Association of computed tomography measures of muscle and adipose tissue and progressive changes throughout treatment with clinical endpoints in patients with advanced lung cancer treated with immune checkpoint inhibitors

To investigate the association between skeletal muscle mass and adiposity measures with disease-free progression (DFS) and overall survival (OS) in patients with advanced lung cancer receiving immunotherapy, we retrospectively analysed 97 patients (age: 67.5 ± 10.2 years) with lung cancer who were treated with immunotherapy between March 2014 and June 2019. From computed tomography scans, we assessed the radiological measures of skeletal muscle mass, and intramuscular, subcutaneous and visceral adipose tissue at the third lumbar vertebra. Patients were divided into two groups based on specific or median values at baseline and changes throughout treatment. A total number of 96 patients (99.0 %) had disease progression (median of 11.3 months) and died (median of 15.4 months) during follow-up. Increases of 10 % in intramuscular adipose tissue were significantly associated with DFS (HR: 0.60, 95 % CI: 0.38 to 0.95) and OS (HR: 0.60, 95 % CI: 0.37 to 0.95), while increases of 10 % in subcutaneous adipose tissue were associated with DFS (HR: 0.59, 95 % CI: 0.36 to 0.95). These results indicate that, although muscle mass and visceral adipose tissue were not associated with DFS or OS, changes in intramuscular and subcutaneous adipose tissue can predict immunotherapy clinical outcomes in patients with advanced lung cancer

Numerical Study of Low Salinity Water Flooding in Naturally Fractured Oil Reservoirs

Due to the increase of the activities in the oil industries, higher interest has been given to enhance the recover the trapped oil and produce more oil from the matured reservoirs. Worldwide, enhanced oil recovery (EOR) is implemented in most reservoirs to recover additional amounts of oil that are not recovered during secondary recovery by water flood or gas injection. Recently, a numerous techniques such as thermal, miscible, immiscible and chemical has proposed to enhanced oil recovery and to increase the producible oil from oil reservoirs. The suitability and the success of a specific EOR process are highly sensitive to reservoir and fluid characteristics, recovery efficiency, availability of injected fluids, and costs. One of the common techniques which have been proposed recently is low salinity water flooding where the sea water with a controlled salinity and salt content is used to alter the rock wettability or enhance the fine migration and resulted in higher oil production. This study aims to investigate the possibility of using low salinity water flooding in naturally fractured reservoirs. The wettability changes are taking into account in terms of oil/water relative, saturation and capillary pressure as these parameters play a key role during the simulation of brine injection. The results show that the oil recovery significantly increases specially for water wet reservoirs as the reason behind is the decreasing water production after the breakthrough of the low saline brines

The Use of Cumulative Disciplinary Score in an Integrated Curriculum to Prevent Deliberate Omission of Course Content

Background & Objective: Student assessment is one of the most challenging issues of an integrated curriculum. While calculating an overall score is in line with the goals of integrated curriculum, it poses the risk that some students will deliberately leave out the content of some disciplines, based on the fact that they have lower credits in each block exam. In the present study, we describe the experience of Tehran University of Medical Sciences, Iran, where an integrated medical curriculum has been launched since September 2011 as part of curriculum reform initiative. Methods: In the first academic year, students passed 4 blocks: Molecule and Cell; Tissue; Development and Function; Cardiovascular Function; Blood circulation; and Blood-Respiratory Function. Each block included anatomy, histology, physiology, and embryology. The overall block score was reported at the end of each block. In addition, a cumulative disciplinary score was calculated at the end of the academic year through the summation of the weighted subscores of each discipline in each block. Results: At the end of the year, the number of students who had failed in histology, anatomy, embryology, and physiology were 15, 17, 44, and 3, respectively. They were required to take a disciplinary examination before the beginning of the next academic year. Conclusion: A comparison of the number of students who failed disciplines with low credits (e.g. histology) with those who failed disciplines with high credits (e.g. physiology) suggests that the former had systematically been ignored by some students. The calculation of a cumulative disciplinary score may reduce the deliberate omission of course content in integrated blocks. Key Words: Integration, Student assessment, Cumulative disciplinary scor

A Single Center Survey of Patients With Congenital Neutropenia: Report From Northwestern Iran

Neutropenia is characterized by a decrease in circulating neutrophil counts and consequent infections.  The present study was performed so as to describe the clinical and laboratory findings of patients with congenital neutropenia in northwestern Iran. The patients' records of 31 patients with congenital neutropenia out of 280 neutropenic patients who had been referred to Tabriz Children's Hospital during a 3-year period (2011-2014), were reviewed. Thirty-one cases (17 female and 14 male), with a mean age of 5.3 ± 5.7 years, were diagnosed to suffer from congenital neutropenia. The disorders associated with congenital neutropenia were combined immunodeficiency (8 cases), severe congenital neutropenia (6 cases), common variable immunodeficiency (4 cases), severe combined immunodeficiency (2 cases) and metabolic syndrome (1 case). The median age of the onset of disease was 26.2 ± 60.8 months. The most common clinical manifestations during the course of illness were otitis media (13 cases), pneumonia (12 cases), recurrent aphthous stomatitis, lymphadenopathy and gingivitis (11 cases). Four neutropenic patients died because of recurrent infections. Neutropenia may occur in the context of the primary immunodeficiency disorders. Unusual, persistent or severe infections always pose a speculation to search for an underlying immunodeficiency syndrome and neutropenia, so as to avoid further life-threatening complications as a result of any delay in diagnosis

Controlling the Growth of the Skin Commensal Staphylococcus epidermidis Using d-Alanine Auxotrophy.

Using live microbes as therapeutic candidates is a strategy that has gained traction across multiple therapeutic areas. In the skin, commensal microorganisms play a crucial role in maintaining skin barrier function, homeostasis, and cutaneous immunity. Alterations of the homeostatic skin microbiome are associated with a number of skin diseases. Here, we present the design of an engineered commensal organism, Staphylococcus epidermidis, for use as a live biotherapeutic product (LBP) candidate for skin diseases. The development of novel bacterial strains whose growth can be controlled without the use of antibiotics or genetic elements conferring antibiotic resistance enables modulation of therapeutic exposure and improves safety. We therefore constructed an auxotrophic strain of S. epidermidis that requires exogenously supplied d-alanine. The S. epidermidis NRRL B-4268 Δalr1 Δalr2 Δdat strain (SEΔΔΔ) contains deletions of three biosynthetic genes: two alanine racemase genes, alr1 and alr2 (SE1674 and SE1079), and the d-alanine aminotransferase gene, dat (SE1423). These three deletions restricted growth in d-alanine-deficient medium, pooled human blood, and skin. In the presence of d-alanine, SEΔΔΔ colonized and increased expression of human β-defensin 2 in cultured human skin models in vitro. SEΔΔΔ showed a low propensity to revert to d-alanine prototrophy and did not form biofilms on plastic in vitro. These studies support the potential safety and utility of SEΔΔΔ as a live biotherapeutic strain whose growth can be controlled by d-alanine.IMPORTANCE The skin microbiome is rich in opportunities for novel therapeutics for skin diseases, and synthetic biology offers the advantage of providing novel functionality or therapeutic benefit to live biotherapeutic products. The development of novel bacterial strains whose growth can be controlled without the use of antibiotics or genetic elements conferring antibiotic resistance enables modulation of therapeutic exposure and improves safety. This study presents the design and in vitro evidence of a skin commensal whose growth can be controlled through d-alanine. The basis of this strain will support future clinical studies of this strain in humans

A Case Based-Shared Teaching Approach in Undergraduate Medical Curriculum: A Way for Integration in Basic and Clinical Sciences

To present a multiple-instructor, active-learning strategy in the undergraduate medical curriculum. This educational research is a descriptive one. Shared teaching sessions, were designed for undergraduate medical students in six organ-system based courses. Sessions that involved in-class discussions of integrated clinical cases were designed implemented and moderated by at least 3 faculties (clinicians and basic scientists). The participants in this study include the basic sciences medical students of The Tehran University of Medical Sciences. Students’ reactions were assessed using an immediate post-session evaluation form on a 5-point Likert scale. Six two-hour sessions for 2 cohorts of students, 2013 and 2014 medical students during their two first years of study were implemented from April 2014 to March 2015. 17 faculty members participated in the program, 21 cases were designed, and participation average was 60 % at 6 sessions. Students were highly appreciative of this strategy. The majority of students in each course strongly agreed that this learning practice positively contributed to their learning (78%) and provided better understanding and application of the material learned in an integrated classroom course (74%). They believed that the sessions affected their view about medicine (73%), and should be continued in future courses (80%). The percentage demonstrates the average of all courses. The program helped the students learn how to apply basic sciences concepts to clinical medicine. Evaluation of the program indicated that students found the sessions beneficial to their learning

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Pathogen Identification in Suspected Cases of Pyogenic Spondylodiscitis

Pyogenic spinal infection continues to represent a worldwide problem. In approximately one-third of patients with pyogenic spondylodiscitis, the infectious agent is never identified. Of the cases that lead to organismal identification, bacteria are more commonly isolated from the spine rather than fungi and parasites. This study applied universal prokaryotic 16S rRNA PCR as a rapid diagnostic tool for the detection of bacterial agents in specimens from patients suspected of pyogenic spondylodiscitis. Gram and Ziehl-Neelsen staining were used as a preliminary screening measure for microbiologic evaluation of patient samples. PCR amplification targeting 16S rRNA gene was performed on DNA extracted from 57 cases including specimens from epidural abscesses, vertebral, and disc biopsies. Positive samples were directly sequenced. MRI findings demonstrated that disc destruction and inflammation were the major imaging features of suspected pyogenic spondylodiscitis cases, as 44 cases showed such features. The most common site of infection was the lumbar spine (66.7%), followed by thoracic spine (19%), the sacroiliac joint (9.5%), and lumbar-thoracic spine (4.8%) regions. A total of 21 samples amplified the 16S rRNA-PCR product. Sanger sequencing of the PCR products identified the following bacteriological agents: Mycobacterium tuberculosis (n = 9; 42.9%), Staphylococcus aureus (n = 6; 28.5%), Mycobacterium abscessus (n = 5; 23.8%), and Mycobacterium chelonae (n = 1; 4.8%). 36 samples displayed no visible 16S rRNA PCR signal, which suggested that non-bacterial infectious agents (e.g., fungi) or non-infectious processes (e.g., inflammatory, or neoplastic) may be responsible for some of these cases. The L3–L4 site (23.8%) was the most frequent site of infection. Single disc/vertebral infection were observed in 9 patients (42.85%), while 12 patients (57.15%) had 2 infected adjacent vertebrae. Elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) inflammatory markers were noted in majority of the patients. In conclusion, microbiological methods and MRI findings are vital components for the proper diagnosis of pyogenic spondylodiscitis. Our findings suggest that molecular methods such as clinical application of 16S rRNA PCR and sequencing may be useful as adjunctive diagnostic tools for pyogenic spondylodiscitis. The rapid turnaround time of 16S rRNA PCR and sequencing submission and results can potentially decrease the time to diagnosis and improve the therapeutic management and outcome of these infections. Although S. aureus and M. tuberculosis were the most common causes of pyogenic spinal infections in this study, other infectious agents and non-infectious etiologies should be considered. Based on study results, we advise that antibiotic therapy should be initiated after a definitive etiological diagnosis

Lithium and GSK3-β promoter gene variants influence white matter microstructure in bipolar disorder

Lithium is the mainstay for the treatment of bipolar disorder (BD) and inhibits glycogen synthase kinase 3-β (GSK3-β). The less active GSK3-β promoter gene variants have been associated with less detrimental clinical features of BD. GSK3-β gene variants and lithium can influence brain gray matter structure in psychiatric conditions. Diffusion tensor imaging (DTI) measures of white matter (WM) integrity showed widespred disruption of WM structure in BD. In a sample of 70 patients affected by a major depressive episode in course of BD, we investigated the effect of ongoing long-term lithium treatment and GSK3-β promoter rs334558 polymorphism on WM microstructure, using DTI and tract-based spatial statistics with threshold-free cluster enhancement. We report that the less active GSK3-β rs334558*C gene-promoter variants, and the long-term administration of the GSK3-β inhibitor lithium, were associated with increases of DTI measures of axial diffusivity (AD) in several WM fiber tracts, including corpus callosum, forceps major, anterior and posterior cingulum bundle (bilaterally including its hippocampal part), left superior and inferior longitudinal fasciculus, left inferior fronto-occipital fasciculus, left posterior thalamic radiation, bilateral superior and posterior corona radiata, and bilateral corticospinal tract. AD reflects the integrity of axons and myelin sheaths. We suggest that GSK3-β inhibition and lithium could counteract the detrimental influences of BD on WM structure, with specific benefits resulting from effects on specific WM tracts contributing to the functional integrity of the brain and involving interhemispheric, limbic, and large frontal, parietal, and fronto-occipital connections