Medicine by Alexandros G.Sfakianakis: 04/03/18

Τρίτη 3 Απριλίου 2018

RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA mutated breast cancer

Abstract

Background

BRCA1 and BRCA2 (BRCA1/2)-deficient tumors display impaired homologous recombination repair (HRR) and enhanced sensitivity to DNA damaging agents or to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). Their efficacy in germline BRCA1/2 (gBRCA1/2)-mutated metastatic breast cancers has been recently confirmed in clinical trials. Numerous mechanisms of PARPi resistance have been described, whose clinical relevance in gBRCA-mutated breast cancer is unknown. This highlights the need to identify functional biomarkers to better predict PARPi sensitivity.

Patients and Methods

We investigated the in vivo mechanisms of PARPi resistance in gBRCA1 patient-derived tumor xenografts (PDXs) exhibiting differential response to PARPi. Analysis included exome sequencing and immunostaining of DNA damage response proteins to functionally evaluate HRR. Findings were validated in a retrospective sample set from gBRCA1/2-cancer patients treated with PARPi.

Results

RAD51 nuclear foci, a surrogate marker of HRR functionality, was the only common feature in PDX and patient samples with primary or acquired PARPi resistance. Consistently, low RAD51 was associated with objective response to PARPi. Evaluation of the RAD51 biomarker in untreated tumors was feasible due to endogenous DNA damage. In PARPi-resistant gBRCA1 PDXs, genetic analysis found no in-frame secondary mutations, but BRCA1 hypomorphic proteins in 60% of the models, TP53BP1-loss in 20% and RAD51-amplification in one sample, none mutually exclusive. Conversely, one of three PARPi-resistant gBRCA2 tumors displayed BRCA2 restoration by exome sequencing. In PDXs, PARPi resistance could be reverted upon combination of a PARPi with an ATM inhibitor.

Conclusion

Detection of RAD51 foci in gBRCA tumors correlates with PARPi resistance regardless of the underlying mechanism restoring HRR function. This is a promising biomarker to be used in the clinic to better select patients for PARPi therapy. Our study also supports the clinical development of PARPi combinations such as those with ATM inhibitors.

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Induction Chemotherapy in Locally Advanced Squamous Cell Carcinoma of the Head and Neck: Role, Controversy, and Future Directions

Abstract

Background

The value of induction chemotherapy (ICT) remains under investigation despite decades of research. New advancements in the field, specifically regarding the induction regimen of choice, have reignited interest in this approach for patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). Sufficient evidence has accumulated regarding the benefits and superiority of TPF (docetaxel, cisplatin, and fluorouracil) over the chemotherapy doublet PF (cisplatin and fluorouracil). We therefore sought to collate and interpret the available data and further discuss the considerations for delivering ICT safely and optimally selecting suitable post-ICT regimens.

Design

We nonsystematically reviewed published phase 3 clinical trials on TPF ICT in a variety of LA SCCHN patient populations conducted between 1990 and 2017.

Results

TPF may confer survival and organ preservation benefits in a subgroup of patients with functionally inoperable or poor-prognosis LA SCCHN. Additionally, patients with operable disease or good prognosis (who are not candidates for organ preservation) may benefit from TPF induction in terms of reducing local and distant failure rates and facilitating treatment deintensification in selected populations. The safe administration of TPF requires treatment by a multidisciplinary team at an experienced institution. The management of adverse events associated with TPF and post-ICT radiotherapy-based treatment is crucial. Finally, post-ICT chemotherapy alternatives to cisplatin concurrent with radiotherapy (ie, cetuximab or carboplatin plus radiotherapy) appear promising and must be investigated further.

Conclusions

TPF is an evidence-based ICT regimen of choice in LA SCCHN and confers benefits in suitable patients when it is administered safely by an experienced multidisciplinary team and paired with the optimal post-ICT regimen, for which, however, no consensus currently exists.

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Should decisions on adding adjuvant chemotherapy in early stage ER positive breast cancer be based on gene expression testing or clinicopathologic factors or both?

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Neo-adjuvant chemotherapy followed by chemoradiation and surgery with and without cetuximab in patients with resectable esophageal cancer: a randomized, open-label, phase III trial (SAKK 75/08)

Abstract

Background

This open-label, phase lll trial compared chemoradiation followed by surgery with or without neoadjuvant and adjuvant cetuximab in patients with resectable esophageal carcinoma.

Patients and Methods

Patients were randomly assigned (1:1) to 2 cycles of chemotherapy (docetaxel 75 mg/m², cisplatin 75 mg/m²) followed by chemoradiation (45 Gy, docetaxel 20 mg/m² and cisplatin 25 mg/m², weekly for 5 weeks) and surgery, with or without neoadjuvant cetuximab 250 mg/m² weekly and adjuvant cetuximab 500 mg/m² fortnightly for 3 months. The primary endpoint was progression-free survival (PFS).

Results

In total, 300 patients (median age, 61 years; 88% male; 63% adenocarcinoma; 85% cT3/4a, 90% cN+) were assigned to cetuximab (n = 149) or control (n = 151). The R0-resection rate was 95% for cetuximab versus 97% for control. Postoperative treatment-related mortality was 6% in both arms. Median PFS was 2.9 years (95% CI, 2.0 to not reached) with cetuximab and 2.0 years (95% CI, 1.5 to 2.8) with control (HR, 0.79; 95% CI, 0.58 to 1.07; P = .13). Median overall survival (OS) time was 5.1 years (95% CI, 3.7 to not reached) versus 3.0 years (95% CI, 2.2 to 4.2) for cetuximab and control, respectively (HR, 0.73; 95% CI, 0.52 to 1.01; P = .055). Time to loco-regional failure after R0-resection was significantly longer for cetuximab (HR 0.53; 95% CI, 0.31 to 0.90; P = .017); time to distant failure did not differ between arms (HR, 1.01; 95% CI, 0.64 to 1.59, P = .97). Cetuximab did not increase adverse events in neoadjuvant or postoperative settings.

Conclusion

Adding cetuximab to multimodal therapy significantly improved loco-regional control, and led to clinically relevant, but not-significant improvements in PFS and OS in resectable esophageal carcinoma.

Clinical trial information

NCT01107639

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Circulating tumor DNA detection in hepatocellular carcinoma

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Eribulin in BRAF V600E mutant metastatic colorectal cancer: Case series and potential rationale

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Knockdown of Sox2 Inhibits OS Cells Invasion and Migration via Modulating Wnt/β-Catenin Signaling Pathway

Abstract

Osteosarcoma (OS) was a prevalent malignant bone tumor which threatens people's health worldwide. Wnt/β catenin signaling pathway had been proved significant in various cancers, indicating its possible function in OS as well. Sox2, a crucial member among SOX family could regulate cells biologically. How Sox2 modulated Wnt/β catenin signaling pathway in OS remained to be discussed. The study aimed to investigate the effects of Sox2 on the invasion and migration of OS cells and the related molecular mechanisms. Twenty-four human OS and adjacent tissue samples were involved in this study. Human OS cell lines MG63 and HOS were selected for further investigation. The liposome carrier si-Sox2 which could interfere with the expression of Sox2 gene was built to transfect MG63 and HOS cells). QRT-PCR assay and western blot were utilized to analyze the expression of mRNA and proteins of Sox2. Transwell assay and wound healing assay were conducted to test the invasion and migration level of cells. The expression of GSK3, β-catenin, cyclin D1 and c-myc proteins were detected by western blot assay after transfection with si-Sox2. Compared with normal tissues and cells, the expression of Sox2 in OS tissues and cells was significantly higher. The mRNA and protein levels of Sox2 significantly decreased after transfection with si-Sox2. The invasion and migration of OS cells were down-regulated significantly through the inhibition of Sox2 by inactivating Wnt/β-catenin signaling pathway related proteins. Knockdown of Sox2 could inhibit invasion and migration of OS cells via modulating Wnt/β-catenin signaling pathway.

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Clinical and pathological characteristics of KEAP1- and NFE2L2- mutated non-small cell lung carcinoma (NSCLC)

Background: KEAP1 and NFE2L2 mutations are associated with impaired prognosis in many cancers and with squamous cell carcinoma formation in non-small cell lung cancer (NSCLC). However, few is known about frequency, histology-dependence, molecular and clinical presentation as well as response to systemic treatment in NSCLC. Patients and methods: Tumor tissue of 1391 patients with NSCLC was analyzed using next-generation sequencing (NGS). Clinical and pathologic characteristics, survival and treatment outcome of patients with KEAP1 or NFE2L2 mutations were assessed. Results: KEAP1 mutations occurred with a frequency of 11.3% (n=157) and NFE2L2 mutations with a frequency of 3.5% (n=49) in NSCLC patients. In the vast majority of patients, both mutations did not occur simultaneously. KEAP1 mutations were found mainly in adenocarcinoma (AD) (72%), while NFE2L2 mutations were more common in squamous cell carcinoma (LSCC) (59%). KEAP1 mutations were spread over the whole protein, whereas NFE2L2 mutations were clustered in hot-spot regions. In over 80% of patients both mutations co-occurred with other cancer-related mutations, among them targetable aberrations like activating EGFR mutations or MET amplification. Both patient groups showed different patterns of metastases, stage and performance state. No patient with KEAP1 mutation had a response on systemic treatment in 1st-, 2nd- or 3rd-line setting. Of NFE2L2 mutated patients, none responded to 2nd- or 3rd-line therapy. Conclusion: KEAP1 and NFE2L2 mutated NSCLC patients represent a highly heterogeneous patient cohort. Both are associated with different histologies and are found together with other cancer-related, partly targetable, aberrations. Both markers seem to be predictive for chemotherapy resistance.

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An Effective Epigenetic-PARP inhibitor Combination Therapy for Breast and Ovarian Cancers Independent of BRCA-mutations

Purpose: Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are primarily effective against BRCA1/2-mutated breast and ovarian cancers but resistance due to reversion of mutated BRCA1/2 and other mechanisms is common. Based on previous reports demonstrating a functional role for DNMT1 in DNA repair (DDR) and our previous studies demonstrating DNMTis ability to resensitize tumors to primary therapies, we hypothesized that combining a DNMTi with PARPi would sensitize PARPi resistant breast and ovarian cancers to PARPi therapy, independent of BRCA status. Experimental Design: Breast and ovarian cancer cell lines (BRCA- wildtype/-mutant) were treated with PARPi talazoparib and DNMTi guadecitabine. Effects on cell survival, reactive oxygen species (ROS) accumulation, and cAMP levels were examined. In vivo, mice bearing either BRCA-proficient breast or ovarian cancer cells were treated with talazoparib and guadecitabine, alone or in combination. Tumor progression, gene expression and overall survival were analyzed. Results: Combination guadecitabine and talazoparib synergized to enhance PARPi efficacy, irrespective of BRCA mutation status. Co-administration of guadecitabine with talazoparib increased accumulation of ROS, promoted PARP activation and further sensitized, in a cAMP/PKA-dependent manner, breast and ovarian cancer cells to PARPi. In addition, DNMTi enhanced PARP 'trapping' by talazoparib. Guadecitabine plus talazoparib decreased xenograft tumor growth and increased overall survival in BRCA-proficient high-grade serous ovarian and triple negative breast cancer models. Conclusions: The novel combination of the next generation DNMTi guadecitabine and the first-in-class PARPi talazoparib inhibited breast and ovarian cancers harboring either wildtype- or mutant-BRCA, supporting further clinical exploration of this drug combination in PARPi-resistant cancers.

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Molecular diagnosis of diffuse gliomas through sequencing of cell-free circulating tumour DNA from cerebrospinal fluid

Purpose: Diffuse gliomas are the most common primary tumour of the brain and include different subtypes with diverse prognosis. The genomic characterization of diffuse gliomas facilitates their molecular diagnosis. The anatomical localization of diffuse gliomas complicates access to tumour specimens for diagnosis, in some cases incurring high-risk surgical procedures and stereotactic biopsies. Recently, cell-free circulating tumour DNA (ctDNA) has been identified in the cerebrospinal fluid (CSF) of patients with brain malignancies. Experimental Design: Diffuse gliomas are the most common primary tumour of the brain and include different subtypes with diverse prognosis. The genomic characterization of diffuse gliomas facilitates their molecular diagnosis. The anatomical localization of diffuse gliomas complicates access to tumour specimens for diagnosis, in some cases incurring high-risk surgical procedures and stereotactic biopsies. Recently, cell-free circulating tumour DNA (ctDNA) has been identified in the cerebrospinal fluid (CSF) of patients with brain malignancies. Results: Analysis of the mutational status of the IDH1, IDH2, TP53, TERT, ATRX, H3F3A and HIST1H3B genes allowed the classification of 79% of the 648 diffuse gliomas analysed, into IDH-wildtype glioblastoma, IDH-mutant glioblastoma/diffuse astrocytoma and oligodendroglioma, each subtype exhibiting diverse median overall survival (1.1, 6.7, 11.2 respectively). We developed a sequencing platform to simultaneously and rapidly genotype these seven genes in CSF ctDNA allowing the sub-classification of diffuse gliomas. Conclusions:The genomic analysis of IDH1, IDH2, TP53, ATRX, TERT, H3F3A and HIST1H3B gene mutations in CSF ctDNA facilitates the diagnosis of diffuse gliomas in a timely manner to support the surgical and clinical management of these patients.

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Cell-free DNA modification dynamics in abiraterone acetate-treated prostate cancer patients

Purpose: Primary resistance to abiraterone acetate (AA), a key medication for the treatment of metastatic castration-resistant prostate cancer, occurs in 20-40% of patients. We aim to identify predictive biomarkers for AA-treatment response and understand the mechanisms related to treatment resistance. Experimental Design: We used the Infinium Human Methylation 450K BeadChip to monitor modification profiles of cell-free circulating DNA (cfDNA) in 108 plasma samples collected from 33 AA-treated patients. Results: Thirty cytosines showed significant modification differences (FDR q < 0.05) between the AA-sensitive and AA-resistant patients during the treatment, of which 21 cytosines were differentially modified prior to treatment. In addition, the AA-sensitive patients, but not AA-resistant patients, lost inter-individual variation of cfDNA modification shortly after starting AA-treatment, but such variation returned to initial levels in the later phases of treatment. Conclusions: Our findings provide a list of potential biomarkers for prediction of AA-treatment response, highlight the prognostic value of using cytosine modification variance as biomarkers, and shed new insights into the mechanisms of prostate cancer relapse in AA-sensitive patients.

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Genetic analysis of 779 advanced differentiated and anaplastic thyroid cancers.

Purpose: To define the genetic landscape of advanced differentiated and anaplastic thyroid cancer and identify genetic alterations of potential diagnostic, prognostic and therapeutic significance. Experimental design: The genetic profiles of 583 advanced differentiated and 196 anaplastic thyroid cancers (ATC) generated with targeted next-generation sequencing cancer-associated gene panels MSK-IMPACT and FoundationOne were analyzed. Results: ATC had more genetic alterations per tumor, and pediatric papillary thyroid cancer had fewer genetic alterations per tumor when compared to other thyroid cancer types. DNA mismatch repair deficit and activity of APOBEC cytidine deaminases were identified as mechanisms associated with high mutational burden in a subset of differentiated and anaplastic thyroid cancers. Copy number losses and mutations of CDKN2A and CDKN2B, amplification of CCNE1, amplification of receptor tyrosine kinase genes KDR, KIT and PDGFRA, amplification of immune evasion genes CD274, PDCD1LG2 and JAK2 and activating point mutations in small GTPase RAC1 were associated with ATC. An association of KDR, KIT and PDGFRA amplification with the sensitivity of thyroid cancer cells to lenvatinib was shown in vitro. Three genetically distinct types of ATC are proposed. Conclusions: This large-scale analysis describes genetic alterations in a cohort of thyroid cancers enriched in advanced cases. Many novel genetic events previously not seen in thyroid cancer were found. Genetic alterations associated with anaplastic transformation were identified. An updated schematic of thyroid cancer genetic evolution is proposed.

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ZIP4 Promotes Pancreatic Cancer Progression by Repressing ZO-1 and claudin-1 through a ZEB1-Dependent Transcriptional Mechanism.

Purpose: ZIP4 is overexpressed in human pancreatic cancer and promotes tumor growth. However, little is known about the role of ZIP4 in advanced stages of this dismal neoplasm. Our goal is to study the underlying mechanism and define a novel signaling pathway controlled by ZIP4 modulating pancreatic tumor metastasis. Experimental Design: The expression of ZIP4, ZO-1, claudin-1, and ZEB1 in human pancreatic cancer tissues, genetically engineered mouse model, xenograft tumor model and pancreatic cancer cell lines were examined, and the correlations between ZIP4 and those markers were also analyzed. Functional analysis of ZO-1, claudin-1, and ZEB1 was investigated in pancreatic cancer cell lines and orthotopic xenografts. Results: Genetic inactivation of ZIP4 inhibited migration and invasion in pancreatic cancer, and increased the expression of ZO-1 and claudin-1. Conversely, overexpression of ZIP4 promoted migration and invasion, and increased the expression of ZEB1 and downregulation of the aforementioned epithelial genes. ZIP4 downregulation of ZO-1 and claudin-1 requires the transcriptional repressor ZEB1. Further analysis demonstrated that ZIP4-mediated repression of ZO-1 and claudin-1 lead to upregulation of their targets FAK and Paxillin. Silencing of ZIP4 caused reduced phosphorylation of FAK and Paxillin, which was rescued by simultaneous blocking of ZO-1 or claudin-1. Clinically, we demonstrated that ZIP4 positively correlates with the levels of ZEB1 and inversely associates with the expression of ZO-1 and claudin-1. Conclusions: These findings suggest a novel pathway activated by ZIP4 controlling pancreatic cancer invasiveness and metastasis, which could serve as a new therapeutic target for this devastating disease.

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Mechanistic insights of an immunological adverse event induced by an anti-KIT antibody drug conjugate and mitigation strategies

Purpose: Hypersensitivity reactions (HSR) were observed in three patients dosed in a phase I clinical trial treated with LOP628, a KIT targeted antibody drug conjugate. Mast cell degranulation was implicated as the root cause for the HSR. Underlying mechanism of this reported HSR was investigated with an aim to identifying potential mitigation strategies. Experimental Design: Biomarkers for mast cell degranulation were evaluated in patient samples and in human peripheral blood cell-derived mast cell (PBC-MC) cultures treated with LOP628. Mitigation strategies interrogated include pretreatment of mast cells with small molecule inhibitors that target KIT or signaling pathways downstream of FcR1, FcR, and treatment with Fc silencing antibody formats. Results: Transient elevation of serum tryptase was observed in patients one hour post-treatment of LOP628. In agreement with the clinical observation, LOP628 and its parental antibody LMJ729 induced degranulation of human PBC-MCs. Unexpectedly, KIT small molecule inhibitors did not abrogate mast cell degranulation. By contrast, small molecule inhibitors that targeted pathways downstream of Fc receptors blunted degranulation. Furthermore, interference of the KIT antibody to engage Fc receptors by pre-incubation with IgG or using engineered Fc silencing mutations reduced or prevented degranulation. Characterization of Fcg receptors revealed human PBC-MCs expressed both FcRII and low levels of FcRI. Interestingly, increasing the level of FcRI upon addition of IFN, significantly enhanced LOP628-mediated mast cell degranulation. Conclusions: Our data suggests LOP628-mediated mast cell degranulation is the likely cause of HSR observed in the clinic due to co-engagement of the FcR and KIT, resulting in mast cell activation.

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Mutation profiling of key cancer genes in primary breast cancers and their distant metastases

Although the repertoire of somatic genetic alterations of primary breast cancers has been extensively catalogued, the genetic differences between primary and metastatic tumors have been less studied. In this study, we compared somatic mutations and gene copy number alterations of primary breast cancers and their matched metastases from patients with estrogen receptor (ER)-negative disease, with higher incidence of brain metastases than ER-positive/HER2-negative cancers. DNA samples obtained from formalin-fixed paraffin-embedded ER-negative/HER2-positive (n=9) and ER-, progesterone receptor (PR-), HER2-negative (n=8) primary breast cancers and from paired brain or skin metastases and normal tissue were subjected to a hybridization capture-based massively parallel sequencing assay, targeting 341 key cancer genes. A large subset of non-synonymous somatic mutations (45%) and gene copy number alterations (55%) were shared between the primary tumors and paired metastases. However, mutations restricted to either a given primary tumor or its metastasis, the acquisition of loss of heterozygosity of the wild-type allele and clonal shifts of genes affected by somatic mutations such as TP53 and RB1 were observed in the progression from primary tumors to metastases. No metastasis location-specific alterations were identified, but synchronous metastases showed higher concordance with the paired primary tumor than metachronous metastases. Novel potentially targetable alterations were found in the metastases relative to their matched primary tumors. These data indicate that repertoires of somatic genetic alterations in ER-negative metastatic breast cancers may differ from those of their primary tumors, even by the presence of driver and targetable somatic genetic alterations.

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Adoptive immunotherapy using PRAME-specific T cells in medulloblastoma

Medulloblastoma is the most frequent malignant childhood brain tumor with a high morbidity. Identification of new therapeutic targets would be instrumental in improving patient outcomes. We evaluated the expression of the tumor-associated antigen PRAME in biopsies from 60 medulloblastoma patients. PRAME expression was detectable in 82% of tissues independent of molecular and histopathologic subgroups. High PRAME expression also correlated with worse overall survival. We next investigated the relevance of PRAME as a target for immunotherapy. Medulloblastoma cells were targeted using genetically modified T cells with a PRAME-specific TCR (SLL TCR T cells). SLL TCR T cells efficiently killed medulloblastoma HLA-A*02+ DAOY cells as well as primary HLA-A*02+ medulloblastoma cells. Moreover, SLL TCR T cells controlled tumor growth in an orthotopic mouse model of medulloblastoma. To prevent unexpected T cell-related toxicity,an inducible caspase 9 (iC9) gene was introduced in frame with the SLL TCR; this safety switch triggered prompt elimination of genetically-modified T cells. Altogether, these data indicate that T cells genetically modified with a high-affinity, PRAME-specific TCR and iC9 may represent a promising innovative approach for treating HLA-A*02+ medulloblastoma patients.

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Screening Tool for Gynecologic Cancers Assessed [News in Brief]

PapSEEK diagnoses endometrial and ovarian cancers based on DNA mutations and aneuploidy.

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Evaluation of antioxidant properties of lemon verbena (Lippia citriodora) essential oil and its capacity in sunflower oil stabilization during storage time

Food Science &Nutrition, EarlyView.

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Distinct and complementary roles of CD4 T cells in protective immunity to influenza virus

Andrea J Sant | Katherine A Richards | Jennifer Nayak

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Transcriptional programming of tissue-resident memory CD8+ T cells

J Justin Milner | Ananda W Goldrath

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Medicine in small doses

ANZ Journal of Surgery, Volume 88, Issue 4, Page 266-266, April 2018.

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Issue information ‐ TOC

ANZ Journal of Surgery, Volume 88, Issue 4, Page 256-257, April 2018.

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The conundrum of quality in colonoscopy

ANZ Journal of Surgery, Volume 88, Issue 4, Page 263-264, April 2018.

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Operating room culture affects patient outcomes, and we should operate accordingly

ANZ Journal of Surgery, Volume 88, Issue 4, Page 264-265, April 2018.

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A retroperitoneal mass needs respect

ANZ Journal of Surgery, Volume 88, Issue 4, Page 261-262, April 2018.

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25, 50 & 75 years ago

ANZ Journal of Surgery, Volume 88, Issue 4, Page 267-268, April 2018.

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Re: Free‐flap salvage: muscle only versus skin paddle – an Australian experience

ANZ Journal of Surgery, Volume 88, Issue 4, Page 387-388, April 2018.

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Surgeons: cause for complaint

ANZ Journal of Surgery, Volume 88, Issue 4, Page 259-260, April 2018.

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Novel use of Patent Blue V dye to facilitate repair of lymph leak after groin debridement

ANZ Journal of Surgery, Volume 88, Issue 4, Page 386-387, April 2018.

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Anal tone may predict recurrence after botulinum toxin for chronic anal fissure

ANZ Journal of Surgery, Volume 88, Issue 4, Page 385-386, April 2018.

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Response to Re: Recurrent sigmoid volvulus in pregnancy

ANZ Journal of Surgery, Volume 88, Issue 4, Page 385-385, April 2018.

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Association between nonsteroidal anti‐inflammatory drugs and atrial fibrillation among a middle‐aged population: a nationwide population‐based cohort

British Journal of Clinical Pharmacology, EarlyView.

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Nursing Students Not Always ID'ing Fundamental Care Needs

TUESDAY, April 3, 2018 -- When presented with different care scenarios, nursing students are not correctly identifying all the fundamental care needs of patients, according to a study published online March 11 in the Journal of Clinical Nursing. Eva...

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Older Adults Believe Marijuana Can Be Effective for Pain

TUESDAY, April 3, 2018 -- Older adults believe marijuana to be effective for pain relief, and many support its use, according to the results of a National Poll on Healthy Aging, conducted for the University of Michigan. A national sample of about...

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Noninvasive Brain Stimulation May Help Prevent Migraines

TUESDAY, April 3, 2018 -- A noninvasive stimulation device may help prevent migraine attacks, according to a study published online March 4 in Cephalalgia. Amaal J. Starling, M.D., from the Mayo Clinic in Phoenix, and colleagues evaluated the...

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Most Parents Willing to Enroll Child in Food Allergen Trials

TUESDAY, April 3, 2018 -- The majority of caregivers of children with food allergy are willing to consider participation in clinical trials for food allergy immunotherapy, according to a research letter published in the March issue of the Annals of...

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Stabilisation of acute‐on‐chronic liver failure patients before liver transplantation predicts post‐transplant survival

Alimentary Pharmacology &Therapeutics, EarlyView.

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Gold Nanoplate‐Enhanced Chemiluminescence and Macromolecular Shielding for Rapid Microbial Diagnostics

Advanced Healthcare Materials, EarlyView.

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Nanomedicine Approaches Against Parasitic Worm Infections

Advanced Healthcare Materials, EarlyView.

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Mechanical Considerations for Electrospun Nanofibers in Tendon and Ligament Repair

Advanced Healthcare Materials, EarlyView.

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Metal Nanoparticles for Diagnosis and Therapy of Bacterial Infection

Advanced Healthcare Materials, EarlyView.

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A Cascade‐Targeting Nanocapsule for Enhanced Photothermal Tumor Therapy with Aid of Autophagy Inhibition

Advanced Healthcare Materials, EarlyView.

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3D Interconnected Mesoporous Alumina with Loaded Hemoglobin as a Highly Active Electrochemical Biosensor for H2O2

Advanced Healthcare Materials, EarlyView.

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Integrin Clustering Matters: A Review of Biomaterials Functionalized with Multivalent Integrin‐Binding Ligands to Improve Cell Adhesion, Migration, Differentiation, Angiogenesis, and Biomedical Device Integration

Advanced Healthcare Materials, EarlyView.

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Atmospheric Plasma Deposition of Methacrylate Layers Containing Catechol/Quinone Groups: An Alternative to Polydopamine Bioconjugation for Biomedical Applications

Advanced Healthcare Materials, EarlyView.

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Neurosurgery: A Silk Cranial Fixation System for Neurosurgery (Adv. Healthcare Mater. 6/2018)

Advanced Healthcare Materials, Volume 7, Issue 6, March 21, 2018.

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Toward Immunocompetent 3D Skin Models

Advanced Healthcare Materials, EarlyView.

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Carbon‐Dot‐Decorated TiO2 Nanotubes toward Photodynamic Therapy Based on Water‐Splitting Mechanism

Advanced Healthcare Materials, EarlyView.

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Biomaterial Scaffolds as Pre‐metastatic Niche Mimics Systemically Alter the Primary Tumor and Tumor Microenvironment

Advanced Healthcare Materials, EarlyView.

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Tissue Engineering: Silicon Carbide Nanoparticles as an Effective Bioadhesive to Bond Collagen Containing Composite Gel Layers for Tissue Engineering Applications (Adv. Healthcare Mater. 5/2018)

Advanced Healthcare Materials, Volume 7, Issue 5, March 7, 2018.

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Advances and Opportunities in Nanoparticle‐ and Nanomaterial‐Based Vaccines against Bacterial Infections

Advanced Healthcare Materials, EarlyView.

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Surface‐Enhanced Raman Scattering for Rapid Detection and Characterization of Antibiotic‐Resistant Bacteria

Advanced Healthcare Materials, EarlyView.

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Site‐Controlled Single‐Photon Emitters Fabricated by Near‐Field Illumination

Advanced Materials, EarlyView.

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Responsive Block Copolymer Photonic Microspheres

Advanced Materials, EarlyView.

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Glassomer—Processing Fused Silica Glass Like a Polymer

Advanced Materials, EarlyView.

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Versatility of Carbon Enables All Carbon Based Perovskite Solar Cells to Achieve High Efficiency and High Stability

Advanced Materials, EarlyView.

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Chirality Dependent Charge Transfer Rate in Oligopeptides

Advanced Materials, EarlyView.

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In Situ Encapsulating α‐MnS into N,S‐Codoped Nanotube‐Like Carbon as Advanced Anode Material: α → β Phase Transition Promoted Cycling Stability and Superior Li/Na‐Storage Performance in Half/Full Cells

Advanced Materials, EarlyView.

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Self‐Assembled Semiconducting Polymer Nanoparticles for Ultrasensitive Near‐Infrared Afterglow Imaging of Metastatic Tumors

Advanced Materials, EarlyView.

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Directed Nanoscale Self‐Assembly of Low Molecular Weight Hydrogelators Using Catalytic Nanoparticles

Advanced Materials, EarlyView.

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Few‐Layer GeAs Field‐Effect Transistors and Infrared Photodetectors

Advanced Materials, EarlyView.

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Oxidized Laser‐Induced Graphene for Efficient Oxygen Electrocatalysis

Advanced Materials, EarlyView.

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Porous Graphene Films with Unprecedented Elastomeric Scaffold‐Like Folding Behavior for Foldable Energy Storage Devices

Advanced Materials, EarlyView.

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Controlled Homoepitaxial Growth of Hybrid Perovskites

Advanced Materials, EarlyView.

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Phase Transition Control for High Performance Ruddlesden–Popper Perovskite Solar Cells

Advanced Materials, EarlyView.

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Contributors

AMAL MATTU, MD, FAAEM, FACEP

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Amal Mattu

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Pediatric Pain Management

Nearly 20 years ago, standards were established for hospitals to assess and treat pain in all patients. Research continues to demonstrate evolving trends in the measurement and effective treatment of pain in children. Behavioral research demonstrating long-lasting effects of inadequate pain control during childhood supports the concepts of early and adequate pain control for children suffering from painful conditions in the acute care setting. The authors discuss pain concepts, highlighting factors specific to the emergency department, and include a review of evidence for pharmacologic and nonpharmacologic treatments.

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Imaging Gently

Advances in medical imaging are invaluable in the care of pediatric patients in the emergent setting. The diagnostic accuracy offered by studies using ionizing radiation, such as plain radiography, computed tomography, and fluoroscopy, are not without inherent risks. This article reviews the evidence supporting the risk of ionizing radiation from medical imaging as well as discusses clinical scenarios in which clinicians play an important role in supporting the judicious use of imaging studies.

https://ift.tt/2IolpgO

Pediatric Ventilator Management in the Emergency Department

Pediatric mechanical ventilation is first initiated by emergency physicians when performing active airway management in a critically ill or injured child. When initiating and adjusting mechanical ventilation, the child has unique anatomy and physiology to consider. The EP is the first to respond to ventilator alarm triggers, and the initial medical provider to resuscitate the ventilated pediatric patient who is deteriorating while in the emergency department. This article uses cases to provide a framework to initiate and troubleshoot mechanical ventilation of pediatric patients in the emergency department.

https://ift.tt/2GIWZBN

Emergency Care of Pediatric Burns

Although the overall incidence of and mortality rate associated with burn injury have decreased in recent decades, burns remain a significant source of morbidity and mortality in children. Children with major burns require emergent resuscitation. Resuscitation is similar to that for adults, including pain control, airway management, and administration of intravenous fluid. However, in pediatrics, fluid resuscitation is needed for burns greater than or equal to 15% of total body surface area (TBSA) compared with burns greater than or equal to 20% TBSA for adults. Unique to pediatrics is the additional assessment for non-accidental injury and accurate calculation of the percentage of total burned surface area (TBSA) in children with changing body proportions are crucial to determine resuscitation parameters, prognosis, and disposition.

https://ift.tt/2EeQ91A

Inborn Errors of Metabolism in the Emergency Department (Undiagnosed and Management of the Known)

An inborn error of metabolism should be considered in any neonate who presents to the emergency department in extremis and in any young child who presents with altered mental status and vomiting. In children with unknown diagnoses, it is crucial to draw the appropriate laboratory studies before the institution of therapy, although treatment needs rapid institution to mitigate neurologic damage and avoid worsening metabolic crisis. Although there are hundreds of individual genetic disorders, they are roughly placed into groups that present similarly. This article reviews the approach to the patient with unknown metabolic diagnosis and up-to-date management pearls for children with known disorders.

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Pediatric Minor Head Injury 2.0

Visits for pediatric minor blunt head trauma continue to increase. Variability exists in clinician evaluation and management of this generally low-risk population. Clinical decision rules identify very low-risk children who can forgo neuroimaging. Observation before imaging decreases neuroimaging rates. Outcome data can be used to risk stratify children into more discrete categories. Decision aids improves knowledge and accuracy of risk perception and facilitates identification of caregiver preferences, allowing for shared decision making. For children in whom imaging is performed and is normal or shows isolated linear skull fractures, deterioration and neurosurgical intervention are rare and hospital admission can be avoided.

https://ift.tt/2EeQ5yS

Pediatric Emergencies

There are few presentations that strike more fear in the hearts of emergency physicians than the presentation of a sick child. Why is that? Perhaps it is because a child is supposed to be happy and playful, a source of bubbly energy with decades of future productive life and joy, and therefore, there is far more to lose if things go south. Or perhaps it is because devastating illness is so unexpected in children…it is simply not supposed to happen. Or perhaps it is simply because we fear what we do not understand.

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Forthcoming Issues

Hematology Oncology Emergencies

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Pediatric Emergencies: The Common and the Critical

Caring for children in the emergency department (ED) is both rewarding and challenging. Children have a tremendous ability to remind us about the importance of our role in the medical care environment. They provide us the opportunity to make critical interventions when they are the most impactful. They also remind us of the humanitarian aspects of our vocation, and they, often, make us smile even during the most difficult of shifts, proving to be a redemptive resource even amid chaos.

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Copyright

ELSEVIER

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Pediatric Emergency Medicine

EMERGENCY MEDICINE CLINICS OF NORTH AMERICA

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CME Accreditation Page

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Kratom-containing Products by Triangle Pharmanaturals: Mandatory Recall - Risk of Salmonella

Audience: Consumer [Posted 04/03/2018] ISSUE: FDA issued a mandatory recall order for all food products containing powdered kratom manufactured, processed, packed, or held by Triangle Pharmanaturals LLC, after several were found to contain...

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Kratom-containing Products by Triangle Pharmanaturals: Mandatory Recall - Risk of Salmonella

Healthcare Use Patterns and Economic Burden of Chronic Musculoskeletal Pain in Children before Diagnosis

To evaluate the healthcare use and costs of amplified musculoskeletal pain syndrome (AMPS) in children before diagnosis.

https://ift.tt/2ImI8tC

Natural History of Postnatal Cardiopulmonary Adaptation in Infants Born Extremely Preterm and Risk for Death or Bronchopulmonary Dysplasia

To study the natural history of postnatal cardiopulmonary adaptation in infants born extremely preterm and establish its association with death or bronchopulmonary dysplasia (BPD).

https://ift.tt/2Itk88v

Cost Analysis of Treating Neonatal Hypoglycemia with Dextrose Gel

To evaluate the costs of using dextrose gel as a primary treatment for neonatal hypoglycemia in the first 48 hours after birth compared with standard care.

https://ift.tt/2GUUmwR

Evidence of Echocardiographic Markers of Pulmonary Vascular Disease in Asymptomatic Infants Born Preterm at One Year of Age

To test the hypothesis that echocardiographic markers of pulmonary vascular disease (PVD) exist in asymptomatic infants born preterm at 1-year corrected age.

https://ift.tt/2H8gqSc

Toll-like Receptor 9 Contains Two DNA Binding Sites that Function Cooperatively to Promote Receptor Dimerization and Activation

TLR9 recognizes DNAs with unmethylated CpG motifs and activates innate immune responses. Ohto et al. identify another TLR9 binding motif, the 5′-xCx DNA motif, and determine the tertiary structure of TLR9 in complex with CpG and 5′-xCx DNAs to reveal a cooperative activation mechanism of TLR9 by two types of DNAs.

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Treatment response assessment with ( R )-[ 11 CPAQ PET in the MMTV-PyMT mouse model of breast cancer

Abstract

Background

The goal of the study was to assess the potential of the vascular endothelial growth factor receptor (VEGFR)-2-targeting carbon-11 labeled (R)-N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methyl-3-piperidinyl)methoxy)-4-quinazolineamine ((R)-[¹¹C]PAQ) as a positron emission tomography (PET) imaging biomarker for evaluation of the efficacy of anticancer drugs in preclinical models.

Methods

MMTV-PyMT mice were treated with vehicle alone (VEH), murine anti-VEGFA antibody (B20-4.1.1), and paclitaxel (PTX) in combination or as single agents. The treatment response was measured with (R)-[¹¹C]PAQ PET as standardized uptake value (SUV)_mean, SUV_max relative changes at the baseline (day 0) and follow-up (day 4) time points, and magnetic resonance imaging (MRI)-derived PyMT mammary tumor volume (TV) changes. Expression of Ki67, VEGFR-2, and CD31 in tumor tissue was determined by immunohistochemistry (IHC). Non-parametric statistical tests were used to evaluate the relation between (R)-[¹¹C]PAQ radiotracer uptake and therapy response biomarkers.

Results

The (R)-[¹¹C]PAQ SUV_max in tumors was significantly reduced after 4 days in the B20-4.1.1/PTX combinational and B20-4.1.1 monotherapy groups (p < 0.0005 and p < 0.003, respectively). No significant change was observed in the PTX monotherapy group. There was a significant difference in the SUV_max change between the VEH group and B20-4.1.1/PTX combinational group, as well as between the VEH group and the B20-4.1.1 monotherapy group (p < 0.05). MRI revealed significant decreases in TV in the B20-4.1.1/PTX treatment group (p < 0.005) but not the other therapy groups. A positive trend was observed between the (R)-[¹¹C]PAQ SUV_max change and TV reduction in the B20-4.1.1/PTX group. Statistical testing showed a significant difference in the blood vessel density between the B20-4.1.1/PTX combinational group and the VEH group (p < 0.05) but no significant difference in the Ki67 positive signal between treatment groups.

Conclusions

The results of this study are promising. However, additional studies are necessary before (R)-[¹¹C]PAQ can be approved as a predictive radiotracer for cancer therapy response.

https://ift.tt/2GQ4JSy

Sacroiliac joint dysfunction patients exhibit altered movement strategies when performing a sit-to-stand task

Publication date: Available online 3 April 2018
Source:The Spine Journal
Author(s): Robyn A. Capobianco, Daniel F. Feeney, Jana R. Jeffers, Erika Nelson-Wong, Joseph Morreale, Alena M. Grabowski, Roger M. Enoka
Summary of background dataThe ability to rise from a chair is a basic functional task that is frequently compromised in individuals diagnosed with orthopedic disorders in the low back and hip. There is no published literature that describes how this task is altered by sacroiliac joint dysfunction (SIJD).PurposeTo compare lower extremity biomechanics and the onset of muscle activity when rising from a chair in individuals with SIJD and healthy persons.Study designSix women with unilateral SIJD and six age-matched healthy controls performed a sit-to-stand task while we measured kinematics, kinetics, and muscle activity.MethodsSubjects stood up at a preferred speed from a seated position on an armless and backless adjustable stool. We measured kinematics with a 10-camera motion capture system, ground reaction forces for each leg with force plates, and muscle activity with surface electromyography. Joint angles and torques were calculated using inverse dynamics. Leg loading rate was quantified as the average slope of vertical ground reaction force during the 500-ms interval preceding maximal knee extension.ResultsBetween-leg differences in loading rates and peak vertical ground reaction forces were significantly greater for the SIJD group than the control group. Maximal hip angles were significantly less for the SIJD group (p = 0.001). Peak hip moment in the SIJD group was significantly greater in the unaffected leg (0.75 ± 0.22 N•m/kg) than the affected leg (0.47 ± 0.29 N•m/kg, p = 0.005). There were no between-leg or between-group differences for peak knee or ankle moments. The onset of activity in the latissimus dorsi muscle on the affected side in the SIJD group was delayed and the erector spinae muscles were activated earlier than in Controls.ConclusionsIndividuals with SIJD have a greater vertical ground reaction force on the unaffected leg, generate a greater peak hip moment in the unaffected leg, use a smaller range of motion at the hip joint of the affected leg, and delay the onset of a key muscle on the affected side when rising from a seated position.

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Use of motor evoked potentials during lateral lumbar interbody fusion reduces postoperative deficits

Publication date: Available online 3 April 2018
Source:The Spine Journal
Author(s): Michael R. Riley, Adam T. Doan, Richard W. Vogel, Alexander O. Aguirre, Kayla S. Pieri, Edward H. Scheid
Background ContextIntraoperative neurophysiological monitoring (IONM) has gained rather widespread acceptance as a method to mitigate risk to the lumbar plexus during lateral lumbar interbody fusion (LLIF) surgery. The most common approach to IONM involves using only electromyography (EMG) monitoring, and the rate of postoperative deficit remains unacceptably high. Other test modalities, such as transcranial electric motor-evoked potentials (tcMEPs) and somatosensory-evoked potentials, may be more suitable for monitoring neural integrity, but they have not been widely adopted during LLIF. Recent studies have begun to examine their utility in monitoring LLIF surgery with favorable results.PurposeThis study aimed to evaluate the efficacy of different IONM paradigms in the prevention of iatrogenic neurologic sequelae during LLIF and to specifically evaluate the utility of including tcMEPs in an IONM strategy for LLIF surgery.Study Design/SettingA non-randomized, retrospective analysis of 479 LLIF procedures at a single institution over a 4-year period was conducted. During the study epoch, three different IONM strategies were used for LLIF procedures: (1) surgeon-directed T-EMG monitoring ("SD-EMG"), (2) neurophysiologist-controlled T-EMG monitoring ("NC-EMG"), and (3) neurophysiologist-controlled T-EMG monitoring supplemented with MEP monitoring ("NC-MEP").Patient SampleThe patient population comprised 254 men (53.5%) and 221 women (46.5%). Patient age ranged from a minimum of 21 years to a maximum of 89 years, with a mean of 56.6 years.Outcome MeasuresPhysician-documented physiological measures included manual muscle test grading of hip-flexion, hip-adduction, or knee-extension, as well as hypo- or hyperesthesia of the groin or anterolateral thigh on the surgical side. Self-reported measures included numbness or tingling in the groin or anterolateral thigh on the surgical side.MethodsPatient progress notes were reviewed from the postoperative period up to 12 months after surgery. The rates of postoperative sensory-motor deficit consistent with lumbar plexopathy or peripheral nerve palsy on the surgical side were compared between the three cohorts.ResultsUsing the dependent measure of neurologic deficit, whether motor or sensory, patients with NC-MEP monitoring had the lowest rate of immediate postoperative deficit (22.3%) compared with NC-EMG monitoring (37.1%) and SD-EMG monitoring (40.4%). This result extended to sensory deficits consistent with lumbar plexopathy (pure motor deficits being excluded); patients with NC-MEP monitoring had the lowest rate (20.5%) compared with NC-EMG monitoring (34.3%) and SD-EMG monitoring (36.9%). Additionally, evaluation of postoperative motor deficits consistent with peripheral nerve palsy (pure sensory deficits being excluded) revealed that the NC-MEP group had the lowest rate (5.7%) of motor deficit compared with the SD-EMG (17.0%) and NC-EMG (17.1%) cohorts. Finally, when assessing only those patients whose last follow-up was greater than or equal to 12 months (n=251), the rate of unresolved motor deficits was significantly lower in the NC-MEP group (0.9%) compared with NC-EMG (6.9%) and SD-EMG (11.0%). A comparison of the NC-MEP versus NC-EMG and SD-EMG groups, both independently and combined, was statistically significant (>95% confidence level) for all analyses.ConclusionsThe results of the present study indicate that preservation of tcMEPs from the adductor longus, quadriceps, and tibialis anterior muscles are of paramount importance for limiting iatrogenic sensory and motor injuries during LLIF surgery. In this regard, the inclusion of tcMEPs serves to compliment EMG and allows for the periodic, functional assessment of at-risk nerves during these procedures. Thus, tcMEPs appear to be the most effective modality for the prevention of both transient and permanent neurologic injury during LLIF surgery. We propose that the standard paradigm for protecting the nervous system during LLIF be adapted to include tcMEPs.

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Malformed vertebrae: a clinical and imaging review

Abstract

A variety of structural developmental anomalies affect the vertebral column. Malformed vertebrae can arise secondary to errors of vertebral formation, fusion and/or segmentation and developmental variation. Malformations can be simple with little or no clinical consequence, or complex with serious structural and neurologic implications. These anomalies can occasionally mimic acute trauma (bipartite atlas versus Jefferson fracture, butterfly vertebra versus burst fracture), or predispose the affected individual to myelopathy. Accurate imaging interpretation of vertebral malformations requires knowledge of ageappropriate normal, variant and abnormal vertebral morphology and the clinical implications of each entity. This knowledge will improve diagnostic confidence in acute situations and confounding clinical scenarios.

This review article seeks to familiarize the reader with the embryology, normal and variant anatomy of the vertebral column and the imaging appearance and clinical impact of the spectrum of vertebral malformations arising as a consequence of disordered embryological development.

Teaching points

• Some vertebral malformations predispose the affected individual to trauma or myelopathy.

• On imaging, malformed vertebrae can be indistinguishable from acute trauma.

• Abnormalities in spinal cord development may be associated and must be searched for.

• Accurate interpretation requires knowledge of normal, variant and abnormal vertebral morphology.

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Outcomes-Based Pricing Doesn't Cut Costs of PCSK9 Inhibitors

TUESDAY, April 3, 2018 -- Outcomes-based pricing does not reduce the costs of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, according to a research letter published online April 3 in the Annals of Internal Medicine. Dhruv S....

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Dietary Supplements by Nutrizone: Recall - Potential for Salmonella Contamination

Audience: Consumer [Posted 04/03/2018] ISSUE: NutriZone, LLC is recalling 4 different dietary supplements because it has the potential to be contaminated with Salmonella. The potential for contamination was noted after routine sampling and testing...

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Dietary Supplements by Nutrizone: Recall - Potential for Salmonella Contamination

Lipid Index Determination by Liquid Fluorescence Recovery in the Fungal Pathogen Ustilago Maydis

Here, we describe a protocol to obtain the lipid droplet index (LD index) to study the dynamics of triacylglycerols in cells cultured in high-throughput experiments. The LD index assay is an easy and reliable method that uses BODIPY 493/503. This assay does not need dispendious lipid extraction or microscopy analysis.

https://ift.tt/2EdXePT

Most Patients Select Suboptimal Medications for Allergic Rhinitis

TUESDAY, April 3, 2018 -- The majority of pharmacy customers with rhinitis select suboptimal medications, according to a study published online March 29 in the Journal of Allergy and Clinical Immunology: In Practice. Rachel Tan, from the Woolcock...

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Diabetes, HbA1c Linked to Adverse Outcomes After Surgery

TUESDAY, April 3, 2018 -- For surgical inpatients aged ≥54 years, diabetes and increased hemoglobin A1c (HbA1c) are associated with increased risk of adverse outcomes, according to a study published online March 26 in Diabetes Care. Priscilla H....

https://ift.tt/2Jje7MS

Overweight, Obesity Contributing to Cancers in Young Adults

TUESDAY, April 3, 2018 -- Overweight and obesity may be contributing to specific malignancies at younger ages, according to research published online March 23 in Obesity. Nathan A. Berger, M.D., from the Case Western Reserve University School of...

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Anomalous Brain Structure ID'd in Preschoolers With ADHD

TUESDAY, April 3, 2018 -- Anomalous brain development is evident among medication-naive preschoolers with attention-deficit/hyperactivity disorder (ADHD), according to a study published in the April issue of the Journal of the International...

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Energy-Based Devices Work Well for Feminine Rejuvenation

TUESDAY, April 3, 2018 -- Energy-based devices are both safe and effective methods of nonsurgical treatment for feminine rejuvenation, according to a review published online March 10 in the Journal of Cosmetic Dermatology. Michael Gold, M.D., from...

https://ift.tt/2JgPfW3

Early Alcohol Use in Pregnancy Tied to Gastroschisis

TUESDAY, April 3, 2018 -- Alcohol consumption early in pregnancy may be a risk factor for the development of gastroschisis in neonates, according to a study published recently in the Journal of Maternal-Fetal & Neonatal Medicine. Jean R....

https://ift.tt/2q3ZWT3

CDC: Overdose Deaths Up Across Drug Categories in 2015 to 2016

TUESDAY, April 3, 2018 -- From 2015 to 2016, there were increases in deaths across all drug categories examined, with 63,632 drug overdose deaths in 2016, according to research published in the March 30 issue of the U.S. Centers for Disease Control...

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Preconception Blood Pressure Tied to Risk of Pregnancy Loss

TUESDAY, April 3, 2018 -- In healthy women, preconception blood pressure is associated with miscarriage, according to a study published online April 2 in Hypertension. Carrie J. Nobles, Ph.D., from the Eunice Kennedy Shriver National Institute of...

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Genotype-Guided Antiplatelet Therapy Feasible, Effective

TUESDAY, April 3, 2018 -- Using CYP2C19 genotype-guided dual antiplatelet therapy (DAPT) selection is feasible in a real-world setting, although frequency of testing may be difficult to maintain, according to a study published online April 3 in...

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Three-dimensional Inflammatory Human Tissue Equivalents of Gingiva

The goal of the protocol is to build an inflammatory human gingiva model in vitro. This tissue model co-cultivates three types of human cells, HaCaT keratinocytes, gingival fibroblasts, and THP-1 macrophages, under three-dimensional conditions. This model can be applied to investigating periodontal diseases, such as gingivitis and periodontitis.

https://ift.tt/2q0N0xY

Experimental Methods of Dust Charging and Mobilization on Surfaces with Exposure to Ultraviolet Radiation or Plasmas

Dust charging and mobilization is demonstrated in three experiments with exposure to thermal plasma with beam electrons, beam electrons only, or ultraviolet (UV) radiation only. These experiments present the advanced understanding of electrostatic dust transport and its role in shaping the surfaces of airless planetary bodies.

https://ift.tt/2q2YvUR

Treatment response assessment with ( R )-[ 11 CPAQ PET in the MMTV-PyMT mouse model of breast cancer

Abstract

Background

Methods

Results

Conclusions

The results of this study are promising. However, additional studies are necessary before (R)-[¹¹C]PAQ can be approved as a predictive radiotracer for cancer therapy response.

https://ift.tt/2GQ4JSy

AJCC 8th Edition: Colorectal Cancer

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Analysis of the Vascular Interrelationships Among the First Jejunal Vein, the Superior Mesenteric Artery, and the Middle Colic Artery

Abstract

Background

The technical difficulty of laparoscopic surgery for transverse colon cancer is partly due to the vascular variability around the middle colic vessels. Although individual variations in the arteries or veins in this area were previously investigated, the vascular interrelationships between these vessels remain unknown. This study was designed to investigate the vascular interrelationships between the arteries and veins around the middle colic vessels and to provide practically useful classifications.

Methods

This study included 105 consecutive patients who underwent colorectal surgery for colorectal tumors in our institution in 2016. Patients with a history of colectomy were excluded. Vascular anatomical classifications were analyzed by evaluating thin-slice images of preoperative contrast-enhanced computed tomography.

Results

Vascular anatomical patterns were classified according to whether the first jejunal vein ran behind (type A) or in front (type B) of the superior mesenteric artery. Type B was subclassified into two subtypes, depending on whether the middle colic artery originated cephalad (type B1) or caudad (type B2) to the first jejunal vein. We identified 83 (79.0%) cases of type A, 11 (10.5%) of type B1, and 11 (10.5%) of type B2. In 17 cases, the middle colic vein drained into the inferior mesenteric vein, and all of these were type A (P = 0.0202). Furthermore, in eight cases, the middle colic vein drained into the first jejunal vein, and all of these were type B (P < 0.0001).

Conclusions

This study elucidated the vascular interrelationships around the middle colic vessels. Our findings provided important knowledge for laparoscopic surgery in treating transverse colon cancer.

https://ift.tt/2H6sOC4

LVIS Jr Device for Y-Stent-Assisted Coil Embolization of Wide-Neck Intracranial Aneurysms: A Multicenter Experience

Background and Purpose: Complex wide-neck intracranial aneurysms are challenging to treat. We report a multicenter experience using the LVIS Jr stent for "Y-stent"-assisted coiling embolization of wide-neck bifurcation aneurysms. Methods: Seven centers provided retrospective data on patients who underwent Y-stenting. Technical complications, immediate posttreatment angiographic results, clinical outcomes, and imaging follow-up were assessed. Results: Thirty patients/aneurysms were treated: 15 basilar tip, 8 middle cerebral artery, 4 anterior communicating artery, 1 pericallosal, and 2 posterior inferior cerebellar artery aneurysms. The mean aneurysm size was 11 mm and the mean dome-to-neck ratio was 1.3 mm. Twenty-four aneurysms were unruptured and treated electively, and 6 were acutely ruptured. Fifty-eight LVIS Jr stents were successfully deployed without any technical issue. One procedural and transient in-stent thrombosis resolved with the intravenous infusion of a glycoprotein IIb/IIIa inhibitor. Five periprocedural complications (within 30 days) occurred: 2 periprocedural neurological complications (1 small temporal stroke that presented with transient aphasia and 1 posterior cerebral artery infarct) and 3 nonneurological periprocedural complications (2 retroperitoneal hematomas, and 1 patient developed a disseminated intravascular coagulopathy). One permanent complication (3.3%) directly related to Y-stenting was reported in the patient who suffered the posterior cerebral artery infarct. Immediate complete obliteration (Raymond-Roy Occlusion Classification [RROC] I–II) was achieved in 26 cases (89.6%). Twenty-four patients had clinical and imaging follow-up (mean 5.2 months). Complete angiographic occlusion (RROC I–II) was observed in 23 patients (96%). A good functional outcome with a modified Rankin Scale score ≤2 was achieved in 26 cases. Conclusions: In this multicenter case series, Y-stent-assisted coiling of wide-neck aneurysms with the LVIS Jr device was feasible and relatively safe. Follow-up imaging demonstrated very low recanalization rates.
Intervent Neurol 2018;7:271–283

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Genome-wide RNAi Screening to Identify Host Factors That Modulate Oncolytic Virus Therapy

Here we describe a protocol for employing high-throughput RNAi screening to uncover host targets that can be manipulated to enhance oncolytic virus therapy, specifically rhabodvirus and vaccinia virus therapy, but it can be readily adapted to other oncolytic virus platforms or for discovering host genes that modulate virus replication generally.

https://ift.tt/2IsQHDx

High-pressure, High-temperature Deformation Experiment Using the New Generation Griggs-type Apparatus

Rock deformation needs to be quantified at high pressure. A description of the procedure to perform deformation experiments in a newly designed solid-medium Griggs-type apparatus is here given. This provides technological basis for future rheological studies at pressures up to 5 GPa.

https://ift.tt/2GT9URK

A Circular RNA Protects Dormant Hematopoietic Stem Cells from DNA Sensor cGAS-Mediated Exhaustion

Disrupting the balance between self-renewal and differentiation of HSCs leads to severe pathologic consequences. Xia et al. identify a circular RNA cia-cGAS that is highly expressed in the nucleus of LT-HSCs. Under homeostatic conditions, cia-cGAS binds DNA sensor cGAS to block its synthase activity, protecting dormant LT-HSCs from cGAS-mediated exhaustion.

https://ift.tt/2uIazAi

Multiple balloon-like lesions in the small intestine of an adult with chronic diarrhoea

Clinical presentation

A 28-year-old woman presented with a 3-year history of chronic watery diarrhoea along with abdominal pain and bloating, which could mostly be alleviated after defecation. Her symptom of diarrhoea, at least three times a day, could be relieved by neither probiotics nor antidiarrhoeal agents. She had also lost 5 kg in the last month. She denied family history, poor vaccine responses or significant infections in early childhood except for an allergy history to intravenous immunoglobulin (Ig) with immediate dyspnoea, palpitations and hypotension. Laboratory investigations suggested that the stool specimens were negative for viruses, parasites or bacteria. Laboratory evaluation revealed a low serum globulin level, 14.5 (reference range, 20–30 g/L); serum Ig levels were significantly abnormal: IgA <0.27 (0.7–4 g/L), IgM 0.24 (0.4–2.3 g/L), IgG 1.3 (7–16 g/L); white cell count 15.4x10⁹/L (3.69–9.16x10⁹/L); C-reactive protein (CRP) 20.5 (normal <10 mg/L); CD4+ lymphocyte/CD8+ lymphocyte 1.09% (1.5%–2%). Other laboratory findings were unremarkable, for example, tumour markers, autoantibodies and HIV, and so on. CT showed mesenteric nodule-like...

https://ift.tt/2Eh73ML

Comparison of prognostic models to predict the occurrence of colorectal cancer in asymptomatic individuals: a systematic literature review and external validation in the EPIC and UK Biobank prospective cohort studies

Objective

To systematically identify and validate published colorectal cancer risk prediction models that do not require invasive testing in two large population-based prospective cohorts.

Design

Models were identified through an update of a published systematic review and validated in the European Prospective Investigation into Cancer and Nutrition (EPIC) and the UK Biobank. The performance of the models to predict the occurrence of colorectal cancer within 5 or 10 years after study enrolment was assessed by discrimination (C-statistic) and calibration (plots of observed vs predicted probability).

Results

The systematic review and its update identified 16 models from 8 publications (8 colorectal, 5 colon and 3 rectal). The number of participants included in each model validation ranged from 41 587 to 396 515, and the number of cases ranged from 115 to 1781. Eligible and ineligible participants across the models were largely comparable. Calibration of the models, where assessable, was very good and further improved by recalibration. The C-statistics of the models were largely similar between validation cohorts with the highest values achieved being 0.70 (95% CI 0.68 to 0.72) in the UK Biobank and 0.71 (95% CI 0.67 to 0.74) in EPIC.

Conclusion

Several of these non-invasive models exhibited good calibration and discrimination within both external validation populations and are therefore potentially suitable candidates for the facilitation of risk stratification in population-based colorectal screening programmes. Future work should both evaluate this potential, through modelling and impact studies, and ascertain if further enhancement in their performance can be obtained.

https://ift.tt/2JgunOD

Long-term proton pump inhibitors use and risk of gastric cancer: a meta-analysis of 926 386 participants

We read with interest the study by Cheung et al1 reporting that long-term use of proton pump inhibitors (PPIs) was associated with an increased risk of gastric cancer (GC) in participants after Helicobacter pylori eradication. Considering PPIs were widely used for the treatment of acid-related disorders, and previous studies about PPIs use and risk of GC did not have a consistent result. To better understand this issue, we conducted this meta-analysis that investigated the associations between long-term PPIs use and risk of GC.

We searched the PubMed, Embase and Web of Science for potential studies published before March 2018. The inclusion criteria were (1) randomised controlled trail, case–control study or cohort study; (2) defined GC and exposure to PPIs clearly; and (3) reported the relative risk (RR), ORs or other measures of association. The quality of included study was evaluated according to the Newcastle–Ottawa Scale. The pooled OR and 95% CIs were...

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Development and clinical validation of the Genedrive point-of-care test for qualitative detection of hepatitis C virus

Objective

Recently approved direct acting antivirals provide transformative therapies for chronic hepatitis C virus (HCV) infection. The major clinical challenge remains to identify the undiagnosed patients worldwide, many of whom live in low-income and middle-income countries, where access to nucleic acid testing remains limited. The aim of this study was to develop and validate a point-of-care (PoC) assay for the qualitative detection of HCV RNA.

Design

We developed a PoC assay for the qualitative detection of HCV RNA on the PCR Genedrive instrument. We validated the Genedrive HCV assay through a case–control study comparing results with those obtained with the Abbott RealTime HCV test.

Results

The PoC assay identified all major HCV genotypes, with a limit of detection of 2362 IU/mL (95% CI 1966 to 2788). Using 422 patients chronically infected with HCV and 503 controls negative for anti-HCV and HCV RNA, the Genedrive HCV assay showed 98.6% sensitivity (95% CI 96.9% to 99.5%) and 100% specificity (95% CI 99.3% to 100%) to detect HCV. In addition, melting peak ratiometric analysis demonstrated proof-of-principle for semiquantification of HCV. The test was further validated in a real clinical setting in a resource-limited country.

Conclusion

We report a rapid, simple, portable and accurate PoC molecular test for HCV, with sensitivity and specificity that fulfils the recent FIND/WHO Target Product Profile for HCV decentralised testing in low-income and middle-income countries. This Genedrive HCV assay may positively impact the continuum of HCV care from screening to cure by supporting real-time treatment decisions.

Trial registration number

NCT02992184.

https://ift.tt/2GSDTsT

How to use the Kaiser score as a clinical decision rule for diagnosis in multiparametric breast MRI: a pictorial essay

Abstract

Due to its superior sensitivity, breast MRI (bMRI) has been established as an important additional diagnostic tool in the breast clinic and is used for screening in patients with an elevated risk for breast cancer. Breast MRI, however, is a complex tool, providing multiple images containing several contrasts. Thus, reading bMRI requires a structured approach. A lack of structure will increase the rate of false-positive findings and sacrifice most of the advantages of bMRI as additional work-up will be required. While the BI-RADS (Breast Imaging Reporting And Data System) lexicon is a major step toward standardised and structured reporting, it does not provide a clinical decision rule with which to guide diagnostic decisions. Such a clinical decision rule, however, is provided by the Kaiser score, which combines five independent diagnostic BI-RADS lexicon criteria (margins, SI-time curve type, internal enhancement and presence of oedema) in an intuitive flowchart. The resulting score provides probabilities of malignancy that can be used for evidence-based decision-making in the breast clinic. Notably, considerable benefits have been demonstrated for radiologists with initial and intermediate experience in bMRI. This pictorial essay is a practical guide to the application of the Kaiser score in the interpretation of breast MRI examinations.

Teaching Points

• bMRI requires standardisation of patient-management, protocols, and reading set-up.

• Reading bMRI includes the assessment of breast parenchyma, associated findings, and lesions.

• Diagnostic decisions should be made according to evidence-based clinical decision rules.

• The evidence-based Kaiser score is applicable independent of bMRI protocol and scanner.

• The Kaiser score provides high diagnostic accuracy with low inter-observer variability.

https://ift.tt/2GxUanS

Experience with eribulin in patients with breast cancer and cutaneous metastases: case studies

Future Oncology, Volume 14, Issue 7s, Page 37-44, March 2018.

https://ift.tt/2H6a0mD

Experience with eribulin in the treatment of elderly women with metastatic breast cancer: case studies

Future Oncology, Volume 14, Issue 7s, Page 21-27, March 2018.

https://ift.tt/2EejAR7

Foreword

Future Oncology, Volume 14, Issue 7s, Page 1-3, March 2018.

https://ift.tt/2GL1Hir

Experience with eribulin in patients with metastatic breast cancer and associated hepatic impairment: case studies

Future Oncology, Volume 14, Issue 7s, Page 29-36, March 2018.

https://ift.tt/2EgsJJ1

Experience with eribulin in HR+/HER2- metastatic breast cancer, including a male

Future Oncology, Volume 14, Issue 7s, Page 5-12, March 2018.

https://ift.tt/2H7r5MP

Experience with eribulin in triple-negative metastatic breast cancer: case studies

Future Oncology, Volume 14, Issue 7s, Page 13-20, March 2018.

https://ift.tt/2EgqMMQ

Poor Prognostic Factors in Patients with Malignant Pleural Mesothelioma Classified as Pathological Stage IB According to the Eighth Edition TNM Classification

Abstract

Introduction

The change in TNM classification of malignant pleural mesothelioma (MPM) between the seventh and eighth edition classifications has resulted in the downstaging of many advanced-stage patients into pathological stage IB. Many mesotheliomas without lymph node metastasis have been classified as stage IB in the eighth edition classification. Stage IB mesotheliomas comprised a heterogeneous group with different prognosis. It is necessary to clarify the prognostic factors in this group.

Methods

Between September 2009 and August 2016, a total of 89 patients with MPM underwent curative intent surgery [pleurectomy decortication n = 57 (64.1%), extrapleural pneumonectomy n = 32 (35.9%)] at our institution. Of these, 40 were reclassified as stage IB according to the eighth edition TNM classification. Independent unfavorable prognostic factors were identified by univariate analyses using the log-rank test and Cox proportional hazards regression models.

Results

Three independent significant factors were identified that indicated an unfavorable prognosis: a nonepithelioid subtype, lymphovascular invasion, and preoperative forced expiratory volume in 1 s (FEV1) < 2000 ml. Patients with no, one, and two of these risk factors showed 3-year overall survival probabilities of 94.7, 62.5, and 0%, respectively. The 3-year survival of patients with one factor did not differ significantly from that of patients with stage III MPM, whereas that of patients with two factors was significantly shorter (p = 0.015).

Conclusions

Independent poor prognostic factors for patients with stage IB MPM patients, allowing subgroups with poorer and more favorable prognoses to be identified. This should help personalize decisions on adjuvant chemotherapy.

https://ift.tt/2Imkmhx

Positive Association between EDN1 rs5370 (Lys198Asn) Polymorphism and Large Artery Stroke in a Ukrainian Population

There are a lot of convincing evidences about the involvement of endothelin pathway proteins in the pathogenesis of atherosclerosis and its fatal complications. In this study, the analysis of a possible association between EDN1 rs5370 and EDNRA rs5335 gene polymorphisms and the risk of large artery stroke (LAS) in a Ukrainian population was conducted. 200 LAS patients and 200 unrelated controls were enrolled in a case-control study. The polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP) was used for SNP genotyping. Our results revealed that EDN1 rs5370 polymorphism was associated with LAS development both before and after adjustment for atherosclerosis risk factors (sex, age, body mass index, arterial hypertension, type 2 diabetes mellitus, and smoking). The risk for a LAS incident in rs5370-T allele carriers was 1.6 times higher (CI = 1.066–2.403; ) than in subjects with the GG genotype. No link between EDNRA rs5335 and LAS risk in a Ukrainian population was found. The present study indicated that EDN1 rs5370, but not EDNRA rs5335, can be the strong genetic predictor for LAS development in a Ukrainian population.

https://ift.tt/2GNAH1x

A protocol for a prospective observational study using chest and thumb ECG: transient ECG assessment in stroke evaluation (TEASE) in Sweden

Introduction

Atrial fibrillation (AF) causes ischaemic stroke and based on risk factor evaluation warrants anticoagulation therapy. In stroke survivors, AF is typically detected with short-term ECG monitoring in the stroke unit. Prolonged continuous ECG monitoring requires substantial resources while insertable cardiac monitors are invasive and costly. Chest and thumb ECG could provide an alternative for AF detection poststroke.

The primary objective of our study is to assess the incidence of newly diagnosed AF during 28 days of chest and thumb ECG monitoring in cryptogenic stroke. Secondary objectives are to assess health-related quality of life (HRQoL) using short-form health survey (SF-36) and the feasibility of the Coala Heart Monitor in patients who had a stroke.

Methods

Stroke survivors in Region Gävleborg, Sweden, will be eligible for the study from October 2017. Patients with a history of ischaemic stroke without documented AF before or during ECG evaluation in the stroke unit will be evaluated by the chest and thumb ECG system Coala Heart Monitor. The monitoring system is connected to a smartphone application which allows for remote monitoring and prompt advice on clinical management. Over a period of 28 days, patients will be monitored two times a day and may activate the ECG recording at symptoms. On completion, the system is returned by mail. This system offers a possibility to evaluate the presence of AF poststroke, but the feasibility of this system in patients who recently suffered from a stroke is unknown. In addition, HRQoL using SF-36 in comparison to Swedish population norms will be assessed. The feasibility of the Coala Heart Monitor will be assessed by a self-developed questionnaire.

Ethics and dissemination

The study was approved by The Regional Ethical Committee in Uppsala (2017/321). The database will be closed after the last follow-up, followed by statistical analyses, interpretation of results and dissemination to a scientific journal.

Trial registration number

NCT03301662; Pre-results.

https://ift.tt/2q2HQAL

Cost-effectiveness of interventions to control cardiovascular diseases and diabetes mellitus in South Asia: a systematic review

Objectives

More than 80% of cardiovascular diseases (CVD) and diabetes mellitus (DM) burden now lies in low and middle-income countries. Hence, there is an urgent need to identify and implement the most cost-effective interventions, particularly in the resource-constraint South Asian settings. Thus, we aimed to systematically review the cost-effectiveness of individual-level, group-level and population-level interventions to control CVD and DM in South Asia.

Methods

We searched 14 electronic databases up to August 2016. The search strategy consisted of terms related to 'economic evaluation', 'CVD', 'DM' and 'South Asia'. Per protocol two reviewers assessed the eligibility and methodological quality of studies using standard checklists, and extracted incremental cost-effectiveness ratios of interventions.

Results

Of the 2949 identified studies, 42 met full inclusion criteria. Critical appraisal of studies revealed 15 excellent, 18 good and 9 poor quality studies. Most studies were from India (n=37), followed by Bangladesh (n=3), Pakistan (n=2) and Bhutan (n=1). The economic evaluations were based on observational studies (n=9), randomised trials (n=12) and decision models (n=21). Together, these studies evaluated 301 policy or clinical interventions or combination of both. We found a large number of interventions were cost-effective aimed at primordial prevention (tobacco taxation, salt reduction legislation, food labelling and food advertising regulation), and primary and secondary prevention (multidrug therapy for CVD in high-risk group, lifestyle modification and metformin treatment for diabetes prevention, and screening for diabetes complications every 2–5 years). Significant heterogeneity in analytical framework and outcome measures used in these studies restricted meta-analysis and direct ranking of the interventions by their degree of cost-effectiveness.

Conclusions

The cost-effectiveness evidence for CVD and DM interventions in South Asia is growing, but most evidence is from India and limited to decision modelled outcomes. There is an urgent need for formal health technology assessment and policy evaluations in South Asia using local research data.

PROSPERO registration number

CRD42013006479.

https://ift.tt/2GxzEDS

Longitudinal study of occupational noise exposure and joint effects with job strain and risk for coronary heart disease and stroke in Swedish men

Objectives

The aims were to investigate whether occupational noise increased the risk for coronary heart disease (CHD) and stroke and to elucidate interactions with stressful working conditions in a cohort of Swedish men.

Design

This is a prospective cohort study on CHD and stroke in Swedish men followed until death, hospital discharge or until 75 years of age, using Swedish national registers on cause of death and hospital discharges. Baseline data on occupation from 1974 to 1977 were used for classification of levels of occupational noise and job demand-control. Cox regression was used to analyse HRs for CHD and stroke.

Setting

Swedish men born in 1915–1925.

Primary and secondary outcome measures

CHD and stroke.

Participants

The participants of the study were men from the Primary Prevention Study, a random sample of 10 000 men born in 1915–1925 in Gothenburg. Subjects with CHD or stroke at baseline or were not employed were excluded. The remaining subjects with complete baseline data on occupation, weight, height, hypertension, diabetes, serum cholesterol and smoking constituted the study sample (5753 men).

Results

There was an increased risk for CHD in relation to noise levels 75–85 dB(A) and >85 dB(A) compared with <75 dB(A) (HR 1.15, 95% CI 1.01 to 1.31, and HR 1.27, 95% CI 0.99 to 1.63, respectively). Exposure to noise peaks also increased the risk for CHD (HR 1.19, 95% CI 1.03 to 1.38). Among those with high strain (high demands and low control) combined with noise >75 dB(A), the risk for CHD further increased (HR 1.80, 95% CI 1.19 to 2.73). There was no significantly increased risk for stroke in any noise category.

Conclusions

Exposure to occupational noise was associated with an increased risk for CHD and the risk further increased among those with concomitant exposure to high strain. None of the analysed variables were related to increased risk for stroke.

https://ift.tt/2q2bPsx

Postpartum family planning integration with maternal, newborn and child health services: a cross-sectional analysis of client flow patterns in India and Kenya

Objectives

Maternal, newborn and child health (MNCH) services represent opportunities to integrate postpartum family planning (PPFP). Objectives were to determine levels of MNCH–family planning (FP) integration and associations between integration, client characteristics and service delivery factors in facilities that received programmatic PPFP support.

Design and setting

Cross-sectional client flow assessment conducted during May–July 2014, over 5 days at 10 purposively selected public sector facilities in India (4 hospitals) and Kenya (2 hospitals and 4 health centres).

Participants

2158 client visits tracked (1294 India; 864 Kenya). Women aged 18 or older accessing services while pregnant and/or with a child under 2 years.

Interventions

PPFP/postpartum intrauterine device—Bihar, India (2012–2013); Jharkhand, India (2009–2014); Embu, Kenya (2006–2010). Maternal, infant and young child nutrition/FP integration—Bondo, Kenya (2011–2014).

Primary outcome measures

Proportion of visits where clients received integrated MNCH–FP services, client characteristics as predictors of MNCH–FP integration and MNCH–FP integration as predictor of length of time spent at facility.

Results

Levels of MNCH–FP integration varied widely across facilities (5.3% to 63.0%), as did proportion of clients receiving MNCH–FP integrated services by service area. Clients travelling 30–59 min were half as likely to receive integrated services versus those travelling under 30 min (OR 0.5, 95% CI 0.4 to 0.7, P<0.001). Clients receiving MNCH–FP services (vs MNCH services only) spent an average of 10.5 min longer at the facility (95% CI –0.1 to 21.9, not statistically significant).

Conclusions

Findings suggest importance of focused programmatic support for integration by MNCH service area. FP integration was highest in areas receiving specific support. Integration does not seem to impose an undue burden on clients in terms of time spent at the facility. Clients living furthest from facilities are least likely to receive integrated services.

https://ift.tt/2GxztII

Prospective, single UK centre, comparative study of the predictive values of contrast-enhanced ultrasound compared to time-resolved CT angiography in the detection and characterisation of endoleaks in high-risk patients undergoing endovascular aneurysm repair surveillance: a protocol

Introduction

Diagnosis of endoleaks is imperative to prevent failure of endovascular aneurysm repairs (EVARs). The gold standard for diagnosis of endoleaks is catheter-directed subtraction angiography, which is not a practicable choice for surveillance. CT angiography (CTA) is the historical surveillance modality of choice. Concerns over cost, potential nephrotoxicity of contrast agents and repeated radiation exposure led to colour duplex ultrasound scan (CDUS) becoming an established alternative. CDUS has a lower sensitivity and specificity for endoleaks detection compared to CTA. Contrast-enhanced ultrasound scan (CEUS) represents an improvement of ultrasound imaging but comparisons against CTA report widely varying results, likely due to technical factors of CEUS and limitations of single-phase CTA.

The development of time-resolved CTA (tCTA) offers timing information that much more closely mirrors the dynamic information available from CEUS. Theoretically, these two imaging modalities have the best potential for diagnostic accuracy. The aim of this study will be to compare CEUS to tCTA and investigate the utility of other measurements available from tCTA.

Methods and analysis

This is a prospective, single UK centre, comparative study of paired binary diagnostic imaging modalities. Patients identified in routine post-EVAR surveillance as at risk of having a graft-related endoleak will undergo a CEUS and tCTA on the same day. This will allow the first comparison of CEUS to a semidynamic form of CTA. CEUS sensitivity and specificity to endoleak detection will be calculated.

Ethics and dissemination

The study has achieved ethical approval. We hope the results will define the diagnostic accuracy of CEUS in comparison to a semidynamic form of CTA, representing a methodological improvement from previous studies. Results will be submitted for presentation at national and international vascular surgeryandradiology meetings. The full results are planned to be published in a medical journal.

Trial registration number

NCT02688751.

https://ift.tt/2q2HPNd

Home interventions and light therapy for the treatment of vitiligo (HI-Light Vitiligo Trial): study protocol for a randomised controlled trial

Introduction

Vitiligo is a condition resulting in white patches on the skin. People with vitiligo can suffer from low self-esteem, psychological disturbance and diminished quality of life. Vitiligo is often poorly managed, partly due to lack of high-quality evidence to inform clinical care. We describe here a large, independent, randomised controlled trial (RCT) assessing the comparative effectiveness of potent topical corticosteroid, home-based hand-held narrowband ultraviolet B-light (NB-UVB) or combination of the two, for the management of vitiligo.

Methods and analysis

The HI-Light Vitiligo Trial is a multicentre, three-arm, parallel group, pragmatic, placebo-controlled RCT. 516 adults and children with actively spreading, but limited, vitiligo are randomised (1:1:1) to one of three groups: mometasone furoate 0.1% ointment plus dummy NB-UVB light, vehicle ointment plus NB-UVB light or mometasone furoate 0.1% ointment plus NB-UVB light. Treatment of up to three patches of vitiligo is continued for up to 9 months with clinic visits at baseline, 3, 6 and 9 months and four post-treatment questionnaires.

The HI-Light Vitiligo Trial assesses outcomes included in the vitiligo core outcome set and places emphasis on participants' views of treatment success. The primary outcome is proportion of participants achieving treatment success (patient-rated Vitiligo Noticeability Scale) for a target patch of vitiligo at 9 months with further independent blinded assessment using digital images of the target lesion before and after treatment. Secondary outcomes include time to onset of treatment response, treatment success by body region, percentage repigmentation, quality of life, time-burden of treatment, maintenance of response, safety and within-trial cost-effectiveness.

Ethics and dissemination

Approvals were granted by East Midlands—Derby Research Ethics Committee (14/EM/1173) and the MHRA (EudraCT 2014-003473-42). The trial was registered 8 January 2015 ISRCTN (17160087). Results will be published in full as open access in the NIHR Journal library and elsewhere.

Trial registration number

ISRCTN17160087.

https://ift.tt/2Gtgw9X

A discrete choice experiment to determine facility-based delivery services desired by women and men in rural Ethiopia

Objectives

Despite global efforts to increase facility-based delivery (FBD), 90% of women in rural Ethiopia deliver at home without a skilled birth attendant. Men have an important role in increasing FBD due to their decision-making power, but this is largely unexplored. This study aimed to determine the FBD care attributes preferred by women and men, and whether poverty or household decision-making are associated with choice to deliver in a facility.

Setting and participants

We conducted a cross-sectional discrete choice experiment in 109 randomly selected households in rural Ethiopia in September–October 2015. We interviewed women who were pregnant or who had a child <2 years old and their male partners.

Results

Both women and men preferred health facilities where medications and supplies were available (OR=3.08; 95% CI 2.03 to 4.67 and OR=2.68; 95% CI 1.79 to 4.02, respectively), a support person was allowed in the delivery room (OR=1.69; 95% CI 1.37 to 2.07 and OR=1.74; 95% CI 1.42 to 2.14, respectively) and delivery cost was low (OR=1.15 95% CI 1.12 to 1.18 and OR=1.14; 95% CI 1.11 to 1.17, respectively). Women valued free ambulance service (OR=1.37; 95% CI 1.09 to 1.70), while men favoured nearby facilities (OR=1.09; 95% CI 1.06 to 1.13) with friendly providers (OR=1.30; 95% CI 1.03 to 1.64). Provider preferences were complex. Neither women nor men preferred female doctors to health extension workers (HEW) (OR=0.92; 95% CI 0.59 to 1.42 and OR=0.74; 95% CI 0.47 to 1.14, respectively), male doctors to HEW (OR=1.33; 95% CI 0.89 to 1.99 and OR=0.75; 95% CI 0.50 to 1.12, respectively) or female over male nurses (OR=0.68; 95% CI 0.94 to 1.71 and OR=1.03; 95% CI 0.77 to 2.94, respectively). While both women and men preferred male nurses to HEW (OR=1.86; 95% CI 1.23 to 2.80 and OR=1.95; 95% CI 1.30 to 2.95, respectively), men (OR=1.89; 95% CI 1.29 to 2.78), but not women (OR=1.47; 95% CI 1.00 to 2.13) preferred HEW to female nurses. Both women and men preferred female doctors to male nurses (OR=1.71; 95% CI 1.27 to 2.29 and OR=1.44; 95% CI 1.07 to 1.92, respectively), male doctors to female nurses (OR=1.95; 95% CI 1.44 to 2.62 and OR=1.41; 95% CI 1.05 to 1.90, respectively) and male doctors to male nurses (OR=2.47; 95% CI 1.84 to 3.32 and OR=1.46; 95% CI 1.09 to 1.95, respectively), while only women preferred male doctors to female doctors (OR=1.45; 95% CI 1.09 to 1.93 and OR=1.01; 95% CI 0.76 to 1.35, respectively) and only men preferred female nurses to female doctors (OR=1.34; 95% CI 0.98 to 1.84 and OR=1.39; 95% CI 1.02 to 1.89, respectively). Men were disproportionately involved in making household decisions (X² (1, n=216)=72.18, p<0.001), including decisions to seek healthcare (X² (1, n=216)=55.39, p<0.001), yet men were often unaware of their partners' prenatal care attendance (X² (1, n=215)=82.59, p<0.001).

Conclusion

Women's and men's preferences may influence delivery service choices. Considering these choices is one way the Ethiopian government and health facilities may encourage FBD in rural areas.

https://ift.tt/2q3ADR1

Piloting the addition of contingency management to best practice counselling as an adjunct treatment for rural and remote disordered gamblers: study protocol

Introduction

Problematic gambling is a significant Canadian public health concern that causes harm to the gambler, their families, and society. However, a significant minority of gambling treatment seekers drop out prior to the issue being resolved; those with higher impulsivity scores have the highest drop-out rates. Consequently, retention is a major concern for treatment providers. The aim of this study is to investigate the efficacy of internet-delivered cognitive behavioural therapy (CBT) and internet-delivered CBT and contingency management (CM+) as treatments for gambling disorder in rural Albertan populations. Contingency management (CM) is a successful treatment approach for substance dependence that uses small incentives to reinforce abstinence. This approach may be suitable for the treatment of gambling disorder. Furthermore, internet-delivered CM may hold particular promise in rural contexts, as these communities typically struggle to access traditional clinic-based counselling opportunities.

Methods and analysis

54 adults with gambling disorder will be randomised into one of two conditions: CM and CBT (CM+) or CBT alone (CBT). Gambling will be assessed at intake, every treatment session, post-treatment, and follow-up. The primary outcome measures are treatment attendance, gambling abstinence, gambling, gambling symptomatology, and gambling urge. In addition, qualitative interviews assessing study experiences will be conducted with the supervising counsellor, graduate student counsellors, study affiliates, and a subset of treatment seekers. This is the first study to use CM as a treatment for gambling disorder in rural and remote populations.

Ethics and dissemination

This study was approved by the University of Lethbridge's Human Subject Research Committee (#2016–080). The investigators plan to publish the results from this study in academic peer-reviewed journals. Summary information will be provided to the funder.

Trial registration number

NCT02953899; Pre-results.

https://ift.tt/2GtMcMd

Prevalence and determinants of unplanned pregnancy in HIV-positive and HIV-negative pregnant women in Cape Town, South Africa: a cross-sectional study

Objectives

Prevention of unplanned pregnancy is a crucial aspect of preventing mother-to-child HIV transmission. There are few data investigating how HIV status and use of antiretroviral therapy (ART) may influence pregnancy planning in high HIV burden settings. Our objective was to examine the prevalence and determinants of unplanned pregnancy among HIV-positive and HIV-negative women in Cape Town, South Africa.

Design

Cross-sectional analysis.

Settings

Single primary-level antenatal care clinic in Cape Town, South Africa.

Participants

HIV-positive and HIV-negative pregnant women, booking for antenatal care from March 2013 to August 2015, were included.

Main outcome measures

Unplanned pregnancy was measured at the first antenatal care visit using the London Measure of Unplanned Pregnancy (LMUP). Analyses examined LMUP scores across four groups of participants defined by their HIV status, awareness of their HIV status prior to the current pregnancy and/or whether they were using antiretroviral therapy (ART) prior to the current pregnancy.

Results

Among 2105 pregnant women (1512 HIV positive; 593 HIV negative), median age was 28 years, 43% were married/cohabiting and 20% were nulliparous. Levels of unplanned pregnancy were significantly higher in HIV-positive versus HIV-negative women (50% vs 33%, p<0.001); and highest in women who were known HIV positive but not on ART (53%). After adjusting for age, parity and marital status, unplanned pregnancy was most common among women newly diagnosed and women who were known HIV positive but not on ART (compared with HIV-negative women, adjusted OR (aOR): 1.43; 95% CI 1.05 to 1.94 and aOR: 1.57; 95% CI 1.13 to 2.15, respectively). Increased parity and younger age (<24 years) were also associated with unplanned pregnancy (aOR: 1.42; 95% CI 1.25 to 1.60 and aOR: 1.83; 95% CI 1.23 to 2.74, respectively).

Conclusions

We observed high levels of unplanned pregnancy among HIV-positive women, particularly among those not on ART, suggesting ongoing missed opportunities for improved family planning and counselling services for HIV-positive women.

https://ift.tt/2q6g9aq

Frequency-risk relationships between second-hand smoke exposure and respiratory symptoms among adolescents: a cross-sectional study in South China

Objectives

Although previous studies have suggested an association between second-hand smoke (SHS) exposure and respiratory symptoms, current evidence is inconsistent. Additionally, it remains unclear whether there are frequency–risk relationships between SHS exposure and respiratory symptoms among adolescents.

Methods

A cross-sectional survey was conducted using a stratified cluster sampling method to obtain a representative sample of high school students in Guangzhou, China. The respiratory symptoms were defined as persistent cough or sputum for three consecutive months during the past 12 months. Self-reported SHS exposure was defined as non-smokers' inhalation of the smoke exhaled from smokers on ≥1 day a week in the past 7 days. The univariable and multivariable logistic regression models were fitted to explore the potential frequency–risk relationships between SHS exposure and respiratory symptoms.

Results

Among 3575 students, the overall prevalence of SHS exposure was 69.2%, including 49.5% for SHS in public places, 34.5% in homes, 22.7% in indoor campuses and 29.2% in outdoor campuses. There were significantly increased risks of having respiratory symptoms corresponding to SHS exposure in public places (OR=1.60, 95% CI 1.30 to 1.95), in homes (OR=1.53, 95% CI 1.25 to 1.87), in indoor campuses (OR=1.43, 95% CI 1.14 to 1.79) and in outdoor campuses (OR=1.37, 95% CI 1.10 to 1.69) using no exposure as reference. Notably, we observed monotonic frequency–risk relationships between setting-specific(eg, homes, public places and campuses) SHS exposure and respiratory symptoms.

Conclusion

Our findings suggest that setting-specific SHS exposure is associated with a significant, dose-dependent increase in risk of respiratory symptoms.

https://ift.tt/2JhdGCE

Reconstructing the molecular life history of gliomas

Abstract

At the time of their clinical manifestation, the heterogeneous group of adult and pediatric gliomas carries a wide range of diverse somatic genomic alterations, ranging from somatic single-nucleotide variants to structural chromosomal rearrangements. Somatic abnormalities may have functional consequences, such as a decrease, increase or change in mRNA transcripts, and cells pay a penalty for maintaining them. These abnormalities, therefore, must provide cells with a competitive advantage to become engrained into the glioma genome. Here, we propose a model of gliomagenesis consisting of the following five consecutive phases that glioma cells have traversed prior to clinical manifestation: (I) initial growth; (II) oncogene-induced senescence; (III) stressed growth; (IV) replicative senescence/crisis; (V) immortal growth. We have integrated the findings from a large number of studies in biology and (neuro)oncology and relate somatic alterations and other results discussed in these papers to each of these five phases. Understanding the story that each glioma tells at presentation may ultimately facilitate the design of novel, more effective therapeutic approaches.

https://ift.tt/2q3pjUO

Screening and Molecular Identification of Pectinase Producing Microbes from Coffee Pulp

Application of enzymes in biotechnological process has expanded considerably in recent years. In food and related industry, major importance was being attached to the use of enzymes in upgrading quality, increasing yields of extractive processes, product stabilization, and improvement of flavor and byproduct utilization. Pectinases or pectinolytic enzymes are today one of the upcoming enzymes of the commercial sector. It has been reported that microbial pectinases account for 25% of the global food enzymes sales. For this reason, this study was undertaken with aims of screening microorganisms for the pectinase activity from coffee pulp samples and molecular identification of the potential pectinolytic isolates. In the present investigation, in total, ninety-five (95) isolates were identified from thirty coffee pulp samples. Based on characterization on the selective growth media, the isolates were grouped as actinomycete (21.06%), bacteria (65.26%), and fungi (13.68%). Among these, 31.58% showed colonies surrounded by clear zones which indicate the presence of pectinase activity. After rigorous screening steps, the isolates with high potential pectinase activity were identified molecularly by sequencing 16S rDNA region of the isolates. Based on the molecular identifications, about 70% of the isolates are under genus Bacillus.

https://ift.tt/2Ji5GS0

Co-inhibitory Molecule B7 Superfamily Member 1 Expressed by Tumor-Infiltrating Myeloid Cells Induces Dysfunction of Anti-tumor CD8+ T Cells

Mechanisms driving T cell exhaustion have not been understood. Li et al. demonstrate that B7S1 on tumor-infiltrating myeloid cells initiates exhaustion of activated CD8+ TILs through upregulating Eomes, thus proposing B7S1 as a promising target to enhance the efficacy of anti-PD-1 therapy.

https://ift.tt/2GQg30Y

KLRG1+ Effector CD8+ T Cells Lose KLRG1, Differentiate into All Memory T Cell Lineages, and Convey Enhanced Protective Immunity

Herndler-Brandstetter et al. demonstrate that KLRG1+IL-7Rα+ effector CD8+ T cells downregulate KLRG1 in a Bach2-dependent manner and differentiate into long-lived circulating and tissue-resident "exKLRG1" memory cells. Developmental plasticity of KLRG1+ effector cells therefore drives functional diversity within memory T cell lineages and promotes enhanced anti-influenza and anti-tumor immunity.

https://ift.tt/2IrvyJP

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Αναζήτηση αυτού του ιστολογίου

Τρίτη 3 Απριλίου 2018

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