bluuebunny/crossref_metadata_2025 huggingface dataset:
Socioeconomic status and self-rated health in China
Authors: Yu Tong , Jiang Yan , Gamber Michelle , Ali Gholam , Xu Tan , Sun Wenjie
Published: March 2019

To investigate whether socioeconomic status is associated with the self-rated health (SRH) status among Chinese.

A cross sectional study including a national sample was conducted among Chinese adults in 2008. In total, 3225 participants were selected by a multistage cluster sampling method. Both general self-rated health and time-comparative self-rated health were measured by a standardized questionnaire. Logistic regression models were used to estimate the odds ratios (ORs) (95% confidence intervals, CIs) of occupation with SRH by occupation, and adjusted for age, sex, education, area, marriage, smoking, drinking, and health status.

Overall, 34.4% of study participants reported “good” on the general SRH (male: 35.8%; female: 32.9%) and 26.2% reported “good” on the time-comparative SRH (male: 27.2%; female: 25.3%). The prevalence of “good” general SRH varied from 28.8% to 52.8% and the prevalence of time-comparative SHR varied from 21.7% to 33.9% in different occupations. The adjusted OR (Odd Ratio) for “good” on the general SRH was 1.35 (95% CI: 1.20–1.52) for the occupation of civil servants, 2.23 (95% CI: 1.96–2.54) for farmers, and 1.15 (95%CI: 1.01–1.31) for businessmen. The full adjusted OR of “good” on the time-comparative SRH was 1.36 (95% CI: 1.17–1.58) for students and was 1.25 (95% CI: 1.10–1.42) for civil servants.

In presented study, 34.4% of the participants reported “good” on the general SRH, and 26.2% participants reported “good” on the time-comparative SRH. The prevalence of “good” general SRH and “good” time-comparative SRH varied among occupations.
Influence of endurance and endurance–strength training on mineral status in women with abdominal obesity: a randomized trial
Authors: Skrypnik Damian , Bogdański Paweł , Skrypnik Katarzyna , Mądry Edyta , Karolkiewicz Joanna , Szulińska Monika , Suliburska Joanna , Walkowiak Jarosław
Published: March 2019

Background:

Obesity and exercise are associated with disturbances of mineral metabolism, which can lead to physical inefficiency. Our study aimed to compare the influence of endurance and endurance–strength training on mineral status in women with abdominal obesity.

Methods:

Thirty-eight abdominally obese women were randomized into groups A and B and underwent 3 months long training: group A—endurance training and group B—endurance–strength training. Anthropometric and body composition measurements were carried out and the Graded Exercise Test was performed. Blood, urine, and hair samples were collected for mineral content analysis.

Results:

Endurance training decreased serum Fe and Zn concentrations as well as hair Zn and Cu content, and increased urine Zn concentration. Endurance–strength training increased serum Mg and Cu concentrations, decreased serum Fe and Zn concentrations, decreased hair Ca and Mg content, and increased urine Ca and Zn concentrations. After training, serum and urine Fe concentration was higher in group A, while urine Ca concentration was higher in group B. A number of correlations was found.

Conclusions:

Both endurance and endurance–strength training have a significant effect on mineral metabolism in obese women; the favorable effects of endurance–strength exercise predominate in iron, magnesium, zinc, and copper balance.
Association between NAT2 polymorphisms and acute leukemia risk
Authors: Zhu Xiaoxiao , Liu Yanbing , Chen Guangwu , Guo Qiang , Zhang Zhen , Zhao Lin , Wei Ran , Yin Xunqiang , Zhang Yunhong , Wang Bin , Li Xia
Published: March 2019

Background:

N-acetyl-transferase 2 (NAT2) polymorphisms have been demonstrated to be associated with acute leukemia (AL); however, the results remain controversial. The present meta-analysis was performed to provide more precise results.

Methods:

Pubmed, Embase, Cochrane Library, China National Knowledge Infrastructure, and Wanfang databases were used to identify eligible studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between NAT2 polymorphisms and AL risk.

Results:

Increased risk was found under both heterozygous (OR 1.24, 95% CI 1.02–1.51) and recessive model (OR 1.28, 95% CI 1.06–1.55) for rs1801280. The slow acetylator phenotype (OR 1.22, 95% CI 1.07–1.40) also increased AL risk. Subgroup analysis demonstrated that rs1801280 increased AL risk under the recessive model (OR 1.14, 95% CI 0.93–1.41) in Caucasian population and the co-dominant (OR 1.77, 95% CI 1.40–2.23), homozygous (OR 3.06, 95% CI 1.88–4.99), dominant (OR 2.22, 95% CI 1.56–3.17), recessive model (OR 2.06, 95% CI 1.35–3.16) in the Mixed populations. Association between rs1799929 and decreased AL risk was found in the co-dominant (OR 0.82, 95% CI 0.70–0.97), homozygous (OR 0.65, 95% CI 0.46–0.93), heterozygous (OR 0.71, 95% CI 0.51–1.00), and the recessive model (OR 0.68, 95% CI 0.49–0.94) in the Caucasian group. As for rs1799931, the same effects were found in the co-dominant (OR 0.68, 95% CI 0.49–0.94) and the dominant model (OR 0.68, 95% CI 0.48–0.97) in the mixed group.

Conclusion:

rs1801280 and the slow acetylator phenotype are risk factors for AL.
Sentinel node biospy using intravital blue dye
Authors: Bara Tivadar , Gurzu Simona , Jung Ioan , Borz Cristian , Banias Laura , Bara Tivadar
Published: March 2019

As the lymph node status remains the main prognostic factor of gastric cancer (GC), several lymph node-based staging systems have been recently proposed for an appropriate postoperative therapy. The identification of sentinel lymph nodes (SLNs) might improve the postoperative protocols. The aim of this study was to present our experience in detecting SLNs in GC using methylene blue dye.

We have performed an observational study and retrospectively analyzed all of the consecutive cases of GC operated by the same surgical team and managed by the same pathologists during 2013 to 2015. In all of the cases SLN status was determined using the methylene blue that was intraoperatively administered in the peritumoral subserosal tissue. All blue colored nodes were histopathologically examined. In the node negative cases immunohistochemical stains using AE1/AE3 keratin were performed.

The blue SLNs were identified in 48 out of the 50 cases included in the study, with a 96% sensitivity and 87.50% specificity. From the 48 cases, 34 (70.83%) presented positive SLNs; in the other 14 cases the SLNs were negative (29.17%). False negativity was observed in 6 of the 14 cases. In 2 of the cases the false negativity of the group 20 was induced by the anthracotic pigment. In other 2 false negative cases, although no regional metastases were founded, sentinel skip metastases in the group 8 and 15, respectively, were identified.

Mapping of the SLNs is a simple and cheap method that might improve the accuracy of LN-based staging of patients with GC and favor identification of skip metastases.
Relationship between arterial stiffness and circadian pattern of blood pressure
Authors: Park Jin-Sun , Shin Joon-Han , Park Jeong-Bae , Choi Dong-Ju , Youn Ho-Joong , Park Chang-Gyu , Kwan Jun , Ahn Youngkeun , Kim Dong-Woon , Rim Se-Joong , Park Seung-Woo , Sung Jidong , Bae Jang-Ho
Published: March 2019

Arterial stiffness is a risk factor for cardiovascular morbidity and mortality. The relationship between the arterial stiffness and the circadian pattern of blood pressure (BP) has been controversial. The objective of the present study was to investigate the relationship between arterial stiffness by pulse wave analysis (PWA) and variables of 24-hour ambulatory BP monitoring (ABPM) in patients with high normal BP or hypertension (HTN).

Five hundred forty-eight patients (304 males, 48 ± 12-year-old) with high normal BP or HTN were enrolled. BP was measured at the outpatient clinic and 24-hour ABPM was performed. Using radial applanation tonometry, PWA was performed for evaluation of systemic arterial stiffness. Patients were classified into four groups according to the dipping patterns: a nocturnal dipping group, an isolated systolic non-dipping group, an isolated diastolic non-dipping group and a both systolic and diastolic non-dipping group. For adjustment of age, population was divided to 2 groups: old group ≥55 year-old (n = 158, 75 males), young group <55 year-old (n = 390, 229 males).

According to the dipping patterns, augmentation pressure (AP), augmentation index (AI) and heart rate (75 bpm) adjusted AI (AI@HR75) showed statistically significant difference (P = .011, .009, and .018, respectively). Multivariate analysis showed that isolated diastolic non-dipping was correlated with arterial stiffness expressed as AI and AI@HR 75, only in young group (β-coefficient = 12.6, P = .04 and β-coefficient = 7.503, P = .028, respectively).

Arterial stiffness might be closely related with the pattern of non-dipping in young patients with HTN and high normal BP.
Opioid induced adrenal insufficiency: what is new?
Authors: Donegan Diane
Published: March 2019

Purpose of review

Despite the declaration of an opioid epidemic, opioid use remains prevalent. Side-effects of chronic opioid use continue to be problematic. Opioid-induced endocrinopathies have been well documented, yet opioid-induced adrenal insufficiency (OIAI) remains underappreciated. This review summarizes what is currently known regarding the prevalence, predictive factors for the development and effect of treatment of OIAI.

Recent findings

Although several case reports have highlighted the development of adrenal crisis among those receiving chronic opioids, only a few studies have systematically assessed patients for OIAI. The heterogeneity of these small studies presents challenges when trying to assess prevalence of or potential risk factors for OIAI. The estimated prevalence of OIAI among those treated with chronic opioids ranges from 8.3 to 29% and is more likely in those receiving higher doses of opioids. Reduced health-related quality of life variables and altered pain perception has been associated with lower cortisol levels; however, the effect of glucocorticoid replacement on the parameters remains unknown.

Further research is critical to better identify those at greatest risk and guide optimal management of OIAI. Frontline providers should remain vigilant for possibility of OIAI among chronic opioid users.
Neutrophil-to-lymphocyte ratio is independently associated with inflammatory activity and fibrosis grade in nonalcoholic fatty liver disease
Authors: Khoury Tawfik , Mari Amir , Nseir Wiliam , Kadah Anas , Sbeit Wisam , Mahamid Mahmud
Published: March 2019

Background and aim

The progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) is believed to be the driver for future development of fibrosis and cirrhosis. Nevertheless, there remains a lack of noninvasive methods for the diagnosis of NASH. The aim of the present study was to determine the role of neutrophil-to-lymphocyte ratio (NLR) in predicting histological severity in NAFLD.

Patients and methods

We performed a single-center retrospective study in EMMS Nazareth Hospital from July 2014 to May 2017. Liver biopsies were evaluated using the steatosis, activity, and fibrosis scoring system, which includes three components: (i) steatosis (0–3), (ii) activity grade (0–4), and (iii) fibrosis (0–4). Patients were divided into two groups. The first group was considered to have NAFLD when fibrosis grade was 0–1 and inflammatory activity was 0–1, whereas the second group included patients with fibrosis grade of 2–4 and inflammatory activity grade of 2–3, considered to have NASH.

Results

Ninety-one (91) patients with biopsy-proven fatty liver were included. The average age was 42.13 ± 11.5 (18–74) years. Fifty-seven (62.6%) patients were male. Univariate analysis revealed several factors to be associated with advanced fibrosis and inflammatory activity, including NLR, C-reactive protein, and HOMA-IR, which correlated with fibrosis [odds ratio (OR): 1.405, 95% confidence interval (CI): 1.21–1.63, P < 0.0001; OR: 1.329, 95% CI: 1.05–1.68, P = 0.016; and OR: 1.922, 95% CI: 1.18–3.11, P = 0.007, respectively], and NLR, triglycerides, and HOMA-IR, which correlated with hepatocyte inflammation (OR: 1.210, 95% CI: 1.08–1.35, P = 0.0009; OR: 0.984, 95% CI: 0.97–0.99, P = 0.01; and OR: 2.069, 95% CI: 1.28–3.34, P = 0.003, respectively). On multivariate logistic regression analysis, NLR remains independently associated with advanced fibrosis grade and inflammatory activity (OR: 0.734, 95% CI: 0.631–0.854, P < 0.0001, area under the curve: 0.8622 and OR: 0.836, 95% CI: 0.74–0.95, P = 0.006, area under the curve: 0.7845, respectively). Our second major finding was defining an NLR cut-off point that was associated with inflammatory activity and fibrosis grade using receiver operating characteristic analysis based on the Youden index (J), which is defined by the maximal sensitivity and specificity.

Conclusion

NLR showed significant independent correlation with advanced inflammation and fibrosis in patients with NAFLD. This simple available laboratory tool may be incorporated into future diagnostic scores.
Bile acid alterations in nonalcoholic fatty liver disease, obesity, insulin resistance and type 2 diabetes: what do the human studies tell?
Authors: Chávez-Talavera Oscar , Haas Joel , Grzych Guillaume , Tailleux Anne , Staels Bart
Published: March 2019

Purpose of review

The purpose of this review is to discuss the influence of obesity, insulin resistance, type 2 diabetes (T2D), and nonalcoholic fatty liver disease (NAFLD) on bile acid metabolism and to analyze whether these findings reinforce current beliefs about the role of bile acids in the pathophysiology of these diseases.

Recent findings

Discordant results on plasma bile acid alterations in NAFLD patients have been reported. Obesity, insulin resistance, and T2D, common comorbidities of NAFLD, have been associated with bile acid changes, but the individual bile acid species variations differ between studies (summarized in this review), perhaps because of clinicobiological differences between the studied patient populations and the heterogeneity of statistical analyses applied.

The regulatory role of bile acids in metabolic and cellular homeostasis renders bile acids attractive candidates as players in the pathophysiology of NAFLD. However, considering the complex relationship between NAFLD, obesity, insulin resistance and T2D, it is difficult to establish clear and independent associations between bile acid alterations and these individual diseases. Though bile acid alterations may not drive NAFLD progression, signaling pathways activated by bile acids remain potent therapeutic targets for its treatment. Further studies with appropriate matching or adjustment for potential confounding factors are necessary to determine which pathophysiological conditions drive the alterations in bile acid metabolism.
Long-term ventilation for children with chronic lung disease of infancy
Authors: Baker Christopher D.
Published: March 2019

Purpose of review

Modern medical advances have resulted in an increased survival after extremely preterm birth. However, some infants will develop severe bronchopulmonary dysplasia (BPD) and fail to wean from invasive or noninvasive positive pressure support. It remains unclear which infants will benefit from tracheostomy placement for chronic ventilation. Once the decision to pursue chronic ventilation has been made, questions remain with respect to the timing of tracheotomy surgery, optimal strategies for mechanical ventilation, and multidisciplinary care in both the inpatient and outpatient settings. The appropriate time for weaning mechanical ventilation and tracheostomy decannulation has similarly not been determined.

Recent findings

Although there remains a paucity of randomized controlled trials involving infants with severe BPD, a growing body of evidence suggests that chronic ventilation via tracheostomy is beneficial to support the growth and development of severely affected preterm children. However, delivering such care is not without risk. Chronic ventilation via tracheostomy requires complex care coordination and significant resource utilization.

When chronic respiratory insufficiency limits a preterm infant's ability to grow and develop, chronic invasive ventilation may facilitate neurodevelopmental progress and may lead to an improved long-term outcome.
Using the International Classification of Functioning, Disability and Health to Document Hospice Eligibility
Authors: Nation Lola
Published: March 2019

Hospice documentation is an integral part of patient care as it not only paints the picture of hospice eligibility, but also tells the final chapter of a patient’s life. Increasingly, hospices are under scrutiny by regulators to clearly define the admission and ongoing eligibility of the hospice patient. There is a lack of national standardization of documentation. The World Health Organization, in an effort to develop a common language among providers, developed the International Classification of Functioning, Disability and Health (ICF). Utilizing the ICF can assist with the documentation that establishes the eligibility of the hospice patient. Concepts from the ICF are applied to a case study of a patient with Parkinson’s disease. The ICF has barriers and limitations for documentation of the eligibility of the hospice patient, but overall, its use is recommended by the hospice interdisciplinary team.
Repurposing Food and Drug Administration–Approved Drugs to Promote Antitumor Immunity
Authors: Sukhatme Vidula V. , Ramalingam Suresh S. , Ahmed Rafi , Sukhatme Vikas P.
Published: March 2019

There has been a major resurgence of interest in immune-based approaches to treat cancer, based largely on the success of checkpoint inhibitors (anti–cytotoxic T-lymphocyte–associated antigen 4, anti–programmed cell death 1, and anti–programmed cell death ligand 1 antibodies) in several malignancies. However, not all tumors respond to checkpoint therapy, and there is clearly a need for additional approaches for enhancing tumor immunity. We summarize the critical elements necessary for mounting an efficacious T-cell response to a tumor. We cite drugs approved by the Food and Drug Administration for no-cancer indications that could be repurposed and used as part of an antitumor immune cocktail. We also list cancer drugs not initially intended to impact tumor immunity (soft repurposing) but that have been found to modulate the immune system. We highlight those drugs that might be used in combination with checkpoint inhibitors to increase response rates and survival of cancer patients. Our focus will be on drugs for which there are limited but existing human data. We cite supporting mechanistic mouse data as well. Repurposing drugs to modulate antitumor immunity is an opportunity to rapidly bring new, effective, and affordable treatments to cancer patients.
Refractory Cutaneous Dermatomyositis With Severe Scalp Pruritus Responsive to Apremilast
Authors: Charlton Devon , Moghadam-Kia Siamak , Smith Kristin , Aggarwal Rohit , English Joseph C. , Oddis Chester V.
Published: March 2019

Dermatomyositis (DM) is a subset of idiopathic inflammatory myopathy with characteristic cutaneous manifestations and muscle weakness. Conventional treatments for DM include glucocorticoids and other immunosuppressive or immunomodulatory agents including hydroxychloroquine, methotrexate, azathioprine, mycophenolate mofetil, tacrolimus, cyclosporine, and intravenous immunoglobulin. Refractory patients require more aggressive or novel therapies. Apremilast has not been studied for the management of refractory cutaneous DM. We report a case of a patient with refractory DM with severe scalp pruritus treated with apremilast who demonstrated significant improvement in her skin disease and complete resolution of scalp pruritus.
A Bibliometric Analysis of the Most Cited Articles in Global Reconstructive Surgery
Authors: Čebron Urška , Zuo Kevin J. , Kasrai Leila
Published: March 2019

Background

A substantial global inequality exists between surgical need and the availability of safe, affordable surgical care. Low- and middle-income countries have the greatest burden of untreated surgical disease and addressing this inequity is the goal of the Global Surgery movement. Reconstructive surgery is a fundamental component of Global Surgery as it is central to the appropriate treatment of trauma, burns, wounds, and congenital malformations. The objective of this study was to analyze the most frequently cited articles in the field of global reconstructive surgery to understand the main publication trends.

Methods

The 25 most cited articles relating to global reconstructive surgery were identified from all available journals through the Web of Science online database. The following data were extracted from each included article: title, source journal, publication year, total citations, average citations per year, authors, main subject, reconstructive surgery subspecialty, country, and institution of origin.

Results

The average number of citations per article was 21.7 (median, 19; range, 10–40). Most articles originated from the United States, and only 1 originated from a low-income country. The majority of the articles focused on cleft lip and palate (CLP) (72%), with few articles discussing burns or trauma. The main discussion themes were the quality of care provided in low- and middle-income countries both by local and visiting teams, the burden of diseases in relation to global reconstructive surgery, and the impact of surgical interventions economically and on patients.

Conclusions

The number of research articles and citations related to global reconstructive surgery are limited. Despite having a lower incidence than burns or trauma, there is a preponderance of reports focusing on missions treating CLP. These findings suggest that more research funding could be invested in global reconstructive surgery for conditions other than CLP.
Everolimus Initiation With Early Calcineurin Inhibitor Withdrawal in De Novo Heart Transplant Recipients: Long-term Follow-up From the Randomized SCHEDULE Study
Authors: Gustafsson Finn , Andreassen Arne K. , Andersson Bert , Eiskjær Hans , Rådegran Göran , Gude Einar , Jansson Kjell , Solbu Dag , Karason Kristjan , Arora Satish , Dellgren Göran , Gullestad Lars
Published: March 2019

Background.

A calcineurin inhibitor (CNI)-free immunosuppressive regimen has been demonstrated to improve renal function early after heart transplantation, but long-term outcome of such a strategy has not been well described.

Methods.

In the randomized SCHEDULE trial, de novo heart transplant recipients received (1) everolimus with reduced-exposure CNI (cyclosporine) followed by CNI withdrawal at week 7–11 posttransplant or (2) standard-exposure cyclosporine, both with mycophenolate mofetil and corticosteroids; 95/115 randomized patients were followed up at 5–7 years posttransplant.

Results.

Mean measured glomerular filtration rate was 74.7 mL/min and 62.4 mL/min with everolimus and CNI, respectively. The mean difference was in favor of everolimus by 11.8 mL/min in the intent-to-treat population (P = 0.004) and 17.2 mL/min in the per protocol population (n = 75; P < 0.001). From transplantation to last follow-up, the incidence of biopsy-proven acute rejection (BPAR) was 77% (37/48) and 66% (31/47) (P = 0.23) with treated BPAR in 50% and 23% (P < 0.01) in the everolimus and CNI groups, respectively; no episode led to hemodynamic compromise. Coronary allograft vasculopathy (CAV) assessed by coronary intravascular ultrasound was present in 53% (19/36) and 74% (26/35) of everolimus- and CNI-treated patients, respectively (P = 0.037). Graft dimensions and function were similar between the groups. Late adverse events were comparable.

Conclusions.

These results suggest that de novo heart transplant patients randomized to everolimus and low-dose CNI followed by CNI-free therapy maintain significantly better long-term renal function as well as significantly reduced CAV than patients randomized to standard CNI treatment. Increased BPAR in the everolimus group during year 1 did not impair long-term graft function.
Advance in genetics of migraine
Authors: de Boer Irene , van den Maagdenberg Arn M.J.M. , Terwindt Gisela M.
Published: March 2019

Purpose of review

Migraine is a primary headache disorder and one of the most common and disabling neurological diseases worldwide. Genome-wide association studies have identified ≈40 genetic loci associated with migraine. How these and other genetic findings are used to expand our knowledge on the pathophysiological mechanism of common migraine and rare migraine variants will be discussed.

Recent findings

The genetic load, based on common polygenic variation, is higher in familial migraine cases than in nonfamilial cases, and higher for migraine with aura and hemiplegic migraine. Migraine shares common genetic variant risks with depression. Specific clinical features of common migraine seem to be determined by genetic factors. A stronger family history of migraine is associated with lower age-at-onset, higher frequency and number of medication days and the migraine with aura subtype. Mild hemiplegic migraine is likely caused by complex polygenic interaction of multiple gene variants and environmental factors, like in common migraine subtypes. Phenotypical features in hemiplegic migraine patients may guide physicians in providing adequate genetic counseling.

Integration of genetic, phenotypic and epigenetic data will help to identify the biological mechanisms by which genetic factors contribute to migraine pathogenesis. Recent studies show the impact of genetics on clinical features and comorbidities in migraine and may guide clinicians to an adequate genetic advice for patients.
Cutaneous geotrichosis due to Geotrichum candidum in a burn patient
Authors: Keene Sarah , Sarao Manbeer S. , McDonald Philip J. , Veltman Jennifer
Published: March 2019

Geotrichum candidum is a saprophytic yeast known to colonize the human skin, respiratory tract and gastrointestinal tract. It can cause local or disseminated disease (geotrichosis), mainly in the immunocompromised host. Trauma, indwelling catheter use, prolonged broad-spectrum antibiotic treatment and critical illness have also been implicated as risk factors. Here we report the first case, to our knowledge, of cutaneous G. candidum infection in a burn patient. The isolate had a high amphotericin B minimum inhibitory concentration (MIC) and the patient experienced concomitant Candida
orthopsilosis fungaemia, and so was treated with a combination of voriconazole and micafungin. This case highlights the importance of source control, rapid identification of G. candidum infection and MIC determination to guide antifungal therapy, which typically consists of amphotericin B with or without flucytosine or voriconazole alone. Clinicians should be aware of geotrichosis as a clinical entity in burn patients as well as in the immunocompromised. Antifungal resistance and breakthrough disease are an ongoing concern due to the increasing number of immunocompromised at-risk patients and the use of routine mould prophylaxis.
Assessment of urinary pharmacokinetic and pharmacodynamic profiles of faropenem against extended-spectrum β-lactamase-producing Escherichia coli with canine ex vivo modelling: a pilot study
Authors: Harada Kazuki , Shimizu Takae , Miyashita Naoki , Hikasa Yoshiaki
Published: March 2019

This study was carried out to investigate the urinary pharmacokinetics and pharmacodynamics of faropenem administered orally at 5 mg kg−1 in six healthy dogs to assess the efficacy of the drug for canine urinary tract infections (UTIs) with extended-spectrum β-lactamase (ESBL)-producing bacteria. Six strains of ESBL-producing

Escherichia coli

(ESBL-EC) with the following faropenem minimum inhibitory concentrations (MICs) were used: 1 µg ml−1 (n=2), 2 µg ml−1 (n=2), 4 µg ml−1 (n=1) and 16 µg ml−1 (n=1). Urine samples were obtained every 4 h for the first 12 h after administration to measure urinary drug concentration and urinary bactericidal titres (UBTs). Both the urine concentration of faropenem and the UBTs for all tested strains peaked at 0–4 h after administration, and decreased markedly at 8–12 h. The mean urinary concentration of faropenem at 8–12 h (23±5.2 µg ml−1) exceeded the MIC of 1 µg ml−1 by fourfold, which is required to inhibit the growth of 90  % of ESBL-EC. These findings indicate that faropenem administered twice daily at a dose of 5 mg kg−1 is acceptable for the treatment of most dogs with ESBL-EC-related UTIs.
Variations in Structural MRI Quality Significantly Impact Commonly-Used Measures of Brain Anatomy
Authors: Gilmore Alysha , Buser Nicholas , Hanson Jamie L.
Published: March 2019

Subject motion can introduce noise into neuroimaging data and result in biased estimations of brain structure. In-scanner motion can compromise data quality in a number of ways and varies widely across developmental and clinical populations. However, quantification of structural image quality is often limited to proxy or indirect measures gathered from functional scans; this may be missing true differences related to these potential artifacts. In this study, we take advantage of novel informatic tools, the CAT12 toolbox, to more directly measure image quality from T1-weighted images to understand if these measures of image quality: 1) relate to rigorous quality-control checks visually completed by human raters; 2) are associated with sociodemographic variables of interest; 3) influence regional estimates of cortical surface area, cortical thickness, and subcortical volumes from the commonly-used Freesurfer tool suite. We leverage public-access data that includes a community-based sample of children and adolescents, spanning a large age-range (N=388; ages 5-21). Interestingly, even after visually inspecting our data, we find image quality significantly impacts derived cortical surface area, cortical thickness, and subcortical volumes from multiple regions across the brain (∼23.4% of all areas investigated). We believe these results are important for research groups completing structural MRI studies using Freesurfer or other morphometric tools. As such, future studies should consider using measures of image quality to minimize the influence of this potential confound in group comparisons or studies focused on individual differences.
Dictyostelium discoideumflotillin homologues are essential for phagocytosis and participate in plasma membrane recycling and lysosome biogenesis
Authors: Bosmani Cristina , Bach Frauke , Leuba Florence , Hanna Nabil , Burdet Frédéric , Pagni Marco , Hagedorn Monica , Soldati Thierry
Published: March 2019

The metazoan flotillins are lipid rafts residents involved in membrane trafficking and recycling of plasma membrane proteins.Dictyostelium discoideum, a social soil amoeba, uses phagocytosis to digest, kill and feed on bacteria.D. discoideumpossesses three flotillin-like proteins, termed VacA, VacB and the recently identified VacC. All three vacuolins gradually accumulate on postlysosomes and, like flotillins, are strongly associated with membranes and partly with lipid rafts. Vacuolins are absolutely required for uptake of various particles. Their absence impairs particle recognition possibly because of defective recycling of plasma membrane or cortex-associated proteins. In addition, vacuolins are involved in phagolysosome biogenesis, although this does not impact digestion and killing of a wide range of bacteria. Furthermore, vacuolin knockout affects early recruitment of the WASH complex on phagosomes, suggesting that vacuolins may be involved in the WASH-dependent plasma membrane recycling. Altogether, these results indicate that vacuolins act as the functional homologues of flotillins inD. discoideum.
Region-specific blood-brain barrier transporter changes leads to increased sensitivity to amisulpride in Alzheimer’s disease
Authors: Sekhar Gayathri Nair , Fleckney Alice L. , Boyanova Sevda Tomova , Rupawala Huzefa , Lo Rachel , Wang Hao , Farag Doaa B. , Rahman Khondaker Miraz , Broadstock Martin , Reeves Suzanne , Thomas Sarah Ann
Published: March 2019

Research into amisulpride use in Alzheimer’s disease (AD) implicates blood-brain barrier (BBB) dysfunction in antipsychotic sensitivity. Solute carrier function in AD has not been widely studied. This study tests the hypothesis that organic cation transporters contribute to the BBB delivery of antipsychotics and is disrupted in AD.

In vitroBBB studies indicated that [3H]amisulpride and [3H]haloperidol were transported by OCT1. Amisulpride also utilized PMAT. Molecular docking predicted that amisulpride and haloperidol are OCT1, PMAT and MATE1 substrates, and amisulpride is not a P-gp substrate. Amisulpride brain uptake increased in 3xTgAD compared to wildtype mice. PMAT and MATE1 expression was reduced in brain from AD patients compared to controls. The increased sensitivity of Alzheimer’s patients to amisulpride is related to previously unreported changes in OCT1, PMAT and MATE1 function/expression at the BBB. Dose adjustments may be required for drugs that are substrates of these transporters when prescribing for AD patients.
CRISPR-BEST: a highly efficient DSB-free base editor for filamentous actinomycetes
Authors: Tong Yaojun , Robertsen Helene L. , Blin Kai , Klitgaard Andreas K. , Weber Tilmann , Lee Sang Yup
Published: March 2019

Filamentous actinomycetes serve as major producers of various natural products including antimicrobial compounds. Although CRISPR-Cas9 systems have been developed for more robust genetic manipulations, concerns of genome instability caused by the DNA double-strand breaks (DSB) and the toxicity of Cas9 remain. To overcome these limitations, here we report development of the DSB-free, single-nucleotide resolution genome editing system CRISPR-BEST (CRISPR-Base Editing SysTem). Specifically targeted by an sgRNA, the cytidine deaminase component of CRISPR-BEST efficiently converts C:G to T:A within a window of approximately seven-nucleotides. The system was validated and successfully used in different Streptomyces species.
Continuous dynamic modeling of regulated cell adhesion
Authors: Ko J. M. , Lobo D.
Published: March 2019

Cell-cell adhesion is essential for tissue growth and multicellular pattern formation, and crucial for the cellular dynamics during embryogenesis and cancer progression. Understanding the dynamical gene regulation of cell adhesion molecules (CAMs) responsible for the emerging spatial tissue behaviors is a current challenge due to the complexity of these non-linear interactions and feedback loops at different levels of abstraction—from genetic regulation to whole-organism shape formation. Continuous mathematical models of cell adhesion are ideal for the modeling of the spatial dynamics of large cell populations, where different cell types define inherent adhesion strengths. However, biologically the adhesive properties of the cell arise dynamically from differential expression of CAMs, which are precisely regulated during development and cancer progression. To extend our understanding of cell and tissue behaviors due to the regulation of adhesion molecules, here we present a novel model for the spatial dynamics of cellular patterning, growth, and shape formation due to the differential expression of CAMs and their regulation. Capturing the dynamic interplay between genetic regulation, CAM expression, and differential cell adhesion, the proposed continuous model can recapitulate the complex and emergent spatial behaviors of cell populations that change their adhesion properties dynamically due to inter- and intracellular genetic regulation. This approach can demonstrate the mechanisms responsible for classical cell sorting behaviors, cell intercalation in proliferating populations, and the involution of germ layer cells induced by a diffusing morphogen during gastrulation. Integrating the emergent spatial tissue behaviors with the regulation of genes responsible for essential cellular properties such as adhesion will pave the way towards understanding the genetic regulation of large-scale complex patterns and shapes formation in developmental, regenerative, and cancer biology.
Tissue-specific MicroRNA Expression Alters Cancer Susceptibility Conferred by aTP53Noncoding Variant
Authors: Deng Qipan , Hu Hui , Yu Xinfang , Liu Shuanglin , Wang Lei , Chen Weiqun , Zhang Chi , Zeng Zhaoyang , Cao Ya , Li Ling , Zhang Mingzhi , Rosenfeld Steven , Bao Shideng , Hsi Eric , Young Ken H , Lu Zhongxin , Li Yong
Published: March 2019

Patients carryingTP53germline mutations develop Li-Fraumeni syndrome (LFS), a rare genetic disorder with high risk of several cancers, most notably breast cancer, sarcoma, and brain tumors. A noncoding polymorphism (rs78378222) inTP53, carried by scores of millions of people, was associated with moderate risk of brain, colon, and prostate tumors, and other neoplasms. We found a positive association between this variant and soft tissue sarcoma (odds ratio [OR] = 4.55,P= 3.3 x 10−5). In sharp contrast, this variant was protective against breast cancer (OR = 0.573,P= 0.0078). We generated a mouse line carrying this variant and found that this variant accelerated spontaneous tumorigenesis and tumor development at the brain, prostate, colon, and skeletal muscle, but strikingly, it significantly delayed mammary tumorigenesis. The variant created a miR-382 targeting site and compromised a miR-325 targeting site. Their differential expression resulted in p53 downregulation in the brain and several other tissues, but p53 upregulation in the mammary gland of the mutant mice compared to that of wild-type littermates. Thus, thisTP53variant is at odds with LFS mutants in breast cancer predisposition yet consistent with LFS mutants in susceptibility to soft tissue sarcoma and glioma. Our findings elucidate an underlying mechanism of cancer susceptibility that is conferred by genetic variation and yet altered by microRNA expression.
Patterns of diverse gene functions in genomic neighborhoods predict gene function and phenotype
Authors: Mihelčić Matej , Šmuc Tomislav , Supek Fran
Published: March 2019

Genes with similar roles in the cell are known to cluster on chromosomes, thus benefiting from coordinated regulation. This allows gene function to be inferred by transferring annotations from genomic neighbors, following the guilt-by-association principle. We performed a systematic search for co-occurrence of >1000 gene functions in genomic neighborhoods across 1669 prokaryotic, 49 fungal and 80 metazoan genomes, revealing prevalent patterns that cannot be explained by clustering of functionally similar genes. It is a very common occurrence that pairs of dissimilar gene functions – corresponding to semantically distant Gene Ontology terms – are significantly co-located on chromosomes. These neighborhood associations are often as conserved across genomes as the known associations between similar functions, suggesting selective benefits from clustering of certain diverse functions, which may conceivably play complementary roles in the cell. We propose a simple encoding of chromosomal gene order, the neighborhood function profiles (NFP), which draws on diverse gene clustering patterns to predict gene function and phenotype. NFPs yield a 26-46% increase in predictive power over state-of-the-art approaches that propagate function across neighborhoods, thus providing hundreds of novel, high-confidence gene function inferences per genome. Furthermore, we demonstrate that the effect of structural variation on gene function distribution across chromosomes may be used to predict phenotype of individuals from their genome sequence.
Nuclear pores as versatile reference standards for quantitative superresolution microscopy
Authors: Thevathasan Jervis Vermal , Kahnwald Maurice , Cieśliński Konstanty , Hoess Philipp , Peneti Sudheer Kumar , Reitberger Manuel , Heid Daniel , Kasuba Krishna Chaitanya , Hoerner Sarah Janice , Li Yiming , Wu Yu-Le , Mund Markus , Matti Ulf , Pereira Pedro Matos , Henriques Ricardo , Nijmeijer Bianca , Kueblbeck Moritz , Sabinina Vilma Jimenez , Ellenberg Jan , Ries Jonas
Published: March 2019

Quantitative fluorescence and superresolution microscopy are often limited by insufficient data quality or artifacts. In this context, it is essential to have biologically relevant control samples to benchmark and optimize the quality of microscopes, labels and imaging conditions.

Here we exploit the stereotypic arrangement of proteins in the nuclear pore complex as in situ reference structures to characterize the performance of a variety of microscopy modalities. We created four genome edited cell lines in which we endogenously labeled the nucleoporin Nup96 with mEGFP, SNAP-tag or HaloTag or the photoconvertible fluorescent protein mMaple. We demonstrate their use a) as 3D resolution standards for calibration and quality control, b) to quantify absolute labeling efficiencies and c) as precise reference standards for molecular counting.

These cell lines will enable the broad community to assess the quality of their microscopes and labels, and to perform quantitative, absolute measurements.
Trans-generational effects on diapause and life-history-traits of an aphid parasitoid
Authors: K. Tougeron , M. Devogel , J. van Baaren , C. Le Lann , T. Hance
Published: March 2019

Transgenerational effects act on a wide range of insects’ life-history traits and can be involved in the control of developmental plasticity, such as diapause expression. Decrease in or total loss of winter diapause expression recently observed in some species could arise from inhibiting maternal effects. In this study, we explored transgenerational effects on diapause expression and traits in one industrial and one wild strain of the aphid parasitoidAphidius ervi. These strains were reared under short photoperiod (8:16 h LD) and low temperature (14 °C) conditions over two generations. Diapause levels, developmental times, physiological and morphological traits were measured. Diapause levels increased after one generation in the wild but not in the industrial strain. For both strains, the second generation took longer to develop than the first one. Tibia length and wing surface decreased over generations while fat content increased. A crossed-generations experiment focusing on the industrial parasitoid strain showed that offspring from mothers reared at 14 °C took longer to develop, were heavier, taller with wider wings and with more fat reserves than those from mothers reared at 20 °C (8:16 h LD). No effect of the mother rearing conditions was shown on diapause expression. Additionally to direct plasticity of the offspring, results suggest transgenerational plasticity effects on diapause expression, development time, and on the values of life-history traits. We demonstrated that populations showing low diapause levels may recover higher levels through transgenerational plasticity in response to diapause-induction cues, provided that environmental conditions are reaching the induction-thresholds specific to each population. Transgenerational plasticity is thus important to consider when evaluating how insects adapt to changing environments.
CRISPR/Cas9-based mutagenesis frequently provokes on-target mRNA misregulation
Authors: Tuladhar Rubina , Yeu Yunku , Piazza John Tyler , Tan Zhen , Clemenceau Jean Rene , Wu Xiaofeng , Barrett Quinn , Herbert Jeremiah , Mathews David H. , Kim James , Hwang Tae Hyun , Lum Lawrence
Published: March 2019

The introduction of insertion-deletions (INDELs) by activation of the error-prone non-homologous end-joining (NHEJ) pathway underlies the mechanistic basis of CRISPR/Cas9-directed genome editing. The ability of CRISPR/Cas9 to achieve gene elimination (knockouts) is largely attributed to the emergence of a pre-mature termination codon (PTC) from a frameshift-inducing INDEL that elicits non-sense mediated decay (NMD) of the mutant mRNA. Yet, the impact on gene expression as a consequence of CRISPR/Cas9-introduced INDELs into RNA regulatory sequences has been largely left uninvestigated. By tracking DNA-mRNA-protein relationships in a collection of CRISPR/Cas9-edited cell lines that harbor frameshift-inducing INDELs in various targeted genes, we detected the production of foreign mRNAs or proteins in ∼50% of the cell lines. We demonstrate that these aberrant protein products are derived from the introduction of INDELs that promote internal ribosomal entry, convert pseudo-mRNAs into protein encoding molecules, or induce exon skipping by disruption of exon splicing enhancers (ESEs). Our results using CRISPR/Cas9-introduced INDELs reveal facets of an epigenetic genome buffering apparatus that likely evolved to mitigate the impact of such mutations introduced by pathogens and aberrant DNA damage repair, and that more recently pose challenges to manipulating gene expression outcomes using INDEL-based mutagenesis.
The use of a virus-derived targeting peptide to selectively kill staphylococcus bacteria with antimicrobial peptides
Authors: Ashiqul Islam S M , Choudhury Ankan , Ghidey Meron R. , Kearney Christopher Michel
Published: March 2019

Background

Targeted therapies seek to selectively eliminate a pathogen without disrupting the microbiome community. Bacteriophages provide a rich, well-documented source of bacterium-specific binding proteins for use as targeting peptides fused to antimicrobial peptides. Though resistance may develop as with any antibiotic, the wealth of variants available in natural bacteriophage populations adds to the robustness of this system.

Results

Here, we target two cationic antimicrobial peptides (AMPs), plectasin and eurocin, by genetically fusing their coding sequence to that of the host-binding protein of bacteriophage A12C, which selectively infectsStaphylococcus. Surprisingly, we noted that targeting brought no change in the toxicity of the AMP when applied to two different staphylococci,S. aureusandS. epidermidis, but found a drastic decrease in toxicity against the negative controls,Enterococcus faecalisandBacillus subtilis. Thus, the differential selectivity in this case is a loss of toxicity against the non-target species rather than the gain of toxicity against the target species which was reported in previous studies with other types of targeting antimicrobial peptides.

Conclusion

This is the first report of the use of virus-derived peptide sequences to target antimicrobial peptides. Considering the very large databank of bacteriophages and their bacterial hosts, this targeting approach should be generally applicable to a wide range of bacterial pathogens.
Scalable generalized linear mixed model for region-based association tests in large biobanks and cohorts
Authors: Zhou Wei , Zhao Zhangchen , Nielsen Jonas B. , Fritsche Lars G. , LeFaive Jonathon , Gagliano Taliun Sarah A. , Bi Wenjian , Gabrielsen Maiken E. , Daly Mark J. , Neale Benjamin M. , Hveem Kristian , Abecasis Goncalo R. , Willer Cristen J. , Lee Seunggeun
Published: March 2019

With very large sample sizes, population-based cohorts and biobanks provide an exciting opportunity to identify genetic components of complex traits. To analyze rare variants, gene or region-based multiple variant aggregate tests are commonly used to increase association test power. However, due to the substantial computation cost, existing region-based rare variant tests cannot analyze hundreds of thousands of samples while accounting for confounders, such as population stratification and sample relatedness. Here we propose a scalable generalized mixed model region-based association test that can handle large sample sizes and accounts for unbalanced case-control ratios for binary traits. This method, SAIGE-GENE, utilizes state-of-the-art optimization strategies to reduce computational and memory cost, and hence is applicable to exome-wide and genome-wide region-based analysis for hundreds of thousands of samples. Through the analysis of the HUNT study of 69,716 Norwegian samples and the UK Biobank data of 408,910 White British samples, we show that SAIGE-GENE can efficiently analyze large sample data (N > 400,000) with type I error rates well controlled.