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Background While the overall incidence rate of colorectal cancer (CRC) in Canada has been decreasing, some countries show an increasing incidence in those under the age of 50. We examined the trends in CRC incidence and associated lifestyle risk factors in Canadians aged 15⿿49. Methods Incidence data for colorectal, colon and rectum/rectosigmoid cancers were obtained for 1969⿿2010 from the Canadian Cancer Registry, and trends in age-standardized incidence rates (ASIRs) were examined by Joinpoint regression for three age groups (15⿿29, 30⿿39, 40⿿49 years) and by sex. Trends in the prevalence of some CRC risk factors were similarly examined from national health surveys for various periods ranging from 1970 to 2012. Results In both sexes combined, ASIRs rose by 6.7%/year (1997⿿2010) for 15⿿29-year-olds, 2.4%/year (1996⿿2010) for 30⿿39-year-olds, and 0.8%/year (1997⿿2010) for 40⿿49-year-olds. Similar trends were observed by sex. The rise in ASIR was more rapid for cancers of the rectum/rectosigmoid compared to colon for all age groups. Risk factor trends varied: excess weight rose substantially, vegetables and fruit consumption increased slightly, physical inactivity rates declined but remained high, alcohol consumption changed little, and smoking rates declined. Data on red/processed meat consumption were unavailable. Conclusion The ASIR of CRC in young Canadians has increased since about the mid-1990s. The rising prevalence of excess weight in younger generations has likely played a role in the CRC trend, but more research is needed.

Since its clinical inception, tamoxifen (TAM) has proved to be a powerful tool in treating estrogen receptor-positive breast cancers while exhibiting manageable side effects. Although TAM was synthesized as an estrogen receptor antagonist, reports have found that a significant fraction of women with estrogen receptor-negative cancers have benefitted from TAM treatment, suggesting the possibility of an alternate anti-cancer mechanism. In this paper, we present a review of recent and past literature in an attempt to clarify how TAM inhibits cell proliferation and induces apoptosis in cells lacking the estrogen receptor. Our analysis indicates that micromolar concentrations of TAM selectively elevate intracellular calcium concentrations in malignant cells, possibly by inversely agonizing cannabinoid receptors, producing considerable mitochondrial distress followed by the rapid production of reactive oxygen species. In response, cytoplasmic proteins such as JNK1 are activated, which mediates the activation of caspase-8. Fyn kinase auto phosphorylates in response to increased reactive oxygen species and directs the ubiquitin ligase c-Cbl to tag growth factor receptors for ubiquitination, potentially abrogating constitutively active survival pathways that are hallmarks of cancer progression. We attempt to differentiate the effect that TAM has on purified Protein Kinase C (PKC) compared to that in an intact cell, suggesting that low micromolar concentrations of TAM indirectly inhibit PKC by inducing EGFR destruction and high micromolar concentrations of TAM inhibits PKC through a direct binding mechanism.

Assessing the extent of absorption of topical drugs into the various skin layers has been one of the biggest challenges of recent dermatological research. Although skin biopsy samples can be used to directly measure topical drug absorption, biopsies are invasive and not practical for obtaining kinetic data. Common alternative techniques used to assess the bioavailability of topical drugs include in vitro (Franz cell chamber), ex vivo (isolated perfused skin models), and in vivo (vasoconstrictor assay, tape stripping/dermatopharmacokinetics, and microdialysis) techniques. Despite the popularity of these techniques, each technique has its own advantages and disadvantages that limit its use. Consideration of each technique requires that there is a rational linkage to the drug's clinical endpoint and/or site of action. In this article, we review these in vitro, ex vivo, and in vivo techniques, focusing on the basic concepts and the advantages and disadvantages of each technique.

Modafinil is an approved drug for the treatment of narcolepsy and have a strong market presence in many countries. The drug is widely consumed for off-label uses and currently listed as a restricted drug. Modafinil has very low water solubility. To enhance the aqueous solubility of modafinil by the formation of a ternary complex with Hydroxypropyl-β-cyclodextrin and two hydrophilic polymers was the main objective of the present study. Pyrrolidone (PVP K30) and a water soluble chitosan derivative, trimethyl chitosan (TMC) were studied by solution state and solid state characterization methods for their discriminatory efficiency in solubility enhancement of modafinil. Phase solubility study depicted the highest complexation efficiency (2.22) of cyclodextrin derivative in the presence of TMC compared to the same in the presence of PVP K30 (0.08) and in the absence of any polymer (0.92). FT-IR analysis of binary and ternary complex expressed comparable contribution of both polymers in formation of inclusion complex. The thermal behaviour of binary and ternary complex, involving individual polymers disclosed the influence of TMC on polymorphism of the drug. DSC study revealed efficiency of TMC to prevent conversion of metastable polymorphic form to stable polymorphic form. Ternary complex, involving TMC enhanced water solubility of the drug 1.5 times more compared to the binary complex of the drug whereas PVP K30 reduced the Solubility.

Sudden onset myopia is seen in several local or systemic conditions.1 Local conditions include blunt ocular trauma and ocular inflammation. Systemic conditions include diabetes, pregnancy and certain drugs like hydrochlorothiazide and topiramate.1 However Systemic Lupus Erythematosus (SLE) as a cause of transient myopia is so rare that it has not been reported in these articles. Neither has sudden onset transient myopia been included in the ocular manifestations of SLE.2, 3 A case of SLE which presented with acute myopia is presented herewith.

The original version of the article unfortunately contained an error in the first name and the surname of the third author.

The increasing prevalence of carbon nanotubes (CNTs) as components of new functional materials has the unintended consequence of causing increases in CNT concentrations in aqueous environments. Aqueous systems are reservoirs for bacteria, including human and animal pathogens, that can form biofilms. At high concentrations, CNTs have been shown to display biocidal effects; however, at low concentrations, the interaction between CNTs and bacteria is more complicated, and antimicrobial action is highly dependent upon the properties of the CNTs in suspension. Here, impact of low concentrations of multiwalled CNTs (MWCNTs) on the biofilm-forming opportunistic human pathogen Pseudomonas aeruginosa is studied. Using phase contrast and confocal microscopy, flow cytometry, and antibiotic tolerance assays, it is found that sub-lethal concentrations (2 mg/L) of MWCNTs promote aggregation of P. aeruginosa into multicellular clusters. However, the antibiotic tolerance of these “young” bacterial-CNT aggregates is similar to that of CNT-free cultures. Overall, our results indicate that the co-occurrence of MWCNTs and P. aeruginosa in aqueous systems, which promotes the increased number and size of bacterial aggregates, could increase the dose to which humans or animals are exposed.

An estimated 14.2% (9.34 million people) of people living in the UK in 2019 were international migrants. Despite this, there are no large-scale national studies of their healthcare resource utilisation and little is known about how migrants access and use healthcare services. One ongoing study of migration health in the UK, the Million Migrants study, links electronic health records (EHRs) from hospital-based data, national death records and Public Health England migrant and refugee data. However, the Million Migrants study cannot provide a complete picture of migration health resource utilisation as it lacks data on migrants from Europe and utilisation of primary care for all international migrants. Our study seeks to address this limitation by using primary care EHR data linked to hospital-based EHRs and national death records. Our study is split into a feasibility study and a main study. The feasibility study will assess the validity of a migration phenotype, a transparent reproducible algorithm using clinical terminology codes to determine migration status in Clinical Practice Research Datalink (CPRD), the largest UK primary care EHR. If the migration phenotype is found to be valid, the main study will involve using the phenotype in the linked dataset to describe primary care and hospital-based healthcare resource utilisation and mortality in migrants compared to non-migrants. All outcomes will be explored according to sub-conditions identified as research priorities through patient and public involvement, including preventable causes of inpatient admission, sexual and reproductive health conditions/interventions and mental health conditions. The results will generate evidence to inform policies that aim to improve migration health and universal health coverage.

Introduction: Factors such as anatomic complexity and extensive surgical procedures increase the risk of serious, sometimes fatal complications post-surgical treatment for head and neck cancer squamous cell carcinoma (HNSCC). Thirty-day (30-day) mortality is a common quality metric that evaluates short-term survival; however, no study has described disparities associated with 30-day mortality following surgery in HNSCC United States population. The aim of this study was to identify disparities and factors (clinical and nonclinical) associated with 30-day postoperative mortality in patients with HNSCC treated with and without adjuvant therapy. Methods: In this retrospective study, we utilized a patient cohort of 102,877 confirmed HNSCC cases from the National Cancer Database (2004-2013) who were treated surgically with curative intent for the primary head and neck cancer. The effects of adjuvant therapy and other clinical and nonclinical factors on 30-day postoperative mortality were estimated via multivariate logistic regression with adjustment for time-varying nature of adjuvant therapy. Outcome was defined as any-cause-death within 30 days after definitive surgery of primary cancer. We controlled for several clinical and nonclinical covariates, including age, race, sex, health insurance status, primary tumor site, stage of presentation, and Charlson-Deyo comorbidity score. Results: There were 859 patients who died within 30 days of definitive surgery for cancer, yielding a 30-day mortality rate of 0.83%. Treatment differences were associated with mortality, and patients who received adjuvant therapy had were significantly more likely to die within 30 days compared with those treated with surgery alone (aOR: 3.51; 95% CI 1.85, 6.66). Increasing number of comorbidities was also associated with greater odds of 30-day mortality (Charlson-Deyo comorbidity scores of 1: aOR: 1.45; 95% CI 1.23, 1.71, and Charlson-Deyo comorbidity scores of 2+ aOR: 2.52; 95% CI 2.05, 3.09). There were also sociodemographic disparities associated with 30-day mortality. Odds of 30-day mortality were significantly increased among patients with Medicaid insurance (aOR: 1.99; 95% CI 1.48, 2.68), as well as those who lived in neighborhoods with little education (≥ 29% missing high school diploma: aOR: 1.43; 95% CI 1.08, 1.88). Conclusions: Disparities impact short-term mortality in the head and neck cancer population. Patients that were significantly more likely to die within 30 days of surgical treatment were those treated with adjuvant therapy, those with greater burden of comorbidities, those with little education, and those covered by Medicaid. To our knowledge, this is the largest study to document short term (30-day) mortality disparities among patients with head and neck cancer post-surgery in the United States. To improve short-term survival among head and neck cancer patients, it is important to account for these disparities found in this study. Citation Format: Aleksandr R. Bukatko, Parth Patel, Vindhya Kakarla, Matthew C. Simpson, Eric A. Boakye, Katherine A. Stamatakis, Nosayaba Osazuwa-Peters. Disparities and factors associated with 30-day mortality following surgical treatment for squamous cell head and neck cancer with or without adjuvant therapy [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B085.

Heterozygous truncating variants in titin (TTNtv) are the major genetic cause of dilated cardiomyopathy (DCM). Though variants which disrupt essential splicing dinucleotides (GT/AG) are readily recognized as TTNtv, the effects of other nearby sequence variations on splicing is uncertain. We

Dual ligand 3D MOF {[Co(BDC)(L)]·2H2O.xG}n (CoMOF-2; G = guest) was synthesized via simple room temperature stirring method. Bulk Phase purity of CoMOF-2 was assessed by various physicochemical methods including X‐ray diffraction (XRD). CO2 adsorption isotherms indicate that activated CoMOF-2 is efficient in CO2 uptake, which has been utilized for the CO2-Epoxide cycloaddition. The catalytic ability of CoMOF-2 as a binary catalyst revealed excellent results for variety of monosubstituted epoxide under solvent‐free conditions (1 bar/40 °C/12 h). Interestingly CoMOF-2/KI also showed great potential as a heterogeneous catalyst for disubstituted epoxide (10 bar/120 °C/24 h) with high yields/selectivity. The catalytic efficiency of the present investigation for scantly explored disubstituted epoxide is better/on par with the earlier reports and the recyclability of the catalyst is an added advantage. Probable mechanism for the catalytic reaction is deduced and verified the representative energy profile for cycloaddition of CO2-Cyclohexane oxide (CHO) by DFT calculation.

Background: Modern diagnostic strategies for venous thromboembolism (VTE) incorporate pretest probability (PTP; prevalence) assessment. The ability of diagnostic tests to correctly identify or exclude VTE is influenced by VTE prevalence and test accuracy characteristics. Objective: These evidence-based guidelines are intended to support patients, clinicians, and health care professionals in VTE diagnosis. Diagnostic strategies were evaluated for pulmonary embolism (PE), deep vein thrombosis (DVT) of the lower and upper extremity, and recurrent VTE. Methods: The American Society of Hematology (ASH) formed a multidisciplinary panel including patient representatives. The McMaster University GRADE Centre completed systematic reviews up to 1 October 2017. The panel prioritized questions and outcomes and used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess evidence and make recommendations. Test accuracy estimates and VTE population prevalence were used to model expected outcomes in diagnostic pathways. Where modeling was not feasible, management and accuracy studies were used to formulate recommendations. Results: Ten recommendations are presented, by PTP for patients with suspected PE and lower extremity DVT, and for recurrent VTE and upper extremity DVT. Conclusions: For patients at low (unlikely) VTE risk, using D-dimer as the initial test reduces the need for diagnostic imaging. For patients at high (likely) VTE risk, imaging is warranted. For PE diagnosis, ventilation-perfusion scanning and computed tomography pulmonary angiography are the most validated tests, whereas lower or upper extremity DVT diagnosis uses ultrasonography. Research is needed on new diagnostic modalities and to validate clinical decision rules for patients with suspected recurrent VTE.

We study the thermal evolution of a highly spin-imbalanced, homogeneous Fermi gas with unitarity limited interactions, from a Fermi liquid of polarons at low temperatures to a classical Boltzmann gas at high temperatures. Radio-frequency spectroscopy gives access to the energy, lifetime, and short-range correlations of Fermi polarons at low temperatures $T$. In this regime, we observe a characteristic $T^2$ dependence of the spectral width, corresponding to the quasiparticle decay rate expected for a Fermi liquid. At high $T$, the spectral width decreases again towards the scattering rate of the classical, unitary Boltzmann gas, $\propto T^{-1/2}$. In the transition region between the quantum degenerate and classical regime, the spectral width attains its maximum, on the scale of the Fermi energy, indicating the breakdown of a quasiparticle description. Density measurements in a harmonic trap directly reveal the majority dressing cloud surrounding the minority spins and yield the compressibility along with the effective mass of Fermi polarons., Accepted version at PRL

This chapter presents a comprehensive picture of work-readiness and employability among Indian graduates transitioning from university to careers in the Indian labour market. More particularly, it presents macro and micro data from various industry sectors in India to chart the dimensions and trends in graduate work transitions in India. Furthermore, the chapter presents an empirical view of three main stakeholders’ (policymakers, employers and educational stakeholders) assessments of the work-readiness competence deficits of Indian graduates and their possible causes. Finally, it discusses recommended solutions by these stakeholders for making Indian graduates work-ready.

This paper shows the prediction of fluctuation in the future price of cryptocurrencies. Users’ comments and tweets from twitter using Apache Flume and Price data was fetched from exchanges. Bitcoin first documented by allies Satoshi Nakamoto, the first decentralized currency payment system has gained a considerable attention in the financial system, economics, social media and computer science due to its combination of peer-to-peer nature, encryption technology, and monetary unit. Predicting the price of Bitcoin and other cryptocurrencies is a great challenge because it is immensely complex and dynamic in nature. In this paper, we have tried to predict the future price of cryptocurrencies like Bitcoin using LSTM (Long Short-Term Memory) and used Twitter data to predict public mood. By combining both market sentiment and social sentiment because bitcoin price shows mixed properties. We also have selected some other important features from the blockchain information which has a major impact on Bitcoin’s supply and demand and using them to train model that improves the predictive power of the future Bitcoin price. We have performed a deep study of how data from social media affect the price of Bitcoin and so we have included the twitter data in model training. Our model shows that how well LSTM predict the price of Bitcoin considering the high volatility. The precision given by our model is 60% and accuracy is 50%. More focus is not given to accuracy, in this case, considering the highly volatile market.

The aim of this study was to compare hospital outcomes for patients in a motorcycle collision with and without helmet use. The study was conducted as a retrospective analysis of the National Trauma Data Bank's 2013 data set, which included reported data from 100 hospitals across the United States.Inclusion criterion for this study is a motorcycle crash involving a driver or passenger. The total number of patients in motorcycle crashes as reported by the National Trauma Data Bank in 2013 was 10,345. Helmet use, hospital stay, ICU and ventilation days, mortality, Glasgow Coma Score, Injury Severity Score, patient payer mix, and complication data were obtained.Patients were divided into two groups: those wearing a helmet (n = 6250) and those without (n = 4095). Patients not wearing a helmet had an increased risk of admission to the ICU (OR = 1.36, P 0.001, CI 1.25-1.48), requiring ventilation support (OR = 1.55, P 0.001, CI 1.39-1.72), presenting with a Glasgow Coma Score of eight or below (OR = 2.15, P 0.001), and in-patient mortality (OR = 2.00, P 0.001, CI 1.58-2.54). Unhelmeted patients were more likely to have government insurance or be uninsured than those patients wearing a helmet (P 0.001).It is not well understood why many states are repealing or have repealed universal helmet laws. Lack of helmet use increases the severity of injury in traumatized patients leading to a substantial financial impact on health care costs. Our analysis suggests the need to revisit the issue regarding laws that require protective headwear while riding motorcycles because of the individual and societal impact.III.

In this article, we report the synthesis of nitrogen-rich carbon layer-encapsulated Ni(0) nanoparticles as a core–shell structure (Ni@N/C-g-800) for the catalytic hydrogenation of furfural to furfuryl alcohol. The nickel nanoparticles were stabilized by the nitrogen-rich graphitic framework, which formed during the agitation of nickel acetate-impregnated cucurbit[6]uril surface in a reducing atmosphere. Furthermore, the catalyst was characterized using various physicochemical methods such as powder X-ray diffraction, Raman, field emission-scanning electron microscopy, high-resolution transmission electron microscopy, X-ray photoelectron spectroscopy, Brunauer–Emmett–Teller surface area, CO2-temperature-programmed desorption, inductive coupled plasma, and CHN analyses. The nitrogen-rich environment of the solid support with metallic Ni nanoparticles was found to be active and selective for the catalytic hydrogenation of furfural with molecular H2 in an aqueous medium at 100 °C. To understand the reaction m...

Small RNAs are key regulators in plant growth and development. One subclass, phased siRNAs (phasiRNAs) require a trigger microRNA for their biogenesis. In grasses, two pathways yield abundant phasiRNAs during anther development; miR2275 triggers one class, 24-nt phasiRNAs, coincident with meiosis, while a second class of 21-nt phasiRNAs are present in premeiotic anthers. Here we report that the 24-nt phasiRNA pathway is widely present in flowering plants, indicating that 24-nt reproductive phasiRNAs likely originated with the evolutionary emergence of anthers. Deep comparative genomic analyses demonstrated that this miR2275/24-nt phasiRNA pathway is widely present in eudicots plants, however, it is absent in legumes and in the model plant Arabidopsis, demonstrating a dynamic evolutionary history of this pathway. In Solanaceae species, 24-nt phasiRNAs were observed, but the miR2275 trigger is missing and some loci displaying 12-nt phasing. Both the miR2275-triggered and Solanaceae 24-nt phasiRNAs are enriched in meiotic stages, implicating these phasiRNAs in anther and/or pollen development, a spatiotemporal pattern consistent in all angiosperm lineages that deploy them., 24-nt phased siRNA (phasiRNA) regulate reproduction in grasses, yet are absent from Arabidopsis, and were thought to be monocot-specific. Here, Xia et al. show that 24-nt phasiRNAs are in fact broadly distributed among eudicots and are consistently enriched during meiosis, despite possibly arising from distinct biogenesis pathways.

Herein, a zinc(ii)-based 3D mixed ligand metal organic framework (MOF) was synthesized via versatile routes including green mechanochemical synthesis. The MOF {[Zn(ATA)(L)·H2O]}n (ZnMOF-1-NH2) has been characterized by various physico-chemical techniques, including SCXRD, and composed of the bipyridyl-based Schiff base (E)-N'-(pyridin-4-ylmethylene)isonicotinohydrazide (L) and 2-aminoterephthalic acid (H2ATA) ligands as linkers. The MOF material has been explored as a multifunctional heterogeneous catalyst for the cycloaddition of alkyl and aryl epoxides with CO2 and sulfoxidation reactions of aryl sulfides. The influence of various reaction parameters is examined to optimize the performance of the catalytic reactions. It is found that solvent-free catalytic reaction conditions offer good catalytic conversion in the case of cyclic carbonates, and for sulfoxide, good conversion and selectivity are achieved in the presence of DCM as a solvent medium under ambient reaction conditions. The chemical and thermal stability of the catalyst are excellent and it is active for up to four catalytic cycles without significant loss in activity. Furthermore, based on the catalytic activity and structural evidence, a plausible mechanism for both catalytic reactions is proposed.

Two-dimensional Zn

Patient selection flow chart. Schematic of selection of patients included in the study. (PDF 112 kb)

Verification of antibodies. Full immunoblots for the P2X1 and P2X7 antibodies used for flow cytometric detection of the P2 receptors on the erythrocytes, with or without peptide pre-adsorption. The proteins used were isolated plasma membranes for human erythrocytes. (PDF 112 kb)

The trabecular bone score (TBS) is a novel tool using grayscale variograms of the lumbar spine bone mineral density (BMD) to assess trabecular bone microarchitecture. Studies in patients with chronic kidney disease (CKD) suggest it may be helpful in assessing fracture risk. However, TBS has not been validated as a measure of trabecular architecture against transiliac bone biopsy with histomorphometry in CKD patients. We hypothesized that TBS would reflect trabecular architecture at the iliac crest in CKD patients. We obtained tetracycline double labeled transiliac crest bone biopsy, areal BMD of the spine, total hip, femoral neck (FN) and spine TBS by dual energy X-ray absorptiometry (DXA), and cortical and trabecular volumetric density and microarchitecture by high resolution peripheral quantitative computed tomography (HR-pQCT) in CKD patients from two centers: twenty-two patients from Columbia University Medical Center, USA and thirty patients from Hospital das Clinicas - Universidade de São Paulo, Brazil. Two patients were excluded for outlier status. Univariate and multivariate relationships between TBS and measures from DXA, HR-pQCT and histomorphometry were determined. Patients were 50.2 ± 15.8 years old, 23 (46%) were men, and 33 (66%) were on dialysis. TBS was1.31 in 21 (42%) patients and 22%, 14% and 10% had T-scores ≤ -2.5 at spine, FN and total hip respectively. In univariate regression, TBS was significantly associated with trabecular bone volume (BV/TV), trabecular width (Tb.Wi), trabecular spacing, cortical width but not with trabecular number or cortical porosity. FN Z-score and height were also associated with cancellous BV/TV and Tb.Wi, In multivariate analysis, TBS remained an independent predictor of BV/TV and Tb.Wi. There were no relationships between TBS and dynamic parameters from histomorphometry. These data suggest that TBS reflected trabecular microarchitecture and cortical width measured by bone biopsy in CKD patients. Future studies should address its utility in the identification of CKD patients who may benefit from fracture prevention strategies.

Background: 258 million people - 3% of the world's adult population - reside outside of their country of birth, yet there has been no previous global systematic review and meta-analysis of mortality data for these international migrants. We undertook a systematic review and meta-analysis to investigate current knowledge about mortality in international migrants. Methods: The review was carried out in line with PRISMA guidelines and was registered on Prospero (CRD42017073608). We searched the MEDLINE, EMBASE, and Global Health databases for studies on international migrants published between 1 Jan 2001 and 31 March 2017. Primary outcomes were standardised mortality ratios (SMRs) and absolute mortality rates. Meta-analyses were conducted using random effects models. Findings: We identified 12480 articles, of which 106 met our inclusion criteria. Data were included from all global regions and for 92 countries. 5498 SMR or absolute mortality estimates on more than 15.2 million migrants were included. The summary estimate of all-cause SMR for international migrants was lower than one (indicating lower mortality) when compared to the general population in host countries to which they migrate 0·70 (95%CI: 0·65-0·76;I2=99·8%). We estimated that all-cause SMR was lower in both male (0·72 [0·63-0·81]; I2=99·8%) and female (0·75 [0·66-0·84]; I2=99·8%) international migrants compared to the host population. The mortality advantage was evident for refugees (0.50 [0.46-0.56];I2=89·8%), but not for asylum seekers (1.05 [0.89-1.24];I2=54·4%), though there were limited data on these groups. SMRs for all causes of mortality were lower in migrants compared to the host population in the destination country with only two exceptions - infectious diseases and external causes - out of 13 ICD-10 categories. Heterogeneity was high across analyses. Point estimates of age-standardised mortality ranged from 488 in women to 874 in men per 100,000 population. Interpretation: Our analyses found that international migrants experience a mortality advantage compared to host populations, and this advantage persisted across the majority of ICD-10 disease categories. This finding is in contrast to the portrayal of migrants as a health burden and demonstrates that international migrants provide a major health benefit for host countries. Our research also highlights the need for better data on underrepresented and potentially more marginalised groups such as asylum seekers and undocumented migrants. Funding Statement: Wellcome Trust, NIHR, MRC, Alliance for Health Policy and Systems Research, DFID, Fogarty International Center, Grand Challenges Canada, International Development Research Center Canada, Inter-American Institute for Global Change Research, National Cancer Institute, National Heart, Lung and Blood Institute, National Institute of Mental Health, Swiss National Science Foundation, World Diabetes Foundation, UK National Institute for Health Research Imperial Biomedical Research Centre and the the Imperial College Healthcare Charity. Declaration of Interests: RWA and IA undertook paid consultancy work in support of the Doctors of the World 2017 Observatory report - Falling through the cracks: The Failure of Universal Healthcare Coverage in Europe. JSF, LBN, and SH have collaborated on research projects with Doctors of the World UK, which includes research commissioned by the Equality and Human Rights Commission on barriers and enablers to care for asylum seekers and refused asylum seekers in the UK. RWA is supported by a Wellcome Trust Clinical Research Career Development Fellowship (206602/Z/17/Z). SB is supported by an NIHR research methods fellowship. JJM acknowledges receiving additional support from the Alliance for Health Policy and Systems Research (HQHSR1206660), DFID/MRC/Wellcome Global Health Trials (MR/M007405/1), Fogarty International Center (R21TW009982, D71TW010877), Grand Challenges Canada (0335-04), International Development Research Center Canada (106887, 108167), Inter-American Institute for Global Change Research (IAI CRN3036), Medical Research Council (MR/P008984/1, MR/P024408/1, MR/P02386X/1), National Cancer Institute (1P20CA217231), National Heart, Lung and Blood Institute (HHSN268200900033C, 5U01HL114180, 1UM1HL134590), National Institute of Mental Health (1U19MH098780), Swiss National Science Foundation (40P740-160366), Wellcome Trust (074833/Z/04/Z, 205177/Z/16/Z) and the World Diabetes Foundation (WDF15-1224). LBN, SH, and JSF receive funding from the UK National Institute for Health Research Imperial Biomedical Research Centre and the Imperial College Healthcare Charity; SH and LN are funded by the Wellcome Trust (Grant number 209993/Z/17/Z) with co-applicants of RWA, JSF and IA for this work. The views expressed are those of the authors and not those of the Wellcome Trust, NIHR, NHS, NHS Research Scotland, Medical Research Council, Chief Scientist’s Office. Ethics Approval Statement: The review was carried out in line with PRISMA guidelines and was registered on Prospero (CRD42017073608).

Hereditary Nonpolyposis Colorectal Cancer (HNPCC), also known as Lynch Syndrome, is an autosomal dominant, tumor predisposing disorder usuallycaused by germline mutations in mismatch repair (MMR) genes. A subset of HNPCC, Muir-Torre Syndrome (MTS) also involves MMR gene defects and is generally accepted as a variant of HNPCC. MTS is typicallycharacterized by at least one visceral malignancy and one cutaneous neoplasm of sebaceous differentiation, with or without keratoacanthomas. In either version of the disorder, nonfunctional MMR systems lead tothe loss of genomic integrity, marked commonly by mismatches in repetitive DNA sequences, resulting in microsatellite instabilities. Deleterious nucleotide alterations ultimately drive the process of tumorigenesis in both HNPCC and MTS. The following article reviews the epidemiology, genetics, clinical presentation, and management of HNPCC and its MTS variant.

Langerhans cell histocytosis (LCH) and Erdheim-Chester disease are two rare histiocytic disorders. Their occurrence in the same patient is more infrequent, but has been described. We report a case of a 38-year-old woman who presented with a diagnosis of single system cutaneous LCH. Subsequently, she developed multiple papules on her extremities consistent with a non-LCH xanthogranuloma type lesion. BRAF(V600E) mutation immunostain, VE1 was positive in the skin lesion, which was confirmed by molecular polymerase chain reaction (PCR) studies, initiating a complete systemic workup for Erdheim-Chester disease. Systemic involvement was confirmed with bilateral sclerotic bone lesions and retroperitoneal and pelvic fibrosing disease. She was also found to have a BRAF(V600E) mutation positive papillary thyroid carcinoma. New suspicious cutaneous lesions presenting in patients with a history of LCH need to be biopsied. A BRAF(V600E) mutation in a non-LCH histiocytic lesion with a xanthogranuloma phenotype (CD163/CD68/CD14/fascin/Factor 13a) should prompt an Erdheim-Chester disease workup. This is a unique case of a woman with BRAF(V600E) mutation positive Erdheim-Chester disease and cutaneous LCH, while also being, to our knowledge, the first reported case in the English literature of it occurring in a patient with a BRAF(V600E) mutation positive papillary thyroid carcinoma.

INTRODUCTION In dermatology, topical therapies are usually the first line and mainstay of treatment for the majority of skin conditions. Most topical preparations are available in a variety of potencies and delivery systems. Practitioners must carefully choose from this vast array based on the potency required, location of intended use, product elegance, and likelihood of patient compliance. Unfortunately, information concerning which preparation is truly best, regarding actual penetration and delivery to the site of action, is not readily available. In general, many practitioners believe that ointments and foams enhance penetration when compared to creams, gels, and powders. However, this is not always the case. Aside from vehicles, there are a variety of chemical and physical enhancement techniques that influence topical penetration. As physician-scientists, dermatologists should be aware of the basic mechanisms involved in topical absorption and should be able to assess whether a preparation is likely to exert its desired effect. In this article, we explore the inherent properties of the epidermis and the physiology of passive diffusion and aim to clarify the definition of the terms “absorption” and “penetration.”

Alzheimer's disease (AD) is a neurodegenerative disease that inhibits cognitive functions and has no cure. This report reviews the current diagnostic standards for AD with an emphasis on early diagnosis using the cerebrospinal fluid (CSF) biomarkers amyloid-beta, t-tau, and p-tau and fluorodeoxyglucose positron emission tomography imaging. Abnormal levels of these CSF biomarkers and decreased cerebral uptake of glucose have recently been used in the early diagnosis of AD in experimental studies. These promising biomarkers can be measured using immunoassays performed in singleplex or multiplex formats. Although presently, there are no Food and Drug Administration-approved in vitro diagnostics (IVDs) for early detection of AD, a multiplex immunoassay measuring a panel of promising AD biomarkers in CSF may be a likely IVD candidate for the clinical AD diagnostic market. Specifically, the INNO-BIA AlzBio3 immunoassay kit, performed using bead arrays on the xMAP Luminex analyzer, allows simultaneous quantification of amyloid-beta, t-tau, and p-tau biomarkers. AD biomarkers can also be screened using enzyme-linked immunosorbent assays that are offered as laboratory-developed tests.

Mevalonate diphosphate decarboxylase (MDD; EC 4.1.1.33) is an important enzyme in the mevalonic acid pathway catalyzing the Mg(2+)-ATP dependant decarboxylation of mevalonate 5-diphosphate (MVAPP) to isopentenyl diphosphate (IPP). Bacopa monniera recombinant MDD (BmMDD) protein was overexpressed in Escherichia coli BL21 (DE3) strain and purified to apparent homogeneity. Km and Vmax for MVAPP were 144 μM and 52 U mg(-1) respectively. The values of turnover (kcat) and kcat/Km for mevalonate 5-diphosphate were determined to be 40s(-1) and 2.77×10(5) M(-1) s(-1) and kcat and kcat/Km values for ATP were found to be 30 s(-1) and 2.20×10(4) M(-1) s(-1), respectively. pH activity profile indicated the involvement of carboxylate ion, lysine and arginine for the activity of enzyme. The apparent activation energy for the BmMDD catalyzed reaction was 12.7 kJ mol(-1). Optimum pH and temperature for the forward reaction was found to be 8.0 and 45 °C. The enzyme was most stable at pH 7 at 20 °C with the deactivation rate constant (Kd(*)) of 1.69×10(-4) and half life (t1/2) of 68 h. The cation studies suggested that BmMDD is a cation dependant enzyme and optimum activity was achieved in the presence of Mg(2+).

Protein targeting is critical in all living organisms and involves a signal recognition particle (SRP), an SRP receptor and a translocase. In co-translational targeting, interactions between these proteins is mediated by the ribosome. In chloroplasts, the light-harvesting chlorophyll-binding protein (LHCP) in the thylakoid membrane is targeted post-translationally without a ribosome. A multi-domain chloroplast-specific subunit of the SRP, cpSRP43, is proposed to take on the role of coordinating the sequence of targeting events. Here, we demonstrate that cpSRP43 exhibits significant inter-domain dynamics, which reduce upon binding its SRP binding partner, cpSRP54. We showed that the affinity of cpSRP43 for the binding motif of LHCP (L18) increases when cpSRP43 is complexed to the binding motif of cpSRP54 (cpSRP54pep). These results support the conclusion that substrate binding to the chloroplast SRP is modulated by protein structural dynamics, in which a major role of cpSRP54 is to improve substrate-binding efficiency to the cpSRP.

Genetic engineering of secondary metabolic pathways is an emerging area of research for production and improvement of natural products in plant biotechnology. Here, we describe a systematic approach to manipulate a key regulatory step of isoprenoid biosynthetic pathway in Withania somnifera to study its effect on withanolide production. We generated T0 W. somnifera plants overexpressing squalene synthase (WsSQS) by Agrobacterium tumefaciens mediated transformation, which were analyzed by Gus biochemical assay and PCR of hygromycin phosphotransferase (hptII) and WsSQS. qRT-PCR analyses of various transformed tissues indicated 2–5 fold increase in WsSQS transcripts in both T0 and T1 generations. The tissue specific protein expression studies revealed 2–3 fold increase in WsSQS, which was further confirmed by enzyme activity. These observations were corroborated with the 1.5–2 fold increase in total withanolide content of the transformed tissues. However, in leaf tissue, the levels of Withaferin A and Withanolide A increased significantly up to 4–4.5 fold. These findings demonstrate genetic engineering of isoprenoid pathway in W. somnifera resulting in enhanced production of withanolides, and also provide insights into such metabolic pathways for their manipulation to improve the pharmacological content of different medicinally important plants.

Background: Various adjuvants are being used with local anesthetics for prolongation of intraoperative and post-operative analgesia. Dexmedetomidine, a highly selective alpha2 adrenergic agonist, is a new neuraxial adjuvant gaining popularity. The purpose of this study was to compare the onset, duration of sensory and motor block, hemodynamic effects, post-operative analgesia, and adverse effects of dexmedetomidine and clonidine with hyperbaric 0.5% bupivacaine for spinal anesthesia. Methods: 60 patients belonging to ASA Grade 1 and 2 undergoing elective gynecological surgery under spinal anesthesia were studied in this prospective. The patients were allocated in two groups (30 patients each). Group bupivacaine + clonidine (BC) received 17.5 mg of bupivacaine supplemented 45 mcg clonidine and Group bupivacaine + dexmedetomidine (BD) received 17.5 mg bupivacaine supplemented 5 mcg dexmedetomidine. The onset time of sensory and motor level, time to reach peak sensory and motor level, the regression time of sensory and motor level, hemodynamic changes, and side effects were recorded. Results: Patients in Group BD had significantly longer sensory and motor block time than patients in Group BC. The onset time to reach dermatome T4 and modified Bromage3 motor block were not significantly different between two groups. Dexmedetomidine group showed significantly less and delayed requirement of rescue analgesic. Conclusion: Intrathecal dexmedetomidine is associated with prolonged motor and sensory block, hemodynamic stability and reduced demand of rescue analgesic in 24 hrs as compared to clonidine.

Introduction: The major proportion of the population suffering from nutritional deficiency and continues to grow worldwide, especially in developing countries like India, and it is the most common cause of morbidity and mortality. Aim: To evaluate the oral health-related quality of life (OHRQOL) and nutrition status and association between nutritional status, and OHRQOL in the elderly. Materials and Methods: A cross-sectional study was conducted among the elderly of Karad city. The elderly were subjected to type 3 oral examination. Data regarding the nutritional status and OHRQOL were obtained using Geriatric Oral Health Assessment Index (GOHAI) and mini nutritional assessment (MNA) index. Descriptive statistics was used to analyze data using SPSS version 21. Results: The sample included 200 elderly, of which 59% consisted of males, and 41% are females. The majority of study subjects (46%) were between age group 61 and 70 years. Among the assessed subjects, nearly 95% of them had total scores of GOHAI between 12 and 57 which require "needed dental care." As per MNA, 3.5% had adequate nutrition, 60% were at risk of malnutrition, and remaining 36.5% of subjects were malnourished. There was a significant correlation between GOHAI and MNA scores. Conclusion: Nutritional status was associated with the poor OHRQOL among the elderly. A strong association was found between mean GOHAI and MNA scores and nutrition status and OHRQOL.

Angiotensin-I-converting enzyme (ACE) inhibitors have been very effective in treating cardiac hypertension since their clinical inception over four decades ago. Since then, it has been established that angiotensin II, the product of ACE, has oncogenic and pro-proliferative qualities, which begs the question as to whether ACE inhibitors may have oncolytic characteristics. In fact, scattered reports suggest that ACE inhibitors are oncolytic and oncopreventive, but the available literature has yet to be thoroughly examined. In the present review, we examine the available literature and determine that ACE inhibitors would have great utility in the prevention and treatment of cancer. At the same time, they would augment the efficacy of chemo- and radiotherapy as well as mitigating damage to healthy tissue by standard chemotherapeutic regimens. We review some of the mounting clinical evidence and show that ACE inhibitors have oncolytic activity in multiple types of cancer and discuss the ability of ACE inhibitors to prevent cardiotoxicity of multiple chemotherapies. Our analysis demonstrates that the actions of ACE inhibitors converge on vascular endolthelial growth factor to reduce its levels in tumors and prevent construction of blood vessels to masses, leaving them nutrient-depleted and subsequently hindering their growth. Given that ACE inhibitors are approved by the Federal Drug Administration and the therapeutic dose for hypertension treatment also slows the growth of multiple cancers types, ACE inhibitors are in a perfect position to be repurposed as oncolytic agents, that would widely increase their utility in the clinic.

Phased, secondary siRNAs (phasiRNAs) are found widely in plants, from protein-coding transcripts and long, non-coding RNAs; animal piRNAs are also phased. Integrated methods characterizing “PHAS” loci are unavailable, and existing methods are quite limited and inefficient in handling large volumes of sequencing data. The PHASIS suite described here provides complete tools for the computational characterization of PHAS loci, with an emphasis on plants, in which these loci are numerous. Benchmarked comparisons demonstrate that PHASIS is sensitive, highly scalable and fast. Importantly, PHASIS eliminates the requirement of a sequenced genome and PARE/degradome data for discovery of phasiRNAs and their miRNA triggers.

Neurotrophins are a family of growth factors that are vital to the proper development of the central nervous system. Their effects on cells are governed by the expression and activation of the tyrosine kinase receptors TrkA, TrkB and TrkC. TrkB has been immensely implicated in mediating neuronal migration, development and differentiation. It has also been shown to protect several neuronal cell types from an array of cytotoxic stressors after activation by its conjugate ligand brain-derived neurotrophic factor (BDNF). Over the past two decades, it has been shown that TrkB and BDNF are up-regulated in many types of cancers, conferring aggressive phenotypes underpinned by their resistance to several standard chemotherapeutic agents. This resistance to chemotherapy is modulated by the downstream targets of the TrkB receptor which include the well-characterized PI3K /Akt growth pathway, a hallmark of uncontrolled cancer cell growth and proliferation. Pre-clinical efforts to develop inhibitors of this receptor are promising, and such inhibitors also seem to sensitize cancer cells to standard chemotherapies. However, new evidence suggests that BDNF overexpression in the hypothalamus has immunoaugmenting properties, eliciting an increased anti-tumor immune response and reducing the activity of several proteins that would normally confer resistance to chemotherapeutic agents. In the current work, we provide a global analysis of the physiological consequences of TrkB receptor activation in vitro and discuss the dynamic consequences of TrkB activation in vivo. Finally, we propose a clinically-feasible option for increasing BDNF expression in the hypothalamus to more readily utilize the oncolytic effects of BDNF.