bluuebunny/crossref_metadata_2025 huggingface dataset:
In Vitro
and
In Vivo
Activities of DS-2969b, a Novel GyrB Inhibitor, against Clostridium difficile
Authors: Mathur Tarun , Barman Tarani Kanta , Kumar Manoj , Singh Diksha , Kumar Ram , Khera Manoj Kumar , Yamada Makiko , Inoue Shin-ichi , Upadhyay Dilip Jatashankar , Masuda Nobuhisa
Published: February 2018

DS-2969b is a novel GyrB inhibitor that is currently under clinical development for the treatment of
Clostridium difficile
infection (CDI). In this study, the
in vitro
and
in vivo
activities of DS-2969b were evaluated. DS-2969b inhibited the supercoiling activity of
C. difficile
DNA gyrase. DS-2969b showed potent
in vitro
activity against
C. difficile
clinical isolates with a MIC
90
of 0.06 μg/ml, which was 2-, 32-, and 16-fold lower than the MIC
90
s of fidaxomicin, vancomycin, and metronidazole, respectively. DS-2969b did not select spontaneously resistant mutants of various
C. difficile
strains at 4× MIC, and the frequency of resistance development was less than 4.8 × 10
−9
. In a hamster CDI model, 5-day oral administration of DS-2969b conferred complete protection from recurrence and mortality at 0.3 mg/kg of body weight once a day, in contrast to a 50% survival rate with fidaxomicin at 3 mg/kg once a day and 0% with vancomycin at a 50-mg/kg/dose twice a day. Even a single oral administration of 1 mg/kg of DS-2969b in the CDI model exhibited 100% animal survival without recurrence. DS-2969b was also efficacious by 5-day subcutaneous administration in the CDI model. DS-2969b showed similar levels of fecal excretion after intravenous and oral administrations in rats. These data support further development of DS-2969b as a drug for oral and intravenous treatment of CDI.
Optimization of Brucella abortus Protocols for Downstream Molecular Applications
Authors: Hull Noah , Miller Jonathan , Berry David , Laegreid William , Smith Ashley , Klinghagen Callie , Schumaker Brant
Published: February 2018

We compared the performances of various DNA extraction kits for their ability to recover
Brucella abortus
strain 19 inoculated into
Brucella
-free bovine tissues. Tissues were homogenized in a FastPrep bead homogenizer and extracted in triplicate by using one of five kits (Qiagen DNeasy, GE Illustra, Omega Bio-tek E.Z.N.A., Quanta Extracta, and IBI Science DNA Tissue kit). Whole blood was also taken from animals prior to chemical euthanasia, aliquoted, and then fractioned into buffy coat, red blood cells, and plasma. DNA was extracted from whole blood, buffy coat, and plasma by using four kits (Qiagen DNeasy, Omega Bio-tek E.Z.N.A., IBI Science DNA Blood kit, and 5PRIME PerfectPure). Previously reported primers targeting strain 19 were used to amplify extracted DNA and identify the optimal extraction kit. Real-time PCR was performed, and kits were compared for statistical differences by using quantification cycles as an outcome measure. Omega Bio-tek E.Z.N.A. was superior (
P
< 0.0068) in its lower quantification cycle values across all tissue kits. The IBI Science DNA Blood kit was superior to Qiagen DNeasy, 5PRIME PerfectPure, and Quanta Extracta (
P
< 0.0001,
P
= 0.0004, and
P
= 0.0013, respectively) but was not different from Omega Bio-tek E.Z.N.A. (
P
= 1.0). In summary, the optimal extraction kit for
B. abortus
strain 19 for tissues is Omega Bio-tek E.Z.N.A., and that for blood and its fractions is the IBI Science Mini Genomic DNA kit. Eluted DNA was also concentrated by using the Zymo Research DNA Clean & Concentrator-25 kit. Concentrated eluted DNA with the target was superior (
P
= <0.0001) to unconcentrated eluted DNA.
Fifteen-minute consultation: The child with an incidental finding of elevated aminotransferases
Authors: Hegarty Robert , Dhawan Anil
Published: February 2018

It is not unusual to encounter abnormal liver enzyme levels on routine blood tests. When the abnormal elevation in aminotransferases persist, they require prompt and appropriate investigations as liver diseases in children are often insidious in onset and clinically silent. This article aims to provide (1) an explanation to the aetiologies of elevated aminotransferases; (2) an investigational approach to these children and (3) an insight into further investigations performed at a liver centre.
Impact of malnutrition on survival and healthcare utilization in Medicare beneficiaries with diabetes: a retrospective cohort analysis
Authors: Ahmed Naseer , Choe Yong , Mustad Vikkie A , Chakraborty Sumita , Goates Scott , Luo Menghua , Mechanick Jeffrey I
Published: February 2018

Objective

The aim of this study was to examine the impact of pre-existing malnutrition on survival and economic implications in elderly patients with diabetes.

Research design and methods

A retrospective observational study was conducted to examine the impact of malnutrition with or without other significant health conditions on survival time and healthcare costs using the Centers for Medicare and Medicaid Services (CMS) data from 1999 to 2014 for beneficiaries with a confirmed first date of initial diagnosis of diabetes (n=15 121 131). The primary outcome was survival time, which was analyzed using all available data and after propensity score matching. Healthcare utilization cost was a secondary outcome.

Results

A total of 801 272 beneficiaries were diagnosed with malnutrition. The analysis on propensity score-matched data for the effect of common conditions on survival showed that the risk for death in beneficiaries with diabetes increased by 69% in malnourished versus normo-nourished (HR, 1.69; 99.9% CI 1.64 to 1.75; P<0.0001) beneficiaries. Malnutrition increased the risk for death within each of the common comorbid conditions including ischemic heart disease (1.63; 1.58 to 1.68), chronic obstructive pulmonary disorder (1.60; 1.55 to 1.65), stroke or transient ischemic attack (1.57; 1.53 to 1.62), heart failure (1.54; 1.50 to 1.59), chronic kidney disease (1.50; 1.46 to 1.55), and acute myocardial infarction (1.47; 1.43 to 1.52). In addition, the annual total spending for the malnourished beneficiaries was significantly greater than that for the normo-nourished beneficiaries ($36 079 vs 20 787; P<0.0001).

Conclusions

Malnutrition is a significant comorbidity affecting survival and healthcare costs in CMS beneficiaries with diabetes. Evidence-based clinical decision pathways need to be developed and implemented for appropriate screening, assessment, diagnosis and treatment of malnourished patients, and to prevent malnutrition in normo-nourished patients with diabetes.
Applying a health system perspective to the evolving Farmácia Popular medicines access programme in Brazil
Authors: Luiza Vera L , Chaves Luisa A , Campos Monica R , Bertoldi Andrea D , Silva Rondineli M , Bigdeli Maryam , Ross-Degnan Dennis , Emmerick Isabel C M
Published: February 2018

The Farmácia Popular Program (FPP) launched a subsidy system in Brazil, but in coexistence with the ongoing regular governmental access to medicines (Unified Health System (SUS) dispensings) mechanisms, causing overlaps in terms of financing and target population. This characteristic is quite different from most countries with medicines cost-sharing schemes. This paper aims to analyse the FPP under a health systems perspective considering the different health system levels. We analysed the findings from the study ‘Impact of consecutive subsidies policies on access to and use of medicines in Brazil – ISAUM-Br’, designed with the objective of describing and evaluating the impact of the government medicines subsidy policies implemented between 2004 and 2011. Patient share of copayment increased with the implementation of the intervention, which decreased the reference price and decreased with SNP (Saúde Não Tem Preço; zero copayment for patients). There was an increased number of FPP dispensations over time, but SUS dispensings remained the most important source for medicines, especially for hypertension and diabetes. FPP allowed the establishment of a well-designed pharmaceutical information system in the country. Despite the improvement on control mechanism, fraud remained a problem. There were important effects on the pharmaceutical market and sales of generic medicines. FPP has proven to be a very important policy for promoting access to medicines for hypertension and diabetes in Brazil. Examining this policy with a health system perspective has allowed us to highlight many of its important consequences, including for the first time a broad and consistent information system on access to medicines in the country.
Does high-carbohydrate intake lead to increased risk of obesity? A systematic review and meta-analysis
Authors: Sartorius Kurt , Sartorius Benn , Madiba Thandinkosi E , Stefan Cristina
Published: February 2018

Objectives

The present study aimed to test the association between high and low carbohydrate diets and obesity, and second, to test the link between total carbohydrate intake (as a percentage of total energy intake) and obesity.

Setting, participants and outcome measures

We sought MEDLINE, PubMed and Google Scholar for observation studies published between January 1990 and December 2016 assessing an association between obesity and high-carbohydrate intake. Two independent reviewers selected candidate studies, extracted data and assessed study quality.

Results

The study identified 22 articles that fulfilled the inclusion and exclusion criteria and quantified an association between carbohydrate intake and obesity. The first pooled strata (high-carbohydrate versus low-carbohydrate intake) suggested a weak increased risk of obesity. The second pooled strata (increasing percentage of total carbohydrate intake in daily diet) showed a weak decreased risk of obesity. Both these pooled strata estimates were, however, not statistically significant.

Conclusions

On the basis of the current study, it cannot be concluded that a high-carbohydrate diet or increased percentage of total energy intake in the form of carbohydrates increases the odds of obesity. A central limitation of the study was the non-standard classification of dietary intake across the studies, as well as confounders like total energy intake, activity levels, age and gender. Further studies are needed that specifically classify refined versus unrefined carbohydrate intake, as well as studies that investigate the relationship between high fat, high unrefined carbohydrate–sugar diets.

PROSPERO registration number

CRD42015023257.
Moving towards a better path? A mixed-method examination of China’s reforms to remedy medical corruption from pharmaceutical firms
Authors: Shi Jianwei , Liu Rui , Jiang Hua , Wang Chunxu , Xiao Yue , Liu Nana , Wang Zhaoxin , Shi Leiyu
Published: February 2018

Objectives

Few studies have systematically examined the effects of the existing regulations for alleviating corruption in China. This study assesses the effectiveness of China’s reforms to curb medical corruption.

Methods

We used mixed methods for the evaluation of existing countermeasures. First, qualitative informant interviews based on the Donabedian model were conducted to obtain experts’ evaluation of various kinds of countermeasures. Second, using data from ‘China Judgements Online’, we analysed the trend of occurrence and the characteristics of the medical corruption cases in recent years to reflect the overall effects of these countermeasures in China.

Results

Since 1990s, China has implemented three main categories of countermeasures to oppose medical corruption: fines and criminal penalties, health policy regulations, and reporting scheme policy. Information from the interviews showed that first the level of fines and criminal penalties for medical corruption behaviours may not be sufficient. Second, health policy regulations are also insufficient. Although the National Reimbursement Drug List and Essential Drug List were implemented, they were incomplete and created additional opportunities for corruption. Moreover, the new programme that centralised the purchase of pharmaceuticals found that most purchasing committees were not independent, and the selection criteria for bidding lacked scientific evidence. Third, the reporting scheme for commercial bribery records by the health bureau was executed poorly. In addition, quantitative online data showed no obvious decrease of institutional medical corruption in recent years, and most criminals have been committing crimes for a long time before getting detected, which further demonstrated the low effectiveness of the above countermeasures.

Conclusions

Although existing countermeasures have exerted certain effects according to Chinese experts, more rigorous legislation and well-functioning administrative mechanisms are needed. Fundamentally, financial incentives for hospitals/physicians and the health insurance system should be improved.
Sport and exercise medicine consultants are reliable in assessing tendon neovascularity using ultrasound Doppler
Authors: Watson James , Barker-Davies Robert M , Bennett Alexander N , Fong Daniel T P , Wheeler Patrick C , Lewis Mark , Ranson Craig
Published: February 2018

Objective

Several lower limb tendinopathy treatment modalities involve identification of pathological paratendinous or intratendinous neovascularisation to target proposed co-location of painful neoneuralisation. The ability to reliably locate and assess the degree of neovascularity is therefore clinically important. The Modified Ohberg Score (MOS) is frequently used to determine degree of neovascularity, but reliability has yet to be established among Sport and Exercise Medicine (SEM) consultants. This study aims to determine inter-rater and intra-rater reliability of an SEM consultant cohort when assessing neovascularity using the 5-point MOS.

Method

Eleven participants (7 male and 4 female) provided 16 symptomatic Achilles and patella tendons. These were sequentially examined using power Doppler (PD) enabled ultrasound (US) imaging by 6 SEM consultants who rated neovascular changes seen using the MOS. Representative digital scan images were saved for rescoring 3 weeks later. Inter-rater and intra-rater reliability of the MOS was examined using intraclass correlation coefficient (ICC) and Kappa Agreement scores.

Results

Neovascular changes were reported in 65.6% of 96 scans undertaken. ICC for inter-rater reliability was 0.86 and Fleiss Kappa 0.52. ICC for intra-rater reliability was 0.95 and Weighted Kappa 0.91.

Conclusions

Neovascular changes were present in two-thirds of symptomatic tendons. Excellent SEM consultant inter-rater and intra-rater reliability was demonstrated. These findings support the use of PD-enabled US to assess neovascularity by appropriately experienced SEM consultants. Furthermore, future interventional research using a similarly experienced SEM consultant cohort can be undertaken with assurance that assessment of neovascularity will be reliable.
Hospital-treated injuries from horse riding in Victoria, Australia: time to refocus on injury prevention?
Authors: O’Connor Siobhán , Hitchens Peta L , Fortington Lauren V
Published: February 2018

Background

The most recent report on hospital-treated horse-riding injuries in Victoria was published 20 years ago. Since then, injury countermeasures and new technology have aimed to make horse riding safer for participants. This study provides an update of horse-riding injuries that required hospital treatment in Victoria and examines changes in injury patterns compared with the earlier study.

Methods

Horse-riding injuries that required hospital treatment (hospital admission (HA) or emergency department (ED) presentations) were extracted from routinely collected data from public and private hospitals in Victoria from 2002–2003 to 2015–2016. Injury incidence rates per 100 000 Victorian population per financial year and age-stratified and sex-stratified injury incidence rates are presented. Poisson regression was used to examine trends in injury rates over the study period.

Results

ED presentation and HA rates were 31.1 and 6.6 per 100 000 person-years, increasing by 28.8% and 47.6% from 2002 to 2016, respectively. Female riders (47.3 ED and 10.1 HA per 100 000 person-years) and those aged between 10 and 14 years (87.8 ED and 15.7 HA per 100 000 person-years) had the highest incidence rates. Fractures (ED 29.4%; HA 56.5%) and head injuries (ED 15.4%; HA 18.9%) were the most common injuries. HA had a mean stay of 2.6±4.1 days, and the mean cost per HA was $A5096±8345.

Conclusion

Horse-riding injuries have remained similar in their pattern (eg, types of injuries) since last reported in Victoria. HA and ED incidence rates have increased over the last 14 years. Refocusing on injury prevention countermeasures is recommended along with a clear plan for implementation and evaluation of their effectiveness in reducing injury.
Hospital end-of-life care in haematological malignancies
Authors: Beaussant Yvan , Daguindau Etienne , Chauchet Adrien , Rochigneux Philippe , Tournigand Christophe , Aubry Régis , Morin Lucas
Published: February 2018

Objective

To investigate patterns of care during the last months of life of hospitalised patients who died from different haematological malignancies.

Methods

Nationwide register-based study, including all hospitalised adults ≥20 years who died from haematological malignancies in France in 2010–2013. Outcomes included use of invasive cancer treatments and referral to palliative care. Percentages are adjusted for sex and age using direct standardisation.

Results

Of 46 629 inpatients who died with haematological malignancies, 24.5% received chemotherapy during the last month before death, 48.5% received blood transfusion, 12.3% were under invasive ventilation and 18.1% died in intensive care units. We found important variations between haematological malignancies. The use of chemotherapy during the last month of life varied from 8.6% among patients with chronic myeloid leukaemia up to 30.1% among those with non-Hodgkin’s lymphoma (P<0.001). Invasive ventilation was used in 10.2% of patients with acute leukaemia but in 19.0% of patients with Hodgkin’s lymphoma (P<0.001). Palliative status was reported 30 days before death in only 14.8% of patients, and at time of death in 46.9% of cases. Overall, 5.5% of haematology patients died in palliative care units.

Conclusion

A high proportion of patients who died from haematological malignancies receive specific treatments near the end of life. There is a need for a better and earlier integration of the palliative care approach in the standard practice of haematology. However, substantial variation according to the type of haematological malignancy suggests that the patients should not be considered as one homogeneous group. Implementation of palliative care should account for differences across haematological malignancies.
Development and validation of diagnostic triage criteria for liver disease from a minimum data set enabling the ‘intelligent LFT’ pathway for the automated assessment of deranged liver enzymes
Authors: Miller Michael Hugh , Fraser Andrew , Leggett Gillian , MacGilchrist Alastair , Gibson George , Orr James , Forrest Ewan H , Dow Ellie , Bartlett William , Weatherburn Chirstopher , Laurell Axel , Grant Kirsty , Scott Kathryn , Neville Ronald , Dillon John F
Published: February 2018

Background

Liver function tests (LFTs) are commonly abnormal; most patients with ‘incidental’ abnormal LFTs are not investigated appropriately and for those who are, current care pathways are geared to find an explanation for the abnormality by a lengthy process of investigation and exclusion, with costs to the patient and to the health service.

Objective

To validate an intelligent automatable analysis tool (iLFT) for abnormal liver enzymes, which diagnoses common liver conditions, provides fibrosis stage and recommends management

Design

A retrospective case note review from three tertiary referral liver centres, with application of the iLFT algorithm and comparison with the clinician’s final opinion as gold standard.

Results

The iLFT algorithm in 91.3% of cases would have correctly recommended referral or management in primary care. In the majority of the rest of the cases, iLFT failed safe and recommended referral even when the final clinical diagnosis could have been managed in primary care. Diagnostic accuracy was achieved in 82.4% of cases, consistent with the fail-safe design of the algorithm. Two cases would have remained in primary care as per the algorithm outcome, however on clinical review had features of advanced fibrosis.

Conclusion

iLFT analysis of abnormal liver enzymes offers a safe and robust method of risk stratifying patients to the most appropriate care pathway as well as providing reliable diagnostic information based on a single blood draw, without repeated contacts with health services. Offers the possibility of high quality investigation and diagnosis to all patients rather than a tiny minority.
Gun retailers as storage partners for suicide prevention: what barriers need to be overcome?
Authors: Pierpoint Lauren A , Tung Gregory J , Brooks-Russell Ashley , Brandspigel Sara , Betz Marian , Runyan Carol W
Published: February 2018

Introduction

Safe storage of guns outside the household while someone is at risk for suicide is important for suicide prevention. Some gun retailers offer temporary firearm storage as a community resource. Others may be willing if perceived barriers can be addressed.

Methods

We invited all gun retailers in eight Mountain West states to respond to a questionnaire about the barriers they perceive in offering temporary, voluntary gun storage for community members.

Results

Ninety-five retailers responded (25% response rate). Fifty-eight percent believed federal laws make it harder to store guns and 25% perceived state laws to be obstacles. Over 60% cited legal liability in storing and returning guns as barriers. Other important barriers included cost, space and logistical issues of drop off and pick up.

Conclusions

Strategies to reduce legal and other barriers will need to be addressed to better engage gun retailers as a community resource for safe gun storage.
Does the addition of hyperbaric oxygen therapy to conventional treatment modalities influence the outcome of soldiers with idiopathic sudden sensorineural hearing loss?
Authors: Chi Tzu-Hang , Chiang M C , Chen R F , Yuan C H
Published: February 2018

Background

Idiopathic sudden sensorineural hearing loss (ISSNHL) is defined as a 30-decibel (dB) loss in hearing over three contiguous frequencies within 3 days. The cause remains unknown, and there is currently no consensus in the literature as to how it is best treated. Conventional treatment in our unit comprises steroids, pentoxyphiline and dextran, with the potential addition of hyperbaric oxygen therapy (HBOT).

Methods

A prospective randomised trial was performed on all soldiers diagnosed with ISSNHL in our institution from 1 January 2007 to 31 December 2016. Participants were randomly allocated to one of two groups. Group A was treated with conventional treatment plus HBOT. Group B was treated with conventional treatment only. Data collection included age, gender, clinical symptoms, pure-tone audiometry results and treatment outcome.

Results

60 participants were enrolled (53 male, 7 female) with ages ranging from 18 to 65 years (mean age of 30.3). No significant differences were observed in the baseline characteristics between the two groups, including gender, age, site, associated symptoms, duration of symptoms and severity of hearing loss. Hearing recovery using Siegel’s criteria on days 8 and 13 showed no significant differences between treatment groups. However, the hearing recovery on day 180 was significantly better in those who received the conventional treatment plus HBOT (P<0.05). Additionally, no significant side effects were observed in either group.

Conclusions

HBOT plus existing conventional treatment was associated with a better outcome than conventional treatment alone. We would recommend the addition of HBOT is recommended as a first-line treatment modality for all soldiers presenting with ISSNHL.
Legitimacy in bioethics: challenging the orthodoxy
Authors: Smith William R
Published: February 2018

Several prominent writers including Norman Daniels, James Sabin, Amy Gutmann, Dennis Thompson and Leonard Fleck advance a view of legitimacy according to which, roughly, policies are legitimate if and only if they result from democratic deliberation, which employs only public reasons that are publicised to stakeholders. Yet, the process described by this view contrasts with the actual processes involved in creating the Affordable Care Act (ACA) and in attempting to pass the Health Securities Act (HSA). Since the ACA seems to be legitimate, as the HSA would have been had it passed, there seem to be counterexamples to this view. In this essay, I clarify the concept of legitimacy as employed in bioethics discourse. I then use that clarification to develop these examples into a criticism of the orthodox view–that it implies that legitimacy requires counterintuitively large sacrifices of justice in cases where important advancement of healthcare rights depends on violations of publicity. Finally, I reply to three responses to this challenge: (1) that some revision to the orthodox view salvages its core commitments, (2) that its views of publicity and substantive considerations do not have the implications that I claim and (3) that arguments for it are strong enough to support even counterintuitive results. My arguments suggest a greater role for substantive considerations than the orthodox view allows.
Non-enhanced MR imaging for preinterventional assessment of the angioarchitecture in vein of Galen malformations
Authors: Dürr Nikola Reinhard , Brinjikji Waleed , Pohrt Anne , Lanfermann Henrich , Brassel Friedhelm , Meila Dan
Published: February 2018

Background and purpose

Endovascular treatment of vein of Galen malformations (VGMs) requires sufficient preceding MR imaging. Standardized, preinterventional, non-invasive imaging has not been established. Our study is the first to examine the role of a dedicated, standardized, non-invasive imaging protocol in the evaluation of VGM angioarchitecture by non-contrast MRI/MR angiography.

Materials and methods

We retrospectively evaluated a consecutive series of VGM patients who underwent a 1.5 T MRI protocol, including standard T2 weighted images (T2WI), arterial time of flight (TOF), and thin T2WI without flow compensation (T2OffPh). The primary outcome was the proportion of patients in whom VGM subtypes and all arterial feeders (anterior (AChA) and posterior (PChA) choroidal arteries, pericallosal arteries, basilar tip, and leptomeningeal supply) could be accurately identified compared with a DSA gold standard.

Results

A total of 26 VGM patients who underwent 108 studies were used in the statistical analysis. VGM subtype was best seen in axial T2OffPh (92.1%) and TOF (89.8%). AChA feeders were best seen in TOF (86.5%) and axial T2OffPh (72.2%). PChA feeders were best seen in TOF (95.1%) and axial T2OffPh (88.1%). Pericallosal feeders were best seen in axial T2OffPh (95.4%) and TOF (95.1%). Basilar tip feeders were best seen in TOF (90.6%) and axial T2OffPh (88.4%).

Conclusion

VGM angioarchitecture is best seen in TOF and axial T2OffPh. It can be used as an alternative to global angiographic series.
Direct oral anticoagulants versus warfarin: is new always better than the old?
Authors: Burn John , Pirmohamed Munir
Published: February 2018

About 1.4 British million people are at risk of strokes due to non-valvular atrial fibrillation (AF) necessitating long-term anticoagulation. The vitamin K antagonist, warfarin, has a long half-life and narrow therapeutic range necessitating regular monitoring and is a common cause of iatrogenic hospital admission. Direct-acting oral anticoagulants (DOACs), dabigatran, rivaroxaban, apixaban and edoxaban are not required to have monitoring but are sensitive to changes in renal function and are associated with poorer adherence. There are good grounds to believe that DOACs are not always superior to warfarin in routine practice particularly with an older population. Much higher levels of therapeutic effectiveness can be achieved using a simple genotype guidance to identify those who are highly sensitive and by adoption of home monitoring. These adjustments could make warfarin the preferred drug for most people and would reduce the dramatic rise in health service expenditure.
Mild cognitive impairment impacts health outcomes of patients with atrial fibrillation undergoing a disease management intervention
Authors: Ball Jocasta , Løchen Maja-Lisa , Carrington Melinda J , Wiley Joshua F , Stewart Simon
Published: February 2018

Objective

Mild cognitive impairment (MCI) is prevalent in atrial fibrillation (AF) and has the potential to contribute to poor outcomes. We investigated the influence of MCI on survival and rehospitalisation in patients with chronic forms of AF undergoing a home-based, AF-specific disease management intervention (home-based intervention (HBI)) or standard management (SM).

Methods

The Montreal Cognitive Assessment tool was administered at baseline (a score of <26/30 indicated MCI) in patients with AF randomised to HBI versus SM. Post hoc analyses of mortality and rehospitalisations during a minimum 24-month follow-up were conducted in the overall cohort and in each study group separately.

Results

Of 260 patients (mean age 72±11, 47% female), 65% demonstrated MCI on screening (34% in SM; 31% in HBI). Overall, the number of days spent alive and out-of-hospital during follow-up (P=0.012) and all-cause rehospitalisation were influenced by MCI during follow-up (OR 3.16 (95% CI 1.46 to 6.84)) but MCI did not influence any outcomes in the SM group. However, survival was negatively influenced by MCI in the HBI group (P=0.036); those with MCI in this group were 5.6 times more likely to die during follow-up (OR 5.57 (95% CI 1.10 to 28.1)). Those with MCI in the HBI group also spent less days alive and out-of-hospital than those with no MCI (P=0.022). MCI was also identified as a significant independent correlate of shortest duration of event-free survival (OR 3.48 (95% CI 1.06 to 11.4)), all-cause rehospitalisation (OR 3.30 (95% CI 1.25 to 8.69)) and cardiovascular disease (CVD)-related rehospitalisation (OR 2.35 (95% CI 1.12 to 4.91)) in this group.

Conclusions

The effectiveness of home-based, disease management for patients with chronic forms of AF is negatively affected by comorbid MCI. The benefit of adjunctive support for patients with MCI on CVD-related health outcomes requires further investigation.
Imaging in diagnosis, outcome prediction and monitoring of large vessel vasculitis: a systematic literature review and meta-analysis informing the EULAR recommendations
Authors: Duftner Christina , Dejaco Christian , Sepriano Alexandre , Falzon Louise , Schmidt Wolfgang Andreas , Ramiro Sofia
Published: February 2018

Objectives

To perform a systematic literature review on imaging techniques for diagnosis, outcome prediction and disease monitoring in large vessel vasculitis (LVV) informing the European League Against Rheumatism recommendations for imaging in LVV.

Methods

Systematic literature review (until 10 March 2017) of diagnostic and prognostic studies enrolling >20 patients and investigating ultrasound, MRI, CT or positron emission tomography (PET) in patients with suspected and/or established primary LVV. Meta-analyses were conducted, whenever possible, obtaining pooled estimates for sensitivity and specificity by fitting random effects models.

Results

Forty-three studies were included (39 on giant cell arteritis (GCA), 4 on Takayasu arteritis (TAK)). Ultrasound (‘halo’ sign) at temporal arteries (8 studies, 605 patients) and MRI of cranial arteries (6 studies, 509 patients) yielded pooled sensitivities of 77% (95% CI 62% to 87%) and 73% (95% CI 57% to 85%), respectively, compared with a clinical diagnosis of GCA. Corresponding specificities were 96% (95% CI 85% to 99%) and 88% (95% CI 81% to 92%). Two studies (93 patients) investigating PET for GCA diagnosis reported sensitivities of 67%–77% and specificities of 66%–100% as compared with clinical diagnosis or temporal artery biopsy. In TAK, one study each evaluated the role of magnetic resonance angiography and CT angiography for diagnostic purposes revealing both a sensitivity and specificity of 100%. Studies on outcome prediction and monitoring disease activity/damage were limited and mainly descriptive.

Conclusions

Ultrasound and MRI provide a high diagnostic value for cranial GCA. More data on the role of imaging for diagnosis of extracranial large vessel GCA and TAK, as well as for outcome prediction and monitoring in LVV are warranted.
Rutin attenuates cerebral ischemia–reperfusion injury in ovariectomized rats via estrogen-receptor-mediated BDNF–TrkB and NGF–TrkA signaling
Authors: Liu Hong , Zhong Lili , Zhang Yuwei , Liu Xuewei , Li Ji
Published: February 2018

Rutin, a flavonoid glycoside, has been reported to exert neuroprotective effects. Loss of endogenous estrogen and dysregulation of the estrogen receptor (ER) signaling pathway are associated with the increased risk of stroke in women after menopause. This study was performed to investigate whether rutin could protect against cerebral ischemia by modulating the ER pathway. Ovariectomized (OVX) rats were given intraperitoneal injections of vehicle (dimethyl sulfoxide), rutin (100 mg/kg body mass) or 17β-estradiol (100 μg/kg body mass) for 5 consecutive days. Then, the rats were subjected to middle cerebral artery occlusion (MCAO) for 1 h followed by a 24 h reperfusion to establish the cerebral ischemia–reperfusion (I/R) injury. We found that rutin improved the sensorimotor performance and recognition memory of rats subjected to I/R, decreased the infarct size, and attenuated neuron loss. Rutin treatment also increased the levels of ERα, ERβ, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), tropomyosin receptor kinase A (TrkA), TrkB, and phospho-cAMP-responsive element binding protein (p-CREB) in rat hippocampus and cerebral cortex. The protective effects of rutin were comparable to that of 17β-estradiol, and were partially blocked by ICI182780, an ER antagonist. The above results suggest that rutin preconditioning ameliorates cerebral I/R injury in OVX rats through ER-mediated BDNF–TrkB and NGF–TrkA signaling.
A Black-Box Construction of Strongly Unforgeable Signature Scheme in the Leakage Setting
Authors: Huang Jianye , Huang Qiong , Pan Chunhua
Published: February 2018

Traditional cryptography considers the security of cryptosystems when the attackers have no access to the secret key. However, due to the imperfect implementation of cryptosystems, the attackers are able to obtain partial secret state of the systems via side-channel attacks, which are not considered in the traditional security notions of cryptographic primitives, including digital signature, and thus break their security. Leakage-resilient cryptography was then proposed to solve the problem. Recently, Wang et al. showed that any signature scheme can be transformed to a strongly unforgeable one in the leakage setting. However, their transformation requires to change the key pair of the scheme. In this paper, we present a key-modification-free solution in both the bounded leakage model and the auxiliary input model. Specifically, we propose a black-box construction of strongly unforgeable signature scheme in the leakage setting, and show that if the underlying building blocks are leakage-resilient, so is the resulting scheme.
Knot physics on entangled vortex-membranes: Classification, dynamics and effective theory
Authors: Kou Su-Peng
Published: February 2018

In this paper, knot physics on entangled vortex-membranes are studied including classification, knot dynamics and effective theory. The physics objects in this paper are entangled vortex-membranes that are called composite knot-crystals. Under projection, a composite knot-crystal is reduced to coupled zero-lattices. In the continuum limit, the effective theories of coupled zero-lattices become quantum field theories. After considering the topological interplay between knots and different types of zero-lattices, gauge interactions emerge. Based on a particular composite knot-crystal (we call it a standard knot-crystal), the derived effective model becomes the Standard Model. As a result, the knot physics may provide an alternative interpretation on quantum field theory.
Lessons from Applying Market-Based Incentives in Watershed Management
Authors: Muchapondwa Edwin , Stage Jesper , Mungatana Eric , Kumar Pushpam
Published: February 2018

Watershed management is a complex activity with constraints on funding and human resources in many parts of the world, and there is a need for global effort to identify strategies that can work. To complement regulatory approaches, attention is now also being given to market-based incentives because of their potential cost-effectiveness. This study seeks to provide impetus to the use of the most successful market-based incentives to promote sustainable watershed practices through strengthening and increasing direct participation by local communities and the private sector. To identify proven market-based incentives for use to catalyze local community and private sector participation, a review of a sample of 26 purposively selected case studies from different contexts in Africa, Asia, Europe and the Americas is conducted. In reviewing those case studies, emphasis is placed on understanding the threats to specific watersheds, the market-based incentives used, the countrywide policy environment, the outcomes from the interventions, the factors for success and failure, and the pertinent policy issues in support of upscaling and the uptake of appropriate market-based approaches. The study identifies seven key policies that Governments should consider to upscale and facilitate the uptake of market-based incentives to promote participation by local communities and the private sector in watershed management.
Updated Recommendations for Athletes with Heart Disease
Authors: Lampert Rachel , Zipes Douglas P.
Published: February 2018

Professional society recommendations to decrease sudden cardiac death in athletes, including eligibility requirements with disqualification for athletes with diagnosed disease as well as preparticipation screening and emergency preparedness, were updated in 2015. The update includes new sections on aortic disease, channelopathies, and sickle cell trait, as well as a change in format from the previous binary yes/no format to the more nuanced and contemporary “class and level of evidence” format. Eighty-four of the 246 recommendations now carry Class II designation—“reasonable,” or “may be considered.” New language in the document emphasizes counseling as part of the decision process. New data on athletes with implantable cardioverter-defibrillators, and on those with long QT syndrome, have led to a change from blanket restriction of competitive sports participation to a Class IIB “may be considered” recommendation.
Recombinant Poliovirus for Cancer Immunotherapy
Authors: Gromeier Matthias , Nair Smita K.
Published: February 2018

Mechanisms to elicit antiviral immunity, a natural host response to viral pathogen challenge, are of eminent relevance to cancer immunotherapy. “Oncolytic” viruses, naturally existing or genetically engineered viral agents with cell type-specific propagation in malignant cells, were ostensibly conceived for their tumor cytotoxic properties. Yet, their true therapeutic value may rest in their ability to provoke antiviral signals that engage antitumor immune responses within the immunosuppressive tumor microenvironment. Coopting oncolytic viral agents to instigate antitumor immunity is not an easy feat. In the course of coevolution with their hosts, viruses have acquired sophisticated strategies to block inflammatory signals, intercept innate antiviral interferon responses, and prevent antiviral effector responses, e.g., by interfering with antigen presentation and T cell costimulation. The resulting struggle of host innate inflammatory and antiviral responses versus viral immune evasion and suppression determines the potential for antitumor immunity to occur. Moreover, paradigms of early host:virus interaction established in normal immunocompetent organisms may not hold in the profoundly immunosuppressive tumor microenvironment. In this review, we explain the mechanisms of recombinant nonpathogenic poliovirus, PVSRIPO, which is currently in phase I clinical trials against recurrent glioblastoma. We focus on an unusual host:virus relationship defined by the simple and cytotoxic replication strategy of poliovirus, which generates inflammatory perturbations conducive to tumor antigen-specific immune priming.
New Therapeutic Approaches for Familial Hypercholesterolemia
Authors: Ajufo Ezim , Rader Daniel J.
Published: February 2018

Familial hypercholesterolemia (FH) is a common genetic condition characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C), premature atherosclerotic cardiovascular disease, and considerable unmet medical need with conventional LDL-C-lowering therapies. Between 2012 and 2015, the US Food and Drug Administration approved four novel LDL-C-lowering agents for use in patients with FH based on the pronounced LDL-C-lowering efficacy of these medicines. We review the four novel approved agents, as well as promising LDL-C-lowering agents in clinical development, with a focus on their mechanism of action, efficacy in FH cohorts, and safety.
New Molecular Diagnostic Approaches to Bacterial Infections and Antibacterial Resistance
Authors: Tsalik Ephraim L. , Bonomo Robert A. , Fowler Vance G.
Published: February 2018

Recent advances in the field of infectious disease diagnostics have given rise to a number of host- and pathogen-centered diagnostic approaches. Most diagnostic approaches in contemporary infectious disease focus on pathogen detection and characterization. Host-focused diagnostics have recently emerged and are based on detecting the activation of biological pathways that are highly specific to the type of infecting pathogen (e.g., viral, bacterial, protozoan, fungal). Although this progress is encouraging, it is unlikely that any single diagnostic platform will fully address the clinician's need for actionable data with short turnaround times in all settings.
Pathogenesis of Peripheral T Cell Lymphoma
Authors: Pizzi Marco , Margolskee Elizabeth , Inghirami Giorgio
Published: February 2018

Peripheral T cell lymphomas (PTCLs) are highly heterogeneous tumors, displaying distinct clinical and biological features. The pathogenesis and normal counterpart of such entities have been elusive for decades. Recent studies have, however, disclosed key mechanisms of peripheral T cell transformation, including (a) the deregulation of signaling pathways controlling T cell development, differentiation, and maturation; (b) the remodeling of the peritumor microenvironment; and (c) the virus-mediated rewiring of T cell biology. Uncovering the molecular mechanisms of T cell transformation will help elucidate the peculiar clinical and pathological features of each PTCL entity and will lead to the characterization of novel antitumor therapies. These therapies will combine conventional and new-generation compounds with immune-modulating agents to ablate both the neoplastic cells and the tumor-supporting microenvironment. This review addresses the pathogenic mechanisms of PTCLs, with special attention paid to novel therapeutic strategies for the clinical management of such aggressive tumors.
Identifying the mechanical and neural properties of the sternocleidomastoid muscles
Authors: Luciani Bhillie D. , Desmet David M. , Alkayyali Amani A. , Leonardis Joshua M. , Lipps David B.
Published: February 2018

Neck muscles are preferentially activated in specific force directions, but the constraints that the central nervous system considers when programming these preferred directions of muscle activity are unknown. The current study used ultrasound shear wave elastography (SWE) to investigate whether the material properties of the sternocleidomastoid (SCM) muscles exhibit preferred directions similar to their preferred direction of muscle activity during an isometric task. Twenty-four healthy participants matched isometric forces in 16 axial directions. All force targets were scaled to 20% of a maximum voluntary contraction. Muscle activity was recorded with surface electromyography (EMG) from six muscles (the bilateral SCMs, upper trapezius, and splenius capitis muscles), and shear wave velocities (SWVs) were recorded with SWE from both SCM muscles. We observed statistically significant differences between the preferred directions of muscle activity and SWVs for both the left SCM ( P = 0.002) and the right SCM ( P < 0.001), with the SWE data exhibiting a more lateral preferred direction. Significant differences in the spatial focus ( P < 0.001) were also observed, with the dispersion of SWV data covering a greater angular range than the EMG data during isometric tasks. The preferred directions of muscle activity and material properties for the SCM muscles were closer than previous comparisons of muscle activity and moment arms, suggesting muscle mechanics could play a more important role than anatomy in how the central nervous system spatially tunes muscle activation.

NEW & NOTEWORTHY Our study used a novel combination of surface electromyography and ultrasound shear wave elastography to investigate the neuromuscular control of the neck. Our work highlights differences in how the activation and material properties of the sternocleidomastoid muscles are modulated as the central nervous system stabilizes the neck during isometric force production. These findings provide normative data for future studies to investigate pathologic changes to both the activation and material properties of the sternocleidomastoid muscles.