Stable carbon and nitrogen isotopes explain methylmercury concentrations in stream food webs of Lake George, New York (USA).

Mercury has been studied extensively in lakes due to health risks associated with the consumption of contaminated fish, while stream ecosystems have received less attention. To better understand mercury bioavailability in the lower food web of streams, we collected macroinvertebrates (predators and detritivore) along with autochthonous (epilithic algae) and allochthonous (leaf litter) basal resources in eight streams entering Lake George. Samples were analyzed for methylmercury (MeHg), total mercury, and carbon and nitrogen isotopes (δ13C & δ15N) to determine how mercury concentrations in basal resources, biomagnification rates, and environmental factors (watershed characteristics and water chemistry) effected MeHg concentrations in predatory macroinvertebrates. While biomagnification rates, calculated as trophic magnification slope, explained between 68% and 98% of MeHg variability within a stream food web, the range was small (0.310-0.387) resulting in the biotic components following a consistent pattern of increasing MeHg among streams. The stream order was negatively related to basin slope for all biotic components and explained 70% of MeHg variability in predatory macroinvertebrates. Methylmercury concentrations were significantly and negatively related to δ13C in predators, epilithic algae, and leaf litter. We believe the biofilms on leaf litter utilized bacterial-respired carbon dioxide decreasing δ13C (<-28‰) and increasing MeHg while epilithic algal δ13C increased due to enhanced primary production resulting in biodilution of MeHg. Methylmercury in basal resources responded to δ13C similarly but through different processes. Our findings show shallow slopes elevate MeHg in basal resources and explain most of the predator MeHg variation among streams with little influence of biomagnification rates.

Detection of drug-responsive B lymphocytes and antidrug IgG in patients with ß-lactam hypersensitivity.

BACKGROUND: Delayed-type ß-lactam hypersensitivity develops in subset of patients. The cellular immunological processes that underlie the drug-specific response have been described; however, little is known about involvement of the humoral immune system. Thus, the aim of this study was to utilize piperacillin hypersensitivity as an exemplar to (i) develop cell culture methods for the detection of drug-specific B-cell responses, (ii) characterize drug-specific IgG subtypes and (iii) assess reactivity of IgG antibodies against proteins modified to different levels with piperacillin haptens. METHODS: IgG secretion and CD19+ CD27+ expression on B cells were measured using ELISPOT and flow cytometry, respectively. A piperacillin-BSA adduct was used as an antigen in ELISA antibody binding studies. Adducts generated using different ratios of drug to protein were used to determine the degree of conjugation required to detect IgG binding. RESULTS: B cells from hypersensitive patients, but not controls, were stimulated to secrete IgG and increase CD27 expression when cultured with soluble piperacillin. A piperacillin-BSA adduct with cyclized and hydrolysed forms of the hapten bound to eight lysine residues was used to detect hapten-specific IgG 1-4 subclasses in patient plasma. Hapten inhibition and the use of structurally unrelated hapten-BSA adducts confirmed antigen specificity. Antibody binding was detected with antigens generated at piperacillin/BSA ratios of 10:1 and above, which corresponded to a minimum epitope density of 1 for antibody binding. CONCLUSION: These data show that antigen-specific B lymphocytes and T lymphocytes are activated in piperacillin-hypersensitive patients. Further work is needed to define the role different IgG subtypes play in regulating the iatrogenic disease.

Defining and quantifying frustration in the energy landscape: Applications to atomic and molecular clusters, biomolecules, jammed and glassy systems.

The emergence of observable properties from the organisation of the underlying potential energy landscape is analysed, spanning a full range of complexity from self-organising to glassy and jammed systems. The examples include atomic and molecular clusters, a ß-barrel protein, the GNNQQNY peptide dimer, and models of condensed matter that exhibit structural glass formation and jamming. We have considered measures based on several different properties, namely, the Shannon entropy, an equilibrium thermodynamic measure that uses a sample of local minima, and indices that require additional information about the connections between local minima in the form of transition states. A frustration index is defined that correlates directly with key properties that distinguish relaxation behaviour within this diverse set. The index uses the ratio of the energy barrier to the energy difference with reference to the global minimum. The contributions for each local minimum are weighted by the equilibrium occupation probabilities. Hence we obtain fundamental insight into the connections and distinctions between systems that cover the continuum from efficient structure-seekers to landscapes that exhibit broken ergodicity and rare event dynamics.

Developing research priorities for palliative care of people with intellectual disabilities in Europe: a consultation process using nominal group technique.

BACKGROUND: Empirical knowledge around palliative care provision and needs of people with intellectual disabilities is extremely limited, as is the availability of research resources, including expertise and funding. This paper describes a consultation process that sought to develop an agenda for research priorities for palliative care of people with intellectual disabilities in Europe. METHODS: A two-day workshop was convened, attended by 16 academics and clinicians in the field of palliative care and intellectual disability from six European countries. The first day consisted of round-table presentations and discussions about the current state of the art, research challenges and knowledge gaps. The second day was focused on developing consensus research priorities with 12 of the workshop participants using nominal group technique, a structured method which involved generating a list of research priorities and ranking them in order of importance. RESULTS: A total of 40 research priorities were proposed and collapsed into eleven research themes. The four most important research themes were: investigating issues around end of life decision making; mapping the scale and scope of the issue; investigating the quality of palliative care for people with intellectual disabilities, including the challenges in achieving best practice; and developing outcome measures and instruments for palliative care of people with intellectual disabilities. CONCLUSIONS: The proposal of four major priority areas and a range of minor themes for future research in intellectual disability, death, dying and palliative care will help researchers to focus limited resources and research expertise on areas where it is most needed and support the building of collaborations. The next steps are to cross-validate these research priorities with people with intellectual disabilities, carers, clinicians, researchers and other stakeholders across Europe; to validate them with local and national policy makers to determine how they could best be incorporated in policy and programmes; and to translate them into actual research studies by setting up European collaborations for specific studies that require such collaboration, develop research proposals and attract research funding.

BCL11A enhancer haplotypes and fetal hemoglobin in sickle cell anemia.

BACKGROUND: Fetal hemoglobin (HbF) levels in sickle cell anemia patients vary. We genotyped polymorphisms in the erythroid-specific enhancer of BCL11A to see if they might account for the very high HbF associated with the Arab-Indian (AI) haplotype and Benin haplotype of sickle cell anemia. METHODS AND RESULTS: Six BCL112A enhancer SNPs and their haplotypes were studied in Saudi Arabs from the Eastern Province and Indian patients with AI haplotype (HbF ~20%), African Americans (HbF ~7%), and Saudi Arabs from the Southwestern Province (HbF ~12%). Four SNPs (rs1427407, rs6706648, rs6738440, and rs7606173) and their haplotypes were consistently associated with HbF levels. The distributions of haplotypes differ in the 3 cohorts but not their genetic effects: the haplotype TCAG was associated with the lowest HbF level and the haplotype GTAC was associated with the highest HbF level and differences in HbF levels between carriers of these haplotypes in all cohorts were approximately 6%. CONCLUSIONS: Common HbF BCL11A enhancer haplotypes in patients with African origin and AI sickle cell anemia have similar effects on HbF but they do not explain their differences in HbF.

Laparoscopy shows superiority over endoscopy for early detection of malignant atrophic papulosis gastrointestinal complications: a case report and review of literature.

BACKGROUND: The malignant form of atrophic papulosis (Köhlmeier-Degos disease) is a rare thrombo-occlusive vasculopathy that can affect multiple organ systems. Patients typically present with distinctive skin lesions reflective of vascular drop out. The small bowel is the most common internal organ involved, resulting in considerable morbidity and mortality attributable to ischemic microperforations. Determination of the presence of gastrointestinal lesions is critical in distinguishing systemic from the benign, cutaneous only disease and in identifying candidates for treatment. CASE PRESENTATION: We describe an 18 year old male who first presented with cutaneous atrophic papulosis but became critically ill from small bowel microperforations. He had an almost immediate and dramatic response to treatment. Prior to his presentation with acute abdomen he had upper and lower endoscopy showing areas of nonspecific patchy erythema. At laparotomy, innumerable characteristic lesions with central pearly hue and erythematous border were seen. PubMed was used for a literature search using the keywords malignant atrophic papulosis, Degos disease, endoscopy, laparoscopy and laparotomy. This search yielded 200 articles which were further analyzed for diagnostic procedures and findings. Among the 200 articles we identified only 11 cases in which endoscopy was performed. Results of endoscopy and laparotomy in our patient with malignant atrophic papulosis were compared to those in the literature. Endoscopy of the gastrointestinal tract has shown gastritis and non-specific inflammation whereas laparoscopy shows white plaques with red borders on the serosal surface of the small bowel and the peritoneum. From personal communications with other physicians worldwide, we identified three additional unpublished cases in which endoscopy revealed only minimal changes while laparoscopy showed dramatic lesions. From our experience the endoscopic findings are often subtle and nonspecific, whereas laparascopy or laparotomy will reveal pathognomic lesions on the serosal surface of the intestine. CONCLUSION: Our report contrasts the endoscopic and laparoscopic findings in malignant atrophic papulosis which suggest laparoscopy is the more powerful means of detecting gastrointestinal involvement. Imaging studies may serve as a key indicator of systemic progression. Based on our experience, laparoscopy should be performed when there is a high index of suspicion for gastrointestinal malignant atrophic papulosis, even if endoscopic examination is non-diagnostic or normal.

Cytidine deaminase single-nucleotide polymorphism is predictive of toxicity from gemcitabine in patients with pancreatic cancer: RTOG 9704.

The aim of this study is to validate the prognostic and predictive value of the non-synonymous cytidine deaminase (CDA) Lys²7Gln polymorphism for hematological toxicity and survival using a randomized phase III adjuvant trial (Radiation Therapy Oncology Group (RTOG) 9704) in pancreatic cancer in which one treatment arm received gemcitabine. CDA is involved in gemcitabine inactivation, and there is conflicting data on the role of the non-synonymous CDA Lys²7Gln polymorphism in predicting toxicity and survival in cancer patients treated with gemcitabine. RTOG 9704 randomized 538 patients after pancreatic resection to receive radiotherapy with either 5-fluorouracil (5-FU) or gemcitabine. CDA Lys²7Gln polymorphism genotype was analyzed. We tested an association between CDA single-nucleotide polymorphism genotype and the survival outcome by the Cox proportional hazard model adjusting for other covariates, as well as toxicity by the logistic regression model. There is statistically significant more severe hematological toxicity in patients treated with gemcitabine with either the homozygote wild-type genotype (Lys/Lys) alone (odds ratio (OR)=0.06, P=0.01), or in combination with the heterozygote (Lys/Gln; OR=0.14, P=0.03) when compared with homozygote variant genotype (Gln/Gln) when adjusted for other covariates. This was not seen in the non-gemcitabine treated arm. There are no genotype differences with respect to survival outcome. In conclusion, in this prospective randomized adjuvant study of patients with pancreatic cancer, the CDA Lys²7Gln polymorphism is validated as a predictive marker of gemcitabine hematological toxicity, but not with treatment response or survival.

Osteoarthritis-like changes in the heterozygous sedc mouse associated with the HtrA1-Ddr2-Mmp-13 degradative pathway: a new model of osteoarthritis.

OBJECTIVE: To test the hypothesis that the spondyloepiphyseal dysplasia congenita (sedc) heterozygous (sedc/+) mouse, a COL2A1 mutant, is a model for the study of osteoarthritis (OA) in the absence of dwarfism and to investigate the presence of HtrA1, Ddr2, and Mmp-13 and their possible involvement in a universal mechanism leading to OA. DESIGN: Whole mount skeletons of adult animals were analyzed to determine whether sedc/+ mice exhibit dwarfism. To characterize progression of osteoarthritic degeneration over time, knee and temporomandibular joints from sedc/+ and wild-type mice were analyzed histologically, and severity of articular cartilage degradation was graded using the Osteoarthritis Research Society International (OARSI) scoring system. Immunohistochemistry was used to detect changes in expression of HtrA1, Ddr2, and Mmp-13 in articular cartilage of knees. RESULTS: As previously reported, the sedc/+ skeleton morphology was indistinguishable from wild type, and skeletal measurements revealed no significant differences. The sedc/+ mouse did, however, show significantly higher OARSI scores in knee (9, 12 and 18 months) and temporomandibular joints at all ages examined. Histological staining showed regions of proteoglycan degradation as early as 2 months in both temporomandibular and knee joints of the mutant. Cartilage fissuring and erosion were observed to begin between 2 and 6 months in temporomandibular joints and 9 months in knee joints from sedc/+ mice. Immunohistochemistry of mutant knee articular cartilage showed increased expression of HtrA1, Ddr2, and Mmp-13 compared to wild type, which upregulation preceded fibrillation and fissuring of the articular surfaces. CONCLUSIONS: With regard to skeletal morphology, the sedc/+ mouse appears phenotypically normal but develops premature OA as hypothesized. We conclude that the sedc/+ mouse is a useful model for the study of OA in individuals with overtly normal skeletal structure and a predisposition for articular cartilage degeneration.

Imagining and constraining ferrovolcanic eruptions and landscapes through large-scale experiments.

Ferrovolcanism, yet to be directly observed, is the most exotic and poorly understood predicted manifestation of planetary volcanism. Large-scale experiments carried out at the Syracuse Lava Project offer insight into the emplacement dynamics of metallic flows as well as coeval metallic and silicate flows. Here, we find that, under the same environmental conditions, higher-density/lower-viscosity metallic lava moves ten times faster than lower-density/higher-viscosity silicate lava. The overall morphology of the silicate flow is not significantly affected by the co-emplacement of a metallic flow. Rather, the metallic flow is largely decoupled from the silicate flow, occurring mainly in braided channels underneath the silicate flow and as low-relief breakouts from the silicate flow front. Turbulent interactions at the metallic-silicate flow interface result in mingling of the two liquids, preserved as erosional surfaces and sharp contacts. The results have important implications for the interpretation of possible ferrovolcanic landscapes across our solar system.

Strongly dispersive transient Bragg grating for high harmonics.

We create a transient Bragg grating in a high-harmonic generation medium using two counterpropagating pulses. The Bragg grating disperses the harmonics in angle and can diffract a large bandwidth with temporal resolution limited only by the source size.

Aligning the Good Practice MASK With the Objectives of the European Innovation Partnership on Active and Healthy Ageing.

The reference sites of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) were renewed in 2019. The DG Santé good practice Mobile Airways Sentinel networK was reviewed to meet the objectives of the EIP on AHA. It included 1) Management of care process, 2) Blueprint of digital transformation, 3) EIP on AHA, innovation to market, 4) Community for monitoring and assessment framework, 5) Political, organizational, technological and financial readiness, 6) Contributing to European co-operation and transferability, 7) Delivering evidence of impact against the triple win approach, 8) Contribution to the European Digital Transformation of Health and Care and 9) scale of demonstration and deployment of innovation.

The Frailty of the Invincible.

The COVID-19 pandemic has unveiled the frailty of our societies from too many points of view to look away. We need to understand why we were all caught unprepared. On the one hand, we have all short memories. As we forget too quickly, we were unable to recognize key factors influencing response and preparedness to public health threats. For many years, economic evaluation pushed governments all over the world to cut resources for public health systems, with COVID-19 pandemic the question arises: do we spend too much or too little on health care? What is the right amount to spend on health? Moreover, in many countries, the privatisation, or semi-privatisation, of healthcare may give rise to inequitable access to health care for everyone. Although COVID-19 is very "democratic", its consequences aren't. According to OECD, income inequality in OECD countries is at its highest level for the past half century. Three main causes have been recognized, technological revolution, globalization, and "financialisation". In this scenario, lockdown measures adopted to save lives are showing dramatic economic consequences. To address post COVID-19 reconstruction we need to go beyond GDP. As an economic measure this has many shortcomings in describing the real well-being of a country, and since what we measure affects what we do, new paradigms will have to guide the post COVID-19 reconstruction strategies, as the fate of countries and their citizens is at stake.

Calibration of a high harmonic spectrometer by laser induced plasma emission.

We present a method that allows for a convenient switching between high harmonic generation (HHG) and accurate calibration of the vacuum ultraviolet (VUV) spectrometer used to analyze the harmonic spectrum. The accurate calibration of HHG spectra is becoming increasingly important for the determination of electronic structures. The wavelength of the laser harmonics themselves depend on the details of the harmonic geometry and phase matching, making them unsuitable for calibration purposes. In our calibration mode, the target resides directly at the focus of the laser, thereby enhancing plasma emission and suppressing harmonic generation. In HHG mode, the source medium resides in front or after the focus, showing enhanced HHG and no plasma emission lines. We analyze the plasma emission and use it for a direct calibration of our HHG spectra.

Treatment of cooling tower blowdown water containing silica, calcium and magnesium by electrocoagulation.

This research investigated the effectiveness of electrocoagulation using iron and aluminium electrodes for treating cooling tower blowdown (CTB) waters containing dissolved silica (Si(OH)(4)), Ca(2 + ) and Mg(2 + ). The removal of each target species was measured as a function of the coagulant dose in simulated CTB waters with initial pH values of 5, 7, and 9. Experiments were also performed to investigate the effect of antiscaling compounds and coagulation aids on hardness ion removal. Both iron and aluminum electrodes were effective at removing dissolved silica. For coagulant doses < or =3 mM, silica removal was a linear function of the coagulant dose, with 0.4 to 0.5 moles of silica removed per mole of iron or aluminium. Iron electrodes were only 30% as effective at removing Ca(2 + ) and Mg(2 + ) as compared to silica. There was no measurable removal of hardness ions by aluminium electrodes in the absence of organic additives. Phosphonate based antiscaling compounds were uniformly effective at increasing the removal of Ca(2 + ) and Mg(2 + ) by both iron and aluminium electrodes. Cationic and amphoteric polymers used as coagulation aids were also effective at increasing hardness ion removal.

The Reference Site Collaborative Network of the European Innovation Partnership on Active and Healthy Ageing.

Seventy four Reference Sites of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) have been recognised by the European Commission in 2016 for their commitment to excellence in investing and scaling up innovative solutions for active and healthy ageing. The Reference Site Collaborative Network (RSCN) brings together the EIP on AHA Reference Sites awarded by the European Commission, and Candidate Reference Sites into a single forum. The overarching goals are to promote cooperation, share and transfer good practice and solutions in the development and scaling up of health and care strategies, policies and service delivery models, while at the same time supporting the action groups in their work. The RSCN aspires to be recognized by the EU Commission as the principal forum and authority representing all EIP on AHA Reference Sites. The RSCN will contribute to achieve the goals of the EIP on AHA by improving health and care outcomes for citizens across Europe, and the development of sustainable economic growth and the creation of jobs.

Risk of malignancy in resected cystic tumors of the pancreas < or =3 cm in size: is it safe to observe asymptomatic patients? A multi-institutional report.

Recent international consensus guidelines propose that cystic pancreatic tumors less than 3 cm in size in asymptomatic patients with no radiographic features concerning for malignancy are safe to observe; however, there is little published data to support this recommendation. The purpose of this study was to determine the prevalence of malignancy in this group of patients using pancreatic resection databases from five high-volume pancreatic centers to assess the appropriateness of these guidelines. All pancreatic resections performed for cystic neoplasms < or =3 cm in size were evaluated over the time period of 1998-2006. One hundred sixty-six cases were identified, and the clinical, radiographic, and pathological data were reviewed. The correlation with age, gender, and symptoms (abdominal pain, nausea and vomiting, jaundice, presence of pancreatitis, unexplained weight loss, and anorexia), radiographic features suggestive of malignancy by either computed tomography, magnetic resonance imaging, or endoscopic ultrasound (presence of solid component, lymphadenopathy, or dilated main pancreatic duct or common bile duct), and the presence of malignancy was assessed using univariate and multivariate analysis. Among the 166 pancreatic resections for cystic pancreatic tumors < or =3 cm, 135 cases were benign [38 serous cystadenomas, 35 mucinous cystic neoplasms, 60 intraductal papillary mucinous neoplasms (IPMN), 1 cystic papillary tumor, and 1 cystic islet cell tumor], whereas 31 cases were malignant (14 mucinous cystic adenocarcinomas and 13 invasive carcinomas and 4 in situ carcinomas arising in the setting of IPMN). A greater incidence of cystic neoplasms was seen in female patients (99/166, 60%). Gender was a predictor of malignant pathology, with male patients having a higher incidence of malignancy (19/67, 28%) compared to female patients (12/99, 12%; p < 0.02). Older age was associated with malignancy (mean age 67 years in patients with malignant disease vs 62 years in patients with benign lesions (p < 0.05). A majority of the patients with malignancy were symptomatic (28/31, 90%). Symptoms that correlated with malignancy included jaundice (p < 0.001), weight loss (p < 0.003), and anorexia (p < 0.05). Radiographic features that correlated with malignancy were presence of a solid component (p < 0.0001), main pancreatic duct dilation (p = 0.002), common bile duct dilation (p < 0.001), and lymphadenopathy (p < 0.002). Twenty-seven of 31(87%) patients with malignant lesions had at least one radiographic feature concerning for malignancy. Forty-five patients (27%) were identified as having asymptomatic cystic neoplasms. All but three (6.6%) of the patients in this group had benign disease. Of the patients that had no symptoms and no radiographic features, 1 out of 30 (3.3%) had malignancy (carcinoma in situ arising in a side branch IPMN). Malignancy in cystic neoplasms < or =3 cm in size was associated with older age, male gender, presence of symptoms (jaundice, weight loss, and anorexia), and presence of concerning radiographic features (solid component, main pancreatic duct dilation, common bile duct dilation, and lymphadenopathy). Among asymptomatic patients that displayed no discernable radiographic features suggestive of malignancy who underwent resection, the incidence of occult malignancy was 3.3%. This study suggests that a group of patients with small cystic pancreatic neoplasms who have low risk of malignancy can be identified, and selective resection of these lesions may be appropriate.

Erratum to: Scaling up strategies of the chronic respiratory disease programme of the European Innovation Partnership on Active and Healthy Ageing (Action Plan B3: Area 5).

[This corrects the article DOI: 10.1186/s13601-016-0116-9.].

Building Bridges for Innovation in Ageing: Synergies between Action Groups of the EIP on AHA.

The Strategic Implementation Plan of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) proposed six Action Groups. After almost three years of activity, many achievements have been obtained through commitments or collaborative work of the Action Groups. However, they have often worked in silos and, consequently, synergies between Action Groups have been proposed to strengthen the triple win of the EIP on AHA. The paper presents the methodology and current status of the Task Force on EIP on AHA synergies. Synergies are in line with the Action Groups' new Renovated Action Plan (2016-2018) to ensure that their future objectives are coherent and fully connected. The outcomes and impact of synergies are using the Monitoring and Assessment Framework for the EIP on AHA (MAFEIP). Eight proposals for synergies have been approved by the Task Force: Five cross-cutting synergies which can be used for all current and future synergies as they consider overarching domains (appropriate polypharmacy, citizen empowerment, teaching and coaching on AHA, deployment of synergies to EU regions, Responsible Research and Innovation), and three cross-cutting synergies focussing on current Action Group activities (falls, frailty, integrated care and chronic respiratory diseases).

Radiation modifiers: treatment overview and future investigations.

Many radiosensitizers are in current clinical use. In addition, a myriad of potential new targeted therapies, which may also interact with radiation, are in clinical development. The clinical utility of new targeted therapies, in combination with existing radiation sensitizers (chemotherapies) requires further evaluation, as does the understanding of their acute and late radiation effects. Free radical scavengers appear to show promise as radioprotectors, but data for mucoprotection are less convincing.