Nappy tech: inspired by babies

All you need to aim to create the driest, most comfortable nappies is a lab full of playing babies and some bright minds

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Brachytherapy: An Effective Treatment for Tongue Cancer - Daijiworld.com

Brachytherapy: An Effective Treatment for Tongue Cancer Daijiworld.com Cancer of base of tongue (BOT), that is the posterior most part of the tongue before the throat, is very common in India. Unlike other cancers affecting the oral cavity, cancers developing in BOT region are very difficult to diagnose as the part is not ...

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IJMS, Vol. 18, Pages 268: Integral Characterization of Defective BDNF/TrkB Signalling in Neurological and Psychiatric Disorders Leads the Way to New Therapies

Enhancement of brain-derived neurotrophic factor (BDNF) signalling has great potential in therapy for neurological and psychiatric disorders. This neurotrophin not only attenuates cell death but also promotes neuronal plasticity and function. However, an important challenge to this approach is the persistence of aberrant neurotrophic signalling due to a defective function of the BDNF high-affinity receptor, tropomyosin-related kinase B (TrkB), or downstream effectors. Such changes have been already described in several disorders, but their importance as pathological mechanisms has been frequently underestimated. This review highlights the relevance of an integrative characterization of aberrant BDNF/TrkB pathways for the rational design of therapies that by combining BDNF and TrkB targets could efficiently promote neurotrophic signalling.

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Transition from LDR to HDR brachytherapy for cervical cancer: Evaluation of tumor control, survival, and toxicity

Publication date: Available online 27 January 2017
Source:Brachytherapy
Author(s): K.D. Romano, K.J. Pugh, D.M. Trifiletti, B. Libby, T.N. Showalter
PurposeIn 2012, our institution transitioned from low-dose-rate (LDR) brachytherapy to high dose-rate (HDR) brachytherapy. We report clinical outcomes after brachytherapy for cervical cancer at our institution over a continuous 10-year period.Methods and MaterialsFrom 2004 to 2014, 258 women (184 LDR and 74 HDR) were treated with tandem and ovoid brachytherapy in the multidisciplinary management of International Federation of Gynecology and Obstetrics Stages IA–IVB cervical cancer. Clinical and treatment-related prognostic factors including age, stage, smoking status, relevant doses, and toxicity data were recorded.ResultsMedian followup for the LDR and HDR groups was 46 months and 12 months, respectively. The majority of patients (92%) received external beam radiotherapy as well as concurrent chemotherapy (83%) before the start of brachytherapy. For all stages, the 1-year local control and overall survival (OS) rates were comparable between the LDR and HDR groups (87% vs. 81%, p = 0.12; and 75% vs. 85%, p = 0.16), respectively. Factors associated with OS on multivariate analysis include age, stage, and nodal involvement. On multivariate analysis, severe toxicity (acute or chronic) was higher with HDR than LDR (24% vs. 10%, p = 0.04). Additional prognostic factors associated with increased severe toxicity include former/current smokers and total dose to lymph nodes.ConclusionsThis comparative retrospective analysis of a large cohort of women treated with brachytherapy demonstrates no significant difference in OS or local control between the LDR and HDR. Acute and chronic toxicity increased shortly after the implementation of HDR, highlighting the importance of continued refinement of HDR methods, including integrating advanced imaging.



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The utilization of MRI in the operating room

Publication date: Available online 27 January 2017
Source:Brachytherapy
Author(s): C. Ménard, J.-F. Pambrun, S. Kadoury
Online image guidance in the operating room using ultrasound imaging led to the resurgence of prostate brachytherapy in the 1980s. Here we describe the evolution of integrating MRI technology in the brachytherapy suite or operating room. Given the complexity, cost, and inherent safety issues associated with MRI system integration, first steps focused on the computational integration of images rather than systems. This approach has broad appeal given minimal infrastructure costs and efficiencies comparable with standard care workflows. However, many concerns remain regarding accuracy of registration through the course of a brachytherapy procedure. In selected academic institutions, MRI systems have been integrated in or near the brachytherapy suite in varied configurations to improve the precision and quality of treatments. Navigation toolsets specifically adapted to prostate brachytherapy are in development and are reviewed.



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Brachytherapy improves outcomes in young men (≤60 years) with prostate cancer: A SEER analysis

Publication date: Available online 27 January 2017
Source:Brachytherapy
Author(s): Hani Ashamalla, Adel Guirguis, Kyle McCool, Shauna McVorran, Malcolm Mattes, Daniel Metzger, Clara Oromendia, Karla V. Ballman, Bahaa Mokhtar, Mounzer Tchelebi, Evangelia Katsoulakis, Sameer Rafla
PurposeThe aim of the study was to compare prostate cancer–specific mortality (PCSM) in young men with clinically localized prostate cancer treated by either external beam radiation (EBRT) alone or brachytherapy with or without external beam radiation.Methods and MaterialsUtilizing the Surveillance, Epidemiology and End Results database, 15,505 patients ≤60 years of age diagnosed with prostate cancer between 2004 and 2009 and treated with radiation therapy alone were identified. Incidence of PCSM was determined for both groups and compared using competing risk models.ResultsThe overall 8-year PCSM for the study population was 1.9% (95% confidence interval [CI]: 1.6–2.2). For patients treated with EBRT or brachytherapy with or without external beam, the 8-year PCSM was found to be 2.8% (CI: 2.2–3.4) and 1.2% (CI: 0.9–1.6), respectively (p < 0.001). Univariable analysis demonstrated that brachytherapy was associated with lower PCSM risk (hazard ratio = 0.40; CI: 0.30–0.54; p < 0.001). High Gleason risk category, black race, higher Tumor (T) stage, and higher grade were all associated with greater mortality risk (p < 0.01). On multivariable analysis, brachytherapy continued to be associated with a significantly lower mortality risk (hazard ratio = 0.65; CI: 0.47–0.89; p = 0.008). Subgroup analyses found that among those with Gleason score ≥8, younger patients had increased risk of PCSM (p = 0.001).ConclusionsIn men ≤60 years of age with prostate cancer, radiation therapy continues to offer excellent outcomes. After adjusting for relevant variables, the use of brachytherapy was associated with reduced PCSM compared to treatment with EBRT alone.



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Outpatient template-guided permanent interstitial brachytherapy using 131Cs in gynecologic malignancies: Initial report

Publication date: Available online 27 January 2017
Source:Brachytherapy
Author(s): Jonathan Feddock, Prakash Aryal, Cole Steber, Jason Edwards, Dennis Cheek, Marcus Randall
PurposeOptimal curative intent brachytherapy for certain gynecologic cancers requires interstitial brachytherapy, often using template-guided techniques such as a Syed–Neblett implant. Whether high or low dose rate (LDR), these procedures pose significant risks to patients, partly attributable to the prolonged period of bed rest. Published results of free-handed permanent interstitial brachytherapy (PIB) with ¹³¹Cs demonstrate it to be an effective modality for the management of small volume gynecologic cancers. This report is the first to describe a permanent template-guided interstitial technique using ¹³¹Cs for gynecologic cancers, performed as an LDR outpatient procedure.Methods and MaterialsFive sequential patients with recurrent or primary gynecologic malignancies underwent template-guided PIB using ¹³¹Cs. A posttreatment planning CT was obtained immediately after the procedure and again 3–4 weeks later. Both CT data sets were fused and the relative positions compared to assess for migration in the x, y, and z planes. Seed positions as well as dosimetric parameters including D90, D100, V100, and the dose to 2 cc of rectum and bladder were compared to quantify migration of sources and the resulting effect, if any, on the treatment.ResultsThe median age was 69 years (range 64–85). All patients received a template-guided ¹³¹Cs PIB implant to treat gross disease. All 5 patients had significant medical comorbidities that limited treatment options. Considering all 5 patients, a total of 40 interstitial needles were placed. Ten needles carried only Vicryl-stranded sources, and 30 needles carried a combination of stranded ¹³¹Cs seeds and free seeds. Needle count was between 6 and 10 needles per patient, with active lengths of 4–10 cm. The median dose was 30 Gy (range 25–55 Gy) to permanent decay, enabling a cumulative median biological effective dose 91.5 Gy (range 60.9–92.1 Gy) and equivalent dose at 2 Gy per fraction 75.9 Gy (range 50.7–76.8 Gy). All implants were performed as outpatient procedures with only the first patient admitted for 23-hour observation. All calculated median migration distances were less than 1 cm in the axial, sagittal, or coronal planes. In 69.2% cases, the individual seed migration was <5 mm. Strand migration appeared directly related to peripheral placement and the use of stranded sources. The median D90, D100, and V100 were compared between study sets, and no significant differences were identified. No Grade 3 or higher complications occurred.ConclusionsPermanent LDR template-guided PIB using ¹³¹Cs can be safely performed on an outpatient basis. Compared to currently used template-guided techniques, the use of ¹³¹Cs avoids prolonged bed rest and hospitalization, significantly lowers cost, and enables a higher cumulative dose. Seed migration is minimal with this technique. Early experience suggests that the technique is safe and merits further study.



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Prostate MRI for brachytherapists: Diagnosis, imaging pitfalls, and post-therapy assessment

Publication date: Available online 27 January 2017
Source:Brachytherapy
Author(s): A.M. Venkatesan, R.J. Stafford, C. Duran, P.D. Soni, A. Berlin, P.W. McLaughlin
Optimal integration of multiparametric MRI (mp MRI) into prostate brachytherapy practice necessitates an understanding of imaging findings pertinent to prostate cancer detection and staging. This review will summarize prostate cancer imaging findings and tumor staging on mp MRI, including an overview of the Prostate Imaging Reporting and Data System (PIRADS)–structured reporting schema, mp MRI findings observed in the post-therapy setting including cases of post-treatment recurrence, and MRI concepts integral to successful salvage brachytherapy.



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Postoperative single-dose interstitial high–dose-rate brachytherapy in therapy-resistant keloids

Publication date: Available online 27 January 2017
Source:Brachytherapy
Author(s): C.J.H. Hafkamp, O. Lapid, R. Dávila Fajardo, A.L. van de Kar, C. Koedooder, L.J. Stalpers, B.R. Pieters
PurposePatients with keloids complain of the cosmetic aspect, pain, and pruritus. Many different therapies are being used for keloids. The aim of this study was to evaluate the recurrence rate and outcome after resection followed by a single-dose brachytherapy.Methods and materialsPatients treated by resection of the keloid plus a single dose of 13 Gy high–dose-rate brachytherapy were evaluated at least 1 year after treatment. Clinical response and cosmesis were assessed by a plastic surgeon and by the patients using the Patient and Observer Scar Assessment Scale.ResultsOnly 24 of the 61 invited patients responded to participate with the study; 29 keloids were evaluated. The recurrence rate was 24.1% after a median followup of 53 months (19–95 months). Patients scored on average 24.3 for their total Patient and Observer Scar Assessment Scale score (range 6–52), whereas the observer scored on average 14.6 (range 6–42).ConclusionsThis treatment has a higher recurrence rate than that reported in most other studies. This may be explained by differences in recurrence definition, differences in followup time among studies, and selection bias because of not contributing to the study. The cosmetic outcome for evaluated patients is relatively good. This treatment policy has the advantage that patients are treated in a single day.



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Salvage of locally recurrent prostate cancer after external beam radiation using reduced-dose brachytherapy with neoadjuvant plus adjuvant androgen deprivation

Publication date: Available online 27 January 2017
Source:Brachytherapy
Author(s): Brian C. Baumann, John C. Baumann, John P. Christodouleas, Edward Soffen
PurposeLocal recurrence (LR) of prostate cancer after external beam radiotherapy (EBRT) is a serious problem. Our purpose was to determine if reduced-dose salvage brachytherapy could achieve high rates of biochemical control with acceptable toxicity if combined with androgen deprivation therapy (ADT).Methods and MaterialsThirty-three consecutive patients with LR after EBRT were treated with salvage brachytherapy plus ADT from 1998 to 2013. All had pathologically confirmed LR, disease-free interval ≥18 months after EBRT, no distant/nodal metastasis, and International Prostate Symptom Score ≤15. Whole-gland salvage treatment was delivered using low-dose-rate (median 100 Gy with ¹⁰³Pd, n = 25) or high-dose-rate brachytherapy (30 Gy in 6 fractions over 4 weeks, n = 8) plus 4–6 months of neoadjuvant plus adjuvant ADT.ResultsFifty-five percent had high-risk disease at diagnosis. Median EBRT dose was 70.2 Gy; median prostate-specific antigen nadir was 0.8 ng/mL. Median time to recurrence was 56 months; median presalvage prostate-specific antigen was 5.0 ng/mL. Median postbrachytherapy followup was 61 months (range 7–150 months). Five and 7-year relapse-free survival, distant metastasis-free survival, and overall survival were 79% and 67%; 93% and 86%; and 94% and 85%, respectively. Freedom from late Grade 3 GU toxicity at 5 years was 85%. There were no late Grade ≥2 GI toxicities.ConclusionsThis is the largest series of salvage brachytherapy combined with neoadjuvant plus adjuvant ADT and uses reduced-dose brachytherapy. Results suggest that reduced-dose salvage brachytherapy is feasible and reasonably well tolerated when combined with ADT. Compared to prior series, this approach was associated with favorable relapse-free survival. Prospective studies of reduced-dose salvage brachytherapy plus ADT are warranted.



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Neurocognitive outcomes among children who experienced seizures during treatment for acute lymphoblastic leukemia

Abstract

Background

Limited information is available regarding neurocognitive outcomes of children who experience seizures during treatment for acute lymphoblastic leukemia (ALL). Accordingly, the main objectives of this study were to determine the incidence and risk factors for treatment-related seizures among children with ALL, and the neurocognitive outcomes associated with treatment-related seizures.

Procedure

Prospective neuropsychological assessment and magnetic resonance imaging (MRI) were planned for all 498 patients with newly diagnosed ALL enrolled on the St. Jude Total Therapy XV (TOTXV) protocol at three time points. The study database was reviewed retrospectively to identify those with treatment-related seizure. To assess neurocognitive changes associated with seizure, each patient with treatment-related seizure was matched with two cohort patients without seizure for age at treatment, gender, race, and treatment intensity.

Results

Nineteen patients developed seizure, with a 2-year cumulative risk of 3.82 ± 0.86% (SE). No risk factors were identified to be associated with the development of seizure, with a possible exception of intensive chemotherapy used on the standard/high-risk arm as compared to the low-risk arm. Neuropsychological performance of the seizure group, as compared to normative scores and nonseizure control cohort, indicated problems in attention, working memory, and processing speed. Cognitive deficits persisted 2 years after therapy, with additional declines in intellectual function observed. MRI indicated early neurotoxicity among the seizure group, as evidenced by greater leukoencephalopathy on initial examinations.

Conclusion

Treatment-related seizures were associated with leukoencephalopathy and decreased neuropsychological performance. Prospective studies are needed to detect changes in neurocognitive status associated with long-term functional impairment.

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Novel recurrent chromosome anomalies in Shwachman–Diamond syndrome

Abstract

Background

Two chromosome anomalies are frequent in the bone marrow (BM) of patients with Shwachman–Diamond syndrome (SDS): an isochromosome of the long arm of chromosome 7, i(7)(q10), and an interstitial deletion of the long arm of chromosome 20, del(20)(q). These anomalies are associated with a lower risk of developing myelodysplasia (MDS) and/or acute myeloid leukemia. The chromosome anomalies may be due to an SDS-specific karyotype instability, reflected also by anomalies that are not clonal, but found in single cells in the BM or in peripheral blood (PB).

Procedure

Starting in 1999, we have monitored the cytogenetic picture of a cohort of 91 Italian patients with SDS by all suitable cytogenetic and molecular methods.

Results

Here, we report clonal chromosome anomalies that are different from the aforementioned, as well as changes found in single cells in BM/PB of the same patients.

Conclusions

Some of the newly recognized clonal anomalies in BM reported here are recurrent, especially unbalanced structural anomalies of chromosome 7, a further complex rearrangement of the del(20)(q) with duplicated and deleted portions, and an unbalanced translocation t(3;6), with partial trisomy of the long arm of chromosome 3 and partial monosomy of the long arm of chromosome 6. Firm conclusions on the possible prognostic relevance of these anomalies would require further study with larger patient cohorts, but our data are sufficient to suggest that these patients necessitate more frequent cytogenetic monitoring. The results on anomalies found in single cells confirm the presence of an SDS-specific karyotype instability.

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Family: Know the drill - New Straits Times Online

Family: Know the drill New Straits Times Online One of my sons had this so often that his tonsils were removed. ... However, for someone who has low immunity or fighting diseases like cancer or HIV, the common cold can trigger off other complications, set back their recovery and even be life ...

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Patient preferences, knowledge and beliefs about kidney allocation: qualitative findings from the UK-wide ATTOM programme

Objective

To explore how patients who are wait-listed for or who have received a kidney transplant understand the current UK kidney allocation system, and their views on ways to allocate kidneys in the future.

Design

Qualitative study using semistructured interviews and thematic analysis based on a pragmatic approach.

Participants

10 deceased-donor kidney transplant recipients, 10 live-donor kidney transplant recipients, 12 participants currently wait-listed for a kidney transplant and 4 participants whose kidney transplant failed.

Setting

Semistructured telephone interviews conducted with participants in their own homes across the UK.

Results

Three main themes were identified: uncertainty of knowledge of the allocation scheme; evaluation of the system and participant suggestions for future allocation schemes. Most participants identified human leucocyte anitgen matching as a factor in determining kidney allocation, but were often uncertain of the accuracy of their knowledge. In the absence of information that would allow a full assessment, the majority of participants consider that the current system is effective. A minority of participants were concerned about the perceived lack of transparency of the general decision-making processes within the scheme. Most participants felt that people who are younger and those better matched to the donor kidney should be prioritised for kidney allocation, but in contrast to the current scheme, less priority was considered appropriate for longer waiting patients. Some non-medical themes were also discussed, such as whether parents of dependent children should be prioritised for allocation, and whether patients with substance abuse problems be deprioritised.

Conclusions

Our participants held differing views about the most important factors for kidney allocation, some of which were in contrast to the current scheme. Patient participation in reviewing future allocation policies will provide insight as to what is considered acceptable to patients and inform healthcare staff of the kinds of information patients would find most useful.

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Cohort profile: prevalence of valvular heart disease in community patients with suspected heart failure in UK

Purpose

The aim of this study was to evaluate the proportion of suspected heart failure patients with significant valvular heart disease. Early diagnosis of valve disease is essential as delay can limit treatment and negatively affect prognosis for undiagnosed patients. The prevalence of unsuspected valve disease in the community is uncertain.

Participants

We prospectively evaluated 79 043 patients, between 2001 and 2011, who were referred to a community open access echocardiography service for suspected heart failure. All patients underwent a standard transthoracic echocardiogram according to British Society of Echocardiography guidelines.

Findings to date

Of the total number, 29 682 patients (37.5%) were diagnosed with mild valve disease, 8983 patients (11.3%) had moderate valve disease and 2134 (2.7%) had severe valve disease. Of the total number of patients scanned, the prevalence of aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation was 10%, 8.4%, 1%, and 12.5% respectively. 18% had tricuspid regurgitation. 5% had disease involving one or more valves.

Conclusions

Of patients with suspected heart failure in the primary care setting, a significant proportion have important valvular heart disease. These patients are at high risk of future cardiac events and will require onward referral for further evaluation. We recommend that readily available community echocardiography services should be provided for general practitioners as this will result in early detection of valve disease.

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Health research capacity development in low and middle income countries: reality or rhetoric? A systematic meta-narrative review of the qualitative literature

Objectives

Locally led health research in low and middle income countries (LMICs) is critical for overcoming global health challenges. Yet, despite over 25 years of international efforts, health research capacity in LMICs remains insufficient and development attempts continue to be fragmented. The aim of this systematic review is to identify and critically examine the main approaches and trends in health research capacity development and consolidate key thinking to identify a more coherent approach.

Methods

This review includes academic and grey literature published between January 2000 and July 2013. Using a predetermined search strategy, we systematically searched PubMed, hand-searched Google Scholar and checked reference lists. This process yielded 1668 papers. 240 papers were selected based on a priori criteria. A modified version of meta-narrative synthesis was used to analyse the papers.

Results

3 key narratives were identified: the effect of power relations on capacity development; demand for stronger links between research, policy and practice and the importance of a systems approach. Capacity development was delivered through 4 main modalities: vertical research projects, centres of excellence, North–South partnerships and networks; all were controversial, and each had their strengths and weaknesses. A plurality of development strategies was employed to address specific barriers to health research. However, lack of empirical research and monitoring and evaluation meant that their effectiveness was unclear and learning was weak.

Conclusions

There has been steady progress in LMIC health research capacity, but major barriers to research persist and more empirical evidence on development strategies is required. Despite an evolution in development thinking, international actors continue to use outdated development models that are recognised as ineffective. To realise newer development thinking, research capacity outcomes need to be equally valued as research outputs. While some development actors are now adopting this dedicated capacity development approach, they are in the minority.

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Obstetrical brachial plexus injury (OBPI): Canada's national clinical practice guideline

Objective

The objective of this study was to establish an evidence-based clinical practice guideline for the primary management of obstetrical brachial plexus injury (OBPI). This clinical practice guideline addresses 4 existing gaps: (1) historic poor use of evidence, (2) timing of referral to multidisciplinary care, (3) Indications and timing of operative nerve repair and (4) distribution of expertise.

Setting

The guideline is intended for all healthcare providers treating infants and children, and all specialists treating upper extremity injuries.

Participants

The evidence interpretation and recommendation consensus team (Canadian OBPI Working Group) was composed of clinicians representing each of Canada's 10 multidisciplinary centres.

Outcome measures

An electronic modified Delphi approach was used for consensus, with agreement criteria defined a priori. Quality indicators for referral to a multidisciplinary centre were established by consensus. An original meta-analysis of primary nerve repair and review of Canadian epidemiology and burden were previously completed.

Results

7 recommendations address clinical gaps and guide identification, referral, treatment and outcome assessment: (1) physically examine for OBPI in newborns with arm asymmetry or risk factors; (2) refer newborns with OBPI to a multidisciplinary centre by 1 month; (3) provide pregnancy/birth history and physical examination findings at birth; (4) multidisciplinary centres should include a therapist and peripheral nerve surgeon experienced with OBPI; (5) physical therapy should be advised by a multidisciplinary team; (6) microsurgical nerve repair is indicated in root avulsion and other OBPI meeting centre operative criteria; (7) the common data set includes the Narakas classification, limb length, Active Movement Scale (AMS) and Brachial Plexus Outcome Measure (BPOM) 2 years after birth/surgery.

Conclusions

The process established a new network of opinion leaders and researchers for further guideline development and multicentre research. A structured referral form is available for primary care, including referral recommendations.

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Methodology used in comparative studies assessing programmes of transition from paediatrics to adult care programmes: a systematic review

Objective

To explore the methodologies employed in studies assessing transition of care interventions, with the aim of defining goals for the improvement of future studies.

Design

Systematic review of comparative studies assessing transition to adult care interventions for young people with chronic conditions.

Data sources

MEDLINE, EMBASE, ClinicalTrial.gov.

Eligibility criteria for selecting studies

2 reviewers screened comparative studies with experimental and quasi-experimental designs, published or registered before July 2015. Eligible studies evaluate transition interventions at least in part after transfer to adult care of young people with chronic conditions with at least one outcome assessed quantitatively.

Results

39 studies were reviewed, 26/39 (67%) published their final results and 13/39 (33%) were in progress. In 9 studies (9/39, 23%) comparisons were made between preintervention and postintervention in a single group. Randomised control groups were used in 9/39 (23%) studies. 2 (2/39, 5%) reported blinding strategies. Use of validated questionnaires was reported in 28% (11/39) of studies. In terms of reporting in published studies 15/26 (58%) did not report age at transfer, and 6/26 (23%) did not report the time of collection of each outcome.

Conclusions

Few evaluative studies exist and their level of methodological quality is variable. The complexity of interventions, multiplicity of outcomes, difficulty of blinding and the small groups of patients have consequences on concluding on the effectiveness of interventions. The evaluation of the transition interventions requires an appropriate and common methodology which will provide access to a better level of evidence. We identified areas for improvement in terms of randomisation, recruitment and external validity, blinding, measurement validity, standardised assessment and reporting. Improvements will increase our capacity to determine effective interventions for transition care.

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Compensatory changes in energy balance during dapagliflozin treatment in type 2 diabetes mellitus: a randomised double-blind, placebo-controlled, cross-over trial (ENERGIZE)--study protocol

Introduction

Sodium glucose cotransporter 2 (SGLT2) inhibitors are effective blood-glucose-lowering medications with beneficial effects on body weight in patients with type 2 diabetes mellitus (T2DM). However, observed weight loss is less than that predicted from quantified glycosuria, suggesting a compensatory increase in energy intake or a decrease in energy expenditure. Studies using dual-energy X-ray absorptiometry (DEXA) have suggested most body weight change is due to loss of adipose tissue, but organ-specific changes in fat content (eg, liver, skeletal muscle) have not been determined. In this randomised, double-blind, placebo-controlled crossover study, we aim to study the compensatory changes in energy intake, eating behaviour and energy expenditure accompanying use of the SGLT2 inhibitor, dapagliflozin. Additionally, we aim to quantify changes in fat distribution using MRI, in liver fat using proton magnetic resonance spectroscopy (¹H-MRS) and in central nervous system (CNS) responses to food images using blood oxygen level dependent (BOLD) functional MRI (fMRI).

Methods and analysis

This outpatient study will evaluate the effect of dapagliflozin (10 mg), compared with placebo, on food intake and energy expenditure at 7 days and 12 weeks. 52 patients with T2DM will be randomised to dapagliflozin or placebo for short-term and long-term trial interventions in a within participants, crossover design. The primary outcome is the difference in energy intake during a test meal between dapagliflozin and placebo. Intake data are collected automatically using a customised programme operating a universal eating monitor (UEM). Secondary outcomes include (1) measures of appetite regulation including rate of eating, satiety quotient, appetite ratings (between and within meals), changes in CNS responses to food images measured using BOLD-fMRI, (2) measures of energy expenditure and (3) changes in body composition including changes in liver fat and abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT).

Ethical approval

This study has been approved by the North West Liverpool Central Research Ethics Committee (14/NW/0340) and is conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice (GCP).

Trial registration number

ISRCTN14818531. EUDRACT number 2013-004264-60.

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Cost-effectiveness research in cancer therapy: a systematic review of literature trends, methods and the influence of funding

Objective

To perform a first-time analysis of the cost-effectiveness (CE) literature on chemotherapies, of all types, in cancer, in terms of trends and change over time, including the influence of industry funding.

Design

Systematic review.

Setting

A wide range of cancer-related research settings within healthcare, including health systems, hospitals and medical centres.

Participants

All literature comparative CE research of drug-based cancer therapies in the period 1986 to 2015.

Primary and secondary outcome measures

Primary outcomes are the literature trends in relation to journal subject category, authorship, research design, data sources, funds and consultation involvement. An additional outcome measure is the association between industry funding and study outcomes.

Analysis

Descriptive statistics and the ², Fisher exact or Somer's D tests were used to perform non-parametric statistics, with a p value of <0.05 as the statistical significance measure.

Results

Total 574 publications were analysed. The drug-related CE literature expands over time, with increased publishing in the healthcare sciences and services journal subject category (p<0.001). The retrospective data collection in studies increased over time (p<0.001). The usage of prospective data, however, has been decreasing (p<0.001) in relation to randomised clinical trials (RCTs), but is unchanging for non-RCT studies. The industry-sponsored CE studies have especially been increasing (p<0.001), in contrast to those sponsored by other sources. While paid consultation involvement grew throughout the years, the declaration of funding for this is relatively limited. Importantly, there is evidence that industry funding is associated with favourable result to the sponsor (p<0.001).

Conclusions

This analysis demonstrates clear trends in how the CE cancer research is presented to the practicing community, including in relation to journals, study designs, authorship and consultation, together with increased financial sponsorship by pharmaceutical industries, which may be more influencing study outcomes than other funding sources.

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Use of magnesium sulfate before 32 weeks of gestation: a European population-based cohort study

Objectives

The use of magnesium sulfate (MgSO₄) in European obstetric units is unknown. We aimed to describe reported policies and actual use of MgSO₄ in women delivering before 32 weeks of gestation by indication.

Methods

We used data from the European Perinatal Intensive Care in Europe (EPICE) population-based cohort study of births before 32 weeks of gestation in 19 regions in 11 European countries. Data were collected from April 2011 to September 2012 from medical records and questionnaires. The study population comprised 720 women with severe pre-eclampsia, eclampsia or HELLP and 3658 without pre-eclampsia delivering from 24 to 31 weeks of gestation in 119 maternity units with 20 or more very preterm deliveries per year.

Results

Among women with severe pre-eclampsia, eclampsia or HELLP, 255 (35.4%) received MgSO₄ before delivery. 41% of units reported use of MgSO₄ whenever possible for pre-eclampsia and administered MgSO₄ more often than units reporting use sometimes. In women without pre-eclampsia, 95 (2.6%) received MgSO₄. 9 units (7.6%) reported using MgSO₄ for fetal neuroprotection whenever possible. In these units, the median rate of MgSO₄ use for deliveries without severe pre-eclampsia, eclampsia and HELLP was 14.3%. Only 1 unit reported using MgSO₄ as a first-line tocolytic. Among women without pre-eclampsia, MgSO₄ use was not higher in women hospitalised before delivery for preterm labour.

Conclusions

Severe pre-eclampsia, eclampsia or HELLP are not treated with MgSO₄ as frequently as evidence-based medicine recommends. MgSO₄ is seldom used for fetal neuroprotection, and is no longer used for tocolysis. To continuously lower morbidity, greater attention to use of MgSO₄ is needed.

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Computerised cognitive-behavioural therapy for depression in adolescents: feasibility results and 4-month outcomes of a UK randomised controlled trial

Objectives

Computer-administered cognitive–behavioural therapy (CCBT) may be a promising treatment for adolescents with depression, particularly due to its increased availability and accessibility. The feasibility of delivering a randomised controlled trial (RCT) comparing a CCBT program (Stressbusters) with an attention control (self-help websites) for adolescent depression was evaluated.

Design

Single centre RCT feasibility study.

Setting

The trial was run within community and clinical settings in York, UK.

Participants

Adolescents (aged 12–18) with low mood/depression were assessed for eligibility, 91 of whom met the inclusion criteria and were consented and randomised to Stressbusters (n=45) or websites (n=46) using remote computerised single allocation. Those with comorbid physical illness were included but those with psychosis, active suicidality or postnatal depression were not.

Interventions

An eight-session CCBT program (Stressbusters) designed for use with adolescents with low mood/depression was compared with an attention control (accessing low mood self-help websites).

Primary and secondary outcome measures

Participants completed mood and quality of life measures and a service Use Questionnaire throughout completion of the trial and 4 months post intervention. Measures included the Beck Depression Inventory (BDI) (primary outcome measure), Mood and Feelings Questionnaire (MFQ), Spence Children's Anxiety Scale (SCAS), the EuroQol five dimensions questionnaire (youth) (EQ-5D-Y) and Health Utility Index Mark 2 (HUI-2). Changes in self-reported measures and completion rates were assessed by treatment group.

Results

From baseline to 4 months post intervention, BDI scores and MFQ scores decreased for the Stressbusters group but increased in the website group. Quality of life, as measured by the EQ-5D-Y, increased for both groups while costs at 4 months were similar to baseline. Good feasibility outcomes were found, suggesting the trial process to be feasible and acceptable for adolescents with depression.

Conclusions

With modifications, a fully powered RCT is achievable to investigate a promising treatment for adolescent depression in a climate where child mental health service resources are limited.

Trial registration number

ISRCTN31219579.

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Increasing general practitioners' confidence and self-efficacy in managing obesity: a mixed methods study

Objectives

Internationally, general practitioners (GPs) are being encouraged to take an active role in the care of their patients with obesity, but as yet there are few tools for them to implement within their clinics. This study assessed the self-efficacy and confidence of GPs before and after implementing a weight management programme in their practice.

Design

Nested mixed methods study within a 6-month feasibility trial.

Setting

4 urban general practices and 1 rural general practice in Australia.

Participants

All vocationally registered GPs in the local region were eligible and invited to participate; 12 GPs were recruited and 11 completed the study.

Interventions

The Change Programme is a structured GP-delivered weight management programme that uses the therapeutic relationship between the patient and their GP to provide holistic and person-centred care. It is an evidence-based programme founded on Australian guidelines for the management of obesity in primary care.

Primary outcome measures

Self-efficacy and confidence of the GPs when managing obesity was measured using a quantitative survey consisting of Likert scales in conjunction with pro forma interviews.

Results

In line with social cognitive theory, GPs who experienced performance mastery during the pilot intervention had an increase in their confidence and self-efficacy. In particular, confidence in assisting and arranging care for patients was improved as demonstrated in the survey and supported by the qualitative data. Most importantly from the qualitative data, GPs described changing their usual practice and felt more confident to discuss obesity with all of their patients.

Conclusions

A structured management tool for obesity care in general practice can improve GP confidence and self-efficacy in managing obesity. Enhancing GP ‘professional self-efficacy’ is the first step to improving obesity management within general practice.

Trial registration number

ACTRN12614001192673; Results.

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Safe clinical practice for patients hospitalised in a suicidal crisis: a study protocol for a qualitative case study

Introduction

Suicide prevention in psychiatric care is arguably complex and incompletely understood as a patient safety issue. A resilient healthcare approach provides perspectives through which to understand this complexity by understanding everyday clinical practice. By including suicidal patients and healthcare professionals as sources of knowledge, a deeper understanding of what constitutes safe clinical practice can be achieved.

Methods

This planned study aims to adopt the perspective of resilient healthcare to provide a deeper understanding of safe clinical practice for suicidal patients in psychiatric inpatient care. It will describe the experienced components and conditions of safe clinical practice and the experienced practice of patient safety. The study will apply a descriptive case study approach consisting of qualitative semistructured interviews and focus groups. The data sources are hospitalised patients in a suicidal crisis and healthcare professionals in clinical practice.

Ethics and dissemination

This study was approved by the Regional Ethics Committee (2016/34). The results will be disseminated through scientific articles, a PhD dissertation, and national and international conferences. These findings can generate knowledge to be integrated into the practice of safety for suicidal inpatients in Norway and to improve the feasibility of patient safety measures. Theoretical generalisations can be drawn regarding safe clinical practice by taking into account the experiences of patients and healthcare professionals. Thus, this study can inform the conceptual development of safe clinical practice for suicidal patients.

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Ibobbly mobile health intervention for suicide prevention in Australian Indigenous youth: a pilot randomised controlled trial

Objectives

Rates of youth suicide in Australian Indigenous communities are 4 times the national youth average and demand innovative interventions. Historical and persistent disadvantage is coupled with multiple barriers to help seeking. Mobile phone applications offer the opportunity to deliver therapeutic interventions directly to individuals in remote communities. The pilot study aimed to evaluate the effectiveness of a self-help mobile app (ibobbly) targeting suicidal ideation, depression, psychological distress and impulsivity among Indigenous youth in remote Australia.

Setting

Remote and very remote communities in the Kimberley region of North Western Australia.

Participants

Indigenous Australians aged 18–35 years.

Interventions

61 participants were recruited and randomised to receive either an app (ibobbly) which delivered acceptance-based therapy over 6 weeks or were waitlisted for 6 weeks and then received the app for the following 6 weeks.

Primary and secondary outcome measures

The primary outcome was the Depressive Symptom Inventory—Suicidality Subscale (DSI-SS) to identify the frequency and intensity of suicidal ideation in the previous weeks. Secondary outcomes were the Patient Health Questionnaire 9 (PHQ-9), The Kessler Psychological Distress Scale (K10) and the Barratt Impulsivity Scale (BIS-11).

Results

Although preintervention and postintervention changes on the (DSI-SS) were significant in the ibobbly arm (t=2.40; df=58.1; p=0.0195), these differences were not significant compared with the waitlist arm (t=1.05; df=57.8; p=0.2962). However, participants in the ibobbly group showed substantial and statistically significant reductions in PHQ-9 and K10 scores compared with waitlist. No differences were observed in impulsivity. Waitlist participants improved after 6 weeks of app use.

Conclusions

Apps for suicide prevention reduce distress and depression but do not show significant reductions on suicide ideation or impulsivity. A feasible and acceptable means of lowering symptoms for mental health disorders in remote communities is via appropriately designed self-help apps.

Trial registration number

ACTRN12613000104752.

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Evaluation of IL-12RB1, IL-12B, CXCR-3 and IL-17a expression in cases affected by a non-healing form of cutaneous leishmaniasis: an observational study design

Introduction

Seldom cutaneous leishmaniasis (CL) may present as a lasting and active lesion(s), known as a non-healing form of CL (NHCL). Non-functional type 1 T helper (Th1) cells are assumed the most important factor in the outcome of the disease. The present study aims to assess some molecular defects that potentially contribute to Th1 impairment in NHCL.

Methods and analysis

This prospective observational study will be implemented among five groups. The first and second groups comprise patients afflicted with non-healing and healing forms of CL, respectively. The third group consists of those recovered participants who have scars as a result of CL. Those participants who have never lived or travelled to endemic areas of leishmaniasis will comprise the fourth group. The fifth group comprises participants living in hyperendemic areas for leishmaniasis, although none of them have been afflicted by CL. The aim is to recruit 10 NHCL cases and 30 participants in each of the other groups. A leishmanin skin test (LST) will be performed to assess in vivo immunity against the Leishmania infection. The cytokine profile (interleukin (IL)-12p70, interferon (IFN)-, C-X-C motif chemokine ligand (CXCL)-11 and IL-17a) of the isolated peripheral blood mononuclear cells (PBMCs) will be evaluated through ELISA. Real-time PCR will determine the C-X-C motif chemokine receptor (CXCR)-3 and IL-17a gene expression and expression of IL-12Rβ1 will be assessed by flow cytometry. Furthermore, IL-12B and IL-12RB1 mutation analysis will be performed.

Discussion

It is anticipated that the outcome of the current study will identify IL-12B and IL-12RB1 mutations, which lead to persistent lesions of CL. Furthermore, our expected results will reveal an association between NHCL and pro-inflammatory cytokines (IL-12p70, IFN- IL-17a and CXCL-11), as well as CXCR-3 expression.

Ethics and dissemination

This study has been approved by a local ethical committee. The final results will be disseminated through peer-reviewed journals and scientific conferences.

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Challenges in data quality: the influence of data quality assessments on data availability and completeness in a voluntary medical male circumcision programme in Zimbabwe

Objectives

To assess availability and completeness of data collected before and after a data quality audit (DQA) in voluntary medical male circumcision (VMMC) sites in Zimbabwe to determine the effect of this process on data quality.

Setting

4 of 10 VMMC sites in Zimbabwe that received a DQA in February, 2015 selected by convenience sampling.

Participants

Retrospective reviews of all client intake forms (CIFs) from November, 2014 and May, 2015. A total of 1400 CIFs were included from those 2 months across four sites.

Primary and secondary outcomes

Data availability was measured as the percentage of VMMC clients whose CIF was on file at each site. A data evaluation tool measured the completeness of 34 key CIF variables. A comparison of pre-DQA and post-DQA results was conducted using ² and t-tests.

Results

After the DQA, high record availability of over 98% was maintained by sites 3 and 4. For sites 1 and 2, record availability increased by 8.0% (p=0.001) and 9.7% (p=0.02), respectively. After the DQA, sites 1, 2 and 3 improved significantly in data completeness across 34 key indicators, increasing by 8.6% (p<0.001), 2.7% (p=0.003) and 3.8% (p<0.001), respectively. For site 4, CIF data completeness decreased by 1.7% (p<0.01) after the DQA.

Conclusions

Our findings suggest that CIF data availability and completeness generally improved after the DQA. However, gaps in documentation of vital signs and adverse events signal areas for improvement. Additional emphasis on data completeness would help support high-quality programme implementation and availability of reliable data for decision-making.

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Functional outcome after Mason II-III radial head and neck fractures: study protocol for a systematic review in accordance with the PRISMA statement

Introduction

Fractures of the radial head and neck are the most common fractures of the elbow, and account for approximately one-third of all elbow fractures. Depending on the fracture type the treatment is either conservative or surgical. There is no absolute consensus regarding optimal treatment for different fracture types. The aim of this protocol is to present the method that will be used to collect, describe and analyse the current evidence regarding the treatment of Mason II–III radial head and neck fractures.

Method and analysis

We will conduct a systematic review in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocol (PRISMA-P) guidelines statement. We will search a number of databases with a predefined search strategy to collect both randomised and non-randomised studies. The articles will be summarised with descriptive statistics. If applicable a meta-analysis will be conducted.

Ethics and dissemination

Ethical approval is not required since this is a protocol for a systematic review and no primary data will be collected. The authors will publish findings from this review in a peer-reviewed scientific journal.

Trial registration number

CRD42016037627.

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Guided internet-administered self-help to reduce symptoms of anxiety and depression among adolescents and young adults diagnosed with cancer during adolescence (U-CARE: YoungCan): a study protocol for a feasibility trial

Introduction

A subgroup of adolescents and young adults diagnosed with cancer during adolescence reports elevated levels of anxiety and depressive symptoms and unmet needs for psychological support. Evidence-based psychological treatments tailored for this population are lacking. This protocol describes a feasibility study of a guided-internet-administered self-help programme (YoungCan) primarily targeting symptoms of anxiety and depression among young persons diagnosed with cancer during adolescence and of the planned study procedures for a future controlled trial.

Methods/analysis

The study is an uncontrolled feasibility trial with a pre-post and 3-month follow-up design. Potential participants aged 15–25 years, diagnosed with cancer during adolescence, will be identified via the Swedish Childhood Cancer Registry. 30 participants will be included. Participants will receive YoungCan, a 12-week therapist-guided, internet-administered self-help programme consisting primarily of cognitive–behavioural therapy organised into individually assigned modules targeting depressive symptoms, worry and anxiety, body dissatisfaction and post-traumatic stress. Interactive peer support and psychoeducative functions are also available. Feasibility outcomes include: recruitment and eligibility criteria; data collection; attrition; resources needed to complete the study and programme; safety procedures; participants' and therapists' adherence to the programme; and participants' acceptability of the programme and study methodology. Additionally, mechanisms of impact will be explored and data regarding symptoms of anxiety, depression, post-traumatic stress, body dissatisfaction, reactions to social interactions, quality of life, axis I diagnoses according to the Mini International Neuropsychiatric Interview and healthcare service use will be collected. Exploratory analyses of changes in targeted outcomes will be conducted.

Ethics/dissemination

This feasibility protocol was approved by the Regional Ethical Review Board in Uppsala, Sweden (ref: 2016/210). Findings will be disseminated to relevant research, clinical, health service and patient communities through publications in peer-reviewed and popular science journals and presentations at scientific and clinical conferences.

Trial registration number

ISRCTN97835363.

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Proposal of quality indicators for cardiac rehabilitation after acute coronary syndrome in Japan: a modified Delphi method and practice test

Objectives

Cardiac rehabilitation is underused and its quality in practice is unclear. A quality indicator is a measurable element of clinical practice performance. This study aimed to propose a set of quality indicators for cardiac rehabilitation following an acute coronary event in the Japanese population and conduct a small-size practice test to confirm feasibility and applicability of the indicators in real-world clinical practice.

Design and setting

This study used a modified Delphi technique (the RAND/UCLA appropriateness method), a consensus method which involves an evidence review, a face-to-face multidisciplinary panel meeting and repeated anonymous rating. Evidence to be reviewed included clinical practice guidelines available in English or Japanese and existing quality indicators. Performance of each indicator was assessed retrospectively using medical records at a university hospital in Japan.

Participants

10 professionals in cardiac rehabilitation for the consensus panel.

Results

In the literature review, 23 clinical practice guidelines and 16 existing indicators were identified to generate potential indicators. Through the consensus-building process, a total of 30 indicators were assessed and finally 13 indicators were accepted. The practice test (n=39) revealed that 74% of patients underwent cardiac rehabilitation. Median performance of process measures was 93% (IQR 46–100%). ‘Communication with the doctor who referred the patient to cardiac rehabilitation’ and ‘continuous participation in cardiac rehabilitation’ had low performance (32% and 38%, respectively).

Conclusions

A modified Delphi technique identified a comprehensive set of quality indicators for cardiac rehabilitation. The single-site, small-size practice test confirmed that most of the proposed indicators were measurable in real-world clinical practice. However, some clinical processes which are not covered by national health insurance in Japan had low performance. Further studies will be needed to clarify and improve the quality of care in cardiac rehabilitation.

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New predictive model for microsurgical outcome of intracranial arteriovenous malformations: study protocol

Introduction

Although microsurgical resection is currently the first-line treatment modality for arteriovenous malformations (AVMs), microsurgery of these lesions is complicated due to the fact that they are very heterogeneous vascular anomalies. The Spetzler-Martin grading system and the supplementary grading system have demonstrated excellent performances in predicting the risk of AVM surgery. However, there are currently no predictive models based on multimodal MRI techniques. The purpose of this study is to propose a predictive model based on multimodal MRI techniques to assess the microsurgical risk of intracranial AVMs.

Methods and analysis

The study consists of 2 parts: the first part is to conduct a single-centre retrospective analysis of 201 eligible patients to create a predictive model of AVM surgery based on multimodal functional MRIs (fMRIs); the second part is to validate the efficacy of the predictive model in a prospective multicentre cohort study of 400 eligible patients. Patient characteristics, AVM features and multimodal fMRI data will be collected. The functional status at pretreatment and 6 months after surgery will be analysed using the modified Rankin Scale (mRS) score. The patients in each part of this study will be dichotomised into 2 groups: those with improved or unchanged functional status (a decreased or unchanged mRS 6 months after surgery) and those with worsened functional status (an increased mRS). The first part will determine the risk factors of worsened functional status after surgery and create a predictive model. The second part will validate the predictive model and then a new AVM grading system will be proposed.

Ethics and dissemination

The study protocol and informed consent form have been reviewed and approved by the Institutional Review Board of Beijing Tiantan Hospital Affiliated to Capital Medical University (KY2016-031-01). The results of this study will be disseminated through printed media.

Trial registration number

NCT02868008.

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Shock wave therapy associated with eccentric strengthening versus isolated eccentric strengthening for Achilles insertional tendinopathy treatment: a double-blinded randomised clinical trial protocol

Background

There is no consensus regarding the treatment of Achilles insertional tendinopathies. Eccentric training remains the main choice in the conservative treatment of this illness; however, the good results in the management of non-insertional Achilles tendinopathy were not replicated in the insertional condition. Low energy shock wave therapy has been described as an alternative to these patients, but has yet to be empirically tested.

Hypothesis

Shock wave therapy, adjunctive to the eccentric strengthening protocol, will improve measures of pain and function.

Design

Double blind, placebo-controlled, parallel groups, randomised clinical trial.

Materials and methods

93 patients with a diagnosis of chronic insertional tendinopathy, referred from primary or secondary healthcare services, will be assessed and enrolled in this study. They will be divided into two groups (randomised by sequentially numbered identical envelopes, which will be administered serially to participants), one containing the combination of low energy shock wave and eccentric exercises, as treatment and the other comprehending the exercises and the placebo treatment (an apparatus placed in the therapeutic head). The assessments will occur in 2, 4, 6, 12 and 24 weeks. Patients will be evaluated primarily by the Victorian Institute of Sport Assessment-Achilles questionnaire and secondarily by the visual analogue scale, Algometry, the American Orthopedic Foot and Ankle Society scale, the Foot and Ankle Outcome Score and the 12-item Short Form Health Survey. We will use comparison of two proportions via relative frequency analysis, the Pearson Correlation the ² test and the analysis of variance for statistical analyses.

Discussion

This study intends to demonstrate if the association of the eccentric exercise programme with the shock wave therapy can produce good results regarding the treatment of the Achilles insertional tendinopathy. In an attempt to prevent the high costs and complications associated with the surgical intervention, we will try to prove this combination as a viable therapeutic option in the conservative management of this prevalent condition. The strengths of the study are the design and the novelty of the combination of methods. The main limitation is the short follow-up course.

Ethics and dissemination

The study is registered in the Clinical Trials database (protocol number: 8094833648737701) and was approved by the University Ethics Committee (number: 1373481).

Trial registration number

8094833648737701 (NCT02757664); Pre-results.

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Psychological distress and type 2 diabetes mellitus: a 4-year policemen cohort study in China

Objectives

This study investigated whether psychological distress predicts the development of type 2 diabetes mellitus (T2DM) and if the association differs between populations at a high or low diabetes risk level among Chinese police officers.

Design

Prospective cohort study.

Setting

Single centre.

Participants

6559 participants underwent clinical measurements at the hospital in April 2007. 5811 police officers participated in the follow-up consisting of new-onset diabetes (NOD) events occurring annually between 2008 and 2011.

Primary outcome measures

Baseline data were collected from policemen who completed the Symptom Checklist 90-Revised (SCL-90-R) questionnaire and a self-designed questionnaire. Psychological distress was measured by the SCL-90-R questionnaire. Hong Kong Chinese Diabetes Risk Score (HKCDRS) was used to evaluate the risk of T2DM, and the participants were divided into low-risk group and high-risk group based on the HKCDRS. Cox proportional hazards regression was used to calculate the HRs of the incidence of T2DM related to psychological distress and further stratified the analysis based on HKCDRS.

Results

Among 5811 participants, 179 subjects developed NOD during the 4-year follow-up. 54 subjects (1.63%) with a HKCDRS 0–7 vs 125 subjects (4.98%) with a HKCDRS>7 developed NOD (p<0.05). There was a significant association between psychological distress and T2DM (HR=1.46; 95% CI 1.05 to 2.02). Among the participants with a high-risk score (HKCDRS>7), 7.07% of those with psychological distress developed T2DM compared with 4.43% of participants without psychological distress (p<0.05). The corresponding adjusted HR for psychological distress was 1.61 (95% CI 1.10 to 2.37).

Conclusions

Psychological distress is an independent risk factor for T2DM in this prospective cohort study. Stratification analysis indicated that psychological distress was associated with T2DM in a high-risk level population.

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A Review of NICE Methods and Processes Across Health Technology Assessment Programmes: Why the Differences and What is the Impact?

Abstract

Background

Decisions made by the National Institute for Health and Care Excellence (NICE) exert an influence on the allocation of resources within ‘fixed’ National Health Service budgets. Yet guidance for different types of health interventions is handled via different ‘programmes’ within NICE, which follow different methods and processes.

Objective

The objective of this research was to identify differences in the processes and methods of NICE health technology assessment programmes and to explore how these could impact on allocative efficiency within the National Health Service.

Methods

Data were extracted from the NICE technology appraisal programme, medical technologies guidance, diagnostic assessment programme, highly specialised technologies programme, and clinical guidelines process and methods manuals to undertake a systematic comparison. Five qualitative interviews were carried out with NICE members of staff and committee members to explore the reasons for the differences found.

Results

The main differences identified were in the required evidence review period, or lack thereof, mandatory funding status, the provision of a reference case for economic evaluation, the requirement for and the type of economic analysis undertaken, and the decision making criteria used for appraisal.

Conclusion

Many of the differences found can be justified on grounds of practicality and relevance to the health technologies under assessment. Nevertheless, from a strict utilitarian view, there are several potential areas of inefficiency that could lead to the misallocation of resources within the National Health Service, although some of these might be eliminated or reduced if an egalitarian view is taken. The challenge is determining where society is willing to trade health gains between different people.

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Corrigendum to “MicroRNA-196a/-196b promote cell metastasis via negative regulation of radixin in human gastric cancer” [Cancer Lett 351 (2014) 222–231]

The authors regret that in Fig. 3b the RDX/Actin expression in AZ-521 were mistakenly used the same image of SC-M1 with different exposure time. The correct blot for the data is now provided. The conclusions drawn from the figures or the findings reported in the paper are not affected.

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MRI follow-up is unnecessary in patients with macroprolactinomas and long-term normal prolactin levels on dopamine agonist treatment

Objective

Both antitumor and antisecretory efficacies of dopamine agonists (DA) make them the first-line treatment of macroprolactinomas. However, there is no guideline for MRI follow-up once prolactin is controlled. The aim of our study was to determine whether a regular MRI follow-up was necessary in patients with long-term normal prolactin levels under DA.

Patients and methods

We conducted a retrospective multicenter study (Marseille, Paris La Pitie Salpetriere and Nancy, France; Liege, Belgium) including patients with macroprolactinomas (largest diameter: >10 mm and baseline prolactin level: >100 ng/mL) treated by dopamine agonists, and regularly followed (pituitary MRI and prolactin levels) during at least 48 months once normal prolactin level was obtained.

Results

In total, 115 patients were included (63 men and 52 women; mean age at diagnosis: 36.3 years). Mean baseline prolactin level was 2224 ± 6839 ng/mL. No significant increase of tumor volume was observed during the follow-up. Of the 21 patients (18%) who presented asymptomatic hemorrhagic changes of the macroprolactinoma on MRI, 2 had a tumor increase (2 and 7 mm in the largest size). Both were treated by cabergoline (1 mg/week) with normal prolactin levels obtained for 6 and 24 months. For both patients, no further growth was observed on MRI during follow-up at the same dose of cabergoline.

Conclusion

No significant increase of tumor size was observed in our patients with controlled prolactin levels on DA. MRI follow-up thus appears unnecessary in patients with biologically controlled macroprolactinomas.

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Bone material strength index as measured by impact microindentation is altered in patients with acromegaly

Objective

Acromegaly is a rare disease caused by excess growth hormone (GH) production by the pituitary adenoma. The skeletal complications of GH and IGF-1 excess include increased bone turnover, increased cortical bone mass and deteriorated microarchitecture of trabecular bone, associated with a high risk of vertebral fractures in the presence of relatively normal bone mineral density (BMD). We aimed to evaluate tissue-level properties of bone using impact microindentation (IMI) in well-controlled patients with acromegaly aged ≥18 years compared to 44 controls from the outpatient clinic of the Centre for Bone Quality.

Design and methods

In this cross-sectional study, bone material strength index (BMSi) was measured in 48 acromegaly patients and 44 controls with impact microindentation using the osteoprobe.

Results

Mean age of acromegaly patients (54% male) was 60.2 years (range 37.9–76.5), and 60.5 years (range 39.8–78.6) in controls (50% male). Patients with acromegaly and control patients had comparable BMI (28.2 kg/m² ± 4.7 vs 26.6 kg/m² ± 4.3, P = 0.087) and comparable BMD at the lumbar spine (1.04 g/cm² ± 0.21 vs 1.03 g/cm² ± 0.13, P = 0.850) and at the femoral neck (0.84 g/cm² ± 0.16 vs 0.80 g/cm² ± 0.09, P = 0.246). BMSi was significantly lower in acromegaly patients than that in controls (79.4 ± 0.7 vs 83.2 ± 0.7; P < 0.001).

Conclusion

Our data indicates that tissue-level properties of cortical bone are significantly altered in patients with controlled acromegaly after reversal of long-term exposure to pathologically high GH and IGF-1 levels. Our findings also suggest that methods other than DXA should be considered to evaluate bone fragility in patients with acromegaly.

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Clinical features and practice patterns of treatment for adrenal crisis: a nationwide cross-sectional study in Japan

Context

Adrenal crisis is an endocrine emergency that requires prompt diagnosis and treatment. However, the clinical features and practice patterns of treatment for adrenal crisis are not completely understood.

Objective

To investigate patient characteristics, comorbidities and treatments of adrenal crisis.

Methods

We conducted a cross-sectional study of patients who received intravenous glucocorticoids for adrenal crisis at admission from 1 July 2007 to 31 March 2014, using a national inpatient database in Japan.

Results

Among approximately 34 million inpatients in the database, we identified 799 patients diagnosed with adrenal crisis and coexisting primary or secondary adrenal insufficiency at admission. The median (interquartile range) age was 58 (28–73) years, and the overall in-hospital mortality was 2.4% (19 of 799 patients). The most common comorbidity at admission was infections excluding pneumonia and gastroenteritis (15.0%). There were 68 (8.5%) patients with gastroenteritis, and no deaths occurred among these patients. The patients with secondary adrenal insufficiency showed significantly higher proportions of admission to ICU, extracellular fluid resuscitation, insulin therapy and catecholamine use than the patients with primary adrenal insufficiency. There were no significant between-group differences in mortality rate and variation in intravenous glucocorticoids (short-acting glucocorticoid, hydrocortisone; moderate-acting glucocorticoid, prednisolone or methylprednisolone; long-acting glucocorticoid, dexamethasone or betamethasone). Of the 19 dead patients, 15 were aged above 60 years, 12 had impaired consciousness at admission and 13 received insulin therapy.

Conclusions

Clinicians should be aware that older patients with impaired consciousness and diabetes mellitus are at relatively high risk of death from adrenal crisis.

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IJMS, Vol. 18, Pages 276: Development and Long-Term Stability of a Novel Microbial Fuel Cell BOD Sensor with MnO2 Catalyst

A novel microbial fuel cell (MFC)-based biosensor was designed for continuous monitoring of biochemical oxygen demand (BOD) in real wastewater. To lower the material cost, manganese dioxide (MnO2) was tested as an innovative cathode catalyst for oxygen reduction in a single chamber air-cathode MFC, and two different crystalline structures obtained during synthesis of MnO2 (namely β- and γ-MnO2) were compared. The BOD sensor was studied in a comprehensive way, using both sodium acetate solution and real domestic wastewater (DWW). The optimal performance of the sensor was obtained with a β-MnO2 catalyst, with R2 values of 0.99 and 0.98 using sodium acetate solution and DWW, respectively. The BOD values predicted by the β-MnO2 biosensor for DWW were in agreement with the BOD5 values, determined according to standard methods, with slight variations in the range from 3% to 12%. Finally, the long-term stability of the BOD biosensor was evaluated over 1.5 years. To the best of our knowledge, this is the first report of an MFC BOD sensor using an MnO2 catalyst at the cathode; the feasibility of using a low-cost catalyst in an MFC for online measurement of BOD in real wastewater broadens the scope of applications for such devices.

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Prenatal exposure to tobacco smoke sex dependently influences methylation and mRNA levels of the Igf axis in lungs of mouse offspring

Background: Prenatal smoke exposure is a risk factor for abnormal lung development and increased sex-dependent susceptibility for asthma and COPD. Birth cohort studies show genome wide DNA methylation changes in children from smoking mothers, but evidence for sex-dependent smoke-induced effects is limited. The insulin-like growth factor (IGF) system plays an important role in lung development. We hypothesized that prenatal exposure to smoke induces lasting changes in promoter methylation patterns of Igf1 and Igf1r, thus influencing transcriptional activity, and contributing to abnormal lung development. Method: We measured and compared mRNA levels along with promoter methylation of Igf1 and Igf1r and their protein concentrations in lung tissue of 30-day-old mice which had been prenatally exposed to cigarette smoke (PSE) or filtered air (control). Body weight at 30 days after birth was measured as global indicator of normal development. Results: Female PSE mice showed lower mRNA levels of Igf1 and its receptor (Igf1: p = 0.05; Igf1r: p = 0.03). Furthermore, CpG site specific methylation changes were detected in Igf1r in a sex-dependent manner and the body weight of female offspring was reduced after prenatal exposure to smoke, while protein concentrations were unaffected. Conclusion: Prenatal exposure to smoke induces a CpG-site specific loss of Igf1r promoter methylation, which can be associated with body weight. These findings highlight the sex-dependent and potentially detrimental effects of in utero smoke exposure on DNA methylation and Igf1 and Igf1r mRNA levels. The observations support a role for Igf1 and Igf1r in abnormal development.

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Vagal Innervation is Required for Pulmonary Function Phenotype in Htr4-/- Mice

Human genome-wide association studies (GWASs) have identified over 50 loci associated with pulmonary function and related phenotypes, yet follow-up studies to determine causal genes or variants are rare. Single nucleotide polymorphisms (SNPs) in serotonin receptor 4 (HTR4) are associated with human pulmonary function in genome-wide association studies and follow-up animal work has demonstrated that Htr4 is causally associated with pulmonary function in mice, although the precise mechanisms were not identified. We sought to elucidate the role of neural innervation and pulmonary architecture in the lung phenotype of Htr4^-/- animals. We report here that the Htr4^-/- phenotype in mouse is dependent on vagal innervation to the lung. Both, ex vivo tracheal ring reactivity and in vivo flexiVent™ pulmonary functional analyses demonstrate that vagotomy abrogates the Htr4^-/- airway hyperresponsiveness phenotype. Hyperpolarized ³He gas magnetic resonance imaging and stereological assessment of wild-type and Htr4^-/- mice reveal no observable differences in lung volume, inflation characteristics, or pulmonary-microarchitecture. Finally, control of breathing experiments reveal substantive differences in baseline breathing characteristics between mice with/without functional HTR4 in breathing frequency, relaxation time, flow rate, minute volume, time of inspiration and expiration and breathing pauses. These results suggest that HTR4's role in pulmonary function likely relates to neural innervation and control of breathing.

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Hypoxia Inhibits Expression and Function of Mitochondrial Thioredoxin 2 to Promote Pulmonary Hypertension

Pulmonary hypertension (PH) is characterized by increased pulmonary vascular resistance, pulmonary vascular remodeling, and increased pulmonary vascular pressures that often result in right ventricular dysfunction, leading to right heart failure. Evidence suggests that reactive oxygen species (ROS) contribute to PH pathogenesis by altering pulmonary vascular cell proliferation and intracellular signaling pathways. However, the role of mitochondrial antioxidants and oxidant-derived stress signaling in the development of hypoxia-induced PH is largely unknown. Therefore, we examined the role of the major mitochondrial redox regulator, thioredoxin 2 (Trx2). Levels of Trx2 mRNA and protein were examined in human pulmonary arterial endothelial cells (HPAECs) and smooth muscle cells (HPASMCs) exposed to hypoxia, a common stimulus for PH, for 72 hours. Hypoxia decreased Trx2 mRNA and protein levels. In vitro overexpression of Trx2 reduced hypoxia-induced H2O2 production. The effects of increased Trx2 protein level were examined in transgenic mice expressing human Trx2 (TghTrx2) that were exposed to hypoxia (10% O2) for 3 weeks. TghTrx2 mice exposed to hypoxia had exacerbated increases in right ventricular systolic pressures, right ventricular hypertrophy, and increased ROS in the lung tissue. Trx2 overexpression did not attenuate hypoxia-induced increases in Trx2 oxidation or Nox4 expression. Expression of a dominant negative C93S Trx2 mutant that mimics Trx2 oxidation exacerbated hypoxia-induced increases in HPASMC H2O2 levels and cell proliferation. In conclusion, Trx2 overexpression failed to attenuate hypoxia-induced HPASMC proliferation in vitro or hypoxia-induced PH in vivo. These findings indicate that strategies to enhance Trx2 expression are unlikely to exert therapeutic effects in PH pathogenesis.

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IMPACT OF THROMBOSIS ON PULMONARY ENDOTHELIAL INJURY AND REPAIR FOLLOWING SEPSIS

The prevailing morbidity and mortality in sepsis are largely due to multiple organ dysfunction (MOD), most commonly lung injury, as well as renal and cardiac dysfunction. Despite recent advances in defining many aspects of the pathogenesis of sepsis-related MOD, including acute respiratory distress syndrome (ARDS), there are currently no effective pharmacological or cell-based treatments for the disease. Human and animal studies have shown that pulmonary thrombosis is common in sepsis-induced ARDS, and pre-clinical studies have shown that anti-coagulation may improve outcome following sepsis challenge. The potential beneficial effect of anti-coagulation on outcome is unconvincing in clinical studies, however, and these discrepancies may arise from the multiple and sometimes opposing actions of thrombosis on the pulmonary endothelium following sepsis. It has been suggested, for example, that mild pulmonary thrombosis prevents escape of bacterial infection into the circulation, while severe thrombosis causes hypoxia and results in pulmonary endothelial damage. Evidence from both human and animal studies has demonstrated the key role of microvascular leakage in determining the outcome of sepsis. In this review, we describe thrombosis-dependent mechanisms that regulate pulmonary endothelial injury and repair following sepsis, including activation of the coagulation cascade by tissue factor, and stimulation of vascular repair by hypoxia-inducible factors. Targeting such mechanisms through anti-coagulant, anti-inflammatory, and reparative methods may represent a novel approach for the treatment of septic patients.

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Protein Biomarkers Associated with Primary Graft Dysfunction Following Lung Transplantation

Severe primary graft dysfunction affects 15-20% of lung transplantation recipients and carries a high mortality risk. In addition to known donor, recipient, and perioperative clinical risk factors, numerous biologic factors are thought to contribute to primary graft dysfunction. Our current understanding of the pathogenesis of lung injury and primary graft dysfunction emphasizes multiple pathways leading to lung endothelial and epithelial injury. Biomarkers specific to these pathways can be measured in the plasma, bronchoalveolar lavage fluid, and lung tissue. Clarification of the pathophysiology and timing of primary graft dysfunction could illuminate predictors of dysfunction, allowing for better risk stratification, earlier identification of susceptible recipients, and development of targeted therapies. Here, we review much of what has been learned in biomarker studies about the pathogenesis of primary graft dysfunction, and evaluate the potential prognostic value of biomarkers for primary graft dysfunction at different measurement time-points.

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Leonardo da Vinci: engineer, bioengineer, anatomist and artist

Leonardo da Vinci (1452-1519) enjoys a reputation as one of the most talented people of all time in the history of science and the arts. However little attention has been given to his contributions to physiology. One of his main interests was engineering, and he was fascinated by structural problems, and the flow patterns of liquids. He also produced a large number of ingenious designs for warfare, and a variety of highly original flying machines. But of particular interest to us are his contributions to bioengineering, and how he used his knowledge of basic physical principles to throw light on physiological function. For example he produced new insights into the mechanics of breathing including the action of the ribs and diaphragm. He was the first person to understand the different roles of the internal and external intercostal muscles. He had novel ideas about the airways including the mode of airflow in them. He also worked on the cardiovascular system and had a special interest in the pulmonary circulation. But interestingly he was not able to completely divorce his views from those of Galen, in that although he could not see pores in the interventricular septum of the heart, one of his drawings included them. Leonardo was a talented anatomist who made many striking drawings of the human body. Finally his reputation for many people is based on his paintings including the Mona Lisa that apparently attracts more viewers than any other painting in the world.

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Hydrogen peroxide is a critical regulator of the hypoxia-induced alterations of store-operated Ca2+ entry into rat pulmonary arterial smooth muscle cells

To investigate the association between store-operated Ca2+ entry (SOCE) and reactive oxygen species (ROS) during hypoxia, this study determined the changes of transient receptor potential canonical 1 (TRPC1) and Orai1, two candidate proteins for store-operated Ca2+ (SOC) channels and their gate regulator, stromal interaction molecule 1 (STIM1) in a hypoxic environment and their relationship with ROS in pulmonary arterial smooth muscle cells (PASMCs). Exposing to hypoxia, a transient Ca2+ spike and subsequent Ca2+ plateau of SOCE in PASMCs were intensified when TRPC1, STIM1 and Orai1 were upregulated. SOCE in cells transfected with specific small hairpin RNA (shRNA) constructs was almost completely eliminated by the knockdown of TRPC1, STIM1 or Orai1 alone and was no longer affected by hypoxia exposure. Hypoxia-induced SOCE enhancement was further strengthened by PEG-SOD but attenuated by PEG-catalase, with correlated changes to intracellular hydrogen peroxide (H2O2) levels and protein levels of TRPC1, STIM1 and Orai1. Exogenous H2O2 could mimic alterations of the interactions of STIM1 with TRPC1 and Orai1 in hypoxic cells. These findings suggest that TRPC1, STIM1 and Orai1 are essential for the initiation of SOCE in PASMCs. Hypoxia-induced ROS promoted the expression and interaction of the SOC channel molecules and their gate regulator via their converted product, H2O2.

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Ca2+/Calmodulin-Dependent Protein Kinase II{beta} and II{delta} Mediate TGF{beta}-Induced Transduction of Fibronectin and Collagen in Human Pulmonary Fibroblasts

It is now clear that in addition to activating several complex kinase pathways (Smad, MAP kinase, PI3 kinase), TGFβ also acts by elevating [Ca2+] within the cytosol of human pulmonary fibroblasts. Ca2+/calmodulin-dependent protein kinase II (CamK II) is also known to regulate gene expression in fibroblasts. In this study, we examined the interactions between calcium signaling, activation of CamK and other kinases, and extracellular matrix (ECM) gene expression. Human pulmonary fibroblasts were cultured and stimulated with artificially-generated Ca2+-pulses in the absence of TGFβ, or with TGFβ (1 nM) or vehicle in the presence of various blockers of Ca2+ signaling. PCR and Western blotting were used to measure gene expression and protein levels, respectively. We found that Ca2+-pulses in the absence of TGFβ increased ECM gene expression in a pulse frequency-dependent manner, and that blocking Ca2+ signaling and the CamK II pathway significantly reduced TGFβ-mediated ECM gene expression, without having any effects on other kinase pathways (Smad, PI3 kinase or MAP kinase). We also found that TGFβ elevated the expression of CamK IIβ and CamK II, while siRNA silencing of those two subtypes significantly reduced TGFβ-mediated expression of collagen A1 and Fibronectin 1. Our data suggest that TGFβ induces the expression of CamK IIβ and CamK II, which in turn are activated by TGFβ-evoked Ca2+ waves in a frequency-dependent manner, leading to increased expression of ECM proteins.

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Magnetic Resonance Imaging of Disease Progression and Resolution in a Transgenic Mouse Model of Pulmonary Fibrosis

Pulmonary fibrosis contributes to morbidity and mortality in a range of diseases, and there are no approved therapies for reversing its progression. To understand the mechanisms underlying pulmonary fibrosis and assess potential therapies, mouse models are central to basic and translational research. Unfortunately, metrics commonly used to assess murine pulmonary fibrosis require animals to be grouped and sacrificed, increasing experimental difficulty and cost. We examined the ability of three magnetic resonance imaging (MRI)-derived metrics (mean weighted lung signal, percent high signal volume, and signal coefficient of variation) to non-invasively assess lung fibrosis progression and resolution in a doxycycline (Dox) regulatable, transgenic mouse model that overexpresses transforming growth factor alpha (TGF-α) under control of a lung-epithelial-specific promoter. During seven weeks of Dox-treatment, fibrotic lesions were readily observed as high-signal tissue. Mean weighted signal and percent signal volume were found to be the most robust MRI-derived measures of fibrosis, and these metrics correlated significantly with pleural thickness, histology scores, and hydroxyproline content (R=0.75-0.89). When applied longitudinally, percent high signal volume increased by 1.5% week^-1 (p<0.001), and mean weighted signal increased at a rate of 0.0065 week^-1 (p=0.0062). Following Dox-treatment, lesions partially resolved, with percent high signal volume decreasing by -3.2% week^-1 (p=0.0034) and weighted mean signal decreasing at -0.015 week^-1 (p=0.0028). Additionally, longitudinal MRI revealed dynamic remodeling in a subset of lesions-a previously unobserved behavior in this model. These results demonstrate MRI can non-invasively assess experimental lung fibrosis progression and resolution and provide unique insights into its pathobiology.

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Psychosocial Factors in the Relationship between Socioeconomic Status and Cardiometabolic Risk: the HCHS/SOL Sociocultural Ancillary Study

Abstract

Background

U.S. Hispanics/Latinos display a high prevalence of metabolic syndrome (MetSyn), a group of co-occurring cardiometabolic risk factors (abdominal obesity, impaired fasting glucose, dyslipidemia, elevated blood pressure) associated with higher cardiovascular disease and mortality risk. Low socioeconomic status (SES) is associated with higher risk for MetSyn in Hispanics/Latinos, and psychosocial factors may play a role in this relationship.

Purpose

This cross-sectional study examined psychosocial factors in the association of SES and MetSyn components in 4,996 Hispanic/Latino adults from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Sociocultural Ancillary Study.

Methods

MetSyn components were measured at the baseline examination. Participants completed interviews to determine psychosocial risks (e.g., depression) and resources (e.g., social support) within 9 months of baseline (< 4 months in 72.6% of participants). Confirmatory factor analysis (CFA) and structural equation modeling (SEM) were used to identify latent constructs and examine associations.

Results

Participant mean age was 41.7 years (SE = 0.4) and 62.7% were female. CFA identified single latent factors for SES and psychosocial indicators, and three factors for MetSyn [blood pressure, lipids, metabolic factors]. SEMs showed that lower SES was related to MetSyn factors indirectly through higher psychosocial risk/lower resources (Y-Bχ² (df = 420) = 4412.90, p < .05, RMSEA = .042, SRMR = .051). A statistically significant effect consistent with mediation was found from lower SES to higher metabolic risk (glucose/waist circumference) via psychosocial risk/resource variables (Mackinnon’s 95% asymmetric CI = −0.13 to −0.02).

Conclusions

SES is related to metabolic variables indirectly through psychosocial factors in U.S. Hispanics/Latinos of diverse ancestries.

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Transcervical ultrasonographic examination of palatine tonsil size and its correlation with age, gender and body-mass index in healthy children

Our aim was to assess the palatine tonsil size with transcervical ultrasonography in healthy children and to analyze whether the palatine tonsil size is correlated with age, gender and body-mass index (BMI).

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A single non-synonymous NCOA5 variation in type 2 diabetic patients with hepatocellular carcinoma impairs the function of NCOA5 in cell cycle regulation

Type 2 Diabetes (T2D) is a risk factor for hepatocellular carcinoma (HCC). We have previously described that haploinsufficiency of nuclear receptor coactivator 5 (NCOA5) is a genetic defect linking glucose intolerance to HCC. Here we report identification and characterization of a single nucleotide variation (T445A) in NCOA5, causing an amino acid Thr to Ala substitution, in adjacent non-tumorous liver tissues derived from patients with concurrent HCC and T2D. By using Tet-On inducible expression cells, we show that ectopic expression of NCOA5wt suppressed proliferation of HCC cells via induction of G2/M arrest, while ectopic expression of NCOA5T445A had a significantly lesser effect compared to ectopic expression of NCOA5wt.

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Mitochondrial Omi/HtrA2 Promotes Caspase Activation Through Cleavage of HAX-1 in Aging Heart

Rejuvenation Research , Vol. 0, No. 0.


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Free Dermal Fat Graft Reconstruction of the Head and Neck: An Alternate Reconstructive Option

Ablative procedures of the head and neck often result in significant facial and cervical irregularities and cosmetic asymmetry. The deformity resulting from ablative procedures of the head and neck is a significant source of cosmetic morbidity and postoperative dissatisfaction. Reconstruction of post-ablative defects in the head and neck can employ a broad range of techniques, ranging from primary closure to free tissue transfer. The free dermal fat graft (FDFG) is one such option and has been used to repair volume defects of varying sizes after common head and neck procedures such as parotidectomy.

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CYP27A1 loss dysregulates cholesterol homeostasis in prostate cancer

In this study, we used a bioinformatic approach to identify genes whose expression is dysregulated in human prostate cancers. One of the most dramatically downregulated genes identified encodes CYP27A1, an enzyme involved in regulating cellular cholesterol homeostasis. Importantly, lower CYP27A1 transcript levels were associated with shorter disease-free survival and higher tumor grade. Loss of CYP27A1 in prostate cancer was confirmed at the protein level by immunostaining for CYP27A1 in annotated tissue microarrays. Restoration of CYP27A1 expression in cells where its gene was silenced attenuated their growth in vitro and in tumor xenografts. Studies performed in vitro revealed that treatment of prostate cancer cells with 27-hydroxycholesterol (27HC), an enzymatic product of CYP27A1, reduced cellular cholesterol content in prostate cancer cell lines by inhibiting the activation of sterol regulatory-element binding protein 2 (SREBP2) and downregulating low-density lipoprotein receptor (LDLR) expression. Our findings suggest that CYP27A1 is a critical cellular cholesterol sensor in prostate cells and that dysregulation of the CYP27A1/27HC axis contributes significantly to prostate cancer pathogenesis.

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HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells

Ferroptosis is a form of regulated cell death driven by oxidative injury promoting lipid peroxidation, although detailed molecular regulators are largely unknown. Here we show that heat shock 70kDa protein 5 (HSPA5) negatively regulates ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, activating transcription factor 4 (ATF4) resulted in the induction of HSPA5, which in turn bound glutathione peroxidase 4 (GPX4) and protected against GPX4 protein degradation and subsequent lipid peroxidation. Importantly, the HSPA5-GPX4 pathway mediated ferroptosis resistance, limiting the anticancer activity of gemcitabine. Genetic or pharmacological inhibition of the HSPA5-GPX4 pathway enhanced gemcitabine sensitivity by disinhibiting ferroptosis in vitro and in both subcutaneous and orthotopic animal models of PDAC. Collectively, these findings identify a novel role of HSPA5 in ferroptosis and suggest a potential therapeutic strategy for overcoming gemcitabine resistance.

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Effective combination therapies for B cell lymphoma predicted by a virtual disease model

The complexity of cancer signaling networks limits the efficacy of most single-agent treatments and brings about challenges in identifying effective combinatorial therapies. In this study, we used chronic active B cell receptor (BCR) signaling in diffuse large B cell lymphoma (DLBCL) as a model system to establish a computational framework to optimize combinatorial therapy in silico. We constructed a detailed kinetic model of the BCR signaling network, which captured the known complex crosstalk between the NFκB, ERK, and AKT pathways and multiple feedback loops. Combining this signaling model with a data-derived tumor growth model, we predicted viability responses of many single drugs and drug combinations in agreement with experimental data. Under this framework, we exhaustively predicted and ranked the efficacy and synergism of all possible combinatorial inhibitions of eleven currently targetable kinases in the BCR signaling network. Ultimately, our work establishes a detailed kinetic model of the core BCR signaling network and provides the means to explore the large space of possible drug combinations. Major Findings: Using chronic active B cell receptor (BCR) signaling in diffuse large B cell lymphoma (DLBCL) as a model system, we developed a kinetic-modeling based computational framework for predicting effective combination therapy in silico. By integrative modeling of signal transduction, drug kinetics and tumor growth, we were able to directly predict drug-induced cell viability responses at various dosages, which were in agreement with published cell line experimental data. We implemented computational screening methods that identified potent and synergistic combinations in silico and validated our independent predictions in vitro.

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