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Luminescent trivalent lanthanide (Ln 3+ ) complexes are compounds of technological interest due to their unique photophysical properties, particularly anionic tetrakis complexes, given their higher stability and emission quantum yields. However, structural studies on the cation-anion interaction in these complexes and the relation of such to luminescence are still lacking. Herein, the cation-anion interactions in two luminescent anionic tetrakis(2-thenoyltrifluoroacetonato)europate(III) complexes with alkylimidazolium cations, specifically 1-ethyl-3-methylimidazolium and 1-butyl-3-methylimidazolium are investigated. The Eu 3+ complexes were synthesized and characterized by elemental analysis, mass spectrometry, and single-crystal X-ray crystallography, and their luminescence spectra were recorded at 77 K. Quantum chemical calculations were also performed. X-ray crystallography revealed hydrogen bonds between the enolate ligands and imidazolium ring hydrogens. The 1-butyl-3-methylimidazolium complex had two crystallographic Eu 3+ sites, also confirmed by luminescence spectroscopy. The 1-ethyl-3-methylimidazolium complex exhibited an unusual 300 cm -1 splitting in the 5 D 0 → 7 F 1 transition, as reproduced by ligand field calculations, suggesting a stronger hydrogen bonding due to the smaller substituent. We hypothesize that this strong bonding likely causes angular distortions, resulting in high ligand field splittings.

Background: Reports have shown that women suffered from anxiety, stress, depression, and fatigue during the COVID-19 pandemic more than men. No study so far has examined the effect of the pandemic among the Arab minority in Israel., Objectives: To examine the associations between levels of pandemic fatigue and stress of Israeli Arab women, and their anxiety and depression, along with their socio-demographic and socio-economic characteristics., Methods: A Cohen and Williamson questionnaire, which was based on a Likert scale, was distributed by the snowball method through social networks. Bivariate associations between the psycho-social and demographic characteristics and anxiety and depression were assessed using t-tests, chi-square tests, Z tests, and Pearson correlations. Multiple linear regressions were used to evaluate the associations with anxiety and depression, and the mediation model was examined with path analysis with bootstrapping., Results: Among 2294 Israeli Arab mothers who participated in the study, 63.7% were in the clinical range for anxiety, 67.4% for depression, and 57.5% for both anxiety and depression. Low economic status, pandemic fatigue, living in closed communities, and stress were related to anxiety and depression. Pandemic fatigue was positively related to stress, which was positively related to both anxiety and depression (standardized indirect effect = 0.137, SE = 0.014, 95%CI = 0.111, 0.164, p < .001; vs. 0.133, SE = 0.013, 95%CI = 0.108, 0.160, p < .001 respectively). The contribution of stress to anxiety and depression was significantly greater than that of pandemic fatigue (Z = 19.43 and Z = 18.04, p < .001, for anxiety and depression, respectively)., Conclusions: Demographic characteristics may put Arab women at a higher risk of anxiety and depression. Elevated stress alongside high fatigue may trigger mental health difficulties. The welfare of minorities should be addressed by policymakers in relation to their demographic needs., (© 2024. The Author(s).)

A new class of lanthanide mixed-carboxylate ligands compounds with formula {[Ln 2 (phthgly) 4 (bdc)(H 2 O) 6 ]·(H 2 O) 4 } ∞ , labelled as Ln 3+ : Eu (1) and Gd (2) coordination polymers (CP) were synthesized under mild reaction conditions between lanthanide nitrate salts and a solution of N-phthaloylglycine (phthgly) and terephthalic (bdc) ligands. The (1) and (2) coordination polymers were formed by symmetric binuclear units, in which phthgly and bdc carboxylate ligands are coordinated to the lanthanide ions by different coordination modes. Surprisingly, all organic ligands participate in hydrogen bonding interactions, forming an extremally rigid crystalline structure. The red narrow emission bands from the 5 D 0 → 7 F J transitions of the Eu 3+ ion show a high colour purity. The intramolecular energy transfer process from L→Eu 3+ ion has been discussed. The experimental intensity parameters (Ω 2,4 ) reflect lower angular distortion and polarizability of the chemical environment around the metal ion compared with other Eu 3+ compounds reported in the literature. This novel class of coordination polymer offers a more attractive platform for developing luminescent functional materials for different applications., (© 2023 John Wiley & Sons Ltd.)

Hypertension is a frequent comorbidity in patients with heart failure; therefore, blood pressure management for these patients is widely recommended in medical guidelines. Bee pollen and postbiotics that contain inactivated probiotic cells and their metabolites have emerged as promising bioactive compounds sources, and their potential role in mitigating cardiovascular (CV) risks is currently being unveiled. Therefore, this preliminary study aimed to investigate the impact of a lactic-fermented bee pollen postbiotic (FBPP) on the CV microbiota via in vitro tests. A new isolated Lactobacillus spp. strain from the digestive tract of bees was used to ferment pollen, obtaining liquid and dried atomized caps postbiotics. The modulating effects on a CV microbiota that corresponds to the pathophysiology of hypertension were investigated using microbiological methods and qPCR and correlated with the metabolic profile. Both liquid and dried FBPPs increased the number of the beneficial Lactobacillus spp. and Bifidobacterium spp. bacteria by up to 2 log/mL, while the opportunistic pathogen E. coli , which contributes to CV pathogenesis, decreased by 3 log/mL. The short-chain fatty acid (SCFA) profile revealed a significant increase in lactic (6.386 ± 0.106 g/L) and acetic (4.284 ± 0.017 g/L) acids, both with known antihypertensive effects, and the presence of isovaleric acid, which promotes a healthy gut microbiota. Understanding the impact of the FBPP on gut microbiota could lead to innovative strategies for promoting heart health and preventing cardiovascular diseases.

Introduction: A low response to COVID-19 vaccination was observed among the Arab population in Israel. Efforts to improve this achieved moderate results., Objectives: The aim of this study was to examine the extent to which demographic and cultural factors, the media, trust, perceptions, and government policies influence the willingness of Arabs to be vaccinated against COVID-19., Methods: A cross-sectional survey was conducted among Israeli Arabs (558 respondents). The questionnaire was distributed through social networks between January 16 and 26, 2021. The t-tests, Chi-square tests, Z tests, which were used to evaluate the significance of variables, and Pearson correlations calculated for the study variables were used for statistical analysis. Hierarchical logistic regression was calculated to assess the extent of background influence on the odds for vaccination, and mediation was examined using the Process procedure., Results: Moderate means were found for attitudes towards vaccination, vulnerability, vaccine effectiveness, and pandemic fatigue. A lower score was found for accessibility to medical services, social norms, and emotional barriers. Trust was highest in health-related authorities, whereas trust in government and the media was the lowest. Higher pandemic fatigue was associated with lower trust and lower odds for vaccination., Discussion: Lack of awareness of the specific needs of the Arab minority in Israel, lack of vaccination campaigns in Arabic language, long neglect of Arabs in the Israeli health system, mistrust of governmental authorities by the Arabs, and low socioeconomic background of Israeli Arabs might have led to lower trust levels and incompliance with governmental policies among Arabs. Addressing these issues may benefit the entire population. The authors believe that "A chain (in population health) is only as strong as its weakest link.", (© 2022. W. Montague Cobb-NMA Health Institute.)

Background: Esophageal atresia is a major anomaly of varying severity. The complexity of surgical correction depends on the presence of a distal fistula., Objective: This study aimed to determine the feasibility and accuracy of prenatal ultrasound detection of the distal fistula in fetuses diagnosed with esophageal atresia., Study Design: This was an observational study conducted at a single tertiary care center between 2019 and 2021. Included were pregnant patients carrying a fetus prenatally diagnosed with esophageal atresia that was confirmed postnatally during corrective surgery or at postmortem autopsy. During the scan, the performing investigator determined the presence or absence of a distal fistula by scanning the location of the lower esophagus during fetal breathing. Cases in which the lower esophagus was observed distending with amniotic fluid during breathing were deemed "fistula present," and the remaining cases "fistula absent." Test feasibility and performance indices, including sensitivity, specificity, and positive and negative predictive value were calculated. The offline clips and images were reviewed by 2 investigators for the assessment of interoperator agreement using Cohen's Kappa formula., Results: Included were 16 fetuses with esophageal atresia scanned between 2019 and 2021. All fetuses were successfully scanned with sufficient resolution of the area of interest during at least 3 cycles of breathing. It took a median of 8.5 minutes to determine the presence or absence of a distal fistula. The feasibility of the test was 100% (16/16). The test's sensitivity, specificity, and positive and negative predictive values were 80% (95% confidence interval, 55-100), 100% (95% confidence interval, 60-100), 100% (95% confidence interval, 65-100), and 75% (95% confidence interval, 45-100), respectively. The Cohen's Kappa for interoperator agreement was calculated to be 1, P<.001, corresponding to a "perfect" level of agreement., Conclusion: Distal fistulas in esophageal atresia can be demonstrated prenatally by targeted scanning using appropriate technique. The method provided is feasible, reproducible, and has excellent performance indices. This novel technique and observations may improve the prenatal diagnosis and counseling of esophageal atresia., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Five novel Eu(III)-β-diketonate complexes containing ruthenocene ancillary ligands (1,1'-bis(diphenylphosphoryl)ruthenocene─RcBPO) were synthesized and characterized. The coordination compounds presented the general formula [Eu(β-dik) 3 (RcBPO)], where β-dik stands for 2-thenoyltrifluoroacetonate (tta), 3-benzoyl-1,1,1-trifluoroacetone (btf), 2-dibenzoylmethanate (dbm), 2-acetyl-1,3-indandionate (aind), and 2-benzoyl-1,3-indandionate (bind), and RcBPO stands for 1,1'-bis(diphenylphosphoryl)ruthenocene. The [Eu(aind) 3 (RcBPO)] complex crystallizes in a monoclinic Cc non-centrosymmetric space group with the europium site environment, assuming a bicapped trigonal prism coordination polyhedron with the symmetry point group close to C 2 v . Photoluminescent properties for the solid-state samples were described in terms of excitation, emission, lifetime decay curves, and intrinsic and overall quantum yields. The replacement of the two coordinated H 2 O molecules by the RcBPO ancillary ligand leads to great enhancements of the overall quantum yields ( Q Eu L ), with the minimum increment by a factor of 5 for the case of [Eu(btf) 3 (RcBPO)] and the maximum enhancement of 270 times for the case of the [Eu(dbm) 3 (RcBPO)] complex. In addition, theoretical calculations were carried out to model the spectroscopic properties of the investigated compounds. To obtain theoretical Judd-Ofelt parameters (Ω λ , λ = 2, 4, and 6) and intramolecular energy transfer rates, the JOYSpectra web platform was employed using the structure obtained from density functional theory calculations. Hence, a rate equation model provided theoretical overall quantum yields, which are in great agreement with measured data.

Background: Implementing the JCI Accreditation process as an organizational culture may face resistance. However, the skepticism and involvement of different hospital sectors (medical, nursing, paramedical, and administrative/logistic) in the process may vary. Conducting organizational change needs tools to decrease resistance., Objectives: To investigate the attitudes, cultural norms, and satisfaction of the different sectors regarding the accreditation process, and to suggest ways to integrate the process as part of the organizational culture., Materials and Methods: A cross-sectional survey was conducted among 462 respondents (187 nurses, 95 physicians, 92 administrative, 88 paramedical) at Rambam Health Care Campus, a tertiary hospital in Israel. The hospital employees' attitudes, cultural norms, and satisfaction were assessed. ANOVA tests were used to examine the differences among the different sectors. The association between the satisfaction from the process and the preferred type of training was examined using Pearson's correlation coefficient., Results: Significant differences were found among the sectors in the scores related to attitude, cultural norms, and satisfaction from the accreditation process (F (3, 456) = 17.95, p < 0.001, η 2  = 0.10). Gabriel post-hoc test revealed significantly lower scores between the medical and paramedical sectors. A positive correlation was found between the degree of satisfaction with the process and the satisfaction with the training type. Frontal education and video demonstrations were rated significantly higher among all 10 training types., Conclusions: More efforts should be made to increase involvement among physicians and paramedical teams in the accreditation process. Each sector leadership involvement is essential for their involvement too. Early involvement of the Israeli Medical Association in the process might have achieved better physicians' collaboration. Frontal education and video demonstrations may help decrease skepticism and increase positive attitudes., (© 2021. The Author(s).)

Mn(III) meso -tetrakis( N -ethylpyridinium-2-yl)porphyrin chloride (MnTE-2-PyPCl 5 , BMX-010, and AEOL10113) is among the most studied superoxide dismutase (SOD) mimics and redox-active therapeutics, being currently tested as a drug candidate in a phase II clinical trial on atopic dermatitis and itch. The thermal stability of active pharmaceutical ingredients (API) is useful for estimating the expiration date and shelf life of pharmaceutical products under various storage and handling conditions. The thermal decomposition and kinetic parameters of MnTE-2-PyPCl 5 were determined by thermogravimetry (TG) under nonisothermal and isothermal conditions. The first thermal degradation pathway affecting Mn-porphyrin structural integrity and, thus, activity and bioavailability was associated with loss of ethyl chloride via N -dealkylation reaction. The thermal stability kinetics of the N -dealkylation process leading to MnTE-2-PyPCl 5 decomposition was investigated by using isoconversional models and artificial neural network. The new multilayer perceptron (MLP) artificial neural network approach allowed the simultaneous study of ten solid-state kinetic models and showed that MnTE-2-PyPCl 5 degradation is better explained by a combination of various mechanisms, with major contributions from the contraction models R1 and R2. The calculated activation energy values from isothermal and nonisothermal data were about 90 kJ mol -1 on average and agreed with one another. According to the R1 modelling of the isothermal decomposition data, the estimated shelf life value for 10% decomposition ( t 90% ) of MnTE-2-PyPCl 5 at 25°C was approximately 17 years, which is consistent with the high solid-state stability of the compound. These results represent the first study on the solid-state decomposition kinetics of Mn(III) 2- N -alkylpyridylporphyrins, contributing to the development of this class of redox-active therapeutics and SOD mimics and providing supporting data to protocols on purification, handling, storage, formulation, expiration date, and general use of these compounds., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Clarissa G. C. Maia et al.)

Background: During the COVID-19 outbreak, (March 1 - June 15, 2020) citizens expressed sympathy and gratitude towards medical staff through the media, while the entire hospital staff faced the same danger of infection as other citizens. This might have made hospital staff develop sympathy, understanding for the patients` and family's needs, and a better communication., Objectives: To investigate if there is a relation between the mutual change in attitude between citizens and hospital staff during the first COVID-19 outbreak, and the incidence of violence cases., Materials and Methods: This is a cross sectional study conducted at Rambam Medical Center (RMC) in Israel. The data about the number of violence cases were collected from the security department, and the data about hospital wards activity were collected from the hospital Business Intelligence (BI) software. The number of violence cases in relation to the number of Emergency Department (ED) visits, admissions to hospital wards, and length of stay (LOS) were compared during the COVID-19 outbreak to the corresponding period in 2019 using the T- test. The difference in the incidence of violence between general population and people with a psychiatric or social disorder (like drug abuse and criminal background) in both periods were also compared using the Fisher exact test., Results: During the first COVID-19 outbreak, there were 6 violence cases against medical staff out of 24,740 visits to the ED, vs. 21 cases out of 30,759 visits during the same periods in 2019 (P < 0.05). There were 19 violence cases in the whole hospital with 14,482 admissions in 2020 vs. 51 violence cases of 17,599 admissions in 2019 (P < 0.05). Violence against security guards in the entire hospital dropped from 20 to 11 cases, and in the set of the ED, from 13 to 4 cases in both periods respectively. A 20 % decrease in the number of visits to the ED, might have influenced the average LOS during the study period, 2020 compared to 2019 (4.4 + 0.45 vs. 5.4 + 0.36 h. (P < 0.001). The ratio of violence among general population vs. people with a psychiatric or social background revealed a non-significant change in both periods (P = 0.75 and P = 0.69) respectively., Discussion: The COVID-19 outbreak supplied some evidence that a change in environmental conditions, trust, waiting time, personal attitude and communication might have reduced violence against hospital staff., Conclusions: Except for violence coming from patients with psychiatric or social disorders, most other violence cases might be reduced if the environment conditions and attitudes of both citizens and staff are improved.

Advantages in several fields of research and industry are expected with the rise of quantum computers. However, the computational cost to load classical data in quantum computers can impose restrictions on possible quantum speedups. Known algorithms to create arbitrary quantum states require quantum circuits with depth O(N) to load an N-dimensional vector. Here, we show that it is possible to load an N-dimensional vector with exponential time advantage using a quantum circuit with polylogarithmic depth and entangled information in ancillary qubits. Results show that we can efficiently load data in quantum devices using a divide-and-conquer strategy to exchange computational time for space. We demonstrate a proof of concept on a real quantum device and present two applications for quantum machine learning. We expect that this new loading strategy allows the quantum speedup of tasks that require to load a significant volume of information to quantum devices.

Objectives Hospitals are the most common place of death in Australia. Bereavement care is recognised by national standards as being central to providing high-quality care at the end of life, and has significant health implications on morbidity, mortality and health service usage. Despite this, bereavement care is not routinely or systematically provided in most Australian hospitals. This study aimed to develop a comprehensive, evidence-based model of bereavement care specific to the needs of an acute Australian adult tertiary hospital. Methods This study used a multiple-methods design, which included a scoping literature review, a survey of current institutional bereavement practices, interviews with bereaved family members and staff focus groups and the development of a model of bereavement care for the acute hospital service through advisory group and expert consensus. Results Staff and bereaved family members strongly supported a systematic approach to bereavement, perceiving the need for greater support, training, coordination and follow-up. In all, 10 core elements were developed to support a structured model of bereavement care provision and follow-up for the acute hospital organisation. Conclusions This evidence-generated model of care promotes the provision of quality and systematic bereavement care in the acute hospital setting. What is known about the topic? Acute hospitals are the most common place to die in Australia, yet there is a lack of understanding of how bereavement care is or should be provided in these environments. The bereavement period is associated with increased use of health services and worse morbidity and mortality, and thus has significant implications for public health. The provision of bereavement care in acute hospitals is often sporadic, often involving untrained staff who may not provide evidence-based care. What does this paper add? This paper describes the development of a comprehensive, evidence-based model of bereavement care specific to the needs of an Australian acute hospital. What are the implications for practitioners? Developing a consistent approach to bereavement for the acute care sector has the potential to support staff, minimise conflict at the end of life, facilitate recognition of those suffering from difficult bereavement and proactively engage services for these people. It is hoped that such a model of care can find relevance across acute hospitals in Australia, to improve the quality and consistency of bereavement care.

This paper reports on the preparation, characterization, and photoluminescence properties of novel hybrid materials, in which the EDTA-Ln-L complexes (where L: H 2 O, acac, bzac, dbm, and tta ligands, and Ln: Eu, Gd, and Tb) were covalently linked to the precursor medium molecular weight chitosan surface (CS) matrices or on the chitosan surfaces previously crosslinked with epichlorohydrin (CSech). The emission spectra of these materials were characterized by intraconfigurational-4fN transitions centred on the Eu 3+ and Tb 3+ ions. Some broad bands from the polymeric matrix were also observed in the emission spectra, however the relative intensities of the intraconfigurational bands increased significantly for systems containing diketonate ligands when the antenna effect became more efficient. The values of the radiative rates (A rad ) were higher for crosslinked hybrid systems with epichlorohydrin, while nonradiative rates (A nrad ) presented the opposite behaviour. These data contributed to an increase in the values of emission quantum efficiency (η) for crosslinked materials. The effect of the modification process and antenna ligand on the values of intensities, intensity parameters Ω 2 e Ω 4 of the Eu 3+ complexes were also investigated. The results showed that the crosslinked biopolymer surfaces have great potential for applications in molecular devices light converters., (© 2020 John Wiley & Sons, Ltd.)

Immunotherapy directed at the PD-L1/PD-1 axis has produced treatment advances in various human cancers. Unfortunately, progress has not extended to glioblastoma (GBM), with phase III clinical trials assessing anti-PD-1 monotherapy failing to show efficacy in newly diagnosed and recurrent tumors. Myeloid-derived suppressor cells (MDSCs), a subset of immunosuppressive myeloid derived cells, are known to infiltrate the tumor microenvironment of GBM. Growing evidence suggests the CCL2-CCR2 axis is important for this process. This study evaluated the combination of PD-1 blockade and CCR2 inhibition in anti-PD-1-resistant gliomas. CCR2 deficiency unmasked an anti-PD-1 survival benefit in KR158 glioma-bearing mice. CD11b + /Ly6C hi /PD-L1 + MDSCs within established gliomas decreased with a concomitant increase in overall CCR2 + cells and MDSCs within bone marrow of CCR2-deficient mice. The CCR2 antagonist CCX872 increased median survival as a monotherapy in KR158 glioma-bearing animals and further increased median and overall survival when combined with anti-PD-1. Additionally, combination of CCX872 and anti-PD-1 prolonged median survival time in 005 GSC GBM-bearing mice. In both models, CCX872 decreased tumor associated MDSCs and increased these cells within the bone marrow. Examination of tumor-infiltrating lymphocytes revealed an elevated population, increased IFNγ expression, indicating enhanced cytolytic activity, as well as decreased expression of exhaustion markers in CD4 + and CD8 + T cells following combination treatment. These data establish that combining CCR2 and PD-1 blockade extends survival in clinically relevant murine glioma models and provides the basis on which to advance this combinatorial treatment toward early-phase human trials., Competing Interests: Competing interest statement: J.J.C., I.F.C., R.S., and T.J.S. are all employed by ChemoCentryx and are stockholders. D.A.M. holds patented technologies that have been licensed or have exclusive options to license to Celldex Therapeutics, Annias, Immunomic Therapeutics, and iOncologi. D.A.M. receives research funding from Immunomic Therapeutics. D.A.M. serves as an advisor/consultant to Bristol-Myers Squibb, Tocagen, and Oncorus. D.A.M. is cofounder of iOncologi, Inc., an immunooncology biotechnology company. Neither any reagent nor any funding from these organizations was used in this study. J.A.F.-T., D.L., A.G., M.R.S., M.D., and J.K.H. have no competing interests to report. R.K.J. received honorarium from Amgen; consultant fees from Chugai, Merck, Ophthotech, Pfizer, SPARC, SynDevRx, XTuit; owns equity in Enlight, Ophthotech, SynDevRx; and serves on the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, the Tekla Healthcare Opportunities Fund, and the Tekla World Healthcare Fund. Neither any reagent nor any funding from these organizations was used in this study.

C-C chemokine receptor 2 (CCR2) is a key driver of monocyte/macrophage trafficking to sites of inflammation and has long been considered a target for intervention in autoimmune disease. However, systemic administration of CCR2 antagonists is associated with marked increases in CCL2, a CCR2 ligand, in the blood. This heretofore unexplained phenomenon complicates interpretation of in vivo responses to CCR2 antagonism. We report that CCL2 elevation after pharmacological CCR2 blockade is due to interruption in a balance between CCL2 secretion by a variety of cells and its uptake by constitutive internalization and recycling of CCR2. We observed this phenomenon in response to structurally diverse CCR2 antagonists in wild-type mice, and also found substantially higher CCL2 plasma levels in mice lacking the CCR2 gene. Our findings suggest that CCL2 is cleared from blood in a CCR2-dependent but G protein (Gα i , Gα s or Gα q/11 )-independent manner. This constitutive internalization is rapid: on a given monocyte, the entire cell surface CCR2 population is turned over in <30 minutes. We also found that constitutive receptor internalization/recycling and ligand uptake are not universal across monocyte-expressed chemokine receptors. For example, CXCR4 does not internalize constitutively. In summary, we describe a mechanism that explains the numerous preclinical and clinical reports of increased CCL2 plasma levels following in vivo administration of CCR2 antagonists. These findings suggest that constitutive CCL2 secretion by monocytes and other cell types is counteracted by constant uptake and internalization by CCR2-expressing cells. The effectiveness of CCR2 antagonists in disease settings may be dependent upon this critical equilibrium., (Copyright © 2019 by The American Association of Immunologists, Inc.)

The blood-brain barrier (BBB) is limiting transcellular and paracellular movement of molecules and cells, controls molecular traffic, and keeps out toxins. However, this protective function is the major hurdle for treating brain diseases such as brain tumors, Parkinson's disease, Alzheimer's disease, etc. It was previously demonstrated that high pulsed electrical fields (PEFs) can disrupt the BBB by inducing electroporation (EP) which increases the permeability of the transcellular route. Our goal was to study the effects of low PEFs, well below the threshold of EP on the integrity and function of the BBB. Ten low voltage pulses (5-100 V) were applied to a human in vitro BBB model. Changes in permeability to small molecules (NaF) were studied as well as changes in impedance spectrum and trans-endothelial electric resistivity. Viability and EP were evaluated by Presto-Blue and endogenous Lactate dehydrogenase release assays. The effect on tight junction and adherent junction protein was also studied. The results of low voltage experiments were compared to high voltage experiments (200-1400 V). A significant increase in permeability was found at voltages as low as 10 V despite EP only occurring from 100 V. The changes in permeability as a function of applied voltage were fitted to an inverse-exponential function, suggesting a plateau effect. Staining of VE-cadherin showed specific changes in protein expression. The results indicate that low PEFs can transiently disrupt the BBB by affecting the paracellular route, although the mechanism remains unclear.

Objective: The objective of this study is to examine the frequency of abnormal Chromosomal Microarray (CMA) analyses among fetuses with isolated non-visualization of fetal gallbladder., Methods: Data from CMA analyses performed due to isolated non-visualization of fetal gallbladder between January 2013 and September 2016 were retrospectively acquired from a computerized database of the Israeli Ministry of Health. The results were compared with the rate for clinically significant CMA findings in general population, based on a large cohort of 5541 pregnancies undergoing CMA due to maternal request, and a systematic review of 9272 cases with normal ultrasound., Results: Of 45 pregnancies with isolated non-visualization of fetal gallbladder, CMA testing yielded one (2.22%) gain-of-copy-number variant at 16p11.2, categorized as "pathogenic". In addition, one finding of unknown significance was demonstrated. The risk for clinically meaningful CMA findings among pregnancies with isolated absent gallbladder was not significantly increased compared to control population., Conclusions: To the best of our knowledge, this study is the first report describing the rate of pathogenic CMA results in fetuses with isolated non-visualization of fetal gallbladder. The results, in conjunction with previous studies, show that the risk for abnormal CMA results in pregnancies diagnosed with non-visualized gallbladder is not significantly different from pregnancies with normal ultrasound.

Neutrophil chemotactic defects have been reported previously in patients with hyper-IgE syndrome. Bi-allelic mutations in dedicator of cytokinesis 8 (DOCK8) gene usually cause an autosomal recessive hyper-IgE syndrome phenotype. Data are lacking about expression of DOCK8 protein in neutrophils or the possible role of DOCK8 in neutrophil function. We sought to determine if DOCK8 protein is expressed in neutrophils and if DOCK8 plays a role in neutrophil function. The expression of DOCK8 protein was assessed in neutrophils from healthy volunteers with and without activators. Neutrophil chemotaxis, phagocytosis and superoxide generation were studied in neutrophils from DOCK8-deficient patients compared to neutrophils from healthy controls before and after stimulation with activators: phorbol 12-myristate 13-acetate (PMA) or N-Formylmethionyl-leucyl-phenylalanine (fMLP). DOCK8 protein is expressed in resting neutrophils from healthy controls, with a significant increase in DOCK8 expression after stimulation. Neutrophil functions were assessed in 6 DOCK8-deficient patients. All patients had the same non-sense mutation (c.C5134A, p.S1711X). Normal chemotaxis was recorded in 4/6 patients while a mild to moderate chemotaxis defect was recorded in 2/6. Superoxide generation was mainly normal in neutrophils from all six patients and phagocytosis was normal in five patients tested. We conclude that DOCK8 protein is expressed in resting human neutrophils and DOCK8 expression is increased after stimulation with either PMA or fMLP. Most patients with a disease-causing mutation in DOCK8 have normal neutrophil functions, while a minority showed a mild to moderate chemotactic defect.

Spermatogenesis is the process of the proliferation and differentiation of spermatogonial stem cells (SSCs) to generate sperm. Leukemia patients show impairment in some of the endocrine hormones that are involved in spermatogenesis. They also show a decrease in semen parameters before and after thawing of cryopreserved samples compared to a control. The mechanisms behind these effects have not yet been described. This review summarizes the effect of leukemia on semen parameters from adult patients and highlights feasible suggested mechanisms that may affect impairment of spermatogenesis in these patients. We suggest the possible involvement of leukemia in disturbing hormones involved in spermatogenesis, and the imbalance in testicular paracrine/autocrine factors involved in the formation of SSC niches that control their proliferation and differentiation. Understanding the mechanisms of leukemia in the impairment of spermatogenesis may lead to the development of novel therapeutic strategies mainly for prepubertal boys who do not yet produce sperm.

Several types of psoriasiform dermatitis are associated with increased IL-36 cytokine activity in the skin. A rare, but severe, psoriasis-like disorder, generalized pustular psoriasis (GPP), is linked to loss-of-function mutations in the gene encoding IL-36RA, an important negative regulator of IL-36 signaling. To understand the effects of IL-36 dysregulation in a mouse model, we studied skin inflammation induced by intradermal injections of preactivated IL-36α. We found the immune cells infiltrating IL-36α-injected mouse skin to be of dramatically different composition than those infiltrating imiquimod-treated skin. The IL-36α-induced leukocyte population comprised nearly equal numbers of CD4 + αβ T cells, neutrophils, and inflammatory dendritic cells, whereas the imiquimod-induced population comprised γδ T cells and neutrophils. Ligands for chemokine receptors CCR6 and CXCR2 are increased in both GPP and IL-36α-treated skin, which led us to test an optimized small-molecule antagonist (CCX624) targeting CCR6 and CXCR2 in the IL-36α model. CCX624 significantly reduced the T cell, neutrophil, and inflammatory dendritic cell infiltrates and was more effective than saturating levels of an anti-IL-17RA mAb at reducing inflammatory symptoms. These findings put CCR6 and CXCR2 forward as novel targets for a mechanistically distinct therapeutic approach for inflammatory skin diseases involving dysregulated IL-36 signaling, such as GPP., (Copyright © 2019 by The American Association of Immunologists, Inc.)

Objective: The objective of this study is to determine the true incidence of early neonatal hypoglycemia and to confirm potential risk factors., Study Design: The study was conducted at tertiary Medical Center in Israel, between June and September 2014. First blood glucose concentrations of all infants admitted to the nursery were measured using a "point of care" analyzer (Accu-Chek). We recorded risk factors for hypoglycemia such as birth weight, gestational age, maternal diabetes and demographics and analyzed their association with two hypoglycemia cutoffs: 40 and 47 mg/dl., Results: Of 4000 newborns admitted during that period, 3595 were analyzed after excluding 405 who had missing data. Glucose level was obtained at a mean age of 74 ± 30 min. One hundred and twenty-four newborns (3.4%) had blood glucose levels below 40 mg/dl and 435 (12.1%) below 47 mg/dl. Univariate analyses revealed that gestational age, maternal diabetes, low birth weight (<2500 g), and twin delivery were associated with early neonatal hypoglycemia. Other risk factors (e.g. large or small for gestational age, birth weight >3800 g) were not. In multivariate analysis, gestational age remained the strongest association, while maternal diabetes and low birth weight became non-significant., Conclusions: We showed a high occurrence of early hypoglycemia in normal newborns using universal screening. The strongest risk factor was early gestational age. Surprisingly, incidence of early hypoglycemia in the presence of other classical risk factors was like that of the general population.

Objectives: To confirm our previous findings of less cognitive impairments (based on cognitive screening tools) among methadone maintenance treatment (MMT) patients who achieved take-home dose (THD) privileges., Methods: a random sample of 65 Israeli MMT patients were studied using computerised, age and education standardised, cognitive domains (attention, executive function, memory, motor skills), and non-computerised phonetic and semantic verbal fluency., Results: Cognitive scores were within ±1 standard deviation (SD) of average for most domains, including non-verbal IQ, attention and motor skills. Verbal fluency and memory were >1 SD below average (mean = 84; z = -1.1 for both). Females were younger than the males and had poorer motor skills (P = 0.005) but better verbal memory (P < 0.0005). Opiate usage duration correlated with reaction time (P = 0.05) and inversely with verbal memory (P = 0.01). Overall cognitive function was poorest among 25 (38.5%) current drug users, and 6 (9.2%) lifetime schizophrenia patients. Cognitive domains were comparable between THD privileges subgroups., Conclusions: Despite heterogeneity in MMT duration, abuse duration, substance use and psychiatric comorbidity, all performed within ±1 SD of average for age and education in most cognitive domains. Our findings challenge the notion of MMT as being synonymous with compromised cognition and may lead to reduced bias regarding cognitive function of MMT patients.

Background: There is a paucity of data on the use of biologic therapy in recalcitrant pediatric psoriasis. The current study presents pediatric psoriasis cases treated with biologic agents in a tertiary referral center., Methods: In this retrospective case series, data were collected on all patients ≤18 years old with severe psoriasis treated with biological therapy from 2010 through 2016 in a tertiary children's hospital. We included demographic data, previous systemic treatments, reason for discontinuation or switch to other systemic treatments, efficacy and side effects., Results: There were 10 patients, mean age 5.75 (±3.3) years treated with biologic agents in our center; Etanercept was the most frequent biological treatment prescribed (n = 9) followed by adalimumab (n = 5) ustekinumab (n = 3) and infliximab (n = 2). Additional systemic therapy was added to the biological therapy in seven cases: Methotreaxate (n = 5), phototherapy (n = 4), cyclosporine A and colchicine (1 case each). The most common reason for discontinuation was secondary failure (5 for etanercept, 3 for adalimumab). Six patients failed one biological treatment and three patients failed two biological treatments. Four patients are still being treated with a first line biologic (Etanercept in all). Adverse events were rare., Conclusion: Biologic therapy is effective and safe in recalcitrant pediatric psoriasis. Larger series are needed to confirm our observation.

The chemokine CCL7 (MCP3) is known to promote the recruitment of many innate immune cell types including monocytes and neutrophils to sites of bacterial and viral infection and eosinophils and basophils to sites of allergic inflammation. CCL7 upregulation has been associated with many inflammatory settings including infection, cardiovascular disease, and the tumor microenvironment. CCL7's pleotropic effects are due in part to its ability to bind numerous chemokine receptors, namely CCR1, CCR2, CCR3, CCR5, and CCR10. CCL7-blockade or CCL7-deficiency is often marked by decreased inflammation and poor pathogen control. In the context of Leishmania major infection, CCL7 is specifically upregulated in the skin one-2 weeks after infection but its role in L. major control is unclear. To determine CCL7's impact on the response to L. major we infected WT and CCL7 -/- C57BL/6 mice. L. major infection of CCL7-deficient mice led to an unexpected increase in inflammation in the infected skin 2 weeks post-infection. A broad increase in immune cell subsets was observed but was dominated by enhanced neutrophilic infiltration. Increased neutrophil recruitment was associated with an enhanced IL-17 gene profile in the infected skin. CCL7 was shown to directly antagonize neutrophil migration in vitro and CCL7 add-back in vivo specifically reduced neutrophil influx into the infected skin revealing an unexpected role for CCL7 in limiting neutrophil recruitment during L. major infection. Enhanced neutrophilic infiltration in CCL7-deficient mice changed the balance of L. major infected host cells with an increase in the ratio of infected neutrophils over monocytes/macrophages. To determine the consequence of CCL7 deficiency on L. major control we analyzed parasite load cutaneously at the site of infection and viscerally in the draining LN and spleen. The CCL7 -/- mice supported robust cutaneous parasite control similar to their WT C57BL/6 counterparts. In contrast, CCL7-deficiency led to greater parasite dissemination and poor parasite control in the spleen. Our studies reveal a novel role for CCL7 in negatively regulating cutaneous inflammation, specifically neutrophils, early during L. major infection. We propose that CCL7-mediated dampening of the early immune response in the skin may limit the ability of the parasite to disseminate without compromising cutaneous control.

Purpose : To describe the distribution, clinical findings, visual outcomes, treatment, and complications of children with uveitis at a tertiary referral ophthalmic center. Methods : Retrospective cohort study. We reviewed the medical records of all patients ≤16 years with uveitis referred to Massachusetts Eye Research and Surgery Institution from March 2005 to July 2016. Results : Of 286 included children, 62.24% were female. Mean age of onset was 8.4 years. The uveitis was mainly anterior (61.9%), recurrent (68.53%), bilateral (81.82%), and noninfectious (96.5%). Idiopathic cases accounted for 51.4%. The most frequent systemic association was juvenile idiopathic arthritis (34.96%). The majority of patients (78.32%) experienced complications. All patients, except one, needed systemic therapy. Conclusion : Pediatric uveitis is challenging to diagnose and manage, with frequent and potentially severe complications. Most cases were bilateral, recurrent, and idiopathic. Prompt referral to uveitis-specialized centers and an appropriate systemic therapy are mandatory for good visual outcomes.

Following the introduction of universal immunization against rotavirus, concerns were raised regarding pathogen-replacement of rotavirus by norovirus. The study aim was to examine the incidence and characteristics and norovirus gastroenteritis before and after the introduction of universal rotavirus immunization in Israel. We studied 1179 stool samples collected between November 2007 and December 2014 for a prospective hospital-based surveillance study of children aged 0-59 months hospitalized for gastroenteritis. A real-time RT-PCR assay was used to identify genogroup II (GII) norovirus in extracted fecal RNA samples. Overall, the weighted percentage of norovirus positive patients was 10.9%. Norovirus positivity was similar in the pre-universal rotavirus immunisation years (2008-2010) and the universal years (2011-2014), the respective average annual incidence of norovirus gastroenteritis was 1.6 (95% CI 0.6-2.3) per 1000 and 1.1 (95% CI 0.8-1.4) per 1000 children. Rotavirus was detected in 36.8% and 19.6% of the patients in the pre-vaccine years and the universal vaccine years, with an estimated incidence of 5.5 (95% CI 3.4-7.6) per 1000 and 2.1 (95% CI 1.6-2.7) per 1000 children, respectively. Most patients (59.1%) with norovirus gastroenteritis were infants aged 0-11 months. Norovirus was detected all year round with a significant 3-month peak from September through November. In conclusion, norovirus continues to be a leading cause of acute gastroenteritis associated with hospitalizations in young children. Future norovirus vaccines should target young infants. There was no evidence of pathogen-replacement by norovirus following the introduction of universal rotavirus immunization in Israel.

Regulating immunity is a leading target for cancer therapy. Here, we show that the anti-tumor immune response can be modulated by the brain's reward system, a key circuitry in emotional processes. Activation of the reward system in tumor-bearing mice (Lewis lung carcinoma (LLC) and B16 melanoma) using chemogenetics (DREADDs), resulted in reduced tumor weight. This effect was mediated via the sympathetic nervous system (SNS), manifested by an attenuated noradrenergic input to a major immunological site, the bone marrow. Myeloid derived suppressor cells (MDSCs), which develop in the bone marrow, became less immunosuppressive following reward system activation. By depleting or adoptively transferring the MDSCs, we demonstrated that these cells are both necessary and sufficient to mediate reward system effects on tumor growth. Given the central role of the reward system in positive emotions, these findings introduce a physiological mechanism whereby the patient's psychological state can impact anti-tumor immunity and cancer progression.

Background: Palliative care patients consistently nominate home as their preferred care environment. This is challenging without support from laycarers, especially if patients require subcutaneously administered symptom relief. Laycarers typically lack confidence with this task and request professional guidance., Aim: To explore differences in laycarers' confidence in administering subcutaneous injections depending upon whether a laycarer, registered nurse or pharmacist prepared injections for subsequent administration by laycarers., Design: Prospective randomized controlled trial with three intervention arms: laycarer prepares, labels and stores injections; registered nurse prepares injections; and pharmacist prepares injections for later administration by laycarer., Setting/participants: In all, 93 laycarers, from 24 urban and rural community services, completed the study., Results: The primary outcome of interest was laycarer confidence with injection administration; analysis of variance revealed no significant differences between the three intervention arms; mean values ranged from 5.9 to 6.1 out of 7 ( F(2, 90) = 0.50, p = 0.61). Comparison of confidence after laycarer preparation versus other (nurse or pharmacist) was not statistically significant ( t = 0.7, df = 90, p = 0.49). Averaged over intervention arms, confidence levels increase significantly with injecting experience, from 5.3 to 6.1 ( F(1, 75) = 47.6, p < 0.001)., Conclusion: Upskilled laycarers can confidently administer subcutaneous injections for loved ones, regardless of who prepares injections. This finding can improve patient outcomes and potentially decrease unwanted admissions to inpatient facilities.

Aim: To identify the factors, risks, and mortality associated with unplanned out-of-hospital births., Material and Methods: This observational, retrospective, case-control study was conducted between 2005 and 2013 through a review of medical records from the hospital network of a county of Brazil. Mother-child dyads were divided into in-hospital births and unplanned out-of-hospital births. For hypothesis testing involving quantitative variables, parametric and nonparametric methods (t-test or Mann-Whitney test, respectively) were used as appropriate after ascertaining normality of distribution via the Kolmogorov-Smirnov or Shapiro-Wilk tests. The chi-square test, Fisher's exact test, odds ratios, and 95% confidence intervals were used to assess the relationship between categorical variables. A binary logistic regression was applied for pooled analysis of those variables that, when analyzed in isolation, had significant p-values on hypothesis testing. In all tests, p-values <0.05 were considered statistically significant., Results: Of the 420 records, 117 corresponded to out-of-hospital births dyads. Mothers were predominantly nonwhite (p<0.001), with a history of inadequate antenatal care (p<0.001), multiparous (p<0.001), aged >25 years (p=0.031), and had more puerperal complications (p<0.001). Their newborns had low birth weight (Odds Ratios: 2.22; 95% CI: [1.4-3.4]; p<0.001), higher morbidity (p=0.009), a higher rate of admission to neonatal intensive care and stepdown units (p=0.030), and prolonged length of stay (p<0.001)., Conclusion: The risk of maternal and neonatal complications, as well as the neonatal mortality rate, were higher for unplanned out-of-hospital deliveries. It occurred predominantly in nonwhite, older, multiparous women who had received incomplete antenatal care and who lived far from perinatal care centers., Competing Interests: Conflict of Interest: No conflict of interest was declared by the authors.

Purpose: Anemia has been reported to be associated with diabetes, but the association between new-onset diabetes after transplantation (NODAT) and anemia has not been reported., Methods: Patients who underwent kidney transplantation and did not have diabetes prior to transplantation were included in this study. Hemoglobin levels and the prevalence of anemia (hemoglobin <12 g/dL in females and <13 g/dL in males) were evaluated at three time points (prior to transplantation, 6 months following transplantation or 1 month before the development of NODAT, 2 years following transplantation, or following the development of NODAT) and were compared between those who developed NODAT and those who did not. Variables associated with the development of anemia were compared between the two groups., Results: A total of 266 kidney transplant recipients were included, of which 71 (27%) developed NODAT during the time of the follow-up. Hemoglobin and hematocrit levels and the prevalence of anemia were similar in those with and without NODAT at all three time points evaluated. Ferritin levels, prior to transplantation and mean corpuscular volume (MCV) posttransplantation post-NODAT development, were slightly but significantly lower in those with NODAT, although both were within the normal range., Conclusions: Pretransplantation ferritin levels and posttransplantation post-NODAT development MCV are inversely associated with the development of NODAT in kidney transplants.

Background: Symptom control is a primary goal in asthma. We hypothesized that administrative data regarding rescue inhaler purchases may correlate with asthma symptom control., Methods: We identified all patients who purchased short-acting beta-agonist (SABA) inhalers during the course of one year in the database of a Health Maintenance Organization (HMO). Primary physicians identified asthma patients and classified their asthma symptom control into three groups according to the Global Initiative for Asthma (GINA) guidelines. Asthma patients were asked to answer symptom questionnaires and grade their asthma control. SABA inhaler purchases were compared between asthma control groups as classified by the guidelines, the physicians and the patients. We also compared the agreement on asthma control between the three methods of classification., Results: Of 241 asthma patients, 83 completed the questionnaires. Using the GINA guidelines criteria, 26 were symptom controlled, 46 were partially controlled and 11 were uncontrolled. SABA inhaler purchases were not significantly lower in the controlled group. Using patients' overall impression of their asthma control, the mean numbers of SABA inhalers purchased were 1.5, 4.4 and 6.4 per year in the controlled, partially controlled and uncontrolled groups, respectively (p = 0.03). Patients' classification of asthma control had better agreement (kappa = 0.34) with GINA guidelines than physician's' agreement (kappa = 0.05)., Conclusion: When using administrative data for asthma patients, 2 or more SABA inhaler purchases in one year should alert the physician for the need for asthma control evaluation. Purchase of at least 4 SABA inhalers a year may be regarded as a marker for asthma that is not controlled.

Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma. Patients with stage I disease are usually treated with radiotherapy (RT). In previous studies, mostly from the pre positron emission tomography-computed tomography (PET-CT) era, the 5 year progression-free survival (PFS) and overall survival (OS) rates of stage I disease were 60-80% and 80-93%, respectively. This study retrospectively evaluated the outcome of stage I FL which was treated with involved field RT in the PET-CT era between 2002 and 2015. Ninety-one patients were enrolled. Five year PFS and OS rates were 73% and 97%, respectively. Relapse occurred in 19 (21%) patients, 74% occurring outside the radiation field. In conclusion, PET-CT staging of clinical stage I FL may contribute to the improved prognosis in patients treated with RT compared to historical cohorts, possibly due to better identification of "genuine" stage I disease.

Background: Fractionated therapy with 177 Lu-DOTATATE has been reported to be an effective treatment for patients with metastasized neuroendocrine tumors. To optimize the treatment, absorbed doses to risk organs are calculated for the individual patient. For each organ, absorbed dose due to activity in the organ itself (self-dose) and that originating from other organs (cross-dose) are calculated from serial measurements to obtain the activity distribution following treatment. The main aim of the present work were to calculate the cross-dose contribution to the total absorbed kidney dose., Methods: Five hundred patients with neuroendocrine tumors undergoing therapy with 177 Lu-DOTATATE were included. Scintigraphic planar whole body images and single photon emission computed tomography/computed tomography (SPECT/CT) over the abdomen were acquired at 1, 4 and 7 days after treatment. Kidney self-dose was calculated based on radioactivity distribution obtained from SPECT/CT. Cross-dose to kidneys was estimated using organ-based analysis of planar whole body images and cross-fire dose factors from Olinda/EXM 1.1., Results: Cross-dose to kidneys in the majority of patients were less than 2% and almost all cross-doses were less than 10%. Cross-dose exceeded 10% only in rare cases of patients with high tumor burden and low absorbed doses to kidneys., Conclusions: The absorbed dose from 177 Lu-octreotate to solid organs due to cross-fire is generally low and can usually be neglected.

The purpose of this study was to analyse the association between free beta hCG (fβhCG) increased levels and pregnancy complications (PC), foetal growth restriction (FGR) and preeclampsia (PE). This connection was evaluated in two stages (i) investigating the association between those PC with first trimester fβhCG and second trimester intact hCG (ihCG), and (ii) studying the association between these two analytes in the same pregnancy. This was a retrospective study in two settings: medical centre that provided data on fβhCG and ihCG levels in pregnancies with FGR and PE, and central laboratory that provided fβhCG and ihCG levels that were compared in the same pregnancy. No association was found between those PC and the hCG analytes, except for elevated ihCG levels and FGR. Elevated fβhCG (>3.00 MoM) was found in 570/16,849 (3.4%) women. However, only 14% of whom had elevated second trimester ihCG. A positive correlation was found between the magnitude of first trimester fβhCG levels and the percentage of women who had elevated second trimester ihCG. This association was determined by the magnitude of the elevation of fβhCG levels. Impact statement What is already known on this subject: The two analytes, first trimester fβhCG and second trimester ihCG, are independently produced and parameters of the biochemical screening during pregnancy. What the results of this study add: Referring to 3.00 MoM as cut-off levels, most pregnancies with elevated levels of first trimester fβhCG will have normal ihCG second trimester levels. What the implications are of these findings for clinical practice and/or further research: The risk of developing pregnancy complications, FGR and PE should be associated with second trimester ihCG levels. About 3.5% of women had high fβhCG levels during the first trimester. However, only 14% also had increased ihCG levels, defined as >3.00 MoM; additional studies are needed to explore the association between increased first trimester fβhCG levels and the risk of developing pregnancy complications, independent of ihCG levels in the second trimester.

Focal segmental glomerulosclerosis (FSGS) comprises a group of uncommon disorders that present with marked proteinuria, nephrotic syndrome, progressive renal failure and characteristic glomerular lesions on histopathology. The current standard of care for patients with FSGS include immunosuppressive drugs such as glucocorticoids followed by calcineurin inhibitors, if needed for intolerance or inadequate response to glucocorticoids. Renin-angiotensin-aldosterone (RAAS) blockers are also used to control proteinuria, an important signature of FSGS. Existing treatments, however, achieved only limited success. Despite best care, treatment failure is common and FSGS is causal in a significant proportion of end stage renal disease. Thus, an unmet need exists for novel disease modifying treatments for FSGS. We employed two widely-used murine models of FSGS to test the hypothesis that systemic inhibition of chemokine receptor CCR2 would have therapeutic benefit. Here we report that administration CCX872, a potent and selective small molecule antagonist of CCR2, achieved rapid and sustained attenuation of renal damage as determined by urine albumin excretion and improved histopathological outcome. Therapeutic benefit was present when CCX872 was used as a single therapy, and moreover, the combination of CCX872 and RAAS blockade was statistically more effective than RAAS blockade alone. In addition, the combination of CCR2 and RAAS blockade was equally as effective as endothelin receptor inhibition. We conclude that specific inhibition of CCR2 is effective in the Adriamycin-induced and 5/6 nephrectomy murine models of FSGS, and thus holds promise as a mechanistically distinct therapeutic addition to the treatment of human FSGS.

Data regarding clinical characteristics, therapy, maternal and fetal outcomes of pregnancy-associated acute myeloid leukemia (PA-AML) are limited. This study (including 138 cases published between 1955 and 2013) provides comprehensive assessment of these clinical parameters and may serve as a platform for developing management recommendations. Most patients (58%) received anthracycline-cytarabine-based regimens (ACBRs), which were associated with significantly increased complete remission (CR: 91%). Yet, the maternal overall survival (OS: ∼30%) was relatively low, probably reflecting reduced application of risk-adapted consolidation and allogeneic stem cell transplantation (allo-SCT). Fetal exposure to ACBRs resulted in a live birth rate of 87%, with complications (16%) diagnosed only in chemotherapy-subjected neonates. This study demonstrates safety and efficacy of ACBRs during pregnancy. Therapy and delivery schedule should allow early referral of high-risk patients to allo-SCT. Generation of a pool of high-quality data on PA-AML could contribute to providing evidence-based therapy and lead to improved maternal and fetal survival.

Neurolymphomatosis (NL) often represents unidentified non-Hodgkin lymphoma relapses. Considering its severity, early detection and treatment are crucial. We outline one hospital's 18 F-FDG-PET-CT imaging findings of NL, along with the patients' clinical characteristics. Clinical records and imaging findings of 19 NL patients, PET-CT diagnosed, were retrospectively reviewed. Patient data, FDG-PET-CT findings and the presence of coexisting diseases, especially CNS involvement, were documented. Available MRI and clinical data verified the findings. All cases had increased linear FDG uptake along anatomic nerve sites. CTs showed varying degrees of corresponding soft-tissue-thickening. Clinical correlations also contributed to the diagnosis. In 4/19 patients, lymphoma presented with NL, in 15/19 it appeared with disease recurrence/progression. In 9/19, clinical symptoms suggested neural involvement while 10/19 had nonspecific symptoms. Eleven died of lymphoma within 0.9 years of diagnosis despite directed-therapy. Eight, however, survived up to 7.82 years post-diagnosis. Whole-body FDG-PET-CT can assist in early NL diagnosis, possibly enhancing survival.

mAbs that neutralize IL-17 or its receptor have proven efficacious in treating moderate-to-severe psoriasis, confirming IL-17 as an important driver of this disease. In mice, a rare population of T cells, γδT17 cells, appears to be a dominant source of IL-17 in experimental psoriasis. These cells traffic between lymph nodes and the skin, and are identified by their coexpression of the TCR variable regions γ4 and δ4. These cells are homologous to the Vγ9Vδ2 T cell population identified in human psoriatic plaques. In this study we report that a potent and specific small molecule antagonist of the CCR6 chemokine receptor, CCX2553, was efficacious in reducing multiple aspects of psoriasis in two different murine models of the disease. Administration of CCX2553 ameliorated skin inflammation in both the IL-23-induced ear swelling model and the topical imiquimod model, and significantly reduced the number of γδT17 cells in inflamed skin. γδT17 cells were greatly reduced in imiquimod-treated skin of CCR6 -/- mice, but adoptively transferred wild-type (CCR6 +/+ ) γδT17 cells homed normally to the skin of imiquimod-treated CCR6 -/- mice. Our data suggest that γδT17 cells are completely dependent on CCR6 for homing to psoriasiform skin. Thus, CCR6 may constitute a novel target for a mechanistically distinct therapeutic approach to treating psoriasis., (Copyright © 2017 by The American Association of Immunologists, Inc.)

Soldiers are often required to carry loads which impose biomechanical strain on the human body. This can adversely affect physical performances. Recently, wheel-based devices (WBD) were designed to reduce the load on the soldier. In the present study, a prototype of this newly developed WBD was evaluated. Thirteen volunteers performed three exercise protocols on a treadmill as follows: (1) no load; (2) carrying 40% of their bodyweight with a backpack or; (3) with the WBD. Data acquisition included: gait parameters, vertical ground reaction forces (VGRF) and contact pressure acting on the shoulder. Biomechanical analysis showed that the WBD decreased the contact pressure on the shoulder and the VGRF. However, greater gait variability, in terms of cycle-to-cycle gait line generation, was observed, which might point to a difficulty in maintaining stability while walking. The study suggests that WBD has a potential to reduce the biomechanical strain on the soldier while carrying heavy loads. Future potential adjustments for the development of a better WBD-based solution are suggested. Practitioner Summary: The present research observed the potential biomechanical advantages of using a wheel-based device designed to reduce the load on the soldier. It contributed to a lower mechanical force on the soldier's body, yet causing modulations in gait control. Future design adjustments should be made to optimise the platform.

Background/Study Context: Approximately one third of older adults over the age of 65, and over 40% of those over 80 years, fall each year, leading to fractures, morbidity, and mortality. Annual direct medical costs due to falls in the United States are approximately $19.2 billion. The identification of new treatable risk factors for falls has the potential to advance their prevention and rehabilitation., Methods: A cross-sectional study of 127 community-dwelling adults aged 67-99 years was conducted. An electronic gait walkway was used to assess gait coordination, measured as the Phase Coordination Index during normal speed walking. A motion capture system was used to assess rhythmic interlimb antiphase ankle coordination, measured as the standard deviation of ankle relative phase. Having fallen in the previous year was self-reported retrospectively. Odds ratios for falling as a function of coordination quartiles were determined using multivariable logistic regression., Results: Adjusting for age, sex, body mass index, number of chronic conditions, Mini-Mental State Examination score, gait speed, and the variability of step length, time, and width, the odds ratios for falling based upon being in the 4th (the poorest) quartiles of gait or ankle coordination were 5.5 (95% confidence interval [CI]: 1.2-24.7) and 8.2 (95% CI: 2.2-31.3), respectively, and 3.7 (95% CI: 1.0-13.8) for the 3rd quartile of gait coordination, compared with the best (the 1st) coordination quartiles. Similar results were found in regression without adjustment for gait characteristics., Conclusion: The results support the hypothesis that impaired gait and rhythmic interlimb ankle coordination are associated with a history of falls in the past year. Prospective longitudinal research is needed to determine the possible direction of causality between falls and impaired coordination.

Objective: To determine whether older Mexican-Americans who cannot speak and/or understand spoken English have higher rates of mobility limitations or fear of falling than their English-speaking counterparts., Design: We conducted a cross-sectional analysis of 1169 community-dwelling Mexican-Americans aged 72-96 years from the 2000-2001 wave of the Hispanic Established Population for the Epidemiological Study of the Elderly. Mobility limitations were defined as having a Short Physical Performance Battery score ≤9, and fear of falling by participant report of being somewhat, fairly, or very afraid of falling. We determined the rates and odds ratios, for having mobility limitations and fear of falling as a function of English ability in those who were 72-96, <80, and ≥80 years of age., Results: Among participants who were unable to speak and/or understand spoken English 85.7% had mobility limitations and 61.6% were afraid of falling, compared to 77.6% and 57.5%, respectively, of English speakers. Before adjusting for covariates, participants who did not speak and/or understand spoken English were more likely to have mobility limitations (odds ratio: 1.7; 95% CI: 1.3-2.4) but not fear of falling, compared to English speakers. Among those aged ≥80 years, but not those <80 years, who did not speak or understand English were more likely to have mobility limitations (odds ratio: 4.8; 95% CI:2.0-11.5) and fear of falling (odds ratio: 2.0; 95% CI:1.3-3.1)., Conclusion: Older Mexican-Americans who do not speak or understand spoken English have a higher rate of mobility limitations and fear of falling than their English-speaking counterparts.

Background: In an attempt to address severe medical manpower shortages in several medical disciplines, the Israeli Ministry of Health offered grants to residents who chose one of these fields., Methods: A total of 220 residents from various disciplines were surveyed on demographic, academic, and professional data, and asked to rank considerations in the choice of their field of residency., Results: Residents in targeted fields attributed significantly more importance to the grant in their decision-making process (U = 3704.5, p < 0.001). This effect remained significant in a multivariate model (OR 1.67, 95%CI 1.32-2.10, p < 0.001). Higher age (OR 1.15, 95%CI 1.01-1.31, p = 0.031) and attribution of significance to the working conditions compared to other residency fields (OR 1.69, 95%CI 1.23-2.32, p = 0.001) were significantly associated with receptivity toward the grant in a multivariate analysis., Discussion: Receptivity toward the offered grants correlated with real-life data shows a rise in physician in these fields, and the weak association between such receptivity and most variables tested may suggest that the grants were perceived as a property of the specific choice rather than a special bonus., Conclusions: Grants may be useful in diverting medical manpower. Further analysis and modeling are required to determine causal relationship and budgetary feasibility.

Hodgkin Lymphoma (HL), a common early adulthood malignancy, has a complex etiology. We conducted a migrant cohort study to assess immigration status and origin as predictors of HL in Israel, which has among the highest rates of HL worldwide. Nationwide data on 2,285,009 16-19-year-old Jewish adolescents, collected from 1967-2011, were linked to Israel's Cancer Registry to obtain the incidence of HL until 2012. Two thousand and ninety-three HL cases were detected during 47.0 million person-years of follow-up. Using multivariable-adjusted Cox proportional hazards modeling, risk was higher for Israeli-born compared to immigrants, similarly across origin groups (HR = 1.59; 95%CI 1.32-1.92 for the dominant nodular sclerosis subtype). Risk of HL was greater for more recent year of birth, higher BMI, taller stature, and apparently for women. These findings suggest that exposure to as yet unidentified elements of the Israeli environment increase the risk of nodular sclerosis HL, and should aid in directing research efforts.

Background: Antivenom has been successfully used to treat systemic and progressive, local manifestations of envenomation inflicted by Vipera (V.) palaestinae, the most common venomous snake in Israel. The objective of this study was to evaluate the fixed dose V. palaestinae monovalent (equine) immunoglobulin G antivenom used in two pediatric emergency departments. In particular, we wanted to assess the need for repeated antivenom administration and the rate of adverse antivenom effects in children., Methods: A retrospective chart review was performed for all children admitted with definite or probable signs of V. palaestinae envenomation to Chaim Sheba Medical Center and Kaplan Medical Center between 1 March 2008 and 1 March 2014. Extracted data included: age, location of bite, time to hospital arrival, time to antivenom administration if indicated, outcomes, and complications of the envenomation and adverse effects to the antivenom., Results: 57 patients met inclusion criteria; they ranged from 1 to 17 years in age and median age was 9.5 years. Clinical manifestations were evident in 55 (96.4%) of victims: 18 presented with minimal local signs and 37 showed marked progressive, local features (rapidly progressing edema) and signs of systemic envenomation: tachycardia (20), vomiting (17), abdominal pain (11) and hypotension (6). Two patients developed compartment syndrome and underwent surgical decompression (both received only a loading dose of antivenom with no subsequent maintenance dose). One patient developed thrombocytopenia and three patients presented with mild coagulopathy. Antivenom was administered to 25 (42%) children. Indications for antivenom administration included moderate to severe local signs (19 patients) and systemic signs (6 patients). None of these patients developed adverse reactions, serum sickness, or other side effects to the antivenom. One patient received a single additional 30mL dose of antivenom, due to hypotension and syncope, with good response., Conclusions: In children, 50 ml dosing of V. palaestinae antivenom is efficacious and safe for the treatment of systemic and progressive local manifestations of envenomation by V. palaestinae.

Objective: The current study aimed to evaluate the profile of women who are most likely to undergo caesarean delivery on maternal request (CDMR) and clarify their reasons for this decision., Methods: For this multicentre case-control study, data were collected from 429 women who underwent CDMR and 429 matched controls who delivered vaginally from June, 2008 through February, 2009. Participants were interviewed by telephone regarding sociodemographic variables, health and lifestyle., Results: CDMR predictors were as follows: increasing age (OR = 1.09/year; 95%CI: 1.05-1.14), family status (unmarried without a steady partner versus married - OR = 3.60; 95%CI: 1.08-11.97), decreasing level of religiosity (secular versus ultra-orthodox - OR = 11.82; 95%CI: 3.75-37.21), and never having engaged, or ceasing sports activity during pregnancy (OR = 1.79; 95%CI: 1.09-2.91 and 2.38; 95%CI: 1.28-4.43, respectively). Above average income reduced the probability of CDMR (OR = 0.56; 95%CI: 0.33-0.94). The most frequent reasons for choosing CDMR were concern for pain (21.9%), concern for their own or baby's health (20.4% and 16.5%, respectively) and emotional aspects (10.0%)., Conclusions: Older, unmarried and/or secular women had increased probability of CDMR. Addressing specific concerns regarding vaginal delivery may provide the basis for a patient-oriented intervention for preventing unnecessary surgery.

Randomized clinical trials that compared chlorambucil to different regimens, for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) do not support an overall survival (OS) benefit. To assess the efficacy and safety of chlorambucil as frontline treatment, we conducted a systematic review and meta-analysis of randomized controlled trials. OS was the primary outcome. Meta-analysis of 18 trials that compared purine analogs, alkylators, alemtuzumab and ibrutinib to chlorambucil demonstrated no OS benefit for therapy without chlorambucil over chlorambucil (pooled HR 0.99, 95% CI 0.91-1.08; 4133 patients). PFS was longer with purine analogs compared with chlorambucil with an increased risk of infection. The risk of secondary malignancies was not increased with chlorambucil. In conclusion, our study showed that chlorambucil is an acceptable chemotherapy backbone for unfit patients with CLL. Purine analogs should be preferred in fit younger patients because of longer PFS. Future trials should focus on unfit patients who are underrepresented in clinical trials.

To determine the effect of sexual abuse history on chronic pain and its relation to opioid addiction and methadone maintenance treatment (MMT), we studied current women MMT patients, and women patients from a sexual abuse treatment center with no history of opioid addiction. Questionnaires included Chronic Pain, Chronic Severe Pain, the Yale-Brown Obsessive Compulsive Scale, the Dissociative Experiences Scale (DES), and the Structured Interview for Disorders of Extreme Stress (complex-PTSD). Chronic severe pain was most prevalent among sexually abused women with no history of opioid addiction (64% of 25), followed by sexually abused MMT women (30.9% of 68), and MMT women with no history of sexual abuse (25% of 8, p = 0.01). Pain severity correlated with dissociation and complex-PTSD scores. The sexually abused non-MMT women had higher rates of high dissociation scores (DES ≥ 30) and complex-PTSD, but fewer obsessive-compulsive disorder symptoms (scored ≥16) than the MMT sexually abused women. Chronic pain was found to be highly prevalent among sexually abused women, independent of being methadone-maintained with an addiction history. The high known prevalence of chronic pain among MMT patients, which may be attributable to opioid-induced hyperalgesia, may partially reflect the sexual abuse history, and should be targeted in future studies evaluating pain indices.