bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficient haplotype matching between a query and a panel for genealogical search
Authors: Naseri Ardalan , Holzhauser Erwin , Zhi Degui , Zhang Shaojie
Published: May 2019

Motivation

With the wide availability of whole-genome genotype data, there is an increasing need for conducting genetic genealogical searches efficiently. Computationally, this task amounts to identifying shared DNA segments between a query individual and a very large panel containing millions of haplotypes. The celebrated Positional Burrows-Wheeler Transform (PBWT) data structure is a pre-computed index of the panel that enables constant time matching at each position between one haplotype and an arbitrarily large panel. However, the existing algorithm (Durbin’s Algorithm 5) can only identify set-maximal matches, the longest matches ending at any location in a panel, while in real genealogical search scenarios, multiple ‘good enough’ matches are desired.

Results

In this work, we developed two algorithmic extensions of Durbin’s Algorithm 5, that can find all L-long matches, matches longer than or equal to a given length L, between a query and a panel. In the first algorithm, PBWT-Query, we introduce ‘virtual insertion’ of the query into the PBWT matrix of the panel, and then scanning up and down for the PBWT match blocks with length greater than L. In our second algorithm, L-PBWT-Query, we further speed up PBWT-Query by introducing additional data structures that allow us to avoid iterating through blocks of incomplete matches. The efficiency of PBWT-Query and L-PBWT-Query is demonstrated using the simulated data and the UK Biobank data. Our results show that our proposed algorithms can detect related individuals for a given query efficiently in very large cohorts which enables a fast on-line query search.

Availability and implementation

genome.ucf.edu/pbwt-query

Supplementary information

Supplementary data are available at Bioinformatics online.
PathFXweb: a web application for identifying drug safety and efficacy phenotypes
Authors: Wilson Jennifer L , Wong Mike , Chalke Ajinkya , Stepanov Nicholas , Petkovic Dragutin , Altman Russ B
Published: May 2019

Limited efficacy and intolerable safety limit therapeutic development and identification of potential liabilities earlier in development could significantly improve this process. Computational approaches which aggregate data from multiple sources and consider the drug’s pathways effects could add to identification of these liabilities earlier. Such computational methods must be accessible to a variety of users beyond computational scientists, especially regulators and industry scientists, in order to impact the therapeutic development process. We have previously developed and published PathFX, an algorithm for identifying drug networks and phenotypes for understanding drug associations to safety and efficacy. Here we present a streamlined and easy-to-use PathFX web application that allows users to search for drug networks and associated phenotypes. We have also added visualization, and phenotype clustering to improve functionality and interpretability of PathFXweb.

Availability and implementation

https://www.pathfxweb.net/.

Supplementary information

Supplementary data are available at Bioinformatics online.
‘It’s My Secret Space’: The Benefits of Mindfulness for Social Workers
Authors: Kinman Gail , Grant Louise , Kelly Susan
Published: May 2019

Social workers are at high risk of job-related stress that can impair their well-being and professional practice. Although organisational support is a fundamental requirement, it has been argued that social workers need to develop emotional resilience to help them manage the demands of the job. This mixed method study examines the effects of an eight-week mindfulness training course on several resources previously found to underpin resilience in social workers (emotional self-efficacy, psychological flexibility, reflective ability and self-compassion) together with aspects of well-being relevant to the role (compassion fatigue, compassion satisfaction and perceived stress). Participants’ perceptions of the benefits of mindfulness for their well-being and professional practice are further explored via the content analysis of open-ended questions and semi-structured interviews. Emotional self-efficacy, psychological flexibility and compassion satisfaction increased following the intervention and compassion fatigue and perceived stress were reduced. No significant changes were found in reflective ability and self-compassion. The qualitative data provided greater insight into the potential benefits of mindfulness for the well-being and job performance of social workers and factors that might encourage and discourage its use.
Influenza Vaccine Effectiveness: Defining the H3N2 Problem
Authors: Belongia Edward A , McLean Huong Q
Published: May 2019

Observational studies have consistently shown that influenza vaccine effectiveness (VE) is lower for H3N2 relative to H1N1pdm09 and type B, and this is not entirely explained by antigenic match. The triad of virus, vaccine, and host immunity provides a framework to examine contributing factors. Antigenic evolution facilitates H3N2 immune escape, and increasing glycosylation of the hemagglutinin shields antigenic sites from antibody binding. Egg passage adaptation of vaccine viruses generates mutations that alter glycosylation, impair the neutralizing antibody response, and reduce VE. Complex host immune factors may also influence H3N2 VE, including early childhood imprinting and repeated vaccination, but their role is uncertain. Of the triad of contributing factors, only changes to the vaccine are readily achievable. However, it is unclear whether current licensed non–egg-based vaccines generate superior protection against H3N2. The optimal strategy remains to be defined, but newer vaccine technology platforms offer great potential.
Aldosterone induces trained immunity: the role of fatty acid synthesis
Authors: van der Heijden Charlotte D C C , Keating Samuel T , Groh Laszlo , Joosten Leo A B , Netea Mihai G , Riksen Niels P
Published: May 2019

Aims

Supranormal levels of aldosterone are associated with an increased cardiovascular risk in humans, and with accelerated atherosclerosis in animal models. Atherosclerosis is a low-grade inflammatory disorder, with monocyte-derived macrophages as major drivers of plaque formation. Monocytes can adopt a long-term pro-inflammatory phenotype after brief stimulation with microbial pathogens or endogenous atherogenic lipoproteins via a process termed trained immunity. In this study, we aimed to investigate whether aldosterone can induce trained immunity in primary human monocytes in vitro and explored the underlying mechanism.

Methods and results

We exposed human monocytes to aldosterone for 24 h, after which they were rested to differentiate into monocyte-derived macrophages for 5 days, and re-stimulated with toll-like receptor 2 and 4 ligands on day 6. We demonstrated that aldosterone augments pro-inflammatory cytokine production and reactive oxygen species production in monocyte-derived macrophages after re-stimulation, via the mineralocorticoid receptor. Fatty acid synthesis was identified as a crucial pathway necessary for this induction of trained immunity and pharmacological inhibition of this pathway blunted aldosterone-induced trained immunity. At the level of gene regulation, aldosterone promoted enrichment of the transcriptionally permissive H3K4me3 modification at promoters of genes central to the fatty acid synthesis pathway.

Conclusion

Aldosterone induces trained immunity in vitro, which is dependent on epigenetically mediated up-regulation of fatty acid synthesis. These data provide mechanistic insight into the contribution of aldosterone to inflammation, atherosclerosis, and cardiovascular disease.
Unreal Wages? Real Income and Economic Growth in England, 1260–1850
Authors: Humphries Jane , Weisdorf Jacob
Published: May 2019

Estimates of historical workers’ annual incomes suffer from the fundamental problem that they are inferred from day wage rates without knowing how many days of work day-labourers undertook per year. We circumvent the problem by building an income series based on the payments made to workers employed by the year rather than by the day. Our data suggest that earlier annual income estimates based on day wages overestimate medieval labour incomes but underestimate labour incomes during the Industrial Revolution. Our revised estimates indicate that modern economic growth began more than two centuries earlier than commonly thought and was driven by an ‘Industrious Revolution’. They also suggest that the current global downturn in labour's share is not exceptional but fits within the range of historical fluctuations.
Risk factors and clinical significance of elevated mitral valve gradient following valve repair for degenerative disease
Authors: Tomšič Anton , Hiemstra Yasmine L , Arabkhani Bardia , Mertens Bart J A , van Brakel Thomas J , Versteegh Michel I M , Marsan Nina Ajmone , Klautz Robert J M , Palmen Meindert
Published: May 2019

OBJECTIVES

The risk factors and clinical effect of elevated mitral valve (MV) gradients after valve repair for degenerative valve disease remain insufficiently understood.

METHODS

Between January 2004 and December 2015, a total of 484 patients underwent valve repair for degenerative disease. A true-sized full annuloplasty ring was implanted in all cases. We analysed the effect of preoperative and intraoperative factors on the postrepair gradient. Additionally, we explored the effect of postrepair gradients on long-term outcomes.

RESULTS

On linear regression analysis, postrepair MV gradients were associated with patient age (coefficient = −0.110, standard error = 0.005, P = 0.034), body surface area (coefficient = 0.905, standard error = 0.340, P = 0.008), implanted annuloplasty ring size (coefficient = −0.181, standard error = 0.018, P < 0.001) and the use of Physio I ring (coefficient = 0.414, standard error = 0.122, P = 0.001). On multivariable analysis, postrepair MV gradient was not associated with overall survival [hazard ratio (HR) 1.034, 95% confidence interval (CI) 0.889–1.203; P = 0.66] or freedom from atrial fibrillation (HR 0.849, 95% CI 0.682–1.057; P = 0.14), but did emerge as a risk factor for MV reintervention (HR 1.378, 95% CI 1.033–1.838; P = 0.029). Two out of 11 reinterventions were performed due to MV stenosis and in both patients, high postrepair gradients were seen readily on predischarge echocardiography.

CONCLUSIONS

Following valve repair for degenerative MV disease, elevated gradients occur even when true-sized annuloplasty is performed. The late clinical results of valve repair with elevated postrepair gradient are impaired and further studies are needed to explore preventive measures aimed at resolving the issue.
The association between weight stability and parenteral nutrition characteristics and survival in patients with colorectal cancer
Authors: Liu Wenli , Qdaisat Aiham , Lee Eric , Yeung Jason , Vu Khanh , Lin Jun-Zhong , Canada Todd , Zhou Shouhao , Cohen Lorenzo , Bruera Eduardo , Yeung Sai-Ching J
Published: May 2019

Objective

Knowledge about the impact of metabolic disturbances and parenteral nutrition (PN) characteristics on the survival of cancer patients receiving PN is limited. We aimed to assess the association between clinical and PN characteristics and survival in colorectal-cancer patients receiving PN support.

Methods

Our study included 572 consecutive colorectal-cancer patients who had received PN support between 2008 and 2013. Patient characteristics, body mass index, weight, medical/surgical history, indication for PN, PN data and survival were recorded. Associations between clinical and PN characteristics and survival were analysed with important confounding factors.

Results

The final cohort included 437 evaluable patients, with a mean age of 57 years. Eighty-one percent of the study population had advanced stage of colorectal cancer. Unstable weight (weight change ≥2.5%) prior to PN initiation [hazard ratio (HR) = 1.41, P = 0.023] was adversely associated with survival after adjusting for multiple factors including cancer stage. Bowel obstruction (HR = 1.75, P = 0.017) as a PN indication was associated with worse survival when compared with without bowel obstruction. Higher PN amino acid by ideal body weight (g•kg−1) (HR = 0.59, P = 0.029) was associated with longer survival, whereas a higher percentage of non-PN intravenous calories (HR = 1.04, P = 0.011) was associated with shorter survival independently of confounding factors.

Conclusions

Body mass index and weight stability can be useful nutritional indices for survival prediction in cancer patients receiving PN. PN planning should take into account of non-PN calories to achieve optimal energy support and balance. Future research is needed to define optimal PN amino-acid requirement and energy balance.
Association Between Dietary Intakes of B Vitamins in Midlife and Cognitive Impairment in Late-Life: The Singapore Chinese Health Study
Authors: Sheng Li-Ting , Jiang Yi-Wen , Pan Xiong-Fei , Feng Lei , Yuan Jian-Min , Pan An , Koh Woon-Puay
Published: May 2019

Background

Dietary intakes of B vitamins (eg, folate) are related to cognitive function according to epidemiological studies in western countries. But prospective studies in Asian populations are scarce. This study evaluated the relationships of dietary intakes of six B vitamins in midlife with cognitive impairment in old age in a Chinese population living in Singapore.

Methods

This study included 16,948 participants from the Singapore Chinese Health Study, a population-based prospective cohort. Baseline dietary intakes of B vitamins were assessed using a validated 165-item food frequency questionnaire when the participants were aged 45–74 years (1993–1998). After an average follow-up of 20 years, cognitive function was examined using a Singapore-modified version of Mini-Mental State Examination scale in 2014–2016, and cognitive impairment was defined using education-specific cutoffs. Logistic regression models were applied to estimate the association between B vitamins and cognitive impairment. All the six B vitamins were mutually adjusted in the final model.

Results

In the 2014–2016 interview, 2,443 participants were defined as cognitive impairment. Riboflavin and folate were significantly and independently associated with cognitive impairment in a dose-dependent manner: the odds ratio (95% confidence interval) comparing the highest with the lowest quartile was 0.82 (0.69, 0.97) for riboflavin and 0.83 (0.70, 0.98) for folate (both p-trend <.05). Dietary intakes of thiamine, niacin, vitamin B-6, and B-12 were not significantly associated with risk of cognitive impairment.

Conclusions

Higher dietary intakes of riboflavin and folate in midlife were associated with a lower risk of cognitive impairment in late-life in the Chinese population.
Power Sharing and the Rule of Law in the Aftermath of Civil War
Authors: Hartzell Caroline A , Hoddie Matthew
Published: May 2019

What effect do power-sharing institutions agreed to as part of civil war settlements have on the development of the rule of law in post–civil war states? We contend that power-sharing measures facilitate the emergence of the rule of law in two ways. First, they establish a form of institutional constraint that promotes judicial autonomy and independence. Second, they foster a sense of security among judges and other political actors that bolsters commitment to the law. We demonstrate the plausibility of a positive relationship between power sharing and the rule of law through an analysis of post–civil war states between the years 1948 and 2006. Our findings suggest that civil war settlements can help to establish the rule of law when they include mechanisms aimed at allaying the insecurities of political actors in the postconflict environment.
An Electronic Clinical Decision-Making Tool for Patients with Suspected Colorectal Cancer—Preliminary Evaluation in Patients Presenting with Rectal Bleeding
Authors: Forbes Nauzer , Cooray Mohan , Hackett Michael , Shah Nishwa , Yuan Yuhong , Antiperovitch Pavel , Corner Tracey , Chan David , Mills Michael , Armstrong David , Xenodemetropoulos Ted
Published: May 2019

Background and Objectives

The CarePath-CRC electronic clinical decision-making application was designed to assist physicians with evaluation of patients with suspected colorectal cancer (CRC). The physician completes an interactive checklist of evidence-based clinical parameters, and a recommended referral urgency is generated based on the post-test probability of CRC. This study aimed toward validation of the tool in symptomatic patients presenting with rectal bleeding.

Methods

The medical records of a sample of patients with histologically confirmed CRC from 2010 to 2014 were reviewed. The CarePath-CRC tool was applied retrospectively to all patients who initially presented with rectal bleeding, to determine its sensitivity for detecting CRC in this population. A generated recommendation of ‘immediate referral’ (referral ≤24 hours, expected endoscopy ≤2 weeks) or ‘urgent referral’ (expected consultation and endoscopy ≤4 and ≤8 weeks) was considered a positive test result. An a priori sensitivity of 90% was deemed adequate, based on test characteristics of the tool’s individual clinical criteria.

Results

The tool was applied to 281 patients. A total of 69 (24.6%) and 211 (75.1%) patients met criteria for immediate and urgent referral, respectively. The remaining patient (0.4%) met criteria for ‘possible priority referral’, while none met criteria for ‘no specific action recommended’. This resulted in a calculated sensitivity of 99.6% (95% confidence interval 98.0 to 99.9%).

Conclusions

The CarePath-CRC tool is sensitive in the prediction of CRC in patients presenting with rectal bleeding. A prospective cohort study is being designed to allow for acquisition of comprehensive test performance characteristics and full validation of the instrument.
The Influence of Self-Generated and Third-Party Claims Online: Perceived Self-Interest as an Explanatory Mechanism
Authors: DeAndrea David C , Vendemia Megan A
Published: May 2019

Over the past two decades, communication technology scholars have examined how viewers evaluate the authenticity of information online, with particular attention given to how self versus third-party claims differ in their degree of influence. We examine how self-interest perceptions serve an important explanatory function in the logic of warranting theory and help account for how people evaluate content online. Our results document how the source and valence of a message can interact to affect perceptions of source self-interest, which, in turn, affect perceptions of source trustworthiness, message accuracy, and, ultimately, evaluations of an online target. The findings establish boundary conditions for the warranting principle and our discussion offers insight into the production and evaluation of online claims.
Part II Evolution and Theoretical Bases of the Law of International Watercourses, 3 The Evolution of the Law of International Watercourses
Authors: Stephen C McCaffrey
Published: May 2019

This chapter traces the history of the use of water by human societies, discusses impediments to the development of the law in this field, and introduces the theoretical challenge inherent in application of international norms to resources within a state’s borders. The law of international watercourses has developed in tandem with the evolution of human social organization and the intensification of use by human societies of fresh water. Evidence of early canals and dikes suggests that small communities and city-states had found it necessary to cooperate in order to control and utilize effectively the waters of major rivers. When the growth of other uses—such as irrigation and the generation of hydroelectric power—began to give rise to disputes, the first reaction was often to try to apply rules from other branches of international law to the problem.
Association of Syndemic Unhealthy Alcohol Use, Cigarette Use, and Depression With All-Cause Mortality Among Adults Living With and Without HIV Infection: Veterans Aging Cohort Study
Authors: Chichetto Natalie E , Kundu Suman , Freiberg Matt S , Butt Adeel A , Crystal Stephen , So-Armah Kaku A , Cook Robert L , Braithwaite R Scott , Fiellin David A , Khan Maria R , Bryant Kendall J , Gaither Julie R , Barve Shirish S , Crothers Kristina , Bedimo Roger J , Warner Alberta L , Tindle Hilary A ,   Veterans Aging Cohort Study
Published: May 2019

Background

The prevalence and risk of concurrent unhealthy drinking, cigarette use, and depression on mortality among persons living with HIV (PLWH) is unclear. This study applied a syndemic framework to assess whether these co-occurring conditions increase mortality and whether such risk is differential by HIV status.

Methods

We evaluated 6721 participants (49.8% PLWH) without baseline cancer from the Veterans Aging Cohort Study, a prospective, observational cohort of PLWH and matched uninfected veterans enrolled in 2002 and followed through 2015. Multivariable Cox proportional hazards regressions estimated risk of a syndemic score (number of conditions: that is, unhealthy drinking, cigarette use, and depressive symptoms) on all-cause mortality by HIV status, adjusting for demographic, health status, and HIV-related factors.

Results

Fewer than 10% of participants had no conditions; 25.6% had 1, 51.0% had 2, and 15.0% had all 3. There were 1747 deaths (61.9% PLWH) during the median follow-up (11.4 years). Overall, age-adjusted mortality rates/1000 person-years increased with a greater number of conditions: (0: 12.0; 1: 21.2; 2: 30.4; 3: 36.3). For 3 conditions, the adjusted hazard ratio of mortality was 36% higher among PLWH compared with uninfected participants with 3 conditions (95% confidence interval, 1.07–1.72; P = .013), after adjusting for health status and HIV disease progression. Among PLWH and uninfected participants, mortality risk persisted after adjustment for time-updated health status.

Conclusions

Syndemic unhealthy drinking, cigarette use, and depression are common and are associated with higher mortality risk among PLWH, underscoring the need to screen for and treat these conditions.
The Polls—Trends Economic Evaluations and Political Change in Chile, 1966 to 2018
Authors: Enns Peter K , Sanchez Gomez Jose T
Published: May 2019

Over the past half century, Chile has fluctuated wildly in terms of economic prosperity and democratic health. Using 78 surveys archived at the Roper Center for Public Opinion Research, we document the evolution of Chileans’ perceptions of their personal, family, and national economic conditions during major political and economic changes. The data show that prior to the Pinochet dictatorship, despite a growing economic crisis, Chileans’ perceptions of their family’s economic situation—particularly among the lower socio-economic class—improved, suggesting that Allende’s social and economic policies may have had their intended effect. In contrast, through the democratic transition and the contemporary period, economic evaluations typically tracked objective economic conditions. We conclude by discussing how these patterns can inform public opinion research in Latin America and beyond.
Association of systemic lupus erythematosus (SLE) genetic susceptibility loci with lupus nephritis in childhood-onset and adult-onset SLE
Authors: Webber Declan , Cao Jingjing , Dominguez Daniela , Gladman Dafna D , Levy Deborah M , Ng Lawrence , Paterson Andrew D , Touma Zahi , Urowitz Murray B , Wither Joan E , Silverman Earl D , Hiraki Linda T
Published: May 2019

Objective

LN is one of the most common and severe manifestations of SLE. Our aim was to test the association of SLE risk loci with LN risk in childhood-onset SLE (cSLE) and adult-onset SLE (aSLE).

Methods

Two Toronto-based tertiary care SLE cohorts included cSLE (diagnosed <18 years) and aSLE patients (diagnosed ⩾18 years). Patients met ACR and/or SLICC SLE criteria and were genotyped on the Illumina Multi-Ethnic Global Array or Omni1-Quad arrays. We identified those with and without biopsy-confirmed LN. HLA and non-HLA additive SLE risk-weighted genetic risk scores (GRSs) were tested for association with LN risk in logistic models, stratified by cSLE/aSLE and ancestry. Stratified effect estimates were meta-analysed.

Results

Of 1237 participants, 572 had cSLE (41% with LN) and 665 had aSLE (30% with LN). Increasing non-HLA GRS was significantly associated with increased LN risk [odds ratio (OR) = 1.26; 95% CI 1.09, 1.46; P = 0.0006], as was increasing HLA GRS in Europeans (OR = 1.55; 95% CI 1.07, 2.25; P = 0.03). There was a trend for stronger associations between both GRSs and LN risk in Europeans with cSLE compared with aSLE. When restricting cases to proliferative LN, the magnitude of these associations increased for both the non-HLA (OR = 1.30; 95% CI 1.10, 1.52; P = 0.002) and HLA GRS (OR = 1.99; 95% CI 1.29, 3.08; P = 0.002).

Conclusion

We observed an association between known SLE risk loci and LN risk in children and adults with SLE, with the strongest effect observed among Europeans with cSLE. Future studies will include SLE-risk single nucleotide polymorphisms specific to non-European ancestral groups and validate findings in an independent cohort.
Mixed Vehicle Emissions Induces Angiotensin II and Cerebral Microvascular Angiotensin Receptor Expression in C57Bl/6 Mice and Promotes Alterations in Integrity in a Blood-Brain Barrier Coculture Model
Authors: Suwannasual Usa , Lucero JoAnn , Davis Griffith , McDonald Jacob D , Lund Amie K
Published: May 2019

Exposure to traffic-generated pollution is associated with alterations in blood-brain barrier (BBB) integrity and exacerbation of cerebrovascular disorders. Angiotensin (Ang) II signaling through the Ang II type 1 (AT1) receptor is known to promote BBB disruption. We have previously reported that exposure to a mixture of gasoline and diesel vehicle engine emissions (MVE) mediates alterations in cerebral microvasculature of C57Bl/6 mice, which is exacerbated through consumption of a high-fat (HF) diet. Thus, we investigated the hypothesis that inhalation exposure to MVE results in altered central nervous system microvascular integrity mediated by Ang II-AT1 signaling. Three-month-old male C57Bl/6 mice were placed on an HF or low-fat diet and exposed via inhalation to either filtered air (FA) or MVE (100 μg/m3 PM) 6 h/d for 30 days. Exposure to HF+MVE resulted in a significant increase in plasma Ang II and expression of AT1 in the cerebral microvasculature. Results from a BBB coculture study showed that transendothelial electrical resistance was decreased, associated with reduced expression of claudin-5 and occludin when treated with plasma from MVE+HF animals. These effects were attenuated through pretreatment with the AT1 antagonist, Losartan. Our BBB coculture showed increased levels of astrocyte AT1 and decreased expression of aryl hydrocarbon receptor and glutathione peroxidase-1, associated with increased interleukin-6 and transforming growth factor-β in the astrocyte media, when treated with plasma from MVE-exposed groups. Our results indicate that inhalation exposure to traffic-generated pollutants results in altered BBB integrity, mediated through Ang II-AT1 signaling and inflammation, which is exacerbated by an HF diet.
Long-term effects of opioids on the cardiovascular system
Authors: Corbett Keegan , Dugan Amelia , Vitale Christina , Gravel Tammy
Published: May 2019

This article provides an integrative review of the literature on long-term opioid use, its effects on the cardiovascular system, and its implications for nurses.
Midazolam Sedation Induces Upper Limb Coordination Deficits That Are Reversed by Flumazenil in Patients with Eloquent Area Gliomas
Authors: Lin Nan , Han Ruquan , Hui Xuan , Zhang Kaiying , Gelb Adrian W.
Published: May 2019

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New

Background

Midazolam has been found to exacerbate or unmask limb motor dysfunction in patients with brain tumors. This study aimed to determine whether the exacerbated upper limb motor-sensory deficits are mediated through benzodiazepine sites by demonstrating reversibility by flumazenil in patients with gliomas in eloquent areas.

Methods

This was an interventional, parallel assignment, nonrandomized trial. Study subjects were admitted in the operating room. Patients with supratentorial eloquent area gliomas and volunteers of similar age without neurologic disease were sedated with midazolam, but still responsive and cooperative. Motor and sensory functions for upper extremities were evaluated by the Nine-Hole Peg Test before and after midazolam, as well as after flumazenil reversal.

Results

Thirty-two cases were included: 15 in the glioma group and 17 in the control group. The total dose of midazolam and flumazenil were comparable between the groups. In the glioma group, the times to task completion after midazolam in the contralateral hand (P = 0.001) and ipsilateral hand (P = 0.002) were 26.5 (95% CI, 11.3 to 41.7) and 13.7 (95% CI, 5.0 to 22.4) seconds slower than baseline, respectively. After flumazenil reversal, the contralateral hand (P = 0.99) and ipsilateral hand (P = 0.187) performed 1.2 (95% CI, −3.3 to 5.8) and 1.5 (95% CI, −0.5 to 3.5) seconds slower than baseline, respectively. In the control group, the dominant (P < 0.001) and nondominant hand (P = 0.006) were 2.9 (95% CI, 1.4 to 4.3) and 1.7 (95% CI, 0.5 to 2.9) seconds slower than baseline, respectively. After flumazenil, the dominant hand (P = 0.99) and nondominant hand (P = 0.019) performed 0.2 (95% CI, −0.7 to 1.0) and 1.3 (95% CI, −0.2 to 2.4) seconds faster than baseline, respectively.

Conclusions

In patients with eloquent area gliomas, mild sedation with midazolam induced motor coordination deficits in upper limbs. This deficit was almost completely reversed by the benzodiazepine antagonist flumazenil, suggesting that this is a reversible abnormality linked to occupation of the receptor by midazolam.
Dextromethorphan Analgesia in a Human Experimental Model of Hyperalgesia
Authors: Martin E. , Narjoz C. , Decleves X. , Labat L. , Lambert C. , Loriot M.-A. , Ducheix G. , Dualé C. , Pereira B. , Pickering G.
Published: May 2019

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New

Background

Central pain sensitization is often refractory to drug treatment. Dextromethorphan, an N-methyl-d-aspartate receptor antagonist, is antihyperalgesic in preclinical pain models. The hypothesis is that dextromethorphan is also antihyperalgesic in humans.

Methods

This randomized, double-blind, placebo-controlled, crossover study explores the antihyperalgesic effect of single and repeated 30-mg dose of oral dextromethorphan in 20 volunteers, using the freeze-injury pain model. This model leads to development of primary and secondary hyperalgesia, which develops away from the site of injury and is associated with central sensitization and activation of N-methyl-d-aspartate receptor in the spinal cord. The primary outcome was antihyperalgesia calculated with the area under the curve of the percentage change in mechanical pain threshold (electronic von Frey) on the area of secondary hyperalgesia. The secondary outcomes were mechanical pain threshold on the area of primary hyperalgesia and cognitive (reaction time) effect.

Results

Single 30-mg results are reported. Antihyperalgesia (% · min) is significantly higher on the area of secondary hyperalgesia with dextromethorphan than placebo (median [interquartile range]: 3,029 [746; 6,195] vs. 710 [–3,248; 4,439], P = 0.009, Hedge’s g = 0.8, 95% CI [0.1; 1.4]). On primary hyperalgesia area, mechanical pain threshold 2 h after drug intake is significantly higher with dextromethorphan (P = 0.011, Hedge’s g = 0.63, 95% CI [0.01; 1.25]). No difference in antinociception is observed after thermal painful stimuli on healthy skin between groups. Reaction time (ms) is shorter with placebo than with dextromethorphan (median [interquartile range]: 21.6 [–37.4; 0.1] vs. –1.2 [–24.3; 15.4], P = 0.015, Hedge’s g = 0.75, 95% CI [0.12; 1.39]). Nonserious adverse events occurrence (15%, 3 of 20 volunteers) was similar in both groups.

Conclusions

This study shows that low-dose (30-mg) dextromethorphan is antihyperalgesic in humans on the areas of primary and secondary hyperalgesia and reverses peripheral and central neuronal sensitization. Because dextromethorphan had no intrinsic antinociceptive effect in acute pain on healthy skin, N-methyl-d-aspartate receptor may need to be sensitized by pain for dextromethorphan to be effective.
Lung Pharmacokinetics of Tobramycin by Intravenous and Nebulized Dosing in a Mechanically Ventilated Healthy Ovine Model
Authors: Dhanani Jayesh A. , Diab Sara , Chaudhary Jivesh , Cohen Jeremy , Parker Suzanne L. , Wallis Steven C. , Boidin Clément , Barnett Adrian , Chew Michelle , Roberts Jason A. , Fraser John F.
Published: May 2019

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New

Background

Nebulized antibiotics may be used to treat ventilator-associated pneumonia. In previous pharmacokinetic studies, lung interstitial space fluid concentrations have never been reported. The aim of the study was to compare intravenous and nebulized tobramycin concentrations in the lung interstitial space fluid, epithelial lining fluid, and plasma in mechanically ventilated sheep with healthy lungs.

Methods

Ten anesthetized and mechanically ventilated healthy ewes underwent surgical insertion of microdialysis catheters in upper and lower lobes of both lungs and the jugular vein. Five ewes were given intravenous tobramycin 400 mg, and five were given nebulized tobramycin 400 mg. Microdialysis samples were collected every 20 min for 8 h. Bronchoalveolar lavage was performed at 1 and 6 h.

Results

The peak lung interstitial space fluid concentrations were lower with intravenous tobramycin 20.2 mg/l (interquartile range, 12 mg/l, 26.2 mg/l) versus the nebulized route 48.3 mg/l (interquartile range, 8.7 mg/l, 513 mg/l), P = 0.002. For nebulized tobramycin, the median epithelial lining fluid concentrations were higher than the interstitial space fluid concentrations at 1 h (1,637; interquartile range, 650, 1,781, vs. 16 mg/l, interquartile range, 7, 86, P < 0.001) and 6 h (48, interquartile range, 17, 93, vs. 4 mg/l, interquartile range, 2, 9, P < 0.001). For intravenous tobramycin, the median epithelial lining fluid concentrations were lower than the interstitial space fluid concentrations at 1 h (0.19, interquartile range, 0.11, 0.31, vs. 18.5 mg/l, interquartile range, 9.8, 23.4, P < 0.001) and 6 h (0.34, interquartile range, 0.2, 0.48, vs. 3.2 mg/l, interquartile range, 0.9, 4.4, P < 0.001).

Conclusions

Compared with intravenous tobramycin, nebulized tobramycin achieved higher lung interstitial fluid and epithelial lining fluid concentrations without increasing systemic concentrations.
Geriatric olecranon fractures treated with plate fixation have low complication rates
Authors: Campbell Sean T. , DeBaun Malcolm R. , Goodnough L. Henry , Bishop Julius A. , Gardner Michael J.
Published: May 2019

Background:

A recent randomized controlled trial compared operative with nonoperative treatment of olecranon fractures in patients 75 yr and older. The study was notable for high complication rates, and operative treatment was cautioned against. The purpose of this study was to determine the complication rate among geriatric patients with an olecranon fracture treated surgically with plate fixation.

Methods:

The records of patients 75 yr and older treated with plate fixation for an olecranon fracture at a single level I trauma center were reviewed. Variables recorded included basic demographic data, complications, need for reoperation, and union at final follow-up.

Results:

Thirty-six patients met inclusion criteria, with a mean follow-up of 10 mo. Thirty-four of the 36 patients went on to union successfully prior to any subsequent surgery (94%). The overall reoperation rate was 11% (4 of 36 patients).

Conclusions:

The complication and reoperation rates after plate fixation of geriatric olecranon fractures were low. Loss of reduction was uncommon, and most patients went on to uneventful fracture union. These results support plate fixation of olecranon fractures in geriatric patients as a viable alternative to nonoperative management.
A systematic review of treatment of frozen shoulder by hydrodistension with or without steroid or intraarticular steroid injection
Authors: Raghavan Roshan , Dwyer Amitabh J.
Published: May 2019

Background:

Hydrodistension is a popular mode of treatment for frozen shoulder. Hydrodistension of the shoulder joint capsule is either performed with or without use of a steroid. A simple intraarticular corticosteroid injection into the shoulder joint is also used in treatment of frozen shoulder. This article reviews randomized controlled studies that have shown and compared evidence on efficacy of these two treatment methods.

Methods:

A systematic review of the literature was done using online database EMBASE, Pubmed, Cochrane database, Medline, and CINAHL. Only randomized studies that compared hydrodistension with or without steroid to intraarticular steroid injection alone were included.

Results:

Of the five studies identified, three showed no difference between steroid injections alone when compared to distension with steroids. One showed better results with distension with steroid and with intraarticular steroid alone when compared with distension alone. One showed better results with distension with steroids than with intraarticular steroid alone at short-term follow-up of 3 mo.

Conclusions:

Our systematic review demonstrated that patients treated by any of the three modalities improved with no significant difference among them over a period of 6 to 12 mo. However, at 3 mo distension with steroids and steroid injection alone were superior to distension alone.
Effect of a Dynamic Fixation Construct on Syndesmosis Reduction: A Cadaveric Study
Authors: Honeycutt M. Wesley , Riehl John T.
Published: May 2019

Objectives:

To explore what effect a dynamic fixation construct would have on the final reduction of the syndesmosis.

Methods:

Syndesmotic ligaments were sectioned in 10 cadaveric specimens. The syndesmosis was intentionally malreduced with a clamp, and the distance from the anterior edge of the fibula to the anterior incisura of the tibia was measured to quantify the sagittal syndesmotic displacement (SSD). A 3.5-mm quadricortical screw was then placed, the clamp was removed, and the SSD measured. The clamp was then replaced, and a suture-button construct (Knotless Tightrope; Arthrex Inc, Naples, FL) was then placed through the bone tunnel, the clamp was again removed, and the SSD was measured.

Results:

In all cases, the fibula reduced to within 1 mm of its native anatomical position with the dynamic construct. The static screw construct, however, maintained an identical SSD measurement as the clamped malreduction. The dynamic suture-button construct reliably improved the SSD (P < 0.0001).

Conclusions:

Our study demonstrates that dynamic fixation constructs can help restore anatomical alignment in the case of syndesmotic malreduction. The size difference between the suture diameter and drill hole effectively allows the fibula to be pulled and seated into the tibial incisura fibularis. These findings should not be viewed as a justification to ignore the syndesmotic reduction; however, they do validate an important benefit of dynamic fixation that has been found in the recent clinical literature.

Level of Evidence:

Therapeutic Level III.
Long-term Results of Matrix-assisted Autologous Chondrocyte Transplantation Combined With Autologous Bone Grafting for the Treatment of Juvenile Osteochondritis Dissecans
Authors: Roffi Alice , Andriolo Luca , Di Martino Alessandro , Balboni Federica , Papio Tiziana , Zaffagnini Stefano , Filardo Giuseppe
Published: May 2019

Background:

Osteochondritis dissecans is a pathology affecting young patients that involves the entire osteochondral unit. In the case of unfixable fragments, regenerative cartilage treatments are a viable solution, but little is known about the use of these procedures for the treatment of juvenile osteochondritis dissecans (JOCD). The aim of this study was to evaluate the long-term results offered by matrix-assisted autologous chondrocyte transplantation combined with autologous bone grafting for the treatment of JOCD.

Methods:

Nineteen patients have been enrolled. The mean age at the time of treatment was 16.8±1.5 years, with a mean body mass index of 22.9±2.7. The average size of the defects was 2.8±1.2 cm2. All patients were evaluated prospectively before surgery and at 12, 24, 60, and at a final follow-up of 120 months with International Knee Documentation Committee scores, EuroQol-Visual Analogue Scale, and the Tegner Score.

Results:

A statistically significant improvement in all clinical scores was observed from baseline evaluation to 120 months of final follow-up. In particular, the International Knee Documentation Committee subjective score improved from the preoperative evaluation of 38.7±17.3 to 74.0±21.8 at 12 months (P<0.0005), with scores remaining stable for up to 120 months (83.8±20.7), with all follow-ups showing a statistically significant improvement compared with the basal value (P<0.0005). Three patients failed at 12 months, for a failure rate of 16% at 10 years of follow-up. Lesions >3.5 cm2 obtained worse subjective results. In addition, lesion size and female sex were significantly associated with failures.

Conclusions:

The matrix-assisted autologous chondrocyte transplantation technique with autologous bone grafting is a valid treatment option for JOCD in case of unfixable fragments. The clinical improvement obtained is significant and stable, with good results maintained for up to 10 years of follow-up and an overall low failure rate. Lesion size and sex could influence the clinical outcome and should be considered in the treatment choice.

Level of Evidence:

Level IV—case series.
Co-occurrence of Sensory Overresponsivity with Obsessive-Compulsive Symptoms in Childhood and Early Adolescence
Authors: Van Hulle Carol A. , Esbensen Karyn , Goldsmith H. Hill
Published: May 2019

Objective:

Sensory overresponsivity (SOR) is characterized by challenges in integrating and responding to everyday sensory experiences. Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts, ritualistic behaviors, and sensory phenomena. There is some evidence that individuals with co-occurring symptoms of SOR and OCD experience more severe anxiety than those with symptoms of OCD alone, but most studies employed small numbers of participants (typically with an OCD diagnosis) assessed at a single time point. Our 2-fold objective was to replicate previous research showing an association between OCD symptoms and SOR symptoms concurrently and to extend these analyses longitudinally in a large, birth-register-based sample.

Method:

Twins (N = 1613) and their primary caregivers participated in a multimodal, multimethod, longitudinal study. Primary caregivers completed the SOR inventory for their offspring at the age of 8 years, and twins completed the adult sensory profile at the age of 13 years. Parents completed the OCD module of the Diagnostic Interview Schedule for Children-IV when twins were 8 years; twins completed the same module at 13 years. Linear regression models tested for the concurrent and longitudinal associations between SOR and OCD controlling for socioeconomic status.

Results:

Concurrently, participants' likelihood of exhibiting OCD symptoms increased with each symptom of tactile or auditory overresponsivity at 8 years and 13 years (odds ratio = 1.1–2.7). However, SOR measured at age 8 years was unrelated to adolescent OCD symptoms at 13 years and vice versa.

Conclusion:

SOR symptoms, although significantly related to concurrent OCD symptoms, do not appear to precede OCD symptoms, suggesting that SOR symptoms may reflect another type of OCD sensory phenomenon rather than a comorbid condition.
New Antiviral Agents for Treatment of Hepatitis C
Authors: EGERMAN ROBERT S.
Published: May 2019

Between 70 and 170 million people worldwide are infected with hepatitis C virus (HCV) which frequently causes chronic liver disease and cirrhosis. There are several genotypes and many subtypes of HCV. Direct-acting antiviral agents are effective at eradicating HCV in the vast majority of patients, producing much higher cure rates than were seen with interferon and ribavirin regimens only a few years ago. The chapter reviews the epidemiology and virology of HCV infection. Treatment regimens are complex but a straightforward approach to selection of patients, choice of direct-acting antiviral agents and follow-up is presented.
Unplanned Readmissions After Acute Myocardial Infarction: 1-Year Trajectory Following Discharge From a Safety Net Hospital
Authors: Shah Ishan T. , Keeley Ellen C.
Published: May 2019

Background:

Financial penalties rendered by the Centers for Medicare and Medicaid Services have brought about new challenges for safety net hospitals that serve a vulnerable patient population with risk factors associated with high readmission rates. Our goal was to determine the 1-year trajectory of unplanned readmissions in post-myocardial infarction (MI) patients, and to identify factors associated with readmission.

Methods:

A total of 261 acute MI patients admitted from April 2015 to April 2016 were evaluated in a multidisciplinary cardiology clinic within 10 days of hospital discharge and baseline characteristics and medical comorbidities were collected. Readmission and mortality data were obtained at 1 year through chart review and telephone follow-up.

Results:

At 1 year, there were 90 (34%) unplanned readmissions of which half were for noncardiac diagnoses. Of these, 69 patients (77%) were readmitted once, 16 (18%) were readmitted twice, 2 (2%) were readmitted 3 times, and 3 (3%) were readmitted 4 times over the subsequent year. Cardiac causes of 1-year readmission included recurrent MI in 23 (9%) and decompensated heart failure in 18 (7%) patients. Depressed left ventricular systolic function (hazard ratio, 2.23; 95% confidence interval, 2.00–2.44; P = 0.0003) and diabetes mellitus (hazard ratio, 1.60; 95% confidence interval, 1.38–1.82; P = 0.029) were associated with a significantly higher risk of readmission at 1 year.

Conclusion:

Following acute MI, patients are readmitted for cardiac and noncardiac diagnoses well beyond the 30-day mark. This is likely a function of the vulnerability of the patient population rather than a reflection of the medical care provided. More frequent surveillance may attenuate this problem.