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Δευτέρα 10 Σεπτεμβρίου 2018

Gender differences in doxorubicin pharmacology for subjects with chemosensitive cancers of young adulthood

Abstract

Purpose

For many cancers, adolescents and young adults (AYA) have worse outcomes than for children and adults. Many factors may contribute to the AYA survival gap, including differences in biology, therapeutic intent, and adherence to therapy. It has been observed that male AYAs have poorer outcomes than females. The purpose of this work was to test the proposition that gender-related pharmacologic factors may account for a component of the AYA survival gap.

Patients and methods

A prospective, multi-institutional pharmacologic study of 79 patients in total with chemosensitive cancers (Ewing sarcoma, osteosarcoma and Hodgkin lymphoma) was conducted, with conventional doxorubicin treatment. Pharmacokinetic data of 13 children, 40 AYAs and 13 adults were valid for analysis. Population pharmacokinetics models were developed for doxorubicin and its metabolite doxorubicinol based on the data created in this study. Consequently, model-based analysis was conducted to investigate the relevant topics.

Results

The clearance of doxorubicinol (normalized to body surface area), the main active metabolite of doxorubicin, appears faster in male AYAs than female (p = 0.04, 95% CI 0.1–3.9 L/h). The exposure of doxorubicinol (normalized to dose) is lower in male AYA than female (p = 0.03, 95% CI − 0.005 to − 0.0002 h/L). These might be correlated to the observed difference on nadir neutrophil count between male AYA and female (p = 0.027, 95% CI 0.09–1.4).

Conclusion

Gender-related differences in doxorubicin pharmacology may account for worse outcomes for male AYAs with chemosensitive cancers compared to females. These findings may reduce the AYA survival gap compared to other age groups.



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Intracranial bleeding (ICB) as a catastrophic complication of Streptococcus gordonii infective endocarditis (IE) in an immunocompetent patient

We present an interesting case of late-onset intracranial bleeding (ICB) as a complication of Streptococcus gordonii causing infective endocarditis. A previously healthy young woman was diagnosed with infective endocarditis. While she was already on treatment for 2 weeks, she had developed seizures with a localising neurological sign. An urgent non-contrasted CT brain showed massive left frontoparietal intraparenchymal bleeding. Although CT angiogram showed no evidence of active bleeding or contrast blush, massive ICB secondary to vascular complication of infective endocarditis was very likely. An urgent decompressive craniectomy with clot evacuation was done immediately to release the mass effect. She completed total 6 weeks of antibiotics and had postoperative uneventful hospital stay despite having a permanent global aphasia as a sequel of the ICB.



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Rare cause of gastric outlet obstruction: xanthogranulomatous cholecystitis

Description 

A 62-year-old Indian female patient presented with right upper quadrant pain and multiple episodes of vomiting for 10 days. She denied history of fever, jaundice, past anorexia/weight loss and previous surgeries. She was dehydrated, tachycardia (120/min) was present, and there was tenderness in the right upper quadrant. Routine investigations revealed presence of anaemia (haemoglobin 9.1 g/dL), raised total leucocyte counts (17 x10^9/L) and hypokalaemia (2.8 mEq/L). All other blood tests (liver function/kidney function/blood sugar and coagulation profile) were normal. Patient was stabilised with intravenous fluids, antibiotics and other supportive management. Imaging with ultrasound (USG) was suboptimal due to the massive intestinal gas and uncooperative nature of the patient. A collapsed gallbladder (GB) and a mass with a smooth curvilinear surface and posterior acoustic shadowing in the distal part of the duodenum were the only distinguishable findings. Due to repeated episodes of vomiting, the patient underwent an upper gastrointestinal endoscopy, which was...



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Tubercular septal abscess in a postoperative patient: a novel entity

Extrapulmonary tuberculosis is a rather uncommon and potentially challenging phenomenon. Such manifestation, particularly in the scenario of a late postoperative period, is extremely rare and requires a high index of suspicion, prompt diagnosis and appropriate treatment.

We present the case scenario of a patient with history of successfully treated pulmonary tuberculosis many years earlier, without any signs of recurrence, who developed primary nasal septal tuberculosis after undergoing septoplasty to correct his septal deviation. His postoperative course remained uneventful for 4 months. He then presented with a spontaneous nasal septal abscess, which proved to be tubercular in nature on investigations. Appropriate diagnosis was established, and the patient was treated successfully with antituberculous therapy.

Recurrent tuberculosis may present a diagnostic challenge for healthcare professionals. Only a high index of suspicion, modern diagnostic tools and institution of appropriate treatment including surgical intervention as required will ensure a promising outcome.



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Penile cutaneous horn: still an enigma

Description

A 60-year-old man with history of Johanson's staged urethroplasty for pan anterior urethral stricture due to lichen sclerosus et atrophicus 3 months previously presented to us with a cutaneous horn over his glans penis. This horn was previously excised superficially, and now had recurred over the same site in the last 1 month. It was initially small in size and then gradually increased to a size of around 2.5 cm (figure 1). The patient had no documents mentioning the histopathology of previously excised horn. The patient had been circumcised in childhood. He had no history of genital malignancy or other factors that could have been implicated in cutaneous horn formation. He was managed with excision of the horn along with deep biopsy from base of the lesion to rule out any malignant pathology. The excision site healed well, and biopsy revealed benign pathology. At present, patient has...



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Unusual right internal carotid artery supraclinoid segment fenestration associated with multiple aneurysms treated with flow diversion and coiling

Description 

The supraclinoid (carotid-ophthalmic) segment of the internal carotid artery (ICA) under the Bouthillier classification is defined as the segment between the ophthalmic and posterior-communicating arteries.1 We describe an unusual congenital anomaly of the supraclinoid internal carotid artery characterised by a large fenestration of its carotid-ophthalmic segment, associated with multiple aneurysms.

A 60-year-old female patient underwent investigation for persistent headaches and was found to have what appeared to be irregular fusiform dilatation of the intracranial right internal carotid artery on 1.5 T magnetic resonance angiography (MRA) time-of-flight imaging. Cerebral digital subtraction angiography (DSA) performed to further characterise this abnormality demonstrated two discrete aneurysms, one measuring 5 mm and the other 2 mm, arising from the posterior limb of a supraclinoid ICA fenestration (figure 1A).

Figure 1

(A) Three-dimensional reconstruction of a rotational digital subtraction angiogram (DSA) demonstrating the supraclinoid right internal  carotid  artery  (ICA) fenestration....



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Drug-induced autoimmune hepatitis associated with turmeric dietary supplement use

Turmeric dietary supplement sales, which accounted for US$69 million in spending in 2016, have been increasing exponentially in the USA, making this one of the most popular botanical supplements sold in the USA. Herbal supplement use, which is generally regarded as safe by consumers, is not usually reported to healthcare providers. We reported here on a case of autoimmune hepatitis, occurring in a 71-year-old woman taking turmeric dietary supplements for the maintenance of cardiovascular health, which resolved rapidly following discontinuation of the turmeric supplements. Of particular note, turmeric use was not documented in the patient's medical records and the potential causative role of the turmeric supplementation was ultimately identified by the patient rather than the healthcare providers. To our knowledge, this is the first documented report of turmeric supplement-induced autoimmune hepatitis.



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Study protocol for a randomised controlled trial of consenting processes and their effects on patient decision-making when undergoing spinal injections: the Risks In Spinal Consenting for Surgery (RISCS) trial

Introduction

There are major differences between legal and medical approaches to informed consent. Medically, consent is obtained prospectively for an intended procedure, to inform the patient of choices, risks and benefits, and to manage expectations. Legally, consent is reviewed retrospectively, usually following unmet expectations and/or the occurrence of complications. Recent legal cases relating to clinical negligence define the establishment of causation and breach of duty related to informed consent. However, there is no prospective evidence to validate the current judicial perspectives on causation and thus clinical negligence. The aim of this randomised controlled trial (RCT) is to investigate whether variations in consenting processes for the same procedure lead to changes in patient decision-making related to consent for that procedure.

Methods and analysis

The Risks In Spinal Consenting for Surgery trial is a single-centre, non-inferiority RCT, where 220 patients, aged over 18 years, receiving an elective, day case spinal injection, will be randomised to either a 'legally styled' consent form with 55 risks identified in the world literature, or a 'medically styled' consent form with the 13 serious or most common risks usually quoted by reference to specialist society guidelines. Following explanation of the medical reasons for considering an injection therapy and consent to the trial, participants will be randomly allocated to one of two groups (1:1). The patients are then given the opportunity to discuss any concerns relating to the procedure and/or risks with a single specialist practitioner. The primary outcome will be rates of consent withdrawal due to the risks explained. Secondary outcomes include scores from the State-Trait Anxiety Inventory, Visual Analogue Scale, EuroQol 5-dimension questionnaire and Oswestry Disability Index.

Ethics and dissemination

Results will be presented in peer-reviewed journals and at international conferences. This study is approved by the Health Research Authority: REC 16/SC/0510.

Trial registration number

ISRCTN67513618; Pre-results.



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Role of cognitive ability in the association between functional health literacy and mortality in the Lothian Birth Cohort 1936: a prospective cohort study

Objectives

We investigated the role that childhood and old age cognitive ability play in the association between functional health literacy and mortality.

Design

Prospective cohort study.

Setting

This study used data from the Lothian Birth Cohort 1936 (LBC1936) study, which recruited participants living in the Lothian region of Scotland when aged 70 years, most of whom had completed an intelligence test at age 11 years.

Participants

795 members of the LBC1936 with scores on tests of functional health literacy and cognitive ability in childhood and older adulthood.

Primary and secondary outcome measures

Participants were followed up for 8 years to determine mortality. Time to death in days was used as the primary outcome measure.

Results

Using Cox regression, higher functional health literacy was associated with lower risk of mortality adjusting for age and sex, using the Shortened Test of Functional Health Literacy in Adults (HR 0.95, 95% CI 0.92 to 0.98), the Newest Vital Sign (HR 0.88, 95% CI 0.80 to 0.97) and a functional health literacy composite measure (HR 0.77, 95% CI 0.65 to 0.92), but not the Rapid Estimate of Adult Literacy in Medicine (HR 0.95, 95% CI 0.90 to 1.01). Adjusting for childhood intelligence did not change these associations. When additionally adjusting for fluid-type cognitive ability in older age, associations between functional health literacy and mortality were attenuated and non-significant.

Conclusions

Current fluid ability, but not childhood intelligence, attenuated the association between functional health literacy and mortality. Functional health literacy measures may, in part, assess fluid-type cognitive abilities, and this may account for the association between functional health literacy and mortality.



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Do statins improve outcomes for patients with non-small cell lung cancer? A systematic review and meta-analysis protocol

Introduction

Lung cancer is the most common neoplasm and the leading cause of cancer-related death worldwide. Non-small cell lung cancer (NSCLC), accounting for 85% of all lung cancer cases, is frequently diagnosed at an advanced and metastatic stage. In addition, survival of patients with NSCLC has not improved significantly over the recent decades. Statins are used as a cholesterol-lowering agent, but recently preclinical and clinical studies have revealed their anticancer effects. Thus, this systematic review and meta-analysis aims to clarify whether statins improve the prognosis of patients with NSCLC.

Methods and analysis

We will search MEDLINE (PubMed), EMBASE, Web of Science, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov with no restriction on language. Both randomised controlled trials (RCTs) and observational cohort studies evaluating the prognostic role of statins in patients with NSCLC will be included. The primary outcome will be overall survival, and the secondary outcomes will include cancer-specific survival, disease-free survival and cancer recurrence. Two assessors will assess the RCTs using the Cochrane Collaboration's risk of bias tool and the observational cohort studies according to ROBINS-I. Publication bias will be assessed by funnel plot using the STATA software v.13.1.

Ethics and dissemination

No ethical issues are predicted. This systematic review and meta-analysis aims to describe the prognostic effects of statins in patients with NSCLC, which would help clinicians to optimise treatment for patients with NSCLC. These findings will be published in a peer-reviewed journal and presented at national and international conferences.

PROSPERO registration number

CRD42016047524.



https://ift.tt/2oV69QW

Can occupational therapist-led home environmental assessment prevent falls in older people? A modified cohort randomised controlled trial protocol

Introduction

Falls and fall-related injuries are a serious cause of morbidity and cost to society. Environmental hazards are implicated as a major contributor to falls among older people. A recent Cochrane review found an environmental assessment, undertaken by an occupational therapist, to be an effective approach to reducing falls. However, none of the trials included a cost-effectiveness evaluation in the UK setting. This protocol describes a large multicentre trial investigating the clinical and cost-effectiveness of environmental assessment and modification within the home with the aim of preventing falls in older people.

Methods and analysis

A two-arm, modified cohort randomised controlled trial, conducted within England, with 1299 community-dwelling participants aged 65 years and above, who are at an increased risk of falls. Participants will be randomised 2:1 to receive either usual care or home assessment and modification. The primary outcome is rate of falls (falls/person/time) over 12 months assessed by monthly patient self-report falls calendars. Secondary self-reported outcome measures include: the proportion of single and multiple fallers, time to first fall over a 12-month period, quality of life (EuroQoL EQ-5D-5L) and health service utilisation at 4, 8 and 12 months. A nested qualitative study will examine the feasibility of providing the intervention and explore barriers, facilitators, workload implications and readiness to employ these interventions into routine practice. An economic evaluation will assess value for money in terms of cost per fall averted.

Ethics and dissemination

This study protocol (including the original application and subsequent amendments) received a favourable ethical opinion from National Health Service West of Scotland REC 3. The trial results will be published in peer-reviewed journals and at conference presentations. A summary of the findings will be sent to participants.

Trial registration number

ISRCTN22202133; Pre-results.



https://ift.tt/2O85syA

A mixed-methods study to explore opinions of research translation held by researchers working in a Centre of Research Excellence in Australia

Objective

There is a growing need for researchers to demonstrate impact, which is reliant on successful research translation. The Australian National Health and Medical Research Council funded a Centre of Research Excellence in Stroke Rehabilitation and Brain Recovery (CRE-Stroke) to enhance collaborations between researchers conducting different types of stroke rehabilitation research. The purpose of this study was to explore opinions about research translation held by CRE-Stroke researchers conducting preclinical and clinical research, in terms of scope, importance, responsibility and perceived skills and knowledge.

Design

Mixed-methods study, comprising a paper-based survey and semistructured interviews. Interview data were inductively coded and thematically analysed. Survey and interview data were compared and synthesised.

Participants

55 (7 preclinical, 48 clinical) researchers attending a CRE-Stroke research forum completed a paper-based survey. Semistructured interviews with 22 CRE-Stroke (5 preclinical, 17 clinical) researchers were conducted.

Results

Research translation was described as translating to other research and translating to clinical practice and policy. Most researchers (n=54, 98%) reported that research translation was important, particularly in terms of generating research impact, but the most common sign of project completion reported by researchers (n=7, 100% preclinical; n=37, 77% clinical) was publication. Most researchers (preclinical n=4, 57%; clinical n=37, 77%) reported having responsibility for translating research, but less than half reported having the necessary skills (n=1, 14% preclinical; n=17, 35% clinical) and knowledge (n=3, 43% preclinical; n=19, 40% clinical). Differing opinions about who should be responsible for translating findings to clinical practice were expressed.

Conclusions

Stroke rehabilitation researchers appear confident to translate their research via the traditional mechanism of publications. To optimise impact, clarity is needed regarding who is best placed to translate research findings to clinical practice and policy. Education and skills development to apply broader translation processes are needed to maximise the use of research at all stages.



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Design and rationale of a randomised controlled trial comparing apixaban to phenprocoumon in patients with atrial fibrillation on chronic haemodialysis: the AXADIA-AFNET 8 study

Introduction

Patients with end-stage kidney disease requiring maintenance haemodialysis treatment experience a dramatic cardiovascular morbidity and mortality. Due to the high atherosclerotic and arteriosclerotic burden and profound alterations in haemostasis, they frequently suffer and die from both thromboembolic and bleeding events. This is a particular concern in patients on haemodialysis with atrial fibrillation (AF). Controlled trials on the optimal anticoagulation in patients with AF on haemodialysis are not available. The randomised controlled phase IIIb AXADIA–AFNET 8 trial will evaluate the safety and efficacy of the factor Xa inhibitor apixaban in patients with AF requiring haemodialysis.

Methods and analysis

A total of 222 patients will be randomised in an open-labelled, 1:1 design to receive either apixaban 2.5 mg twice daily or dose-adjusted vitamin K antagonist therapy (target international normalised ratio 2.0–3.0). All patients will be treated and followed up for a minimum of 6 months up to a maximum of 24 months. The primary outcome is major or clinically relevant, non-major bleedings or death of any cause. Secondary outcomes include stroke, cardiovascular death and other thromboembolic events, thus exploring the efficacy of apixaban. The first patient was randomised in June 2017.

Ethics and dissemination

The study protocol was approved by the Ethical Committee of the Landesaertzekammer, Westfalen-Lippe and the Medical Faculty of the University of Muenster, Muenster, Germany (reference number: 2016-598 f-A). Written informed consent will be obtained from all patients prior to study participation, including their consent for long-term follow-up. AXADIA–AFNET 8 is an investigator-initiated trial. Sponsor is AFNET, Muenster, Germany. Study findings will be disseminated to Bristol-Myers Squibb, Munich, Germany, and Pfizer, Berlin, Germany, to the participating centres, at research conferences and in peer-reviewed journals.

Trial registration numbers

NCT02933697,Pre-results.



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What evidence is used to underpin the design of strength-based exercise interventions evaluated in randomised controlled trials for rheumatoid arthritis? A systematic review protocol

Introduction

Healthcare researchers designing strength-based exercise interventions must choose an appropriate dose to test before evaluating its effect using a definitive/phase-III randomised controlled trial (RCT). Compared with early phase testing employed by pharmaceutical trials, it is questionable whether exercise-based trials employ the same rigour for establishing tolerated dosage. Consequently, it is unclear if participants are initially prescribed optimal doses of exercise, which may potentially impact on study outcomes. Using trials of strength-based exercise interventions in adults with rheumatoid arthritis (RA) as an exemplar, the aims of this review are to (1) identify the proportion of RCTs that use phase I/II trials with dose escalation methodology for setting prescription parameters, (2) determine type and level of evidence used to justify prescription parameters of strength-based exercise interventions evaluated by RCTs, (3) explore consistency and applicability of the evidence underpinning prescription parameters in RCTs and (4) explore if a relationship exists between risk of bias for RCTs evaluating strength-based interventions and the level of evidence used to underpin prescription parameters.

Methods and analysis

Focusing on RCT's evaluating strength-based exercise interventions in adults with RA published after 2000, the following databases will be searched: Allied and Complementary Medicine Database, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Excerpta Medica Database, Medline and Physiotherapy Evidence Database. For each RCT, we will identify the evidence used to underpin prescription parameters. Both trial and underpinning evidence will have key information about the intervention extracted using the template for intervention description and replication checklist. Risk of bias will be assessed according to Cochrane. Levels of evidence will be assessed against the Oxford Centre for Evidence-Based Medicine and relationships between RCT and underpinning evidence explored and described narratively. Two independent assessors will be involved throughout data selection and extraction with recourse to a third reviewer should agreement not be reached.

Ethics and dissemination

No ethical issues are identified. Dissemination will be via publication.

PROSPERO registration number

CRD42018090963.



https://ift.tt/2O7durE

Singing for people with aphasia (SPA): a protocol for a pilot randomised controlled trial of a group singing intervention to improve well-being

Introduction

The singing for people with aphasia (SPA) intervention aims to improve quality of life and well-being for people with poststroke aphasia. A definitive randomised controlled trial (RCT) is required to assess the clinical and cost effectiveness of SPA. The purpose of this pilot study is to assess the feasibility of such a definitive trial and inform its design.

Methods and analysis

A two-group, assessor-blinded, randomised controlled external pilot trial with parallel mixed methods process evaluation and economic evaluation. Forty-eight participants discharged from clinical speech and language therapy will be individually randomised 1:1 to SPA (10 group sessions plus a resource booklet) or control (resource booklet only). Outcome assessment at baseline, 3 and 6 months postrandomisation include: ICEpop CAPability measure for adults, Stroke and Aphasia Quality of Life, EQ-5D-5L, modified Reintegration into Normal Living Index, Communication Outcome After Stroke, Very Short Version of the Minnesota Aphasia Test, Service Receipt Inventory and Care Related Quality of Life. Feasibility, acceptability and process outcomes include recruitment and retention rates, with measurement burden and trial experiences being explored in qualitative interviews (15 participants, 2 music facilitators and 2 music champions). Analyses include: descriptive statistics, with 95% CIs where appropriate; qualitative themes; intervention fidelity from videos and session checklists; rehearsal of health economic analysis.

Ethics and dissemination

NHS National Research Ethics Service and the Health Research Authority confirmed approval in April 2017; recruitment commenced in June 2017. Outputs will include: pilot data to inform whether to proceed to a definitive RCT and support a funding application; finalised intervention manual for multicentre replication of SPA; presentations at conferences, public involvement events; internationally recognised peer reviewed journal publications, open access sources and media releases.

Trial registration number

NCT03076736.



https://ift.tt/2oUTcqa

Optimal duration of prone positioning in patients with acute respiratory distress syndrome: a protocol for a systematic review and meta-regression analysis

Introduction

Several systematic reviews and meta-analyses have demonstrated that prolonged (≥16 hours) prone positioning can reduce the mortality associated with acute respiratory distress syndrome (ARDS). However, the effectiveness and optimal duration of prone positioning was not fully evaluated. To fill these gaps, we will first investigate the effectiveness of prone positioning compared with the conventional management of patients with ARDS, regarding outcomes using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Second, if statistical heterogeneity in effectiveness with regard to short-term mortality (intensive care unit death or ≤30-day mortality) is shown, we will conduct a meta-regression analysis to explore the association between duration and effectiveness, and determine the optimal duration of prone positioning.

Method and analysis

Relevant studies are collected using PubMed/MEDLINE, Embase, Cochrane Central Register of Controlled Trials and the WHO International Clinical Trials Platform Search Portal. Randomised controlled trials comparing prone and supine positioning in adults with ARDS will be included in the meta-analysis. Two independent investigators will screen trials obtained by search eligibility and extract data from selected studies to standardised data recording forms. For each selected trial, the risk of bias and quality of evidence will be evaluated using the GRADE system. Meta-regression analyses will be performed to identify the most important factors associated with short-term mortality, and subgroup analysis will be used to analyse the following: duration of mechanical ventilation in the prone position per day, patient severity, tidal volume and cause of ARDS. If heterogeneity or inconsistency among the studies is detected, subgroup analysis will be conducted on factors that may cause heterogeneity.

Ethics and dissemination

This study requires no ethical approval. The results obtained from this systematic review and meta-analysis will be disseminated through international conference presentations and publication in a peer-reviewed journal.

PROSPERO registration number

CRD42017078340.



https://ift.tt/2O7tIRE

Neighbourhood deprivation and lung cancer risk: a nested case-control study in the USA

Objectives

To examine the association between neighbourhood deprivation and lung cancer risk.

Design

Nested case–control study.

Setting

Southern Community Cohort Study of persons residing in 12 states in the southeastern USA.

Participants

1334 cases of lung cancer and 5315 controls.

Primary outcome measure

Risk of lung cancer.

Results

After adjustment for smoking status and other confounders, and additional adjustment for individual-level measures of socioeconomic status (SES), there was no monotonic increase in risk with worsening deprivation score overall or within sex and race groups. There was an increase among current and shorter term former smokers (p=0.04) but not among never and longer term former smokers. There was evidence of statistically significant interaction by sex among whites, but not blacks, in which the effect of worsening deprivation on lung cancer existed in males but not in females.

Conclusions

Area-level measures of SES were associated with lung cancer risk in current and shorter term former smokers only in this population.



https://ift.tt/2oYlEaK

Conservative care with or without manipulative therapy in the management of back and/or neck pain in Danish children aged 9-15: a randomised controlled trial nested in a school-based cohort

Background

A substantial number of children experience spinal pain, that is, back and/or neck pain. Today, no 'gold-standard' treatment for spinal pain in children exists, but manipulative therapy is increasingly being used in spite of a lack of evidence of its effectiveness. This study investigates the effectiveness of adding manipulative therapy to other conservative care for spinal pain in a school-based cohort of Danish children aged 9–15 years.

Methods and findings

The design was a two-arm pragmatic randomised controlled trial, nested in a longitudinal open cohort study in Danish public schools. 238 children from 13 public schools were randomised individually from February 2012 to April 2014. A text message system and clinical examinations were used for data collection. Interventions included either (1) advice, exercises and soft-tissue treatment or (2) advice, exercises and soft-tissue treatment plus manipulative therapy. The primary outcome was number of recurrences of spinal pain. Secondary outcomes were duration of spinal pain, change in pain intensity and Global Perceived Effect.

We found no significant difference between groups in the primary outcome (control group median 1 (IQR 1–3) and intervention group 2 (IQR 0–4), p=0.07). Children in the group receiving manipulative therapy reported a higher Global Perceived Effect: OR 2.22, (95% CI 1.19 to 4.15). No adverse events were reported. Main limitations are the potential discrepancy between parental and child reporting and that the study population may not be comparable to a normal care-seeking population.

Conclusions

Adding manipulative therapy to other conservative care in school children with spinal pain did not result in fewer recurrent episodes. The choice of treatment—if any—for spinal pain in children therefore relies on personal preferences, and could include conservative care with and without manipulative therapy. Participants in this trial may differ from a normal care-seeking population.

Trial registration number

NCT01504698; Results.



https://ift.tt/2O7tIB8

Systematic bias between blinded independent central review and local assessment: literature review and analyses of 76 phase III randomised controlled trials in 45 688 patients with advanced solid tumour

Objective

Unbiased assessment of tumour response is crucial in randomised controlled trials (RCTs). Blinded independent central review is usually used as a supplemental or monitor to local assessment but is costly. The aim of this study is to investigate whether systematic bias existed in RCTs by comparing the treatment effects of efficacy endpoints between central and local assessments.

Design

Literature review, pooling analysis and correlation analysis.

Data sources

PubMed, from 1 January 2010 to 30 June 2017.

Eligibility criteria for selecting studies

Eligible articles are phase III RCTs comparing anticancer agents for advanced solid tumours. Additionally, the articles should report objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) or time to progression (TTP); the treatment effect of these endpoints, OR or HR, should be based on central and local assessments.

Results

Of 76 included trials involving 45 688 patients, 17 (22%) trials reported their endpoints with statistically inconsistent inferences (p value lower/higher than the probability of type I error) between central and local assessments; among them, 9 (53%) trials had statistically significant inference based on central assessment. Pooling analysis presented no systematic bias when comparing treatment effects of both assessments (ORR: OR=1.02 (95% CI 0.97 to 1.07), p=0.42, I2=0%; DCR: OR=0.97 (95% CI 0.92 to 1.03), p=0.32, I2=0%); PFS: HR=1.01 (95% CI 0.99 to 1.02), p=0.32, I2=0%; TTP: HR=1.04 (95% CI 0.95 to 1.14), p=0.37, I2=0%), regardless of funding source, mask, region, tumour type, study design, number of enrolled patients, response assessment criteria, primary endpoint and trials with statistically consistent/inconsistent inferences. Correlation analysis also presented no sign of systematic bias between central and local assessments (ORR, DCR, PFS: r>0.90, p<0.01; TTP: r=0.90, p=0.29).

Conclusions

No systematic bias could be found between local and central assessments in phase III RCTs on solid tumours. However, statistically inconsistent inferences could be made in many trials between both assessments.



https://ift.tt/2O5Q7i1

Human Early Life Exposome (HELIX) study: a European population-based exposome cohort

Purpose

Essential to exposome research is the collection of data on many environmental exposures from different domains in the same subjects. The aim of the Human Early Life Exposome (HELIX) study was to measure and describe multiple environmental exposures during early life (pregnancy and childhood) in a prospective cohort and associate these exposures with molecular omics signatures and child health outcomes. Here, we describe recruitment, measurements available and baseline data of the HELIX study populations.

Participants

The HELIX study represents a collaborative project across six established and ongoing longitudinal population-based birth cohort studies in six European countries (France, Greece, Lithuania, Norway, Spain and the UK). HELIX used a multilevel study design with the entire study population totalling 31 472 mother-child pairs, recruited during pregnancy, in the six existing cohorts (first level); a subcohort of 1301 mother-child pairs where biomarkers, omics signatures and child health outcomes were measured at age 6–11 years (second level) and repeat-sampling panel studies with around 150 children and 150 pregnant women aimed at collecting personal exposure data (third level).

Findings to date

Cohort data include urban environment, hazardous substances and lifestyle-related exposures for women during pregnancy and their offspring from birth until 6–11 years. Common, standardised protocols were used to collect biological samples, measure exposure biomarkers and omics signatures and assess child health across the six cohorts. Baseline data of the cohort show substantial variation in health outcomes and determinants between the six countries, for example, in family affluence levels, tobacco smoking, physical activity, dietary habits and prevalence of childhood obesity, asthma, allergies and attention deficit hyperactivity disorder.

Future plans

HELIX study results will inform on the early life exposome and its association with molecular omics signatures and child health outcomes. Cohort data are accessible for future research involving researchers external to the project.



https://ift.tt/2oVXFJm

Association between serum magnesium concentration and metabolic syndrome, diabetes, hypertension and hyperuricaemia in knee osteoarthritis: a cross-sectional study in Hunan Province, China

Objectives

To examine the associations between serum magnesium (Mg) concentration with the prevalence of metabolic syndrome (MetS), diabetes mellitus (DM), hypertension (HP) and hyperuricaemia (HU) in patients with radiographic knee osteoarthritis (OA).

Methods

The present study was conducted at the Health Management Center of Xiangya Hospital. Radiographic OA was evaluated for patients aged over 40 years with basic characteristics and blood biochemical assessment. Serum Mg concentration was measured using the chemiluminescence method. MetS, DM, HP and HU were diagnosed based on standard protocols. The associations between serum Mg concentration with MetS, DM, HP and HU were evaluated by conducting multivariable adjusted logistic regression.

Results

A total of 962 patients with radiographic knee OA were included. Compared with the lowest quintile, the multivariable adjusted ORs and related 95% CIs of DM were 0.40 (95% CI 0.23 to 0.70, p=0.001), 0.33 (95% CI 0.18 to 0.60, p<0.001), 0.27 (95% CI 0.14 to 0.52, p<0.001) and 0.22 (95% CI 0.11 to 0.44, p<0.001) in the second, third, fourth and highest quintiles of serum Mg, respectively (p for trend <0.001); the multivariable adjusted ORs of HU were 0.33 (95% CI 0.19 to 0.59, p<0.001), 0.52 (95% CI 0.30 to 0.91, p=0.022) and 0.39 (95% CI 0.22 to 0.70, p=0.001) in the third, fourth and highest quintiles of serum Mg, respectively (p for trend <0.001); and the multivariable adjusted ORs of MetS were 0.59 (95% CI 0.36 to 0.94, p=0.027) in the second and 0.56 (95% CI 0.34 to 0.93, p=0.024) in the highest quintiles of serum Mg. However, the inverse association between serum Mg and the prevalence of MetS was non-linear (p for trend=0.067). There was no significant association between serum Mg and HP in patients with OA.

Conclusions

The serum Mg concentration was inversely associated with the prevalence of MetS, DM and HU in patients with radiographic knee OA.

Level of evidence

Level III, cross-sectional study.



https://ift.tt/2O85qqs

The Role of the Specialist Nurse in Gynaecological Cancer

Abstract

Purpose of Review

To explore the role of the specialist nurse within gynaecological cancer.

Recent Findings

There are many different job titles associated with the role of the specialist nurse. Nursing roles are evolving not only to meet the increasing demands on services but also within the ever changing landscape of cancer treatments and improvement in survival. Women and their families need specialist nurses to guide and support them on their cancer journey, along the treatment trajectory and into survivorship.

Summary

This paper explores specialist nurse roles generally, and within our service which have been adapted to meet service and patient needs within a gynaecological cancer centre. Irrelevant of title, specialist nurses are best suited to meet the patients' needs. The fundamental ethos of the care should always remain having the patients' best interest at heart, acting as their advocate - in essence giving them a voice when they need it.



https://ift.tt/2oYYm4G

Evaluating the Use of 18F-FDG PET CT for External Beam Radiotherapy Planning in Gynaecological Malignancies

Abstract

Purpose of Review

To evaluate the evidence for the use of fluorine-18-fluorodeoyglucose (18F-FDG) PET CT in external beam radiotherapy planning for treatment of gynaecological malignancies.

Recent Findings

Our review confirms that the incorporation of 18F-FDG PET CT during radiotherapy planning may decrease inter-observer variability during target delineation. It can also provide useful functional information regarding the tumour, which may facilitate the development of techniques for dose escalation and 'dose painting' not only for primary disease, especially in cervical cancer, but also nodal metastasis.

Summary

The utilisation of this functional modality in external beam radiotherapy planning, particularly in locally advanced cervical malignancy, is an exciting topic that warrants further prospective research. Perhaps the most valuable role may be the potential to deliver dose escalation to 18F-FDG PET CT avid targets previously limited by organ at risk constraints, now that we have significantly more advanced radiotherapy planning tools at our disposal.



https://ift.tt/2MiSrk4

Radioactive Iodine-Refractory Differentiated Thyroid Cancer in the Elderly

Abstract

Most common thyroid cancers are differentiated thyroid cancers (DTCs) and have papillary, follicular, or Hürthle cell morphology. Papillary thyroid carcinoma (PTC) is the most common malignant tumor of the thyroid gland. The incidence of DTC increases with age. While most of the patients with DTC have an excellent prognosis, the outcome can be poor when diagnosed in elderly patients.

Purpose of Review

Current treatment approach for DTC includes surgery, thyroid-stimulating hormone (TSH) suppression, radioactive iodine, external beam radiotherapy, or systemic treatments such as kinase inhibitors. Radioactive iodine therapy (RAI) is the primary first-line systemic treatment for advanced DTC. However, during the course of treatment, the tumor may become refractory to RAI. Elderly patients are more likely to be diagnosed with advanced disease that can be refractory to RAI.

Recent Findings

The advent of TKIs (tyrosine kinase inhibitors) and their usage in RAI refractory disease has shown improved progression-free survival. These agents are, however, associated with increased toxicity.

Summary

The variable nature of disease and toxicity associated with the systemic therapy makes it important to have an individualized approach to management, especially in the elderly population who can be more susceptible to toxicities.



https://ift.tt/2oUS7P8

BRAFi/MEKi in patients with metastatic melanoma: predictive factors of complete response

Future Oncology, Ahead of Print.


https://ift.tt/2oXr4mD

Oncogenic MYD88 mutations in lymphoma: novel insights and therapeutic possibilities

Abstract

Oncogenic MYD88 mutations, most notably the Leu 265 Pro (L265P) mutation, were recently identified as potential driver mutations in various B-cell non-Hodgkin Lymphomas (NHLs). The L265P mutation is now thought to be common to virtually all NHLs and occurs in between 4 and 90% of cases, depending on the entity. Since it is tumor-specific, the mutation, and the pathways it regulates, might serve as advantageous therapeutic targets for both conventional chemotherapeutic intervention, as well as immunotherapeutic strategies. Here, we review recent progress on elucidating the molecular and cellular processes affected by the L265P mutation of MYD88, describe a new in vivo model for MyD88 L265P-mediated oncogenesis, and summarize how these findings could be exploited therapeutically by specific targeting of signaling pathways. In addition, we summarize current and explore future possibilities for conceivable immunotherapeutic approaches, such as L265P-derived peptide vaccination, adoptive transfer of L265P-restricted T cells, and use of T-cell receptor-engineered T cells. With clinical trials regarding their efficacy rapidly expanding to NHLs, we also discuss potential combinations of immune checkpoint inhibitors with the described targeted chemotherapies of L265P signaling networks, and/or with the above immunological approaches as potential ways of targeting MYD88-mutated lymphomas in the future.



https://ift.tt/2x2TGhH

Weipixiao attenuate early angiogenesis in rats with gastric precancerous lesions

Angiogenesis is a pathobiological hallmark of gastric cancer. However, rare studies focus on angiogenesis in gastric precancerous lesions (GPL). Weipixiao (WPX), a Chinese herbal preparation, is proved clinica...

https://ift.tt/2x3MpOQ

Sargassum horneri (Turner) C. Agardh ethanol extract inhibits the fine dust inflammation response via activating Nrf2/HO-1 signaling in RAW 264.7 cells

Among the different kinds of pollution, air pollution continues to increase globally. East Asia is considered to be significantly affected. As a result, the populations in these regions face serious health iss...

https://ift.tt/2NzjOLr

Polyglobulia in patients with hemangioblastomas is related to tumor size but not to serum erythropoietin

Abstract

Background

Hemangioblastomas are associated with elevated hemoglobin (Hb) levels (polyglobulia), which is associated with a higher risk for cerebral stroke, cardiac infarction and pulmonary embolism. The pathomechanism of polyglobulia remains unclear and different theories have been postulated. Among those are elevated serum erythropoietin (EPO) levels caused by secretion of the tumor or associated tumor cyst.

Methods

To elucidate the pathomechanism, we systematically investigated the relation between polyglobulia, serum EPO level, size of the solid tumor and associated cyst in hemangioblastomas. We prospectively evaluated hemoglobin and EPO levels in a series of 33 consecutive patients operated on hemangioblastomas in our center. We measured the size of the solid tumor and associated cyst in magnetic resonance imaging. Statistical evaluations were performed using the Fisher's exact test and student's t-test.

Results

As a result five patients had elevated hemoglobin levels. Only one of these had an elevated serum EPO level. Of 26 patients with normal hemoglobin levels, 4 patients had elevated EPO levels.

Patients with low or normal hemoglobin levels (84%) had an average tumor size of 0.8 cm3, which differed significantly from patients with elevated hemoglobin levels (16%), who had an average solid tumor size of 8.0 cm3 (p < 0.05). We did not observe a significant correlation between EPO levels or polyglobulia and associated cysts.

Conclusions

We therefore conclude that in contrast to previous case reports and interpretations, our data show no correlation between polyglobulia and EPO levels or associated cysts in patients with hemangioblastomas. In fact, it is the size of the solid tumor that correlates with polyglobulia.

The study was retrospectively registered in the German Clinical Trial Registry on 10 July 2014; Trial registration: DRKS00006310.



https://ift.tt/2MjPY8V

From guidelines to uniform pan-healthcare professional practice: development of an international consensus Care Pathway for the diagnosis and management of Primary Biliary Cholangitis (PBC)

PBC is an infrequent but important, lifelong autoimmune cholestatic liver disease that leads to liver fibrosis, cirrhosis and, ultimately, the need for liver transplantation. Its clinical course is heterogeneous, making it difficult for clinicians to diagnose and risk stratify patients with confidence. Patient management is frequently shared across primary and secondary care, and between physicians, nurse specialists and physician assistants. A key recommendation of recent EASL treatment guidelines was the development of a Care Pathway, to facilitate standardized approaches to management based on current practice.

https://ift.tt/2MiwbXI

Hepatobiliary and non-hepatobiliary malignancies in PSC patients from Southern Europe: a comparative study in two European centers

Primary Sclerosing Cholangitis is a risk factor for the development of hepatobiliary malignancies (HPB) and non-HPB.

https://ift.tt/2oYyVQw

Autoimmune liver disease serology in acute hepatitis E virus infection

Introduction: Existing data show an increased seroprevalence of HEV among AIH patients, raising the question as to whether HEV as a role as a potential AIH trigger. Our aim was to investigate whether acute HEV infection is associated with the presence of AIH-relevant autoantibodies.

https://ift.tt/2MhCVoE

A chromosome X-wide association study in primary biliary cholangitis allowed the identification of 5 novel susceptibility loci

Genome-wide association studies (GWAS) in primary biliary cholangitis (PBC) failed to find X chromosome genetic variants associated with the disease, but analytical problems arising from X unique mode of inheritance were not taken in account. Aim of our study was to explore the specific contribution of the X chromosome to the genetic architecture of PBC by performing a chromosome X-wide association study (XWAS).

https://ift.tt/2oYyVA0

Non-invasive B-cell clonality markers may help in the rational approach to HCV SVR cryoglobulinemic patients with persisting manifestations

Background: Mixed cryoglobulinemia (MC), a both autoimmune and lymphoproliferative disorder (LPD), is characterized by the clonal expansion of B-cell populations, mostly in the liver and, less frequently, in the bone marrow or blood. DAAs can improve or heal MC vasculitis, but persistence or recurrence may be observed after SVR. Rituximab (RTX) is the first-choice therapy in such cases. However, MC persistence may also be due to other causes, including the occurrence of irreversible organ/tissue damage.

https://ift.tt/2MiFCGs

Epidemiology of primary biliary cholangitis in Italy: novel insights on gender and comorbidities

Primary biliary cholangitis (PBC) is a rare autoimmune liver disease, that mostly affects females. Usually associated with other autoimmune diseases, very little is known about non-autoimmune comorbidities.

https://ift.tt/2oWQel3

Epidemiology and clinical impact of non-viral acute hepatitis in a tertiary unit of Hepatology in Italy

Introduction and Aims: Autoimmune hepatitis have a variable occurrence, clinical phenotype and outcome, and the factors contributing to this variability are uncertain. The goal of this study is to evaluate, through a retrospective analysis, data of severe acute hepatitis (SAH) requiring hospital admission between 1/2017 and 6/2018 in a tertiary inpatient Hepatological Unit. Incidence, clinical impact and outcome of non-viral/autoimmune acute hepatitis (AAH) were analyzed. AAH diagnosis was made using AAH scoring: definite diagnosis when AAH score was >15 pre-treatment and >17 post-treatment, or probable diagnosis when it was <15 and <17 respectively.

https://ift.tt/2MkntIm

Editorial Board



https://ift.tt/2oYhdgh

Magnetic resonance cholangiography and biochemical predictive criteria of response to endoscopic treatment of severe strictures in patients with primary sclerosing Cholangitis

Background: The aim of this study was to assess whether magnetic resonance cholangiography (MRC), clinical and biochemical criteria are able to predict improvement after endoscopic treatment (ET) for dominant stenosis (DS) in patient with primary sclerosing cholangitis (PSC).

https://ift.tt/2MivMVc

Two simple magnetic resonance scores are able to predict survival in patients with Primary Sclerosing Cholangitis

Background: Primary sclerosing cholangitis (PSC) has a variable course. To predict clinical outcome in a single patient is a major need. Magnetic resonance (MR) imaging with 3D-MR cholangiography is the modality of choice for diagnosis. Two MR scores are able to predict radiologic progression of PSC.

https://ift.tt/2oYhcZL

Ageing-related expression of Twinfilin-1 regulates cholangiocyte biological response to injury

Background and Aims: Ageing is a complex biological process that affects the functional capacity of multiple organs and is associated to the development of many diseases. Disorders affecting the biliary tree develop and progress differently according to the patient age. The aim of the study was to identify molecular pathways associated to cholangiocytes ageing and to verify their effects in the biological response to injury of biliary epithelial cells.

https://ift.tt/2MlB9TH

Oncogenic MYD88 mutations in lymphoma: novel insights and therapeutic possibilities

Abstract

Oncogenic MYD88 mutations, most notably the Leu 265 Pro (L265P) mutation, were recently identified as potential driver mutations in various B-cell non-Hodgkin Lymphomas (NHLs). The L265P mutation is now thought to be common to virtually all NHLs and occurs in between 4 and 90% of cases, depending on the entity. Since it is tumor-specific, the mutation, and the pathways it regulates, might serve as advantageous therapeutic targets for both conventional chemotherapeutic intervention, as well as immunotherapeutic strategies. Here, we review recent progress on elucidating the molecular and cellular processes affected by the L265P mutation of MYD88, describe a new in vivo model for MyD88 L265P-mediated oncogenesis, and summarize how these findings could be exploited therapeutically by specific targeting of signaling pathways. In addition, we summarize current and explore future possibilities for conceivable immunotherapeutic approaches, such as L265P-derived peptide vaccination, adoptive transfer of L265P-restricted T cells, and use of T-cell receptor-engineered T cells. With clinical trials regarding their efficacy rapidly expanding to NHLs, we also discuss potential combinations of immune checkpoint inhibitors with the described targeted chemotherapies of L265P signaling networks, and/or with the above immunological approaches as potential ways of targeting MYD88-mutated lymphomas in the future.



https://ift.tt/2x2TGhH

Two Days in New York City

Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.


https://ift.tt/2QiWU9H

The subtleties of cognitive decline in multiple sclerosis: an exploratory study using hierarchichal cluster analysis of CANTAB results

It is essential to investigate cognitive deficits in multiple sclerosis (MS) to develop evidence-based cognitive rehabilitation strategies. Here we refined cognitive decline assessment using the automated test...

https://ift.tt/2wZKTx6

Could local surgery improve survival in de novo stage IV breast cancer?

Abstract

Background

Resection of the primary tumor is recommended for symptom relief in de novo stage IV breast cancer. We explored whether local surgery could provide a survival benefit in these patients and attempted to characterize the population that could benefit from surgery.

Methods

Metastatic Breast cancer patients (N = 313) with intact primary tumor between January 2006 and April 2013 were separated into two groups according to whether or not they had undergone surgery. The difference in characteristics between the two groups was analyzed using chi-square test, Fisher's exact test and Mann-Whitney test. Univariable and multivariable Cox regression and stratified survival analysis were used to assess the effect of surgery on survival.

Results

Of the 313 patients, 188 (60.1%) underwent local surgery. Patients with local surgery had a 47% reduction in mortality risk vs. those with no surgery (median survival 78 months vs. 37 months; HR = 0.53; 95% CI, 0.36–0.78) after adjustment for clinical and tumor characteristics. Stratified survival analysis showed that patients with bone metastasis alone (and primary tumor ≤5 cm), soft tissue metastasis, or ≤ 3 metastasis sites benefit from surgery.

Conclusion

Surgical resection of the primary tumor can improve survival in selected de novo stage IV breast cancer patients.



https://ift.tt/2x0yGco

Systems Genetics Approach to Biomarker Discovery: GPNMB and Heart Failure

We describe a simple bioinformatics method for biomarker discovery that is based on the analysis of global transcript levels in a population of inbred mouse strains showing variation for disease-related traits. This method has advantages such as controlled environment and accessibility to heart and plasma tissue in the preclinical selection stage. We illustrate the approach by identifying candidate heart failure (HF) biomarkers by overlaying mouse transcriptome and clinical traits from 91 Hybrid Mouse Diversity Panel (HMDP) inbred strains and human HF transcriptome from the Myocardial Applied Genomics Network (MAGNet) consortium. We found that some of the top differentially expressed genes correlated with known human HF biomarkers, such as galectin-3 and tissue inhibitor of metalloproteinase 1. Using ELISA assays, we investigated one novel candidate, Glycoprotein NMB, in a mouse model of chronic β-adrenergic stimulation by isoproterenol (ISO) induced HF. We observed significantly lower GPNMB plasma levels in the ISO model compared to the control group (p-value=0.007). In addition, we assessed GPNMB plasma levels among 389 HF cases and controls from the METabolic Syndrome In Men (METSIM) study. Lower levels of GPNMB were also observed in patients with HF from the METSIM study compared to non-HF controls (p-value<0.0001). In summary, we have identified several candidate biomarkers for HF using the cardiac transcriptome data in a population of mice that may be directly relevant and applicable to human populations.



https://ift.tt/2oXGbw7

T-Cell Clustering in Neoplastic Follicles of Follicular Lymphoma

Abstract

The nonneoplastic microenvironment is abundant in follicular lymphoma. Its composition has been reported to be associated with the course of the disease. Lack of animal models hampers studies of interaction between lymphoma and bystander cells. We aimed to identify indicators of cellular interaction exemplified by nonrandom distribution of cell types within neoplastic follicles. Physiological germinal centers and follicles in follicular lymphoma were stained to identify macrophages, all T, follicular T-helper, dendritic and B cells. Density of cell types and cell distribution (spatial point pattern) were analyzed by digital image analysis. The density of all T, follicular T-helper and dendritic cells was higher in the dark zone than in the light zone of physiological germinal centers. Densities of cell types in follicular lymphoma were intermediate between the light and the dark zone. All cell types analyzed showed a completely random spatial distribution pattern within the dark and the light zone, respectively. In follicular lymphoma B cells and macrophages displayed complete spatial randomness. In contrast, all T cells, follicular T-helper cells and dendritic cells showed clustering of each individual cell type within a radius of 6–10 μm in the lymphoma. We conclude that the distribution of nonneoplastic cells within follicles of follicular lymphoma is not random. T cells and dendritic cells form clusters within the follicles, suggestive of sites of interaction between microenvironment and lymphoma cells. These clusters might help to understand the interaction of lymphoma cells with the microenvironment and might provide a structure for therapeutic intervention.



https://ift.tt/2MkqckX

The effect of antibiotic stewardship interventions with stakeholder involvement in hospital settings: a multicentre, cluster randomized controlled intervention study

There is limited evidence from multicenter, randomized controlled studies to inform planning and implementation of antibiotic stewardship interventions in hospitals.

https://ift.tt/2CGgNEO

Cancer Stem cells, CD44 and outcomes following chemoradiation in locally advanced cervical cancer: Results from a prospective study

The prospective translational research study tested impact of stem cell and CD44 expression on disease outcomes in patients with locally advanced cervical cancer treated with chemoradiation. Moderate to high expression of stem cell proteins (SOX2/OCT4/Nanog) along with low expression of CD44 predicted for reduced loco-regional control. FIGO stage and response to external radiation continued to be predictors of disease free survival.

https://ift.tt/2NvvuyR

MR Imaging Evaluation of Hepatocellular Carcinoma Treated with Stereotactic Body Radiation Therapy (SBRT): Long Term Imaging Follow-Up

Persistent arterial phase hyperenhancement is a common finding post stereotactic body radiation for hepatocellular carcinoma and does not indicate viable neoplasm. Standard response assessment by mRECIST should be used with caution. Local progression is better defined by growth of >5 mm or new arterial phase hyperenhancement as post SBRT, most patients developed geographic delayed phase hyperenhancement.

https://ift.tt/2O5lxVL

Preoperative Intensity-Modulated Radiotherapy Compared To Three-Dimensional Conformal Radiotherapy For High-Grade Extremity Sarcomas In Children: Analysis of the Childrens Oncology Group Study Arst0332

We assessed differences in target coverage and dose to functional structures at risk in pediatric patients with extremity non-rhabomyosarcoma soft tissue sarcomas treated with preoperative radiotherapy using IMRT versus 3D-CRT. Preoperative IMRT was associated with improved target coverage and reduced volume of skin and nearby joint treated to higher doses, warranting further investigation to understand if acute wound complications and late musculoskeletal injury might be influenced by treatment technique.

https://ift.tt/2Nz1an1

EUS-guided cholecystostomy versus endoscopic transpapillary cholecystostomy for acute cholecystitis in high-risk surgical patients

Endoscopic gallbladder drainage (GBD) has been performed as an alternative to percutaneous drainage for acute cholecystitis. To date, there has been no comparative study between endoscopic ultrasound-guided cholecystostomy (EUSC) and endoscopic transpapillary cholecystostomy (ETC). The aim of this study was to compare the outcomes of EUSC and ETC.

https://ift.tt/2x0R1G3

A First-in-Human Study of Novel Cereblon Modulator Avadomide (CC-122) in Advanced Malignancies

Purpose: Avadomide is a novel, small molecule therapeutic agent that modulates cereblon E3 ligase activity and exhibits potent antitumor and immunomodulatory activities. This first-in-human phase I study (NCT01421524) evaluated the safety and clinical activity of avadomide in patients with advanced solid tumors, non-Hodgkin lymphoma (NHL), and multiple myeloma (MM) Experimental Design: Thirty-four patients were treated with avadomide in 7 dose escalation cohorts using a 3 + 3 design (0.5-3.5 mg, 28-day continuous dosing cycles). The primary objectives were to determine the dose-limiting toxicity (DLT), nontolerated dose (NTD), maximum tolerated dose (MTD), recommended phase II dose, and pharmacokinetics of avadomide. The secondary objective was to determine preliminary avadomide efficacy. Exploratory objectives included evaluation of pharmacodynamic effects of avadomide. Results: DLTs were reported in 2 patients, and grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 14 patients (41%).Themost common TEAEs(≥15%)were fatigue, neutropenia, and diarrhea. The NTD and MTD were 3.5 mg and 3.0 mg, respectively. Of 5 patients with NHL, 1 achieved a complete response, and 2 had partial responses. Although no objective responses were observed in patients with solid tumors, 5 of 6 patients with brain cancer experienced nonprogression of ≥6 months. A dose-dependent relationship between Aiolos degradation in peripheral B and T cells occurred within 5 hours of the first dose of avadomide administered, starting at 0.5 mg. Conclusions: Avadomide monotherapy demonstrated acceptable safety and favorable pharmacokinetics in patients with solid tumors, NHL, and MM. In addition, 3 objective responses were observed in NHL.



https://ift.tt/2N2zVBZ

Evaluation of Novel Prostate-Specific Membrane Antigen-Targeted Near-Infrared Imaging Agent for Fluorescence-Guided Surgery for Prostate Cancer

Purpose: The ability to locate and remove all malignant lesions during radical prostatectomy leads not only to prevent biochemical recurrence (BCR) and possible side effects but also to improve the life expectancy of prostate cancer (PCa) patient. Fluorescence-guided surgery (FGS) has emerged as a technique that uses fluorescence to highlight cancerous cells and guide surgeons to resect tumors in real-time. Thus, development of tumor-specific near-infrared (NIR) agents that target biomarkers solely expressed on PCa cells will enable to assess negative tumor margins and affected lymph nodes. Experimental Design: Since PSMA is overexpressed in PCa cells in > 90% of PCa patient population, a PSMA-targeted NIR agent (OTL78) was designed and synthesized. Optical properties, in vitro and in vivo specificity, tumor-to-background ratio (TBR), accomplishment of negative surgical tumor margins using FGS, pharmacokinetics (PK) properties, and preclinical toxicology of OTL78 were then evaluated in requisite models. Results: OTL78 binds to PSMA-expressing cells with high affinity, concentrates selectively to PSMA-positive cancer tissues, and clears rapidly from healthy tissues with a half-time of 17 min. It also exhibits an excellent TBR (5:1) as well as safety profile in animals. Conclusions: OTL78 is an excellent tumor-specific NIR agent for use in fluorescence-guided radical prostatectomy and FGS of other cancers.



https://ift.tt/2x5MQrK

Discovery and therapeutic exploitation of mechanisms of resistance to MET inhibitors in glioblastoma

Purpose: Glioblastoma (GBM) is the most common and most lethal primary malignant brain tumor. The receptor tyrosine kinase MET is frequently upregulated or over activated in GBM. Although clinically applicable MET inhibitors have been developed, resistance to single modality anti-MET drugs frequently occurs, rendering these agents ineffective. We aimed to determine the mechanisms of MET inhibitor resistance in GBM and use the acquired information to develop novel therapeutic approaches to overcome resistance. Experimental Design: We investigated two clinically applicable MET inhibitors: Crizotinib, an ATP-competitive small molecule inhibitor of MET, and Onartuzumab, a monovalent monoclonal antibody that binds to the extracellular domain of the MET receptor. We developed new MET inhibitor resistant cells lines and animal models and utilized reverse phase protein arrays (RPPA) and functional assays to uncover the compensatory pathways in MET inhibitor resistant GBM. Results: We identified critical proteins that were altered in MET inhibitor resistant GBM including mTOR, FGFR1, EGFR, STAT3 and COX-2. Simultaneous inhibition of MET and one of these upregulated proteins led to increased cell death and inhibition of cell proliferation in resistant cells compared to either agent alone. Additionally, in vivo treatment of mice bearing MET resistant orthotopic xenografts with COX-2 or FGFR pharmacological inhibitors in combination with MET inhibitor restored sensitivity to MET inhibition and significantly inhibited tumor growth. Conclusions:These data uncover the molecular basis of adaptive resistance to MET inhibitors and identifies new FDA-approved multi-drug therapeutic combinations that can overcome resistance.



https://ift.tt/2N5sbPi

Spatial architecture and arrangement of tumor-infiltrating lymphocytes for predicting likelihood of recurrence in early-stage non-small cell lung cancer

Purpose: Presence of a high degree of tumor-infiltrating lymphocytes (TILs) has proven to be associated with outcome in patients with non-small cell lung cancer (NSCLC). However, recent evidence indicate that tissue architecture is also prognostic of disease specific survival and recurrence. We show a set of descriptors (SpaTIL) that capture density and spatial co-localization of TILs and tumor cells across digital images can predict likelihood of recurrence in early-stage NSCLC. Experimental design: The association between recurrence in early-stage NSCLC and SpaTIL features was explored on 301 patients across four different cohorts. Cohort D1 (n=70)was used to identify the most prognostic SpaTIL features and to train a classifier to predict the likelihood of recurrence. The classifier performance was evaluated in cohorts D2 (n=119), D3 (n=112), and D4 (n=112). Two pathologists graded each sample of D1 and D2; intra-observer agreement and association between manual grading and likelihood of recurrence were analyzed. Results: SpaTIL was associated with likelihood of recurrence in all test sets (log rank p<0.02). A multivariate Cox Proportional Hazards analysis revealed a HR of 3.08 (95% confidence interval, 2.1-4.5, p=7.3x10-5). In contrast, agreement among expert pathologists using tumor grade was moderate (Kappa=0.5), and the manual TIL grading was only prognostic for one reader in D2 (p=8.0x10-3). Conclusion: A set of features related to density and spatial architecture of TILs was found to be associated with a likelihood of recurrence of early-stage NSCLC. This information could potentially be used for helping in treatment planning and management of early-stage NSCLC.



https://ift.tt/2x3vgEX

An EEG nicotinic acetylcholine index to assess the efficacy of pro-cognitive compounds

The cholinergic system is involved in cognitive processes such as attention, memory and learning (Jones et al., 1999, Terry et al., 2003, Levin et al., 2006, Nees, 2015) and it holds promise as a therapeutic target due to its role in the pathophysiology of neurodegenerative and psychiatric disorders (Court et al., 2000, Sacco et al., 2004, Parri et al., 2011). Hence, anti-cholinergic pharmacological challenges have been used to induce temporary cognitive disturbances mimicking Alzheimer's disease (AD), scopolamine being the most frequently used challenge drug.

https://ift.tt/2Nv4rnm

Nurse-Led Call After Discharge Doesn't Cut Peds Urgent Care

MONDAY, Sept. 10, 2018 -- A one-time nurse-led telephone call does not decrease the 30-day reutilization rate of urgent health care services in children discharged from the hospital, according to a study published in the Sept. 4 issue of JAMA:...

https://ift.tt/2x41wHN

Cortico-anorectal, Spino-anorectal, and Cortico-spinal Nerve Conduction and Locus of Neuronal Injury in Patients With Fecal Incontinence

The neuropathophysiology of fecal incontinence (FI) is incompletely understood. We examined the efferent brain-anorectal and spino-anorectal motor-evoked potentials (MEP) to characterize the locus of neuronal injury in patients with FI.

https://ift.tt/2CEkfje

Oxycontin's Maker Now Selling Drug to Curb Opioid Addiction

MONDAY, Sept. 10, 2018 -- Purdue Pharma, the maker of Oxycontin who some have blamed for the epidemic of opioid painkiller addictions, has patented a medicine aimed at curbing those disorders. The new anti-addiction drug is a fast-acting form of...

https://ift.tt/2QqcErE

Chronic Pain May Be Contributor to Suicide

MONDAY, Sept. 10, 2018 -- Chronic pain may be an important contributor to suicide, with 8.8 percent of suicide decedents having evidence of chronic pain, according to a study published online Sept. 11 in the Annals of Internal Medicine. Emiko...

https://ift.tt/2Qkpyak

Many Opportunities for Doctors Using Twitter

MONDAY, Sept. 10, 2018 -- Doctors can use Twitter to build networks and learn more about research in real time, according to a blog post published by Penn Medicine News. According to the report, finding an audience is a universal challenge, and...

https://ift.tt/2x3nN8T

FDA Approves New Treatment for Opioid Dependence

MONDAY, Sept. 10, 2018 -- Cassipa (buprenorphine and naloxone), a film designed to be placed under the tongue, has been approved to treat opioid dependence, the U.S. Food and Drug Administration said in a news release. Both buprenorphine and...

https://ift.tt/2QfKdfM

Efficacy and Safety of Induction Therapy With Calcineurin Inhibitors in Combination with Vedolizumab in Patients With Refractory Ulcerative Colitis

Vedolizumab is used to treat patients with ulcerative colitis (UC), although there is a delay before it is effective. Induction therapy with a calcineurin inhibitor (cyclosporine or tacrolimus) in combination with vedolizumab as maintenance therapy could be an option for patients with an active steroid-refractory UC. We assessed the efficacy and safety of this combination.

https://ift.tt/2oY5iz8

Association Between Plasma Level of Collagen Type III alpha 1 Chain and Development of Strictures in Pediatric Patients With Crohn’s Disease

There are few serum biomarkers to identify patients with Crohn's disease (CD) who are at risk for stricture development. The extracellular matrix components, collagen type III alpha 1 chain (COL3A1) and cartilage oligomeric matrix protein (COMP), could contribute to intestinal fibrosis. We investigated whether children with inflammatory CD (B1) who later develop strictures (B2) have increased plasma levels of COL3A1 or COMP at diagnosis, compared to children who remain B1. We compared results to previously studied biomarkers, including autoantibodies against colony stimulating factor 2 (CSF2).

https://ift.tt/2CEJe6k

Numbers and Features of Patients With a Diagnosis of Celiac Disease Without Duodenal Biopsy, Based on a National Survey

According to guidelines, individuals with symptoms of celiac disease should undergo duodenal biopsy analysis to establish a diagnosis, but little is known about physician adherence to these guidelines. We used a patient-powered research network (PPRN) to compare demographics, diagnoses, symptoms, and treatment between groups of patients with celiac disease diagnosed by biopsy analysis and patients with a diagnosis based on results of serology tests.

https://ift.tt/2oUyvdY

Clinical and molecular factors associated with histologic response to topical steroid treatment in patients with eosinophilic esophagitis

Few factors have been identified that can be used to predict response of patients with eosinophilic esophagitis (EoE) to topical steroid treatment. We aimed to determine whether baseline clinical, endoscopic, histologic, and molecular features of EoE can be used to predict histologic response.

https://ift.tt/2CIT1YQ

Incidence of Progression of Persistent Non-Dysplastic Barrett’s Esophagus to Malignancy

The risk of esophageal adenocarcinoma (EAC) in patients with non-dysplastic Barrett's esophagus (NDBE) is low, so there is debate over the role of ongoing surveillance for patients with NDBE. It is important to identify patients at low risk for progression. We assessed cancer risk based on the subsequent number of endoscopies showing persistence of NDBE in a nationwide study in the Netherlands.

https://ift.tt/2oY5cYi

Is Low-Level Viremia Acceptable in Hepatitis B-Infected Patients with Decompensation on Antiviral Therapy?



https://ift.tt/2CISQNa

Antitumour activity of pembrolizumab in advanced mucosal melanoma: a post-hoc analysis of KEYNOTE-001, 002, 006

Antitumour activity of pembrolizumab in advanced mucosal melanoma: a post-hoc analysis of KEYNOTE-001, 002, 006

Antitumour activity of pembrolizumab in advanced mucosal melanoma: a post-hoc analysis of KEYNOTE-001, 002, 006, Published online: 11 September 2018; doi:10.1038/s41416-018-0207-6

Antitumour activity of pembrolizumab in advanced mucosal melanoma: a post-hoc analysis of KEYNOTE-001, 002, 006

https://ift.tt/2x3qmZc

Excess body weight, weight gain and obesity-related cancer risk in women in Norway: the Norwegian Women and Cancer study

Excess body weight, weight gain and obesity-related cancer risk in women in Norway: the Norwegian Women and Cancer study

Excess body weight, weight gain and obesity-related cancer risk in women in Norway: the Norwegian Women and Cancer study, Published online: 11 September 2018; doi:10.1038/s41416-018-0240-5

Excess body weight, weight gain and obesity-related cancer risk in women in Norway: the Norwegian Women and Cancer study

https://ift.tt/2O6FTy7

Movement artefact removal from NIRS signal using multi-channel IMU data

The non-invasive nature of near-infrared spectroscopy (NIRS) makes it a widely accepted method for blood oxygenation measurement in various parts of the human body. One of the main challenges in this method li...

https://ift.tt/2x0T1xu

Next-Generation Evaluation and Treatment of Pediatric Acute Lymphoblastic Leukemia

Advancement in the diagnosis and treatment of pediatric acute lymphoblastic leukemia (ALL) is one of the greatest successes of modern medicine. Over the past 50 years, there has been a rapid increase in overall survival for pediatric ALL (Figure 1). Several factors have led to these remarkable improvements. First is the development of risk-adapted therapy based on both clinical and biological presenting features, as well as early response to treatment.2 Second, the effectiveness of molecularly targeted agents for specific genetic abnormalities has boosted outcomes for some high-risk groups.

https://ift.tt/2QlsPGI

Healthier Choices in School Cafeterias: A Systematic Review of Cafeteria Interventions

To describe school cafeteria interventions in terms of a behavioral economics scheme and to assess which system is more likely to be effective in improving food selection or consumption.

https://ift.tt/2x1v7BH

Cord Blood Metabolites Associated with Newborn Adiposity and Hyperinsulinemia

To evaluate the association between cord blood amino acid and acylcarnitine profiles and measures of adiposity and hyperinsulinemia in healthy newborns.

https://ift.tt/2Ql5sg9

Associations between patient clinical characteristics and the presence of cytomegalovirus DNA in the bronchoalveolar lavage fluid of children with recurrent wheezing

This study aimed to investigate the occurrence of Cytomegalovirus (CMV) DNA in the Bronchoalveolar lavage fluid (BALF) of children with recurrent wheezing and to identify associations with certain patient clin...

https://ift.tt/2oX6QcH

Upper respiratory infections in a rural area with reduced malaria transmission in Senegal: a pathogens community study

Acute Respiratory Infections (ARI) are common causes of febrile illnesses in many settings in Senegal. These infections are usually managed presumptively due to lack of appropriate diagnostic tools. This situa...

https://ift.tt/2O4rRwM

Contamination of microbial pathogens and their antimicrobial pattern in operating theatres of peri-urban eastern Uganda: a cross-sectional study

Microbial contamination of hospital environment, especially in operating theatres (OT) and other specialized units has greatly contributed to continuous and multiple exposure to nosocomial infections by patien...

https://ift.tt/2oU34AF

Predictors for false-negative QuantiFERON-TB Gold assay results in patients with extrapulmonary tuberculosis

Extrapulmonary tuberculosis (EPTB) is a heterogeneous disease, and diagnosis is sometimes difficult. We investigated the diagnostic performance of the QuantiFERON-TB Gold assay (QFT-GIT) according to sites of ...

https://ift.tt/2O4tL0A

Prevalence and risk factors of tungiasis among children of Wensho district, southern Ethiopia

Tungiasis is an ectoparasitic infestation, which still has public health importance in deprived populations of developing countries. Data on the prevalence and risk factors of tungiasis is rare in Ethiopia. He...

https://ift.tt/2oWd2Bx

Effects of positive end-expiratory pressure strategy in supine and prone position on lung and chest wall mechanics in acute respiratory distress syndrome

In acute respiratory distress syndrome (ARDS) patients, it has recently been proposed to set positive end-expiratory pressure (PEEP) by targeting end-expiratory transpulmonary pressure. This approach, which re...

https://ift.tt/2x4WOtk

Antitumour activity of pembrolizumab in advanced mucosal melanoma: a post-hoc analysis of KEYNOTE-001, 002, 006



https://ift.tt/2O6lc5o

Excess body weight, weight gain and obesity-related cancer risk in women in Norway: the Norwegian Women and Cancer study



https://ift.tt/2Nve59u


https://ift.tt/2wZZvNS

Pain, Opioids, and Suicide Mortality in the United States

The study by Petrosky and colleagues provides evidence of the sizable number of suicides that occur among persons with chronic pain. The editorialist believes that these findings underscore that suicide prevention should involve improving the availability of effective pain interventions that extend beyond opioids and should be supplemented with mental health treatments for persons with pain and depressive and anxiety-related symptoms.

https://ift.tt/2oUoJbU

Chronic Pain Among Suicide Decedents, 2003 to 2014: Findings From the National Violent Death Reporting System

Background:
More than 25 million adults in the United States have chronic pain. Chronic pain has been associated with suicidality, but previous studies primarily examined nonfatal suicidal behaviors rather than suicide deaths associated with chronic pain or the characteristics of such deaths.
Objective:
To estimate the prevalence of chronic pain among suicide decedents in a large multistate sample and to characterize suicide decedents with and without chronic pain.
Design:
Retrospective analysis of National Violent Death Reporting System (NVDRS) data. The NVDRS links death certificate, coroner or medical examiner, and law enforcement data collected by investigators, who often interview informants who knew the decedent to gather information on precipitating circumstances surrounding the suicide. Information is abstracted by using standard coding guidance developed by the Centers for Disease Control and Prevention.
Setting:
18 states participating in the NVDRS.
Participants:
Suicide decedents with and without chronic pain who died during 1 January 2003 to 31 December 2014.
Measurements:
Demographic characteristics, mechanism of death, toxicology results, precipitating circumstances (mental health, substance use, interpersonal problems, life stressors), and suicide planning and intent.
Results:
Of 123 181 suicide decedents included in the study, 10 789 (8.8%) had evidence of chronic pain, and the percentage increased from 7.4% in 2003 to 10.2% in 2014. More than half (53.6%) of suicide decedents with chronic pain died of firearm-related injuries and 16.2% by opioid overdose.
Limitation:
The results probably underrepresent the true percentage of suicide decedents who had chronic pain, given the nature of the data and how they were captured.
Conclusion:
Chronic pain may be an important contributor to suicide. Access to quality, comprehensive pain care and adherence to clinical guidelines may help improve pain management and patient safety.
Primary Funding Source:
None.

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Annals Understanding Clinical Research: Interpreting Results With Large P Values

Relying solely on P values to interpret study results is widely recognized as suboptimal, but it remains the dominant method of study interpretation in biomedicine. This tutorial discusses issues to consider and misinterpretations to avoid when encountering P values greater than 0.05.

https://ift.tt/2oVcFXW

A Student Reflection on Doctoring With Confidence: Mind the Gap

In this opinion piece, the author discusses ways in which the field of medicine can work to close the "confidence gap," the discrepancy in confidence between male and female physicians and trainees.

https://ift.tt/2xakqNB

Documented Pain Diagnoses in Adults Prescribed Opioids: Results From the National Ambulatory Medical Care Survey, 2006–2015



https://ift.tt/2oWQO2v

Why is the roof of my mouth swollen?

Many conditions may cause a swollen roof of the mouth, including sores, dehydration, and mucus buildups. In this article, learn about six causes of a swollen roof of the mouth, and possible treatment or home remedies. We also cover more serious conditions affecting the roof of the mouth and when to see a doctor.

https://ift.tt/2CP0eXE

High-throughput Measurement of Dictyostelium discoideum Macropinocytosis by Flow Cytometry

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Macropinocytosis, large-scale non-specific fluid uptake, is important in many areas of clinical biology including immunology, infection, cancer, and neurodegenerative diseases. Here, existing techniques have been adapted to allow high-throughput, single-cell resolution measurement of macropinocytosis in the macropinocytosis model organism Dictyostelium discoideum using flow cytometry.

https://ift.tt/2MiqqJp

Fabrication of Refractive-index-matched Devices for Biomedical Microfluidics

This protocol describes the fabrication of microfluidic devices from MY133-V2000 to eliminate artifacts that often arise in microchannels due to the mismatching refractive indices between microchannel structures and an aqueous solution. This protocol uses an acrylic holder to compress the encapsulated device, improving adhesion both chemically and mechanically.

https://ift.tt/2wYQXqs

CHARACTERIZATION OF INFLUENZA B VIRUS VARIANTS WITH REDUCED NEURAMINIDASE INHIBITOR SUSCEPTIBILITY [Antiviral Agents]

Treatment options for influenza B virus infections are limited to neuraminidase inhibitors (NAIs) which block the neuraminidase (NA) glycoprotein on the virion surface. The development of NAI resistance would therefore result in a loss of antiviral treatment options for influenza B infections. This study characterized two contemporary influenza B viruses with known resistance-conferring NA amino acid substitutions, D197N and H273Y, detected during routine surveillance. The D197N and H273Y variants were characterized in vitro by assessing NA enzyme activity and affinity, as well as replication in cell culture compared to NAI-sensitive wild-type viruses. In vivo studies were also performed in ferrets to assess the replication and transmissibility of each variant. Mathematical models were used to analyse within-host and between-host fitness of variants relative to wild-type viruses. The data revealed that the H273Y variant had similar NA enzyme function relative to its wild-type but had slightly reduced replication and transmission efficiency in vivo. The D197N variant had impaired NA enzyme function but there was no evidence of reduction in replication or transmission efficiency in ferrets. Our data suggest that the influenza B variant with H273Y NA substitution had a more notable reduction in fitness compared to wild-type viruses than the influenza B variant with the D197N NA substitution. Although a D197N variant is yet to become widespread, it is the most commonly detected NAI-resistant influenza B virus in surveillance studies. Our results highlight the need to carefully monitor circulating viruses for the spread of influenza B viruses with the D197N NA substitution.



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Population Pharmacokinetics of Tafenoquine, a Novel Anti-Malarial [Experimental Therapeutics]

Tafenoquine is a novel 8-aminoquinoline anti-malarial drug recently approved by US Food and Drug Administration (FDA) for the radical cure of acute P. vivax malaria – first new treatment in almost 60 years. Population pharmacokinetic (POP PK) analysis was conducted with tafenoquine exposure data following oral administration from 6 clinical studies in Phase 1 through Phase 3 with a nonlinear mixed effects modelling approach. The impact of patient demographics, baseline characteristics and extrinsic factors such as formulation were evaluated. Model performance was assessed using techniques such as bootstrapping, visual predictive checks and external data validation from a Phase 3 study not used in model fitting and parameter estimation. Based on the analysis, the systemic PK of tafenoquine was adequately described using a two-compartment model. The final POP PK model included body weight (allometric scaling) on apparent oral and intercompartmental clearance (CL/F, Q/F respectively), apparent volume of distribution for central and peripheral compartments (V2/F, V3/F respectively), formulation on systemic bioavailability (F1), absorption rate (KA) and health status on apparent volume of distribution. The key tafenoquine population parameters estimates were 2.96 L/hr for CL/F and 915 L for V2/F in P. vivax malaria infected subjects. Additionally, the analyses demonstrated no clinically relevant difference in relative bioavailability across the capsule and tablet formulations administered in these clinical studies. In conclusion, a POP PK model for tafenoquine was developed. Clinical trial simulations based on this model supported bridging the exposures across two different formulations. This POP PK model can be applied to aid and perform clinical trial simulations in other scenarios and populations such as pediatrics.



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Chloroquine analogues as leads against Pneumocystis lung pathogens [Susceptibility]

The impact of Pneumocystis pneumonia (PcP) on morbidity and mortality remains substantial for immunocompromised individuals, including those afflicted by HIV infection, organ transplantation, cancer, auto-immune diseases, or subject to chemotherapy or corticosteroid-based therapies. Previous work from our group has shown that repurposing antimalarial compounds for PcP holds promise for treatment of this opportunistic infection. Following our previous discovery of chloroquine analogues with dual-stage antimalarial action both in vitro and in vivo, we now report the potent action of these compounds on Pneumocystis carinii, in vitro. Identification of chloroquine analogues as anti-PcP leads is an unprecedented finding.



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Isavuconazole for treatment of experimental fungal endophthalmitis caused by Aspergillus fumigatus [Experimental Therapeutics]

Fungal endophthalmitis remains a significant cause of vision impairment and blindness. Moreover, the prognosis is poor, in part, due to delay in diagnosis and limited availability of effective antifungal agents with good ocular penetration. Thus, it is imperative to evaluate the therapeutic efficacy of newer antifungal agents in fungal endophthalmitis. In this study, we assessed the efficacy of isavuconazole in treating Aspergillus fumigatus (AF) endophthalmitis in an exogenous mouse model of the disease. Briefly, endophthalmitis was induced by intravitreal (IVT) injection of AF spores in immunocompetent C57BL/6 (B6) mouse eyes. Mice were randomized into five groups receiving isavuconazole via (1) oral gavage, (2) IVT injections, (3) intravenous, (4) IVT injection followed by oral gavage, and (5) IVT injection followed by intravenous. Our data showed that isavuconazole treatment via all routes reduced fungal burden in AF-infected eyes. This coincided with the preservation of retinal structural integrity (histology analysis) and retinal function (electroretinogram, ERG analysis), resulting in significantly improved disease outcome. Furthermore, isavuconazole treatment reduced the levels of inflammatory cytokines (TNF-α, IL-1β, IL-6) and cellular infiltration in the eyes. Notably, oral administration of isavuconazole was as effective in ameliorating endophthalmitis as intravitreal injection of the drug. Collectively, our study demonstrates that isavuconazole is effective in treating AF endophthalmitis in mice, indicating its potential use in human ocular infections.



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Identification of FDA-approved drugs as antivirulence agents targeting the pqs quorum sensing system of Pseudomonas aeruginosa [Mechanisms of Action]

The long-term use of antibiotics has led to the emergence of multi-drug-resistant bacteria. A promising strategy to combat bacterial infections aims at hampering their adaptability to the host environment without affecting growth. In this context, the intercellular communication system quorum sensing (QS), which controls virulence factor production and biofilm formation in diverse human pathogens, is considered an ideal target.

Here we describe the identification of new inhibitors of the pqs QS system of the human pathogen Pseudomonas aeruginosa, by screening a library of 1,600 FDA-approved drugs. Phenotypic characterization of ad hoc engineered strains and in silico molecular docking demonstrated that the antifungal drugs clotrimazole and miconazole, and an antibacterial compound active against Gram-positive pathogens, clofoctol, inhibit the pqs system, probably by targeting the transcriptional regulator PqsR. The most active inhibitor, clofoctol, specifically inhibited the expression of pqs-controlled virulence traits in P. aeruginosa, such as pyocyanin production, swarming motility, biofilm formation, and expression of genes involved in siderophore production. Moreover, clofoctol protected Galleria mellonella larvae from P. aeruginosa infection and inhibited the pqs QS system in P. aeruginosa isolates from cystic fibrosis patients. Notably, clofoctol is already approved for clinical treatment of pulmonary infections caused by Gram-positive bacterial pathogens, hence this drug has considerable clinical potential as an antivirulence agent for the treatment of P. aeruginosa lung infections.



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Novel self-assembled micelles based on cholesterol-modified antimicrobial peptide (DP7) for safe and effective systemic administration in bacteria-infected animal models [Experimental Therapeutics]

Owing to their broad-spectrum antibacterial properties, multi-target effects and low drug resistance, antimicrobial peptides (AMPs) have played critical roles in the clinical therapy of drug-resistant bacterial infections. However, the potential hazard of haemolysis following systemic administration has greatly limited their application. Here, we developed a novel AMP derivative, DP7-C, by modifying a formerly identified highly active AMP with cholesterol to form an amphiphilic conjugate. The prepared DP7-C easily self-assembled into stable nanomicelles in aqueous solution. Compared to unconjugated counterparts, the DP7-C micelles showed lower haemolytic activity toward human red blood cells and a maximum tolerated dose of 80 mg/kg in mice via intravenous injection, thus demonstrating improved safety. Moreover, by eliciting specific immunomodulatory activities in immune cells, the DP7-C micelles exerted distinct therapeutic effects in zebrafish and mouse infectious models. In conclusion, DP7-C micelles may be an excellent candidate for treatment of bacterial infections in the clinic.



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Expression of Pseudomonas aeruginosa antibiotic resistance genes varies greatly during infections in cystic fibrosis patients [Mechanisms of Resistance]

The lungs of individuals with cystic fibrosis (CF) become chronically infected with Pseudomonas aeruginosa that is difficult to eradicate by antibiotic treatment. Two key P. aeruginosa antibiotic resistance mechanisms are the AmpC β-lactamase that degrades β-lactam antibiotics and MexXYOprM, a three-protein efflux pump that expels aminoglycoside antibiotics from the bacterial cells. Levels of antibiotic resistance gene expression are likely to be a key factor in antibiotic resistance but have not been determined during infection. The aims of this research were to investigate expression of the ampC and mexX genes during infection in patients with CF and in bacteria isolated from the same patients. P. aeruginosa isolates from 36 CF patients were grown in laboratory culture and gene expression measured by reverse transcription quantitative PCR (RT-qPCR). Expression of ampC varied over 20,000-fold and that of mexX over 2000-fold between isolates. Expression levels of both genes were on average increased by the presence of sub-inhibitory concentrations of antibiotics. To measure P. aeruginosa gene expression during infection, we carried out RT-qPCR using RNA extracted from fresh sputum samples obtained from 31 patients. Expression of ampC varied over 4000-fold, while mexX expression varied over 100-fold, between patients. Despite these wide variations, median levels of expression of ampC in sputum were similar to those in laboratory-grown bacteria. Expression of mexX was higher in sputum than in laboratory-grown bacteria. Overall, our data demonstrate that genes that contribute to antibiotic resistance can be highly expressed in patients but there is extensive isolate-to-isolate and patient-to-patient variation.



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Application of CRISPR/Cas9 technologies combined with iPSCs in the study and treatment of retinal degenerative diseases

Abstract

Retinal degeneration diseases, such as age-related macular degeneration and retinitis pigmentosa, affect millions of people worldwide and are major causes of irreversible blindness. Effective treatments for retinal degeneration, including drug therapy, gene augmentation or transplantation approaches, have been widely investigated. Nevertheless, more research should be dedicated to therapeutic methods to improve future clinical treatments. Recently, with the rapid development of genome-editing technology, gene therapy has become a potentially effective treatment for retinal degeneration diseases. A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system has been developed as a powerful genome-editing tool in ophthalmic studies. The CRISPR/Cas9 system has been widely applied in basic research to develop animal models and gene therapies in vivo. With the ability to self-renew and the potential to differentiate into different types of cells, induced pluripotent stem cells (iPSCs) have already been used as a promising tool for understanding disease pathophysiology and evaluating the effect of drug and gene therapeutics. iPSCs are also a cell source for autologous transplantation. In this review, we compared genome-editing strategies and highlighted the advantages and concerns of the CRISPR/Cas9 system. Moreover, the latest progress and applications of the CRISPR/Cas9 system and its combination with iPSCs for the treatment of retinal degenerative diseases are summarized.



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Loss of Biodiversity Dimensions through Shifting Climates and Ancient Mass Extinctions

Abstract
Many aspects of climate affect the deployment of biodiversity in time and space, and so changes in climate might be expected to drive regional and global extinction of both taxa and their ecological functions. Here we examine the association of past climate changes with extinction in marine bivalves, which are increasingly used as a model system for macroecological and macroevolutionary analysis. Focusing on the Cenozoic Era (66 Myr ago to the present), we analyze extinction patterns in shallow-water marine bivalve genera relative to temperature dynamics as estimated from isotopic data in microfossils. When the entire Cenozoic timeseries is considered, extinction intensity is not significantly associated with the mean temperature or the detrended variance in temperature within a given time interval (stratigraphic stage). However, extinction increases significantly with both the rate of temperature change within the stage of extinction and the absolute change in mean temperature from the preceding stage to the stage of extinction. Thus, several extinction events, particularly the extinction pulse near the Pliocene–Pleistocene boundary, do appear to have climatic drivers. Further, the latitudinal diversity gradient today and the Cenozoic history of polar faunas suggest that long-term, regional extinctions associated with cooling removed not just taxa but a variety of ecological functions from high-latitude seas. These dynamics of biodiversity loss contrast with the two mass extinctions bracketing the Mesozoic Era, which had negligible effects on the diversity of ecological functions despite removing nearly as many taxa as the latitudinal gradient does today. Thus, the fossil record raises a key issue: whether the biotic consequences of present-day stresses will more closely resemble the long-term effects of past climate changes or those that cascaded from the mass extinctions.

https://ift.tt/2oTifds

Where Animation and Science Meet

Synopsis
Animation is the collision of art and science. How does an animation studio like DreamWorks Animation use scientific principles and engage in science education to make our films better? By facilitating scientific master-classes, demos, and lectures we give our creators a fundamental understanding of reality that enables them to create the animation caricature known as the Illusion of Life. We leverage principles of biology and physics to create believable performances. I will share insights about our custom programming such as master-classes on Quadruped Anatomy and Flight and how these result in a better image on screen. Conversely, animators offer storytelling tools to the scientific community. Animators often use visualization tools similar to those that many scientists use, but in differing narrative orders and with budgets often far exceeding those of scientists. I will highlight strategies of presentation enhancing understanding and increasing the speed of building bridges to share information with the public. This can help scientists leverage their own scientific principles as they present the importance and excitement of their work to the public, as well as to one another.

https://ift.tt/2CHAfBn

In Vitro Differentiation of Mouse Granulocyte-macrophage-colony-stimulating Factor (GM-CSF)-producing T Helper (THGM) Cells

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Here, we present a protocol to differentiate murine granulocyte-macrophage-colony-stimulating-factor-producing T helper (THGM) cells from naive CD4+ T cells, including isolation of naive CD4+ T cells, differentiation of THGM, and analysis of differentiated THGM cells. This method can be applied to studies of the regulation and function of THGM cells.

https://ift.tt/2wZVoRJ

Comprehensive Evaluation of the Effectiveness and Safety of Placenta-Targeted Drug Delivery Using Three Complementary Methods

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We describe a system that utilizes three methods to evaluate the safety and effectiveness of placenta-targeted drug delivery: in vivo imaging to monitor nanoparticle accumulation, high-frequency ultrasound to monitor placental and fetal development, and HPLC to quantify drug delivery to tissue.

https://ift.tt/2x49G2S

Operant Protocols for Assessing the Cost-benefit Analysis During Reinforced Decision Making by Rodents

A cost-benefit analysis is a weighing-scale approach that the brain performs during the course of decision making. Here, we propose a protocol to train rats on an operant-based decision-making paradigm where rats choose higher rewards at the expense of waiting for 15 s to receive them.

https://ift.tt/2x2FB4C

You Probably Made a Better First Impression Than You Think

After we have conversations with new people, our conversation partners like us and enjoy our company more than we think, according to findings published in Psychological Science, a journal of the Association for Psychological Science.

In our social lives, we're constantly engaged in what researchers call "meta-perception," or trying to figure out how other people see us. Do people think we're boring or interesting, selfish or altruistic, attractive or not?

"Our research suggests that accurately estimating how much a new conversation partner likes us—even though this a fundamental part of social life and something we have ample practice with—is a much more difficult task than we imagine," explain first authors Erica Boothby, a postdoctoral researcher at Cornell University, and Gus Cooney, a postdoctoral researcher at Harvard University.

"We call this a 'liking gap,' and it can hinder our ability to develop new relationships," study coauthor Margaret S. Clark, the John M. Musser Professor of Psychology at Yale University, told Yale News.

Boothby, Cooney, Clark, and Gillian M. Sandstrom, Professor of Psychology at the University of Essex, examined various aspects of the liking gap in a series of five studies.

In one study, the researchers paired participants who had not met before and tasked them with having a 5-minute conversation featuring typical icebreaker questions (e.g., Where are you from? What are your hobbies?). At the end of the conversation, the participants answered questions that gauged how much they liked their conversation partner and how much they thought their conversation partner liked them.

On average, the ratings showed that participants liked their partner more than they thought their partner liked them. Since it can't logically be the case that both people in a conversation like their partner more than their partner likes them, this disparity in average ratings suggests that participants tended to make an estimation error. Indeed, analyses of video recordings suggested that participants were not accounting for their partner's behavioral signals indicating interest and enjoyment.

In a separate study, participants reflected on the conversations they'd just had — according to their ratings, they believed that the salient moments that shaped their partner's thoughts about them were more negative than the moments that shaped their own thoughts about their partner.

"They seem to be too wrapped up in their own worries about what they should say or did say to see signals of others' liking for them, which observers of the conservations see right away," Clark noted.

Additional studies showed that the liking gap emerged regardless of whether people had longer conversations or had conversations in real-world settings. And a study of actual college roommates showed that the liking gap was far from fleeting, enduring over several months.

The phenomenon is interesting because it stands in contrast with the well-established finding that we generally view ourselves more positively than we do others, whether we're thinking about our driving skills, our intelligence, or our chance of experiencing negative outcomes like illness or divorce.

"The liking gap works very differently. When it comes to social interaction and conversation, people are often hesitant, uncertain about the impression they're leaving on others, and overly critical of their own performance," say Boothby and Cooney. "In light of people's vast optimism in other domains, people's pessimism about their conversations is surprising."

The researchers hypothesize that this difference may come down to the context in which we make these self-assessments. When there is another person involved, such as a conversation partner, we may be more cautious and self-critical than in situations when we are rating our own qualities with no other source of input.

"We're self-protectively pessimistic and do not want to assume the other likes us before we find out if that's really true," Clark said.

This self-monitoring may prevent us from pursuing relationships with others who truly do like us.

"As we ease into new neighborhood, build new friendships, or try to impress new colleagues, we need to know what other people think of us," Boothby and Cooney explain. "Any systematic errors we make might have a big impact on our personal and professional lives."

This work was supported by the Templeton Foundation and the Economic and Social Research Council (United Kingdom).

All data have been made publicly available via the Open Science Framework. The complete Open Practices Disclosure for this article is available online. This article has received the badge for Open Data.



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