Medicine by Alexandros G.Sfakianakis: 09/05/17

Τρίτη 5 Σεπτεμβρίου 2017

Local relapse of nasopharyngeal cancer and Voxel-based analysis of FMISO uptake using PET with semiconductor detectors

Abstract

Background

Hypoxic cancer cells are thought to be radioresistant and could impact local recurrence after radiotherapy (RT). One of the major hypoxic imaging modalities is [¹⁸F]fluoromisonidazole positron emission tomography (FMISO-PET). High FMISO uptake before RT could indicate radioresistant sites and might be associated with future local recurrence. The predictive value of FMISO-PET for intra-tumoral recurrence regions was evaluated using high-resolution semiconductor detectors in patients with nasopharyngeal carcinoma after intensity-modulated radiotherapy (IMRT).

Methods

Nine patients with local recurrence and 12 patients without local recurrence for more than 3 years were included in this study. These patients received homogeneous and standard doses of radiation to the primary tumor irrespective of FMISO uptake. The FMISO-PET image before RT was examined via a voxel-based analysis, which focused on the relationship between the degree of FMISO uptake and recurrence region.

Results

In the pretreatment FMISO-PET images, the tumor-to-muscle ratio (TMR) of FMISO in the voxels of the tumor recurrence region was significantly higher than that of the non-recurrence region (p < 0.0001). In the recurrent patient group, a TMR value of 1.37 (95% CI: 1.36–1.39) corresponded to a recurrence rate of 30%, the odds ratio was 5.18 (4.87–5.51), and the area under the curve (AUC) of the receiver operating characteristic curve was 0.613. In all 21 patients, a TMR value of 2.42 (2.36–2.49) corresponded to an estimated recurrence rate of 30%, and the AUC was only 0.591.

Conclusions

The uptake of FMISO in the recurrent region was significantly higher than that in the non-recurrent region. However, the predictive value of FMISO-PET before IMRT is not sufficient for up-front dose escalation for the intra-tumoral high-uptake region of FMISO. Because of the higher mean TMR of the recurrence region, a new hypoxic imaging method is needed to improve the sensitivity and specificity for hypoxia.

http://ift.tt/2wENuO2

Clinical grade manufacturing of genetically modified, CAR-expressing NK-92 cells for the treatment of ErbB2-positive malignancies

Abstract

Background

The NK-92/5.28.z cell line (also referred to as HER2.taNK) represents a stable, lentiviral-transduced clone of ErbB2 (HER2)-specific, second-generation CAR-expressing derivative of clinically applicable NK-92 cells. This study addresses manufacturing-related issues and aimed to develop a GMP-compliant protocol for the generation of NK-92/5.28.z therapeutic doses starting from a well-characterized GMP-compliant master cell bank.

Materials and methods

Commercially available GMP-grade culture media and supplements (fresh frozen plasma, platelet lysate) were evaluated for their ability to support expansion of NK-92/5.28.z. Irradiation sensitivity and cytokine release were also investigated.

Results

NK-92/5.28.z cells can be grown to clinically applicable cell doses of 5 × 10⁸ cells/L in a 5-day batch culture without loss of viability and potency. X-Vivo 10 containing recombinant transferrin supplemented with 5% FFP and 500 IU/mL IL-2 in VueLife 750-C1 bags showed the best results. Platelet lysate was less suited to support NK-92/5.28.z proliferation. Irradiation with 10 Gy completely abrogated NK-92/5.28.z proliferation and preserved viability and potency for at least 24 h. NK-92/5.28.z showed higher baseline cytokine release compared to NK-92, which was significantly increased upon encountering ErbB2(+) targets [GZMB (twofold), IFN-γ (fourfold), IL-8 (24-fold) and IL-10 (fivefold)]. IL-6 was not released by NK cells, but was observed in some stimulated targets. Irradiation resulted in upregulation of IL-8 and downregulation of sFasL, while other cytokines were not impacted.

Conclusion

Our concept suggests NK-92/5.28.z maintenance culture from which therapeutic doses up to 5 × 10⁹ cells can be expanded in 10 L within 5 days. This established process is feasible to analyze NK-92/5.28.z in phase I/II trials.

http://ift.tt/2xNNgmi

High mobility group box 1 enhances hyperthermia-induced seizures and secondary epilepsy associated with prolonged hyperthermia-induced seizures in developing rats

Abstract

Levels of high mobility group box 1 (HMGB1), an important inflammatory mediator, are high in the serum of febrile seizure (FS) patients. However, its roles in FS and secondary epilepsy after prolonged FS are poorly understood. We demonstrate HMGB1's role in the pathogenesis of hyperthermia-induced seizures (HS) and secondary epilepsy after prolonged hyperthermia-induced seizures (pHS). In the first experiment, 14–15-day-old male rats were divided into four groups: high-dose HMGB1 (100 μg), moderate-dose (10 μg), low-dose (1 μg), and control. Each rat was administered HMGB1 intranasally 1 h before inducing HS. Temperature was measured at seizure onset with electroencephalography (EEG). In the second experiment, 10–11-day-old rats were divided into four groups: pHS + HMGB1 (10 μg), pHS, HMGB1, and control. HMGB1 was administered 24 h after pHS. Video-EEGs were recorded for 24 h at 90 and 120 days old; histological analysis was performed at 150 days old. In the first experiment, the temperature at seizure onset was significantly lower in the high- and moderate-dose HMGB1 groups than in the control group. In the second experiment, the incidence of spontaneous epileptic seizure was significantly higher in the pHS + HMGB1 group than in the other groups. Comparison between pHS + HMGB1 groups with and without epilepsy revealed that epileptic rats had significantly enhanced astrocytosis in the hippocampus and corpus callosum. In developing rats, HMGB1 enhanced HS and secondary epilepsy after pHS. Our findings suggest that HMGB1 contributes to FS pathogenesis and plays an important role in the acquired epileptogenesis of secondary epilepsy associated with prolonged FS.

http://ift.tt/2x9XOPu

Second opinion strategies in breast pathology: a decision analysis addressing over-treatment, under-treatment, and care costs

Abstract

Purpose

To estimate the potential near-term population impact of alternative second opinion breast biopsy pathology interpretation strategies.

Methods

Decision analysis examining 12-month outcomes of breast biopsy for nine breast pathology interpretation strategies in the U.S. health system. Diagnoses of 115 practicing pathologists in the Breast Pathology Study were compared to reference-standard-consensus diagnoses with and without second opinions. Interpretation strategies were defined by whether a second opinion was sought universally or selectively (e.g., 2nd opinion if invasive). Main outcomes were the expected proportion of concordant breast biopsy diagnoses, the proportion involving over- or under-interpretation, and cost of care in U.S. dollars within one-year of biopsy.

Results

Without a second opinion, 92.2% of biopsies received a concordant diagnosis. Concordance rates increased under all second opinion strategies, and the rate was highest (95.1%) and under-treatment lowest (2.6%) when all biopsies had second opinions. However, over-treatment was lowest when second opinions were sought selectively for initial diagnoses of invasive cancer, DCIS, or atypia (1.8 vs. 4.7% with no 2nd opinions). This strategy also had the lowest projected 12-month care costs ($5.907 billion vs. $6.049 billion with no 2nd opinions).

Conclusions

Second opinion strategies could lower overall care costs while reducing both over- and under-treatment. The most accurate cost-saving strategy required second opinions for initial diagnoses of invasive cancer, DCIS, or atypia.

http://ift.tt/2wESzpB

Disease-stabilizing treatment based on all-trans retinoic acid and valproic acid in acute myeloid leukemia – identification of responders by gene expression profiling of pretreatment leukemic cells

Abstract

Background

Acute myeloid leukemia (AML) is an aggressive malignancy only cured by intensive therapy. However, many elderly and unfit patients cannot receive such treatment due to an unacceptable risk of treatment-related morbidity and mortality. Disease-stabilizing therapy is then the only possible strategy, one alternative being treatment based on all-trans retinoic acid (ATRA) combined with the histone deacetylase inhibitor valproic acid and possibly low-toxicity conventional chemotherapy.

Methods

Primary AML cells were derived from 43 patients included in two clinical studies of treatment based on ATRA, valproic acid and theophyllamine; low toxicity chemotherapy (low-dose cytarabine, hydroxyurea, 6-mercaptopurin) was also allowed. Pretreatment leukemic cells were analyzed by mutation profiling of 54 genes frequently mutated in myeloid malignancies and by global gene expression profiling before and during in vivo treatment.

Results

Patients were classified as responders and non-responders to the treatment, however response to treatment showed no significant associations with karyotype or mutational profiles. Significance analysis of microarray (SAM) showed that responders and non-responders significantly differed with regard to the expression of 179 different genes. The differentially expressed genes encoding proteins with a known function were further classified based on the PANTHER (protein annotation through evolutionary relationship) classification system. The identified genes encoded proteins that are involved in several important biological functions, but a main subset of the genes were important for transcriptional regulation. These pretherapy differences in gene expression were largely maintained during treatment. Our analyses of primary AML cells during in vivo treatment suggest that ATRA modulates HOX activity (i.e. decreased expression of HOXA3, HOXA4 and HOXA5 and their regulator PBX3), but altered function of DNA methyl transferase 3A (DNMT3A) and G-protein coupled receptor signaling may also contribute to the effect of the overall treatment.

Conclusions

Responders and non-responders to AML stabilizing treatment based on ATRA and valproic acid differ in the pretreatment transcriptional regulation of their leukemic cells, and these differences may be important for the clinical effect of this treatment.

Trial registrations

ClinicalTrials.gov no. NCT00175812; EudraCT no. 2004–001663-22, registered September 9, 2005 and ClinicalTrials.gov no. NCT00995332; EudraCT no. 2007–2007–001995-36, registered October 14, 2009.

http://ift.tt/2eJPxtQ

Application of the thermostable β-galactosidase, BgaB, from Geobacillus stearothermophilus as a versatile reporter under anaerobic and aerobic conditions

Use of thermophilic organisms has a range of advantages, but the significant lack of engineering tools limits their applications. Here we show that β-galactosidase from Geobacillus stearothermophilus (BgaB) can b...

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Effectiveness and cost-effectiveness of a cardiovascular risk prediction algorithm for people with severe mental illness (PRIMROSE)

Objectives

To determine the cost-effectiveness of two bespoke severe mental illness (SMI)-specific risk algorithms compared with standard risk algorithms for primary cardiovascular disease (CVD) prevention in those with SMI.

Setting

Primary care setting in the UK. The analysis was from the National Health Service perspective.

Participants

1000 individuals with SMI from The Health Improvement Network Database, aged 30–74 years and without existing CVD, populated the model.

Interventions

Four cardiovascular risk algorithms were assessed: (1) general population lipid, (2) general population body mass index (BMI), (3) SMI-specific lipid and (4) SMI-specific BMI, compared against no algorithm. At baseline, each cardiovascular risk algorithm was applied and those considered high risk (> 10%) were assumed to be prescribed statin therapy while others received usual care.

Primary and secondary outcome measures

Quality-adjusted life years (QALYs) and costs were accrued for each algorithm including no algorithm, and cost-effectiveness was calculated using the net monetary benefit (NMB) approach. Deterministic and probabilistic sensitivity analyses were performed to test assumptions made and uncertainty around parameter estimates.

Results

The SMI-specific BMI algorithm had the highest NMB resulting in 15 additional QALYs and a cost saving of approximately £53 000 per 1000 patients with SMI over 10 years, followed by the general population lipid algorithm (13 additional QALYs and a cost saving of £46 000).

Conclusions

The general population lipid and SMI-specific BMI algorithms performed equally well. The ease and acceptability of use of an SMI-specific BMI algorithm (blood tests not required) makes it an attractive algorithm to implement in clinical settings.

http://ift.tt/2f2GqSd

Influence of hospital volume on nephrectomy mortality and complications: a systematic review and meta-analysis stratified by surgical type

Objectives

The provision of complex surgery is increasingly centralised to high-volume (HV) specialist hospitals. Evidence to support nephrectomy centralisation however has been inconsistent. We conducted a systematic review and meta-analysis to determine the association between hospital case volumes and perioperative outcomes in radical nephrectomy, partial nephrectomy and nephrectomy with venous thrombectomy.

Methods

Medline, Embase and the Cochrane Library were searched for relevant studies published between 1990 and 2016. Pooled effect estimates for nephrectomy mortality and complications were calculated for each nephrectomy type using the DerSimonian and Laird random-effects model. Sensitivity analyses were performed to examine the effects of heterogeneity on the pooled effect estimates by excluding studies with the heaviest weighting, lowest methodological score and most likely to introduce bias from misclassification of standardised hospital volume.

Results

Some 226 372 patients from 16 publications were included in our review and meta-analysis. Considerable between-study heterogeneity was noted and only a few reported volume–outcome relationships specifically in partial nephrectomy or nephrectomy with venous thrombectomy.

HV hospitals were correlated with a 26% and 52% reduction in mortality for radical nephrectomy (OR 0.74, 95% CI 0.61 to 0.90, p<0.01) and nephrectomy with venous thrombectomy (OR 0.48, 95% CI 0.29 to 0.81, p<0.01), respectively. In addition, radical nephrectomy in HV hospitals was associated with an 18% reduction in complications (OR 0.82, 95% CI 0.73 to 0.92, p<0.01). No significant volume–outcome relationship in mortality (OR 0.84, 95% CI 0.31 to 2.26, p=0.73) or complications (OR 0.85, 95% CI 0.55 to 1.30, p=0.44) was observed for partial nephrectomy.

Conclusions

Our findings suggest that patients undergoing radical nephrectomy have improved outcomes when treated by HV hospitals. Evidence of this in partial nephrectomy and nephrectomy with venous thrombectomy is however not yet clear and could be secondary to the low number of studies included and the small patient number in our analyses. Further investigation is warranted to establish the full potential of nephrectomy centralisation particularly as existing evidence is of low quality with significant heterogeneity.

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Qualitative study to develop processes and tools for the assessment and tracking of African institutions capacity for operational health research

Objectives

Research is key to achieving global development goals. Our objectives were to develop and test an evidence-informed process for assessing health research management and support systems (RMSS) in four African universities and for tracking interventions to address capacity gaps.

Setting

Four African universities.

Participants

83 university staff and students from 11 cadres.

Intervention/methods

A literature-informed 'benchmark' was developed and used to itemise all components of a university's health RMSS. Data on all components were collected during site visits to four African universities using interview guides, document reviews and facilities observation guides. Gaps in RMSS capacity were identified against the benchmark and institutional action plans developed to remedy gaps. Progress against indicators was tracked over 15 months and common challenges and successes identified.

Results

Common gaps in operational health research capacity included no accessible research strategy, a lack of research e-tracking capability and inadequate quality checks for proposal submissions and contracts. Feedback indicated that the capacity assessment was comprehensive and generated practical actions, several of which were no-cost. Regular follow-up helped to maintain focus on activities to strengthen health research capacity in the face of challenges.

Conclusions

Identification of each institutions' strengths and weaknesses against an evidence-informed benchmark enabled them to identify gaps in in their operational health research systems, to develop prioritised action plans, to justify resource requests to fulfil the plans and to track progress in strengthening RMSS. Use of a standard benchmark, approach and tools enabled comparisons across institutions which has accelerated production of evidence about the science of research capacity strengthening. The tools could be used by institutions seeking to understand their strengths and to address gaps in research capacity. Research capacity gaps that were common to several institutions could be a 'smart' investment for governments and health research funders.

http://ift.tt/2w5iW4B

Qualitative meta-synthesis of barriers and facilitators that influence the implementation of community pharmacy services: perspectives of patients, nurses and general medical practitioners

Objectives

The integration of community pharmacy services (CPSs) into primary care practice can be enhanced by assessing (and further addressing) the elements that enable (ie, facilitators) or hinder (ie, barriers) the implementation of such CPSs. These elements have been widely researched from the perspective of pharmacists but not from the perspectives of other stakeholders who can interact with and influence the implementation of CPSs. The aim of this study was to synthesise the literature on patients', general practitioners' (GPs) and nurses' perspectives of CPSs to identify barriers and facilitators to their implementation in Australia.

Methods

A meta-synthesis of qualitative studies was performed. A systematic search in PubMed, Scopus and Informit was conducted to identify studies that explored patients', GPs' or nurses' views about CPSs in Australia. Thematic synthesis was performed to identify elements influencing CPS implementation, which were further classified using an ecological approach.

Results

Twenty-nine articles were included in the review, addressing 63 elements influencing CPS implementation. Elements were identified as a barrier, facilitator or both and were related to four ecological levels: individual patient (n=14), interpersonal (n=24), organisational (n=16) and community and healthcare system (n=9). It was found that patients, nurses and GPs identified elements reported in previous pharmacist-informed studies, such as pharmacist's training/education or financial remuneration, but also new elements, such as patients' capability to follow service's procedures, the relationships between GP and pharmacy professional bodies or the availability of multidisciplinary training/education.

Conclusions

Patients, GPs and nurses can describe a large number of elements influencing CPS implementation. These elements can be combined with previous findings in pharmacists-informed studies to produce a comprehensive framework to assess barriers and facilitators to CPS implementation. This framework can be used by pharmacy service planners and policy makers to improve the analysis of the contexts in which CPSs are implemented.

http://ift.tt/2f27Aso

Feasibility randomised multicentre, double-blind, double-dummy controlled trial of anakinra, an interleukin-1 receptor antagonist versus intramuscular methylprednisolone for acute gout attacks in patients with chronic kidney disease (ASGARD): protocol study

Introduction

Acute gout occurs in people with chronic kidney disease, who are commonly older people with comorbidities such as hypertension, heart disease and diabetes. Potentially harmful treatments are administered to these vulnerable patients due to a lack of clear evidence. Newly available treatment that targets a key inflammatory pathway in acute gout attacks provides an opportunity to undertake the first-ever trial specifically looking treating people with kidney disease. This paper describes the protocol for a feasibility randomised controlled trial (RCT) comparing anakinra, a novel interleukin-1 antagonist versus steroids in people with chronic kidney disease (ASGARD).

Methods and analysis

ASGARD is a two-parallel group double-blind, double-dummy multicentre RCT comparing anakinra 100 mg, an interleukin-1 antagonist, subcutaneous for 5 days against intramuscular methylprednisolone 120 mg. The primary objective is to assess the feasibility of the trial design and procedures for a definitive RCT. The specific aims are: (1) test recruitment and retention rates and willingness to be randomised; (2) test eligibility criteria; (3) collect and analyse outcome data to inform sample and power calculations for a trial of efficacy; (4) collect economic data to inform a future economic evaluation estimating costs of treatment and (5) assess capacity of the project to scale up to a national multicentre trial. We will also gather qualitative insights from participants. It aims to recruit 32 patients with a 1:1 randomisation. Information from this feasibility study will help design a definitive trial and provide general information in designing acute gout studies.

Ethics and dissemination

The London-Central Ethics Committee approved the protocol. The results will be disseminated in peer-reviewed journals and at scientific conferences.

Trial registration number

EudraCT No. 2015-001787-19, NCT/Clinicalstrials.gov No. NCT02578394, pre-results, WHO Universal Trials Reference No. U1111-1175-1977. NIHR Grant PB-PG-0614–34090.

http://ift.tt/2w5jtDx

Changes in mortality inequalities across occupations in Japan: a national register based study of absolute and relative measures, 1980-2010

Objective

Changes in mortality inequalities across socioeconomic groups have been a substantial public health concern worldwide. We investigated changes in absolute/relative mortality inequalities across occupations, and the contribution of different diseases to inequalities in tandem with the restructuring of the Japanese economy.

Methods

Using complete Japanese national death registries from 5 year intervals (1980–2010), all cause and cause specific age standardised mortality rates (ASMR per 100 000 people standardised using the Japanese standard population in 1985, aged 30–59 years) across 12 occupations were computed. Absolute and relative inequalities were measured in ASMR differences (RDs) and ASMR ratios (RRs) among occupations in comparison with manufacturing workers (reference). We also estimated the changing contribution of different diseases by calculating the differences in ASMR change between 1995 and 2010 for occupations and reference.

Results

All cause ASMRs tended to decrease in both sexes over the three decades except for male managers (increased by 71% points, 1995–2010). RDs across occupations were reduced for both sexes (civil servants 233.5 to –1.9 for men; sales workers 63.3 to 4.5 for women) but RRs increased for some occupations (professional workers 1.38 to 1.70; service workers 2.35 to 3.73) for men and decreased for women from 1980 to 2010. Male relative inequalities widened among farmer, fishery and service workers, because the percentage declines were smaller in these occupations. Cerebrovascular disease and cancer were the main causes of the decrease in mortality inequalities among sexes but the incidence of suicide increased among men, thereby increasing sex related inequalities.

Conclusions

Absolute inequality trends in mortality across occupations decreased in both sexes, while relative inequality trends were heterogeneous in Japan. The main drivers of narrowing and widening mortality inequalities were cerebrovascular disease and suicide, respectively. Future public health efforts will benefit from eliminating residual inequalities in mortality by considering the contribution of the causes of death and socioeconomic status stratification.

http://ift.tt/2f2hOJp

Cohort profile: maternal lifestyle and diet in relation to pregnancy, postpartum and infant health outcomes in Vietnam: A multicentre prospective cohort study

Purpose

To determine modifiable maternal risk factors for adverse pregnancy, postpartum maternal and child health outcomes in Vietnam.

Participants

This prospective cohort study included pregnant women seeking prenatal care at six hospitals in three large cities in Vietnam. After enrolment, eligible participants who gave their consent to participate in the study were interviewed at 24–28 weeks' gestation. Glucose testing was conducted and blood pressure was measured during this period. Each participant will be assessed prospectively during their postnatal visits at delivery, 1, 3, 6, 12, 18 and 24 months, and will be followed up for 5 years.

Findings to date

Of 2248 eligible pregnant women, 2030 were recruited (participation rate 90.3%) between August 2015 and July 2016. All participants completed the baseline assessment. Their mean (SD) age was 27.6 (5.3) years. The mean pre-pregnancy body mass index (BMI) was 20.2 (SD 2.6) kg/m², with nearly two-thirds of participants having a normal pre-pregnancy BMI (18.5 to <23.0 kg/m²) and one-quarter being underweight (pre-pregnancy BMI <18.5 kg/m²). Overweight or obese mothers (pre-pregnancy BMI ≥23.0 kg/m²) accounted for 12.8%. No pregnant women reported smoking during their pregnancy while 13.4% of them had continued drinking. 22.8% of participants had hyperglycaemia. Their mean systolic blood pressure was 105.6 (SD 8.2) mm Hg, and diastolic blood pressure was 67.4 (SD 7.5) mm Hg.

Future plans

The relationships of maternal lifestyle and nutritional status with the health outcomes of pregnancy, postpartum maternity and infants will be analysed. Meanwhile, participants will be closely tracked to minimise loss to follow-up.

http://ift.tt/2f1wzMr

Systematic review of the evidence on orthotic devices for the management of knee instability related to neuromuscular and central nervous system disorders

Objectives

To assess the effectiveness of orthotic devices for the management of instability of the knee in adults with a neuromuscular disorder or central nervous system disorder.

Design

A systematic review of primary studies.

Setting

Community.

Participants

Adults with a neuromuscular disorder or central nervous system disorder and impaired walking ability due to instability of the knee.

Interventions

Orthoses with the clinical aim of controlling knee instability, for example, knee-ankle-foot orthoses, ankle-foot orthoses and knee orthoses or mixed design with no restrictions in design or material.

Primary and secondary outcome measures

Condition-specific or generic patient-reported outcome measures assessing function, disability, independence, activities of daily living, quality of life or psychosocial outcomes; pain; walking ability; functional assessments; biomechanical analysis; adverse effects; usage; patient satisfaction and the acceptability of a device; and resource utilisation data.

Results

Twenty-one studies including 478 patients were included. Orthotic devices were evaluated in patients with postpolio syndrome, poststroke syndrome, inclusion body myositis and spinal cord injury. The review included 2 randomised controlled trials (RCTs), 3 non-randomised controlled studies and 16 case series. Most were small, single-centre studies with only 6 of 21 following patients for 1 year or longer. They met between one and five of nine quality criteria and reported methods and results poorly. They mainly assessed outcomes related to gait analysis and energy consumption with limited use of standardised, validated, patient-reported outcome measures. There was an absence of evidence on outcomes of direct importance to patients such as reduction in pain and falls.

Conclusions

There is a need for high-quality research, particularly RCTs, of orthotic devices for knee instability related to neuromuscular and central nervous system conditions. This research should address outcomes important to patients. There may also be value in developing a national registry.

Registration number systematic review

PROSPERO (CRD42014010180).

http://ift.tt/2w4ZqoB

APpropriAteness of percutaneous Coronary interventions in patients with ischaemic HEart disease in Italy: the APACHE pilot study

Objectives

To first explore in Italy appropriateness of indication, adherence to guideline recommendations and mode of selection for coronary revascularisation.

Design

Retrospective, pilot study.

Setting

22 percutaneous coronary intervention (PCI)-performing hospitals (20 patients per site), 13 (59%) with on-site cardiac surgery.

Participants

440 patients who received PCI for stable coronary artery disease (CAD) or non-ST elevation acute coronary syndrome were independently selected in a 4:1 ratio with half diabetics.

Primary and secondary outcome measures

Proportion of patients who received appropriate PCI using validated appropriate use scores (ie, AUS≥7). Also, in patients with stable CAD, we examined adherence to the following European Society of Cardiology recommendations: (A) per cent of patients with complex coronary anatomy treated after heart team discussion; (B) per cent of fractional flow reserve-guided PCI for borderline stenoses in patients without documented ischaemia; (C) per cent of patients receiving guideline-directed medical therapy at the time of PCI as well as use of provocative test of ischaemia according to pretest probability (PTP) of CAD.

Results

Of the 401 mappable PCIs (91%), 38.7% (95% CI 33.9 to 43.6) were classified as appropriate, 47.6% (95% CI 42.7 to 52.6) as uncertain and 13.7% (95% CI 10.5% to 17.5%) as inappropriate. Median PTP in patients with stable CAD without known coronary anatomy was 69% (78% intermediate PTP, 22% high PTP). Ischaemia testing use was similar (p=0.71) in patients with intermediate (n=140, 63%) and with high PTP (n=40, 66%). In patients with stable CAD (n=352) guideline adherence to the three recommendations explored was: (A) 11%; (B) 25%; (C) 23%. AUS was higher in patients evaluated by the heart team as compared with patients who were not (7 (6.8) vs 5 (4.7); p=0.001).

Conclusions

Use of heart team approaches and adherence to guideline recommendations on coronary revascularisation in a real-world setting is limited. This pilot study documents the feasibility of measuring appropriateness and guideline adherence in clinical practice and identifies substantial opportunities for quality improvement.

Trial registration number

NCT02748603.

http://ift.tt/2f27q4g

Effects of external inspection on sepsis detection and treatment: a study protocol for a quasiexperimental study with a stepped-wedge design

Introduction

Inspections are widely used in health care as a means to improve the health services delivered to patients. Despite their widespread use, there is little evidence of their effect. The mechanisms for how inspections can promote change are poorly understood. In this study, we use a national inspection campaign of sepsis detection and initial treatment in hospitals as case to: (1) Explore how inspections affect the involved organizations. (2) Evaluate what effect external inspections have on the process of delivering care to patients, measured by change in indicators reflecting how sepsis detection and treatment is carried out. (3) Evaluate whether external inspections affect patient outcomes, measured as change in the 30-day mortality rate and length of hospital stay.

Methods and analysis

The intervention that we study is inspections of sepsis detection and treatment in hospitals. The intervention will be rolled out sequentially during 12 months to 24 hospitals. Our effect measures are change on indicators related to the detection and treatment of sepsis, the 30-day mortality rate and length of hospital stay. We collect data from patient records at baseline, before the inspections, and at 8 and 14 months after the inspections. We use logistic regression models and linear regression models to compare the various effect measurements between the intervention and control periods. All the models will include time as a covariate to adjust for potential secular changes in the effect measurements during the study period. We collect qualitative data before and after the inspections, and we will conduct a thematic content analysis to explore how inspections affect the involved organisations.

Ethics and dissemination

The study has obtained ethical approval by the Regional Ethics Committee of Norway Nord and the Norwegian Data Protection Authority. It is registered at http://ift.tt/PmpYKN (Identifier: NCT02747121). Results will be reported in international peer-reviewed journals.

Trial Registration

NCT02747121; Pre-results.

http://ift.tt/2f1noLJ

Effects of complex interventions in 'skin cancer prevention and treatment: protocol for a mixed-method systematic review with qualitative comparative analysis

Introduction

Occurring from ultraviolet radiation combined with impairing ozone levels, uncritical sun exposure and use of tanning beds an increasing number of people are affected by different types of skin cancer. But preventive interventions like skin cancer screening are still missing the evidence for effectiveness and therefore are criticised. Fundamental for an appropriate course of action is to approach the defined parameters as measures for effectiveness critically. A prerequisite should be the critical application of used parameter that are defined as measures for effectiveness. This research seeks to establish, through the available literature, the effects and conditions that prove the effectiveness of prevention strategies in skin cancer.

Method and analysis

A mixed-method approach is employed to combine quantitative to qualitative methods and answer what effects can display effectiveness considering time horizon, perspective and organisational level and what are essential and sufficient conditions to prove effectiveness and cost-effectiveness in skin cancer prevention strategies. A systematic review will be performed to spot studies from any design and assess the data quantitatively and qualitatively. Included studies from each key question will be summarised by characteristics like population, intervention, comparison, outcomes, study design, endpoints, effect estimator and so on. Beside statistical relevancies for a systematic review the qualitative method of qualitative comparative analysis (QCA) will be performed. The estimated outcomes from this review and QCA are the accomplishment and absence of effects that are appropriate for application in effectiveness assessments and further cost-effectiveness assessment.

Ethics and dissemination

Formal ethical approval is not required as primary data will not be collected.

Trial registration number

International Prospective Register for Systematic Reviews number CRD42017053859.

http://ift.tt/2f2haeX

Psychological distress following a motor vehicle crash: evidence from a statewide retrospective study examining settlement times and costs of compensation claims

Objective

To determine whether psychological distress associated with musculoskeletal injuries sustained in a motor vehicle crash (MVC), regardless of time of onset, impacts compensation outcomes such as claim settlement times and costs. Second, to identify factors routinely collected by insurance companies that contribute to psychological distress during the compensation process.

Design

Statewide retrospective study.

Data source

Analysis of the New South Wales statewide (Australia) injury register for MVC survivors who lodged a compensation claim from 2011 to 2013.

Participants

6341 adults who sustained a musculoskeletal injury and who settled a claim for injury after an MVC. Participants included those diagnosed with psychological distress (n=607) versus those not (n=5734).

Main outcome measures

Time to settlement and total costs of claims, as well as socio-demographic and injury characteristics that may contribute to elevated psychological distress, such as socio-economic disadvantage, and injury severity.

Results

Psychological distress in those with a musculoskeletal injury was associated with significantly longer settlement times (an additional 17 weeks) and considerably higher costs (an additional $A41 575.00 or 4.3 times more expensive). Multivariate logistic regression analysis identified risk factors for psychological distress including being female, social disadvantage, unemployment prior to the claim, not being at fault in the MVC, requiring ambulance transportation and rehabilitation as part of recovery.

Conclusions

Results provide compelling evidence that psychological distress has an adverse impact on people with musculoskeletal injury as they progress through compensation. Findings suggest that additional resources should be directed toward claimants who are at risk (eg, the socially disadvantaged or those unemployed prior to the claim), the major aim being to reduce risk of psychological distress, such as post-traumatic stress disorder, and associated risk of increased settlement times and claim costs. Prospective studies are now required that investigate treatment strategies for those at risk of psychological distress associated with an MVC.

http://ift.tt/2w5AuNH

Target volume delineation of anal cancer based on magnetic resonance imaging or positron emission tomography

Abstract

Purpose

To compare target volume delineation of anal cancer using positron emission tomography (PET) and magnetic resonance imaging (MRI) with respect to inter-observer and inter-modality variability.

Methods

Nineteen patients with anal cancer undergoing chemoradiotherapy were prospectively included. Planning computed tomography (CT) images were co-registered with 18F–fluorodexocyglucose (FDG) PET/CT images and T2 and diffusion weighted (DW) MR images. Three oncologists delineated the Gross Tumor Volume (GTV) according to national guidelines and the visible tumor tissue (GTV_T). MRI and PET based delineations were evaluated by absolute volumes and Dice similarity coefficients.

Results

The median volume of the GTVs was 27 and 31 cm³ for PET and MRI, respectively, while it was 6 and 11 cm³ for GTV_T. Both GTV and GTV_T volumes were highly correlated between delineators (r = 0.90 and r = 0.96, respectively). The median Dice similarity coefficient was 0.75 when comparing the GTVs based on PET/CT (GTV_PET) with the GTVs based on MRI and CT (GTV_MRI). The median Dice coefficient was 0.56 when comparing the visible tumor volume evaluated by PET (GTV_{T_PET}) with the same volume evaluated by MRI (GTV_{T_MRI}). Margins of 1–2 mm in the axial plane and 7–8 mm in superoinferior direction were required for coverage of the individual observer's GTVs.

Conclusions

The rather good agreement between PET- and MRI-based GTVs indicates that either modality may be used for standard target delineation of anal cancer. However, larger deviations were found for GTV_T, which may impact future tumor boost strategies.

http://ift.tt/2wG7sWZ

Ternary cocktail nanoparticles for sequential chemo-photodynamic therapy

Abstract

Background

Previous clinical trials have already demonstrated that combinations of two or more drugs were more effective in the cancer treatment, especially sequential photodynamic design combing with sequential chemotherapy. In our study, we propose a ternary cocktail NP delivery system based on self-decomposable NPs, which could realize synergistic chemo-photodynamic therapy through double loading chemo-drugs and multi-level programmable PDT treatment.

Methods

PS drug methylene blue (MB) was encapsulated into the center of the NP_small, NP_big&thin, and NP_big&thick carriers through "grown-in" loading mechanism, which was released based on the drug concentration difference of the drug release environment. NP_small, NP_big&thin, and NP_big&thick carriers have three different drug release profiles, which could realize multi-level programmable PDT treatment. At the same time, antitumor drug gemcitabine hydrochloride (GM) and Docetaxel (DTX), were chosen as the double loading chemo-drugs that absorbed onto the NP_big&thin and NP_big&thick surface, respectively. In specific, various particle configurations were used for modulating the inner MB sequential release with three pulse T_max. Also, by adjusting the NP_big&thin and NP_big&thick configuration, the release interval lag time between absorbed GM and DTX can be successfully modulated to achieve maximized chemotherapeutic efficacy.

Results

In vitro and in vivo results demonstrated that these three pulses T_max and the sustained release of MB could maximize the multi-level programmable PDT treatment. And the absorbed GM and DTX also have a release time lag of 12 h, which has been proved as the most effectiveness synergistic interval lag time in the cancer treatment.

Conclusion

Such a precise sequential release manner ternary cocktail NPs provided a promising platform for efficient and safe chemo-photodynamic therapy, which serves as a promising drug delivery system to cure cancer in the future.

http://ift.tt/2wDQHgD

Data indicates that circadian disruption by LL provides a favorable condition for tumor growth by promoting an anabolic metabolism in the host.

http://ift.tt/2eJDpJk

Prognostic consequences of implementing cancer patient pathways in Denmark: a comparative cohort study of symptomatic cancer patients in primary care

Abstract

Background

Cancer Patient Pathways (CPPs) were introduced in 2000–2015 in several European countries, including Denmark, to reduce the time to diagnosis and treatment initiation and ultimately improve patient survival. Yet, the prognostic consequences of implementing CPPs remain unknown for symptomatic cancer patients diagnosed through primary care.

We aimed to compare survival and mortality among symptomatic patients diagnosed through a primary care route before, during and after the CPP implementation in Denmark.

Methods

Based on data from the Danish Cancer in Primary Care (CaP) Cohort, we compared one- and three-year standardised relative survival (RS) and excess hazard ratios (EHRs) before, during and after CPP implementation for seven types of cancer and all combined (n = 7725) by using life-table estimation and Poisson regression. RS estimates were standardised according to the International Cancer Survival Standard (ICSS) weights. In addition, we compared RS and EHRs for CPP and non-CPP referred patients to consider potential issues of confounding by indication.

Results

In total, 7725 cases were analysed: 1202 before, 4187 during and 2336 after CPP implementation. For all cancers combined, the RS_3years rose from 45% (95% confidence interval (CI): 42;47) before to 54% (95% CI: 52;56) after CPP implementation. The excess mortality was higher before than after CPP implementation (EHR_3years before vs. after CPP = 1.35 (95% CI: 1.21;1.51)). When comparing CPP against non-CPP referred patients, we found no statistically significant differences in RS, but we found lower excess mortality among the CPP referred (EHR_1year CPP vs. non-CPP = 0.86 (95% CI: 0.73;1.01)).

Conclusion

We found higher relative survival and lower mortality among symptomatic cancer patients diagnosed through primary care after the implementation of CPPs in Denmark. The observed changes in cancer prognosis could be the intended consequences of finding and treating cancer at an early stage, but they may also reflect lead-time bias and selection bias. The finding of a lower excess mortality among CPP referred compared to non-CPP referred patients indicates that CPPs may have improved the cancer prognosis independently.

http://ift.tt/2xN4ksp

The values of neutrophil-lymphocyte ratio and/or prostate-specific antigen in discriminating real Gleason score ≥ 7 prostate cancer from group of biopsy-based Gleason score ≤ 6

Abstract

Background

The discrepant concordance between biopsy and radical prostatectomy (RP) specimen are well reported. To validate the clinical usefulness of neutrophil-lymphocyte ratio (NLR) in discriminating real GS ≥ 7 PCa from biopsy-based GS ≤ 6 PCa in comparison with serum total prostate-specific antigen (tPSA) and value of their combination.

Methods

One hundred one patients who underwent physical examinations incidentally found elevated tPSA and subsequently received biopsy with a conclusion of GS ≤ 6 and RP with an interval of 4-6 weeks after biopsy were enrolled. NLR and tPSA were obtained within 15 days prior to biopsy. Logistic regression model was applied appropriately; McNemar tests and AUC model were performed to evaluate differences among tPSA, NLR and their combination and corresponding diagnostic power respectively.

Results

The pathological results from RP specimen comprised 61 patients with GS ≤ 6 and 100 patients with GS ≥ 7. Higher tPSA and NLR were significantly associated with patients with actual GS ≥ 7 (All P < 0.05) concurrently. Multivariate logistic regression indicated that tPSA (OR = 1.088, 95% C.I. = 1.029-1.151, P = 0.003) and NLR (OR = 1.807, 95% C.I. = 1.021-3.200, P = 0.042) could be independent predictors for GS groupings. Under cutoff value of 14.09 ng/ml for tPSA and 2.25 for NLR, the sensitivity, specificity and accuracy were 60.0%, 80.3% and 67.7% for tPSA, 42%, 88.5% and 59.6% for NLR, and 71.0%, 75.4% and 72.7% for combination of tPSA and NLR (tPSA + NLR) respectively. The sensitivity of tPSA + NLR was significantly higher in comparison with tPSA (P = 0.001) and NLR (P < 0.001). Except for sensitivity, no significant difference was found between tPSA and NLR in specificity (P = 0.227) and accuracy (P = 0.132). tPSA got the largest AUC with 0.732 (p < 0.001, 95% C.I.: 0.651-0.813).

Conclusions

Serum tPSA and NLR were significantly elevated among GS ≥ 7 PCa concurrently. The combination of tPSA and NLR might have additional benefit to biopsy on discriminating real GS ≥ 7 Pca from biopsy-based GS ≤ 6 PCa. More stratification models and prospectively multicenter studies are necessary.

http://ift.tt/2eJDbBY

Tripeptides Restore the Number of Neuronal Spines under Conditions of In Vitro Modeled Alzheimer’s Disease

In primary culture of mouse hippocampal neurons, peptide EDR (200 ng/ml) under conditions of amyloid synaptotoxicity (a model of Alzheimer's disease) increased the number of mushroom spines by 71% and returned this parameter to the normal level. Under the same conditions, tripeptide KED (200 ng/ml) increased the number of mushroom spines in hippocampal neurons by 20%. Tripeptide EDR can be recommended for further experimental study as a candidate neuroprotective agent for prevention and treatment of Alzheimer's disease.

http://ift.tt/2x9lljE

Columnar metaplasia in the remnant esophagus is a long-term indicator for pneumonia after radical esophagectomy

Abstract

Background

This study investigated the long-term risk factors for pneumonia after esophageal reconstruction using a gastric tube via the posterior mediastinal route following esophagectomy for esophageal cancer. The influence of columnar metaplasia in the remnant esophagus was specifically assessed.

Methods

Among 225 patients who underwent esophagectomy between January 2004 and December 2010, the subjects were 54 patients who could be followed up for more than 5 years. Routine oncologic follow-up consisted of CT scanning of the abdomen and chest every 4–6 months and annual endoscopy. Data on the occurrence of pneumonia were collected by retrospective review of chest CT scans. Risk factors for pneumonia investigated by univariate and multivariate analyses included the age, gender, diameter of the stapler, length of the intrathoracic remnant esophagus, anastomotic stricture, and presence of columnar metaplasia in the remnant esophagus.

Results

The median age was 62.4 years (interquartile range: 55.8–68.0 years). Forty-three patients were men. Pneumonia was detected in 39 patients (72.2%). The incidence of columnar metaplasia in the remnant esophagus increases with time. Anastomotic stricture was significantly related to the absence of columnar metaplasia on endoscopy in the first year after esophagectomy (p = 0.013). Univariate analysis showed that the frequency of pneumonia was significantly related to the intrathoracic remnant esophagus length ≥4.4 cm (p = 0.014), age over 65 years (p = 0.014), and the presence of columnar metaplasia in the remnant esophagus in the fifth year after esophagectomy (p = 0.005). Among them, age over 65 years and the presence of columnar metaplasia in the remnant esophagus in the fifth year after esophagectomy were found to be independent indicators of the postoperative pneumonia by multivariate analysis.

Conclusion

Pneumonia occurred in 72.2% (39/54) of patients after esophagectomy for esophageal cancer. The presence of columnar metaplasia after esophagectomy is an indicator for pneumonia over the long term.

http://ift.tt/2x9uU1V

Descriptive Rules for Achalasia of the Esophagus, June 2012: 4th Edition

http://ift.tt/2xN3g85

Genomics and Susceptibility Profiles of Extensively Drug-Resistant (XDR) Pseudomonas aeruginosa from Spain [PublishAheadOfPrint]

This study assessed the molecular epidemiology, resistance mechanisms and susceptibility profiles of a collection of 150 XDR P. aeruginosa clinical isolates obtained from a 2015 Spanish multicenter study, with a particular focus on resistome analysis in relation to ceftolozane/tazobactam susceptibility. Broth microdilution MICs revealed that nearly all (>95%) of the isolates were nonsusceptible to piperacillin/tazobactam, ceftazidime, cefepime, aztreonam, imipenem, meropenem and ciprofloxacin. Most of them were also resistant to tobramycin (77%), whereas nonsusceptibility rates were lower for ceftolozane/tazobactam (31%), amikacin (7%) and colistin (2%). PFGE-MLST analysis revealed that nearly all of the isolates belonged to previously described high-risk clones. ST175 was detected in all 9 participating hospitals and accounted for 68% (n=101) of the XDR isolates, distantly followed by ST244 (n=16), ST253 (n=12), ST235 (n=8) and ST111 (n=2) detected only in 1-2 hospitals. Through phenotypic and molecular methods, the presence of horizontally-acquired carbapenemases was detected in 21% of the isolates, mostly including VIM (17%) and GES enzymes (4%). At least two representative isolates from each clone and hospital (n=44) were fully sequenced on an Illumina MiSeq®. Classical mutational mechanisms, such as those leading to the overexpression of the β-lactamase AmpC or efflux pumps, OprD inactivation, and/or QRDR mutations, were confirmed in most isolates and correlated well with the resistance phenotypes in the absence of horizontally-acquired determinants. Ceftolozane/tazobactam resistance was not detected in carbapenemase-negative isolates, in agreement with sequencing data showing the absence of ampC mutations. The unique set of mutations responsible for the XDR phenotype of ST175 clone documented 7 years earlier were found to be conserved, denoting the long-term persistence of this specific XDR lineage in Spanish hospitals. Finally, other potentially relevant mutations were evidenced, including those in PBP3, involved in β-lactam (including ceftolozane/tazobactam) resistance, and FusA1, linked to aminoglycoside resistance.

http://ift.tt/2eDoJI5

Mycobacterium abscessus WhiB7 regulates a species -specific repertoire of genes to confer extreme antibiotic resistance [PublishAheadOfPrint]

Mycobacterium abscessus causes acute and chronic broncho-pulmonary infection in patients with chronic lung damage, of which cystic fibrosis (CF) patients are particularly vulnerable. The major threat posed by this organism is its high intrinsic antibiotic resistance. A typical treatment regimen involves a 6-12 month long combination therapy of clarithromycin and amikacin, with cure rates below 50% and multiple side effects, especially due to amikacin. In the present work we show that M. abscessus whiB7, a homologue of M. tuberculosis and M. smegmatis whiB7 with previously demonstrated effects on intrinsic antibiotic resistance, is strongly induced when exposed to clinically relevant antibiotics that target the ribosome - erythromycin, clarithromycin, amikacin, tetracycline and spectinomycin. Deletion of M. abscessus whiB7 results in sensitivity to all of the above antibiotics. Further, we have defined and compared the whiB7 regulon of M. abscessus with the closely related (non-tuberculous mycobacterium) NTM, M. smegmatis to demonstrate the induction of species-specific repertoire of genes. Further we show that one such gene, eis2, is specifically induced in M. abscessus by whiB7, and contributes to its higher levels of intrinsic amikacin resistance. This species-specific pattern of gene induction could account for the differences in drug susceptibilities to other antibiotics and between different mycobacterial species.

http://ift.tt/2j0WIPK

Antagonism between front line antibiotics clarithromycin and amikacin used for the treatment of Mycobacterium abscessus infections is mediated by the whiB7 gene [PublishAheadOfPrint]

Combinations of antibiotics, each individually effective against Mycobacterium abscessus, are routinely co-administered based on the concept that this minimizes the spread of antibiotic resistance. However, our in vitro data contradicts this assumption and instead documents antagonistic interactions between two antibiotics (clarithromycin and amikacin) used to treat M. abscessus infections. Clinically relevant concentrations of clarithromycin induced increased resistance to both amikacin and itself. Induction of resistance was dependent on whiB7, a transcriptional activator of intrinsic antibiotic resistance that is induced by exposure to many different antibiotics. In M. abscessus, deletion of whiB7 (MAB_3508c) resulted in increased sensitivity to a broad range of antibiotics. WhiB7 was required for transcriptional activation of genes that confer resistance to three commonly used anti-M. abscessus drugs: clarithromycin, amikacin, and tigecycline. The whiB7-dependent gene that conferred macrolide resistance was identified as erm(41) (MAB_2297), a ribosomal methyltransferase. The whiB7-dependent gene contributing to amikacin resistance was eis2 (MAB_4532c), a GNAT acetyl transferase. Transcription of whiB7 and resistance genes in its regulon was inducible by subinhibitory concentrations of clarithromycin but not by amikacin. Thus, exposure to clarithromycin, or likely any whiB7-inducing antibiotic, may antagonize the activity of amikacin and other drugs. This has important implications for management of M. abscessus infections, both in cystic fibrosis (CF) and non-CF patients.

http://ift.tt/2eDFpPJ

Evaluation of the innate immune modulator acitretin as a strategy to clear the HIV reservoir [PublishAheadOfPrint]

The persistence of HIV despite suppressive antiretroviral therapy is a major roadblock to HIV eradication. Current strategies focused on inducing the expression of latent HIV fail to clear the persistent reservoir, prompting the development of new approaches for killing HIV+ cells. Recently, acitretin has been proposed as a pharmacological innate cellular-defense network enhancer that led to virus reactivation and preferential death of infected cells. We have evaluated the capacity of acitretin to reactivate and/or facilitate immune-mediated clearance of HIV+ cells. Acitretin did not induce HIV reactivation in latently-infected cell lines (J-Lat or ACH-2). We could only observe a modest induction of HIV reactivation by acitretin in latent GFP-HIV Jurkat cells, comparable to suboptimal concentrations of vorinostat a known latency-reversing agent (LRA). However, acitretin induction was insignificant when compared to LRAs optimal concentrations. Acitretin failed to reactivate HIV in a model of latently infected primary CD4+ T-cells but induced RIG-I and MAVS expression in infected and uninfected cells, confirming the role of acitretin as an innate immune modulator. However, this effect was not associated with selective killing of HIV+ cells. In conclusion, acitretin-mediated stimulation of the RIG-I pathway over HIV reactivation is modest and thus may not meaningfully impact the HIV reservoir. Stimulation of the RIG-I-dependent IFN cascade by acitretin may not significantly affect the selective destruction of HIV+ latently infected cells.

http://ift.tt/2iZgRWk

Efficacy of a new recrystallized enrofloxacin hydrochloride-dihydrate against leptospirosis in a hamster model [PublishAheadOfPrint]

A trial on Syrian hamsters (Mesocricetus auratus) infected with Leptospira interrogans serovar Canicola was established to compare treatment efficacies of daily IM injections of either 10 mg/kg of Baytril® 5% or the same dose of enrofloxacin dihydrate-hydrochloride (enro-C). Hamsters were experimentally infected via oral submucosa with 400 microorganisms/animal, in a sequential time-schedule to align initial treatment day as follows: group BE₂₄ treated with Baytril® daily for 7 days after 24 of infection; group enro-C₂₄ treated with enro-C as in group BE₂₄; group BE₇₄ treated also with Baytril®, but starting 72 h after infection; group enro-C₇₄ treated as group BE₇₄ but injecting enro-C. An untreated-uninfected control group (CG-) and an infected-untreated control group (CG+) were assembled (n =18 in all groups). Hamsters' weights and temperatures were monitored daily for 28 days. Once euthanatized or following death, necropsy, histopathology, macroscopic agglutination tests (MAT), bacterial culture and PCR were performed. Mortality was 38.8% in group BE₂₄ and 100 % in group BE₇₄. No mortality was observed in enro-C₂₄ and 11.1% mortality was recorded in enro-C₇₄. Mortality in groups CG+ and CG- was 100% and zero, respectively. Combined necropsy and histopathologic findings revealed signs of septicemia and organ damage in groups BE₂₄, BE₇₂ and CG⁺. Groups enro-C₂₄ and and CG-showed no lesions. Moderated lesions were registered in 3 hamsters in group enro-C₇₂. MAT was positive in 83.3 % of BE₂₄ hamsters (83.3 %) and 100 % in BE₇₂ and CG+; 16.7% in Enro-C₂₄ and 38.9 % in enro-C₇₂. Only 4/18 were PCR positive in enro-C₇₂ and only one in enro-C₂₄ (P<0.05). It can be concluded that enro-C may be a viable option to treat leptospirosis in hamsters and that this may be the case in other species.

http://ift.tt/2eDEiQd

The global regulatory protein CRP controls multifactorial fluoroquinolone susceptibility in Salmonella enterica serovar Typhimurium [PublishAheadOfPrint]

Fluoroquinolone antibiotics are prescribed for the treatment of Salmonella enterica infections, but resistance to this family of antibiotics is growing. Here we report that loss of the global regulatory protein, CRP, or its allosteric effector, cAMP, reduces susceptibility to fluoroquinolones. A crp mutation was synergistic with the primary fluoroquinolone resistance allele gyrA83, thus can contribute to clinically-relevant resistance. Decreased susceptibility to fluoroquinolones could be partly explained by decreased expression of the outer membrane porin genes ompA and ompF with a concomitant increase in the expression of the ciprofloxacin-resistance efflux pump gene acrB in crp cells. Expression of gyrAB, which encode the DNA supercoiling enzyme GyrAB that is blocked by fluoroquinolones, and expression of topA, which encodes the dominant supercoiling-relaxing enzyme topoisomerase I, were unchanged in crp cells. Yet crp cells maintained a more relaxed state of DNA supercoiling, correlating with an observed increase in topoisomerase IV (parCE) expression. Surprisingly, the crp mutation had the unanticipated effect of enhancing fitness in the presence of fluoroquinolone antibiotics, which can be explained by the observation that exposure of crp cells to ciprofloxacin had the counterintuitive effect of restoring wildtype levels of DNA supercoiling. Consistent with this, crp cells did not become elongated nor induce the SOS response when challenged with ciprofloxacin. These findings implicate the combined action of multiple drug resistance mechanisms in crp cells: reduced permeability and elevated efflux of fluoroquinolones coupled with a relaxed DNA supercoiling state that buffers cells against GyrAB-inhibition by fluoroquinolones.

http://ift.tt/2iZL8o9

High level resistance to colistin mediated by various mutations in the crrB gene among carbapenemase-producing Klebsiella pneumoniae [PublishAheadOfPrint]

Mutations in the crrAB genes encoding a two-component regulator involved in modifications of the lipopolysaccharide were searched for among a collection of colistin-resistant Klebsiella pneumoniae isolates. Four isolates respectively producing carbapenemases NDM-1, OXA-181, or KPC-2 showed mutated CrrB proteins compared to wild-type strains. Complementation assays with a wild-type CrrB protein restored the susceptibility to colistin in all cases, confirming the involvement of the identified substitutions in the resistance phenotype.

http://ift.tt/2eE4OJ7

Triple-edged sword; multiple modes of action of a monoclonal antibody against the multi-drug resistant Escherichia coli clone ST131-H30 [PublishAheadOfPrint]

The multi-drug resistant extra-intestinal pathogenic Escherichia coli clone, ST131-H30 has spread worldwide. This clone expresses a conserved LPS O-antigen, O25b. Previously, we described monoclonal antibodies (mAbs) specific to the O25b antigen and characterized them as diagnostic and therapeutic tools. In this study evidence is provided that besides the previously shown complement mediated bactericidal effect, an O25b-specific humanized mAb, A1124 also enhances opsonophagocytic uptake by the murine macrophage cell line RAW264.1. Both phagocyte-dependent and -independent killing, triggered by A1124, was confirmed in human whole blood. Furthermore, A1124 was shown to neutralize endotoxin activity of purified or naturally shed LPS of clinical isolates. This activity was demonstrated in vitro using both RAW264.7 cells and a human TLR4-reporter cell-line, as well as in a murine model of endotoxemia using purified LPS for challenge. Significant protective efficacy of A1124 at low doses (< 1 mg/kg) was shown in murine and rat models of bacteremia. The contribution of the bactericidal and anti-inflammatory effects was dissected in the mouse bacteremia model through depletion of complement with cobra venom factor (CVF). Protective efficacy was lost in complement-depleted mice, suggesting the essential role of complement-mediated activities for protection in this model. These data suggest that A1124 exhibits different mechanisms of action, namely direct complement-mediated and opsonophagocytic killing as well as endotoxin neutralization in various challenge models. Which of these activities are the most relevant in a clinical setting will need to be addressed by future translational studies.

http://ift.tt/2j0hUp8

Subinhibitory Dalbavancin Attenuates Exotoxin Production from Methicillin-sensitive and Methicillin-resistant Staphylococcus aureus in vitro [PublishAheadOfPrint]

This study investigates the effects of subinhibitory doses of the second-generation lipoglycopeptide antibiotic, dalbavancin, on Staphylococcus aureus toxin production in vitro. S. aureus toxin production was compared with the natural glycopeptide antibiotic, vancomycin, and representative beta-lactam and oxazolidinone antibiotics. While neither dalbavancin nor vancomycin adversely increased toxin production, of these glycopeptide antibiotics, only dalbavancin significantly attenuated toxin production as subinhibitory concentrations. These findings support the recent success of dalbavancin for treatment of staphylococcal infections.

http://ift.tt/2eDMFeH

Structure and dynamics of FosA-mediated fosfomycin resistance in Klebsiella pneumoniae and Escherichia coli [PublishAheadOfPrint]

Fosfomycin exhibits broad-spectrum antibacterial activity, and is being re-evaluated for the treatment of extensively drug-resistant pathogens. Its activity in Gram-negatives, however, can be compromised by expression of FosA, a metal-dependent transferase that catalyzes the conjugation of glutathione to fosfomycin, rendering the antibiotic inactive. In this study, we solved the crystal structures of two of the most clinically relevant FosA enzymes: plasmid-encoded FosA3 from Escherichia coli and chromosomally-encoded FosA from Klebsiella pneumoniae (FosA^KP). The structure, molecular dynamics, catalytic activity, and fosfomycin resistance of FosA3 and FosA^KP were also compared to FosA from Pseudomonas aeruginosa (FosA^PA), for which prior crystal structures exist. Escherichia coli TOP10 transformants expressing FosA3 and FosA^KP conferred significantly greater fosfomycin resistance (MIC, >1,024 μg/ml) compared to FosA^PA (MIC, 16 μg/ml), which could be explained in part by the higher catalytic efficiencies of the FosA3 and FosA^KP enzymes. Interestingly, these differences in enzyme activity could not be attributed to structural differences at their active sites. Instead, molecular dynamics simulations and hydrogen-deuterium exchange experiments of FosA^KP revealed dynamic interconnectivity between its active sites and a loop structure that extends from the active site of each monomer and traverses the dimer interface. This "dimer-interface" loop is longer and more extended in FosA^KP and FosA3 compared to FosA^PA, and kinetic analyses of FosA^KP and FosA^PA loop-swapped chimeric enzymes highlighted its importance in FosA activity. Collectively, these data yield novel insights into fosfomycin resistance that could be leveraged to develop new strategies to inhibit FosA and potentiate fosfomycin activity.

http://ift.tt/2j1mqUx

Immunodeficiency and Intermittent Dosing Promote Acquired Rifamycin Monoresistance in Murine Tuberculosis [PublishAheadOfPrint]

More permissive preclinical models may be useful in evaluating anti-tuberculosis regimens for their propensity to select drug-resistant mutants. To evaluate whether acquired rifamycin monoresistance could be recapitulated in mice and, if so, to evaluate the effects of immunodeficiency, intermittent dosing and drug exposures. Athymic nude and BALB/c mice were infected. Controls received daily rifapentine alone or 2 months of rifampin, isoniazid, pyrazinamide and ethambutol, followed by 4 months of rifampin/isoniazid, either daily or twice-weekly with one of two isoniazid doses. Test groups received the same intensive regimen followed by once-weekly rifapentine, or isoniazid/rifapentine with rifapentine doses of 10, 15 or 20 mg/kg plus one of two isoniazid doses. All combination regimens rendered BALB/c mice culture-negative, but selected mutants resistant to isoniazid (8.5%, 12/140) or rifampin (3.5%, 5/140) in nude mice (P < 0.001). Intermittent intensive phase therapy selected isoniazid and rifampin resistance in 10% (8/80, P < 0.001) and 20% (16/80, P = 0.009) of nude mice, respectively, compared to 0% treated with a daily regimen. Once-weekly rifapentine-containing continuation phase regimens selected rifampin-resistant mutants in 18.0% (18/100, P = 0.035) compared to rifampin/isoniazid regimens. Higher isoniazid doses in the intermittent control regimen and higher rifapentine doses in once-weekly regimens were associated with less selection of isoniazid resistance. Acquired resistance, including rifamycin monoresistance, was more likely to occur in nude mice despite combination therapy. These results recapitulate clinical outcomes, and indicate that nude mice may be useful for evaluating the ability of novel regimens to prevent the selection of resistance.

http://ift.tt/2eDI6Ry

Transcriptional and mutational profiling of an aminoglycoside resistant Pseudomonas aeruginosa small colony variant [PublishAheadOfPrint]

Pseudomonas aeruginosa is a major causative agent of both acute and chronic infections. Although aminoglycoside antibiotics are very potent drugs to fight such infections, antibiotic failure is steadily increasing mainly due to increasing resistance of the bacteria. Many molecular mechanisms that determine resistance such as acquisition of genes encoding for aminoglycoside-inactivating enzymes or overexpression of efflux pumps have been elucidated. However, there are additional, less-well described mechanisms of aminoglycoside resistance. In this study we have profiled a clinical tobramycin resistant P. aeruginosa strain that exhibited a small colony variant (SCV) phenotype. Both, the resistance and the colony morphology phenotypes were lost upon passaging the isolate under rich medium conditions. Transcriptional and mutational profiling revealed that the SCV harbored activating mutations in the two two-component systems AmgRS and PmrAB. Introduction of these mutations singularly into the type strain PA14 conferred tobramycin and colistin resistance, respectively. However, their combined introduction had an additive effect on the tobramycin resistance phenotype. Activation of the AmgRS system slightly reduced the colony size of the PA14 wild-type, whereas the simultaneous overexpression of gacA, the response regulator of the GacSA two component system, further reduced colony size. In conclusion, we uncovered combinatorial influences of two-component systems on clinically relevant phenotypes, such as resistance and the expression of the SCV phenotype. Our results clearly demonstrate that combined activation of P. aeruginosa two-component systems exhibit pleiotropic effects with unforeseen consequences.

http://ift.tt/2j1o9ZZ

Commercial Intravenous Immunoglobulin (IVIg) Preparations Contain Functional Neutralizing Antibodies Against the Staphylococcus aureus Leukocidin LukAB (LukGH) [PublishAheadOfPrint]

The pathogenesis of Staphylococcus aureus is mediated by an array of important virulence factors, including the two-component leukocidin family of toxins. LukAB (also known as LukGH), the most recently discovered leukocidin, is potently lethal to phagocytes, produced during invasive human disease, and present in all known clinical isolates of S. aureus. Intravenous immunoglobulin (IVIg) is often used clinically in severe S. aureus infections. The primary aim of this study was to assess the binding and neutralization potential of IVIg against LukAB. A secondary aim was to examine the lot-to-lot variability of IVIg in the binding and neutralization of LukAB. We studied twenty-four distinct lots of IVIg and compared them to serum from children with invasive S. aureus infection (in the acute and convalescent phases) and healthy, uninfected controls. We found that all lots of IVIg contained functional antibodies targeting LukAB. After adjusting for total antibody content per sample, we found that the amount of anti-LukAB antibody in IVIg was similar to healthy controls and less than patients with invasive S. aureus infection. IVIg samples had relatively lower neutralization capacity compared to healthy controls and children with invasive infection. IVIg had remarkably little lot-to-lot variation in LukAB binding, but had significantly more variation in toxin neutralization. These results are the first report of functional antibodies against the important S. aureus leukocidin LukAB in IVIg. Given the frequent clinical use of IVIg for severe S. aureus infections, improving our understanding of functional antibody properties exhibited by this therapeutic is essential.

http://ift.tt/2eCSsAQ

Hyperbaric oxygen sensitizes anoxic Pseudomonas aeruginosa biofilm to ciprofloxacin [PublishAheadOfPrint]

Chronic Pseudomonas aeruginosa lung infection is characterized by the presence of endobronchial antibiotic-tolerant biofilm subject to strong oxygen (O₂) depletion due to the activity of surrounding polymorphonuclear leukocytes. The exact mechanisms affecting the antibiotic susceptibility of biofilms remain unclear, but accumulating evidence suggests that the efficacy of several bactericidal antibiotics is enhanced by stimulation of aerobic respiration of pathogens, while lack of O₂ increases their tolerance. In fact, the bactericidal effect of several antibiotics depends on active aerobic metabolism activity and the endogenous formation of reactive O₂ radicals (ROS). In this study we aimed to apply hyperbaric oxygen treatment (HBOT) in order to sensitize anoxic P. aeruginosa agarose-biofilms established to mimic situations with intense O₂ consumption by the host response in the cystic fibrosis (CF) lung. Application of HBOT resulted in enhanced bactericidal activity of ciprofloxacin at clinically relevant durations and was accompanied by indications of restored aerobic respiration, involvement of endogenous lethal oxidative stress and increased bacterial growth. The findings highlight that oxygenation by HBOT improves the bactericidal activity of ciprofloxacin on P. aeruginosa biofilm and suggest that bacterial biofilms is sensitized to antibiotics by supplying hyperbaric O₂.

http://ift.tt/2j0WHLG

N-Acetylglucosamine-1-phosphate transferase, WecA, as a validated drug target in Mycobacterium tuberculosis [PublishAheadOfPrint]

The mycobacterial phosphoglycosyltransferase, WecA, which initiates arabinogalactan biosynthesis in Mycobacterium tuberculosis, has been proposed as a target of the caprazamycin derivative, CPZEN-45, a preclinical drug candidate for treatment of tuberculosis. In this report, we describe the functional characterization of mycobacterial WecA and confirm the essentiality of its encoding gene in M. tuberculosis by demonstrating that transcriptional silencing of wecA is bactericidal in vitro and in macrophages. Silencing of wecA also conferred hypersensitivity of M. tuberculosis to the drug, tunicamycin, confirming its target selectivity for WecA in whole cells. Simple radiometric assays performed with mycobacterial membranes and commercially available substrates, allowed chemical validation of other putative WecA inhibitors, as well as resolving their selectivity towards WecA versus another attractive cell wall target - translocase I that catalyzes the first membrane step in biosynthesis of peptidoglycan. These assays and mutant strain described herein will be useful for identifying potential antitubercular leads by screening chemical libraries for novel WecA inhibitors.

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UTHealth ORL & Hurricane Harvey

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UTHealth ORL & Hurricane Harvey

Hurricane Harvey brought catastrophic flooding to the 6 million inhabitants of the greater Houston region. We are happy to report... Read the full article...

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Endoscopy in inflammatory bowel disease: advances in disease management

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Patterns of Intraosseous Recurrence following Stereotactic Body Radiotherapy for Coxal Bone Metastasis

Patterns of intraosseous failure in 17 patients treated with stereotactic body radiation therapy (SBRT) for coxal bone metastases were analyzed retrospectively. Although SBRT achieved good local control at the target, marginal/out-of-field recurrences in the coxal bone were observed in 7 cases. Tumor recurrence occurred at an average distance of more than 30 mm from the initial metastasis.

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Transcriptome Analysis Suggests That Chromosome Introgression Fragments from Sea Island Cotton (Gossypium barbadense) Increase Fiber Strength in Upland Cotton (Gossypium hirsutum)

As high-strength cotton fibers are critical components of high quality cotton, developing cotton cultivars with high strength fibers as well as high yield is a top priority for cotton development. Recently, chromosome segment substitution lines (CSSLs) have been developed from high-yield Upland cotton (Gossypium hirsutum) crossed with high-quality Sea Island cotton (G. barbadense). Here, we constructed a CSSL population by crossing CCRI45, a high-yield Upland cotton cultivar, with Hai1, a Sea Island cotton cultivar with superior fiber quality. We then selected two CSSLs with significantly higher fiber strength than CCRI45 (MBI7747 and MBI7561), and one CSSL with lower fiber strength than CCRI45 (MBI7285) for further analysis. We sequenced all four transcriptomes at four different time points post-anthesis, and clustered the 44,678 identified genes by function. We identified 2200 "common differentially expressed genes (DEGs)": those that were found in both high quality CSSLs (MBI7747 and MBI7561), but not in the low quality CSSL (MBI7285). Many of these genes were associated with various metabolic pathways that affect fiber strength. Upregulated DEGs were associated with polysaccharide metabolic regulation, single-organism localization, cell wall organization, and biogenesis, while the downregulated DEGs were associated with microtubule regulation, the cellular response to stress, and the cell cycle. Further analyses indicated that three genes, XLOC_036333 (mannosyl-oligosaccharide-alpha-mannosidase mns1), XLOC_029945 (FLA8), and XLOC_075372 (snakin-1) were potentially important for the regulation of cotton fiber strength. Our results suggest that these genes may be good candidates for future investigation of the molecular mechanisms of fiber strength formation, and for the improvement of cotton fiber quality through molecular breeding.

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Early closure of fistula using neo-adjuvant intra-arterial chemotherapy in locally advanced anal cancer

Locally advanced anal cancer patients, especially with T4 disease and fistula, have a dismal prognosis. Neo-adjuvant intra-arterial chemotherapy before standard chemoradiation has been shown to be promising in this setting.

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Alcohol consumption and bladder cancer risk with or without the flushing response: The Japan Public Health Center-based Prospective Study

ABSTRACT

The association between alcohol consumption and bladder cancer risk has been insufficiently investigated in East Asian populations, who frequently have the inactive enzyme for metabolizing acetaldehyde. Given that acetaldehyde associated with alcohol consumption is assessed as a carcinogen, consideration of differences in acetaldehyde exposure would aid accuracy in assessing the bladder cancer risk associated with alcohol consumption. Here, we conducted a population-based cohort study in Japan to examine this association, including information on the flushing response as a surrogate marker of the capacity of acetaldehyde metabolism. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariate Cox proportional hazard models. During follow up from 1990 through 2012 for the 95915 subjects (45649 men and 50266 women, aged 40-69 years), 354 men and 110 women were newly diagnosed with bladder cancer. No significant association between alcohol consumption and bladder cancer risk was observed in the overall analysis. Among male flushers, HRs were 1.04 (95% CI 0.70-1.54), 1.67 (1.16-2.42), 1.02 (0.62-1.67) and 0.63 (0.33-1.20) for alcohol consumption of 1-150, 151-300, 301-450, >450 g/week of pure ethanol compared with non- and occasional drinkers, respectively, indicating an inverted U-shaped association between alcohol consumption and bladder cancer risk. In contrast, no significant association was identified among male non-flushers. The marginally significant interaction between alcohol consumption and the flushing response (P for interaction = 0.083) may support our hypothesis that acetaldehyde derived from alcohol consumption is associated with bladder cancer risk. A prospective study considering polymorphisms of genes involved in acetaldehyde metabolism is warranted. This article is protected by copyright. All rights reserved.

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G protein-coupled receptor GPR55 promotes colorectal cancer and has opposing effects to cannabinoid receptor 1

Abstract

The putative cannabinoid receptor GPR55 has been shown to play a tumor-promoting role in various cancers, and is involved in many physiological and pathological processes of the gastrointestinal (GI) tract. While the cannabinoid receptor 1 (CB₁) has been reported to suppress intestinal tumor growth, the role of GPR55 in the development of GI cancers is unclear. We, therefore, aimed at elucidating the role of GPR55 in colorectal cancer (CRC), the third most common cancer worldwide.

Using azoxymethane (AOM)- and dextran sulfate sodium (DSS)-driven CRC mouse models, we found that GPR55 plays a tumor-promoting role that involves alterations of leukocyte populations, i.e. myeloid-derived suppressor cells and T lymphocytes, within the tumor tissues. Concomitantly, expression levels of COX-2 and STAT3 were reduced in tumor tissue of GPR55 knockout mice, indicating reduced presence of tumor-promoting factors. By employing the experimental CRC models to CB₁ knockout and CB₁/GPR55 double knockout mice, we can further show that GPR55 plays an opposing role to CB₁. We report that GPR55 and CB₁ mRNA expression are differentially regulated in the experimental models and in a cohort of 86 CRC patients. Epigenetic methylation of CNR1 and GPR55 was also differentially regulated in human CRC tissue compared to control samples.

Collectively, our data suggest that GPR55 and CB₁ play differential roles in colon carcinogenesis where the former seems to act as oncogene and the latter as tumor suppressor. This article is protected by copyright. All rights reserved.

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Collaborate or treat intra-abdominal metastatic colon cancer of the liver and peritoneum: which is practical for the colorectal surgeon?

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Surgeons and big data

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Laboratory methods cause ultrasensitive prostate-specific antigen fluctuations

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Administrative data: what surgeons should know about big data

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Re: Outcome of bridge to surgery stenting for obstructive left colon cancer

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Issue information - JEB

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Plasma citrulline measurement in the diagnosis of acute mesenteric ischaemia

Background

The differential diagnosis in acute mesenteric ischaemia (AMI) is essential and sometimes life-saving. A marker for early diagnosis is lacking. Citrulline is an amino acid mainly synthesized by small bowel enterocytes from glutamine. In this study, we aimed to evaluate the diagnostic and prognostic values of citrulline with those of the D-dimer in patients with AMI.

Methods

The patients were divided into two groups; group 1: patients with acute abdominal findings which were attributed preoperatively to AMI, and group 2: patients with acute abdominal findings which were attributed preoperatively to causes other than AMI. All patients underwent surgical exploration. Blood samples were taken before surgery. The demographic features, laboratory examinations, citrulline concentration, D-dimer level and surgical findings were evaluated.

Results

Overall, 48 patients were enrolled in the study. AMI was diagnosed in 23 of the 48 patients. There was no significant difference between the groups with regard to gender, leucocyte count and creatinine levels but group 1 was significantly older than group 2. Citrulline, D-dimer and lactate levels were also significantly higher in group 1. Age, lactate, D-dimer and citrulline levels were statistically significant for mortality. The most significant factor was increased lactate level at admission.

Conclusion

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Αρχειοθήκη ιστολογίου

Αναζήτηση αυτού του ιστολογίου

Τρίτη 5 Σεπτεμβρίου 2017

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