The value of "diaphragmatic relaxing incision" for the durability of the crural repair in patients with paraesophageal hernia: a double blind randomized clinical trial.

Background: Surgical repair of paraesophageal hernias (PEHs) is burdened with high recurrence rates, and hitherto various techniques explored to enforce the traditional crural repair have not been successful. The hiatal reconstruction in PEH is exposed to significant tension, which may be minimized by adding a diaphragmatic relaxing incision to enhance the durability of the crural repair. Patients and methods: All individuals undergoing elective laparoscopic repair of a large PEH, irrespective of age, were considered eligible. PEHs were classified into types II-IV. The preoperative work-up program included multidetector computed tomography and symptom assessment questionnaires, which will be repeated during the postoperative follow-up. Patients were randomly divided into a control group with crural repair alone and an intervention group with the addition of a left-sided diaphragmatic relaxing incision at the edge of the upper pole of the spleen. The diaphragmatic defect was then covered by a synthetic mesh. Results: The primary endpoint of this trial was the rate of anatomical PEH recurrence at 1 year. Secondary endpoints included symptomatic gastroesophageal reflux disease, dysphagia, odynophagia, gas bloat, regurgitation, chest pain, abdominal pain, nausea, vomiting, postprandial pain, cardiovascular and pulmonary symptoms, and patient satisfaction in the immediate postoperative course (3 months) and at 1 year. Postoperative complications, morbidity, and disease burden were recorded for each patient. This was a double-blind study, meaning that the operation report was filed in a locked archive to keep the patient, staff, and clinical assessors blinded to the study group allocation. Blinding must not be broken during the follow-up unless required by any emergencies in the clinical management of the patient. Likewise, the patients must not be informed about the details of the operation. Trial Registration: ClinicalTrials.gov, identification number NCT04179578.

Exploring research participants' perceptions of cardiovascular risk information-Room for improvement and empowerment.

OBJECTIVE: The objective of this study was to explore research participants' (adults, age 50-65) perceptions of receiving cardiovascular risk information. METHODS: Five focus group interviews (N = 31) were performed with research participants aged 50-65 who participated in the Swedish CArdioPulmonary BioImage Study (SCAPIS). The interviews were analyzed using qualitative content analysis. RESULTS: The categories; the complexity of cardiovascular risk; insufficient presentation of test result; emotional responses; and health examinations provides confirmation, emerged. The test results were written in medical terms and lacked recommendations for further action which made it difficult for lay people to understand and use, and for some, also caused unnecessary worry. CONCLUSION: There was inadequate guidance concerning the implications of the test results, especially for participants without clinical findings. In order to allow research participants to obtain better cognitive and behavioral control, improvements are needed with regard to how personal risk information is communicated in research projects connected to health services. PRACTICAL IMPLICATIONS: The participants largely relied on physical signs when assessing their own cardiovascular risk. Health examinations are crucial for helping to add nuance to individuals' risk perceptions. For personal health information to have any real value for individuals, it must be designed from a user perspective.

A platform for phenotypic discovery of therapeutic antibodies and targets applied on Chronic Lymphocytic Leukemia.

Development of antibody drugs against novel targets and pathways offers great opportunities to improve current cancer treatment. We here describe a phenotypic discovery platform enabling efficient identification of therapeutic antibody-target combinations. The platform utilizes primary patient cells throughout the discovery process and includes methods for differential phage display cell panning, high-throughput cell-based specificity screening, phenotypic in vitro screening, target deconvolution, and confirmatory in vivo screening. In this study the platform was applied on cancer cells from patients with Chronic Lymphocytic Leukemia resulting in discovery of antibodies with improved cytotoxicity in vitro compared to the standard of care, the CD20-specific monoclonal antibody rituximab. Isolated antibodies were found to target six different receptors on Chronic Lymphocytic Leukemia cells; CD21, CD23, CD32, CD72, CD200, and HLA-DR of which CD32, CD200, and HLA-DR appeared as the most potent targets for antibody-based cytotoxicity treatment. Enhanced antibody efficacy was confirmed in vivo using a patient-derived xenograft model.

Greenland records of aerosol source and atmospheric lifetime changes from the Eemian to the Holocene.

The Northern Hemisphere experienced dramatic changes during the last glacial, featuring vast ice sheets and abrupt climate events, while high northern latitudes during the last interglacial (Eemian) were warmer than today. Here we use high-resolution aerosol records from the Greenland NEEM ice core to reconstruct the environmental alterations in aerosol source regions accompanying these changes. Separating source and transport effects, we find strongly reduced terrestrial biogenic emissions during glacial times reflecting net loss of vegetated area in North America. Rapid climate changes during the glacial have little effect on terrestrial biogenic aerosol emissions. A strong increase in terrestrial dust emissions during the coldest intervals indicates higher aridity and dust storm activity in East Asian deserts. Glacial sea salt aerosol emissions in the North Atlantic region increase only moderately (50%), likely due to sea ice expansion. Lower aerosol concentrations in Eemian ice compared to the Holocene are mainly due to shortened atmospheric residence time, while emissions changed little.

Optimization of soft X-ray phase-contrast tomography using a laser wakefield accelerator.

X-ray phase-contrast imaging allows for non-invasive analysis in low-absorbing materials, such as soft tissue. Its application in medical or materials science has yet to be realized on a wider scale due to the requirements on the X-ray source, demanding high flux and small source size. Laser wakefield accelerators generate betatron X-rays fulfilling these criteria and can be suitable sources for phase-contrast imaging. In this work, we present the first phase-contrast images obtained by using ionization injection-based laser wakefield acceleration, which results in a higher photon yield and smoother X-ray beam profile compared to self-injection. A peak photon yield of 1.9 × 1011 ph/sr and a source size of 3 µm were estimated. Furthermore, the current laser parameters produce an X-ray spectrum mainly in the soft X-ray range, in which laser-plasma based phase-contrast imaging had yet to be studied. The phase-contrast images of a Chrysopa lacewing resolve features on the order of 4 µm. These images are further used for a tomographic reconstruction and a volume rendering, showing details on the order of tens of µm.

Application of Kotter's Theory of Change to Achieve Baby-Friendly Designation.

Creating an environment that optimally supports exclusive breastfeeding can require a cultural transformation. Our initial attempt at obtaining Baby-Friendly Hospital Initiative (BFHI) designation was unsuccessful when surveyors determined insufficient enculturation of BFHI practices. Using Kotter's theory of change, we overcame the barriers, enhanced our practices, and effectively transformed the culture, and our facility ultimately became the first maternity hospital in Pennsylvania to obtain BFHI designation. Nursing leadership was essential to this process. Our experience serves as a template for others seeking to achieve Healthy People 2020 goals related to breastfeeding.

Highly efficient angularly resolving x-ray spectrometer optimized for absorption measurements with collimated sources.

Highly collimated betatron radiation from a laser wakefield accelerator is a promising tool for spectroscopic measurements. Therefore, there is a requirement to create spectrometers suited to the unique properties of such a source. We demonstrate a spectrometer which achieves an energy resolution of <5 eV at 9 keV (E∕ΔE>1800) and is angularly resolving the x-ray emission allowing the reference and spectrum to be recorded at the same time. The single photon analysis is used to significantly reduce the background noise. Theoretical performance of various configurations of the spectrometer is calculated by a ray-tracing algorithm. The properties and performance of the spectrometer including the angular and spectral resolution are demonstrated experimentally on absorption above the K-edge of a Cu foil backlit by a laser-produced betatron radiation x-ray beam.

Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study.

Introduction of new myeloma therapies offers new options for patients refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). In this multicenter study, patients with relapsed multiple myeloma, who have received at least three prior lines of therapy, are refractory to both an IMiD (lenalidomide or pomalidomide) and a PI (bortezomib or carfilzomib), and have been exposed to an alkylating agent were identified. The time patients met the above criteria was defined as time zero (T0). Five hundred and forty-three patients diagnosed between 2006 and 2014 were enrolled in this study. Median age at T0 was 62 years (range 31-87); 61% were males. The median duration between diagnosis and T0 was 3.1 years. The median number of lines of therapy before T0 was 4 (range 3-13). The median overall survival (OS) from T0 for the entire cohort was 13 (95% confidence interval (CI) 11, 15) months. At least one regimen recorded after T0 in 462 (85%) patients, with a median (95% CI) progression-free survival and OS from T0 of 5 (4, 6), and 15.2 (13, 17) months, respectively. The study provides the expected outcome of relapsed multiple myeloma that is refractory to a PI and an IMiD, a benchmark for comparison of new therapies being evaluated.

Revisiting the immunocytochemical detection of Neurogenin 3 expression in mouse and man.

During embryonic development, endocrine cells of the pancreas are specified from multipotent progenitors. The transcription factor Neurogenin 3 (NEUROG3) is critical for this development and it has been shown that all endocrine cells of the pancreas arise from endocrine progenitors expressing NEUROG3. A thorough understanding of the role of NEUROG3 during development, directed differentiation of pluripotent stem cells and in models of cellular reprogramming, will guide future efforts directed at finding novel sources of ß-cells for cell replacement therapies. In this article, we review the expression and function of NEUROG3 in both mouse and human and present the further characterization of a monoclonal antibody directed against NEUROG3. This antibody has been previously been used for detection of both mouse and human NEUROG3. However, our results suggest that the epitope recognized by this antibody is specific to mouse NEUROG3. Thus, we have also generated a monoclonal antibody specifically recognizing human NEUROG3 and present the characterization of this antibody here. Together, these antibodies will provide useful tools for future studies of NEUROG3 expression, and the data presented in this article suggest that recently described expression patterns of NEUROG3 in human foetal and adult pancreas should be re-examined.

Shock assisted ionization injection in laser-plasma accelerators.

Ionization injection is a simple and efficient method to trap an electron beam in a laser plasma accelerator. Yet, because of a long injection length, this injection technique leads generally to the production of large energy spread electron beams. Here, we propose to use a shock front transition to localize the injection. Experimental results show that the energy spread can be reduced down to 10 MeV and that the beam energy can be tuned by varying the position of the shock. This simple technique leads to very stable and reliable injection even for modest laser energy. It should therefore become a unique tool for the development of laser-plasma accelerators.

The Swedish CArdioPulmonary BioImage Study: objectives and design.

Cardiopulmonary diseases are major causes of death worldwide, but currently recommended strategies for diagnosis and prevention may be outdated because of recent changes in risk factor patterns. The Swedish CArdioPulmonarybioImage Study (SCAPIS) combines the use of new imaging technologies, advances in large-scale 'omics' and epidemiological analyses to extensively characterize a Swedish cohort of 30 000 men and women aged between 50 and 64 years. The information obtained will be used to improve risk prediction of cardiopulmonary diseases and optimize the ability to study disease mechanisms. A comprehensive pilot study in 1111 individuals, which was completed in 2012, demonstrated the feasibility and financial and ethical consequences of SCAPIS. Recruitment to the national, multicentre study has recently started.

Hope for a cure and altruism are the main motives behind participation in phase 3 clinical cancer trials.

It is necessary to carry out randomised clinical cancer trials (RCTs) in order to evaluate new, potentially useful treatments for future cancer patients. Participation in clinical trials plays an important role in determining whether a new treatment is the best therapy or not. Therefore, it is important to understand on what basis patients decide to participate in clinical trials and to investigate the implications of this understanding for optimising the information process related to study participation. The aims of this study were to (1) describe motives associated with participation in RCTs, (2) assess if patients comprehend the information related to trial enrolment, and (3) describe patient experiences of trial participation. Questionnaires were sent to 96 cancer patients participating in one of nine ongoing clinical phase 3 trials at the Department of Oncology, Uppsala University Hospital in Sweden. Eighty-eight patients completed the questionnaire (response rate 92%); 95% of these were patients in adjuvant therapy and 5% participated in clinical trials on palliative care. Two main reasons for participation were identified: personal hope for a cure and altruism. Patients show adequate understanding of the information provided to them in the consent process and participation entails high patient satisfaction.

Metformin induces lactate production in peripheral blood mononuclear cells and platelets through specific mitochondrial complex I inhibition.

AIM: Metformin is a widely used antidiabetic drug associated with the rare side effect of lactic acidosis which has been proposed to be linked to drug-induced mitochondrial dysfunction. Using respirometry, the aim of this study was to evaluate mitochondrial toxicity of metformin to human blood cells in relation to that of phenformin, a biguanide analogue withdrawn in most countries due to a high incidence of lactic acidosis. METHODS: Peripheral blood mononuclear cells and platelets were isolated from healthy volunteers, and integrated mitochondrial function was studied in permeabilized and intact cells using high-resolution respirometry. A wide concentration range of metformin (0.1-100 mm) and phenformin (25-500 µm) was investigated for dose- and time-dependent effects on respiratory capacities, lactate production and pH. RESULTS: Metformin induced respiratory inhibition at complex I in peripheral blood mononuclear cells and platelets (IC50 0.45 mm and 1.2 mm respectively). Phenformin was about 20-fold more potent in complex I inhibition of platelets than metformin. Metformin further demonstrated a dose- and time-dependent respiratory inhibition and augmented lactate release at a concentration of 1 mm and higher. CONCLUSION: Respirometry of human peripheral blood cells readily detected respiratory inhibition by metformin and phenformin specific to complex I, providing a suitable model for probing drug toxicity. Lactate production was increased at concentrations relevant for clinical metformin intoxication, indicating mitochondrial inhibition as a direct causative pathophysiological mechanism. Relative to clinical dosing, phenformin displayed a more potent respiratory inhibition than metformin, possibly explaining the higher incidence of lactic acidosis in phenformin-treated patients.

Features of the synovium of individuals at risk of developing rheumatoid arthritis: implications for understanding preclinical rheumatoid arthritis.

OBJECTIVE: Findings from previous studies have suggested that subclinical inflammation of the synovium does not coincide with the appearance of rheumatoid arthritis (RA)-specific autoantibodies. This study was undertaken to examine the relationship between the presence of autoantibodies, changes in the synovium, and development of arthritis over time in a markedly larger, prospective study. METHODS: Fifty-five individuals who were IgM rheumatoid factor positive and/or anti-citrullinated protein antibody (ACPA) positive (detected by the anti-cyclic citrullinated peptide antibody test) and who were without any evidence of arthritis upon physical examination were included in the study. ACPAs were subsequently also detected using a multiplex chip-based assay. All individuals underwent magnetic resonance imaging and mini-arthroscopic synovial biopsy sampling of a knee joint at inclusion and were prospectively followed up. Proportional hazards regression analysis was performed to investigate whether changes in the synovium were associated with the onset of arthritis. RESULTS: Fifteen individuals (27%) developed arthritis after a median followup time of 13 months (interquartile range 6-27 months; range 1-47 months). No overt synovial inflammation was observed, but CD3+ T cell numbers in the biopsy tissue showed a borderline association with subsequent development of clinically manifest arthritis (hazard ratio 2.8, 95% confidence interval [95% CI] 0.9-9.1; P = 0.088). In addition, the presence of CD8+ T cells was associated with ACPA positivity (odds ratio [OR] 16.0, 95% CI 1.7-151.1) and with the total number of ACPAs present (OR 1.4, 95% CI 1.0-1.8). CONCLUSION: These findings confirm and extend previous results showing the absence of clearcut synovial inflammation in individuals having systemic autoimmunity associated with RA. However, subtle infiltration by synovial T cells may precede the signs and symptoms of arthritis in preclinical RA.

Detection of radioactive fragments in patients after radiological or nuclear emergencies using computed tomography and digital radiography.

A comparison has been carried out between standard-dose computed tomography, non-diagnostic computed tomography and digital radiography with respect to their suitability for detecting radioactive fragments associated with nuclear or radiological events such as debris from radiological dispersal devices. The purpose was to investigate if radiographic imaging is justified for the detection and localisation of radioactive fragments in affected patients. Fragments of uranium (U), copper (Cu), iron (Fe) and volcanic ash with effective diameters ranging from (approximately) 100 to 700 µm were selected. The fragments were positioned at two different locations on an anatomical torso phantom and images were produced with standard-dose CT, non-diagnostic CT and digital radiography. Capsules with radionuclides of (137)Cs, (60)Co and (99m)Tc were also positioned in the phantom and the effective doses were estimated for radionuclide exposures as well as for standard-dose CT, non-diagnostic CT and digital radiography. For standard-dose CT and digital radiography, U, Cu and Fe fragments were detected in sizes down to 100-180, 250-300 and 300-400 µm respectively. For the non-diagnostic CT the results were 180-250 µm (for U), 300-400 µm (for Cu) and 400-500 µm (for Fe). The effective dose from the standard-dose CT, non-diagnostic CT and digital radiography was 5.6, 1.9 and 0.76 mSv. Corresponding doses from (137)Co, (60)Co and (99m)Tc positioned at the site of fragments were in the range of 0.07-0.1, 0.32-0.45 and 0.08-0.09 mSv per MBq during 24 h. We conclude that, for a number of gamma emitters with activity levels on the order of magnitude of megabecquerel, imaging using ionising radiation can be justified since the effective dose from the radionuclides will exceed the dose from the radiological examination.

Expert panel consensus statement on the optimal use of pomalidomide in relapsed and refractory multiple myeloma.

In this report, a panel of European myeloma experts discuss the role of pomalidomide in the treatment of relapsed and refractory multiple myeloma (RRMM). Based on the available evidence, the combination of pomalidomide and low-dose dexamethasone is a well-tolerated and effective treatment option for patients with RRMM who have exhausted treatment with lenalidomide and bortezomib. The optimal starting dose of pomalidomide is 4 mg given on days 1-21 of each 28-day cycle, whereas dexamethasone is administered at a dose of 40 mg weekly (reduced to 20 mg for patients aged >75 years). The treatment should continue until evidence of disease progression or unacceptable toxicity. Dose-modification schemes have been established for patients who develop neutropenia, thrombocytopaenia and other grade 3-4 adverse events during pomalidomide therapy. Guidance on the prevention and management of infections and venous thromboembolism is provided, based on the available clinical evidence and the experience of panel members. The use of pomalidomide in special populations, such as patients with advanced age, renal impairment or unfavourable cytogenetic features, is also discussed.

A model of study for human cancer: Spontaneous occurring tumors in dogs. Biological features and translation for new anticancer therapies.

Murine cancer models have been extremely useful for analyzing the biology of pathways involved in cancer initiation, promotion, and progression. Interestingly, several murine cancer models also exhibit heterogeneity, genomic instability and an intact immune system. However, they do not adequately represent several features that define cancer in humans, including long periods of latency, the complex biology of cancer recurrence and metastasis and outcomes to novel therapies. Therefore, additional models that better investigate the human disease are needed. In the pet population, with special references to the dog, cancer is a spontaneous disease and dogs naturally develop cancers that share many characteristics with human malignancies. More than 40 years ago, optimization of bone marrow transplantation protocols was undertaken in dogs and recently novel targeted therapies such as liposomal muramyl tripeptide phosphatidylethanolamine and several tyrosine kinase inhibitors, namely masitinib (AB1010) and toceranib phosphate (SU11654), have been developed to treat dog tumors which have then been translated to human clinical trials. In this review article, we will analyze biological data from dog tumors and comparative features with human tumors, and new therapeutic approaches translated from dog to human cancer.