinics by 92% (103/112), and within reproductive health services by 85% (95/112). Existence of a national strategy to eliminate mother-to-child transmission of HIV and syphilis (EMTCT) was reported by 70% of countries (78/112). Antimicrobial resistance (AMR) monitoring for gonococcal infection (gonorrhoea) was reported by 64% (57/89) of reporting countries with this laboratory capacity. Inclusion of HPV vaccine for young women in the national immunization schedule was reported by 59% (65/110) and availability of cervical cancer screening was reported by 91% (95/104). Stockouts of STI medicines, primarily benzathine penicillin, within the prior four years were reported by 34% (37/110) of countries.ConclusionsMechanisms to support improvements to STI service delivery through national-level policy, commitment, programming and surveillance are needed to operationalize, accelerate and monitor progress towards achievement of the 2030 global STI strategy targets.

IntroductionMore than 70% of new HIV infections in Asia occurred in eight countries in 2020: Cambodia, China, India, Indonesia, Myanmar, Nepal, Thailand, and Vietnam-with a rising incidence among men who have sex with men (MSM). The World Health Organization (WHO) recommends pre-exposure prophylaxis (PrEP) for those at risk of acquiring HIV, yet wide-scale implementation of PrEP, on a daily or event-driven basis, has been limited in Asia.MethodsThe Optima HIV model was applied to examine the impact of scaling-up PrEP over five-years to cover an additional 15% of MSM compared with baseline coverage, a target deemed feasible by regional experts. Based on behavioral survey data, we assume that covering 15% of higher-risk MSM will cover 30% of all sexual acts in this group. Scenarios to compare the impact of generic-brand daily dosing of PrEP with generic event-driven dosing (15 days a month) were modelled from the start of 2022 to the end of 2026. Cost-effectiveness of generic versus branded PrEP was also assessed for China, the only country with an active patent for branded, higher cost PrEP. The impact on new HIV infections among the entire population and cost per HIV-related disability-adjusted life year (DALY) averted were estimated from the beginning of 2022 to the end of 2031 and from 2022 to 2051.ResultsIf PrEP were scaled-up to cover an additional 15% of MSM engaging in higher-risk behavior from the beginning of 2022 to the end of 2026 in the eight Asian countries considered, an additional 100,000 (66,000-130,000) HIV infections (17%) and 300,000 (198,000-390,000) HIV-related DALYs (3%) could be averted over the 2022 to 2031 period. The estimated cost per HIV-related DALY averted from 2022 to 2031 ranged from US$600 for event-driven generic PrEP in Indonesia to US$34,400 for daily branded PrEP in Thailand. Over a longer timeframe from 2022 to 2051, the cost per HIV-related DALY averted could be reduced to US$100-US$12,700.ConclusionPrEP is a critical tool to further reduce HIV incidence in highly concentrated epidemics. Implementing PrEP in Asia may be cost-effective in settings with increasing HIV prevalence among MSM and if PrEP drug costs can be reduced, PrEP could be more cost-effective over longer timeframes.

ObjectiveEarly identification of the basic reproduction number (BRN) is imperative to political decision making during an epidemic. In this study, we estimated the BRN 7, 14, 21 and 28 days after societal lockdown of Denmark during the early stage of the COVID-19 epidemic.MethodWe implemented the SEIR dynamical system for disease spread without vital dynamics. The BRN was modulated using a sigmoid function. Model parameters were estimated on number of admitted patients, number of patients in intensive care and cumulative number of deaths using the simulated annealing Monte Carlo algorithm. Results are presented with 95% prediction intervals (PI).ResultsWe were unable to determine any reliable estimate of the BRN at 7 days following lockdown. The BRN had stabilised at day 14 throughout day 28, with the estimate ranging from 0.95 (95% PI: 0.92-0.98) at day 7 to 0.92 (95% PI: 0.92-0.93) at day 28. We estimated the BRN prior to lockdown to be 3.32 (95% PI: 3.31-3.33). The effect of the lockdown was occurring over a period of a few days centred at March 18th (95% PI: 17th-18th) 2020.ConclusionWe believe our model provides a valuable tool for decision makers to reliably estimate the effect of a politically determined lockdown during an epidemic.

Regulation of the anti-apoptotic BCL2 protein determines cell survival and is frequently abnormal in B cell lymphomas. An evolutionarily conserved post-translational mechanism for over-expression of BCL2 in human B cell lymphomas and the BCL2 paralogue CED-9 in Caenorhabditis elegans results from loss-of-function mutations in human FBXO10 and its C.elegans paralogue DRE-1, a BCL2/CED-9-binding subunit of the SKP-CULLIN-FBOX (SCF) ubiquitin ligase. Here, we tested the role of FBXO10 in BCL2 regulation by producing mice with two different CRISPR/Cas9-engineered Fbxo10 mutations: an Asp54Lys (E54K) missense mutation in the FBOX domain and a Cys55SerfsTer55 frameshift (fs) truncating mutation. Mice homozygous for either mutant allele were born at the expected Mendelian frequency and appeared normal in body weight and appearance as adults. Spleen B cells from homozygous mutant mice did not have increased BCL2 protein, nor were the numbers of mature B cells or germinal centre B cells increased as would be expected if BCL2 was increased. Other lymphocyte subsets that are also regulated by BCL2 levels also displayed no difference in frequency in homozygous Fbxo10 mutant mice. These results support one of two conclusions: either FBXO10 does not regulate BCL2 in mice, or it does so redundantly with other ubiquitin ligase complexes. Possible candidates for the latter include FBXO11 or ARTS-XIAP. The difference between the role of FBXO10 in regulating BCL2 protein levels in C. elegans and in human DLBCL, relative to single-gene deficient mouse leukocytes, should be further investigated.

Background The global utilization of the physician assistant/associate (PA) is growing. Their increasing presence is in response to the rising demands of demographic changes, new developments in healthcare, and physician shortages. While PAs are present on four continents, the evidence of whether their employment contributes to more efficient healthcare has not been assessed in the aggregate. We undertook a systematic review of the literature on PA cost-effectiveness as compared to physicians. Cost-effectiveness was operationalized as quality, accessibility, and the cost of care. Methods and findings Literature to June 2021 was searched across five biomedical databases and filtered for eligibility. Publications that met the inclusion criteria were categorized by date, country, design, and results by three researchers independently. All studies were screened with the Risk of Bias in Non-randomised Studies—of Interventions (ROBIN-I) tool. The literature search produced 4,855 titles, and after applying criteria, 39 studies met inclusion (34 North America, 4 Europe, 1 Africa). Ten studies had a prospective design, and 29 were retrospective. Four studies were assessed as biased in results reporting. While most studies included a small number of PAs, five studies were national in origin and assessed the employment of a few hundred PAs and their care of thousands of patients. In 34 studies, the PA was employed as a substitute for traditional physician services, and in five studies, the PA was employed in a complementary role. The quality of care delivered by a PA was comparable to a physician’s care in 15 studies, and in 18 studies, the quality of care exceeded that of a physician. In total, 29 studies showed that both labor and resource costs were lower when the PA delivered the care than when the physician delivered the care. Conclusions Most of the studies were of good methodological quality, and the results point in the same direction; PAs delivered the same or better care outcomes as physicians with the same or less cost of care. Sometimes this efficiency was due to their reduced labor cost and sometimes because they were more effective as producers of care and activity.

There is evidence to suggest that people with Complex Regional Pain Syndrome (CRPS) can have altered body representations and spatial cognition. One way of studying these cognitive functions is through manual straight ahead (MSA) pointing, in which participants are required to point straight ahead of their perceived body midline without visual feedback of the hand. We therefore compared endpoint errors from MSA pointing between people with CRPS (n = 17) and matched controls (n = 18), and examined the effect of the arm used (Side of Body; affected/non-dominant, non-affected/dominant). For all participants, pointing errors were biased towards the hand being used. We found moderate evidence of no difference between Groups on endpoint errors, and moderate evidence of no interaction with Side of Body. The differences in variability between Groups were non-significant/inconclusive. Correlational analyses showed no evidence of a relationship between MSA endpoint errors and clinical parameters (e.g. CRPS severity, duration, pain) or questionnaire measures (e.g. body representation, "neglect-like symptoms", upper limb disability). This study is consistent with earlier findings of no difference between people with CRPS and controls on MSA endpoint errors, and is the first to provide statistical evidence of similar performance of these two groups. Our results do not support a relationship between clinical or self-reported measures (e.g. "neglect-like symptoms") and any directional biases in MSA. Our findings may have implications for understanding neurocognitive changes in CRPS.

BackgroundAllogeneic hematopoietic stem cell transplantation (HCT) is an often curative intent treatment, however it is associated with significant gastrointestinal (GI) toxicity and treatment related mortality. Graft-versus-host disease is a significant contributor to transplant-related mortality. We performed a phase 2 trial of the somatostatin analog pasireotide to prevent gastrointestinal toxicity and GVHD after myeloablative allogeneic HCT.MethodsPatients received 0.9mg pasireotide every 12 hours from the day prior to conditioning through day +4 after HCT (or a maximum of 14 days). The primary outcomes were grade 3-4 gastrointestinal toxicity through day 30 and acute GVHD. Secondary outcomes were chronic GVHD, overall survival and relapse free survival at one year. Stool and blood samples were collected from before and after HCT for analyses of stool microbiome, local inflammatory markers, and systemic inflammatory and metabolic markers. Results were compared with matched controls.ResultsTwenty-six patients received pasireotide and were compared to 52 matched contemporaneous controls using a 1-2 match. Grade 3-4 GI toxicity occurred in 21 (81%) patients who received pasireotide and 35 (67%) controls (p = 0.33). Acute GVHD occurred in 15 (58%) patients in the pasireotide group and 28 (54%) controls (p = 0.94). Chronic GVHD occurred in 16 patients in the pasireotide group (64%) versus 22 patients in the control group (42%) (p = 0.12). Overall survival at 1 year in the pasireotide group was 63% (95% CI: 47%,86%) versus 82% (95% CI: 72%, 93%) in controls (log-rank p = 0.006). Relapse-free survival rate at one year was 40% (95% CI: 25%, 65%) in the pasireotide group versus 78% (95% CI: 68%, 91%) in controls (log-rank p = 0.002). After controlling for the effect of relevant covariates, patients in the pasireotide group had attenuated post-HCT loss of microbial diversity. Analysis of systemic inflammatory markers and metabolomics demonstrated feasibility of such analyses in patients undergoing allogeneic HCT. Baseline level and pre-to-post transplant changes in several inflammatory markers (including MIP1a, MIP1b, TNFa, IL8Pro, and IL6) correlated with likelihood of survival.ConclusionsPasireotide did not prevent gastrointestinal toxicity or acute GVHD compared to contemporaneous controls. Pasireotide was associated with numerically higher chronic GVHD and significantly decreased OS and RFS compared to contemporaneous controls. Pasireotide may provide a locally protective effect in the stool microbiome and in local inflammation as measured by stool calprotectin, stool beta-defensin, and stool diversity index.

Clinical data suggest that progestins have chemopreventive properties in the development of colorectal cancer. We set out to examine a potential protective effect of progestins and progesterone signaling on colon cancer development. In normal and neoplastic intestinal tissue, we found that the progesterone receptor (PR) is not expressed. Expression was confined to sporadic mesenchymal cells. To analyze the influence of systemic progesterone receptor signaling, we crossed mice that lacked the progesterone receptor (PRKO) to the Apc(Min/+) mouse, a model for spontaneous intestinal polyposis. PRKO-Apc(Min/+) mice exhibited no change in polyp number, size or localization compared to Apc(Min/+). To examine effects of progestins on the intestinal epithelium that are independent of the PR, we treated mice with MPA. We found no effects of either progesterone or MPA on gross intestinal morphology or epithelial proliferation. Also, in rats treated with MPA, injection with the carcinogen azoxymethane did not result in a difference in the number or size of aberrant crypt foci, a surrogate end-point for adenoma development. We conclude that expression of the progesterone receptor is limited to cells in the intestinal mesenchyme. We did not observe any effect of progesterone receptor signaling or of progestin treatment in rodent models of intestinal tumorigenesis.

BackgroundEarly risk stratification for guiding treatment priority in the emergency department (ED) is becoming increasingly important. Existing prediction models typically use demographics, vital signs and laboratory parameters. Laboratory-based models require blood testing, which may cause substantial delay. However, these delays can be prevented by the use of point-of-care testing (POCT), where results are readily available. We aimed to externally validate a laboratory-based model for mortality and subsequently assessed whether a POCT model yields comparable performance.MethodsAll adult patients visiting the ED of a university hospital between January 1st, 2012 and December 31st, 2016 were retrospectively reviewed for inclusion. Primary outcome was defined as 30-day mortality after ED presentation. We externally validated one existing prediction model including age, glucose, urea, sodium, haemoglobin, platelet count and white blood cell count. We assessed the predictive performance by discrimination, expressed as Area under the Curve (AUC). We compared the existing model to an equivalent model using predictors that are available with POCT (i.e. glucose, urea, sodium and haemoglobin). Additionally, we internally validated these models with bootstrapping.ResultsWe included 34,437 patients of whom 1,942 (5.6%) died within 30 days. The AUC of the laboratory-based model was 0.794. We refitted this model to our ED population and found an AUC of 0.812, which decreased only slightly to 0.790 with only POCT parameters.ConclusionsOur POCT-model performs similar to existing laboratory-based models in identifying patients at high risk for mortality, with results available within minutes. Although the model needs further validation and evaluation, it shows the potential of POCT for early risk stratification in the ED.

Marine protected areas (MPAs) are valuable tools for marine conservation that aim to limit human impacts on marine systems and protect valuable species or habitats. However, as species distributions shift due to ocean warming, acidification, and oxygen depletion from climate change, the areas originally designated under MPAs may bear little resemblance to their past state. Different approaches have been suggested for coping with species on the move in conservation. Here, we test the effectiveness of different MPA designs, including dynamic, network, and different directional orientations on protecting shifting species under climate change through ecosystem modeling in a theoretical ecosystem. Our findings suggest that dynamic MPAs may benefit some species (e.g., whiting and anchovy) and fishing fleets, and these benefits can inform the design or adaptation of MPAs worldwide. In addition, we find that it is important to design MPAs with specific goals and to account for the effects of released fishing pressure and species interactions in MPA design.

BACKGROUND:Multidisciplinary rehabilitation has been recommended for multi-trauma patients, but there is only low-quality evidence to support its use with these patients. This study examined whether a Supported Fast track multi-Trauma Rehabilitation Service (Fast Track) was cost-effective compared to conventional trauma rehabilitation service (Care As Usual) in patients with multi-trauma from a societal perspective with a one-year follow-up. METHODS:An economic evaluation alongside a prospective, multi-center, non-randomized, controlled clinical study, was conducted in the Netherlands. The primary outcome measure was the Functional Independence Measure (FIM). Generic Quality of Life and Quality Adjusted Life Years (QALYs) of the patients were derived using the Short-form 36 Health Status Questionnaire. Incremental Cost-Effectiveness Ratios (ICERs) were stated in terms of costs per unit of FIM improvement and costs per QALY. To investigate the uncertainty around the ICERs, non-parametric bootstrapping was used. RESULTS:In total, 132 patients participated, 65 Fast Track patients and 67 Care As Usual patients. Mean total costs per person were €18,918 higher in the Fast Track group than in the Care As Usual group. Average incremental effects on the FIM were 3.7 points (in favor of the Fast Track group) and the incremental (extra) bootstrapped costs were €19,033, resulting in an ICER for cost per FIM improvement of €5,177. Care As Usual dominated Fast Track in cost per QALY as it gave both higher QALYs and lower costs. All sensitivity analyses attested to the robustness of our results. CONCLUSIONS:This study demonstrated that a multidisciplinary rehabilitation program for multi-trauma patients according to the supported fast track principle is promising but cost-effectiveness evidence remains inconclusive. In terms of functional outcome, Fast Track was more expensive but yielded also more effects compared to the Care As Usual group. Looking at the costs per QALYs, unfavorable ICERs were found. Given the lack of a willingness-to-pay threshold for functional recovery and the relatively short time horizon, it is not possible to draw firm conclusions about the first. TRIAL REGISTRATION:(Current Controlled Trials register: ISRCTN68246661).

OBJECTIVE:In hospitalized patients, the risk of sepsis-related mortality can be assessed using the quick Sepsis-related Organ Failure Assessment (qSOFA). Currently, different tools that predict deterioration such as the National Early Warning Score (NEWS) have been introduced in clinical practice in Emergency Departments (ED) worldwide. It remains ambiguous which screening tool for mortality at the ED is best. The objective of this study was to evaluate the predictive performance for mortality of two sepsis-based scores (i.e. qSOFA and Systemic Inflammatory Response Syndrome (SIRS)-criteria) compared to the more general NEWS score, in patients with suspected infection directly at presentation to the ED. METHODS:We performed a retrospective cohort study. Patients who presented to the ED between June 2012 and May 2016 with suspected sepsis in a large tertiary care center were included. Suspected sepsis was defined as initiation of intravenous antibiotics and/or collection of any culture in the ED. Outcome was defined as 10-day and 30-day mortality after ED presentation. Predictive performance was expressed as discrimination (AUC) and calibration using Hosmer-Lemeshow goodness-of-fit test. Subsequently, sensitivity, and specificity were calculated. RESULTS:In total 8,204 patients were included of whom 286 (3.5%) died within ten days and 490 (6.0%) within 30 days after presentation. NEWS had the best performance, followed by qSOFA and SIRS (10-day AUC: 0.837, 0.744, 0.646, 30-day AUC: 0.779, 0.697, 0.631). qSOFA (≥2) lacked a high sensitivity versus SIRS (≥2) and NEWS (≥7) (28.5%, 77.2%, 68.0%), whilst entailing highest specificity versus NEWS and SIRS (93.7%, 66.5%, 37.6%). CONCLUSIONS:NEWS is more accurate in predicting 10- and 30-day mortality than qSOFA and SIRS in patients presenting to the ED with suspected sepsis.

OBJECTIVE:Clinical practice universally assumes that appropriate empirical antibiotic therapy improves survival in patients with bloodstream infection. However, this is not generally supported by previous studies. We examined the association between appropriate therapy and 30-day mortality, while minimizing bias due to confounding by indication. METHODS:We conducted a retrospective cohort study between 2012 and 2017 at a tertiary university hospital in the Netherlands. Adult patients with bloodstream infection attending the emergency department were included. Based on in vitro susceptibility, antibiotic therapy was scored as appropriate or inappropriate. Primary outcome was 30-day mortality. To control for confounding, we performed conventional multivariable logistic regression and propensity score methods. Additionally, we performed an analysis in a more homogeneous subgroup (i.e. antibiotic monotherapy). RESULTS:We included 1.039 patients, 729 (70.2%) received appropriate therapy. Overall 30-day mortality was 10.4%. Appropriately treated patients had more unfavorable characteristics, indicating more severe illness. Despite adjustments, we found no association between appropriate therapy and mortality. For the antibiotic monotherapy subgroup (n = 449), patient characteristics were more homogeneous. Within this subgroup, appropriate therapy was associated with lower mortality (Odds Ratios [95% Confidence Intervals] ranging from: 0.31 [0.14; 0.67] to 0.40 [0.19; 0.85]). CONCLUSIONS:Comparing heterogeneous treatment groups distorts associations despite use of common methods to prevent bias. Consequently, conclusions of such observational studies should be interpreted with care. If possible, future investigators should use our method of attempting to identify and analyze the most homogeneous treatment groups nested within their study objective, because this minimizes residual confounding.

Background/objectivesCognitive impairment is a frequent problem among older patients attending the Emergency Department (ED) and can be the result of pre-existing cognitive impairment, delirium, or neurologic disorders. Another cause can also be acute disturbance of brain perfusion and oxygenation, which may be reversed by optimal resuscitation. This study aimed to assess the relationship between vital signs, as a measure of acute hemodynamic changes, and cognitive impairment in older ED patients.DesignProspective cohort study.SettingED's of two tertiary care and two secondary care hospitals in the Netherlands.Participants2629 patients aged 70-years and older.MeasurementsVital signs were measured at the moment of ED arrival as part of routine clinical care. Cognition was measured using the Six-Item Cognitive Impairment Test (6-CIT).ResultsThe median age of patients was 78 years (IQR 74-84). Cognitive impairment was present in 738 patients (28.1%). When comparing lowest with highest quartiles, a systolic blood pressure of 21/min) was associated with increased risk of impaired cognition (OR 2.16, 95% CI 1.58-2.95) as well as oxygen saturation of ConclusionAbnormal vital signs associated with decreased brain perfusion and oxygenation are also associated with cognitive impairment in older ED patients. This may partially be explained by the association between disease severity and delirium, but also by acute disturbance of brain perfusion and oxygenation. Future studies should establish whether normalization of vital signs will also acutely improve cognition.

[This corrects the article DOI: 10.1371/journal.pone.0206262.].

Breast milk plays an important role in immune development in early life and protects against diseases later in life. A wide range of the beneficial effects of breast milk are attributed to human milk oligosaccharides (HMOs) as well as components such as vitamin D3 (VitD3) or TGFβ. One mechanism by which HMOs might contribute to immune homeostasis and protection against disease is the induction of a local tolerogenic milieu. In this study we investigated the effect of the HMOs 6'-sialyllactose (6'SL) and 2'-fucosyllactose (2'FL) as well as prebiotic galactooligosaccharides (GOS) on DC differentiation and maturation. Isolated CD14+ monocytes were cultured for six days in the presence of GM-CSF and IL-4 with or without 6'SL, 2'FL, GOS, VitD3 or TGFβ. Additionally, immature VitD3DC, TGFβDC and moDC were used as different DC types to investigate the effect of 6'SL, 2'FL and GOS on DC maturation. Surface marker expression and cytokine production was measured by flow cytometry and cytometric bead array, respectively. Unlike TGFβ and vitD3, the oligosaccharides 6'SL, 2'FL and GOS did not influence DC differentiation. Next, we studied the effect of 6'SL, 2'FL and GOS on maturation of moDC, VitD3DC and TGFβDC that showed different profiles of HMO-binding receptors. 6'SL, 2'FL and GOS did not modulate LPS-induced maturation, even though their putative receptors were present on the different DCs types. Thus, whereas VitD3 and TGFβ halt DC differentiation, which results in phenotypically distinct tolerogenic DCs, 6'SL, 2'FL and GOS do not alter DC differentiation or maturation of in vitro differentiated DC types.

[This corrects the article DOI: 10.1371/journal.pone.0186461.].

Overt fibrostenotic disease is a relative contraindication for anti-TNF therapy in Crohn's disease. We hypothesized that subclinical fibrosis may also contribute to an incomplete response to anti-TNF therapy before the onset of symptomatic stenosis.In a previous trial, patients with ileocecal Crohn's disease were randomized to either immediate ileocecal resection or medical treatment with Infliximab. In case of insufficient response to Infliximab, the latter underwent secondary ileocecal resection. We compared specimens from those patients undergoing immediate resection (Infliximab naïve, n = 20) to those who failed Infliximab therapy (n = 20).Infliximab naïve and Infliximab failure patients had similar severity of inflammation when assessed by CRP levels (median 14 vs 9 mg/L) and histology (Geboes-D'Haens-score, median 10 vs 11 points). On immunohistochemistry, collagen-III and fibronectin depositions were increased in patients previously exposed to Infliximab compared to patients naïve to Infliximab. On mRNA level, procollagen peptidase showed significantly more mucosal mRNA expression in Crohn's disease patients who failed Infliximab. Infliximab responders showed no increase of this marker after 4 weeks of successful Infliximab treatment.Failure to Infliximab therapy is associated with subclinical fibrosis in Crohn's disease.

OBJECTIVE:To explore which of 50 self-management strategies are actually used and which are perceived as most helpful by patients in their day-to-day management of depression, in order to empower patients and promote active engagement in their own care. METHODS:Retrospective study using an online self-report survey to assess the use and perceived helpfulness of 50 previously identified self-management strategies in 193 participants who recently recovered from a major depressive episode. RESULTS:Forty-five of the 50 strategies were used by at least half of all participants and about one third of all participants perceived almost 50% of all strategies as (very) helpful. The most used strategies, such as 'finding strategies to create pleasurable distractions', 'engaging in leisure activities' or 'identifying the cause of the depression', were not always perceived as most helpful. In addition, the perceived most helpful strategies, such as 'completing treatment' and 'leaving the house regularly' were not always the most used ones. CONCLUSIONS:Patients use and perceive a wide range of self-management strategies as helpful to recover from their depression. Patients use and perceive strategies about engagement in treatment and physical activities as being most helpful. These finding may contribute to the further development and implementation of self-management programs for the prevention or the rehabilitation of depression.

A correlation between excess mortality from myocardial infarctions (MI) and schizophrenia has already been established. What remains unclear is whether the initial communication between the treating doctor and the corresponding patient contributes to this excess mortality.The aim of this study is to investigate whether a patient with schizophrenia receives the same offers for examination and treatment following a MI compared to a psychiatric healthy control (PHC).This cohort study includes patients diagnosed with schizophrenia at the time of their first MI (n = 47) in the years between 1995-2015 matched 1:2 to psychiatric healthy MI patients on gender, age and year of first MI. All existing hospital files for the 141 patients were thoroughly reviewed and the number of offered and accepted examinations and treatments were extracted for comparisons between the two groups.In general patients with schizophrenia were less likely to be offered and accept examination and at the same time be offered and accept treatment as compared to PHCs (p

Interest in using peptide molecules as therapeutic agents due to high selectivity and efficacy is increasing within the pharmaceutical industry. However, most peptide-derived drugs cannot be administered orally because of low bioavailability and instability in the gastrointestinal tract due to protease activity. Therefore, structural modifications peptides are required to improve their stability. For this purpose, several in-silico software tools have been developed such as PeptideCutter or PoPS, which aim to predict peptide cleavage sites for different proteases. Moreover, several databases exist where this information is collected and stored from public sources such as MEROPS and ExPASy ENZYME databases. These tools can help design a peptide drug with increased stability against proteolysis, though they are limited to natural amino acids or cannot process cyclic peptides, for example. We worked to develop a new methodology to analyze peptide structure and amide bond metabolic stability based on the peptide structure (linear/cyclic, natural/unnatural amino acids). This approach used liquid chromatography / high resolution, mass spectrometry to obtain the analytical data from in vitro incubations. We collected experimental data for a set (linear/cyclic, natural/unnatural amino acids) of fourteen peptide drugs and four substrate peptides incubated with different proteolytic media: trypsin, chymotrypsin, pepsin, pancreatic elastase, dipeptidyl peptidase-4 and neprilysin. Mass spectrometry data was analyzed to find metabolites and determine their structures, then all the results were stored in a chemically aware manner, which allows us to compute the peptide bond susceptibility by using a frequency analysis of the metabolic-liable bonds. In total 132 metabolites were found from the various in vitro conditions tested resulting in 77 distinct cleavage sites. The most frequent observed cleavage sites agreed with those reported in the literature. The main advantages of the developed approach are the abilities to elucidate metabolite structure of cyclic peptides and those containing unnatural amino acids, store processed information in a searchable format within a database leading to frequency analysis of the labile sites for the analyzed peptides. The presented algorithm may be useful to optimize peptide drug properties with regards to cleavage sites, stability, metabolism and degradation products in drug discovery.

To compare human observers to a mathematically derived computer model for differentiation between malignant and benign pulmonary nodules detected on baseline screening computed tomography (CT) scans.A case-cohort study design was chosen. The study group consisted of 300 chest CT scans from the Danish Lung Cancer Screening Trial (DLCST). It included all scans with proven malignancies (n = 62) and two subsets of randomly selected baseline scans with benign nodules of all sizes (n = 120) and matched in size to the cancers, respectively (n = 118). Eleven observers and the computer model (PanCan) assigned a malignancy probability score to each nodule. Performances were expressed by area under the ROC curve (AUC). Performance differences were tested using the Dorfman, Berbaum and Metz method. Seven observers assessed morphological nodule characteristics using a predefined list. Differences in morphological features between malignant and size-matched benign nodules were analyzed using chi-square analysis with Bonferroni correction. A significant difference was defined at p < 0.004.Performances of the model and observers were equivalent (AUC 0.932 versus 0.910, p = 0.184) for risk-assessment of malignant and benign nodules of all sizes. However, human readers performed superior to the computer model for differentiating malignant nodules from size-matched benign nodules (AUC 0.819 versus 0.706, p < 0.001). Large variations between observers were seen for ROC areas and ranges of risk scores. Morphological findings indicative of malignancy referred to border characteristics (spiculation, p < 0.001) and perinodular architectural deformation (distortion of surrounding lung parenchyma architecture, p < 0.001; pleural retraction, p = 0.002).Computer model and human observers perform equivalent for differentiating malignant from randomly selected benign nodules, confirming the high potential of computer models for nodule risk estimation in population based screening studies. However, computer models highly rely on size as discriminator. Incorporation of other morphological criteria used by human observers to superiorly discriminate size-matched malignant from benign nodules, will further improve computer performance.

The effects on health related outcomes of a newly-developed rehabilitation program, called 'supported Fast Track multi-trauma rehabilitation service' (Fast Track), were evaluated in comparison with conventional trauma rehabilitation service (Care as Usual).Prospective, multi-center, non-randomized controlled study. Between 2009 and 2012, 132 adult multi-trauma patients were included: 65 Fast Track and 67 Care as Usual patients with an Injury Severity Score ≥16, complex multiple injuries in several extremities or complex pelvic and/or acetabulum fractures. The Fast Track program involved: integrated coordination between trauma surgeon and rehabilitation physician, shorter stay in hospital with faster transfer to a specialized trauma rehabilitation unit, earlier start of multidisciplinary treatment and 'non-weight bearing' mobilization. Primary outcomes were functional status (FIM) and quality of life (SF-36) measured through questionnaires at baseline, 3, 6, 9 and 12 months post-trauma. Outcomes were analyzed using a linear mixed-effects regression model.The FIM scores significantly increased between 0 and 3 months (p

The retinal pigment epithelium (RPE) is a neural monolayer lining the back of the eye. Degeneration of the RPE leads to severe vision loss in, so far incurable, diseases such as age-related macular degeneration and some forms of retinitis pigmentosa. A promising future replacement therapy may be autologous iris epithelial cell transdifferentiation into RPE in vitro and, subsequently, transplantation. In this study we compared the gene expression profiles of the iris epithelium (IE) and the RPE.We collected both primary RPE- and IE cells from 5 freshly frozen human donor eyes, using respectively laser dissection microscopy and excision. We performed whole-genome expression profiling using 44k Agilent human microarrays. We investigated the gene expression profiles on both gene and functional network level, using R and the knowledge database Ingenuity.The major molecular pathways related to the RPE and IE were quite similar and yielded basic neuro-epithelial cell functions. Nonetheless, we also found major specific differences: For example, genes and molecular pathways, related to the visual cycle and retinol biosynthesis are significantly higher expressed in the RPE than in the IE. Interestingly, Wnt and aryl hydrocarbon receptor (AhR-) signaling pathways are much higher expressed in the IE than in the RPE, suggesting, respectively, a possible pluripotent and high detoxification state of the IE.This study provides a valuation of the similarities and differences between the expression profiles of the RPE and IE. Our data combined with that of the literature, represent a most comprehensive perspective on transcriptional variation, which may support future research in the development of therapeutic transplantation of IE.

BACKGROUND:Large-scale regeneration programmes to improve the personal conditions and living circumstances in deprived areas may affect health and the lifestyle of the residents. Previous evaluations concluded that a large-scale urban regeneration programme in the Netherlands had some positive effects within 3.5 years. The aim of the current study was to evaluate the effects at the longer run. METHODS:With a quasi-experimental research design we assessed changes in the prevalence of general health, mental health, physical activity, overweight, obesity, and smoking between the pre-intervention (2003-04 -mid 2008) and intervention period (mid 2008-2013-14) in 40 deprived target districts and comparably deprived control districts. We used the Difference-in-Difference (DiD) to assess programme impact. Additionally, we stratified analyses by sex and by the intensity of the regeneration programme. RESULTS:Changes in health and health related behaviours from pre-intervention to the intervention period were about equally large in the target districts as in control districts. DiD impact estimates were inconsistent and not statistically significant. Sex differences in DiD estimates were not consistent or significant. Furthermore, DiD impact estimates were not consistently larger in target districts with more intensive intervention programmes. CONCLUSION:We found no evidence that this Dutch urban regeneration programme had an impact in the longer run on self-reported health and related behaviour at the area level.

Vitamin D deficiency is common among pregnant women and since the fetus relies exclusively on maternal supply, deficiency could potentially interfere with fetal development. Vitamin D blood concentrations during pregnancy have been associated with offspring cardio-metabolic health in a few previous studies but the evidence is still inconsistent and only one previous study has followed the offspring into adulthood. The aim of the present study was to investigate the association between maternal serum concentration of vitamin D (25(OH)D) in week 30 of gestation and offspring cardio-metabolic risk factors at 20 years.A follow up study of a Danish birth cohort from 1988-89 (n = 965) was conducted. A blood sample was drawn from the women in week 30 of gestation. In 2008-2009, 95% of the original mother and child dyads could be identified in the central registration registry and were alive and living in Denmark. The offspring were followed up with self-reported anthropometrics (N = 629, 69%) and a clinical examination (N = 410, 45%). Multiple linear regression was used to estimate the association between maternal 25(OH)D and offspring cardio-metabolic risk factors adjusting for potential confounders.No overall association was observed between maternal 25(OH)D in week 30 of gestation and offspring cardio-metabolic risk factors. However, the analyses did suggest a possible inverse association with blood pressure in females.No clear association between maternal 25(OH)D concentration in week 30 of gestation and cardio-metabolic risk factors in the 20 year old offspring was found.

Jumonji Domain-Containing Protein 3 (JMJD3)/lysine demethylase 6B (KDM6B) is an epigenetic modulator that removes repressive histone marks on genes. Expression of KDM6B mRNA is elevated in leukocytes from patients with ANCA-associated vasculitis (AAV) and has been suggested to be the reason for higher proteinase 3 (PR3) mRNA expression in these cells due to derepression of PRTN3 gene transcription. MicroRNA-941 (miR-941) has been shown to target KDM6B mRNA and inhibit JMJD3 production. We therefore investigated whether polymorphonuclear granulocytes (PMNs) from patients suffering from granulomatosis with polyangiitis (GPA) have lower expression of miR-941 than healthy control donors as a biological cause for higher JMJD3 levels. We found no significant difference in the degree of maturation of PMNs from GPA patients (n = 8) and healthy controls (n = 11) as determined from cell surface expression of the neutrophil maturation marker CD16 and gene expression profile of FCGR3B. The expression of PRTN3 and KDM6B mRNAs and miR-941 was not significantly different in GPA patients and healthy controls. Transfection of pre-miR-941 into the neutrophil promyelocyte cell line PLB-985 cells did not result in reduction of the KDM6B mRNA level as shown previously in a hepatocellular carcinoma cell line. The amount of PR3 in PMNs from GPA patients and healthy controls was comparable. In conclusion, we found that PRTN3 mRNA, KDM6B mRNA, and miR-941 expression levels in PMNs do not differ between GPA patients and healthy controls, and that miR-941 does not uniformly regulate KDM6B mRNA levels by inducing degradation of the transcript. Thus, decreased miR-941 expression in PMNs cannot be part of the pathogenesis of GPA.

Our ability to sustain attention for prolonged periods of time is limited. Studies on the relationship between lapses of attention and psychophysiological markers of attentional state, such as pupil diameter, have yielded contradicting results. Here, we investigated the relationship between tonic fluctuations in pupil diameter and performance on a demanding sustained attention task. We found robust linear relationships between baseline pupil diameter and several measures of task performance, suggesting that attentional lapses tended to occur when pupil diameter was small. However, these observations were primarily driven by the joint effects of time-on-task on baseline pupil diameter and task performance. The linear relationships disappeared when we statistically controlled for time-on-task effects and were replaced by consistent inverted U-shaped relationships between baseline pupil diameter and each of the task performance measures, such that most false alarms and the longest and most variable response times occurred when pupil diameter was both relatively small and large. Finally, we observed strong linear relationships between the temporal derivative of pupil diameter and task performance measures, which were largely independent of time-on-task. Our results help to reconcile contradicting findings in the literature on pupil-linked changes in attentional state, and are consistent with the adaptive gain theory of locus coeruleus-norepinephrine function. Moreover, they suggest that the derivative of baseline pupil diameter is a potentially useful psychophysiological marker that could be used in the on-line prediction and prevention of attentional lapses.

Cannabis is the most frequently used illicit drug worldwide. Cross-sectional neuroimaging studies suggest that chronic cannabis exposure and the development of cannabis use disorders may affect brain morphology. However, cross-sectional studies cannot make a conclusive distinction between cause and consequence and longitudinal neuroimaging studies are lacking. In this prospective study we investigate whether continued cannabis use and higher levels of cannabis exposure in young adults are associated with grey matter reductions. Heavy cannabis users (N = 20, age baseline M = 20.5, SD = 2.1) and non-cannabis using healthy controls (N = 22, age baseline M = 21.6, SD = 2.45) underwent a comprehensive psychological assessment and a T1- structural MRI scan at baseline and 3 years follow-up. Grey matter volumes (orbitofrontal cortex, anterior cingulate cortex, insula, striatum, thalamus, amygdala, hippocampus and cerebellum) were estimated using the software package SPM (VBM-8 module). Continued cannabis use did not have an effect on GM volume change at follow-up. Cross-sectional analyses at baseline and follow-up revealed consistent negative correlations between cannabis related problems and cannabis use (in grams) and regional GM volume of the left hippocampus, amygdala and superior temporal gyrus. These results suggests that small GM volumes in the medial temporal lobe are a risk factor for heavy cannabis use or that the effect of cannabis on GM reductions is limited to adolescence with no further damage of continued use after early adulthood. Long-term prospective studies starting in early adolescence are needed to reach final conclusions.

It is argued that trophy hunting of large, charismatic mammal species can have considerable conservation benefits but only if undertaken sustainably. Social-ecological theory suggests such sustainability only results from developing governance systems that balance financial and biological requirements. Here we use lion (Panthera leo) trophy hunting data from Tanzania to investigate how resource ownership patterns influence hunting revenue and offtake levels. Tanzania contains up to half of the global population of free-ranging lions and is also the main location for lion trophy hunting in Africa. However, there are concerns that current hunting levels are unsustainable. The lion hunting industry in Tanzania is run by the private sector, although the government leases each hunting block to companies, enforces hunting regulation, and allocates them a species-specific annual quota per block. The length of these leases varies and theories surrounding property rights and tenure suggest hunting levels would be less sustainable in blocks experiencing a high turnover of short-term leases. We explored this issue using lion data collected from 1996 to 2008 in the Selous Game Reserve (SGR), the most important trophy hunting destination in Tanzania. We found that blocks in SGR with the highest lion hunting offtake were also those that experienced the steepest declines in trophy offtake. In addition, we found this high hunting offtake and the resultant offtake decline tended to be in blocks under short-term tenure. In contrast, lion hunting levels in blocks under long-term tenure matched more closely the recommended sustainable offtake of 0.92 lions per 1000 km2. However, annual financial returns were higher from blocks under short-term tenure, providing $133 per km2 of government revenue as compared to $62 per km2 from long-term tenure blocks. Our results provide evidence for the importance of property rights in conservation, and support calls for an overhaul of the system in Tanzania by developing competitive market-based approaches for block allocation based on long-term tenure of ten years.

Bordetella pertussis circulates even in highly vaccinated countries affecting all age groups. Insight into the scale of concealed reinfections is important as they may contribute to transmission. We therefore investigated whether current single-point serodiagnostic methods are suitable to estimate the prevalence of pertussis reinfection. Two methods based on IgG-Ptx plasma levels alone were used to evaluate the proportion of renewed seroconversions in the past year in a cohort of retrospective pertussis cases ≥ 24 months after a proven earlier symptomatic infection. A Dutch population database was used as a baseline. Applying a classical 62.5 IU/ml IgG-Ptx cut-off, we calculated a seroprevalence of 15% in retrospective cases, higher than the 10% observed in the population baseline. However, this method could not discriminate between renewed seroconversion and waning of previously infection-enhanced IgG-Ptx levels. Two-component cluster analysis of the IgG-Ptx datasets of both pertussis cases and the general population revealed a continuum of intermediate IgG-Ptx levels, preventing the establishment of a positive population and the comparison of prevalence by this alternative method. Next, we investigated the complementary serodiagnostic value of IgA-Ptx levels. When modelling datasets including both convalescent and retrospective cases we obtained new cut-offs for both IgG-Ptx and IgA-Ptx that were optimized to evaluate renewed seroconversions in the ex-cases target population. Combining these cut-offs two-dimensionally, we calculated 8.0% reinfections in retrospective cases, being below the baseline seroprevalence. Our study for the first time revealed the shortcomings of using only IgG-Ptx data in conventional serodiagnostic methods to determine pertussis reinfections. Improved results can be obtained with two-dimensional serodiagnostic profiling. The proportion of reinfections thus established suggests a relatively increased period of protection to renewed infection after clinical pertussis.

In patients with visual hemifield defects residual visual functions may be present, a phenomenon called blindsight. The superior colliculus (SC) is part of the spared pathway that is considered to be responsible for this phenomenon. Given that the SC processes input from different modalities and is involved in the programming of saccadic eye movements, the aim of the present study was to examine whether multimodal integration can modulate oculomotor competition in the damaged hemifield. We conducted two experiments with eight patients who had visual field defects due to lesions that affected the retinogeniculate pathway but spared the retinotectal direct SC pathway. They had to make saccades to an auditory target that was presented alone or in combination with a visual stimulus. The visual stimulus could either be spatially coincident with the auditory target (possibly enhancing the auditory target signal), or spatially disparate to the auditory target (possibly competing with the auditory tar-get signal). For each patient we compared the saccade endpoint deviation in these two bi-modal conditions with the endpoint deviation in the unimodal condition (auditory target alone). In all seven hemianopic patients, saccade accuracy was affected only by visual stimuli in the intact, but not in the blind visual field. In one patient with a more limited quadrantano-pia, a facilitation effect of the spatially coincident visual stimulus was observed. We conclude that our results show that multisensory integration is infrequent in the blind field of patients with hemianopia.

ContextEconomic evaluations are far less frequently reported for medical devices than for drugs. In addition, little is known about the quality of existing economic evaluations, particularly for innovative devices, such as those used in vertebroplasty and kyphoplasty.ObjectiveTo assess the level of evidence provided by the available economic evaluations for vertebroplasty and kyphoplasty.Data sourcesA systematic review of articles in English or French listed in the MEDLINE, PASCAL, COCHRANE and National Health Service Economic Evaluation databases, with limits on publication date (up to the date of the review, March 2014).Study selectionWe included only economic evaluations of vertebroplasty or kyphoplasty. Editorial and methodological articles were excluded.Data extractionData were extracted from articles by two authors working independently and using two analysis grids to measure the quality of economic evaluations.Data synthesisTwenty-one studies met our inclusion criteria. All were published between 2008 and 2014. Eighteen (86%) were full economic evaluations. Cost-effectiveness analysis (CEA) was the most frequent type of economic evaluation, and was present in 11 (52%) studies. Only three CEAs complied fully with the British Medical Journal checklist. The quality of the data sources used in the 21 studies was high, but the CEAs conforming to methodological guidelines did not use high-quality data sources for all components of the analysis.ConclusionsThis systematic review shows that the level of evidence in economic evaluations of vertebroplasty and kyphoplasty is low, despite the recent publication of a large number of studies. This finding highlights the challenges to be faced to improve the quality of economic evaluations of medical devices.

Detailed understanding of a possible decoupling between climatic drivers of plant productivity and the response of ecosystems vegetation is required. We compared trends in six NDVI metrics (1982-2010) derived from the GIMMS3g dataset with modelled biomass productivity and assessed uncertainty in trend estimates. Annual total biomass weight (TBW) was calculated with the LINPAC model. Trends were determined using a simple linear regression, a Thiel-Sen medium slope and a piecewise regression (PWR) with two segments. Values of NDVI metrics were related to Net Primary Production (MODIS-NPP) and TBW per biome and land-use type. The simple linear and Thiel-Sen trends did not differ much whereas PWR increased the fraction of explained variation, depending on the NDVI metric considered. A positive trend in TBW indicating more favorable climatic conditions was found for 24% of pixels on land, and for 5% a negative trend. A decoupled trend, indicating positive TBW trends and monotonic negative or segmented and negative NDVI trends, was observed for 17-36% of all productive areas depending on the NDVI metric used. For only 1-2% of all pixels in productive areas, a diverging and greening trend was found despite a strong negative trend in TBW. The choice of NDVI metric used strongly affected outcomes on regional scales and differences in the fraction of explained variation in MODIS-NPP between biomes were large, and a combination of NDVI metrics is recommended for global studies. We have found an increasing difference between trends in climatic drivers and observed NDVI for large parts of the globe. Our findings suggest that future scenarios must consider impacts of constraints on plant growth such as extremes in weather and nutrient availability to predict changes in NPP and CO2 sequestration capacity.

The human retinal pigment epithelium (RPE) plays an important role in the pathogenesis of age related macular degeneration (AMD). AMD is the leading cause of blindness worldwide. There is currently no effective treatment available. Preclinical studies in AMD mouse models are essential to develop new therapeutics. This requires further in-depth knowledge of the similarities and differences between mouse and human RPE.We performed a microarray study to identify and functionally annotate RPE specific gene expression in mouse and human RPE. We used a meticulous method to determine C57BL/6J mouse RPE signature genes, correcting for possible RNA contamination from its adjacent layers: the choroid and the photoreceptors. We compared the signature genes, gene expression profiles and functional annotations of the mouse and human RPE.We defined sets of mouse (64), human (171) and mouse-human interspecies (22) RPE signature genes. Not unexpectedly, our gene expression analysis and comparative functional annotation suggested that, in general, the mouse and human RPE are very similar. For example, we found similarities for general features, like "organ development" and "disorders related to neurological tissue". However, detailed analysis of the molecular pathways and networks associated with RPE functions, suggested also multiple species-specific differences, some of which may be relevant for the development of AMD. For example, CFHR1, most likely the main complement regulator in AMD pathogenesis was highly expressed in human RPE, but almost absent in mouse RPE. Furthermore, functions assigned to mouse and human RPE expression profiles indicate (patho-) biological differences related to AMD, such as oxidative stress, Bruch's membrane, immune-regulation and outer blood retina barrier.These differences may be important for the development of new therapeutic strategies and translational studies in age-related macular degeneration.

Bronchopulmonary dysplasia (BPD) is a serious complication of preterm birth. Plasma N-terminal pro-B type natriuretic peptide (NT-proBNP) has been suggested as a marker that may predict BPD within a few days after birth.To investigate the association between NT-proBNP day three and bronchopulmonary dysplasia (BPD) or death and further to assess the impact of patent ductus arteriosus (PDA) on this association in neonates born before 32 gestational weeks.A cohort study of 183 neonates born before 32 gestational weeks consecutively admitted to the Neonatal Intensive Care Unit, Aarhus University Hospital, Denmark. On day three plasma samples were collected and echocardiography carried out. NT-proBNP was measured by routine immunoassays. The combined outcome BPD or death was assessed at 36 weeks of postmenstrual age. Receiver operator characteristic (ROC) analysis was performed to determine the discrimination ability of NT-proBNP by the natural log continuous measure to recognize BPD or death. The association of BPD or death was assessed in relation to natural log NT-proBNP levels day three.The risk of BPD or death increased 1.7-fold with one unit increase of natural log NT-proBNP day three when adjusted for gestational age at birth (OR = 1.7, 95% CI 1.3; 2.3). The association was found both in neonates with and without a PDA. Adjusting for GA, PDA diameter, LA:Ao-ratio, or early onset sepsis did not change the estimate.We found NT-proBNP to be associated with BPD or death in very preterm neonates. This association was not only explained by the PDA. We speculate that NT-proBNP may help the identification of neonates at risk of BPD as early as postnatal day three.

Unconventional gas drilling (UGD) has enabled extraordinarily rapid growth in the extraction of natural gas. Despite frequently expressed public concern, human health studies have not kept pace. We investigated the association of proximity to UGD in the Marcellus Shale formation and perinatal outcomes in a retrospective cohort study of 15,451 live births in Southwest Pennsylvania from 2007-2010. Mothers were categorized into exposure quartiles based on inverse distance weighted (IDW) well count; least exposed mothers (first quartile) had an IDW well count less than 0.87 wells per mile, while the most exposed (fourth quartile) had 6.00 wells or greater per mile. Multivariate linear (birth weight) or logistical (small for gestational age (SGA) and prematurity) regression analyses, accounting for differences in maternal and child risk factors, were performed. There was no significant association of proximity and density of UGD with prematurity. Comparison of the most to least exposed, however, revealed lower birth weight (3323 ± 558 vs 3344 ± 544 g) and a higher incidence of SGA (6.5 vs 4.8%, respectively; odds ratio: 1.34; 95% confidence interval: 1.10-1.63). While the clinical significance of the differences in birth weight among the exposure groups is unclear, the present findings further emphasize the need for larger studies, in regio-specific fashion, with more precise characterization of exposure over an extended period of time to evaluate the potential public health significance of UGD.

If the Chlamydia trachomatis (CT) bacterial load is higher in high-risk populations than in the general population, this negatively affects the efficacy of CT screening incentives. In the largest retrospective study to date, we investigated the CT load in specimens collected from 2 cohorts: (1) attendants of a sexually transmitted infection (STI)-clinic and (2) participants of the Dutch population-based screening (PBS).CT load was determined using quantitative PCR in CT-positive male urine and female cervicovaginal swabs. CT loads were converted into tertiles. Using multinominal logistic regression, independent association of cohort, symptoms, risk behaviour and human cell count on load were assessed.CT loads were determined in 889 CT-positives from PBS (n = 529; 71.8% female) and STI-clinics (n = 360; 61.7% female). In men, STI-clinic-cohort, human cell count and urethral discharge were positively associated with CT load. In women, PBS-cohort and cell count were positively associated with CT load. Both cohorts had the same range in CT load.The general population has a similar range of bacterial CT load as a high-risk population, but a different distribution for cohort and gender, highlighting the relevance of population-based CT-screening. When CT loads are similar, possibly the chances of transmission and sequelae are too.

Hydatidiform moles (HMs) are abnormal human pregnancies with vesicular chorionic villi, imposing two clinical challenges; miscarriage and a risk of gestational trophoblastic neoplasia (GTN). The parental type of most HMs are either diandric diploid (PP) or diandric triploid (PPM). We consecutively collected 154 triploid or near-triploid samples from conceptuses with vesicular chorionic villi. We used analysis of DNA markers and/or methylation sensitive-MLPA and collected data from registries and patients records. We performed whole genome SNP analysis of one case of twinning (PP+PM).In all 154 triploids or near-triploids we found two different paternal contributions to the genome (P1P2M). The ratios between the sex chromosomal constitutions XXX, XXY, and XYY were 5.7: 6.9: 1.0. No cases of GTN were observed. Our results corroborate that all triploid human conceptuses with vesicular chorionic villi have the parental type P1P2M. The sex chromosomal ratios suggest approximately equal frequencies of meiosis I and meiosis II errors with selection against the XYY conceptuses or a combination of dispermy, non-disjunction in meiosis I and meiosis II and selection against XYY conceptuses. Although single cases of GTN after a triploid HM have been reported, the results of this study combined with data from previous prospective studies estimate the risk of GTN after a triploid mole to 0% (95% CI: 0-1,4%).

In studies of perfluoroalkyl acids, the validity and comparability of measured concentrations may be affected by differences in the handling of biospecimens. We aimed to investigate whether measured plasma levels of perfluoroalkyl acids differed between blood samples subjected to delay and transportation prior to processing and samples with immediate processing and freezing.Pregnant women recruited at Aarhus University Hospital, Denmark, (n = 88) provided paired blood samples. For each pair of samples, one was immediately processed and plasma was frozen, and the other was delayed and transported as whole blood before processing and freezing of plasma (similar to the Danish National Birth Cohort). We measured 12 perfluoroalkyl acids and present results for compounds with more than 50% of samples above the lower limit of quantification.For samples taken in the winter, relative differences between the paired samples ranged between -77 and +38% for individual perfluoroalkyl acids. In most cases concentrations were lower in the delayed and transported samples, e.g. the relative difference was -29% (95% confidence interval -30; -27) for perfluorooctane sulfonate. For perfluorooctanoate there was no difference between the two setups [corresponding estimate 1% (0, 3)]. Differences were negligible in the summer for all compounds.Transport of blood samples and processing delay, similar to conditions applied in some large, population-based studies, may affect measured perfluoroalkyl acid concentrations, mainly when outdoor temperatures are low. Attention to processing conditions is needed in studies of perfluoroalkyl acid exposure in humans.