Influence of the width of keratinized tissue on the development and resolution of experimental peri‐implant mucositis lesions in humans

Clinical Oral Implants Research, EarlyView.


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Etelcalcetide for Treating Secondary Hyperparathyroidism: An Evidence Review Group Evaluation of a NICE Single Technology Appraisal

Abstract

The manufacturer of the calcimimetic drug etelcalcetide was invited to make an evidence submission as part of the National Institute for Health and Care Excellence (NICE) Single Technology Appraisal (STA) programme. Within this submission, they reported evidence on the clinical and cost effectiveness of etelcalcetide for the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) on haemodialysis. The Southampton Health Technology Assessments Centre (SHTAC), part of the Wessex Institute at the University of Southampton, was the independent Evidence Review Group (ERG) commissioned to appraise the company's submission. This article describes the ERG's review and critique of the company's submission and summarises the NICE Appraisal Committee's subsequent guidance (issued in June 2017). The clinical-effectiveness evidence submitted by the company consisted of two double-blind, randomised controlled trials (RCTs) comparing etelcalcetide with placebo, one RCT comparing etelcalcetide with cinacalcet, two single-arm extension studies of the above trials, and one single-arm study evaluating the effect of switching from cinacalcet to etelcalcetide. No study specifically examined the population specified in the NICE appraisal scope: patients refractory to standard therapy with phosphate binders and vitamin D (PBVD). None of these trials were designed to collect long-term efficacy data for outcomes such as mortality, bone fractures, cardiovascular events, or parathyroidectomies. Instead, biomarker data from the trials were mapped to long-term outcomes by an assumed linear relationship between the trial outcome, reduction of parathyroid hormone (PTH) by > 30%, and the log-hazard ratios for the occurrence of clinical events derived from a large, long-term RCT of cinacalcet (the EVOLVE trial). After submission of a confidential Patient Access Scheme (PAS) discount reducing etelcalcetide drug costs, the incremental cost-effectiveness ratio (ICER) for etelcalcetide versus cinacalcet was £14,778 per quality-adjusted life-year (QALY) gained in the company's base case. While this value is lower than the NICE threshold range of £20,000 and £30,000 per QALY gained, it was the opinion of the ERG that the ICER was highly uncertain due to efficacy data limitations for etelcalcetide, inadequate synthesis of clinical-effectiveness evidence, and strong assumptions connecting short-term biomarker data with long-term clinical outcomes. The ERG produced an alternative base case for etelcalcetide versus cinacalcet, with an ICER of £22,400 per QALY gained, also subject to uncertainty. The NICE Appraisal Committee recommended etelcalcetide as an option for the treatment of SHPT in adults with CKD only if treatment with a calcimimetic is indicated and cinacalcet is not suitable, subject to the company's provision of the agreed PAS discount.

https://ift.tt/2vIcBRF

Rapid Integration of Multi-copy Transgenes Using Optogenetic Mutagenesis in Caenorhabditis elegans

Stably transmitted transgenes are indispensable for labeling cellular components and manipulating cellular functions. In Caenorhabditis elegans, transgenes are generally generated as inheritable multi-copy extrachromosomal arrays, which can be stabilized in the genome through a mutagenesis-mediated integration process. Standard methods to integrate extrachromosomal arrays primarily use protocols involving ultraviolet light plus trimethylpsoralen or gamma- or X-ray irradiation, which are laborious and time-consuming. Here, we describe a one-step integration method, following germline-mutagenesis induced by mini Singlet Oxygen Generator (miniSOG). Upon blue light treatment, miniSOG tagged to histone (Histone-miniSOG) generates reactive oxygen species (ROS) and induces heritable mutations, including DNA double-stranded breaks. We demonstrate that we can bypass the need to first establish extrachromosomal transgenic lines by coupling microinjection of desired plasmids with blue light illumination on Histone-miniSOG worms to obtain integrants in the F₃ progeny. We consistently obtained more than one integrant from 12 injected animals in two weeks. This optogenetic approach significantly reduces the amount of time and labor for transgene integration. Moreover, it enables to generate stably expressed transgenes that cause toxicity in animal growth.

https://ift.tt/2HWbwIe

The evolving role of lymphatics in cancer metastasis

Rae H Farnsworth | Marc G Achen | Steven A Stacker

https://ift.tt/2HW4P94

Phenformin-Induced Mitochondrial Dysfunction Sensitizes Hepatocellular Carcinoma for Dual Inhibition of mTOR

Purpose: Hepatocellular carcinoma (HCC) ranks second in cancer mortality and has limited therapeutic options. We recently described the synergistic effect of allosteric and ATP-site competitive inhibitors against the mammalian target of rapamycin (mTOR) for the treatment of HCC. However, such inhibitors induce glycemia and increase mitochondrial efficiency. Here we determined whether the mitochondrial complex I inhibitor Phenformin could reverse both side effects, impose an energetic-stress on cancer cells and suppress the growth of HCC. Experimental Design: Human HCC cell lines were used in vitro to access the signaling and energetic impact of mTOR inhibitors and Phenformin, either alone or in combination. Next, the therapeutic utility of these drugs alone or in combination was investigated pre-clinically in human orthotopic tumors implanted in mice, by analyzing their impact on the tumor burden and overall survival. Results: We found Phenformin caused mitochondrial dysfunction and fragmentation, inducing a compensatory shift to glycolysis. In contrast, dual inhibition of mTOR impaired cell growth and glycolysis, while increasing mitochondrial fusion and efficiency. In a mouse model of human HCC, dual inhibition of mTOR, together with Phenformin, was highly efficacious in controlling tumor burden. However, more striking, pretreatment with Phenformin sensitized tumors to dual inhibition of mTOR, leading to a dramatic improvement in survival. Conclusion: Treatment of HCC cells in vitro with the biguanide Phenformin causes a metabolic shift to glycolysis, mitochondrial dysfunction and fragmentation, and dramatically sensitizes orthotopic liver tumors to dual inhibition of mTOR. We therefore propose this therapeutic approach should be tested clinically in HCC.

https://ift.tt/2Kb94OY

Immunotherapy for glioblastoma: playing chess, not checkers

Patients with glioblastoma (GBM) exhibit a complex state of immune dysfunction involving multiple mechanisms of local, regional, and systemic immune suppression and tolerance. These pathways are now being identified and their relative contributions explored. Delineating how these pathways are interrelated is paramount to effectively implementing immunotherapy for GBM.

https://ift.tt/2Jp97FA

Validation of a plasma-based comprehensive cancer genotyping assay utilizing orthogonal tissue- and plasma-based methodologies

Purpose: Liquid biopsies are powerful tools that enable non-invasive genotyping of advanced solid tumors; however, comprehensive, structured validation studies employing validated orthogonal comparator methods are lacking. Experimental Design: Analytical validation was conducted according to established principles and guidelines. Blood-to-blood clinical validation comprised blinded external comparison to clinical digital droplet PCR across 222 consecutive biomarker-positive clinical samples. Blood-to-tissue clinical validation comprised comparison of Digital Sequencing calls to those documented in the medical record of 543 consecutive lung cancer patients. Clinical experience was reported from 10,593 consecutive clinical samples. Results: Digital Sequencing technology enabled variant detection down to 0.02%-0.04% allelic fraction/2.12 copies with ≤0.3%/2.24-2.76 copies 95% limits of detection while maintaining high specificity (prevalence-adjusted PPVs >98%). Clinical validation using orthogonal plasma- and tissue-based clinical genotyping across >750 patients demonstrated high accuracy and specificity (PPAs and NPAs >99% and PPVs 92-100%). Clinical use in 10,593 advanced adult solid tumor patients demonstrated high feasibility (>99.6% technical success rate) and clinical sensitivity (85.9%), with high potential actionability (16.7% with FDA-approved on-label treatment options; 72.0% with treatment or trial recommendations), particularly in non-small cell lung cancer where 34.5% of patient samples comprised a directly targetable standard-of-care biomarker. Conclusions: High concordance with orthogonal clinical plasma- and tissue-based genotyping methods supports the clinical accuracy of Digital Sequencing across all four types of targetable genomic alterations. Digital Sequencing's clinical applicability is further supported by high rates of technical success and biomarker target discovery.

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Reciprocal Network between Cancer Stem-Like Cells and Macrophages Facilitates the Progression and Androgen Deprivation Therapy Resistance of Prostate Cancer

Purpose: Cancer stem-like cells (CSCs) contribute to the progression and androgen deprivation therapy (ADT) resistance of prostate cancer. Since CSCs depend on their specific niche, including tumor-associated macrophages (TAMs), elucidating the network between CSCs and TAMs may help to effectively inhibit the progression and ADT resistance of prostate cancer. Experimental Design: The underlying intracellular mechanism that sustains the stem-like characteristics of CSCs in prostate cancer was assessed via RNA-seq, co-IP, ChIP and other assays. A co-culture system and cytokine antibody arrays were employed to examine the interaction network between CSCs and TAMs. In addition, an orthotopic prostate cancer model was established to evaluate the in vivo effects of the combined targeting of CSCs and their interaction with TAMs on ADT resistance. Results: Autophagy-related gene 7 (ATG7) facilitated the transcription of OCT4 via β-catenin which binds to the OCT4 promoter, promoting CSC characteristics in prostate cancer, including self-renewal, tumor initiation and drug resistance. In addition, CSCs remodeled their specific niche by educating monocytes/macrophages towards TAMs, and the CSC-educated TAMs reciprocally promoted the stem-like properties of CSCs, progression and ADT resistance of prostate cancer via interleukin 6 (IL6)/STAT3. Furthermore, the combined targeting of CSCs and their interaction with TAMs by inhibiting ATG7/OCT4 and IL6 receptor effectively ameliorated ADT resistance in an orthotopic prostate cancer model. Conclusions: Targeting CSCs and their niche may prove to be a more powerful strategy than targeting CSCs alone, providing a rational approach to ameliorating ADT resistance in prostate cancer.

https://ift.tt/2FeZWVz

Tryptophan metabolism contributes to radiation-induced immune checkpoint reactivation in glioblastoma

Purpose: Immune checkpoint inhibitors designed to revert tumor-induced immune suppression have emerged as potent anti-cancer therapies. Tryptophan metabolism represents an immune checkpoint and targeting this pathway's rate limiting enzyme IDO1 is actively being investigated clinically. Here, we studied the intermediary metabolism of tryptophan metabolism in glioblastoma and evaluated the activity of the IDO1 inhibitor GDC-0919, both alone and in combination with radiation (RT).  Experimental Design: LC/GC-MS and expression profiling was performed for metabolomic and genomic analyses of patient-derived glioma. Immune competent mice were injected orthotopically with genetically engineered murine glioma cells and treated with GDC-0919 alone or combined with RT. Flow-cytometry was performed on isolated tumors to determine immune consequences of individual treatments. Results: Integrated cross-platform analyses coupling global metabolomic and gene-expression profiling identified aberrant tryptophan metabolism as a metabolic node specific to the mesenchymal and classical subtypes of glioblastoma. GDC-0919 demonstrated potent inhibition of this node and effectively crossed the blood brain barrier. Although GDC-0919 as a single agent did not demonstrate anti-tumor activity, it had a strong potential for enhancing RT response in glioblastoma, which was further augmented with a hypofractionated regimen. RT response in glioblastoma involves immune stimulation, reflected by increases in activated and cytotoxic T-cells, which was balanced by immune checkpoint reactivation, reflected by an increase in IDO1 expression and Tregs.  GDC-0919 mitigated RT-induced Tregs and enhanced T-cell activation. Conclusion:  Tryptophan metabolism represents a metabolic node in glioblastoma and combining RT with IDO1 inhibition enhances therapeutic response by mitigating RT-induced immune suppression.

https://ift.tt/2Kbr3ol

Enhanced Therapeutic Activity of Non-Internalizing Small Molecule-Drug Conjugates Targeting Carbonic Anhydrase IX in Combination With Targeted Interleukin-2

Purpose: Antibody-drug conjugates and small molecule-drug conjugates have been proposed as alternatives to conventional anti-cancer cytotoxic agents, with the potential to deliver bioactive payloads to the site of disease, helping spare normal tissues. Experimental Design: Here we describe a novel small molecule-drug conjugate, based on a high-affinity ligand specific to carbonic anhydrase IX. The product featured a peptidic linker, suitable for cleavage in the tumor extracellular environment, and monomethyl auristatin E as cytotoxic payload. Results: A potent anti-cancer activity was observed in nude mice bearing SKRC-52 renal cell carcinoma xenografts, but no durable complete responses could be observed in this model. However, when the product was administered together with L19-IL2 (a clinical-stage fusion protein capable of delivering interleukin-2 to the tumor neo-vasculature), all treated mice in the combination group could be rendered tumor-free, in a process which favored the influx of natural killer cells into the tumor mass. The combination of L19-IL2 and the new small molecule-drug conjugate also eradicated cancer in 100% of immunocompetent mice, bearing subcutaneously-grafted CT26 colorectal cancer cells, which stably expressed carbonic anhydrase IX. Conclusions: These findings may be of clinical significance, since carbonic anhydrase IX is over-expressed in the majority of clear-cell renal cell carcinomas and in approximately 30% of colorectal cancers. The targeted delivery of interleukin-2 helps potentiate the action of targeted cytotoxics leading to cancer eradication in models that cannot be cured by conventional chemotherapy.

https://ift.tt/2Jo5rE8

Andecaliximab/GS-5745 alone and combined with mFOLFOX6 in advanced gastric and gastroesophageal junction adenocarcinoma: Results from a phase 1 study

Purpose: Matrix metalloproteinase-9 (MMP9) is implicated in pro-tumorigenic processes. Andecaliximab (GS-5745, a monoclonal antibody targeting MMP9) was evaluated as monotherapy and in combination with mFOLFOX6. Experimental Design: Three dosages of andecaliximab monotherapy (200, 600, and 1800 mg IV every 2 weeks [q2w]) were investigated in patients with advanced solid tumors (n=13 in a 3+3 design). After determining a recommended dose, patients with advanced HER2-negative gastric/gastroesophageal junction (GEJ) adenocarcinoma (n=40) received 800 mg andecaliximab + mFOLFOX6 q2w. Pharmacokinetics, pharmacodynamics, safety, and efficacy were assessed. Results: Andecaliximab monotherapy demonstrated no dose-limiting toxicity (DLT) in any cohort, displaying target-mediated drug disposition at the lowest dose (200 mg) and linear pharmacokinetics at higher doses. Based on target engagement, recommended doses for further study are 800 mg q2w or 1200 mg q3w. Maximal andecaliximab target binding, defined as undetectable andecaliximab-free MMP9 in plasma, was observed in the gastric/GEJ adenocarcinoma cohort. We observed no unusual toxicity, although there were 4 deaths on study not attributed to andecaliximab treatment. In first-line patients (n=36), median progression free survival (PFS) was 9.9 months (95% CI 5-13.9 months) and the overall response rate (ORR) was 50%. Among all patients (n=40), median PFS was 7.8 (90% CI, 5.5-13.9) months and ORR was 48%, with a median duration of response of 8.4 months. Conclusions: Andecaliximab monotherapy achieved target engagement without DLT. Andecaliximab + mFOLFOX6 showed encouraging clinical activity without additional toxicity in patients with HER2-negative gastric/GEJ adenocarcinoma. A phase 3 study evaluating mFOLFOX6 +/- andecaliximab in this setting is ongoing.

https://ift.tt/2Keqquo

Undifferentiated sarcomas in children harbor clinically-relevant oncogenic fusions and gene copy-number alterations: A report from the Children's Oncology Group

Purpose: A comprehensive analysis of the genomics of undifferentiated sarcomas (UDS) is lacking.  We analyzed copy number alterations and fusion status in patients with UDS prospectively treated on Children's Oncology Group protocol ARST0332. Experimental Design: Copy number alterations were assessed by Oncoscan FFPE Express on 32 UDS. Whole-exome and transcriptome libraries from 8 tumors with sufficient archived material were sequenced on HiSeq (2x100 bp). Targeted RNA-sequencing using Archer chemistry was performed on two additional cases. Results: Five-year overall survival for patients with UDS was 83% (95% CI: 69% to 97%) with risk adapted therapy (surgery, chemotherapy, radiotherapy). Both focal and arm-level copy number alterations were common including gain of 1q (8/32, 25%) and loss of 1p (7/32, 22%), both of which occurred more often in clinically defined high risk tumors. Tumors with both loss of 1p and gain of 1q carried an especially poor prognosis with a five-year event free survival of 20%. GISTIC analysis identified recurrent amplification of FGF1 on 5q31.3 (q=0.03) and loss of CDKN2A and CDKN2B on 9p21.3 (q=0.07). Known oncogenic fusions were identified in 8 of 10 cases analyzed by next generation sequencing. Conclusions: Pediatric UDS generally has a good outcome with risk-adapted therapy. A high-risk subset of patients whose tumors have copy number loss of 1p and gain of 1q was identified with only 20% survival. Oncogenic fusions are common in UDS and next generation sequencing should be considered for children with UDS to refine the diagnosis and identify potentially targetable drivers.

https://ift.tt/2FdJTHR

Metformin targets Mitochondrial Glycerophosphate Dehydrogenase (mGPDH) to control Rate of Oxidative Phosphorylation and growth of thyroid cancer in vitro and in vivo

Purpose: Mitochondrial glycerophosphate dehydrogenase (mGPDH) is the key enzyme connecting oxidative phosphorylation (OXPHOS) and glycolysis as well as a target of the antidiabetic drug metformin (MF) in the liver. There are no data on the expression and role of mGPDH as a metformin target in cancer. In this study, we evaluated mGPDH as a potential target of metformin in thyroid cancer and investigated its contribution in thyroid cancer metabolism. Experimental design: We analyzed mGPDH expression in 253 thyroid cancer and normal tissues by immunostaining and examined its expression and localization in thyroid cancer-derived cell lines (FTC133, BCPAP) by confocal microscopy. The effects of metformin on mGPDH expression were determined by qRT-PCR and western blot.  Seahorse analyzer was utilized to assess the effects of metformin on OXPHOS and glycolysis in thyroid cancer cells. We analyzed the effects of metformin on tumor growth and mGPDH expression in metastatic thyroid cancer mouse models. Results: We show for the first time that mGPDH is overexpressed in thyroid cancer compared with normal thyroid. We demonstrate that mGPDH regulates human thyroid cancer cell growth and OXPHOS rate in vitro. Metformin treatment is associated with downregulation of mGPDH expression and inhibition of OXPHOS in thyroid cancer in vitro. Cells characterized by high mGPDH expression are more sensitive to OXPHOS-inhibitory effects of metformin in vitro and growth inhibitory effects of metformin in vitro and in vivo. Conclusion: Our study established mGPDH as a novel regulator of thyroid cancer growth and metabolism that can be effectively targeted by metformin.

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Eradicating H. Pylori Reduces Gastric Cancer Risk [News in Brief]

Patients with early disease treated for the bacterial infection were half as likely to develop a subsequent gastric cancer.

https://ift.tt/2HZN6hi

NFATc1 promotes anti-tumoral effector functions and memory CD8+ T cell differentiation during non-small cell lung cancer development

Nuclear factor of activated T cells 1 (NFATc1) is a transcription factor activated by T cell receptor (TCR) and Ca2+-signaling that affects T cell activation and effector function. Upon tumor antigen challenge, TCR and calcium-release-activated channels are induced, promoting NFAT dephosphorylation and translocation into the nucleus. In this study, we report a progressive decrease of NFATc1 in lung tumor tissue and in tumor-infiltrating lymphocytes (TIL) of patients suffering from advanced stage non-small cell lung cancer (NSCLC). Mice harboring conditionally inactivated NFATc1 in T cells (NFATc1ΔCD4) showed increased lung tumor growth associated with impaired T cell activation and function. Furthermore, in the absence of NFATc1, reduced IL 2 influenced the development of memory CD8+ T cells. We found a reduction of effector memory and CD103+ tissue-resident memory (TRM) T cells in the lung of tumor-bearing NFATc1ΔCD4 mice, underlining an impaired cytotoxic T cell response and a reduced TRM tissue-homing capacity. In CD4+ICOS+ T cells, programmed cell death 1 (PD-1) was induced in the draining lymph nodes of these mice and associated with lung tumor cell growth. Targeting PD-1 resulted in NFATc1 induction in CD4+ and CD8+ T cells in tumor-bearing mice and was associated with increased anti-tumor cytotoxic functions. This study reveals a role of NFATc1 in the activation and cytotoxic functions of T cells, in the development of memory CD8+ T cell subsets, and in the regulation of T cell exhaustion. These data underline the indispensability of NFATc1 for successful anti-tumor immune responses in NSCLC patients.

https://ift.tt/2HpICzi

The inhibitory NKR-P1B:Clr-b recognition axis facilitates detection of oncogenic transformation and cancer immunosurveillance

Natural killer (NK) cells express receptors specific for MHC class I (MHC-I) molecules involved in "missing-self" recognition of cancer and virus-infected cells. Here we elucidate the role of MHC-I-independent NKR-P1B:Clr-b interactions in the detection of oncogenic transformation by NK cells. Ras oncogene overexpression was found to promote a real-time loss of Clr-b on mouse fibroblasts and leukemia cells, mediated in part via the Raf/MEK/ERK and PI3K pathways. Ras-driven Clr-b downregulation occurred at the level of the Clrb (Clec2d) promoter, nascent Clr-b transcripts, and cell surface Clr-b protein, in turn promoting missing-self recognition via the NKR-P1B inhibitory receptor. Both Ras- and c-Myc-mediated Clr-b loss selectively augmented cytotoxicity of oncogene-transformed leukemia cells by NKR-P1B+ NK cells in vitro and enhanced rejection by WT mice in vivo. Interestingly, genetic ablation of either one (Clr-b+/-) or two Clr-b alleles (Clr-b-/-) enhanced survival of Eμ-cMyc transgenic mice in a primary lymphoma model despite preferential rejection of Clr-b-/- hematopoietic cells previously observed following adoptive transfer into naïve wild-type mice in vivo. Collectively, these findings suggest that the inhibitory NKR-P1B:Clr-b axis plays a beneficial role in innate detection of oncogenic transformation via NK cell-mediated cancer immune surveillance, in addition to a pathological role in the immune escape of primary lymphoma cells in Eμ-cMyc mice in vivo. These results provide a model for the human NKR-P1A:LLT1 system in cancer immunosurveillance in lymphoma patients and suggest it may represent a target for immune checkpoint therapy.

https://ift.tt/2HWN6hY

High USP6NL levels in breast cancer sustain chronic AKT phosphorylation and GLUT1 stability fueling aerobic glycolysis

USP6NL, also named RN-tre, is a GTPase activating protein (GAP) involved in control of endocytosis and signal transduction. Here we report that USP6NL is overexpressed in breast cancer (BC), mainly of the basal-like/integrative cluster 10 subtype. Increased USP6NL levels were accompanied by gene amplification and were associated with worse prognosis in the METABRIC dataset, retaining prognostic value in multivariable analysis. High levels of USP6NL in BC cells delayed endocytosis and degradation of the epidermal growth factor receptor (EGFR), causing chronic AKT activation. In turn, AKT stabilized the glucose transporter GLUT1 at the plasma membrane, increasing aerobic glycolysis. In agreement, elevated USP6NL sensitized BC cells to glucose deprivation, indicating that their glycolytic capacity relies on this protein. Depletion of USP6NL accelerated EGFR/AKT downregulation and GLUT1 degradation, impairing cell proliferation exclusively in BC cells that harbored increased levels of USP6NL. Overall, these findings argue that USP6NL overexpression generates a metabolic rewiring that is essential to foster the glycolytic demand of BC cells and promote their proliferation.

https://ift.tt/2FeQVfn

Exercise Intervention Doesn't Improve Walking Ability in PAD

TUESDAY, April 24, 2018 -- For patients with peripheral artery disease (PAD), a home-based exercise intervention does not improve walking ability over nine months compared with usual care, according to a study published in the April 24 issue of the...

https://ift.tt/2FdZDe1

Five-Day Nitrofurantoin Beats Single-Dose Fosfomycin for UTI

TUESDAY, April 24, 2018 -- Five-day nitrofurantoin is associated with increased likelihood of clinical and microbiological resolution compared with single-dose fosfomycin among women with lower urinary tract infection (UTI), according to a study...

https://ift.tt/2Kd8iRh

USPSTF Urges Abuse Screening for Reproductive-Aged Women

TUESDAY, April 24, 2018 -- The U.S. Preventive Services Task Force (USPSTF) has found that screening for intimate partner violence (IPV) is beneficial for reproductive-aged women, while there is inadequate evidence to weigh the balance of benefits...

https://ift.tt/2FdZgjD

Ticagrelor + Aspirin Beneficial After Elective CABG

TUESDAY, April 24, 2018 -- For patients undergoing elective coronary artery bypass grafting (CABG), ticagrelor + aspirin is associated with significantly increased saphenous vein graft patency rates compared with aspirin alone, according to a study...

https://ift.tt/2Kd8hNd

American College of Physicians, April 19-21

The American College of Physicians: Internal Medicine Meeting The annual meeting of the American College of Physicians (ACP) was held from April 19 to 21 in New Orleans and attracted more than 6,000 participants from around the world, including...

https://ift.tt/2Jrp0LU

Challenges in recruiting African-American women for a breast cancer genetics study

Abstract

Background

African-American women, especially in the southern United States, are underrepresented in cancer genetics research. A study was designed to address this issue by investigating the germline mutation rate in African-American women in Arkansas with a personal and/or family history of breast cancer. Women were tested for these mutations using a large panel of breast cancer susceptibility genes. In this analysis, we discuss the challenges encountered in recruiting African-American women from an existing biorepository to participate in this study.

Methods

We attempted to contact 965 African-American women with a personal and/or family history of breast cancer who participated in Spit for the Cure (SFTC) between 2007 and 2013 and provided consent to be recontacted. The SFTC participants were invited by telephone and email to participate in the genetic study. Enrollment required completion of a phone interview to obtain a family and medical history and return of a signed consent form.

Results

Among eligible SFTC participants, 39.6% (382/965) were able to be contacted with the phone numbers and email addresses they provided. Of these, 174 (45.5%) completed a phone interview and returned a signed consent form. Others were not able to be contacted (n = 583), declined to participate (n = 57), did not keep phone interview appointments (n = 82), completed the phone interview but never returned a signed consent (n = 54), were deceased (n = 13), or were too confused to consent to participate (n = 2).

Conclusions

Recruiting African-American women into our breast cancer genetics study proved challenging primarily due to difficulty establishing contact with potential participants. Given their prior participation in breast cancer research, we anticipated that this would be a highly motivated population. Indeed, when we were able to contact SFTC participants, only 14.9% declined to participate in our study. Innovative communication, retention, and recruitment strategies are needed in future studies to address the recruitment challenges we faced.

https://ift.tt/2qUutUi

Advances in Management of Esophageal Motility Disorders

The widespread adoption of high-resolution manometry (HRM) has led to a restructuring in the classification of esophageal motility disorder classification summarized in the Chicago Classification, currently in version 3.0. It has become apparent that the cardinal feature of achalasia, impaired lower esophageal sphincter relaxation, can occur in several disease phenotypes: without peristalsis, with premature (spastic) distal esophageal contractions, with panesophageal pressurization, or even with preserved peristalsis.

https://ift.tt/2qZCYN4

Worldwide Practice Patterns in Lynch Syndrome Diagnosis and Management, Based on Data From the International Mismatch Repair Consortium

Families with a history of Lynch syndrome often do not adhere to guidelines for genetic testing and screening. We investigated practice patterns related to Lynch syndrome worldwide, to ascertain potential targets for research and public policy efforts

https://ift.tt/2qXUmlA

Increased Risk of Acute Myocardial Infarction and Heart Failure in Patients With Inflammatory Bowel Diseases

There are conflicting data as to whether inflammatory bowel diseases (IBD) increase risk for cardiovascular disease. We sought to examine the risk of acute myocardial infarction (AMI) and heart failure in patients with IBD.

https://ift.tt/2HtzhL2

Budesonide Suppositories are Effective and Safe for Treating Acute Ulcerative Proctitis

Though proctitis is the most limited form of ulcerative colitis, it causes unpleasant symptoms. Topical mesalamine, the standard treatment, is not always effective. We conducted a randomized phase 2 trial to determine the efficacy and safety of 2 doses of a budesonide suppository vs mesalamine suppositories vs combined budesonide and mesalamine suppositories for proctitis.

https://ift.tt/2qZCKFI

Diets That Promote Colon Inflammation Associate With Risk of Colorectal Carcinomas That Contain Fusobacterium nucleatum

Specific nutritional components are likely to induce intestinal inflammation, which is characterized by increased levels of interleukin 6 (IL6), C-reactive protein (CRP), and TNF receptor superfamily member 1B (TNFRSF1B) in the circulation and promotes colorectal carcinogenesis. The inflammatory effects of a diet can be estimated based on empirical dietary inflammatory pattern (EDIP) score, calculated based on intake of 18 foods associated with plasma levels of IL6, CRP, and TNFRSF1B. An inflammatory environment in the colon (based on increased levels of IL6, CRP, and TNFRSF1B in peripheral blood) contributes to impairment of the mucosal barrier and altered immune cell responses, affecting the composition of the intestinal microbiota.

https://ift.tt/2Hp2Zka

Functional Dyspepsia and Severity of Psychologic Symptoms Associate With Postprandial Symptoms in Patients With Irritable Bowel Syndrome

Patients with irritable bowel syndrome (IBS) have an increased response of postprandial symptoms to a combined lactulose nutrient challenge test, compared with healthy volunteers. We investigated the associations among co-morbid functional dyspepsia (FD), severity of psychologic symptoms, and breath test results in response to this test.

https://ift.tt/2qYpkK7

Course of Esophageal Candidiasis and Outcomes of Patients at a Single Center

https://ift.tt/2Hq4BKv

Why EMS agencies should change their definition of intubation success

Dr. Jeffrey Jarvis, medical director for Williamson County (Texas) EMS, will discuss why delayed sequence intubation is a cure for Rapid Sequenced Death at EMS PRO conference

https://ift.tt/2HMSmag

Learn how to combat sleep deprivation and fatigue in EMS

Amy Eisenhauer to discuss health risks and performance impact of disrupted sleep, as well as strategies for overcoming these challenges, as part of EMS PRO conference

https://ift.tt/2HLs1t7

3 ways to overcome your fear of pediatric patients

Providing effective pediatric care starts with confronting your challenges with children

https://ift.tt/2vHXl7o

The impact of chromoendoscopy for surveillance of the duodenum in patients with MUTYH-associated polyposis and familial adenomatous polyposis

Duodenal polyposis and cancer have become a key issue for patients with familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). Almost all patients with FAP will develop duodenal adenomas, with 5% developing cancer. The incidence of duodenal adenomas in MAP appears to be lower than in FAP but the limited available data suggest a comparable increase in the relative risk and lifetime risk of duodenal cancer. Current surveillance recommendations, however, are the same for FAP and MAP, using the Spigelman score--incorporating polyp number, size, dysplasia, and histology--for risk stratification and determination of surveillance intervals.

https://ift.tt/2HJ2VLz

Helicobacter pylori-induced IL-33 modulates mast cell responses, benefits bacterial growth, and contributes to gastritis

Helicobacter pylori-induced IL-33 modulates mast cell responses, benefits bacterial growth, and contributes to gastritis

<i>Helicobacter pylori</i>-induced IL-33 modulates mast cell responses, benefits bacterial growth, and contributes to gastritis, Published online: 25 April 2018; doi:10.1038/s41419-018-0493-1

Helicobacter pylori-induced IL-33 modulates mast cell responses, benefits bacterial growth, and contributes to gastritis

https://ift.tt/2KbqL0A

Radio-Pathomic Maps of Epithelium and Lumen Density Predict the Location of High-Grade Prostate Cancer

This study aims to combine whole mount prostate pathology with multi-parametric magnetic resonance imaging from 39 patients in order to generate predictive maps of epithelium and lumen density in MRI space. We show that the new image contrasts generated stratify high grade tumors from low grade tumors and healthy tissue. Future studies will explore targeted radiation and clinical disease staging using the Radio-pathomic Mapping technique.

https://ift.tt/2HoeSqu

Radiation induced Secondary Tumors for Pediatric Central Nervous System Tumors Experiences of A Single Institute in Taiwan (1975-2013)

We analyzed the development of secondary tumors in 27 of 681 cases who received radiotherapy for pediatric brain tumors. The mean age was 8.8 years-old, the median radiation dose was 52.5 Gy, and the mean latency period was 14.6 years. Twenty-nine secondary tumors developed in 27 patients, corresponding to a 25-year cumulative incidence of 3.96%. Age below 7 years at irradiation, receipt of two-dimensional irradiation, and cranio-spinal irradiation increased the risk for a secondary tumor.

https://ift.tt/2qT2Dam

Multi-institutional analysis of vaginal brachytherapy alone for women with Stage II endometrial carcinoma

We performed a multi-institutional analysis of surgically staged patients with FIGO stage II endometrioid-type endometrial cancer treated with VBT alone. Majority of patients were grade 1-2, had microscopic cervical invasion, and underwent pelvic lymph node resection. Vaginal and pelvic failures were very low with VBT alone. It is reasonable to consider adjuvant VBT alone in selected patients with grade 1-2 disease and microscopic cervical stromal invasion who underwent pelvic node resection.

https://ift.tt/2qYOXuz

Preliminary study of magnetically controlled capsule gastroscopy for diagnosing superficial gastric neoplasia

Magnetically controlled capsule gastroscopy (MCCG) is a newly developed non-invasive method designed for gastric examination. Although favourable diagnostic accuracy has been reported, there is little if any data about its ability to diagnose gastric cancer.

https://ift.tt/2vG1lFt

Stable Causal Relationships Are Better Causal Relationships

Cognitive Science, EarlyView.


https://ift.tt/2qX2GCM

The Reference of Proper Names: Testing Usage and Intuitions

Cognitive Science, EarlyView.


https://ift.tt/2JmyZBR

The Role of Design and Training in Artifact Expertise: The Case of the Abacus and Visual Attention

Cognitive Science, EarlyView.


https://ift.tt/2qSDGNe

Neonatal Intensive Care Unit Length of Stay Reduction by Heart Rate Characteristics Monitoring

To examine the effect of heart rate characteristics (HRC) monitoring on length of stay among very low birth weight (VLBW; <1500 g birth weight) neonates in the HeRO randomized controlled trial (RCT).

https://ift.tt/2HKoc7n

Enhancing Parent Talk, Reading, and Play in Primary Care: Sustained Impacts of the Video Interaction Project

To determine the early impacts of pediatric primary care parenting interventions on parent cognitive stimulation in low socioeconomic status families and whether these impacts are sustained up to 1.5 years after program completion.

https://ift.tt/2qWgIVj

Closer to Universal Newborn Screening for Congenital Cytomegalovirus Infection but Far Away from Antiviral Therapy in All Infected Infants

In this volume of The Journal, 2 studies address the diagnosis and management of infants with congenital cytomegalovirus (cCMV) infection. Lu et al report on a prospective study evaluating the feasibility of incorporating cytomegalovirus (CMV) and genetic screening for common hearing loss mutations into current newborn hearing screening (NBHS) programs in Taiwan.1 Pasternak et al retrospectively describe their experience with antiviral therapy in a small uncontrolled cohort of infants with cCMV infection who have isolated sensorineural hearing loss (SNHL) but otherwise are asymptomatic.

https://ift.tt/2vJnjao

Learning and Encouragement Effects on Six-Minute Walking Test in Children

To evaluate learning and encouragement effects on the 6-minute walk test in children between 6 and 12 years of age.

https://ift.tt/2vFNLSe

The emergence of top‐down, sensory prediction during learning in infancy: A comparison of full‐term and preterm infants

Developmental Psychobiology, EarlyView.


https://ift.tt/2vHM5Yp

The Isolation and Culture of Primary Epicardial Cells Derived from Human Adult and Fetal Heart Specimens

The epicardium plays a crucial role in the development and repair of the heart by providing cells and growth factors to the myocardial wall. Here, we describe a method to culture human primary epicardial cells that enables the study and comparison of their developmental and adult characteristics.

https://ift.tt/2HpvG0q

Protocol for Acute and Chronic Ecotoxicity Testing of the Turquoise Killifish Nothobranchius furzeri

In this work, we describe an acute, chronic and multigenerational bioassay to study the effects of single and combined stressors on the Turquoise killifish Nothobranchius furzeri. This protocol is designed to study life-history traits (mortality, growth, fecundity, weight) and critical thermal maximum.

https://ift.tt/2qZxy4P

Guidelines Developed for Use of Drugs in Multiple Sclerosis

TUESDAY, April 24, 2018 -- Guidelines have been developed for use of disease-modifying therapies (DMTs) in multiple sclerosis (MS), integrating findings from a systematic review. The review and guidelines were published online April 23 in...

https://ift.tt/2FdkTk5

Preteens Metabolically Comparable to Trained Athletes

TUESDAY, April 24, 2018 -- Prepubertal children are metabolically comparable to adult endurance athletes, and less fatiguable with high intensity exercise than untrained adults, according to a study published online April 24 in the Frontiers in...

https://ift.tt/2KaW2Ri

Evening Preference Linked to Higher BMI in Type 2 Diabetes

TUESDAY, April 24, 2018 -- Evening preference and a later breakfast are associated with elevated body mass index (BMI) in adults with type 2 diabetes, according to a study published online April 13 in Diabetic Medicine. Hataikarn Nimitphong, M.D.,...

https://ift.tt/2FbolLW

Black Men More Likely to Die From Firearm Homicide

TUESDAY, April 24, 2018 -- Firearm homicides are much more common among black men compared to white men, particularly in rust belt states, according to a study published online April 24 in the Annals of Internal Medicine. Corinne A. Riddell, Ph.D.,...

https://ift.tt/2K75g1b

Serlopitant Found to Be Safe, Effective for Chronic Pruritus

TUESDAY, April 24, 2018 -- Serlopitant has potential as a therapy for the treatment of chronic pruritus, according to a study published in the May issue of the Journal of the American Academy of Dermatology. Gil Yosipovitch, M.D., from the...

https://ift.tt/2JkiSoE

E-Cigarette Use Tied to Subsequent Marijuana Use in Teens

TUESDAY, April 24, 2018 -- Electronic cigarette (e-cigarette) use is associated with increased subsequent marijuana use among adolescents, according to a study published online April 23 in Pediatrics. Hongying Dai, Ph.D., from Children's Mercy...

https://ift.tt/2KbHgtR

One in Four Adults Report Having Arthritis

TUESDAY, April 24, 2018 -- Between 1999 and 2014, nearly one-quarter of American adults reported having arthritis, according to a study published recently in the American Journal of Public Health. Juyoung Park, Ph.D., from the Florida Atlantic...

https://ift.tt/2FbohMc

Linear Link for Physical Activity, Amyotrophic Lateral Sclerosis

TUESDAY, April 24, 2018 -- There is a linear correlation for physical activity (PA) with amyotrophic lateral sclerosis (ALS), according to a study published online April 23 in the Journal of Neurology, Neurosurgery & Psychiatry. Anne E. Visser,...

https://ift.tt/2Kebrk6

In Utero Caffeine Exposure Affects Early Childhood Weight

TUESDAY, April 24, 2018 -- Maternal caffeine intake during pregnancy may alter the overall weight growth trajectory of the offspring from 6 weeks to 8 years, according to a study published online April 23 in BMJ Open. Eleni Papadopoulou, from the...

https://ift.tt/2JkiPJu

Alcohol Intake May Influence Oral Microbiome Composition

TUESDAY, April 24, 2018 -- Alcohol consumption, specifically heavy drinking, may influence the oral microbiome composition, according to a study published online April 24 in Microbiome. Xiaozhou Fan, from NYU School of Medicine in New York City, and...

https://ift.tt/2KbHb9x

Deterministic-aided single dataset STAP method based on sparse recovery in heterogeneous clutter environments

Traditional space-time adaptive processing (STAP) usually needs many independent and identically distributed (i.i.d) training datasets for estimating clutter covariance matrix (CCM). But this requirement is ha...

https://ift.tt/2Jn06gk

Correlation feature-based detector for range distributed target in sea clutter

In this paper, a novel correlation feature-based detector is proposed to deal with the challenging problem of detecting a range-distributed target embedded in nonstationary sea clutter. It is well known that s...

https://ift.tt/2HLjvdt

Syntheses, Crystallization, and Spectroscopic Characterization of 3,5-Lutidine N-Oxide Dehydrate

Herein, we report the synthesis and crystallization of 3,5-lutidine N-oxide dehydrate by a simple protocol that differs from the classical synthesis of pyridine N-oxide. This protocol utilizes different starting material and involves less reaction time to yield a new solvated supramolecular structure, which crystallizes under slow evaporation.

https://ift.tt/2qT2zbE

W.Va. fire chief makes TIME’s top 100 influential people list

By EMS1 Staff HUNTINGTON, W.Va. — A fire chief who has gained national attention for being a leader in the fight against the opioid crisis was named one of TIME's Top 100 Influential People of 2018. WSAZ reported that Huntington Fire Department Chief Jan Rader, who was recently featured in the Netflix documentary "Heroin(e)," said she is "honored" to be recognized ...

https://ift.tt/2vGQcUP

Acceleration of carboxylesterase-mediated activation of irinotecan to SN-38 by serum from patients with end-stage kidney disease

Abstract

Purpose

Pharmacokinetics and pharmacodynamics of irinotecan have been reported to be altered in cancer patients with end-stage kidney disease (ESKD). Carboxylesterase (CES) has an important role in metabolism of irinotecan to its active metabolite, SN-38, in human liver. The purpose of the present study was to investigate whether CES activity was altered in ESKD patients.

Methods

The present study investigated the effects of uremic serum, uremic toxins, and fatty acids on the hydrolysis of irinotecan and a typical CES substrate, p-nitrophenyl acetate (PNPA), in human liver microsomes. Normal and uremic serum samples were deproteinized by treatment with methanol were used in the present study.

Results

The present study showed that both normal and uremic serum significantly inhibited CES-mediated metabolism of both irinotecan and PNPA. The inhibition by uremic serum was weaker than that by normal serum, suggesting that CES activity may be higher in ESKD patients. Although four uremic toxins did not affect PNPA metabolism, arachidonic acid inhibited it. There was no difference in inhibitory effect of PNPA metabolism between both mixtures of seven fatty acids used at concentrations equivalent to those present in 10% normal or uremic serum. Interestingly, those mixtures had a more pronounced effect than either 10% normal or uremic serum.

Conclusions

The present study showed that the inhibition of CES activity by uremic serum was weaker than that by normal serum, suggesting that an increase in maximum plasma concentration of SN-38 in cancer patients with ESKD can be attributed to an accelerated CES-mediated irinotecan hydrolysis.

https://ift.tt/2HTYTxj

IL-8 regulates the doxorubicin resistance of colorectal cancer cells via modulation of multidrug resistance 1 (MDR1)

Abstract

Cytokines play important roles in tumorigenesis and progression of cancer cells, while their functions in drug resistance remain to be illustrated. We successfully generated doxorubicin (Dox)-resistant CRC HCT-116 and SW480 cells (namely HCT-116/Dox and SW480/Dox, respectively). Cytokine expression analysis revealed that IL-8, while not FGF-2, EGF, TGF-β, IL-6, or IL-10, was significantly increased in Dox-resistant CRC cells as compared with their corresponding parental cells. Targeted inhibition of IL-8 via siRNAs or its inhibitor reparixin can increase the Dox sensitivity of HCT-116/Dox and SW480/Dox cells. The si-IL-8 can decrease the mRNA and protein expression of multidrug resistance 1 (MDR1, encoded by ABCB1), while has no effect on the expression of multidrug resistance-associated protein 1 (ABCC1), in CRC Dox-resistant cells. IL-8 can increase the phosphorylation of p65 and then upregulate the binding between p65 and promoter of ABCB1. BAY 11-7082, the inhibitor of NF-κB, suppressed the recombination IL-8 (rIL-8) induced upregulation of ABCB1. It confirmed that NF-κB is involved in IL-8-induced upregulation of ABCB1. rIL-8 also increased the phosphorylation of IKK-β, which can further activate NF-κB, while specific inhibitor of IKK-β (ACHP) can reverse rIL-8-induced phosphorylation of p65 and upregulation of MDR1. These results suggested that IL-8 regulates the Dox resistance of CRC cells via modulation of MDR1 through IKK-β/p65 signals. The targeted inhibition of IL-8 might be an important potential approach to overcome the clinical Dox resistance in CRC patients.

https://ift.tt/2HobA2t

Low concentrations of 25-hydroxyvitamin D and long-term prognosis of COPD: a prospective cohort study

Abstract

Role and importance of vitamin D deficiency in long-term prognosis of chronic obstructive pulmonary disease (COPD) still remains undetermined. We tested the hypothesis that among individuals with COPD, those with low concentrations of 25-hydroxyvitamin D have a poorer prognosis compared to those with normal concentrations. We studied 35,153 individuals from the general population aged 20–100 years with 25-hydroxyvitamin D measurements and spirometry, the Copenhagen City Heart Study [median follow-up 21 years (range 13 days–36 years)] and the Copenhagen General Population Study [7.1 years (3 days–13 years)]. Spirometric COPD (n = 5178; 15% of all) was defined as forced expiratory volume in 1 s (FEV₁)/forced vital capacity (FVC) < 0.70 in individuals without asthma and clinical COPD (n = 2033; 6%) as FEV₁/FVC < 0.70 and FEV₁ < 80% of predicted in ever-smokers aged > 40 years without asthma and with cumulative tobacco consumption ≥ 10 pack-years. In spirometric COPD, median age at death in years was 70.2 (95% confidence interval [CI] 64.4–71.2) for individuals with 25-hydroxyvitamin D < 12.5 nmol/L and 80.3 (74.4–83.4) for those with ≥ 50 nmol/L. In clinical COPD, corresponding values were 69.0 (63.3–70.9) and 76.2 (73.8–78.0). In spirometric COPD, multivariable adjusted hazard ratios for individuals with 25-hydroxyvitamin D < 12.5 nmol/L versus those with ≥ 50 nmol/L were 1.35 (95% CI 1.09–1.67) for all-cause mortality, 1.63 (1.00–2.64) for respiratory mortality, 1.14 (0.76–1.70) for cardiovascular mortality, 1.37 (0.90–2.06) for cancer mortality, and 1.61 (1.04–2.49) for other mortality. In clinical COPD, corresponding values were 1.39 (1.07–1.82), 1.57 (0.91–2.72), 0.88 (0.51–1.53), 1.63 (0.99–2.67), and 2.00 (1.12–3.56). Low concentrations of 25-hydroxyvitamin D were associated with an increased risk of death in individuals with COPD. No clear pattern of association could be observed for cause of death; however, there may be an increased risk of respiratory, cancer, and other mortality. It is likely that low concentrations of 25-hydroxyvitamin D is a marker of poor health in COPD.

https://ift.tt/2Jk8AVt

Marine-derived protein kinase inhibitors for neuroinflammatory diseases

Neuroinflammation is primarily characterized by overexpression of proinflammatory mediators produced by glial activation or immune cell infiltration. Several kinases have been shown to be critical mediators in...

https://ift.tt/2JlR8zO

Gamma rays excited radioluminescence tomographic imaging

Radionuclide-excited luminescence imaging is an optical radionuclide imaging strategy to reveal the distributions of radioluminescent nanophosphors (RLNPs) inside small animals, which uses radioluminescence em...

https://ift.tt/2qSfM4s

Tumor-originated exosomal lncUEGC1 as a circulating biomarker for early-stage gastric cancer

Abstract

Conventional tumor markers for non-invasive diagnosis of gastric cancer (GC) exhibit insufficient sensitivity and specificity to facilitate detection of early gastric cancer (EGC). We aimed to identify EGC-specific exosomal lncRNA biomarkers that are highly sensitive and stable for the non-invasive diagnosis of EGC. Hence, in the present study, exosomes from the plasma of five healthy individuals and ten stage I GC patients and from culture media of four human primary stomach epithelial cells and four gastric cancer cells (GCCs) were isolated. Exosomal RNA profiling was performed using RNA sequencing to identify EGC-specific exosomal lncRNAs. A total of 79 and 285 exosomal RNAs were expressed at significantly higher levels in stage I GC patients and GCCs, respectively, than that in normal controls. Through combinational analysis of the RNA sequencing results, we found two EGC-specific exosomal lncRNAs, lncUEGC1 and lncUEGC2, which were further confirmed to be remarkably up-regulated in exosomes derived from EGC patients and GCCs. Furthermore, stability testing demonstrates that almost all the plasma lncUEGC1 was encapsulated within exosomes and thus protected from RNase degradation. The diagnostic accuracy of exosomal lncUEGC1 was evaluated, and lncUEGC1 exhibited AUC values of 0.8760 and 0.8406 in discriminating EGC patients from healthy individuals and those with premalignant chronic atrophic gastritis, respectively, which was higher than the diagnostic accuracy of carcinoembryonic antigen. Consequently, exosomal lncUEGC1 may be promising in the development of highly sensitive, stable, and non-invasive biomarkers for EGC diagnosis.

https://ift.tt/2K6XzrP

Modelling steroidogenesis: a framework model to support hypothesis generation and testing across endocrine studies

Steroid hormones are responsible for the control of a wide range of physiological processes such as development, growth, reproduction, metabolism, and aging. Because of the variety of enzymes, substrates and p...

https://ift.tt/2Kcjb5R

Combination therapy involving radiofrequency ablation and targeted chemotherapy with bevacizumab plus paclitaxel and cisplatin in a rabbit VX2 lung tumor model

Radiofrequency ablation (RFA) is less effective for large tumors > 3 cm in diameter. Various studies of combination therapy using RFA and other treatments have been conducted to improve the results of RFA trea...

https://ift.tt/2JpgMUz

Gonococcal sepsis in a 32-year-old female: a case report

Neisseria gonorrhoeae is a Gram-negative bacterium which affects the urethra, throat, rectum and cervix of patients and often associated with sexually transmitted infections. The global epidemiology of the diseas...

https://ift.tt/2KaFKIl

Effectiveness of implementing a best practice primary healthcare model for low back pain (BetterBack) compared with current routine care in the Swedish context: an internal pilot study informed protocol for an effectiveness-implementation hybrid type 2 trial

Introduction

Low back pain (LBP) is a major health problem commonly requiring healthcare. In Sweden, there is a call from healthcare practitioners (HCPs) for the development, implementation and evaluation of a best practice primary healthcare model for LBP.

Aims

(1) To improve and understand the mechanisms underlying changes in HCP confidence, attitudes and beliefs for providing best practice coherent primary healthcare for patients with LBP; (2) to improve and understand the mechanisms underlying illness beliefs, self-care enablement, pain, disability and quality of life in patients with LBP; and (3) to evaluate a multifaceted and sustained implementation strategy and the cost-effectiveness of the BetterBack☺ model of care (MOC) for LBP from the perspective of the Swedish primary healthcare context.

Methods

This study is an effectiveness-implementation hybrid type 2 trial testing the hypothesised superiority of the BetterBack☺ MOC compared with current routine care. The trial involves simultaneous testing of MOC effects at the HCP, patient and implementation process levels. This involves a prospective cohort study investigating implementation at the HCP level and a patient-blinded, pragmatic, cluster, randomised controlled trial with longitudinal follow-up at 3, 6 and 12 months post baseline for effectiveness at the patient level. A parallel process and economic analysis from a healthcare sector perspective will also be performed. Patients will be allocated to routine care (control group) or the BetterBack☺ MOC (intervention group) according to a stepped cluster dogleg structure with two assessments in routine care. Experimental conditions will be compared and causal mediation analysis investigated. Qualitative HCP and patient experiences of the BetterBack☺ MOC will also be investigated.

Dissemination

The findings will be published in peer-reviewed journals and presented at national and international conferences. Further national dissemination and implementation in Sweden and associated national quality register data collection are potential future developments of the project.

Date and version identifier

13 December 2017, protocol version 3.

Trial registration number

NCT03147300; Pre-results.

https://ift.tt/2Ho9TGh

Cross-sectional study on the prevalence and predictors of pregnancy among women living in HIV discordant relationships in a rural Rakai cohort, Uganda

Objectives

This study examines the prevalence of pregnancy in serodiscordant couples and identifies predictors associated with pregnancy in rural Rakai, Uganda.

Study design

A population-based cross-sectional study that used data from the Rakai Community Cohort Study (RCCS).

Setting and participants

We used data from the RCCS survey round 17 (2015–2016), which included 488 women in serodiscordant relationships. This study was conducted in Rakai district, located in south-western Uganda.

Primary outcomes

Pregnancy status.

Statistical analysis

Multivariable modified Poisson regression using stepwise selection was used to determine characteristics and behaviours associated with pregnancy status.

Results

The prevalence of pregnancy was 12% in women among serodiscordant couples. HIV-negative women in serodiscordant couples had a slightly higher pregnancy prevalence rate (13.6%) compared with HIV-positive women in serodiscordant couples (11%). Factors significantly associated with higher prevalence of pregnancy were; younger age 15–24 years (prevalence risk ratio (PRR)=4.04; 95% CI 1.72 to 9.50), middle age 25–34 years (PRR=2.49; 95% CI 1.05 to 5.89), Christian religion (PRR=2.26; 95% CI 1.41 to 3.63) and inconsistent condom use in the last 12 months (PRR=4.38, 95% CI 1.09 to 17.53). Neither HIV status nor HIV status disclosure was significantly associated with risk of getting pregnant.

Conclusion

Nearly 12% of women in serodiscordant relationships were pregnant, highlighting the need for integrated services to prevent unintended pregnancies and reduce conceptional related risks for those choosing to conceive. Association with younger age and inconsistent condom use suggests a role for early and continued couple-based conception counselling.

https://ift.tt/2Ho9Z0B

Modern contraceptive use among HIV-infected women attending HIV care centres in Togo: a cross-sectional study

Introduction

Contraceptive use among HIV-infected women in Togo is poorly documented. We aim at assessing the prevalence of modern contraceptive use and associated factors among HIV-infected women in Togo.

Design

Cross-sectional study.

Setting

The study was conducted in five HIV care centres in the Centrale and Kara regions in Togo.

Participants

We included 461 HIV-positive women aged between 15 and 49 years and who were sexually active.

Main outcome measure

The outcome variable was HIV-infected women who were using modern contraceptive methods.

Results

A total of 461 HIV-infected women were interviewed, with an average age of 34.3 (±7.1). Among them, 332 (73.1%) women reported using contraceptive methods, mostly condom alone (74.7%) or in combination with hormonal contraceptive (16.9%). In multivariate analysis, education level (primary: adjusted OR (aOR)=1.99, 95% CI (1.05 to 3.76); secondary level and higher: aOR=3.95, 95% CI (2.03 to 7.67)), WHO clinical stage (stage II: aOR=0.7, 95% CI (0.37 to 1.33)), follow-up in private care facilities (aOR=2.54, 95% CI (1.22 to 5.29)) and having a child (aOR=2.51, 95% CI (1.41 to 4.5)) were associated with higher contraceptive use, while marital status (living in union: aOR=0.45, 95% CI (0.28 to 0.74)) and WHO stages III and IV (aOR=0.47, 95% CI (0.24 to 0.94)) were associated with lower contraceptive use.

Conclusion

About three-quarters of sexually active HIV-infected women in Togo were using contraceptive methods, and private health facilities favoured this contraceptive use. It is important to strengthen the implementation of interventions to increase the incentives for HIV-infected women to use contraception in Togo.

https://ift.tt/2qXmiWO

Understanding influences on the uptake of pulmonary rehabilitation in the East of England: an Inclusive Design/mixed-methods study protocol

Introduction

1.2 million people in the UK have chronic obstructive pulmonary disease (COPD) that causes breathlessness, difficulty with daily activities, infections and hospitalisation. Pulmonary rehabilitation (PR), a programme of supervised exercise and education, is recommended for patients with COPD. However, only 1 in 10 of those who need it receive PR. Also, the UK National COPD Audit Programme concluded that the COPD treatment might not be accessible to people with disabilities. This paper applies an Inclusive Design approach to community-based PR service provisions. It aims to inform improvements to the PR service by identifying barriers to the uptake of PR in the COPD care journey in relation to patients' capabilities that can affect their access to PR.

Methods and analysis

The protocol includes four steps. Step 1 will involve interviews with healthcare professionals and patients to gather insight into their experiences and produce a hierarchical task analysis of the COPD care journeys. Step 2 will estimate the service exclusion: the demand of every task on patients' capabilities will be rated by predefined scales, and the proportion of the population excluded from the service will be estimated by an exclusion calculator. Step 3 will identify the challenges of the PR service; a framework analysis will guide the data analysis of the interviews and care journey. Step 4 will propose recommendations to help patients manage their COPD care informed by the challenges identified in step 3 and refine recommendations through interviews and focus groups.

Ethics and dissemination

The Cambridge Central Research Ethics Committee gave the study protocol a positive ethical opinion (17/EE/0136). Study results will be disseminated through peer-reviewed journals, conferences and the British Lung Foundation networks. They will also be fed into a Research for Patient Benefit project on increasing the referral and uptake of PR.

https://ift.tt/2r1Q2Sv

'To be a woman is to make a plan: a qualitative study exploring mothers experiences of the Child Support Grant in supporting childrens diets and nutrition in South Africa

Food security and good nutrition are key determinants of child well-being. There is strong evidence that cash transfers such as South Africa's Child Support Grant (CSG) have the potential to help address some of the underlying drivers of food insecurity and malnutrition by providing income to caregivers in poor households, but it is unclear how precisely they work to affect child well-being and nutrition. We present results from a qualitative study conducted to explore the role of the CSG in food security and child well-being in poor households in an urban and a rural setting in South Africa.

Setting

Mt Frere, Eastern Cape (rural area); Langa, Western Cape (urban township).

Participants

CSG recipient caregivers and community members in the two sites . We conducted a total of 40 in-depth interviews with mothers or primary caregivers in receipt of the CSG for children under the age of 5 years. In addition, five focus group discussions with approximately eight members per group were conducted. Data were analysed using manifest and latent thematic content analysis methods.

Results

The CSG is too small on its own to improve child nutrition and well-being. Providing for children's diets and nutrition competes with other priorities that are equally important for child well-being and nutrition.

Conclusions

In addition to raising the value of the CSG so that it is linked to the cost of a nutritious basket of food, more emphasis should be placed on parallel structural solutions that are vital for good child nutrition outcomes and well-being, such as access to free quality early child development services that provide adequate nutritious meals, access to adequate basic services and the promotion of appropriate feeding, hygiene and care practices.

https://ift.tt/2qSDRqS

Health-related quality of life in Chinese inpatients with lung cancer treatedin large general hospitals: across-sectional study

Objective

In China, psychosocial problems of patients with cancer are under-recognised and undertreated in medical oncology practice. This study examined the health-related quality of life (QOL) in inpatients with lung cancer treated in large general hospitals and explored the demographic, clinical and psychosocial factors associated with QOL.

Design

Cross-sectional study.

Participants and setting

Altogether, 148 inpatients with lung cancer were consecutively recruited from two large general hospitals in Tianjin, China.

Main outcome measured

QOL, pain intensity, depressive and anxiety symptoms, and social support were assessed with WHO QOL Scale Brief Version, four-point Verbal Rating Scale, Hospital Anxiety and Depression Scale and Social Support Rating Scale, respectively.

Results

Compared with the normative data for the Chinese general population, patients had significantly lower scores in physical (t=–25.860, p<0.001) and psychological (t=–18.225, p<0.001) QOL. Being unmarried (β=–2.471, 95% CI –4.908 to –0.034), poor economic status (β=–1.764, 95% CI –2.964 to –0.564), cancer metastasis (β=–1.328, 95% CI –2.632 to –0.024), poor performance status (β=–0.959, 95% CI –1.542 to –0.376), depression (β=–0.465, 95% CI –0.631 to –0.299), anxiety (β=–0.208, 95% CI –0.354 to –0.062) and low utilisation of social support (β=–0.344, 95% CI –0.577 to –0.111) were independently associated with poor physical QOL, while female gender (β=–1.494, 95% CI –0.649 to –2.339), less education years (β=–0.209, 95% CI –0.294 to –0.123), currently receiving chemotherapy (β=–1.536, 95% CI –3.051 to –0.021), small-cell cancer (β=–1.157, 95% CI –2.223 to –0.091), more intense pain (β=–0.535, 95% CI –0.919 to –0.151), poor performance status (β=–0.930, 95% CI –1.383 to –0.477), anxiety (β=–0.178, 95% CI –0.248 to –0.108) and inadequate subjective social support (β=–0.137, 95% CI –0.153 to –0.121) were independently associated with poor psychological QOL.

Conclusions

Inpatients with lung cancer treated in Chinese large general hospitals have poorer QOL than the general population. Effective prevention and management of psychosocial problems are potentially effective to improve their QOL.

https://ift.tt/2Hoa705

Role and prevalence of impaired awareness of hypoglycaemia in ambulance service attendances to people who have had a severe hypoglycaemic emergency: a mixed-methods study

Objectives

(1) To compare the experiences of people who are affected by diabetes-related hypoglycaemia and either do or do not require an emergency attendance and (2) to measure the prevalence of impaired awareness of hypoglycaemia in patients who are attended by an ambulance service due to a severe hypoglycaemic event.

Design

A sequential mixed-methods study.

Setting

A qualitative interview study was undertaken with 31 people with diabetes (types 1 and 2) resident in the central belt of Scotland. A national prevalence survey of 590 Scottish Ambulance Service patients who had recently experienced a severe hypoglycaemic emergency requiring ambulance clinicians attendance. Impaired awareness of hypoglycaemia was measured using two standardised measures.

Results

Considerable differences in impaired awareness of hypoglycaemia were found in the experiences of participants who did or did not require the ambulance service to treat their severe hypoglycaemic events. Those who required an ambulance reported fewer warning signs and symptoms. The prevalence of impaired awareness of hypoglycaemia in ambulance service call-outs as assessed by two standardised measures was 53% and 60%, respectively.

Conclusions

The prevalence of impaired awareness of hypoglycaemia among those who require an ambulance following a hypoglycaemic event is more than twice that found in the general population of people with diabetes. This may be because the experiences of impaired awareness in people who require an ambulance following a severe hypoglycaemic event differ to those who do not. This study provides important information to guide future prehospital clinical practice, and to develop and evaluate theoretically informed interventions. Improvements in prehospital care for this patient population could lead to global improvements in health outcomes and decreased service costs.

https://ift.tt/2r1Q4K7

Sex differences in macronutrient intake and adherence to dietary recommendations: findings from the UK Biobank

Objectives

To characterise sex differences in macronutrient intakes and adherence to dietary recommendations in the UK Biobank population.

Design

Cross-sectional population-based study.

Setting

UK Biobank Resource.

Participants

210 106 (52.5% women) individuals with data on dietary behaviour.

Main outcome measures

Women-to-men mean differences in nutrient intake in grams and as a percentage of energy and women-to-men ORs in non-adherence, adjusting for age, socioeconomic status and ethnicity.

Results

There were sex differences in energy intake and distribution. Men had greater intakes of energy and were less likely to have energy intakes above the estimated average requirement compared with women. Small, but significant, sex differences were found in the intakes of all macronutrients. For all macronutrients, men had greater absolute intakes while women had greater intakes as a percentage of energy. Women were more likely to have intakes that exceeded recommendations for total fat, saturated fat and total sugar. Men were less likely to achieve the minimum recommended intakes for protein, polyunsaturated fat and total carbohydrate. Over 95% of men and women were non-adherent to fibre recommendations. Sex differences in dietary intakes were moderated by age and to some extent by socioeconomic status.

Conclusions

There are significant sex differences in adherence to dietary recommendations, particularly for sugar. However, given the increased focus on food groups and dietary patterns for nutritional policy, these differences alone may not be sufficient for policy and health promotion. Future studies that are able to explore the sex differences in intakes of different food groups that are risk factors for diet-related diseases are warranted to improve the current understanding of the differential impact of diet on health in women and men.

https://ift.tt/2HnF30u

Hypertensive pregnancy complications in women with epilepsy and antiepileptic drugs: a population-based cohort study of first pregnancies in Norway

Objectives

To estimate the risk of hypertensive pregnancy complications in women with epilepsy, with and without antiepileptic drugs, and assess the risk associated with the four most common antiepileptic drugs.

Design

A population-based cohort study using linked data from the Medical Birth Registry of Norway and the Norwegian Prescription Database. Women with epilepsy with and without antiepileptic drugs were compared with women without epilepsy.

Setting

Norway, 2004–2012.

Participants

All first pregnancies of women with epilepsy and women without epilepsy were included.

Primary and secondary outcome measures

Main outcome measures were hypertensive pregnancy complications: a compound variable of any hypertensive disorder, gestational hypertension, mild pre-eclampsia, severe pre-eclampsia, early onset pre-eclampsia, eclampsia and HELLP syndrome (haemolysis, elevated liver enzymes, low platelets).

Results

In total, 1778 pregnancies in women with epilepsy and 221 662 in women without epilepsy were analysed. 682 of the women with epilepsy used antiepileptic drugs, the most common in monotherapy being: lamotrigine (n=280), carbamazepine (n=94), levetiracetam (n=71) and valproate (n=51). There was an increased risk of any hypertensive disorder in women with epilepsy (adjusted OR (aOR) 1.2, 95% CI 1.0 to 1.5) and in the subcategory using valproat (aOR 2.9, 95% CI 1.3 to 6.4). The most frequent hypertensive complication was mild pre-eclampsia and the risk was increased in women with epilepsy (aOR 1.4, 95% CI 1.1 to 1.8) and women with epilepsy with valproat (aOR 3.3, 95% CI 1.2 to 9.4).

Conclusions

Women with epilepsy have an increased risk of mild pre-eclampsia, but not for the severe types of hypertensive pregnancy complications. Lamotrigine and levetiracetam do not predispose for mild pre-eclampsia, whereas valproate was associated with an increased risk of mild pre-eclampsia.

https://ift.tt/2qXQXD5

Nursing workload, patient safety incidents and mortality: an observational study from Finland

Objective

To investigate whether the daily workload per nurse (Oulu Patient Classification (OPCq)/nurse) as measured by the RAFAELA system correlates with different types of patient safety incidents and with patient mortality, and to compare the results with regressions based on the standard patients/nurse measure.

Setting

We obtained data from 36 units from four Finnish hospitals. One was a tertiary acute care hospital, and the three others were secondary acute care hospitals.

Participants

Patients' nursing intensity (249 123 classifications), nursing resources, patient safety incidents and patient mortality were collected on a daily basis during 1 year, corresponding to 12 475 data points. Associations between OPC/nurse and patient safety incidents or mortality were estimated using unadjusted logistic regression models, and models that adjusted for ward-specific effects, and effects of day of the week, holiday and season.

Primary and secondary outcome measures

Main outcome measures were patient safety incidents and death of a patient.

Results

When OPC/nurse was above the assumed optimal level, the adjusted odds for a patient safety incident were 1.24 (95% CI 1.08 to 1.42) that of the assumed optimal level, and 0.79 (95% CI 0.67 to 0.93) if it was below the assumed optimal level. Corresponding estimates for patient mortality were 1.43 (95% CI 1.18 to 1.73) and 0.78 (95% CI 0.60 to 1.00), respectively. As compared with the patients/nurse classification, models estimated on basis of the RAFAELA classification system generally provided larger effect sizes, greater statistical power and better model fit, although the difference was not very large. Net benefits as calculated on the basis of decision analysis did not provide any clear evidence on which measure to prefer.

Conclusions

We have demonstrated an association between daily workload per nurse and patient safety incidents and mortality. Current findings need to be replicated by future studies.

https://ift.tt/2HoakjT

Long-term neuroprotective effect of erythropoietin on executive functions in very preterm children (EpoKids): protocol of a prospective follow-up study

Introduction

Premature infants are particularly vulnerable to brain injuries with associated cognitive and behavioural deficits. The worldwide first randomised interventional multicentre trial investigating the neuroprotective effects of erythropoietin (entitled 'Does erythropoietin improve outcome in very preterm infants?' (NCT00413946)) included 450 very preterm infants in Switzerland. MRI at term equivalent age showed less white matter (WM) injury in the erythropoietin group compared with the placebo group. Despite these promising imaging findings, neurodevelopmental outcome at 2 years showed no beneficial effect of early erythropoietin. One explanation could be that the assessment of more complex cognitive functions such as executive functions (EFs) is only possible at a later age. We hypothesise that due to improved WM development and fewer WM injuries, children born preterm treated with early erythropoietin will have better EF abilities at 7–12 years than those treated with placebo.

Methods and analysis

365 children who were included into the primary analysis of the original trial (NCT00413946) will be eligible in this prospective follow-up study at the age of 7–12 years. 185 children born at term will be control children. Primary outcome measures are EF abilities and processing speed, while secondary outcomes are academic performance, IQ, fine motor abilities and global brain connectivity. A comprehensive test battery will be applied to assess EFs. MRI will be performed to assess global brain connectivity. Cognitive scores and MRI measures will be compared between both groups using the Wilcoxon test. Propensity score matching will be used to balance gender, age, socioeconomic status and other potentially unbalanced variables between the children born preterm and the healthy control children.

Ethics and dissemination

The cantonal ethical committee granted ethical approval for this study (KEK 2017-00521). Written consent will be obtained from the parents. Findings from this study will be disseminated via international and national conference presentations and publications in peer-reviewed journals.

https://ift.tt/2HoabNn

CXCL9/10/11, a regulator of PD-L1 expression in gastric cancer

Abstract

Background

Programmed death-ligand 1 (PD-L1) is an immunosuppressor that plays an important role in cancer treatments. Although majority of the studies demonstrated that PD-L1 expression was regulated by cellular intrinsic and extrinsic controls, and IFN-γ was a key molecule of extrinsic control, other studies imply that other cytokines play important roles in PD-L1 expression. In this study, we investigated the regulation of PD-L1 by chemokine signaling pathway in gastric cancer (GC) cells.

Methods

Bioinformatics was used to explore the PD-L1-related genes in GC and propose a hypothesis. PD-L1 and CXCR3 expression were detected by western blot in SGC7901 and MKN74 cell lines. Meanwhile, PD-L1 and CXCR3 expressions were immunohistochemically assessed for their relevance. Moreover, PD-L1, pSTAT3 and pAkt were detected after treatment with CXCL9/10/11. Furthermore,PD-L1, pSTAT3 and pAkt were evaluated after blocking chemokine signaling in SGC7901 cells.

Results

Based on online database analysis, CXCL9/10/11-CXCR3 is proposed to upregulate PD-L1 expression by activating the STAT and PI3K-Akt pathways. This hypothesis was confirmed by in vitro and vivo experiments. CXCR3 and PD-L1 were expressed in GC cell lines and tissues, and the expression of CXCR3 and PD-L1 was positively related. PD-L1 was upregulated after treatment with CXCL9/10/11, accompanied by activation of STAT3 and Akt. After blocking chemokine signaling, upregulation of PD-L1 and activation of STAT3 and Akt were diminished.

Conclusions

CXCL9/10/11-CXCR3 upregulated the expression of PD-L1 by activating the STAT and PI3K-Akt signaling pathways in GC cells. There was a significant positive correlation between the expression of PD-L1 and CXCR3 in gastric cancer patient tissues.

https://ift.tt/2HsyGVA

Microfluidic Chips for In Situ Crystal X-ray Diffraction and In Situ Dynamic Light Scattering for Serial Crystallography

This protocol describes in detail how to fabricate and operate microfluidic devices for X-ray diffraction data collection at room temperature. Additionally, it describes how to monitor protein crystallization by dynamic light scattering and how to process and analyze obtained diffraction data.

https://ift.tt/2FdI6Ct

Combining Quantitative Food-intake Assays and Forcibly Activating Neurons to Study Appetite in Drosophila

Quantitative food-intake assays with dyed food provide a robust and high-throughput means to evaluate feeding motivation. Combining the food consumption assay with thermogenetic and optogenetic screens is a powerful approach to investigate the neural circuits underlying appetite in adult Drosophila melanogaster.

https://ift.tt/2HVfhxA

Asia-Pacific working group consensus on non-variceal upper gastrointestinal bleeding: an update 2018

Non-variceal upper gastrointestinal bleeding remains an important emergency condition, leading to significant morbidity and mortality. As endoscopic therapy is the 'gold standard' of management, treatment of these patients can be considered in three stages: pre-endoscopic treatment, endoscopic haemostasis and post-endoscopic management. Since publication of the Asia-Pacific consensus on non-variceal upper gastrointestinal bleeding (NVUGIB) 7 years ago, there have been significant advancements in the clinical management of patients in all three stages. These include pre-endoscopy risk stratification scores, blood and platelet transfusion, use of proton pump inhibitors; during endoscopy new haemostasis techniques (haemostatic powder spray and over-the-scope clips); and post-endoscopy management by second-look endoscopy and medication strategies. Emerging techniques, including capsule endoscopy and Doppler endoscopic probe in assessing adequacy of endoscopic therapy, and the pre-emptive use of angiographic embolisation, are attracting new attention. An emerging problem is the increasing use of dual antiplatelet agents and direct oral anticoagulants in patients with cardiac and cerebrovascular diseases. Guidelines on the discontinuation and then resumption of these agents in patients presenting with NVUGIB are very much needed. The Asia-Pacific Working Group examined recent evidence and recommends practical management guidelines in this updated consensus statement.

https://ift.tt/2HnSpWr

No association between urbanisation, neighbourhood deprivation and IBD: a population-based study of 4 million individuals

We read with interest the recently published work in Gut by Imhann et al.1 Although this paper suggests that genetics plays an important role in IBD,1 environmental factors clearly contribute to its aetiology.2 When Ng et al2 reviewed environmental risk factors for IBD in this journal they noted that urbanisation may be linked to both Crohn's disease (CD) and ulcerative colitis (UC).

We used Cox regression to estimate the effect of urbanisation and deprivation during childhood on future IBD.

From the Swedish Total Population Register,3 the government agency Statistics Sweden selected all individuals born in Sweden between 1973 and 2013 (n=4 161 280). Among these there were 3 177 828 siblings nested within 2 331 062 families. Within this cohort we identified individuals with IBD, defined as having ≥2 relevant International Classification of Diseases codes in the Swedish National Patient Register, as earlier described.4 Data from the Swedish Agency for...

https://ift.tt/2HJqAeK

Study of Intraventricular Cerliponase Alfa for CLN2 Disease

Neuronal ceroid lipofuscinosis type 2 (CLN2) disease, a form of Batten's disease, is a rare, autosomal recessive, pediatric neurodegenerative disease resulting from pathogenic variants in the gene encoding lysosomal enzyme tripeptidyl peptidase 1 (TPP1). A deficiency of TPP1 results in accumulation…

https://ift.tt/2JjcVYM

My patient has received fluid. How to assess its efficacy and side effects?

Many efforts have been made to predict, before giving fluid, whether it will increase cardiac output. Nevertheless, after fluid administration, it is also essential to assess the therapeutic efficacy and to lo...

https://ift.tt/2HnbNHj

A Randomized Trial of Early Endovenous Ablation in Venous Ulceration

Venous disease is the most common cause of leg ulceration, and compression therapy improves venous ulcer healing. Superficial venous reflux (varicose veins) is usually present in patients with venous leg ulcers. Endovenous interventions (ultrasound-guided foam sclerotherapy and thermal and…

https://ift.tt/2qXNPan

Mycobacterium chimaera in heater-cooler units used during cardiac surgery – growth and decontamination

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https://ift.tt/2HsMV0Y

The majority of MRSA colonized children not given eradication treatment are still colonized one year later. Systemic antibiotics improve the eradication rate

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https://ift.tt/2qXl265

Antibody responses against Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in children with acute respiratory infection with or without nasopharyngeal bacterial carriage

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https://ift.tt/2HrJyqP

Study of Intraventricular Cerliponase Alfa for CLN2 Disease

Neuronal ceroid lipofuscinosis type 2 (CLN2) disease, a form of Batten's disease, is a rare, autosomal recessive, pediatric neurodegenerative disease resulting from pathogenic variants in the gene encoding lysosomal enzyme tripeptidyl peptidase 1 (TPP1). A deficiency of TPP1 results in accumulation…

https://ift.tt/2JjcVYM

Continuous increase of vancomycin resistance in enterococci causing nosocomial infections in Germany − 10 years of surveillance

Enterococci are frequent pathogens causing nosocomial infections in Germany. Infections due to strains with vancomycin resistance are high when compared with other European states. Therefore, the study aimed t...

https://ift.tt/2qUiJ4k

A systematic review of the epidemiology of carbapenem-resistant Enterobacteriaceae in the United States

Carbapenem-resistant Enterobacteriaceae (CRE) pose an urgent public health threat in the United States. An important step in planning and monitoring a national response to CRE is understanding its epidemiology...

https://ift.tt/2vFlOdj

Favourable response of serum prostate-specific antigen to conjugated oestrogen in castrate-resistant prostate cancer in Jamaica

Andrew Condappa, Maxine Gossell-Williams and William Aiken

https://ift.tt/2HXSPnN

The current state of prostate cancer treatment in Trinidad and Tobago

Satyendra Persaud, Maliza Persaud, Lester Goetz and Dylan Narinesingh

https://ift.tt/2FdguNY

Oncological and reproductive outcomes of adenocarcinoma in situ of the cervix managed with the loop electrosurgical excision procedure

Abstract

Background

The standard treatment for cervical adenocarcinoma in situ (AIS) is hysterectomy, which is a more aggressive treatment than that used for squamous intraepithelial lesions. Several previous studies have primarily demonstrated that the loop electrosurgical excision procedure (LEEP) is as safe and effective as cold knife cone (CKC) biopsy when AIS is unexpectedly found in a loop excision. This study evaluated the safety of LEEP as the initial treatment for patients with AIS who were strictly selected and evaluated before and after loop resection.

Methods

The oncological and reproductive outcomes of a series of AIS patients who underwent LEEP as the initial treatment between February 2006 and December 2016 were retrospectively evaluated.

Results

A total of 44 women were eligible for analysis. The mean age at diagnosis was 36.1 years, and 14 patients were nulliparous. Multiple lesions were identified in 4 (9.1%) patients. Either hysterectomy (6 patients) or repeat cone biopsies (3 patients) were performed in 8 of the 10 patients who presented positive or not evaluable surgical resection margins (SMs) on the initial LEEP specimens. Residual disease was detected in two patients. All patients were closely followed for a mean of 36.9 months via human papillomavirus testing, PAP smears, colposcopy, and endocervical curettage when necessary. No recurrences were detected. Of the 16 patients who desired to become pregnant, 8 (50%) successfully conceived, and the full-term live birth rate was 83.3% among this subgroup.

Conclusions

LEEP with negative SMs was a safe and feasible fertility-sparing surgical procedure for patients with AIS, and the obstetric outcome was satisfactory. However, long-term follow-up is mandatory.

https://ift.tt/2Hr6cM7

Radiogenic angiosarcoma of the breast: case report and systematic review of the literature

Abstract

Background

Radiogenic angiosarcoma of the breast (RASB) is a rare late sequela of local irradiation of the breast or chest wall after breast cancer. The prognosis of women with RASB is poor and there is no standardized therapy for this type of malignancy.

Case presentation

We present the case of a 54 year old woman with RASB (poorly differentiated angiosarcoma of the left breast; pT1, pNX, M0, L0, V0) and a history of invasive-ductal cancer of the left breast (pT1b, G2, pN0, ER positive, PR positive, HER-2/neu negative) treated in July 2012 with breast-conserving surgery, adjuvant chemotherapy with 6 cycles of epirubicin and cyclophosphamide, adjuvant irradiation of the left breast with 50 Gray, and adjuvant endocrine therapy with an aromatase inhibitor. In August 2016, a bilateral salpingo-oophorectomy was performed to remove a tumor of the left ovary, which was diagnosed as breast cancer recurrence. At the same time, a small, purple skin lesion of 1.2 cm in diameter was noted in the inner upper quadrant of the right breast. RASB was diagnosed by punch biopsy and the tumor was excised with clear margins. Imaging studies showed no evidence of further metastases. A systemic chemotherapy with 6 cycles of liposomal doxorubicin was initiated. Five months later, a local recurrence of RASB was diagnosed and mastectomy was performed. Six months later, the patient is alive with no evidence of disease.

Three hundred seven cases of RASB were identified. The pooled incidence rate of RASB was 1/3754 women. The most common treatment of RASB was mastectomy in 83% of cases. Adjuvant radiotherapy or chemotherapy were rarely used with 6 and 4%, respectively, whereas in case of recurrence, chemotherapy was the mainstay of treatment, used in 58% of cases. Radiotherapy and repeated surgery were also common with 30 and 33% of cases, respectively. Overall, the prognosis of women with RASB was poor and the recurrence-free survival was short with a mean of 15.9 months. Mean overall survival was 27.4 months.

Conclusion

RASB is a rare late complication of breast irradiation. The prognosis of women with RASB is poor. Surgery is the mainstay of treatment for localized disease while systemic chemotherapy and re-irradiation are appropriate for women with disseminated or recurrent RASB.

https://ift.tt/2HWtoCJ

Low expression of c-Myc protein predicts poor outcomes in patients with hepatocellular carcinoma after resection

Abstract

Background

Embryonic Liver Fodrin (ELF) is an adaptor protein of transforming growth factor (TGF-β) signaling cascade. Disruption of ELF results in mislocalization of Smad3 and Smad4, leading to compromised TGF-β signaling. c-Myc is an important oncogenic transcription factor, and the disruption of TGF-β signaling promotes c-Myc-induced hepatocellular carcinoma (HCC) carcinogenesis. However, the prognostic significance of c-Myc in HCC is less understood

Methods

The expression of c-Myc protein and mRNA were measured by immunohistochemistry (IHC) and qRT- PCR, respectively. IHC was performed to detect TGF-β1 and ELF expression in HCC tissues. Their relationship with clinicopathological factors and overall survival (OS) and disease free survival (DFS) were examined.

Results

The expression of c-Myc protein and mRNA in HCC tissues were significantly higher in HCC area than those in normal liver tissues. However, the expression were low compared with those adjacent to HCC area. c-Myc protein was independently predictive of DFS and OS, and it was negatively correlated with tumor size (P = 0.031), tumor number (P = 0.038), and recurrence (P = 0.001). Low c-Myc expression was associated with short-term recurrence and poor prognosis. The predictive value of c-Myc combined with TGF-β1 or/and ELF was higher than that of any other single marker. Low c-Myc, high TGF-β1 or/and low ELF expression was associated with the worst DFS and OS.

Conclusions

Low expression of c-Myc protein predicts poor outcomes in patients with HCC with hepatectomy. The combination of the expression of c-Myc, TGF-β1, and ELF can be used to accurately predict outcomes of patients with HCC.

https://ift.tt/2Hrz1YI

Differences in response to antiretroviral therapy in HIV-positive patients being treated for tuberculosis in Eastern Europe, Western Europe and Latin America

Efavirenz-based antiretroviral therapy (ART) regimens are preferred for treatment of adult HIV-positive patients co-infected with tuberculosis (HIV/TB). Few studies have compared outcomes among HIV/TB patients...

https://ift.tt/2qWlQIo

Clinical Efficacy of Jinshuibao Capsules Combined with Angiotensin Receptor Blockers in Patients with Early Diabetic Nephropathy: A Meta-Analysis of Randomized Controlled Trials

Background. Jinshuibao capsules (JSB) have been widely used to treat early diabetic nephropathy (DN), but the specific effects are still inconsistent. A meta-analysis of randomized controlled trials (RCTs) was conducted to evaluate the clinical efficacy of JSB for early DN. Methods. Four international databases and four Chinese databases were searched from publication dates to March 1, 2018. The RCTs reporting the results of JSB's specific effects were included, and comparisons were between JSB combined with Angiotensin Receptor Blockers (ARBs) as experimental intervention and ARBs as the control. Included studies' quality was evaluated and the extracted data were analyzed with RevMan 5.3 software. Results. Twenty-six RCTs including 2198 early DN participants were adopted in the meta-analysis. The results showed that, compared with the ARBs alone, JSB could remarkably improve the ORR (OR = 3.84; 95% CI: 2.37~6.24; ) and decrease 24 h UTP (MD = −93.32; 95% CI: −128.6058.04; ), UAER (MD = −24.02; 95% CI: −30.9317.11; ), BUN (MD = −0.26; 95%: −0.440.08; ), Scr (MD = −9.07; 95% CI: −14.263.88; ), ACR (MD = −17.55; 95% CI: −22.8112.29; ), Cys-C (MD = −0.60; 95% CI: −0.880.32; ), SBP (MD = −3.08; 95% CI: −4.651.52; ), DBP (MD = −2.09; 95% CI: −4.000.19; ), and TG (MD = −0.36; 95% CI: −0.500.21; ). However, it showed no significant differences in TC (MD = −0.32; 95% CI: −0.69~0.04; ), FBG (MD = 0.04; 95% CI: −0.39~0.47; ), (MD = −0.26; 95% CI: −0.59~0.06; ), and -MG (MD = −15.61; 95% CI: −32.95~1.73; ). Conclusions. This study indicates that JSB is an effective accessory therapeutic medicine for patients with early DN. It contributes to decreasing blood pressure and the content of triglyceride and improving the renal function of early DN patients. However, there is still a need to further verify the auxiliary therapeutic effect of JSB with more strictly designed RCTs with large sample and multiple centers in the future.

https://ift.tt/2qUyhVU

Osteomeles schwerinae Extract Prevents Diabetes-Induced Renal Injury in Spontaneously Diabetic Torii Rats

Mesangial cell proliferation contributes to the development of glomerulosclerosis in diabetic nephropathy. This study was aimed at determining whether Osteomeles schwerinae (OSSC) extract can ameliorate renal damage in Spontaneously Diabetic Torii (SDT) rats. OSSC extract (100 and 250 mg/kg/day) was administered to the SDT rats through oral gavage for 17 weeks. At the end of the experiment, glucose, HbA1c, and albuminuria were measured. In addition, the levels of mesangial proliferation-related proteins were determined by western blotting and immunohistochemistry. Our results show that albuminuria, accumulation of the extracellular matrix (ECM), and renal expansion were markedly restored by OSSC extract administration. The OSSC treatment also inhibited α-smooth muscle actin and transforming growth factor-β1 protein expression. In addition, OSSC and its bioactive compounds hyperoside and quercitrin inhibited the platelet-derived growth factor-BB (PDGF-BB)/platelet-derived growth factor-B receptor (PDGFR-β) ligand binding in an in vitro assay. Taken together, these results indicate that OSSC inhibits ECM accumulation and mesangial proliferation of the glomeruli in SDT rats through inhibition of the interaction between PDGF-BB and PDGFR-β. OSSC has ameliorating effects on the initiation and progression of diabetes complications and can be used for the treatment of early diabetic renal dysfunction.

https://ift.tt/2JmW0Vl

Experimental Study of Phlebitis Ointment Administration in Acute Superficial Thrombophlebitis

Acute superficial thrombophlebitis is a venous system disease. Animal models with mannitol induced phlebitis were treated with an orally administered "phlebitis ointment." 24 rabbits were randomly divided into 4 groups. The therapy group was treated with "phlebitis ointment" and a control group received "Mai Luo Shu Tong granules." Levels of blood TNF-α, IL-6, CRP, and IL-1β were measured. The tissue expression levels of NF-КBp65 and PKC genes were evaluated. The therapy group showed a better improvement of the clinical status and similar vascular morphology than the control group. A blank group showed no vascular changes through pathological investigation. In contrast, significant vascular changes were seen in the model group. The control group showed slight vascular modifications. Small thrombi could be found in the lumen despite the intact tunica intima. Both control and therapy group showed less inflammatory cells infiltration than the model group and upregulation of NF-КBp65 and PKC genes. The phlebitis ointment reduced the levels of necrosis factor-α, interleukin-6, C-reactive protein, and interleukin-1ß. The expressions of NF-КBp65 and PKC genes, which are the primary mechanisms underlying the development of thrombophlebitis, were improved significantly in tissues of both therapy group and control group.

https://ift.tt/2HOWk23

PACHE Trainee Spotlight: Roslyn Curry Featured on Thesis Thursday Radio Show

Roslyn Curry, a student at the University of Arizona (UA), was featured on a local radio program, Thesis Thursday, where she discussed her participation in the U54 PACHE Partnership for Native American Cancer Prevention (NACP) as a research trainee in Dr. William Montfort's Lab at the University of Arizona Cancer Center.

https://ift.tt/2Fe1ajV

Epidermal Growth Factor Receptor Mutations and Their Prognostic Value with Carcinoembryonic Antigen in Pathological T1 Lung Adenocarcinoma

Aims. The prognostic value of epidermal growth factor receptor (EGFR) mutations in the context of serum carcinoembryonic antigen levels remains controversial in T1 lung adenocarcinoma. Methods. Clinical and pathological characteristics, preoperational carcinoembryonic antigen levels, EGFR mutations, and disease-free and overall survival were analysed retrospectively in 573 pathological T1 patients in East China. Results. EGFR mutations were detected in 220 of 573 patients (38.4%). Patients with serum carcinoembryonic antigen levels ≥ 2.12 ng/mL had worse disease-free () and overall survival () than had others, although survival was comparable between patients with and without EGFR mutations. However, patients with exon 21 mutations in EGFR had significantly better overall survival than had patients with exon 19 mutations (), although disease-free survival was comparable (). Among patients with serum carcinoembryonic antigen levels ≥ 2.12 ng/mL, disease-free () and overall survival () was also better than that in those with exon 21 mutations. Finally, the exon 19 deletion was found to be an independent predictor of unfavourable overall survival (). Conclusions. EGFR mutations were associated with preoperational serum carcinoembryonic antigen levels ≥ 2.12 ng/mL. In patients with levels above this threshold, those with the exon 19 deletion have less favourable prognosis than have those with the exon 21 mutation.

https://ift.tt/2vGVwrd

Preoperative Digital Subtraction Angiography in Incidental Unruptured Intracranial Aneurysms

Abstract

Purpose

Digital subtraction angiography (DSA) is deemed necessary to precisely visualize intracranial aneurysms and define individual treatment strategies. In patients with unruptured intracranial aneurysms (UIA) who were diagnosed by MRI, a four-vessel DSA is usually performed to detect additional aneurysms. This study aimed to evaluate whether the evaluation of all vessels beyond the aneurysm-harboring artery is really necessary.

Material and methods

Patients with an UIA that was detected on MRA (TOF/ceMRA) were prospectively included. All patients underwent a four-vessel DSA (including 3D-DSA) and two experienced neuroradiologists independently analyzed the MRI sequences before DSA. The number of aneurysms, size and anatomic localization were documented and correlated with the angiographic findings.

Results

The DSA revealed a total of 134 aneurysms in 106 patients. Overall sensitivity and negative predictive value of MRA were 95.6% and 95.6%, respectively. In patients with multiple (≥2) aneurysms, 4 very small aneurysms <3 mm in the A2 segment, posterior communicating artery (PcomA), extradural internal carotid artery (ICA) were missed with MRI alone. In one patient with an ICA aneurysm, an additional small MCA bifurcation aneurysm was overlooked by MRA but detected by DSA. The periprocedural complication rate was 0.9%.

Conclusion

The rate of aneurysms that were detected by DSA but not by MRA was very low, thus potentially justifying visualization of the vessel harboring aneurysm alone; however, the four-vessel angiography detected further small aneurysms in patients with multiple aneurysms and therefore seems to be indicated in this specific subgroup. This approach has the potential to reduce the risk of complications, the intervention time and thus radiation exposure.

https://ift.tt/2KaqsmT

Targeting chemotherapy-resistant leukemia by combining DNT cellular therapy with conventional chemotherapy

Abstract

Background

While conventional chemotherapy is effective at eliminating the bulk of leukemic cells, chemotherapy resistance in acute myeloid leukemia (AML) is a prevalent problem that hinders conventional therapies and contributes to disease relapse, and ultimately patient death. We have recently shown that allogeneic double negative T cells (DNTs) are able to target the majority of primary AML blasts in vitro and in patient-derived xenograft models. However, some primary AML blast samples are resistant to DNT cell therapy. Given the differences in the modes of action of DNTs and chemotherapy, we hypothesize that DNT therapy can be used in combination with conventional chemotherapy to further improve their anti-leukemic effects and to target chemotherapy-resistant disease.

Methods

Drug titration assays and flow-based cytotoxicity assays using ex vivo expanded allogeneic DNTs were performed on multiple AML cell lines to identify therapy-resistance. Primary AML samples were also tested to validate our in vitro findings. Further, a xenograft model was employed to demonstrate the feasibility of combining conventional chemotherapy and adoptive DNT therapy to target therapy-resistant AML. Lastly, blocking assays with neutralizing antibodies were employed to determine the mechanism by which chemotherapy increases the susceptibility of AML to DNT-mediated cytotoxicity.

Results

Here, we demonstrate that KG1a, a stem-like AML cell line that is resistant to DNTs and chemotherapy, and chemotherapy-resistant primary AML samples both became more susceptible to DNT-mediated cytotoxicity in vitro following pre-treatment with daunorubicin. Moreover, chemotherapy treatment followed by adoptive DNT cell therapy significantly decreased bone marrow engraftment of KG1a in a xenograft model. Mechanistically, daunorubicin increased the expression of NKG2D and DNAM-1 ligands on KG1a; blocking of these pathways attenuated DNT-mediated cytotoxicity.

Conclusions

Our results demonstrate the feasibility and benefit of using DNTs as an immunotherapy after the administration of conventional chemotherapy.

https://ift.tt/2FaDmgR

High Incidence of Gastrointestinal Ulceration and Cytogenetic Aberration of Trisomy 8 as Typical Features of Behçet’s Disease Associated with Myelodysplastic Syndrome: A Series of 16 Consecutive Chinese Patients from the Shanghai Behçet’s Disease Database and Comparison with the Literature

This study aimed to investigate the characteristics of Chinese patients with Behçet disease (BD) and myelodysplastic syndrome (MDS) and explore the role played by trisomy 8. This was a retrospective study of patients with BD and MDS from the Shanghai Behçet's disease database who were diagnosed between October 2012 and July 2017. There were 805 patients with BD and 16 also had MDS. Trisomy 8 was examined in patients with BD-MDS and some patients with gastrointestinal (GI) BD. Patients with BD and MDS (16/805; 2%) were more likely to be female and older; display fever and intestinal lesions; have lower leukocyte count, hemoglobin, platelet count; and show higher C-reactive protein and erythrocyte sedimentation rate (ESR) than patients with BD without MDS (all ). Trisomy 8 was common (81.3%) in patients with BD-MDS. Ulcers in the ileocecal region were more frequently seen in intestinal patients with BD-MDS than in BD without MDS (90.0% versus 48.9%; ). GI ulceration is common in patients with BD-MDS. Cytogenetic aberrations, especially trisomy 8, may play a role in the pathogenesis of intestinal involvement in patients with BD-MDS.

https://ift.tt/2HKC2H8

Impact of Participatory Health Research: A Test of the Community-Based Participatory Research Conceptual Model

Objectives. A key challenge in evaluating the impact of community-based participatory research (CBPR) is identifying what mechanisms and pathways are critical for health equity outcomes. Our purpose is to provide an empirical test of the CBPR conceptual model to address this challenge. Methods. A three-stage quantitative survey was completed: (1) 294 US CBPR projects with US federal funding were identified; (2) 200 principal investigators completed a questionnaire about project-level details; and (3) 450 community or academic partners and principal investigators completed a questionnaire about perceived contextual, process, and outcome variables. Seven in-depth qualitative case studies were conducted to explore elements of the model not captured in the survey; one is presented due to space limitations. Results. We demonstrated support for multiple mechanisms illustrated by the conceptual model using a latent structural equation model. Significant pathways were identified, showing the positive association of context with partnership structures and dynamics. Partnership structures and dynamics showed similar associations with partnership synergy and community involvement in research; both of these had positive associations with intermediate community changes and distal health outcomes. The case study complemented and extended understandings of the mechanisms of how partnerships can improve community conditions. Conclusions. The CBPR conceptual model is well suited to explain key relational and structural pathways for impact on health equity outcomes.

https://ift.tt/2Hpq5ar