Solanum lycopersium L.) is the most widely grown vegetable in the world. It was domesticated in Latin America and Italy and Spain are considered secondary centers of diversification. This food crop has experienced severe genetic bottlenecks and modern breeding activities have been characterized by trait introgression from wild species and divergence in different market classes.The tomato  using a custom-made Illumina SNP-panel. Most of the 175 successfully scored SNP loci were found to be polymorphic. Population structure analysis and estimates of genetic differentiation indicated that landraces constitute distinct sub-populations. Furthermore, contemporary varieties could be separated in groups  that are consistent with the recent breeding aimed at market-class specialization. In addition, at the 95% confidence level, we identified 30, 34 and 37 loci under positive selection between landraces and each of the groups of commercial variety . Their number and genomic locations imply the presence of some extended regions with high genetic variation between landraces and contemporary varieties.Our work provides knowledge concerning the level and distribution of genetic variation within cultivated tomato landraces and increases our understanding of the genetic subdivision of contemporary varieties. The data indicate that adaptation and selection have led to a genomic signature in cultivated landraces and that the subpopulation structure of contemporary varieties is shaped by directed breeding and largely of recent origin. The genomic characterization presented here is an essential step towards a future exploitation of the available tomato genetic resources in research and breeding programs.The online version of this article (doi:10.1186/1471-2164-14-835) contains supplementary material, which is available to authorized users. Solanum lycopersicum L.) was probably domesticated in Mexico from wild species that originated in the Andean region, although other hypotheses have been also put forward  for each K value. (JPEG 723 KB)Additional file 7: Figure S1: Estimation of the optimum number of clusters. Estimation of the optimum number of clusters of tomato accessions according to the analysis of variance of the log-likelihood values  of the genotypes based on STRUCTURE and CLUMPP analyses. (XLSX 52 KB)Additional file 9: Table S8: Pairwise estimates of Fst and Nei’s standard genetic distance (Dst) between predefined groups or between groups of tomato accessions as inferred by the Bayesian analysis implemented in the STRUCTURE software. (XLSX 16 KB)Additional file 10: Table S9: Heterogeneity in F-Statistics among loci. (XLSX 11 KB)Additional file 11: Table S10: Candidate loci under positive selection between landraces varieties and the different market-classes of contemporary varieties. (XLSX 10 KB)Additional file 12: Table S11: Marker names and their genomic information. (XLSX 22 KB)


Circulating strains cluster geographically and belong to at least 5 distinct clades. Mastomys natalensis) is the only known reservoir of LASV. Most human infections result from zoonotic transmission. The very diverse LASV genome has 4 major lineages associated with different geographic locations. We used reverse transcription PCR and resequencing microarrays to detect LASV in 41 of 214 samples from rodents captured at 8 locations in Sierra Leone. Phylogenetic analysis of partial sequences of nucleoprotein (NP), glycoprotein precursor (GPC), and polymerase (L) genes showed 5 separate clades within lineage IV of LASV in this country. The sequence diversity was higher than previously observed; mean diversity was 7.01% for nucleoprotein gene at the nucleotide level. These results may have major implications for designing diagnostic tests and therapeutic agents for LASV infections in Sierra Leone.Lassa virus (LASV) is endemic to parts of West Africa and causes highly fatal hemorrhagic fever. The multimammate rat ( Arenaviridae), the etiologic agent of LF (Lassa fever (LF) belongs to a group of viral hemorrhagic fevers characterized by a febrile syndrome and high case-fatality rates , a natural host and reservoir of this pathogen  and high-density resequencing microarrays to detect LASV and amplify fragments of NP, GPC, and L genes. The obtained amplicons were sequenced and compared with previously published sequences from Sierra Leone to obtain a more complete and updated picture of the strains circulating in this country.Mastomys sp. were further identified down to species level by using molecular methods as described previously . Thirteen locations were selected for study in the LF-endemic region of eastern Sierra Leone. The geographic coordinates of the sampling locations and details of rodent trapping methods are available in the online Technical Appendix . Traps wRNA from 10 mg of spleen of each rodent was extracted with TRIzol following the manufacturer’s recommendations. The samples were stored at –80°C.RNA were reverse-transcribed by using the SuperScript III Reverse Transcriptase kit (Life Technologies) according to the manufacturer’s instructions, and RT products were stored at –20°C. Specific oligonucleotide primer pairs were used for the PCR targets of interest  at finalThe resequencing pathogen microarray (RPM) analysis was conducted by using Tropical and Emerging Infections microarrays . The RPM-TEI microarray enables detection of 84 biothreat agents, including all lineages of LASV (http://tree.bio.ed.ac.uk/software/figtree).We conducted the sequence alignment using the MUSCLE algorithm implemented in the MEGA 6.0 software package ; Cricetomys sp. (3 [1.4%] rodents); and Mus sp., Praomys sp., and Hylomyscus sp. (1 [0.5%] rodent each).We collected 681 small mammals during the field survey. Of these, we analyzed 214 for this study on the basis of RNA availability at the time of the study Table 2.We screened all samples for LASV by RT-PCR using pan–Old World arenavirus (OWA) primers .In addition, we screened a randomly selected subset of 51 samples , Largo (8 samples), Bumpeh (7 samples), Ngiehun (4 samples), Koi and Yawei (3 samples each), Taiama (2 samples), and Saama (1 sample) . No LASVAll positive samples came from multimammate rats, which is considered the sole vector species for LASV  was closely related to that of strains from Barlie . In another example, 1 GPC sequence originating from Liberia (523) clustered with Sierra Lone clade A sequences. In some cases , such unusual clustering patterns may be explained by cross contamination or mislabeling of the samples. They also might result from relative proximity of all sampling sites and inadvertent anthropogenic transfer of rodents. Massive population movements that occurred in Sierra Leone during the 1991–2002 civil war could contribute to the process of mixing multimammate rat subpopulations carrying different LASV strains  most likely originated from the Yawei village area because they cluster closely. A few other human isolates  for which no location information is available also clustered with Yawei isolates on the basis of GPC and L sequences, suggesting their origin in the same area. These sequences were obtained in 2002 from United Nations peacekeepers stationed in this part of Sierra Leone (Recent epidemiologic data show that LF was detected in 10 of 13 districts in Sierra Leone, which suggests that the infection is much more common that previously recognized (Molecular characterization of isolates from a wider geographic area of the country is needed to fully understand the diversity of the LASV strains in Sierra Leone and its impact on disease distribution and risk. Such information would be useful for developing efficient viral detection technologies, for example, enabling design of PCR primers and antibodies specific for a broad range of LASV types. These diagnostic tests are extremely relevant to disease surveillance and monitoring and evaluation of interventions to prevent primary LASV infection in humans. More extensive information about sequence diversity affecting the antigenicity of the virus or the function of its RNA-dependent RNA polymerase may help in the development of vaccines and antiviral drugs. It will also lead to deeper understanding of the biology and pathogenesis of LASV.Rodent trapping procedures; coordinates of sampling locations; and list of all analyzed samples.


Figure S1 is incorrect. Please view the correct The seventh sentence of the second paragraph of the Discussion section is also incorrect. The correct sentence is: Only sample 74 had a serine (S), polar neutral, at position 429, while the other samples had phenylalanine (F), which is neutral and hydrophobic.Figure S1Average temporal distribution of precipitation and suspected or confirmed dengue cases.(TIF)Click here for additional data file.


To summarize a first stage of research on implementation of a peer leader suicide prevention program by testing the utility of a method for tracking and reporting each school's success in retaining and preparing Peer Leaders.Peer leader programs that prepare opinion leaders to spread healthy practices through their social networks reduce high-risk sex behaviors and show promise in preventing adolescent substance use and suicidal behavior. However, knowledge of implementation processes is very limited. To address this limitation, we drew on the Stages of Implementation Completion (SIC) framework to measure a key phase of peer leader implementation.40 high schools were randomly assigned to either immediate Sources of Strength (n = 20) or waitlist (n = 20). The schools were underserved by mental health services and over-represented by youth at high risk for suicide . In the 20 implementing schools, 656 students (18-71 per school) received Peer Leader (PL) training. Adult mentors facilitated PL meetings to reinforce program concepts and help PLs plan and execute activities to spread healthy coping practices. Using a framework derived from the Stages of Implementation Completion (SIC), school reports of PL meeting dates/attendance were codified as indices of school success in retaining and preparing PLs. Surveys with 5,712 students showed wide school-level variation in success of PLs in reaching their classmates with the prevention concepts. In analytic models examining predictors of school-level exposure, a higher proportion of student population trained as PLs and greater retention of PLs predicted higher population exposure to the prevention program, congruent with diffusion of innovations theory, whereas frequency of meetings did not.Identified an efficient method (derived from the SIC) for assessing a school's success in preparing/retaining peer leaders. This approach shows promise in providing schools actionable data to increase impact of peer-led programs.NIH R01MH091452.


Although the in vivo anti-tumor efficacy of cannabinoids is mimicked in continuously cultured cancer cells in vitro, cannabinoid potency for direct elicitation of apoptosis in cancer cells is far lower, indicating that other mechanisms (perhaps other cell types within the tumor) are involved in vivo. We have recently obtained evidence that: 1) CB2 agonists mediate inhibition of primary tumor growth and metastasis in vivo, 2) significant infiltration of TAMs occurs within the developing tumor in this murine model, 3) administration of a CB2 agonist increases populations of pro-inflammatory M1 macrophages  in both the primary tumor and in the spleen of tumor bearing mice, and 4) a concurrent increase in the proportion of CD8+ cytotoxic T lymphocytes is also observed within the primary tumor upon CB2 agonist treatment.In human breast cancers, tumor infiltration by tumor associated macrophages (TAMs) correlates with multiple markers of poor prognosis: higher tumor macrophage counts are associated with higher tumor grade, higher tumor vascular density, and reduced overall survival. TAMs sesentation. Recent


Acute aortic dissection is the most common life-threatening vascular disease, with sudden onset of severe pain and a high fatality rate. Clarifying the detailed mechanism for aortic dissection is of great significance for establishing effective pharmacotherapy for this high mortality disease. In the present study, we evaluated the influence of biomechanical stretch, which mimics an acute rise in blood pressure using an experimental apparatus of stretching loads in vitro, on rat aortic smooth muscle cell (RASMC) death. Then, we examined the effects of azelnidipine and mitogen-activated protein kinase inhibitors on mechanical stretch-induced RASMC death. The major findings of the present study are as follows: (1) cyclic mechanical stretch on RASMC caused cell death in a time-dependent manner up to 4 h; (2) cyclic mechanical stretch on RASMC induced c-Jun N-terminal kinase (JNK) and p38 activation with peaks at 10 min; (3) azelnidipine inhibited RASMC death in a concentration-dependent manner as well as inhibited JNK and p38 activation by mechanical stretch; and (4) SP600125 (a JNK inhibitor) and SB203580 (a p38 inhibitor) protected against stretch-induced RASMC death; (5) Antioxidants, diphenylene iodonium and tempol failed to inhibit stretch-induced RASMC death. On the basis of the above findings, we propose a possible mechanism where an acute rise in blood pressure increases biomechanical stress on the arterial walls, which induces RASMC death, and thus, may lead to aortic dissection. Azelnidipine may be used as a pharmacotherapeutic agent for prevention of aortic dissection independent of its blood pressure lowering effect. With the rapid progress of population aging in most developed countries, the number of patients with atherosclerosis has remarkably increased; this is becoming an extremely serious problem requiring urgent attention It is well recognized that aortic dissection occurs when a small tear generated in the inner aortic wall extends along the wall of the aorta and causes blood to flow between the layers of the tunica media and adventitia of the aorta, forcing the layers apart. Despite the pathophysiological interpretation, the detailed mechanism for aortic dissection still remains unclear. Various efforts have been recently made to clarify the possible reasons for aortic dissection. Collins et al. reported that progressive loss of smooth muscle cells is observed in the specimens of acute aortic dissection characterized by aortic medial degeneration Azelnidipine has been approved for the treatment of patients with hypertension and is extensively used in developed countries In the present study, we used an experimental apparatus of stretching loads in vitro that can simulate sudden increases of blood pressure and observed RASMC death induced by biomechanical stretch. Furthermore, we investigated whether azelnidipine inhibited stretch-induced VSMC death. The effect of azelnidipine on changes in intracellular signaling by biomechanical stretch was also examined to provide a possible mechanism by which azelnidipine may be used as a pharmacotherapeutic agent for the prevention of aortic dissection independent of its blood pressure lowering effect.The study design was approved by an ethics review board of guidelines for the use of laboratory animals of Nara Medical University (No. 11011) and this study conducted in accordance with the guide for the Care and Use of Laboratory Animals as adopted and promulgated by the United States National Institutes of Health.2 in a humidified incubator. RASMCs were used for experiments between the third and sixth passages. The cells were cultured in collagen I-coated (70 µg/cm2) silicon chambers . When the cell confluency in culture was estimated to be 70–80%, the medium was replaced with unsupplemented DMEM. The cells were further cultured for 24 h and then subjected to cyclic mechanical stretch  for a given time period using the computer-controlled mechanical Strain Unit . After cyclic stretch, the medium was replaced with DMEM-containing 0.1% FBS. For western blot analysis, a portion of the RASMCs were lysed immediately after stretch stimulation and lysate proteins were collected in the manner described earlier RASMCs were isolated from the thoracic aorta of 8-week-old male Sprague–Dawley rats by enzymatic digestion, as previously described Materials were purchased from Wako (Kyoto) or Nacalai Tesque (Kyoto) unless stated otherwise. Azelnidipine (CS905) was from Daiichi Sankyo, Inc (Osaka). The antibodies used for western blot analyses were as follows: anti-phospho-SAPK/JNK (Thr183/Tyr185) antibody and anti-phospho-p38 MAP kinase (Thr180/Tyr182) antibody were purchased from Cell Signaling Technology, while ECL and ECL plus systems were purchased from GE Healthcare. Collagen I was purchased from Nippon Meat Packers, Inc. (Osaka). All chemical compounds were dissolved in dimethyl sulfoxide (DMSO) at final concentration less than 1% except for special notification.t-test was used to determine significant differences in multiple comparisons. A P value<0.05 was considered to be significant.All experimental values were expressed as mean ± standard deviation. Analysis of variance along with subsequent Student’s The effect of cyclic mechanical stretch on the viability of RASMCs was firstly examined by measuring MTT reduction and LDH released. The effects of cyclic mechanical stretch on the activation of JNK and p38 (members of MAP kinases family proteins) were assessed by western blot analysis . RASMCs In order to clarify the possible mechanisms of how cyclic mechanical stretch influences cell death, the following two experiments were undertaken.The effects of azelnidipine on cyclic mechanical stretch-induced activation of JNK and p38 in RASMCs were firstly examined and the results are shown in It has been reported that azelnidipine has the effects of anti-inflammation and antioxidant in mouse aneurysmal models The major findings of the present study are as follows: (1) cyclic mechanical stretch of RASMC caused cell death in a time-dependent manner up to 4 h; (2) cyclic mechanical stretch of RASMCs induced JNK and p38 activation with peaks at 10 min; (3) azelnidipine, a calcium channel blocker, inhibited the activation of JNK and p38 by cyclic mechanical stretch in a concentration-dependent manner; and (4) azelnidipine and JNK or p38 inhibitors protected against stretch-induced RASMC death; (5) Antioxidants, DPI and tempol failed to inhibit stretch-induced RASMC death.In this work, we recall the assumption that acute biomechanical stretch applied to cultured VSMCs in vitro simulating a sudden increase in blood pressure resulted in VSMC death that led to aortic dissection. As shown in Azelnidipine is a calcium channel antagonist (blocker) that has been applied extensively to the treatment of patients with hypertension all over the world. In the present study, we found that azelnidipine inhibited RASMC death induced by cyclic mechanical stretch . Under tAmong MAP kinases, JNK and p38 were recognized to be related to cell death or apoptosis We have reported in the previous study that p38 and JNK are oxidative stress sensitive In conclusion, azelnidipine inhibited RASMC death induced by acute cyclic mechanical stretch (originating from a simulated increase in blood pressure in vitro). JNK and p38 in RASMCs were activated by cyclic mechanical stretch; however, the activation was inhibited by azelnidipine. Similar to azelnidipine, pharmacological inhibition of JNK and p38 activation by mechanical stretch suppressed cyclic mechanical stretch-induced RASMC death. It is expected that the mechanism of acute aortic dissection will be clarified from further study of the fate of VSMCs by acute cyclic mechanical stretch. Azelnidipine may be an alternative candidate for prevention of acute aortic dissection independent of its blood pressure lowering effect.


PGR, ABCB1, ABCG2, GSTT1, GSTM1, GSTP1, ATM, TP53 and ATP7B genes. Ten genetic modifications were significantly associated with the risk of developing ovarian carcinoma in at least one of the groups under study. PGR gene polymorphisms’ impact on ovarian cancer risk was specific only for the group of the BRCA1 mutation carriers, which proves the difference in the modulation of ovarian cancer risk between sporadic and hereditary malignancies, including the breast-ovarian cancer group (as a cancer-prone group). The analyses showed also the importance of ATP7B gene in ovarian carcinogenesis, both studied variants of which significantly modulated the ovarian cancer risk in three out of four groups. Cumulative risk analysis revealed 3 unfavorable variants that significantly increased the risk of developing ovarian cancer, and also two favorable genotypes which protected against ovarian cancer.Single nucleotide polymorphisms modulate the risk of developing ovarian cancer during lifetime. In this study we analyzed 12 polymorphic variants and 2 deletions in Survival analysis for carriers of favorable versus unfavorable genotypes emphasized the importance of regulation of the cell cycle and active transport of xenobiotics during paclitaxel/cisplatin chemotherapy. The unfavorable variants could facilitate carcinogenic process and once their carriers developed malignancy, their chances of survival were smaller. Our analyses also showed a strong gene-dosage effect with the decrease of progression-free survival for the carriers of two unfavorable genetic factors.


Scientific Reports5: Article number: 1007210.1038/srep10072; published online: 07082015; updated: 08262015The Acknowledgements section in this Article is incomplete.“RM acknowledges the Academy of Finland for support within the FiDiPro scheme.”should read:“RM acknowledges the Academy of Finland for support within the FiDiPro scheme. We acknowledge financial support of the Deutsche Forschungsgemeinschaft (DFG) and the Open Access Publication Fund of the University of Potsdam.”


Hemorrhage in association with microvascular obstruction (MVO) is a new independent predictor of adverse remodeling following acute myocardial infarction (AMI), occurring in ~35% of patients presenting with STEMI , 2. HoweMyocardial hemorrhage was induced in a porcine model of AMI by direct intracoronary injection of collagenase (col) . AnimalsAt day 1, low T2* values in the infarct region confirmed the presence of myocardial hemorrhage in the collagenase groups 2 and 3  whereas group 1 was non-hemorrhagic. Infarct size was significantly greater in group 3 compared to group 1 at all time points  beyond the effects of the initial ischemic insult. Thus, hemorrhage actively contributes to the tissue remodeling processes during infarct healing. A mechanistic view of the consequences of hemorrhage post-AMI will potentially lead to better management and care of the high-risk STEMI patient population.We acknowledge funding support from the Heart & Stroke Foundation of Canada, GIA award #000334, and the D+H Sunnybrook Research Institute (SRI) Summer Student Program.


Efficient neutralization of HIV is a primary goal both for therapeutic and prophylactic HIV vaccines based on induction of neutralizing antibodies (NAbs) , 2. NeutAnti-HIV IgG antibodies 2F5 and 2G12, switched back to IgM isotype, showed increased avidity and neutralization efficacy . It woulin vivo in a highly specific way either by secondary immunization with protein antigens or in response to immunization with the newly formed ICs (Rheumatoid factor (RF) is an autoantibody which specifically binds Fc region of IgG , 11. Aparmed ICs , 11. Newrmed ICs .The level of RF was significantly higher in some of HIV-infected individuals compared to control groups –22. RFs in vivo? Measurements of RF level both in long-term non-progressors Can neutralization-enhancing RF antibodies (NeRFa) be induced after repeated immunization of humans with recombinant gp120 glycoprotein?(ii)Will the power of gp120 immunogen design –31 combi(iii)Could NeRFa help to improve the efficacy of previous  and futu(iv)Might induction of NeRFa be a future promising method not only against malaria as suggested in Ref. , but alsStudies , 17 haveRepeated immunization with gp120 glycoprotein might lead to prolonged induction of neutralization-enhancing RF antibodies with a potential to be explored for finding the ways to extend lives of HIV-infected individuals and to stop current HIV pandemic.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In the United Kingdom (UK), major trauma networks became operational in April 2012. Based at Queen Elizabeth Hospital Birmingham (QEHB), supported by the Ministry of Defence and University of Birmingham, the National Institute of Health Research Surgical Reconstruction and Microbiological Research Centre (SRMRC) is one of the few 24/7 UK trauma research centres. Having demonstrated success in delivering time critical studies, collaboration with West Midlands Ambulance Service (WMAS) has resulted in transferring research to the scene of injury, demonstrated by the success of The Brain Biomarker After Trauma Study, ‘Golden-Hour.’Specialist WMAS staff supported by the Midlands Air Ambulance were trained for ‘Golden-Hour’ enrolling patients with a traumatic brain injury (TBI) or an Injury Severity Score (ISS)>8. Operating Procedures and consumable packs were developed allowing sampling without delaying patient care. Blood samples obtained by WMAS within one hour of injury are passed at handover to QEHB for processing. A 24/7 research team based at QEHB ensure support and sample transfer from WMAS and are responsible for consequent sampling and consenting.Introducing a 24/7 SRMRC team into both pre-hospital and hospital settings has swiftly embedded research into routine trauma care. Whilst ‘Golden-Hour’ continues, enrolment remains ahead of predicted target with over 500 samples collected and recruitment continues to improve rapidly as WMAS staff become familiar with the protocol. The study has proved the concept allowing future collaboration and grant applications, potentially resulting in further innovations for the under-researched trauma population.Delivering research pre-hospital within one hour of injury requires a highly motivated team but is achievable. Effective integration between pre-hospital and research teams are paramount for any study to succeed. As trauma care evolves and research infrastructures within trauma networks improve, there is vast potential for further engagement with the goal of delivering evidence based pre-hospital trauma care.


We report the complete sequences of two West Nile virus strains (FDA-Hu02 and NY99) used for the formulation of CBER/FDA RNA reference reagents and lot release panels for use with nucleic acid technology testing. Flavivirus, family Flaviviridae) is the most widely extended arbovirus in the world. WNV transmission involves a bird-mosquito enzootic cycle that can infect humans, horses, and other vertebrates who act mainly as dead-end hosts. WNV appeared for the first time in the Americas in the United States in 1999 and since then it has disseminated extensively within the country and also to other countries on the continent (West Nile virus (WNV)  and NY99 (obtained from an infected flamingo in 1999). Cell culture supernatants from the second passage of the NY99 strain and third passage of the FDA-Hu02 strain in Vero cells were used for total RNA extraction using the QIAamp Viral RNA minikit (Qiagen). Reverse transcription reactions, PCR amplification, sequencing of overlapping PCR products, and sequence analysis were performed as described previously .The total lengths of the genomes of the WNV NY99 and FDA-Hu02 strains are 11,029 and 11,030 nucleotides (nt), respectively. The isolate FDA-Hu02 showed 20 nucleotide mutations plus one insertion at position 10,497 compared to prototype NY99; 5 mutations resulted in amino acid substitutions. We found no differences between the nucleotide sequences of the original NY99 isolate (AF196835) and the NY99 isolate cultivated and sequenced in our laboratory. Phylogenetic analysis classified FDA-Hu02 as belonging to genotype WN02, whereas strain NY99 is the prototype of the NY99 genotype (AY646354 and KM083619, respectively.The complete sequence of the WNV strains FDA-Hu02 and NY99 have been submitted to the GenBank under the accession numbers


Cardiovascular magnetic resonance (CMR) has expanded its role in the diagnosis and management of congenital heart disease and acquired heart disease in children. However, there are limited studies evaluating the role of cardiac magnetic resonance in delineating the anatomy of coronary arteries along with assessment of first pass myocardial perfusion in children. The purpose of this study is to evaluate the extensive use of CMR for delineating coronary anatomy, evaluating first pass myocardial perfusion and late gadolinium enhancement in children with acquired and congenital heart disease.Retrospective review of 37 consecutive CMR Whole Heart T2 Prep coronary angiography studies of patients with congenital and acquired heart disease. The subjects had CMR from December, 2013 to September, 2014. Results of first pass myocardial perfusion study (at rest and with adenosine stress) and myocardial inversion recovery for delayed myocardial enhancement imaging were also reviewed.The median age at the time of CMR was 11 years with range of 3 months to 25 years; 26 male and 11 female subjects. The origins and proximal course of coronary were well demonstrated by CMR in 92% (34/37) of the cases. Five patients (13.5%) had multiple coronary artery aneurysms related to Kawasaki disease (Cardiac magnetic resonance imaging can reliably evaluate the coronary anatomy, first pass myocardial perfusion defect and myocardial scar in diverse group of children with acquired and congenital heart diseases.None.


Obesity is a risk factor for cardiovascular disease and mortality. Studies in both obese humans and murine models of obesity have identified changes in left ventricular (LV) mechanics , which manifest prior to global changes in cardiac function (ejection fraction) and may represent early markers of cardiovascular disease. These data are generally acquired under resting conditions, which could mask subtle differences in the early stages of disease. We sought to evaluate LV mechanics under inotropic stress conditions with the hypothesis that mechanical deficiencies with obesity would be exacerbated under stress conditions and revealed at earlier stages of disease.C57BL/6J mice were randomized to either a high-fat or control diet  for varying time intervals (n=7-10 subjects per group per time point). At each interval, LV mechanics were quantified under baseline (resting) and stress conditions (40 µg/kg/min continuous infusion of dobutamine) using cine displacement encoding with stimulated echoes (DENSE) on a 7T Bruker ClinScan. Three short-axis and 1-2 long-axis slices were acquired with 11-20 frames per cardiac cycle. Peak strain, systolic strain rates, and torsion were quantified. A linear mixed model was used to compare interactions between time and group with Benjamini-Hochberg adjustments for multiple comparisons.Under rest conditions, reductions in LV peak strains Fig  were obsDifferences in left ventricular mechanics in obese mice are exacerbated under inotropic stress conditions. Compared to evaluation at rest, stress CMR demonstrated a broader array of mechanical dysfunction (changes in systolic strain rates and torsion in addition to peak strains) and revealed these differences at earlier time points (16-22 vs. 42 weeks). A deficit in circumferential peak systolic strain rate at peak stress was the earliest observed marker of obesity-induced ventricular dysfunction. Thus, it may be important to evaluate cardiac function in the setting of obesity under stress conditions in order to fully elucidate the presence of ventricular dysfunction.This work was supported by a Ruth L. Kirschstein National Research Service Award (T32 HL91812); an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the NIH (P20 GM103527); the University of Kentucky Cardiovascular Research Center; the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health (UL1TR000117). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding sources.


Individuals with short bowel syndrome (SBS) have reduced intestinal absorptive capacity and many require home parenteral nutrition (PN) support. One of the common causes of SBS is secondary to intestinal resections in the management of Crohn’s disease (CD). Complication rates and survival in SBS secondary to CD on PN versus other etiologies remains unknown.To determine whether patients with SBS secondary to CD versus SBS secondary to other etiologies on home PN, have increased risk of hospitalizations and complications including central line associated bloodstream infection (CLABSI) and venous thromboembolism and whether there is a difference in overall survival between groups.This is a multicentre prospective cohort study using the Canadian Home Parenteral Nutrition (HPN) Registry on individuals with defined SBS separated into two cohorts: 1) Patients with SBS secondary to Crohn’s disease vs. 2) Patients with SBS secondary to other aetiologies . Patient characteristics and clinical factors are presented as mean (standard deviation) for continuous variables and as frequency (percentage) for categorical variables. Comparison between groups (SBS CD vs SBS other) were performed using 2-sample t-test for continuous variables and Chi-square or Fisher exact tests when appropriate for categorical variable. Survival probabilities will be estimated using the Kaplan-Meier method.The study included a total of 379 patients with short bowel syndrome on home PN. There are 170 (45%) patients with SBS secondary to CD and 209 (55%) patients with SBS from other secondary causes. The average age of those with CD is 52 and 65% female patients. The average age of those with other causes of SBS is 56 with similar percentage of female patients (65%). There were significant differences in baseline medications with higher use of immunosuppressant therapy  in those with CD. There was no significant difference in total number of hospitalizations, hospitalizations related to PN and CLABSI.Individuals with SBS secondary to CD do not appear to be at increased risk of central line infections or hospitalizations compared those with SBS from other causes.NoneNone Declared


A decrease in SUV max of more than 60% in the primary tumour was identified as optimal cut-off value for predicting major pathological response and performed better than computed tomography morphologic partial response measured by a size reduction of the primary tumour of more than 30%. The same result was observed for prediction of prognosis.The authors must be congratulated on systematically assessing the role of fluorodeoxyglucose-positron emission tomography and computed tomography in predicting pathological response and prognosis of locally advanced non-small cell lung cancer (NSCLC) after neoadjuvant chemoradiotherapy . IntegraRelevant differences were identified for the subgroup of T3-4N0-1 patients compared to N2 positive patients and a decrease of <60% of SUVmax was found as an indicator of poor prognosis, particularly in N2 patients. The analysis was focused on metabolic and imaging response in the primary tumour, whereas lymph node status was analysed pathologically.Previous analyses of well-designed prospective trials looking at pre-treatment metabolic tumour volume only showed conflicting results on the impact on 5-year survival rates , whereasIn the current treatment landscape, the presented data will be challenged by several issues. Particularly, the details of pathologic reporting after neoadjuvant treatment are crucial to ensure comparability of trials. In 2020, the ‘International Association for the Study of Lung Cancer’ (IASLC) has reported a multidisciplinary recommendation for pathologic assessment of lung cancer resection specimens after neoadjuvant treatment . The autThe integration of immunotherapy in neoadjuvant treatment algorithms  will leaIn summary, innovative neoadjuvant combination schemes have the potential to substantially change staging algorithms in NSCLC. The paper by Tanahashi and colleagues provides relevant confirmatory reference data on the impact of metabolic response on pathologic response rates and 5-year survival rates after neoadjuvant chemoradiation therapy.


Recent events in the world, wars, pandemics, have once again raised the issue of the need for competent human resources in global public health (GPH). In Georgia, there are master’s degree programs in public health where global health is mostly offered as an elective or core course of the curriculum. University of Georgia (UG) is involved in the ERASMUS + project in GPH (BACE). UG initiated to create new GPH Master Program, which will be response towards local, regional and international challenges and demand.Main objective of developing GPH program was to address and meet national and international global health education needs and challenges. The aim of the study was to identify evidence-based prerequisites for the MPH in GPH (UG). We conducting document review based on the GPH competency model (GPHCM) and evaluated: 1) GPH & MPH programs of the top 20 world university ranking (THE/2022); 2) CUGH associated programs; 3) Georgian MPH programs; 4) Georgian education documents ); 5) Main directions of career development in global health. In addition, interviews with national experts were conducted  using the Delph method.Study found that depending on the scope and content of the program, prerequisites for obtaining MPH in GPH varies. In addition to English competence and a high GPA, working or research experience or interviews or additional exams or other are required. In Georgia, there is no adopted GPHCM, but GNQF allows the establishment of MPH in GPH. UG new Master program (120 ECTS) will include 99 ECTS core (including research practicum & thesis) and 21 ECTS elective courses based on 6 domains of GPHCM. The program will mostly focus on population health management at a global level.Study findings suggest any undergraduates with appropriate conditions could be eligible for admission to the UG (MPH in GPH).• UG admission prerequisites for Health Science undergraduates: National entrance exam, English proficiency B2, working experience and motivation letter.• UG additionally admission prerequisites for Health Science undergraduates: basic knowledge epidemiology and medical terminology (if credits available or test).


Pregabalin is an analogue of gamma-aminobutyric acid (GABA). Recent reports suggest illicit pregabalin use may be increasing among youth, however its addictive potential has not been well established (1).Drug seeking behavior and chronic drug use are associated with defcits in glutamate clearance and activation of postsynaptic glutamatergic receptors (2). Based upon multiple studies, we compare here the addiction and misuse risks of pregabalin with those of traditional psychoactive substances (3).Users of pregabalin were identified from 1st January 2019 to 31 December 2019 in Oran Addictology service, at west Algeria. The aim of the study was to establish the addictive potential of pregabalin and to compare the addiction risks of pregabalin with traditional psychoactive substances in west Algerian population. Clinical diagnosis was established according DSM-5 diagnosis criteria.A total of 92 cases of pregabalin abuse or dependence were identified. The principal population at risk consists of patients with other current or past substance use disorders, for the most part opioid and multi-drug users, the age group were between 17-38 years old, mostly single men. The mean daily dose of pregabalin was 1200 mg. Almost all patients experienced withdrawal symptoms when pregabalin was discontinued.The misuse of pregabalin often leads to abuse and dependence, mostly in the context of multiple drug addiction, especially in youth population.


Currently, Buprenorphine maintenance therapy (BMT) is an evidence-based treatment in retaining patients who are dependent on opioids. However, factors influencing retention are often measured objectively. Studies on patient’s perspectives on take home BMT in developing countries are limited.This study examines the potential factors influencing treatment compliance in the early phase of Buprenorphine maintenance treatment from the patient’s perspectiveParticipants (n=89) who were initiated on BMT were recruited and followed after six weeks. A semi-structured interview was conducted with 62 patients who remained in treatment and 24 patients who dropped out of the studyBased on the semi qualitative analysis some of the factors which facilitated the patient’s retention in treatment were: (1) Effectiveness in blocking withdrawal symptoms (2) effectiveness in reducing their cravings and controlling their opioid use (3) decreased fear of withdrawal and/or missing doses(4) improvement in the quality of life(5) patient-related factors like family support (6) effectiveness of the treatment program. Around nine percent of patients reported family support as the reason for retention, which is not noticed in other studies. Barriers reported by the patients while on medication were: (1) negative effect experienced with medication (2) program related difficulties like distance, unavailability (3) major life event interrupting the treatment (4) patient-related factors like low mood, financial constraints.Understanding factors associated with barriers to treatment provide insights into preventable factors that contribute to premature drop out from BMT and to improve clinical practice, policy decisions, or future research.


Interactions between genetic and environmental risk factors (GxE) contribute to an increased risk of venous thromboembolism (VTE). Understanding how these factors interact provides insight for the early identification of at-risk groups within a population and creates an opportunity to apply appropriate preventive and curative measures.To estimate and compare GxE for VTE risk in the general Hungarian and Roma populations.The study was based on data extracted from a database consisting the results obtained previously in a three pillars complex health survey. DNA was genotyped for rs121909567 (SERPINC1), rs1799963 (F2), rs2036914 (F11), rs2066865 (FGG), rs6025 (F5), and rs8176719 (ABO) polymorphisms. Multivariable linear regression analysis was applied to test the impact of GxE on VTE risk.Interestingly, the rs121909567 (SERPINC1) SNP was not present in the general population, however the risk allele frequency was 1.4% among Roma, which might suggest a founder effect in this minority. The risk of VTE was higher among depressive Roma subjects who carried the risk variant of rs2036914 ; however, not for the general subjects. The joint presence of high level of LDL-C and rs2066865 increased the VTE risk only among Roma . A multiplicative interaction between rs8176719 and cancer was identified and higher for the Roma population . The VTE risk increased in the Roma population  but was higher in the general population  as a result of the multiplicative interaction between CAD and rs2036914 (F11).rs121909567 (SERPINC1) was confirmed as a founder mutation in the Roma population. As a result of higher genetic load and GxE interactions, the minority Roma population is at higher risk of VTE than the general Hungarian population.• Our study revealed some evidence on the burden of the joint presence of genetic and environmental risk factors on VTE.• A marginalized and segregated Roma community could need due attention for the prevention and control of CVDs.


Oculo-auriculo-vertebral spectrum (OAVS) is a rare condition characterized by the involvement of the first branchial arches.To investigate the ear abnormalities of a sample of patients with OAVS.The sample consisted of 12 patients with OAVS seen at the Clinical Genetics Unit, UFCSPA/CHSCPA. The study included only patients who underwent mastoid computed tomography and with normal karyotype. We performed a review of its clinical features, giving emphasis to the ear findings.Nine patients were male, the ages ranged from 1 day to 17 years. Ear abnormalities were observed in all patients and involved the external (n=12), middle (n=10) and inner ear (n=3). Microtia was the most frequent finding (n=12). The most common abnormalities of the middle ear were: opacification (n=2), displacement (n=2) and malformation of the ossicular chain. Agenesis of the internal auditory canal (n=2) was the most frequent alteration of the inner ear.Ear abnormalities are variable in patients with OAVS and often there is no correlation between findings in the external, middle and inner ear. The evaluation of these structures is important in the management of individuals with OAVS. Branchial arch disorders comprise several developmental anomalies including the oculo-auriculo-vertebral spectrum (OAVS), also known as Goldenhar's syndrome, or hemifacial microsomy OMIM 164210)2104, 5, The origin of the OAVS is unclear, but it is a complex and heterogeneous condition. Two pathophysiologic mechanisms have been proposed for the OAVS: a reduced blood flow, and focal hemorrhage in the development region of the first and second branchial arches around 30 to 45 days of pregnancy, in the blastogenesis periodAlthough external ear anomalies have been described in OAVS patients - to the point of being inclusion criteria - middle and especially inner ear alterations have received little attention in the literatureThe sample comprised 12 patients with the OAVS seen at the Clinical Genetics Unit, UFCSPA/CHSCPA. The inclusion criteria were alterations in at least two of the following bodily regions: oro-cranial-facial, ocular, auricular, and vertebral, according to Strömland et al.'s criteria (2007)p<0.05 were considered statistically significant. The institutional review board approved this study (Opinion no. 581/08 of 25/01/2008).The registries of patients were reviewed to gather clinical data and the results of diagnostic tests . Fisher's exact test (bicaudate) was applied to compare the frequencies were found. The software was the PEPI program. Values of There were 9 male and 3 female subjects. The ages at the first visit ranged from 1 day to 17 years (10 were aged 1 year or less). Most of these patients were referred from the pediatrics unit (n= 7); two others were referred from the plastic surgery unit, one from the cardiology unit, one from the otorhinolaryngology unit, and one from the pediatric surgery unit. Eight subjects had two of the inclusion criteria, three subjects had three, and one had four. All subjects had ear anomalies, affecting the external ear n= 12), the middle ear (n= 8), and the inner ear (n= 3). Microtia was the most frequent finding - it was observed in all cases (ranging from grades I to IV). It was mostly unilateral, to the left, and grade III. Four patients had bilateral microtia (33%). The most common middle ear anomaly was opacification (n= 2), and displaced (n= 2) and malformed ossicular chains (n= 2). Agenesis of the inner ear canal (n= 2) was the most frequent inner ear anomaly. The most common finding in the temporal bone was a non-aerated mastoid (n= 5). Additional alterations in other organs or systems consisted of low height (n=4), craniofacial anomalies (n= 11), ophthalmologic anomalies (n= 2), esophageal/ pulmonary anomalies (n= 6), cardiac anomalies (n= 7), abdominal anomalies (n= 4), skeletal anomalies (n= 6), and cerebral anomalies (n= 5) , the mid.Figure 1External ear malformations in OAVS patients ranged from slightly dysmorphic to absent ears (or anotia - the most severe form of microtia)Because the ossicles of the ear develop from the dorsolateral terminations of the cartilage in the first (Meckel's cartilage) and second (Reichert's cartilage) branchial arches, anomalies of these structures are often found in the OAVS. Anomalies in the stapedial and tympanic tensor muscle suggest that these structures originate from the first and second branchial archesAlthough external middle ear anomalies are well known, inner ear alterations are rarely observed; these anomalies vary widely and range from mild to severePoorly pneumatized mastoid antrumEnlarged cartilaginous portion of the Eustachian tube lumen and absence of the cartilaginous lateral lamina of the Eustachian tubeLengthened mastoid antrumPreauricular appendages and pitsEar anomaliesAtresia/stenosis of the outer ear canalUndeveloped tympanic membraneMicrotia/anotiaIncomplete development of the tympanic cavityImmature and malformed ear ossiclesAbsent oval and round windowAbsence of the tympanic tensor muscleAbnormal path of the facial nerve and absence of the chorda tympani nerveDistorted and hypoplasic cochleaAbsence of the cochlear aqueductImmature vestibular system and absence/fusion of semicircular canalsDisplaced endolymphatic ductWidened vestibular aqueductAbsent/abnormally coursing facial nerve canalSmall, wide, and/or duplicated inner ear canalAgenesis of the inner ear canalDuplicated inner ear canalThe frequency of these anomalies in our sample (25%) was similar to previously reported rates (27% to 36%)As mentioned above, the most frequently reported ear anomalies in the OAVS are external and middle ear abnormalities. Thus, secondary conductive hearing loss predominates in these patientsSurgery is difficult because of the complexity of this condition and the number of factors that may affect the outcome of surgical therapy. On the other hand, hearing loss is generally unilateral in the OAVS; the majority of patients develop speech, and their level of hearing enables them to be socially active. However, patients with bilateral mixed profound hearing loss or pure sensorineural hearing loss required more advanced forms of treatment, such as cochlear implants or bone anchored hearing aidsEar anomalies are frequent and varied in OAVS patients; often there is no correlation among external, middle, and inner ear findings. Therefore, it is important to assess these structures using radiologic methods (such as computed tomography of the mastoid) when managing patients with OAVS.


Autoimmune diseases of central nervous system (CNS) are wide spread in children. In some cases, mental disturbances in such patients are barely noticeable in the beginning, which hinders early detection of risks in the child’s mental development.The study focuses on comparative analysis of the structure of mental disorders in pediatric patients with autoimmune diseases of CNS.Research includes two cases: girls aged 14 and 16, one with acute disseminated encephalomyelitis (ADEM), disease onset at 4 years and 11 months, and another with multiple sclerosis (MS), disease onset at 5 years and 5 months. The following methods were used: analysis of patient’s medical record, interview with neurologists, pathopsychological assessment.Common features in both cases: 1) organic brain disorders; 2) patients do not demonstrate intellectual deterioration, can master regular school curriculum; 3) detected mental disturbances reflect risks for mental and personality development. Specific features: 1) the patient with MS demonstrates polymorphism of mental disorders, while the patient with ADEM — homogeneity of mental disorders; 2) main problems of the patient with MS are related to self-regulation, which makes the general picture similar to pseudo-frontal syndrome; the patient with ADEM has major neurodynamic disturbances, which has similarity to psychoorganic syndrome; 3) predictors of personality disorders detected in case of MS determine the negative prognosis for mental development.The delineated features evidence for further psychological study of CNS autoimmune diseases and formulation of criteria for clinical psychological assessment. These patients need to be monitored by psychologists to prevent personality disorders.No significant relationships.


Scientific Reportshttps://doi.org/10.1038/s41598-020-80366-2, published online 21 January 2021Correction to: The original version of this Article contained an error in the Methods section, regarding ethical approvals. The data of three patients included from Hino hospital were not covered by the original ethical approval, which read:“This study was approved by the institutional review board, and the requirement of written informed consent was waived because of the study’s retrospective design .”These patients provided their consent separately and an additional ethical approval was issued by the IRB of Hino Municipal Hospital. Additional information on the approval for study execution by the other participating centres was also included in the corrected version. The approval statement now reads:“This study was approved by the institutional review boards of Keio University School of Medicine Ethics Committee , National Hospital Organization Tokyo Medical Center , Saiseikai Utsunomiya Hospital , Japanese Red Cross Shizuoka Hospital , Inagi Municipal Hospital (dated 23/06/2020), Hiratsuka City Hospital , and Hino Municipal Hospital IRB (dated 24/03/2021). The requirement of written informed consent was waived because of the study’s retrospective design.”The original Article has been corrected.


Hydrocephalus is reported in approximately one-tenth of neurosarcoidosis patients. However, data on clinical characteristics and outcome are lacking. In this retrospective study, we present 11 patients with neurosarcoidosis and hydrocephalus on neuroimaging. Median age was 52 years and seven were female (64%). Presenting symptoms consisted of headache in 8 out of 11 (73%), vertigo in 5 (46%), gait abnormalities in 4 (36%), diplopia in 2 (18%) and decreased visual acuity in 1 (9%). Cranial imaging showed obstructive hydrocephalus in 10 (91%) and non-obstructive hydrocephalus in 1 (9%) out of 11, obstruction occurred at the level of the fourth ventricle in 6 out of 10 (60%). Treatment consisted of glucocorticoids in all the patients with additional methotrexate or azathioprine in 6 (55%) and infliximab in 1 (9%) patient. Neurosurgical intervention was performed in 10 out of 11 (91%) patients. Treatment led to remission, improvement or stabilization of disease in 9 out of 10 (90%) of patients. One patient died due to cerebral herniation despite neurosurgical decompression and CSF shunting. Median modified Rankin scale score at last follow-up was 2 (range 0–6). A systematic review and meta-analysis of studies on hydrocephalus due to neurosarcoidosis identified 36 patients that compared to our patients had a lower median age at onset and a higher mortality. Acute obstructive hydrocephalus due to neurosarcoidosis is a potentially fatal medical emergency requiring neurosurgical intervention and initiation of immunosuppressive therapy. If patients survive the initial phase, the outcome is generally favorable. Sarcoidosis is an inflammatory disorder that can involve multiple organ systems . InvolveWe retrospectively reviewed all case records from adult patients that were seen between June 2015 until June 2020 at the Neurology Department at the Amsterdam University Medical Centers a tertiary referral center for neurosarcoidosis. We included patients diagnosed with (1) neurosarcoidosis  and (2)Detailed history and neurological examination were retrieved from patient files in an electronic database including presenting symptoms, age of onset of symptoms, results of ancillary investigations and data on treatment and treatment response and outcome of hydrocephalus in neurosarcoidosis.A literature search was performed in PubMed using the following terms: (“sarcoidosis” [MeSH Terms] OR sarcoid* [tiab] OR "Neurosarcoidosis" [Supplementary Concept] OR neurosarcoid* [tiab]) AND . We included articles written in English describing one or more adult patients that were published in the last 25 years. The search was followed by a manual search in the reference lists of the publications found. The study conforms with the World Medical Association Declaration of Helsinki, 7th revision 2013 Fortaleza. Ethical approval is not required in the Netherlands for a retrospective study with anonymized patient data such as used in our study.Between June 2015 and June 2020, 303 patients were analyzed because of suspected neurological involvement of sarcoidosis at our outpatient department or clinical department. Of these, 153 patients (50%) were diagnosed with neurosarcoidosis  had a history of sarcoidosis of which one had a history of neurosarcoidosis-associated myelitis (9%) and three used immunosuppressive therapy at symptom onset. Presenting symptoms were headache in eight (73%), vertigo in five (46%), abnormal gait in four (36%), diplopia in two (18%) and decreased visual acuity in one patient (9%). Time from symptom onset of hydrocephalus-related symptoms to first neurological evaluation was 15 weeks (interquartile range 3–38). Abnormalities on neurological examination included nystagmus and impaired consciousness each in four (36%), papilledema and ataxia each in two (18%) and bilateral sixth nerve palsy in one patient (9%). Neurological examination showed no abnormalities in two patients (18%). Median time from onset of symptoms to diagnosis of neurosarcoidosis was 4 months (range 0–34). Other organ systems involved were lymph nodes in four patients (36%), lungs in three (27%) and eyes, liver and bones, respectively, in one patient.Serum angiotensin-converting enzyme (ACE) was analyzed in five patients and was elevated in none of them, soluble Interleukin 2 receptor (sIL-2R) was evaluated in two patients and was elevated in both. Cerebrospinal fluid (CSF) analysis was performed, commonly after external ventricular drain placement, in nine and showed an elevated leukocyte count in eight (89%) patients and elevated total protein in five (56%). One patient had a normal CSF analysis. CSF oligoclonal bands were present in the one patient in which they were tested.Results of cranial imaging were re-evaluated for all patients [ten magnetic resonance imaging (MRI) and one computed tomography (CT)] and showed hydrocephalus in all. The hydrocephalus was non-communicating/obstructive in ten patients and communicating in one. Obstruction was at the level of the fourth ventricle in six patients (60%), the foramen of Monro in three (30%) and the cerebral aqueduct in one 10%). In one patient, there was tonsillar herniation due to the obstruction hydrocephalus  was performed in seven patients with no history of sarcoidosis, and showed abnormalities suggestive of sarcoidosis in all of them. Biopsy was performed in all patients. Leptomeningeal biopsy was performed in one patient and showed non-caseating granulomas (definite neurosarcoidosis), lymph node biopsy was performed in eight patients and showed non-caseating granulomas in seven (probable neurosarcoidosis) and was inconclusive in one (possible neurosarcoidosis), in one patient liver biopsy was performed and showed non-caseating granulomas (probable neurosarcoidosis). In the patient with possible neurosarcoidosis, chest CT was highly suggestive of sarcoidosis.Fluor-18-deoxyglucose positron emission tomography (The median follow-up was 23.5 months (interquartile range 3–50 months). Immunosuppressive treatment was initiated in all 11 patients and consisted of corticosteroid pulse therapy in 7 (64%), corticosteroid maintenance therapy in 9 (82%) and second-line therapy, methotrexate or azathioprine, in 4 patients (36%). Neurosurgical intervention was performed in 10 out of 11 patients (91%) and consisted of external ventricular drain placement followed by ventriculoperitoneal shunt in 3 (30%), ventriculoperitoneal shunt in 5 (50%), ventriculostomy in 3 (30%) and cyst fenestration in 1 patient (10%). All but one patient were treated both with immunosuppressive agents as well as a neurosurgical intervention. Of these ten patients, three underwent neurosurgical intervention prior to immunosuppressive treatment, three received immunosuppressive treatment prior to neurosurgery and in four, neurosurgical and immunosuppressive treatments were initiated simultaneously. Medication was changed during follow-up due to insufficient response to initial therapy, side effects or a relapse of symptoms during follow-up in 5 out of 11 patients (45%). One patient had multiple relapses of symptoms. The relapse of symptoms of neurosarcoidosis was recurrence of hydrocephalus in four (80%) and meningitis without hydrocephalus and myelitis each in one patient (20%). Treatment changes included restarting or increasing the dosage of corticosteroid maintenance therapy in three (80%), corticosteroid pulse therapy in three (60%) and initiation of second-line therapy in five . Third-line therapy (infliximab) was started in one patient (20%). Two patients underwent a second neurosurgical intervention because of failure of CSF shunt or ventriculostomy.Neurological examination at the end of follow-up was available in ten patients and focal neurological deficits were present in only one patient and were attributable to sarcoidosis-associated myelitis. Outcome of neurosarcoidosis at last follow-up was classified as remission in two (18%), improvement in five (45%) and stable disease in three (27%). One patient (9%) died following cerebral herniation as a result of the hydrocephalus. Median modified Rankin scale (mRS) score at last follow-up was 2 (range 0–6).Literature review yielded 95 articles of which 46 were assessed for eligibility based on title and abstract. Of these articles, five consisted of case series of neurosarcoidosis patients that included patients with hydrocephalus but did not report clinical characteristic, ancillary investigations, treatment and outcome of this subgroup –42. The 18FDG-PET. These investigations can help ascertain a potential biopsy site outside of the central nervous system. Histopathological evidence of non-caseating granulomas is necessary for a diagnosis of probable or definite neurosarcoidosis [Our study shows that hydrocephalus is a rare but potentially fatal manifestation of neurosarcoidosis that requires a combination of neurosurgical intervention and immunosuppressive treatment. In the absence of a positive history of (neuro)sarcoidosis, the differential diagnosis of acquired hydrocephalus is diverse and includes among others inflammatory, (post-) infectious, (post-)hemorrhagic and (post-)traumatic disorders and intracranial tumors such as colloid cysts or malignancy , 43, 44.coidosis .Presenting symptoms of hydrocephalus in neurosarcoidosis are (sub)acute and related to increased intracranial pressure. Hydrocephalus in neurosarcoidosis is often non-communicating and caused by obstruction of the outflow from the fourth ventricle or of the cerebral aqueduct due to a chronic meningitis. Acute obstructive hydrocephalus can be fatal and an emergency neurosurgical intervention such as CSF shunting, ventriculostomy or decompression should be considered in all patients. Corticosteroid treatment in adjunct to neurosurgical intervention should be strongly considered in all patients. Intensification of immunosuppressive treatment is required in case of a relapse of symptoms, as a persistent or recurring granulomatous chronic meningitis can lead to an additional site of obstruction or shunt failure through obstruction of the CSF shunt . AlthougAs compared to our case series, the mortality was higher (9% versus 22%) and more patients had a diagnosis of definite neurosarcoidosis (10% versus 58%) in the review of the literature. The difference in mortality may be explained by publication bias as multiple articles reported on patients with sudden death. A previous review of the literature found an even higher mortality of 75% in patients with neurosarcoidosis who presented with seizures and had hydrocephalus . HoweverThis study has several limitations. First, patients evaluated were referred to our tertiary center. This may introduce selection bias leading to overestimation of the impact of hydrocephalus in neurosarcoidosis. Second, the retrospective design of our study resulted in heterogeneous assessment of disease activity as well as missing data in some patients. This prohibits drawing firm conclusions regarding outcome and treatment effect. Third, as mentioned above there might be publication bias regarding hydrocephalus in neurosarcoidosis. Nevertheless, our retrospective single-center cohort study and systematic review provides valuable information on a rare disease as hydrocephalus in neurosarcoidosis.In conclusion, hydrocephalus due to neurosarcoidosis is a medical emergency as onset is often (sub)acute and the hydrocephalus is obstructive in nature. Initiation of treatment should be prompt and include both neurosurgical interventions to lower intracranial pressure and immunosuppressive therapy to reduce granulomatous inflammation. If patients survive the initial phase outcome is generally favorable.


Broad-range metagenomic cell-free DNA testing (Karius®) can identify a variety of pathogens from a single blood sample to help in diagnosis of deep seated and bloodstream infections. Few studies have evaluated the impact of Karius testing on clinical decision making when compared to more conventional diagnostic methods.We performed a retrospective cohort study of adult patients who had Karius tests at University of Iowa Hospitals and Clinics between 01/2020 and 10/2021. Chart review was conducted to obtain patient characteristics and clinical course including patient age, immunocompromising conditions, involvement of Infectious Disease (ID) consultant, reason for the test, and final diagnosis. Results of the Karius tests and conventional tests were compared for concordance. Clinical impact and change in management due to Karius testing were determined using previously established criteria outlined by Hogan et al.:239-245)Out of 26 patients who had Karius testing, 20 patients (77%) had an immunocompromising condition, the most common of which was hematologic malignancy . Twenty-four patients (92%) had received a formal ID consultation prior to the test. The most common finding prior to testing was the presence of pulmonary infiltrates on imaging . Karius testing was positive in 18/26 cases (69%). Organisms detected by Karius and conventional testing were concordant in 9/18 cases (50%). Karius test result had a positive clinical impact in 3 cases (12%), an indeterminant impact in 1 case (3%) and no impact in 22 cases (85%). Reasons for a positive impact are as follows: 1 case with initiation of antituberculosis therapy due to earlier diagnosis of tuberculosis, 1 case with de-escalation of antifungal therapy based on negative Karius results, and 1 case of clearance for urgent lung transplantation based on negative Karius results in the setting of mobile echo density on echocardiogram in the absence of other stigmata of endocarditis.The impact of Karius testing on patient management appears limited. Further studies will be needed to identify patient populations or disease factors in which this testing have clinical impact.All Authors: No reported disclosures.


Death at home is preferred by most people and has become a key indicator of the end-of-life care quality; however cultural attitudes about death and dying may vary by race and ethnicity. This study describes racial and ethnic variation in place of death among Medicare beneficiaries aged 50 years and older who died in 2018 with a dementia diagnosis  and without a dementia diagnosis . Among those with dementia, 60% died at home, with the highest percentage for non-Hispanic white (62%) beneficiaries, followed by Black/African American (55%), Hispanic (61%), Asian American/Pacific Islander (58%), and American Indian/Alaska Native (58%) beneficiaries. Among those without dementia 61% died at home, with the highest percentage for non-Hispanic white (60%) beneficiaries, followed by Black (57%), Hispanic (65%), Asian American (65%), and American Indian (60%) beneficiaries. Among those who died at home, about half without dementia received hospice care compared to the majority with dementia.


Pre-fALS) study showing that an elevation in blood neurofilament light chain (NfL) precedes phenoconversion to clinically manifest disease. Tofersen is an investigational antisense oligonucleotide designed to reduce synthesis of superoxide dismutase 1 (SOD1) protein through degradation of SOD1 mRNA. Informed by Pre-fALS and the tofersen clinical development program, the ATLAS study (NCT04856982) is designed to evaluate the impact of initiating tofersen in presymptomatic carriers of SOD1 variants associated with high or complete penetrance and rapid disease progression who also have biomarker evidence of disease activity (elevated plasma NfL). The ATLAS study will investigate whether tofersen can delay the emergence of clinically manifest ALS. To our knowledge, ATLAS is the first interventional trial in presymptomatic ALS and has the potential to yield important insights into the design and conduct of presymptomatic trials, identification, and monitoring of at-risk individuals, and future treatment paradigms in ALS.Despite extensive research, amyotrophic lateral sclerosis (ALS) remains a progressive and invariably fatal neurodegenerative disease. Limited knowledge of the underlying causes of ALS has made it difficult to target upstream biological mechanisms of disease, and therapeutic interventions are usually administered relatively late in the course of disease. Genetic forms of ALS offer a unique opportunity for therapeutic development, as genetic associations may reveal potential insights into disease etiology. Genetic ALS may also be amenable to investigating earlier intervention given the possibility of identifying clinically presymptomatic, at-risk individuals with causative genetic variants. There is increasing evidence for a presymptomatic phase of ALS, with biomarker data from the Pre-Symptomatic Familial ALS (The online version contains supplementary material available at 10.1007/s13311-022-01237-4. Despite decades of research, there remains a significant unmet need for effective treatments for amyotrophic lateral sclerosis (ALS). The reasons are manifold, but two key considerations have emerged . First, SOD1) gene (SOD1-ALS) ., 24.Pre-The date of emergence of clinically manifest ALS will be defined as the date when the participant first experienced the relevant clinical symptom or, in the absence of symptoms, the date when neurological examination first detected evidence of UMN and/or LMN signs indicative of ALS, whichever is sooner.SOD1 genetic testing to determine or confirm their SOD1 variant. Recognizing the complexities of predictive genetic testing and the potential for emotional, psychosocial, legal, and financial implications [In the ATLAS study, participants undergo centralized ications , 29–31, SOD1 result and anticipating or learning about a NfL level increase, additional counseling is available as needed throughout the study. Genetic counseling will be performed by qualified individuals as per local standard clinical practice; acknowledging that exact qualifications for providing genetic counseling differs around the world [During screening for enrollment in Part A of the study, genetic counseling sessions are required before a DNA sample is collected for testing and at the time that the results are communicated. These sessions, which focus primarily on genetic testing, also include in-depth discussions about NfL — specifically, the uncertain but potential implications of above-threshold NfL levels for the risk of imminent clinical disease. Given the potential for continued psychosocial and emotional impact, especially after receiving a positive he world . In addiSOD1 variant genetic analysis results and their NfL levels — is paramount. If disclosed, positive SOD1 test results and elevated NfL levels could be used in discriminatory ways, with potential implications for both the study participant and their biological relatives in many spheres of life, including finances, insurance , eligibility for educational and recreational activities, family planning, and employment status [The protection of participants’ privacy — in particular, their t status , 33, 34.SOD1 variant carriers in the Pre-fALS study. The utility of this critical observation from the Pre-fALS study underscores the importance and value of high-quality natural history data in advancing therapy development for rare diseases [The ATLAS study incorporates unique design elements to evaluate whether presymptomatic initiation of tofersen can delay the emergence of clinically manifest ALS and/or reduce the loss of clinical function over time. ATLAS is the first interventional trial in ALS that uses neurofilament as an enrichment marker for study eligibility and a trigger for initiation of study treatment. The design of ATLAS was built upon the premise that elevations in NfL precede the emergence of clinically manifest ALS, as observed in rapidly progressive diseases .ATLAS has the potential to aid in the identification and understanding of early markers of disease activity beyond NfL. The collection of CSF (at baseline for Part A and prior to every dose in Parts B/C/D) and urine/blood  will enable the identification of other potential fluid markers of disease activity. Similarly, comprehensive electromyography (EMG) at screening for Part A and Part B may inform the timing of NfL elevation relative to the emergence of EMG abnormalities and the relative sensitivity of these two biomarkers. Through these biomarker assessments, ATLAS will help to inform the conduct of presymptomatic trials in other subsets of the ALS population.SOD1 variants is continuously evolving due to limited reporting and heterogeneity across carriers. To account for this, an independent Mutation Adjudication Committee was formed to adjudicate eligibility of non-protocol-defined SOD1 variants based on the most up-to-date information at the time. The use of clinically manifest ALS as a primary endpoint is not without challenges, given potential perverse incentive to receive open-label tofersen in Part C; it is for this reason that we have established an independent EAC to confirm the emergence of clinically manifest ALS.A list of variants associated with high/complete penetrance and rapid disease progression was defined in the protocol based on the totality of information ascertained in the literature, genetic databases, and clinical experience. However, characterization of Pre-fALS study, ATLAS aims to take into account two key considerations: (1) when and how participants are informed of their genetic risk, and (2) how participants’ privacy, especially regarding their SOD1 genetic variant and NfL biomarker status, can be protected. For both study sites and participants alike, education, training, and resources are essential to help address these concerns. Specifically, the ATLAS study has implemented genetic testing and counseling processes along with firewalls and strategies to protect participant privacy in the context of a clinical research study.Recognizing the potentially serious and life-long implications of positive genetic testing results on study participants and their families, the study also necessitated the development of a supportive infrastructure to inform, support, and protect prospective participants. Informed by experience from the SOD1 variants associated with high or complete penetrance and rapid disease progression who also have biomarker evidence of disease through elevated plasma NfL. Recognizing that therapeutic intervention in earlier phases of ALS has the potential to yield the greatest clinical benefit, ATLAS, together with data from the VALOR study and its open-label extension study, will inform the optimal timing of treatment initiation in SOD1-ALS. As the first interventional trial in presymptomatic ALS, ATLAS has the potential to yield important insights into the design and conduct of presymptomatic trials, identification, and monitoring of at-risk individuals, and future treatment paradigms in ALS and other neurodegenerative diseases.The ATLAS study (NCT04856982) is designed to evaluate the impact of initiating tofersen in presymptomatic carriers of Supplementary file1 (PDF 536 KB)Supplementary file2 (PDF 589 KB)Supplementary file3 (PDF 545 KB)Supplementary file4 (PDF 599 KB)Supplementary file5 (PDF 535 KB)Supplementary file6 (PDF 616 KB)Supplementary file7 (PDF 553 KB)Supplementary file8 (PDF 580 KB)Supplementary file9 (PDF 553 KB)Supplementary file10 (PDF 629 KB)Supplementary file11 (PDF 563 KB)Supplementary file12 (PDF 563 KB)Supplementary file13 (PDF 619 KB)Supplementary file14 (PDF 598 KB)Supplementary file15 (PDF 600 KB)Supplementary file16 (PDF 571 KB)Supplementary file17 (PDF 545 KB)Supplementary file18 (PDF 625 KB)Supplementary file19 (PDF 562 KB)Supplementary file20 (PDF 527 KB)Supplementary file21 (PDF 527 KB)Supplementary file22 (PDF 607 KB)Supplementary file23 (PDF 329 KB)Below is the link to the electronic supplementary material.


The emotional, behavioral and psychosocial effects of chaotic environments following wars and armed conflicts in terms of exposure to trauma and displacement is well recognized. School-age children who are directly exposed to or witnessed negative effects of armed conflicts show an array of emotional and behavioral problems.Our study aimed to examine the mental health conditions of children living in war and conflict zones and attending primary schools in Agdam.The study sample comprised of 617 children , residing in the conflict areas in the southwestern of Azerbaijan. The children were evaluated with the previously validated Azerbaijani version of the Strengths and Difficulties Questionnaire (SDQ) Teacher Form.About a third of children (32.7%) had abnormal total scores, and a fifth (21.4%) were in borderline range. The SDQ subscale scores included emotional problems (19.4%); conduct problems (20.3%), hyperactivity/inattention (12.2%), peer relationship problems (31.1%), and pro-social behavior difficulties (13.1%). As a result, externalizing problem scores were higher in males (p<.001) and internalizing problems in females (p<.05). Due to correlation analysis, age is negatively and significantly related with externalising (p<.05), internalising (p<.01), and total difficulty (p<.05) scores.The findings of the study show that more than half of the children living in the war zone in Azerbaijan suffer from mental health problems and highlight the need for child mental health services and family supports in the region.No significant relationships.


Inflammatory Bowel Diseases (IBD) are increasing globally with westernized countries experiencing a dramatic increase in cases of ulcerative colitis and Crohn’s disease. The corresponding rise in the comorbidities of anxiety and depression are linked to inflammation and microbiome dysbiosis; impacting the gut-brain axis (GBA). Another facet of the GBA are the tryptophan metabolites serotonin (5HT) and kynurenine (Kyn). 5HT and Kyn are metabolites implicated in anxious behaviours and memory deficiencies with dysbiosis influencing metabolite production. In inflammatory conditions, upregulation of Kyn impacts brain homeostasis as Kyn has both positive and negative brain metabolites. As disease outcomes are tied to the severity of depression/anxiety, characterization of the behavioural and tryptophan metabolite profile of an IBD model can allow us to develop better IBD therapies.To characterize the anxiety and memory phenotype with corresponding assessment of tryptophan metabolites 5HT and Kyn across tissues of interest in an spontaneous colitis model.-/-) lack the protective mucin 2 layer in the distal colon, allowing for direct contact between the gut contents and the gut epithelial layer. Over time this contact results in the development of spontaneous colitis. Muc2-/- n=12 per sex were compared to C57Bl/6 mice for behaviour and tryptophan metabolites across brain, colon and serum. Open Field Test and Light/Dark tests were used to assess anxiety levels, Novel Object and Radial Arm maze were performed to assess memory deficits. Mice underwent one anxiety and one memory test and were euthanized following their last maze. Enzyme-linked immunosorbent assay (ELISA) assessment of 5HT and Kyn were performed on brain, colon and serum samples. T-tests were performed and graphs created using PRISM (v9.4.1).Mucin 2 knockout mice (Muc2-/- mice had decreased anxiety (p=0.0113) compared to C57Bl/6 wild type mice in the light/dark maze. Muc2-/- displayed no significant differences in novel object preferences or the number of memory errors in novel object recognition test and radial arm maze respectively. Serum kynurenine was found to be significantly elevated (p=0.0444) in Muc2-/- mice. The sex factor has to be mentioned here in the results not in the conclusions.Muc2-/-and wild-type mice with depressed anxiety responses and heightened serum kynurenine, however the implications of these findings require further investigation. Understanding how inflammation is driving behavioural alterations can provide pathways to ameliorate the behavioural comorbidities in IBD patients suffering from anxiety of memory deficits.IBD is increasing globally and problems with mental health is often comorbid. Within our model we were able to show that behavioural and biochemical differences do exist between our Muc2None Declared


There is a need for improved communication in assisted living communities (ALCs) for staff and family caregivers of persons with dementia. This study is a cluster randomized trial in 10 ALCs  of a PC education (PCEAL) program for dementia care providers facilitated by hospice nurse educators. Baseline, 3- and 6-month data was collected for documentation of advance care planning (ACP) discussions. The PCEAL program had a moderate effect on ACP discussions at the 3-month follow in the treatment (N=17) compared to the control group (N= 6) . The findings indicate that the PCEAL program potentially improves ACP discussions with family members of persons with dementia. We will discuss recommendations for tailoring the PCEAL program to include other direct and administrative staff and to elicit the perspective of families about quality of communication.


We evaluated the concordance of lymphoproliferative disorder (LPD) diagnoses made initially at Kamuzu Central Hospital (KCH) with a limited immunohistochemistry panel and telepathology consultation with University of North Carolina (UNC) at Chapel Hill and second review at UNC with an extensive immunohistochemistry panel available.The prospective KCH Lymphoma Study in Lilongwe has been enrolling patients with LPDs since 2013. Diagnoses are made by pathologists in Malawi and supported by US pathologists and Malawian clinicians at weekly telepathology conferences. Diagnostic tissue blocks are sent quarterly to UNC for secondary review and further confirmatory studies. Concordance of diagnosis from primary to secondary review was scored as: exact match (level 1), differences in granularity of the diagnosis (level 2), a change in classification but not in treatment (level 3), and a change to the diagnosis that would have altered the treatment course (Major Discordance). Cases with insufficient tissue for review at UNC were excluded from concordance evaluation.Three hundred eighty-eight adult patients were enrolled (June 2013-May 2019). Three hundred twenty-seven tissue blocks were sent to UNC for review and 292 LPDs diagnostic samples had sufficient quality for concordance review. The five most common LPDs were diffuse large B-cell lymphoma , Burkitt lymphoma , classical Hodgkin lymphoma , Multicentric Castleman disease , and low grade non-Hodgkin lymphoma . Level 1, 2 and 3 concordance represented 175 (60%), 49 (17%) and 50 (17%) cases, respectively, and a Major Discordance was identified in 18 cases (6%).With a limited, selected immunohistochemistry panel and telepathology consultation, 94% of cases were accurately classified in real-time, leading to appropriate therapy. The evaluation of concordance provides a measure of quality assurance of the telepathology program, confidence in diagnoses for involvement in interventional trials, and useful data for understanding the epidemiology of LPDs in Malawi.


Osteoporosis is common amongst elderly patient populations and is associated with significant morbidity and mortality. We aimed to assess whether national clinical guidelines regarding the identification, assessment and management of osteoporosis and fragility fracture risk were being adhered to on a female later life psychiatry ward. We then aimed to improve the detection and treatment of osteoporosis amongst this patient cohort and subsequently conducted a re-audit of adherence to relevant clinical guidelines.In July 2021, the electronic health records of the 20 most recently discharged patients from a female later life psychiatry ward were reviewed. The proportion of patients who appropriately received FRAX screening, DEXA scanning and pharmacological management of osteoporosis and fragility fracture risk was recorded. The results were compared to standards identified in national clinical guidelines from the National Institute for Health and Care Excellence (NICE) and the National Osteoporosis Guideline Group (NOGG). In addition, the proportion of patients who had FRAX scores communicated to their general practitioners on discharge was recorded. Recommendations were made based on audit findings, and several changes to ward processes were implemented including incorporating fracture risk scoring in a structured ward round template and displaying information posters about osteoporosis in clinical areas. A re-audit was completed in February 2022 using the same methodology as baseline to re-assess adherence to the audit standards.All included patients were female and aged >65 years, and therefore eligible for consideration of fragility fracture risk according to NICE guidelines. 88% (15/17 patients) of those without pre-existing osteoporosis had FRAX scores calculated during their admission on re-audit compared to 50% (8/16 patients) at baseline. 73% (11/15 patients) had FRAX scores communicated to their GP on discharge at completion of the audit cycle compared to 25% (2/8 patients) at baseline. At completion of the audit cycle 10% (1/10 patients) with intermediate fragility fracture risk received measurement of bone mineral density during admission while 30% (3/10) had this recommended to their GP on discharge. None of the high-risk patients (n = 4) were started on bisphosphonate therapy.On completion of the audit cycle, we found excellent compliance with national guidelines regarding the identification of osteoporosis and fragility fracture risk, which demonstrates the feasibility of considering this aspect of physical health in the setting of a later-life psychiatry ward. Areas for improvement include the assessment and management of patients identified as having intermediate or high risk of osteoporosis and fragility fractures.


We used canonical correlation (n=424) to examine the relationships between a set of physical function measures  time, stair climb time and stair climb power) and a set of cognitive measures (Trail Making Test B (sec), Digit Symbol Substitution Test (DSST), the Montreal Cognitive Assessment, and California Verbal Learning Test). Canonical correlation derives synthetic variables comprised of linear combinations within each set of variables  that maximize the correlations between synthetic variables. The FSST was most strongly correlated with the cognitive synthetic variable (- 0.42). The DSST score was the cognitive measure most strongly correlated with the physical synthetic variable (0.48). It is notable that only the timed cognitive and physical tests are inter-associated


The rural areas of southwestern Indiana are challenged with insufficient healthcare workers in the long-term care industry. The University of Southern Indiana (USI) Geriatric Workforce Enhancement Program (GWEP) is collaborating with state agencies to address shortages in licensed administrators, activity professionals and social service designees. These roles, vital in the nursing facility, hold educational requirements through the Indiana State Department of Health (ISDH) and the Indiana Professional Licensing Agency (IPLA). USI gerontology faculty addressed workforce challenges in five phases: 1) Evaluation of state educational requirement and comparison to current USI gerontology courses; 2) Development of new coursework to support state requirements; 3) Expansion of preceptor pool; 4) Proposal to state agencies; 5) USI curriculum modifications. Faculty evaluated the educational and training requirements for these roles and compared the requirements with current courses. Preceptors were needed for students’ field experiences; a preceptor pool was developed through funded training. The requirements and course alignment were included in the program proposal to the state agencies. Upon ISDH, IPLA and University New Program Development Committee approval, additional instructors were recruited. Results of this initiative include a: 1) Fully approved and launched Administrator-in-Training (AIT) residency embedded in curriculum at undergraduate and graduate level; 2) Fully approved Activity Professional Certificate Program; 3) Pool of 10 certified preceptors; and 4) Onset of the social service designee certificate program. This collaborative partnership developed between USI, ISDH and IPLA ensure state agency requirements are met academically for students entering the long-term care workforce.


Scientific Reports 10.1038/s41598-021-86979-5, published online 01 April 2021Correction to: The original version of this Article contained an error. In the Materials and methods section, under the subheading ‘Study design’, the approval number of the Ethics Committee was incorrect.As a result,“The study was conducted with the approval of the Ethics Committee of Nagoya University Hospital and enrolled in the jRCT (CRB4180004).”now reads:“The study was conducted with the approval of the Ethics Committee of Nagoya University Hospital .”The original Article has been corrected.


Photobacterium damselae subsp. piscicida (Pdp) causes photobacteriosis in fish and important financial losses in aquaculture, but knowledge of its virulence factors is still scarce. We here demonstrate that an unstable plasmid (pPHDPT3) that encodes a type III secretion system (T3SS) is highly prevalent in Pdp strains from different geographical origins and fish host species. We found that pPHDPT3 undergoes curing upon in vitro cultivation, and this instability constitutes a generalized feature of pPHDPT3-like plasmids in Pdp strains. pPHDPT3 markers were detected in tissues of naturally-infected moribund fish and in the Pdp colonies grown directly from the fish tissues but were undetectable in a fraction of the colonies produced upon the first passage of the primeval colonies on agar plates. Notably, cured strains exhibited a marked reduction in virulence for fish, demonstrating that pPHDPT3 is a major virulence factor of Pdp. The attempts to stabilize pPHDPT3 by insertion of antibiotic resistance markers by allelic exchange caused an even greater reduction in virulence. We hypothesize that the existence of a high pressure to shed pPHDPT3 plasmid in vitro caused the selection of clones with off-target mutations and gene rearrangements during the process of genetic modification. Collectively, these results show that pPHDPT3 constitutes a novel, hitherto unreported virulence factor of Pdp that shows a high instability in vitro and warn that the picture of Pdp virulence genes has been historically underestimated, since the loss of the T3SS and other plasmid-borne genes may have occurred systematically in laboratories for decades.The marine bacterium  Photobacterium damselae subsp. piscicida (hereafter dubbed Pdp), a bacterium of the family Vibrionaceae, was first isolated in 1963 from natural populations of white perch (Morone americana) and striped bass (Morone saxatilis) affected by an unknown bacterium in the Chesapeake Bay  ) were used. TSA-1 plates supplemented with Cm5 + Kan50 and sucrose (15% [wt/vol]) were used to select double mutant colonies containing the kan gene plus the cat gene.The coding sequence of each of the two rivative . Two fra plasmid  was inse plasmid . The catPdp. The high in vitro instability of pPHDPT3-like plasmids warns that the picture of Pdp virulence genes has been historically biased and underestimated. The realization of the prevalence of plasmids encoding the T3SS and additional genes in Pdp will surely change our view of this pathogen from now on.This study provides evidence that pPHDPT3 plasmid constitutes a novel, hitherto unreported virulence factor of


Describe the progress of developing and monitoring global physical activity policy from the 1990s through the release and implementation of Global Action Plan for Physical Activity-GAPPA;Present findings of a systematic review of instruments for physical activity policy analysis;Describe the methods and progress after 1-year implementation of the Global Observatory for Physical Activity-GoPA! physical activity policy inventory;Present the preliminary findings and lessons learned after 1-year implementation of the Global Observatory for Physical Activity-GoPA! physical activity policy inventory.Physical inactivity is one of the most important factors contributing to global morbidity and mortality, but despite both importance and the recent launch of a WHO action plan, public health policy around physical activity remains poorly developed and monitored.Description of the problemPhysical inactivity accounts for as many as 5 million deaths per year globally but has yet to be addressed effectively by most governments or the World Health Organization(WHO). Many efforts led by WHO, national governments, networks, and academics from the 1990s to the present have tried to turn physical activity into a public health priority. Since its launch in 2015, the Global Observatory for Physical Activity-GoPA! has monitored the progress of national physical activity surveillance, policy and research. The GoPA! Policy Inventory created in 2017, contributes to physical activity policy monitoring and aims to collect data worldwide.In this symposium we will address several key questions about physical activity policy by examining different initiatives such as GAPPA and the experience of monitoring policy globally with the GoPA! policy inventory. We will examine whether it is feasible to track physical activity policy at the global and country levels, if the existence of ?good? physical activity policy is associated with less physical inactivity and how policy indicators may be used for advocacy and guidance in the coming years.Findings show that PA policy monitoring has and still varies substantially by geographic area and country income group. Effectiveness and implementation of PA policies remains challenging worldwide. PA policy indicators can enhance understanding of the links between policy and population levels of PA.GoPA! is committed to continue improving PA policy monitoring for informing and encouraging policy to address physical inactivity worldwide.Agenda and PresentersIntroduction: Michael Pratt (10-minutes)Talk 1: Developing and monitoring physical activity policy: 1990 to today – Michael Pratt (15-minutes)Talk 2: Instruments for the analysis of national-level physical activity and sedentary behaviour policies: a systematic review – Željko Pedišić (15-minutes)Talk 3: The GoPA! Policy Inventory: Progress and methods - Andrea Ramirez (15-minutes)Talk 4: The GoPA! Policy Inventory: preliminary findings and lessons learned – Željko Pedišić (15-minutes)Q&A from the audienceConclusion by discussant Adrian Bauman (20-minutes)


Group Name: Working Group on Neonatal Infectious Diseases of the Section of Neonatology of the Dutch Paediatric SocietyBackground: Central-line–associated bloodstream infections (CLABSIs) are a main focus of infection prevention and control initiatives in neonatal care. Standardized surveillance of neonatal CLABSI enables intra- and interfacility comparisons, which can contribute to quality improvement. To date, there is no national registration system for CLABSI in neonatal care in the Netherlands. Across neonatal intensive care units (NICUs), several different sets of CLABSI criteria and surveillance methods are used for local monitoring of CLABSI incidence rates. To achieve standardized CLABSI surveillance, we conducted a consensus procedure with regard to nationwide neonatal CLABSI surveillance criteria. Method: A modified Delphi consensus procedure for the development of nationwide neonatal CLABSI surveillance criteria was performed between January 2016 and January 2017 in the Netherlands. An expert panel was formed by members of the Working Group on Neonatal Infectious Diseases of the Section of Neonatology of the Dutch Paediatric Society. The consensus procedure consisted of 3 expert panel rounds. Figure Result: The expert panel achieved consensus on Dutch neonatal CLABSI surveillance criteria, which are summarized in Figure 2. Neonatal CLABSI is defined as a bloodstream infection occurring >72 hours after birth, associated with an indwelling central venous or arterial line and laboratory confirmed by 1 or more blood cultures. In addition, the blood culture finding should not be related to an infection at another site and one of the following criteria can be applied: (1) a bacterial or fungal pathogen is identified from 1 or more blood cultures; (2) the patient has clinical symptoms of sepsis and (2A) a common commensal is identified in 2 separate blood cultures or (2B) a common commensal is identified by 1 blood culture and C-reactive protein (CRP) level is >10 mg/L in the first 36 hours following blood culture collection. Conclusion: The newly developed Dutch neonatal CLABSI surveillance criteria are concise, are specific to the neonatal population, and comply with a single blood-culture policy in actual neonatal clinical practice. International agreement upon neonatal CLABSI surveillance criteria is needed to identify best practices for infection prevention and control.Funding: NoDisclosures: None