Association between Morphological Patterns of Myometrial Invasion and Cancer Stem Cell Markers in Endometrial Endometrioid Carcinoma

Abstract

In endometrial endometrioid adenocarcinoma (EEC), the depth of myometrial invasion (MI) is an important parameter for determining whether additional treatment is warranted. The present study investigated the association between MI patterns, cancer stem cell (CSC) phenotypes, and their clinicopathological significance in EEC. A total of 73 cases of EEC with MI were examined in this study. Haematoxylin and eosin-stained tissue specimens were analysed for MI pattern, which was categorised as infiltrating; expansile; adenomyosis (AM)-like; or microcystic, elongated, and fragmented (MELF)-type. The expression of CSC markers such as cluster of differentiation (CD)44, CD133, and Nanog1, as well as oestrogen receptor (ER) and progesterone receptor (PR) was examined by immunohistochemistry. Clinicopathological features including age, DOI, MI pattern, LVI, lymph node (LN) metastasis, disease progression, and survival outcome were recorded. Most examined cases (45/73) were International Federation of Gynecology and Obstetrics (FIGO) stage I. MI showed infiltrating (49.3%), AM-like (26.3%), MELF (15.1%), and expansile (9.6%) patterns. Tumours with the infiltrating pattern were associated with high FIGO grade (P = 0.002), reduced ER and PR, and CD44 expression (P = 0.014, 0.026, and 0.030, respectively); those with a MELF pattern showed LN metastasis (P < 0.001), lymphovascular invasion (P = 0.011), and reduced ER, CD44, and CD133 expression (P = 0.036, 0.006, and 0.016, respectively). EEC with infiltrating/MELF patterns of MI is associated with worse prognosis. These results suggest that CSC expression profiles are an unfavourable indicator of EEC.

http://ift.tt/2y4Grxi

Eye movements in genetic parkinsonisms affecting the α-synuclein, PARK9, and manganese network

Specific saccadic abnormalities follow basal ganglia dysfunction. Eye movements are indeed often analyzed to differentiate parkinsonian syndromes and to provide new insights into the modulatory role of the basal ganglia. Nevertheless, the oculomotor description of most inherited parkinsonisms is still lacking. Here, we analyzed the eye movement characteristics of three inherited parkinsonian syndromes (genetic Parkinson's disease, PDG): Parkinson's disease 9 (or Kufor-Rakeb syndrome, PARK9, #606693), due to recessive mutations in ATP13A2 encoding the lysosomal P-type ATPase PARK9 (Ramirez et al., 2006; Gitler et al., 2009); hypermanganesemia with dystonia, polycythemia, and cirrhosis (HMNDYT1, #613280) due to recessive mutations in SLC30A10 leading to manganese accumulation in the liver, bone marrow, and nervous system (Quadri et al., 2012), and Parkinson's disease 1 (PARK1, #168601) associated with dominant mutations in SNCA encoding α-synuclein (Golbe et al., 1990).

http://ift.tt/2gkOL4o

A1 Slim by Kiriko : Recall - Undeclared Drug Ingredients

Audience: Consumer [Posted 10/06/2017] ISSUE: Kiriko, LLC. is voluntarily recalling all lots of A1 Slim 30 capsules bottle to the consumer level.  FDA laboratory analysis has found the A1 Slim product to be tainted with sibutramine,...

http://ift.tt/2hU4sTH

A1 Slim by Kiriko : Recall - Undeclared Drug Ingredients

Audience: Consumer [Posted 10/06/2017] ISSUE: Kiriko, LLC. is voluntarily recalling all lots of A1 Slim 30 capsules bottle to the consumer level.  FDA laboratory analysis has found the A1 Slim product to be tainted with sibutramine,...

http://ift.tt/2hU4sTH

Cardiac and hemodynamic influence on carotid artery longitudinal wall motion

Abstract

Carotid artery longitudinal wall motion (CALM) has recently attracted interest as an indicator of arterial health; however, the regulation of CALM is poorly understood. We conducted a series of studies aimed at manipulating pulse pressure (PP), left ventricular (LV) motion, and carotid shear rate, which have been previously suggested to regulate various components of CALM pattern and magnitude. To determine the regulatory influences on CALM, fifteen healthy males (22 ± 2 years) were exposed to three acute interventions: the Serial Subtraction Test (SST), the Cold Pressor Test (CPT), and exposure to sublingual nitroglycerine (NTG). The SST elicited increases in PP (P < 0.01), apical LV rotation (P < 0.01), and carotid shear rate (P < 0.01), with no changes in CALM (P > 0.05). Similarly, the CPT elicited increases in PP (P = 0.01), basal LV rotation (P = 0.04) and carotid shear rate (P = 0.01), with no changes in CALM (P > 0.05). Conversely, exposure to NTG elicited no change in PP (P = 0.22), basal (P = 0.65) or apical LV rotation (P = 0.45), but did decrease carotid shear rate (P < 0.01), without altering CALM (P > 0.05). Considerable individual variability in CALM responses prompted further analyses where all three interventions were pooled for change scores. Changes in LV basal rotation were related to changes systolic retrograde CALM (B = −0.025, P = 0.03), while changes in carotid shear rate were related to changes in diastolic CALM displacement (B = 0.0009, P = 0.01). The interventions were underpinned by relationships between CALM and both LV basal rotation and local shear rate at the individual level, indicating that cardiac and hemodynamic factors may influence CALM in humans.

This article is protected by copyright. All rights reserved

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Wide-field endoscopic mucosal resection versus endoscopic submucosal dissection for laterally spreading colorectal lesions: a cost-effectiveness analysis

Objective

To compare the cost-effectiveness of endoscopic submucosal dissection (ESD) and wide-field endoscopic mucosal resection (WF-EMR) for removing large sessile and laterally spreading colorectal lesions (LSLs)> 20 mm.

Design

An incremental cost-effectiveness analysis using a decision tree model was performed over an 18-month time horizon. The following strategies were compared: WF-EMR, universal ESD (U-ESD) and selective ESD (S-ESD) for lesions highly suspicious for containing submucosal invasive cancer (SMIC), with WF-EMR used for the remainder. Data from a large Western cohort and the literature were used to inform the model. Effectiveness was defined as the number of surgeries avoided per 1000 cases. Incremental costs per surgery avoided are presented. Sensitivity and scenario analyses were performed.

Results

1723 lesions among 1765 patients were analysed. The prevalence of SMIC and low-risk-SMIC was 8.2% and 3.1%, respectively. Endoscopic lesion assessment for SMIC had a sensitivity and specificity of 34.9% and 98.4%, respectively. S-ESD was the least expensive strategy and was also more effective than WF-EMR by preventing 19 additional surgeries per 1000 cases. 43 ESD procedures would be required in an S-ESD strategy. U-ESD would prevent another 13 surgeries compared with S-ESD, at an incremental cost per surgery avoided of US$210 112. U-ESD was only cost-effective among higher risk rectal lesions.

Conclusion

S-ESD is the preferred treatment strategy. However, only 43 ESDs are required per 1000 LSLs. U-ESD cannot be justified beyond high-risk rectal lesions. WF-EMR remains an effective and safe treatment option for most LSLs.

Trial registration number

NCT02000141.

http://ift.tt/2y0agBA

Vonoprazan prevents ulcer recurrence during long-term NSAID therapy: randomised, lansoprazole-controlled non-inferiority and single-blind extension study

Objective

To assess the non-inferiority of vonoprazan to lansoprazole for secondary prevention of non-steroidal anti-inflammatory drug (NSAID)-induced peptic ulcer (PU) and the safety of vonoprazan during extended use.

Design

A phase 3, 24-week, multicenter, randomised, double-blind (DB), active-controlled study, followed by a phase 3, ≥28 week, multicenter, single-blind, parallel-group extension study (EXT) in outpatients (n=642) receiving long-term NSAID therapy who are at risk of PU recurrence. The patients received vonoprazan (10 mg or 20 mg) or lansoprazole 15 mg once daily. For DB, non-inferiority of the proportion of patients with recurrent PU within 24 weeks was analysed by Farrington and Manning test (significance level 2.5%, non-inferiority margin 8.3%; primary endpoint), recurrent PU within 12 weeks, bleeding and time-to-event of PU (secondary endpoint) and treatment-emergent adverse events (TEAEs). For EXT, TEAEs (primary endpoint), recurrent PU and safety (secondary) were assessed up to 104 weeks for patients in the extension study.

Results

The non-inferiority of vonoprazan 10 mg and 20 mg to lansoprazole 15 mg was verified (percentage difference –2.2%,95% CI –6.2% to 1.8%, p<0.001; –2.1%,95% CI –6.1% to 2.0%, p<0.001, respectively). The proportion of patients with endoscopically confirmed recurrent PU within 24 weeks was 3.3%, 3.4% and 5.5%, for vonoprazan 10 mg, 20 mg and lansoprazole 15 mg, respectively. No significant safety concerns were identified.

Conclusion

The non-inferiority of vonoprazan (10 and 20 mg) was verified in patients receiving long-term NSAIDs in DB; it was effective and well tolerated in EXT for longer than 1 year, with a safety profile similar to lansoprazole (15 mg).

Trial registration numbers

NCT01452750, NCT01456260; Results.

http://ift.tt/2z5DPPR

The oral microbiota in colorectal cancer is distinctive and predictive

Background and aims

Microbiota alterations are linked with colorectal cancer (CRC) and notably higher abundance of putative oral bacteria on colonic tumours. However, it is not known if colonic mucosa-associated taxa are indeed orally derived, if such cases are a distinct subset of patients or if the oral microbiome is generally suitable for screening for CRC.

Methods

We profiled the microbiota in oral swabs, colonic mucosae and stool from individuals with CRC (99 subjects), colorectal polyps (32) or controls (103).

Results

Several oral taxa were differentially abundant in CRC compared with controls, for example, Streptococcus and Prevotellas pp. A classification model of oral swab microbiota distinguished individuals with CRC or polyps from controls (sensitivity: 53% (CRC)/67% (polyps); specificity: 96%). Combining the data from faecal microbiota and oral swab microbiota increased the sensitivity of this model to 76% (CRC)/88% (polyps). We detected similar bacterial networks in colonic microbiota and oral microbiota datasets comprising putative oral biofilm forming bacteria. While these taxa were more abundant in CRC, core networks between pathogenic, CRC-associated oral bacteria such as Peptostreptococcus, Parvimonas and Fusobacterium were also detected in healthy controls. High abundance of Lachnospiraceae was negatively associated with the colonisation of colonic tissue with oral-like bacterial networks suggesting a protective role for certain microbiota types against CRC, possibly by conferring colonisation resistance to CRC-associated oral taxa and possibly mediated through habitual diet.

Conclusion

The heterogeneity of CRC may relate to microbiota types that either predispose or provide resistance to the disease, and profiling the oral microbiome may offer an alternative screen for detecting CRC.

http://ift.tt/2z66kwD

EUS-guided fine needle biopsy of pancreatic masses can yield true histology: results of a randomised trial

Message

As cytological aspirates from endoscopic-ultrasound-guided fine needle aspiration (EUS-FNA) has limited diagnostic sensitivity and are suboptimal for molecular profiling and morphological characterisation of certain neoplasms, a fine needle biopsy (FNB) with three-pronged (Franseen geometry) cutting edge has been developed to procure histology. In a randomised trial of 46 patients with pancreatic masses, procurement of histological core tissue as evidenced by total tissue and tumour areas was significantly higher for 22G FNB than FNA needle. Also, retention of tissue architecture and presence of desmoplastic fibrosis, which are critical for ancillary testing and molecular profiling, respectively, were significantly higher for FNB.

In more detail

Given the poor outcomes of traditional chemotherapy, there is increased focus on molecular profiling so that pancreatic cancer treatment can be personalised. Pancreatic tissue with architecture containing both tumour cells and desmoplastic stroma is pivotal for molecular analysis. Although EUS-FNA is diagnostically accurate, the cytological aspirate is suboptimal...

http://ift.tt/2y0Pj9A

Remotely Supervised Transcranial Direct Current Stimulation: An Update on Safety and Tolerability

This manuscript provides an updated remote supervision protocol that enables participation in transcranial direct current stimulation (tDCS) clinical trials while receiving treatment sessions from home. The protocol has been successfully piloted in both patients with multiple sclerosis and Parkinson's disease.

http://ift.tt/2fSJyQJ

Pre-culture in endothelial growth medium enhances the angiogenic properties of adipose-derived stem/stromal cells

Abstract

Considerable progress has been made on the development of adipose-derived stem/stromal cells (ASCs) as pro-angiogenic therapeutic tools. However, variable clinical results highlight the need for devising strategies to enhance their therapeutic efficacy. Since ASCs proliferate and stabilize newly formed vessels during the angiogenic phase of adipose tissue formation, we hypothesized that mimicking an angiogenic milieu during culture of ASCs would enhance their capacity to support endothelial cell survival and angiogenesis. To test this, we compared the effect of an endothelial growth medium (EGM-2) and conventional media (αMEM) on the progenitor and angiogenic properties of ASCs. ASCs cultured in EGM-2 (ASC-EGM) displayed the highest clonogenic efficiency, proliferative potential and multilineage potential. After co-culture under growth factor starvation, only ASC-EGM attenuated luciferase-expressing human umbilical vein endothelial cells (HUVEC^luc) apoptosis and supported the formation of endothelial cords in a dose-dependent manner. These effects were recapitulated by the conditioned medium of ASC-EGM, which displayed a 100-fold higher expression of hepatocyte growth factor in comparison with ASC-αMEM. Next, HUVEC^luc and ASCs were co-transplanted subcutaneously into immunodeficient mice, and the survival of HUVEC^luc was monitored by bioluminescent imaging. After 60 days, the survival of HUVEC^luc transplanted alone was equivalent to that of HUVEC^luc co-transplanted with ASC-αMEM (15.0 ± 0.7 vs. 13.0 ± 0.5%). Strikingly, co-transplantation with ASC-EGM increased HUVEC^luc survival to 105.0 ± 3.5%, and the resulting organoids displayed functional vasculature with the highest human-derived vascular area. These findings demonstrate that pre-conditioning of ASCs in endothelial growth medium augment their pro-angiogenic properties and could enhance their therapeutic efficacy against ischemic diseases.

http://ift.tt/2gkmCKu

RNA-seq analysis of Lgr6+ stem cells and identification of an Lgr6 isoform

Abstract

We studied Lgr6⁺ stem cells in experimental UV carcinogenesis in hairless mice. For further characterisation through RNA-seq, these stem cells were isolated by FACS from transgenic hairless mice bearing an EGFP-Ires-CreERT2 reporter cassette inserted into exon-1 of the Lgr6 gene (purity confirmed by human ERT2 expression). Between Lgr6/EGFP⁺ and Lgr6/EGFP^– basal cells (Tg/wt) 682 RNAs were differentially expressed, indicating stemness and expression of cancer-related pathways in Lgr6/EGFP⁺ cells. We discovered that suspected 'Lgr6 null' mice (Tg/Tg) expressed RNA of an Lgr6 isoform (delta-Lgr6, lacking 74 N-terminal aa) which could be functional and explain the lack of a phenotype.

This article is protected by copyright. All rights reserved.

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Utility of Phox2b Immunohistochemical Stain in Neural Crest Tumors and Non-neural Crest Tumors in Pediatric Patients

Abstract

Background

This study evaluated the utility of Phox2b in pediatric tumors. Previously tyrosine hydroxylase (TH) was the most widely utilized sympathoadrenal marker specific for neural crest tumors with neuronal/neuroendocrine differentiation. However, its sensitivity is insufficient. Recently Phox2b has emerged as another specific marker for this entity.

Methods

Phox2b IHC was performed on 159 pediatric tumors including (1) 65 neural crest tumors with neuronal differentiation [peripheral neuroblastic tumors (pNT)]: 15 neuroblastoma undifferentiated (NB-UD), 10 NB poorly differentiated (NB-PD), 10 NB differentiating (NB-D), 10 ganglioneuroblastoma intermixed (GNBi), 10 GNB nodular (GNBn), and 10 ganglioneuroma (GN); (2) 23 neural crest tumors with neuroendocrine differentiation [pheochromocytoma/paraganglioma (PCC/PG)]; (3) 27 other neural crest tumors including one composite rhabdomyosarcoma/neuroblastoma; and (4) 44 non-neural crest tumors. TH IHC was performed on group (1), (2) and (3).

Results

Phox2b was diffusely expressed in pNT (n=65/65): strongly in NB-UD and NB-PD, and in NB-D, GNB and GN with less intensity. Diffuse TH was seen in all NB-PD, NB-D, GNB and GN, but 9/15 NB-UD and a nodule in GNBn didn't express TH (n=55/65). PCC/PG expressed diffuse Phox2b (n=23/23) and diffuse TH except for one tumor (n=22/23). In composite rhabdomyosarcoma, TH was expressed only in neuroblastic cells and Phox2b was diffusely positive in neuroblastic cells and focally in rhabdomyosarcoma. All other tumors were negative for Phox2b (n=0/44).

Conclusion

Phox2b was a specific and sensitive marker for pNT and PCC/PG, especially useful for identifying NB-UD often lacked TH. Our study also presented a composite rhabdomyosarcoma/neuroblastoma of neural-crest origin.

This article is protected by copyright. All rights reserved.

http://ift.tt/2y1n34e

Alveolar herniation in transbronchial lung biopsy: a newly recognized diagnostic pitfall

Abstract

Artifacts in transbronchial lung biopsy (TBLB) related to the procedure or subsequent handling are well described in the literature, and some may lead to a misdiagnosis of non-small cell lung cancer (NSCLC). ^1,2,3 We report a series of 8 cases with another, yet undescribed artifact consisting of displacement of alveolar pneumocytes and macrophages into the bronchial mucosa posing a diagnostic challenge to distinguish it from lung cancer. The 5 men and 3 women aged between 36 and 82 years had a suspected clinical diagnosis of ILD (4x), diffuse ground glass opacities (2x) or bilateral pulmonary nodules (2x), respectively, with no clinical suspicion of lung cancer.

This article is protected by copyright. All rights reserved.

http://ift.tt/2y6lync

Usefulness of water immersion observations to identify the stigmata of hemorrhage in colonic diverticular bleeding

Abstract

One of the important issues associated with colonic diverticular bleeding is the low rate at which the stigmata of recent hemorrhage is identified [1-2]. The space of a colonic diverticulum is often narrow, which makes observations of this area challenging. We attempted to overcome this issue using water immersion.

This article is protected by copyright. All rights reserved.

http://ift.tt/2yPj7T4

Near-Infrared Fluorescent Proteins Engineered from Bacterial Phytochromes in Neuroimaging

Several series of near-infrared (NIR) fluorescent proteins (FPs) were recently engineered from bacterial phytochromes but were not systematically compared in neurons. To fluoresce, NIR FPs utilize an enzymatic derivative of heme, the linear tetrapyrrole biliverdin, as a chromophore whose level in neurons is poorly studied. Here, we evaluated NIR FPs of the iRFP protein family, which were reported to be the brightest in non-neuronal mammalian cells, in primary neuronal culture, in brain slices of mouse and monkey, and in mouse brain in vivo.

http://ift.tt/2ky83b4

Near-Infrared Fluorescent Proteins Engineered from Bacterial Phytochromes in Neuroimaging

Several series of near-infrared (NIR) fluorescent proteins (FPs) were recently engineered from bacterial phytochromes but were not systematically compared in neurons. To fluoresce, NIR FPs utilize an enzymatic derivative of heme, the linear tetrapyrrole biliverdin, as a chromophore whose level in neurons is poorly studied. Here, we evaluated NIR FPs of the iRFP protein family, which were reported to be the brightest in non-neuronal mammalian cells, in primary neuronal culture, in brain slices of mouse and monkey, and in mouse brain in vivo.

http://ift.tt/2ky83b4

Redefining “Learning” in Statistical Learning: What Does an Online Measure Reveal About the Assimilation of Visual Regularities?

Abstract

From a theoretical perspective, most discussions of statistical learning (SL) have focused on the possible "statistical" properties that are the object of learning. Much less attention has been given to defining what "learning" is in the context of "statistical learning." One major difficulty is that SL research has been monitoring participants' performance in laboratory settings with a strikingly narrow set of tasks, where learning is typically assessed offline, through a set of two-alternative-forced-choice questions, which follow a brief visual or auditory familiarization stream. Is that all there is to characterizing SL abilities? Here we adopt a novel perspective for investigating the processing of regularities in the visual modality. By tracking online performance in a self-paced SL paradigm, we focus on the trajectory of learning. In a set of three experiments we show that this paradigm provides a reliable and valid signature of SL performance, and it offers important insights for understanding how statistical regularities are perceived and assimilated in the visual modality. This demonstrates the promise of integrating different operational measures to our theory of SL.

http://ift.tt/2xpyGQs

Tumor-infiltrating immune cells as potential biomarkers predicting response to treatment and survival in patients with metastatic melanoma receiving ipilimumab therapy

Abstract

Monoclonal antibodies targeting immune checkpoints are gaining ground in the treatment of melanoma and other cancers, and considerable effort is made to identify biomarkers predicting the efficacy of these therapies. Our retrospective study was performed on surgical tissue samples (52 lymph nodes and 34 cutaneous/subcutaneous metastases) from 30 patients with metastatic melanoma treated with ipilimumab. Using a panel of 11 antibodies against different immune cell types, intratumoral immune cell densities were determined and evaluated in relation to response to ipilimumab treatment and disease outcome. For most markers studied, median immune cell densities were at least two times higher in lymph node metastases compared to skin/subcutaneous ones; therefore, the prognostic and predictive associations of immune cell infiltration were evaluated separately in the two groups of metastases as well as in all samples as a whole. Higher prevalence of several immune cell types was seen in lymph node metastases of the responders compared to non-responders, particularly FOXP3⁺ cells and CD8⁺ T lymphocytes. In subcutaneous or cutaneous metastases, on the other hand, significant difference could be observed only in the case of CD16 and CD68. Associations of labeled cell densities with survival were also found for most cell types studied in nodal metastases, and for CD16⁺ and CD68⁺ cells in skin/s.c. metastatic cases. Our results corroborate the previous findings suggesting an association between an immunologically active tumor microenvironment and response to ipilimumab treatment, and propose new potential biomarkers for predicting treatment efficacy and disease outcome.

http://ift.tt/2ghTgfU

Write right, quite right: Orthography in Latin anatomical terms

Abstract

Spelling variants are common in Latin anatomical terms. Some of these variants cause confusion with respect to the meaning of the word by altering the base of the word to resemble a different word base. Thus these variants should be considered errors, comparable to errors in declension of nouns and adjectives, and errors in the formation of neologisms. Use of correct Latin words in Latin anatomical terms should increase the rigor, stability and universality of the nomenclature. This article is protected by copyright. All rights reserved.

http://ift.tt/2hVjRmw

The new frontier of studying human anatomy - introducing evidence-based anatomy

http://ift.tt/2fRZfaG

ADAM8 expression in breast cancer derived metastases: Functional implications on MMP-9 expression and transendothelial migration in breast cancer cells

Abstract

Metastatic breast cancer affects long-term survival and is a major cause of cancer death for women worldwide. The Metalloprotease-Disintegrin ADAM8 promotes breast cancer development and brain metastasis in a mouse breast cancer model. Here, abundant ADAM8 expression was detected in primary human breast tumors and associated brain metastases. To investigate the function of ADAM8 in metastasis, MB-231 breast cancer cells with ADAM8 knockdown (MB-231_shA8) and scramble control cells (MB-231_shCtrl) were analyzed for their capability to develop metastases. In vitro, formation of metastatic complexes in hanging drops is dependent on ADAM8 and blocked by ADAM8 inhibition. MB-231_shA8 in contrast to MB-231_shCtrl cells were impaired in transmigration through an endothelial and a reconstituted blood-brain barrier. Out of 23 MMP and 22 ADAM genes, only the MMP-9 gene was affected by ADAM8 knockdown in MB-231_shA8 cells. Following re-expression of wild-type ADAM8 in contrast to ADAM8 lacking the cytoplasmic domain in MB-231_shA8 cells caused increased levels of activated pERK1/2 and pCREB (S133) that were associated with elevated MMP-9 transcription. Application of ADAM8 and MMP-9 antibodies reduced transmigration of MB-231 cells suggesting that ADAM8 affects transmigration of breast cancer cells by MMP-9 regulation. ADAM8-dependent transmigration was confirmed in Hs578t cells overexpressing ADAM8. Moreover, transmigration of MB-231 and Hs578t cells was significantly reduced for cells treated with an antibody directed against P-selectin glycoprotein ligand (PSGL-1), a substrate of ADAM8. From these data we conclude that ADAM8 promotes early metastatic processes such as transendothelial migration by upregulation of MMP-9 and shedding of PSGL-1 from breast cancer cells. This article is protected by copyright. All rights reserved.

http://ift.tt/2yvQ0IC

Tumor-infiltrating immune cells as potential biomarkers predicting response to treatment and survival in patients with metastatic melanoma receiving ipilimumab therapy

Abstract

Monoclonal antibodies targeting immune checkpoints are gaining ground in the treatment of melanoma and other cancers, and considerable effort is made to identify biomarkers predicting the efficacy of these therapies. Our retrospective study was performed on surgical tissue samples (52 lymph nodes and 34 cutaneous/subcutaneous metastases) from 30 patients with metastatic melanoma treated with ipilimumab. Using a panel of 11 antibodies against different immune cell types, intratumoral immune cell densities were determined and evaluated in relation to response to ipilimumab treatment and disease outcome. For most markers studied, median immune cell densities were at least two times higher in lymph node metastases compared to skin/subcutaneous ones; therefore, the prognostic and predictive associations of immune cell infiltration were evaluated separately in the two groups of metastases as well as in all samples as a whole. Higher prevalence of several immune cell types was seen in lymph node metastases of the responders compared to non-responders, particularly FOXP3⁺ cells and CD8⁺ T lymphocytes. In subcutaneous or cutaneous metastases, on the other hand, significant difference could be observed only in the case of CD16 and CD68. Associations of labeled cell densities with survival were also found for most cell types studied in nodal metastases, and for CD16⁺ and CD68⁺ cells in skin/s.c. metastatic cases. Our results corroborate the previous findings suggesting an association between an immunologically active tumor microenvironment and response to ipilimumab treatment, and propose new potential biomarkers for predicting treatment efficacy and disease outcome.

http://ift.tt/2ghTgfU

Reward deficits in behavioural variant frontotemporal dementia include insensitivity to negative stimuli

Abstract

During reward processing individuals weigh positive and negative features of a stimulus to determine whether they will pursue or avoid it. Though patients with behavioural variant frontotemporal dementia display changes in their pursuit of rewards, such as food, alcohol, money, and sex, the basis for these shifts is not clearly established. In particular, it is unknown whether patients' behaviour results from excessive focus on rewards, insensitivity to punishment, or to dysfunction in a particular stage of reward processing, such as anticipation, consumption, or action selection. Our goal was to determine the nature of the reward deficit in behavioural variant frontotemporal dementia and its underlying anatomy. We devised a series of tasks involving pleasant, unpleasant, and neutral olfactory stimuli, designed to separate distinct phases of reward processing. In a group of 25 patients with behavioural variant frontotemporal dementia and 21 control subjects, diagnosis by valence interactions revealed that patients with behavioural variant frontotemporal dementia rated unpleasant odours as less aversive than did controls and displayed lower skin conductance responses when anticipating an upcoming aversive odour. Subjective pleasantness ratings and skin conductance responses did not differ between behavioural variant frontotemporal dementia and controls for pleasant or neutral smells. In a task designed to measure the effort subjects would expend to smell or avoid smelling a stimulus, patients with behavioural variant frontotemporal dementia were less motivated, and therefore less successful than control subjects, at avoiding what they preferred not to smell, but had equivalent success at obtaining stimuli they found rewarding. Voxel-based morphometry of patients with behavioural variant frontotemporal dementia revealed that the inability to subjectively differentiate the valence of pleasant and unpleasant odours correlated with atrophy in right ventral mid-insula and right amygdala. High pleasantness ratings of unpleasant stimuli correlated with left dorsal anterior insula and frontal pole atrophy. These findings indicate that insensitivity to negative information may be a key component of the reward-seeking behaviours in behavioural variant frontotemporal dementia, and may relate to degeneration of structures that are involved in representing the emotional salience of sensory information.

http://ift.tt/2xpyu3v

Reply: MRI findings of visual system alterations in Parkinson’s disease

Sir,

http://ift.tt/2yxv3wZ

Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer’s disease

Abstract

Neuropathological and in vivo studies have revealed a tight relationship between tau pathology and cognitive impairment across the Alzheimer's disease spectrum. However, tau pathology is also intimately associated with neurodegeneration and amyloid pathology. The aim of the present study was therefore to assess whether grey matter atrophy and amyloid pathology contribute to the relationship between tau pathology, as measured with ¹⁸F-AV-1451-PET imaging, and cognitive deficits in Alzheimer's disease. We included 40 amyloid-positive patients meeting criteria for mild cognitive impairment due to Alzheimer's disease (n = 5) or probable Alzheimer's disease dementia (n = 35). Twelve patients additionally fulfilled the diagnostic criteria for posterior cortical atrophy and eight for logopenic variant primary progressive aphasia. All participants underwent 3 T magnetic resonance imaging, amyloid (¹¹C-PiB) positron emission tomography and tau (¹⁸F-AV-1451) positron emission tomography, and episodic and semantic memory, language, executive and visuospatial functions assessment. Raw cognitive scores were converted to age-adjusted Z-scores (W-scores) and averaged to compute composite scores for each cognitive domain. Independent regressions were performed between ¹⁸F-AV-1451 binding and each cognitive domain, and we used the Biological Parametric Mapping toolbox to further control for local grey matter volumes, ¹¹C-PiB uptake, or both. Partial correlations and causal mediation analyses (mediation R package) were then performed in brain regions showing an association between cognition and both ¹⁸F-AV-1451 uptake and grey matter volume. Our results showed that decreased cognitive performance in each domain was related to increased ¹⁸F-AV-1451 binding in specific brain regions conforming to established brain-behaviour relationships (i.e. episodic memory: medial temporal lobe and angular gyrus; semantic memory: left anterior temporal regions; language: left posterior superior temporal lobe and supramarginal gyrus; executive functions: bilateral frontoparietal regions; visuospatial functions: right more than left occipitotemporal regions). This pattern of regional associations remained essentially unchanged—although less spatially extended—when grey matter volume or ¹¹C-PiB uptake maps were added as covariates. Mediation analyses revealed both direct and grey matter-mediated effects of ¹⁸F-AV-1451 uptake on cognitive performance. Together, these results show that tau pathology is related in a region-specific manner to cognitive impairment in Alzheimer's disease. These regional relationships are weakly related to amyloid burden, but are in part mediated by grey matter volumes. This suggests that tau pathology may lead to cognitive deficits through a variety of mechanisms, including, but not restricted to, grey matter loss. These results might have implications for future therapeutic trials targeting tau pathology.

http://ift.tt/2xps2tk

Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in ‘FUSDelta14’ knockin mice

Abstract

Mutations in FUS are causative for amyotrophic lateral sclerosis with a dominant mode of inheritance. In trying to model FUS-amyotrophic lateral sclerosis (ALS) in mouse it is clear that FUS is dosage-sensitive and effects arise from overexpression per se in transgenic strains. Novel models are required that maintain physiological levels of FUS expression and that recapitulate the human disease—with progressive loss of motor neurons in heterozygous animals. Here, we describe a new humanized FUS-ALS mouse with a frameshift mutation, which fulfils both criteria: the FUS Delta14 mouse. Heterozygous animals express mutant humanized FUS protein at physiological levels and have adult onset progressive motor neuron loss and denervation of neuromuscular junctions. Additionally, we generated a novel antibody to the unique human frameshift peptide epitope, allowing specific identification of mutant FUS only. Using our new FUSDelta14 ALS mouse-antibody system we show that neurodegeneration occurs in the absence of FUS protein aggregation. FUS mislocalization increases as disease progresses, and mutant FUS accumulates at the rough endoplasmic reticulum. Further, transcriptomic analyses show progressive changes in ribosomal protein levels and mitochondrial function as early disease stages are initiated. Thus, our new physiological mouse model has provided novel insight into the early pathogenesis of FUS-ALS.

http://ift.tt/2yvKMws

MRI findings of visual system alterations in Parkinson’s disease

Sir,

http://ift.tt/2xpX3O0

Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features

Abstract

Genetic epilepsies are caused by mutations in a range of different genes, many of them encoding ion channels, receptors or transporters. While the number of detected variants and genes increased dramatically in the recent years, pleiotropic effects have also been recognized, revealing that clinical syndromes with various degrees of severity arise from a single gene, a single mutation, or from different mutations showing similar functional defects. Accordingly, several genes coding for GABA_A receptor subunits have been linked to a spectrum of benign to severe epileptic disorders and it was shown that a loss of function presents the major correlated pathomechanism. Here, we identified six variants in GABRA3 encoding the α₃-subunit of the GABA_A receptor. This gene is located on chromosome Xq28 and has not been previously associated with human disease. Five missense variants and one microduplication were detected in four families and two sporadic cases presenting with a range of epileptic seizure types, a varying degree of intellectual disability and developmental delay, sometimes with dysmorphic features or nystagmus. The variants co-segregated mostly but not completely with the phenotype in the families, indicating in some cases incomplete penetrance, involvement of other genes, or presence of phenocopies. Overall, males were more severely affected and there were three asymptomatic female mutation carriers compared to only one male without a clinical phenotype. X-chromosome inactivation studies could not explain the phenotypic variability in females. Three detected missense variants are localized in the extracellular GABA-binding NH₂-terminus, one in the M2-M3 linker and one in the M4 transmembrane segment of the α₃-subunit. Functional studies in Xenopus laevis oocytes revealed a variable but significant reduction of GABA-evoked anion currents for all mutants compared to wild-type receptors. The degree of current reduction correlated partially with the phenotype. The microduplication disrupted GABRA3 expression in fibroblasts of the affected patient. In summary, our results reveal that rare loss-of-function variants in GABRA3 increase the risk for a varying combination of epilepsy, intellectual disability/developmental delay and dysmorphic features, presenting in some pedigrees with an X-linked inheritance pattern.

http://ift.tt/2yv9Nrw

Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia

Abstract

The autosomal dominant cerebellar ataxias, referred to as spinocerebellar ataxias in genetic nomenclature, are a rare group of progressive neurodegenerative disorders characterized by loss of balance and coordination. Despite the identification of numerous disease genes, a substantial number of cases still remain without a genetic diagnosis. Here, we report five novel spinocerebellar ataxia genes, FAT2, PLD3, KIF26B, EP300, and FAT1, identified through a combination of exome sequencing in genetically undiagnosed families and targeted resequencing of exome candidates in a cohort of singletons. We validated almost all genes genetically, assessed damaging effects of the gene variants in cell models and further consolidated a role for several of these genes in the aetiology of spinocerebellar ataxia through network analysis. Our work links spinocerebellar ataxia to alterations in synaptic transmission and transcription regulation, and identifies these as the main shared mechanisms underlying the genetically diverse spinocerebellar ataxia types.

http://ift.tt/2xpyjFA

Nomogram predicting long-term survival after the diagnosis of intrahepatic recurrence of hepatocellular carcinoma following an initial liver resection

http://ift.tt/2kuwmGF

Associations between clinical data and computed tomography features in patients with epidermal growth factor receptor mutations in lung adenocarcinoma

Abstract

Background

To analyse the differences in computed tomography (CT) features between patients with lung adenocarcinoma who have epidermal growth factor receptor (EGFR) mutations and those who have wild-type EGFR.

Methods

Patients with lung adenocarcinoma (n = 156) were enrolled from October 2013 to March 2016, including 56 patients with wild-type EGFR and 100 patients with EGFR mutations. Two independent radiologists evaluated patient characteristics and imaging features. Chi-squared test, Fisher's exact test or ANOVA was applied to discriminate clinical and CT characteristics between the genotypes. A prediction tool for EGFR mutation was devised from principal component analysis.

Results

The proportion of females and non-smokers in the exon 19 deletion and exon 21 missense groups was higher than in the wild-type group (P < 0.01). Severe emphysema was higher in the wild-type group than in the exon 19 deletion group (P < 0.01). The maximum diameter in the mediastinal window (MaxD_mediastinal) in the wild-type group was longer than in the exon 19 deletion and exon 21 missense groups. The minimum diameter in the mediastinal window (MinD_mediastinal) in the wild-type group was also longer than in the exon 21 missense group, with a significant difference (P < 0.05). The tumor shadow disappearance rate (TDR) in the exon 19 deletion group was higher than in the wild-type group. Ground glass opacity (GGO) appeared to be more common in the exon 19 deletion group (P = 0.010). The prediction score for exon 19 deletion mutation was: 0.305 × gender + 0.254 × smoking history + 0.198 × MaxD_mediastinal + TDR × 0.254 + 0.280 × GGO + 0.095 × emphysema. The sensitivity and specificity for predicting exon 19 deletion were 59.09 and 76.79%, respectively. The prediction score for the exon 21 missense mutation was: 0.354 × gender + 0.291 × smoking history + 0.410 × MaxD_mediastinal + 0.408 × MinD_mediastinal. The sensitivity and specificity for predicting exon 21 missense mutation were 72.34 and 78.57%, respectively.

Conclusion

As well as gender, smoking history and GGO, adenocarcinomas with EGFR mutation were significantly associated with emphysema, TDR, and the diameter in the mediastinal window. As exon 19 deletion and 21 missense mutations might be predicted by those features, the scoring system might be valuable for clinical diagnosis.

http://ift.tt/2yO2WFH

A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model of the histone deacetylase (HDAC) inhibitor vorinostat for pediatric and adult patients and its application for dose specification

Abstract

Purpose

This study aimed at recommending pediatric dosages of the histone deacetylase (HDAC) inhibitor vorinostat and potentially more effective adult dosing regimens than the approved standard dosing regimen of 400 mg/day, using a comprehensive physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling approach.

Methods

A PBPK/PD model for vorinostat was developed for predictions in adults and children. It includes the maturation of relevant metabolizing enzymes. The PBPK model was expanded by (1) effect compartments to describe vorinostat concentration–time profiles in peripheral blood mononuclear cells (PBMCs), (2) an indirect response model to predict the HDAC inhibition, and (3) a thrombocyte model to predict the dose-limiting thrombocytopenia. Parameterization of drug and system-specific processes was based on published and unpublished in silico, in vivo, and in vitro data. The PBPK modeling software used was PK-Sim and MoBi.

Results

The PBPK/PD model suggests dosages of 80 and 230 mg/m² for children of 0–1 and 1–17 years of age, respectively. In comparison with the approved standard treatment, in silico trials reveal 11 dosing regimens (9 oral, and 2 intravenous infusion rates) increasing the HDAC inhibition by an average of 31%, prolonging the HDAC inhibition by 181%, while only decreasing the circulating thrombocytes to a tolerable 53%. The most promising dosing regimen prolongs the HDAC inhibition by 509%.

Conclusions

Thoroughly developed PBPK models enable dosage recommendations in pediatric patients and integrated PBPK/PD models, considering PD biomarkers (e.g., HDAC activity and platelet count), are well suited to guide future efficacy trials by identifying dosing regimens potentially superior to standard dosing regimens.

http://ift.tt/2y6Alhe

Safety of shortened infusion times for combined ipilimumab and nivolumab

Abstract

Background

Combined ipilimumab and nivolumab induces encouraging response rates in patients with unresectable or metastatic melanoma. However, the approved protocol for dual checkpoint inhibition (3 mg/kg ipilimumab over 90 min and 1 mg/kg nivolumab over 60 min) is time-intensive and several trials have shown that both single agents can be safely administered at faster infusion rates.

Aim

To investigate whether combined checkpoint inhibition with 3 mg/kg ipilimumab and 1 mg/kg nivolumab can be safely administered over 30 min per agent.

Patients and methods

We reviewed the rate of infusion-related reactions (IRRs) in the first 12 months of our single-institution experience using shortened infusion times for combined checkpoint inhibition with ipilimumab and nivolumab.

Results

Between May 24, 2016 and June 10, 2017, a total of 46 melanoma patients received 100 shortened cycles of combined 3 mg/kg ipilimumab and 1 mg/kg nivolumab. One patient (2.2%; 1/46) had a questionable reaction after administration of 1 mg/kg nivolumab over 30 min, but none of the other patients had a bona fide IRR.

Conclusions

Shortened infusion times for combined ipilimumab and nivolumab treatment are safe, thereby facilitating a more efficient use of outpatient facilities and enhancing patient's convenience.

http://ift.tt/2wCOoIn

Safety of shortened infusion times for combined ipilimumab and nivolumab

Abstract

Background

Combined ipilimumab and nivolumab induces encouraging response rates in patients with unresectable or metastatic melanoma. However, the approved protocol for dual checkpoint inhibition (3 mg/kg ipilimumab over 90 min and 1 mg/kg nivolumab over 60 min) is time-intensive and several trials have shown that both single agents can be safely administered at faster infusion rates.

Aim

To investigate whether combined checkpoint inhibition with 3 mg/kg ipilimumab and 1 mg/kg nivolumab can be safely administered over 30 min per agent.

Patients and methods

We reviewed the rate of infusion-related reactions (IRRs) in the first 12 months of our single-institution experience using shortened infusion times for combined checkpoint inhibition with ipilimumab and nivolumab.

Results

Between May 24, 2016 and June 10, 2017, a total of 46 melanoma patients received 100 shortened cycles of combined 3 mg/kg ipilimumab and 1 mg/kg nivolumab. One patient (2.2%; 1/46) had a questionable reaction after administration of 1 mg/kg nivolumab over 30 min, but none of the other patients had a bona fide IRR.

Conclusions

Shortened infusion times for combined ipilimumab and nivolumab treatment are safe, thereby facilitating a more efficient use of outpatient facilities and enhancing patient's convenience.

http://ift.tt/2wCOoIn

A Semiotic Interpretation of the Innate Releasing Mechanism Concept and Other Ethological Triadic Relations

Abstract

This paper tries to link Ethology to Biosemiotics by analysing the similarities between some triadic relationships like biosemiotics' Object—Representamen—Interpretant and the one established in Ethology between Sign-stimuli— Innate Releasing Mechanism—Modal Action Pattern, or the one potentially established in communication networks comprising Sender—Receiver—Eavesdropper. I argue here that a collaborative relationship is supported by the fact that the observational method used by Ethology is based on the triadic relationship Sender—Receiver—Eavesdropper (Interpreter). This method, by introducing the human observer at the Interpreter/Eavesdropper place, is not only applicable to the direct study of animal communication, but also to the interpretation of all other animal behaviour by assuming that behaviour is a sign/signal system on its own, for us to interpret and decode.

http://ift.tt/2y1QSSj

Assessment of the potential for resistance to antimicrobial violet-blue light in Staphylococcus aureus

Antimicrobial violet-blue light in the region of 405 nm is emerging as an alternative technology for hospital decontamination and clinical treatment. The mechanism of action is the excitation of endogenous por...

http://ift.tt/2g07tBk

Genotype-phenotype correlation in ATAD3A deletions: not just of scientific relevance

Sir,

http://ift.tt/2xnpWz9

Neurological outcome after minimal invasive coronary artery surgery (NOMICS): protocol for an observational prospective cohort study

Introduction

Adverse neurocognitive outcomes are still an important cause of morbidity and mortality after cardiac surgery. The most common neurocognitive disorders after conventional cardiac surgery are postoperative cognitive dysfunction (POCD), stroke and delirium. Minimal invasive cardiac procedures have recently been introduced into practice. Endoscopic coronary artery bypass grafting (Endo-CABG) is a minimal invasive cardiac procedure based on the conventional CABG procedure. Neurocognitive outcome after minimal invasive cardiac surgery, including Endo-CABG, has never been studied. Therefore, the main objective of this study is to examine neurocognitive outcome after Endo-CABG.

Methods and analysis

We will perform a prospective observational cohort study including 150 patients. Patients are categorised into three groups: (1) patients undergoing Endo-CABG, (2) patients undergoing a percutaneous coronary intervention and (3) a healthy volunteer group. All patients in the Endo-CABG group will be treated following a uniform, standardised protocol. To assess neurocognitive outcome after surgery, a battery of six neurocognitive tests will be administered at baseline and at 3-month follow-up. In the Endo-CABG group, a neurological examination will be performed at baseline and postoperatively and delirium will be scored at the intensive care unit. Quality of life (QOL), anxiety and depression will be assessed at baseline and at 3-month follow-up. Satisfaction with Endo-CABG will be assessed at 3-month follow-up. Primary endpoints are the incidence of POCD, stroke and delirium after Endo-CABG. Secondary endpoints are QOL after Endo-CABG, patient satisfaction with Endo-CABG and the incidence of anxiety and depression after Endo-CABG.

Ethics and dissemination

The neurological outcome after minimal invasive coronary artery surgery study has received approval of the Jessa Hospital ethics board. It is estimated that the trial will be executed from December 2016 to January 2018, including enrolment and follow-up. Analysis of data, followed by publication of the results, is expected in 2018.

Trial registration number

NCT02979782.

http://ift.tt/2y5UGns

Search for unpublished data by systematic reviewers: an audit

Objectives

We audited a selection of systematic reviews published in 2013 and reported on the proportion of reviews that researched for unpublished data, included unpublished data in analysis and assessed for publication bias.

Design

Audit of systematic reviews.

Data sources

We searched PubMed and Ovid MEDLINE In-Process & Other Non-Indexed Citations between 1 January 2013 and 31 December 2013 for the following journals: Journal of the American Medical Association, The British Medical Journal, Lancet, Annals of Internal Medicine and the Cochrane Database of Systematic Reviews. We also searched the Cochrane Library and included 100 randomly selected Cochrane reviews.

Eligibility criteria

Systematic reviews published in 2013 in the selected journals were included. Methodological reviews were excluded.

Data extraction and synthesis

Two reviewers independently reviewed each included systematic review. The following data were extracted: whether the review searched for grey literature or unpublished data, the sources searched, whether unpublished data were included in analysis, whether publication bias was assessed and whether there was evidence of publication bias.

Main findings

203 reviews were included for analysis. 36% (73/203) of studies did not describe any attempt to obtain unpublished studies or to search grey literature. 89% (116/130) of studies that sought unpublished data found them. 33% (68/203) of studies included an assessment of publication bias, and 40% (27/68) of these found evidence of publication bias.

Conclusion

A significant fraction of systematic reviews included in our study did not search for unpublished data. Publication bias may be present in almost half the published systematic reviews that assessed for it. Exclusion of unpublished data may lead to biased estimates of efficacy or safety in systematic reviews.

http://ift.tt/2y7j6gk

The prognostic significance of smoking cessation after acute coronary syndromes: an observational, multicentre study from the Melbourne interventional group registry

Objective

We aim to ascertain the prognostic significance of persistent smoking and smoking cessation after an acute coronary syndrome (ACS) in the era of percutaneous coronary intervention (PCI) and optimal secondary prevention pharmacotherapy.

Methods

Consecutive patients from the Melbourne Interventional Group registry (2005–2013) who were alive at 30 days post-ACS presentation were included in our observational cohort study. Patients were divided into four categories based on their smoking status: non-smoker; ex-smoker (quit >1 month before ACS); recent quitter (smoker at presentation but quit by 30 days) and persistent smoker (smoker at presentation and at 30 days). The primary endpoint was survival ascertained through the Australian National Death Index linkage. A Cox-proportional hazards model was used to estimate the adjusted HR and 95% CI for survival.

Results

Of the 9375 patients included, 2728 (29.1%) never smoked, 3712 (39.6%) were ex-smokers, 1612 (17.2%) were recent quitters and 1323 (14.1%) were persistent smokers. Cox-proportional hazard modelling revealed, compared with those who had never smoked, that persistent smoking (HR 1.78, 95% CI 1.36 to 2.32, p<0.001) was an independent predictor of increased hazard (mean follow-up 3.9±2.2 years) while being a recent quitter (HR 1.27, 95% CI 0.96 to 1.68, p=0.10) or an ex-smoker (HR 1.03, 95% CI 0.87 to 1.22, p=0.72) were not.

Conclusions

In a contemporary cohort of patients with ACS, those who continued to smoke had an 80% risk of lower survival while those who quit had comparable survival to lifelong non-smokers. This underscores the importance of smoking cessation in secondary prevention despite the improvement in management of ACS with PCI and pharmacotherapy.

http://ift.tt/2fS0NBD

How information about overdetection changes breast cancer screening decisions: a mediation analysis within a randomised controlled trial

Objectives

In a randomised controlled trial, we found that informing women about overdetection changed their breast screening decisions. We now present a mediation analysis exploring the psychological pathways through which study participants who received the intervention processed information about overdetection and how this influenced their decision-making. We examined a series of potential mediators in the causal chain between exposure to overdetection information and women's subsequently reported breast screening intentions.

Design

Serial multiple mediation analysis within a randomised controlled trial.

Setting

New South Wales, Australia.

Participants

811 women aged 48–50 years with no personal history of breast cancer.

Interventions

Two versions of a decision aid giving women information about breast cancer deaths averted and false positives from mammography screening, either with (intervention) or without (control) information on overdetection.

Main outcome

Intentions to undergo breast cancer screening in the next 2–3 years.

Mediators

Knowledge about overdetection, worry about breast cancer, attitudes towards breast screening and anticipated regret.

Results

The effect of information about overdetection on women's breast screening intentions was mediated through multiple cognitive and affective processes. In particular, the information led to substantial improvements in women's understanding of overdetection, and it influenced—both directly and indirectly via its effect on knowledge—their attitudes towards having screening. Mediation analysis showed that the mechanisms involving knowledge and attitudes were particularly important in determining women's intentions about screening participation.

Conclusions

Even in this emotive context, new information influenced women's decision-making by changing their understanding of possible consequences of screening and their attitudes towards undergoing it. These findings emphasise the need to provide good-quality information on screening outcomes and to communicate this information effectively, so that women can make well-informed decisions.

Trial registration number

This study was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12613001035718) on 17 September 2013.

http://ift.tt/2fS1bQB

Assessment of the effects of decision aids about breast cancer screening: a systematic review and meta-analysis

Objective

The aim of this systematic review and meta-analysis of randomised controlled trials (RCTs) and observational studies is to assess the effect of decision aids (DAs) in women aged 50 and below facing the decision to be screened for breast cancer.

Setting

Screening for breast cancer.

Intervention

DAs aimed to help women make a deliberative choice regarding participation in mammography screening by providing information on the options and outcomes.

Eligible studies

We included published original, non-pilot, studies that assess the effect of DAs for breast cancer screening. We excluded the studies that evaluated only participation intention or actual uptake. The studies' risk of bias was assessed with the Cochrane Collaboration's tool for RCTs and the National Institutes of Health Quality Assessment Tool for non-RCTs.

Primary and secondary outcomes

The main outcome measures were informed choice, decisional conflict and/or confidence, and knowledge. Secondary outcomes were values, attitudes, uncertainty and intention to be screened.

Results

A total of 607 studies were identified, but only 3 RCTs and 1 before-after study were selected. The use of DAs increased the proportion of women making an informed decision by 14%, 95% CI (2% to 27%) and the proportion of women with adequate knowledge by 12%, 95% CI (7% to 16%). We observed heterogeneity among the studies in confidence in the decision. The meta-analysis of the RCTs showed a significant decrease in confidence in the decision and in intention to be screened.

Conclusions

Tools to aid decision making in screening for breast cancer improve knowledge and promote informed decision; however, we found divergent results on decisional conflict and confidence in the decision. Under the current paradigm change, which favours informed choice rather than maximising uptake, more research is necessary for the improvement of DAs.

http://ift.tt/2y5AxOo

Secondhand tobacco smoke exposure and pulmonary function: a cross-sectional study among non-smoking employees of bar and restaurants in Santiago, Chile

Introduction

The workplace remains a significant source of secondhand smoke (SHS) exposure. This pollutant is known to be associated with respiratory and cardiovascular problems, but its effects on specific pulmonary function parameters remain largely unexplored. The objectives of this study were to measure SHS exposure among non-smoking employees of bar and restaurants in Santiago, Chile and to evaluate the effects of such exposure on pulmonary function.

Methods

Cross-sectional design. The study sample included non-smoking workers from 57 restaurants and bars in Santiago, Chile. The outcome variable was pulmonary function and the exposure variables were urine cotinine concentration, a biomarker for current SHS exposure, and years of SHS exposure in the workplace as proxy of chronic exposure. Personal and occupational variables were also recorded. Data analysis was performed using linear regression models adjusted by confounders.

Results

The median age of the workers was 35 years and the median employment duration at the analysed venues was 1 year. Workers in smoking facilities reported greater SHS exposure (36 hours per week) than workers in smoke-free locations (4 hours per week). Urine cotinine levels were inversely correlated with forced vital capacity, but the finding was not statistically significant (β=–0.0002; 95% CI –0.007 to 0.006). Years of exposure to SHS showed to be significantly associated with forced expiratory flow_25/75 (β=–0.006; 95% CI –0.010 to –0.0004).

Conclusion

These findings suggest that cumulative exposure to SHS at work may contribute to deterioration of pulmonary function in non-smoking employees.

http://ift.tt/2fSHyrk

Implementing communication and decision-making interventions directed at goals of care: a theory-led scoping review

Objectives

To identify the factors that promote and inhibit the implementation of interventions that improve communication and decision-making directed at goals of care in the event of acute clinical deterioration.

Design and methods

A scoping review was undertaken based on the methodological framework of Arksey and O'Malley for conducting this type of review. Searches were carried out in Medline and Cumulative Index to Nursing and Allied Health Literature (CINAHL) to identify peer-reviewed papers and in Google to identify grey literature. Searches were limited to those published in the English language from 2000 onwards. Inclusion and exclusion criteria were applied, and only papers that had a specific focus on implementation in practice were selected. Data extracted were treated as qualitative and subjected to directed content analysis. A theory-informed coding framework using Normalisation Process Theory (NPT) was applied to characterise and explain implementation processes.

Results

Searches identified 2619 citations, 43 of which met the inclusion criteria. Analysis generated six themes fundamental to successful implementation of goals of care interventions: (1) input into development; (2) key clinical proponents; (3) training and education; (4) intervention workability and functionality; (5) setting and context; and (6) perceived value and appraisal.

Conclusions

A broad and diverse literature focusing on implementation of goals of care interventions was identified. Our review recognised these interventions as both complex and contentious in nature, making their incorporation into routine clinical practice dependent on a number of factors. Implementing such interventions presents challenges at individual, organisational and systems levels, which make them difficult to introduce and embed. We have identified a series of factors that influence successful implementation and our analysis has distilled key learning points, conceptualised as a set of propositions, we consider relevant to implementing other complex and contentious interventions.

http://ift.tt/2fRE08N

Fabry disease due to D313Y and novel GLA mutations

Objectives

Our aim is to report four novel α-gal A gene (GLA) mutations resulting in Fabry disease (FD) and provide evidence of pathogenicity of the D313Y mutation regarding which contradictory data have been presented in the literature.

Setting and participants

Twenty-five family members of nine unrelated patients with definite FD diagnosis, 10 clinically suspected cases and 18 members of their families were included in this polycentric cohort study.

Primary and secondary outcome measures

Genotyping and measurement of lyso-Gb₃ was performed in all individuals. The α-Gal A activity was measured in all men as well as plasma and urine Gb₃ concentration in selected cases. Optical and electron microscopy was performed in kidney biopsies of selected patients. All the above were evaluated in parallel with the clinical data of the patients.

Results

Fourteen new cases of FD were recognised, four of which were carrying already described GLA mutations. Four novel GLA mutations, namely c.835C>T, c.280T>A, c.924A>C and c.511G>A, resulting in a classic FD phenotype were identified. Moreover, FD was definitely diagnosed in five patients carrying the D313Y mutation. Eight D313Y carriers were presenting signs of FD despite not fulfilling the criteria of the disease, two had no FD signs and two others were apparently healthy.

Conclusions

Four novel GLA pathogenic mutations are reported and evidence of pathogenicity of the D313Y mutation is provided. It seems that the D313Y mutation is related to a later-onset milder phenotype than the typical phenotype with normal lysoGb₃ concentration. Our study underlines the significance of family member genotyping and newborn screening to avoid misdiagnoses and crucial delays in diagnosis and treatment of the disease.

http://ift.tt/2y5Q00R

How do general practitioners put preventive care recommendations into practice? A cross-sectional study in Switzerland and France

Objectives

We previously identified that general practitioners (GPs) in French-speaking regions of Europe had a variable uptake of common preventive recommendations. In this study, we describe GPs' reports of how they put different preventive recommendations into practice.

Design, setting and participants

Cross-sectional study conducted in 2015 in Switzerland and France. 3400 randomly selected GPs were asked to complete a postal (n=1100) or online (n=2300) questionnaire. GPs who exclusively practiced complementary and alternative medicine were not eligible for the study. 764 GPs (response rate: postal 47%, online 11%) returned the questionnaire (428 in Switzerland and 336 in France).

Main outcome measures

We investigated how the GPs performed five preventive practices (screening for dyslipidaemia, colorectal and prostate cancer, identification of hazardous alcohol consumption and brief intervention), examining which age group they selected, the screening frequency, the test they used, whether they favoured shared decision for prostate cancer screening and their definition of hazardous alcohol use.

Results

A large variability was observed in the way in which GPs provide these practices. 41% reported screening yearly for cholesterol, starting and stopping at variable ages. 82% did not use any test to identify hazardous drinking. The most common responses for defining hazardous drinking were, for men, ≥21 drinks/week (24%) and ≥4 drinks/occasion for binge drinking (20%), and for women, ≥14 drinks/week (28%) and ≥3 drinks/occasion (21%). Screening for colorectal cancer, mainly with colonoscopy in Switzerland (86%) and stool-based tests in France (93%), was provided every 10 years in Switzerland (65%) and 2 years in France (91%) to patients between 50 years (87%) and 75 years (67%). Prostate cancer screening, usually with shared decision (82%), was provided yearly (62%) to patients between 50 years (74%) and 75–80 years (32%–34%).

Conclusions

The large diversity in the way these practices are provided needs to be addressed, as it could be related to some misunderstandingof the current guidelines, to barriers for guideline uptake or, more likely, to the absence of agreement between the various recommendations.

http://ift.tt/2fT4U0g

Are there any differences between different testing sites? A cross-sectional study of a Norwegian low-threshold HIV testing service for men who have sex with men

Objective

To describe a Norwegian low-threshold HIV testing service targeting men who have sex with men (MSM).

Design and setting

After the HIV testing consultation, all users of the HIV testing service were invited to answer the study questionnaire. The study setting included the sites where testing was performed, that is, the testing service's office in Oslo, cruising areas, bars/clubs and in hotels in other Norwegian cities.

Participants

MSM users of the testing service.

Primary and secondary outcome measures

Data were collected on demographics, HIV testing and sexual behaviour as well as the participant's motivations for choosing to take an HIV test at this low-threshold HIV testing service. The data are stratified by testing site.

Results

1577 HIV testing consultations were performed, the study sample consisted of 732 MSM users. 11 tested positive for HIV. 21.7% had a non-western background, 27.1% reported having a non-gay sexual orientation. 21.9% had 10 or more male sexual partners during the last year, 27.9% reported also having had a female sexual partner. 56.4% reported having practised unprotected anal intercourse during the last 6 months. 20.1% had never tested for HIV before. Most of these user characteristics varied by testing sites.

Conclusions

The Norwegian low-threshold testing service recruits target groups that are otherwise hard to reach with HIV testing. This may indicate that the testing service contributes to increase HIV testing rates among MSM in Norway.

http://ift.tt/2fPKmW8

Nocardia nova Tenosynovitis and Abscess After a Remote Gunshot Wound.

Nocardia nova is a less commonly isolated Nocardia species that was formerly classified as belonging to the Nocardia asteroides complex. This organism is a rare cause of primary cutaneous nocardiosis. We report a case of N. nova flexor tenosynovitis and abscess involving the right forearm after a remote inoculation injury. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2fZsyvJ

Evaluation of Antimicrobial Therapy Duration for Hospital-Acquired Pneumonia Treatment.

Background: The Infectious Diseases Society of America recommends a 7-day duration of antimicrobial therapy for hospital-acquired pneumonia (HAP); however, this recommendation is based on low-quality evidence. This recommendation is supported by evidence from ventilator-associated pneumonia clinical trials. Use of guideline-recommended antimicrobial durations is variable in clinical practice owing to the lack of literature available. Methods: This was a retrospective, cohort, single-center study. Adult patients admitted with a diagnosis of HAP and received at least 72 hours of antimicrobial therapy were included. The primary outcome was day 7 clinical stability in patients treated with standard (7 days) duration antimicrobial therapy. Secondary outcomes included hospital and intensive care unit length of stay (LOS), 30-day mortality, and 30-day hospital readmission rates. Results: Fifty-three patient encounters were identified. Thirty-two patients (60.4%) received standard duration (6 [4.5-7] days) antimicrobial therapy, and 21 patients (39.6%) received extended duration (14 [11-14] days) antimicrobial therapy (P

http://ift.tt/2y8A3Hr

Pneumocystis Pneumonia and Acute Pulmonary Embolism in Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome: A Rare Co-occurrence.

Severe immunosuppression and the presence of opportunistic infections in human immunodeficiency virus/acquired immunodeficiency syndrome are strongly associated with incidence of venous thromboembolism especially deep venous thrombosis and pulmonary embolism (PE). The co-occurrence of 2 diseases with similar clinical presentation can pose diagnostic and treatment challenges. We describe the case of a 54-year-old male, with no significant past medical history who presented with complaints of a 6-week history of shortness of breath. He was diagnosed with human immunodeficiency virus 1 infection with a CD4 count of 121 cells/[mu]L and severe Pneumocystis jirovecii pneumonia. After 5 days of treatment without significant improvement, we obtained a computed tomography pulmonary angiogram, which showed concurrent acute PE. His clinical condition improved with anticoagulation therapy. Clinicians need to have a high index of suspicion and consider PE in the differential diagnosis of dyspnea and hypoxemia, particularly when P. jirovecii pneumonia infection or other acquired immunodeficiency syndrome defining illnesses are suspected. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2fZaZMo

Sclerokeratouveitis and lens dislocation in a patient with genital ulcer: was the great imitator imitated?

Uveitis is the most common ocular manifestation of syphilis, while scleritis is rare. A case of nodular scleritis, peripheral keratitis and uveitis in a patient with genital ulcer is presented in this report. This patient had a clinical profile suggestive of syphilis, though the serology was negative for treponemal antibodies. Other possible differential diagnosis imitating syphilis are discussed.

http://ift.tt/2fYKpCL

Erythema ab igne in an individual with diabetes and gastroparesis

Description

Prolonged abdominal heat application in an individual with diabetes and gastroparesis leads to the development of erythema ab igne. Practitioners should be aware of the various ways that erythema ab igne can present.1

Erythema ab igne is due to prolonged heat exposure (43–47°C) which causes damage to superficial vascular plexus leading to vasodilation, erythema and haemosiderin deposition which clinically appears as hyperpigmentation.2

A 28-year-old man with type 1 diabetes and gastroparesis had presented with vomiting and abdominal pain. Abdominal examination revealed a erythematous, reticulated, macular and non blanchable pigmentation, (figure 1). The patient used to apply hot water bottles for abdominal pain relief.

Figure 1

Erythema ab igne in an individual with diabetes and gastroparesis.

Erythema ab igne can be associated with epidermal atrophy and scaling.1 The lesions may become keratotic and bullous (rare) with a...

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Primary dural diffuse large B cell lymphoma mimicking parafalcine meningioma

A 58-year-old immunocompetent woman presented with complaints of recent onset recurrent generalised tonic-clonic seizures and left hemiparesis. On MRI a dural-based heterogeneously enhancing mass was seen along the falx cerebri mimicking parafalcine meningioma, causing brain parenchymal compression and vasogenic oedema in the right frontal and parietal lobes. The tumour was completely excised and on subsequent investigation it was diagnosed as diffuse large B cell type primary dural lymphoma. Chemotherapy with CHOP (cyclophosphamide, hydroxyl doxorubicin, vincristine and prednisone) regimen was started; however, the patient later died from episodes of acute pulmonary thromboembolism, aspiration pneumonia and septic shock.

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Small bowel obstruction due to a jejunal enterolith: an unusual complication of jejunal diverticulitis

A 91-year-old woman presented with symptoms of acute bowel obstruction supported by clinical findings. A CT of the abdomen was performed which demonstrated jejunal diverticulosis with a single inflamed, wide necked diverticulum. A large enterolith was found to be impacted in the jejunum just distal to the area of inflammation resulting in small bowel obstruction. The patient underwent emergency laparotomy, which confirmed the CT findings. Small bowel resection was performed. The patient had an uneventful postoperative recovery.

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Asymmetric glaucoma in pseudoplateau iris syndrome

A 39-year-old Caucasian man with bilateral narrow angles, a plateau-like iris configuration on gonioscopy and elevated intraocular pressure (IOP) presented with significant asymmetric glaucoma, left eye affected more than right. Initial management with topical medical therapy, laser iridoplasty and peripheral iridotomy in the left eye was ineffective in lowering the IOP or opening the anterior chamber angle. Ultrasound biomicroscopy demonstrated bilateral ciliary body cysts. The patient ultimately required surgical management, consisting of cataract extraction and endoscopic cyclophotocoagulation of ciliary body cysts in the left eye and trabeculectomy in the right eye, for persistent IOP control to prevent further optic nerve damage and subsequent visual field loss.

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Imaging of foreign bodies: a radiological conundrum

A 24-year-old woman escaped a fire by jumping from the first floor of her house onto a temporary greenhouse. She was brought into the emergency department and later treated surgically. Three years after the initial episode a tender lump in her right thigh was found during regular follow-up for her acute myeloid leukaemia, for which she was in remission. This was treated as a suspicious mass due to her haematological history and further imaging was organised. This was later identified as a piece of the greenhouse that she had landed on 7 years previously. It is a common occurrence for foreign bodies to be missed on initial examination. Fortunately the patient recovered well from her physical wounds and, more importantly, remains humorous when reflecting on her almost 7-year long battle with a piece of plastic.

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Bilateral intracranial calcifications with bilateral facial cutaneous naevus: Sturge Weber syndrome

Sturge Weber syndrome also known as mother spot disease belongs to a group of disorders called phakomatoses (neurocutaneous syndromes involving the central nervous and cutaneous systems). It is a congenital disorder of the vasculature of the meninges, brain, face and eyes. Clinically, it usually presents with seizures and other neurological complications, including mental retardation, contralateral hemiparesis and glaucoma. Its incidence is estimated at one case in 20 000–50 000 persons with equal frequency in boys and girls. We present a case of 18-months-old boy was brought by parents with history of seizures since birth resulting in fall 1 day back. Physical examination showed bilateral port-wine stain on face. CT head examination revealed bilateral intracranial calcification. This is a highly unusual presentation of Sturge Weber syndrome.

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Bilateral large subconjunctival haemorrhages unmasking immune thrombocytopenic purpura during retinopathy of prematurity screening

Although thrombocytopenia is known to be associated with pathogenesis of retinopathy of prematurity (ROP), immune thrombocytopenic purpura (ITP) is rare in infancy and not reported to occur with ROP. A preterm infant with aggressive posterior ROP developed bilateral massive subconjunctival haemorrhage after scleral indentation during screening. On evaluation, the infant was found to have severe ITP. Following intravenous transfusion of platelets and immunoglobulin, platelet counts improved and subconjunctival haemorrhage resolved over time. This case highlights the unusual presentation of ITP and also discusses the association of thrombocytopenia with ROP. Ophthalmologists should get prompt haematological work-up of such occurrences.

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Why in the age of CT scans and MRIs is a brain tumour mistaken for a psychiatric illness?

The first author of this paper operated on two patients with brain tumour, who had been undergoing long-term treatment for depression. In the age of CT scans and MRIs, why are there still cases in which a brain neoplasia is mistaken for a psychiatric condition with consequent serious delays in diagnosis? In this article, we have highlighted what in our experience are three noticeable obstacles in achieving the right diagnosis.

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Oxaliplatin-induced posterior reversible encephalopathy syndrome (PRES)

Posterior reversible encephalopathy syndrome (PRES), first introduced in 1996, is a neurotoxic state characterised by seizures, headache, vision change, paresis, nausea and altered mental status. Risk factors include hypertension, eclampsia/pre-eclampsia, infection/sepsis and cancer chemotherapy. Although exposure to toxic agents is a common occurrence in patients who develop PRES, oxaliplatin has rarely been associated with it, with only 10 cases reported worldwide. We present the case of an oxaliplatin-induced PRES in a 23-year-old male patient who was started on oxaliplatin/capecitabine as adjuvant chemotherapy for anal canal adenocarcinoma. The patient developed symptoms of headache, slurred speech and left-sided facial weakness on the ninth day after the first dose of oxaliplatin that lasted for 6–8 hours. The patient experienced another episode next day with similar symptoms that lasted for 8 hours. Oxaliplatin was withheld and the patient was discharged on capecitabine only. The patient had no new episodes since discharge on follow-up.

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Management of extensive external apical root resorption leading to root perforation

Resorption is both a physiological and pathological process which results in loss of hard tissues of the tooth, i.e , cementum and dentine and the surrounding bone. External resorption is much more common than internal resorption and can occur when tooth is luxated or avulsed. If remained unchecked, resorption can eventually lead to loss of the tooth. Timely management of the affected tooth can slow down the resorptive lesion and increase the prognosis of the survival of the tooth. This case report describes the surgical management of extensive external root resorption leading to perforation of apical one-third of the root area which was managed through root canal along with periapical surgery and bone grafting. A 6-month follow-up showed arrest of the resorptive defect and progressive healing as evident on the cone-beam computed tomography.

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Aspiration of Nasopore nasal packing

We present a case of postoperative Nasopore aspiration in an otherwise fit and well 11-year-old. An endoscopic adenoidectomy had been performed without incident and Nasopore packing placed into each nasal cavity. Immediately after extubation, there was marked hypoxia, tachypnoea and high clinical suspicion of pack aspiration. The patient returned to theatre for emergency rigid bronchoscopy and retrieval of nasal packing.

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Angiogenesis in the Transplanted Donor Graft after Living-Donor Liver Transplantation.

Background: There is no direct evidence for the role of angiogenesis in liver regeneration in humans. This study aimed to determine whether angiogenesis is involved in the regeneration of transplanted donor grafts in human living-donor liver transplantation (LDLT) and to examine the impact of donor graft volume on angiogenesis. Methods: Clinical data and liver tissue characteristics were analyzed in 4 patients who received adult-to-adult LDLT with dual left lobe grafts from 2 living donors. Liver tissues from transplanted donor grafts were obtained and immunohistochemically examined at 3-4 weeks after transplantation using the endothelial marker Ki67+ and CD31+. Results: All recipients showed recovery of normal liver function and a significant increase in the volume of engrafted left lobes after transplantation. Immunohistochemistry showed a remarkable increase in Ki67+ single hepatocyte proliferation, implying the role of hepatocytes in liver reconstitution, and a high density of blood vessels and proliferative endothelium, suggesting in vivo angiogenesis. Furthermore, we found that Ki67+ nuclei in CD31+ sinusoidal endothelial cells were higher in recipients with smaller donor grafts than in those with larger donor grafts. Conclusions: Our results suggested that angiogenesis is involved in the regeneration of transplanted liver in humans in inverse proportion to the donor graft volume. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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