bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular dynamics simulations suggest stabilizing mutations in a de novo designed α/β protein
Authors: Gill Matthew , McCully Michelle E
Published: January 2020

Designing functional proteins that can withstand extreme heat is beneficial for industrial and protein therapeutic applications. Thus, elucidating the atomic-level determinants of thermostability is a major interest for rational protein design. To that end, we compared the structure and dynamics of a set of previously designed, thermostable proteins based on the activation domain of human procarboxypeptidase A2 (AYEwt). The mutations in these designed proteins were intended to increase hydrophobic core packing and inter-secondary-structure interactions. To evaluate whether these design strategies were successfully deployed, we performed all-atom, explicit-solvent molecular dynamics (MD) simulations of AYEwt and three designed variants at both 25 and 100°C. Our MD simulations agreed with the relative experimental stabilities of the designs based on their secondary structure content, Cα root-mean-square deviation/fluctuation, and buried-residue solvent accessible surface area. Using a contact analysis, we found that the designs stabilize inter-secondary structure interactions and buried hydrophobic surface area, as intended. Based on our analysis, we designed three additional variants to test the role of helix stabilization, core packing, and a Phe → Met mutation on thermostability. We performed the additional MD simulations and analysis on these variants, and these data supported our predictions.
Vector Lattices Admitting a Positively Homogeneous Continuous Function Calculus
Authors: Laustsen Niels Jakob , Troitsky Vladimir G
Published: January 2020

We characterize the Archimedean vector lattices that admit a positively homogeneous continuous function calculus by showing that the following two conditions are equivalent for each $n$-tuple $\boldsymbol{x} = (x_1,\ldots ,x_n)\in X^n$, where $X$ is an Archimedean vector lattice and $n\in{\mathbb{N}}$: • there is a vector lattice homomorphism $\Phi _{\boldsymbol{x}}\colon H_n\to X$ such that $$\begin{equation*}\Phi_{\boldsymbol{x}}(\pi_i^{(n)}) = x_i\qquad (i\in\{1,\ldots,n\}),\end{equation*}$$where $H_n$ denotes the vector lattice of positively homogeneous, continuous, real-valued functions defined on ${\mathbb{R}}^n$ and $\pi _i^{(n)}\colon{\mathbb{R}}^n\to{\mathbb{R}}$ is the $i^{\text{}}$th coordinate projection;• there is a positive element $e\in X$ such that $e\geqslant \lvert x_1\rvert \vee \cdots \vee \lvert x_n\rvert$ and the norm$$\begin{equation*}\lVert x\rVert_e = \inf\bigl\{ \lambda\in[0,\infty)\:\colon\:\lvert x\rvert{\leqslant}\lambda e\bigr\},\end{equation*}$$defined for each $x$ in the order ideal $I_e$ of $X$ generated by $e$, is complete when restricted to the closed sublattice of $I_e$ generated by $x_1,\ldots ,x_n$.

Moreover, we show that a vector space which admits a ‘sufficiently strong’ $H_n$-function calculus for each $n\in{\mathbb{N}}$ is automatically a vector lattice, and we explore the situation in the non-Archimedean case by showing that some non-Archimedean vector lattices admit a positively homogeneous continuous function calculus, while others do not.
Influence of non-steroidal anti-inflammatory drugs on the inflammatory sonographic features in erosive hand osteoarthritis: an intervention study
Authors: Xu Qun Xia , Wittoek Ruth
Published: January 2020

Objective

The aim was to examine whether inflammatory US features in erosive hand OA patients change when discontinuing intake of NSAIDs before US examination in a non-randomized study.

Methods

Patients (n = 99) were allocated to the NSAIDs or control group according to their intake at baseline. US was performed at baseline (T0) and 2 weeks after discontinuation of NSAIDs (T1). Inflammatory features (i.e. synovial proliferation, effusion and power Doppler signal) were scored using a semi-quantitative scale (from zero to three). Pain levels were scored on a numerical rating scale. Binomial mixed models were fitted for US features, and odds ratios of having a US score of at least two vs at most one for synovial proliferation and effusion, and zero vs at least one for power Doppler were calculated.

Results

At baseline, both groups [NSAIDs group (n = 47) vs control group (n = 52)] were comparable for numerical rating scale pain, disease duration, number of radiographically affected joints, BMI and US baseline data, but not for age (P = 0.005). At T1, more synovial proliferation and power Doppler signal was seen compared with T0 in the NSAIDs group (P = 0.018 and 0.031, respectively). However, the interaction term time*NSAIDs was not found to be significant for any variable. The numerical rating scale pain at T1 was higher compared with baseline, although statistically non-significant.

Conclusion

No significant changes in inflammatory US features were seen in patients with erosive hand OA after withdrawal of NSAIDs for 2 weeks. This study suggests that an NSAID-free period is not necessary before assessing inflammatory disease activity in erosive hand OA.
Mixed methods study of a new model of care for chronic disease: co-design and sustainable implementation of group consultations into clinical practice
Authors: Russell-Westhead Michele , O’Brien Nicola , Goff Iain , Coulson Elizabeth , Pape Jess , Birrell Fraser
Published: January 2020

Objectives

Group consultations are used for chronic conditions, such as inflammatory arthritis, but evidence of efficacy for treatment to target or achieving tight control is lacking. Our aim was to establish whether group consultation is a sustainable, co-designed routine care option and to explore factors supporting spread.

Methods

The study used mixed methods, observational process/outcome data, plus qualitative exploration of enabling themes. It was set in two community hospitals, in 2008–19, with a third hospital from 2016, and was triangulated with primary care qualitative data. There was a total of 3363 arthritis patient attendances at 183 clinics during 2008–19. The early arthritis cohort comprised 46 patients, followed monthly until the treatment target was achieved, during 2016–19. Focus groups included 15 arthritis and 11 osteoporosis group attendees. Intervention was a 2 h group consultation, attended monthly for early/active disease and annually for stable disease. Measurements included attendance, DAS, satisfaction and enabling themes.

Results

There was a mean number of 18.4 patients per clinic (n = 16, 2010–15; n = 18, 2016; n = 20, 2017; n = 23, 2018–19). Forty per cent (1161/2874) of patients with DAS data reached low disease activity (DAS < 3.2) or remission (DAS < 2.6). Forty-six early arthritis patients followed monthly until they achieved remission responded even better: 50% remission; and 89% low disease activity/remission by 6 months. Qualitative analysis derived five main enabling themes (efficiency, empathy, education, engagement and empowerment) and five promotors to translate these themes into practice (prioritization, personalization, participation, personality and pedagogy). Limitations included the prospectively collected observational data and pragmatic design susceptible to bias.

Conclusion

Co-designed group consultations can be sustainable, clinically effective and efficient for monthly review of early active disease and annual review of stable disease. Promoting factors may support effective training for chronic disease group consultations.
Mortality, Revascularization, and Cardioprotective Pharmacotherapy After Acute Coronary Syndrome in Patients With Psychotic Disorders: A Population-Based Cohort Study
Authors: Chang Wing Chung , Chan Joe Kwun Nam , Wong Corine Sau Man , Hai JoJo Siu Han , Or Philip Chi Fai , Chen Eric Yu Hai
Published: January 2020

Ischemic heart disease is the leading cause of mortality in psychotic disorders. There is a paucity of research comprehensively evaluating short-term mortality, cardiovascular complications, and treatment inequality after cardiac events in patients with psychotic disorders. This population-based cohort study examined 30-day and 1-year all-cause mortality, cardiovascular complication rates, 30-day and 1-year receipt of invasive cardiac procedures, and 90-day post-discharge cardioprotective medication treatment following admission for first-recorded acute coronary syndrome (ACS) among patients with psychotic disorders (n = 703) compared with patients without psychotic disorders (n = 66 989) between January 2006 and December 2016 in Hong Kong (HK). Study data were retrieved from territory-wide medical record database of public healthcare services to 7.5 million HK residents. Multivariate regression analyses (ORs and 95% CIs), adjusting for demographics and medical comorbidities, were conducted to evaluate associations between psychotic disorders and post-ACS outcomes. Our results showed that patients with psychotic disorders had higher 30-day (OR: 1.99 [95% CI: 1.65–2.39]) and 1-year (2.13 [1.79–2.54]) mortality, and cardiovascular complication rates (1.20 [1.02–1.41]), lower receipt of cardiac catheterization (30-d: 0.54 [0.43–0.68]; 1-y: 0.46 [0.38–0.56]), percutaneous coronary intervention (30-d: 0.55 [0.44–0.70]; 1-y: 0.52 [0.42–0.63]) and reduced β-blockers (0.81 [0.68–0.97]), statins (0.54 [0.44–0.66]), and clopidogrel prescriptions (0.66 [0.55–0.80]). Associations between psychotic disorder and increased mortality remained significant even after complications and treatment receipt were additionally adjusted. Our findings indicate that psychotic disorders are associated with increased risks of short-term post-ACS mortality, cardiovascular complications, and inferior treatment. Excess mortality is not substantially explained by treatment inequality. Further investigation is warranted to clarify factors for suboptimal cardiac-care and elevated mortality in psychotic disorders to enhance post-ACS outcome.
The law applicable to third-party effects of transactions in intermediated securities
Authors: Heindler Florian
Published: January 2020

The conflict-of-laws rules applicable to the third-party effects of transactions in intermediated securities have attracted a great deal of interest in legal practice and academia. The article reviews the current legal developments in the European Union (EU), the international trends (Geneva Securities Convention and Hague Securities Convention), and the challenges of technological innovation. The article proposes interpreting the category of conflict-of-laws rules applicable to the third-party effects of transactions in intermediated securities in a concise, short, functional, and abstract way. Furthermore, it puts the discussions on the proper connecting factor into context and comments on the most recent developments in the EU in this respect. Finally, it adds to the discussion on proper connecting factors for digital ledger technology-based settlement systems (blockchain) and other current trends.
Household Impacts of Tariffs: Data and Results from Agricultural Trade Protection
Authors: Artuc Erhan , Porto Guido , Rijkers Bob
Published: January 2020

How do trade reforms impact households in different parts of the income distribution? This paper presents a new database, the Household Impacts of Tariffs data set, which contains harmonized household survey and tariff data for 54 low- and middle-income countries. The data cover highly disaggregated information on household budget and income shares for 53 agricultural products, wage labor income, non-farm enterprise sales and transfers, as well as spending on manufacturing and services. Using a stylized model of the first-order impacts of import tariffs on household real income, this paper quantifies the welfare implications of agricultural trade protection. On average, unilateral elimination of agricultural tariffs would increase household incomes by 2.50 percentage points. Import tariffs have highly heterogeneous effects across countries and within countries across households, consumers, and income earners; the average standard deviation of the gains from trade within a country is 1.01 percentage points.
Neonatal Nurse Practitioner Use of Ultrasonography to Verify Umbilical Venous Catheter Placement in the Neonatal Intensive Care Unit
Authors: Mele Robert , Panesar Laurie E. , Heyden Marybeth , Sridhar Shanthy , Brandon Debra
Published: January 2020

Background:

Literature dating back to 1982 supports the use of ultrasound to confirm UVC position as a more reliable method compared to x-ray. The use of ultrasound to confirm UVC position remains infrequent in the NICU.

Purpose:

To determine the feasibility of training an NNP in the acquisition and interpretation of a parasternal short-axis (PSAX) image of the heart to confirm UVC position.

Methods:

A retrospective review of 48 charts evaluated descriptive data using standard technique of an x-ray to confirm UVC placement. An NNP was trained to acquire and interpret a parasternal short-axis (PSAX) cardiac view by a pediatric cardiologist. The NNP independently and prospectively evaluated 21 neonates and determined whether the UVC was in satisfactory or unsatisfactory position. The same image was blindly over-read by the pediatric cardiologist. Agreement between the NNP and pediatric cardiologist interpretations as well as the pediatric cardiologist and radiologist interpretations was evaluated using the κ-test.

Results:

Initial pediatric cardiology interpretation of UVC position showed the UVC to be malpositioned in 66% of neonates (n = 14). NNP and pediatric cardiology interpretations in UVC position had 86% agreement (κ-0.667). Pediatric cardiology (ultrasound) and radiology interpretations (x-ray) in UVC position had 86% agreement (κ-0.69).

Implications for Practice:

It is feasible to train NNPs to perform and accurately interpret a single PSAX ultrasound image to determine satisfactory UVC position.

Implications for Research:

Increasing the use of ultrasound to determine satisfactory position of UVCs in the NICU can reduce unnecessary exposure to ionizing radiation in neonates.
XEN Gel Stent in Pediatric Glaucoma
Authors: Smith Oluwatosin U. , Grover Davinder S. , Emanuel Mathew E. , Godfrey David G. , Fellman Ronald L.
Published: January 2020

Purpose:

To report a series of 3 eyes of 3 children with congenital glaucoma receiving the XEN gel stent implant.

Patients and Methods:

An interventional case series is reported.

Results:

Three eyes underwent implantation of the gel stent. In 2 cases, the gel implant procedure was performed after failed trabeculotomy, while in the third eye, primary gel stent implantation was performed. One eye received 2 implants. Three procedures were performed via an ab interno approach while the fourth was performed ab externo. No device-related complications were observed. In all 3 eyes, intraocular pressure was controlled without the use of topical medications through 6 to 24 months of follow-up.

Conclusions:

The gel stent implant can be safely used in children with congenital glaucoma and effectively lowers intraocular pressure in these eyes. This procedure is a viable follow-up to, or replacement for, traditional angle surgery in eyes with congenital glaucoma.
Socioeconomic Impact of the Rotavirus Vaccine in Korea
Authors: Cho Hyeonseok , Lee Hankil , Kim Dong Soo , Kim Hwang Min , Kim Ji Hong , Kim Ah-Young , Kang Hye-Young
Published: January 2020

Background:

Since the introduction of 2 rotavirus (RV) vaccines in Korea, the vaccination rate has reached over 80% with out-of-pocket spending in the private market. We investigated the socioeconomic impact of RV vaccines in Korea to assess their value and public health contribution.

Methods:

By using National Health Insurance Service claims data, we compared the epidemiologic and economic characteristics of rotavirus gastroenteritis (RVGE) before and after the introduction of RV vaccines. For each year of the study period, the annual prevalence and national costs of RVGE were estimated based on children under 5 years with at least 1 National Health Insurance Service claims record with a diagnosis of RVGE.

Results:

Compared with the prevaccination period, the prevalence of RVGE decreased in the postvaccination period by 48.9% from 2097 per 100,000 children in 2006 to 1072 per 100,000 children in 2015, implying an increase in the vaccination rate and the prevention effect of the vaccines. The highest reduction was observed among those 12 to <24 months of age (−73.4%), presumably due to the benefit of full vaccination, while children under 2 months, ineligible for the RV vaccine, showed an increase (41.7%). The number of hospitalized RVGE cases per year decreased by 69.0%. The national economic burden of RVGE decreased by 28.6%.

Conclusions:

The substantial reduction in the socioeconomic burden of RVGE after the introduction of RV vaccines confirms their benefit to society. This study would help health policy makers make empirical decisions on incorporating the vaccination into national immunization programs.
Magnetic resonance imaging of neuroinflammation in chronic pain: a role for astrogliosis?
Authors: Jung Changjin , Ichesco Eric , Ratai Eva-Maria , Gonzalez Ramon Gilberto , Burdo Tricia , Loggia Marco L. , Harris Richard E. , Napadow Vitaly
Published: January 2020

Noninvasive measures of neuroinflammatory processes in humans could substantially aid diagnosis and therapeutic development for many disorders, including chronic pain. Several proton magnetic resonance spectroscopy (1H-MRS) metabolites have been linked with glial activity (ie, choline and myo-inositol) and found to be altered in chronic pain patients, but their role in the neuroinflammatory cascade is not well known. Our multimodal study evaluated resting functional magnetic resonance imaging connectivity and 1H-MRS metabolite concentration in insula cortex in 43 patients suffering from fibromyalgia, a chronic centralized pain disorder previously demonstrated to include a neuroinflammatory component, and 16 healthy controls. Patients demonstrated elevated choline (but not myo-inositol) in anterior insula (aIns) (P = 0.03), with greater choline levels linked with worse pain interference (r = 0.41, P = 0.01). In addition, reduced resting functional connectivity between aIns and putamen was associated with both pain interference (whole brain analysis, pcorrected < 0.01) and elevated aIns choline (r = −0.37, P = 0.03). In fact, aIns/putamen connectivity statistically mediated the link between aIns choline and pain interference (P < 0.01), highlighting the pathway by which neuroinflammation can impact clinical pain dysfunction. To further elucidate the molecular substrates of the effects observed, we investigated how putative neuroinflammatory 1H-MRS metabolites are linked with ex vivo tissue inflammatory markers in a nonhuman primate model of neuroinflammation. Results demonstrated that cortical choline levels were correlated with glial fibrillary acidic protein, a known marker for astrogliosis (Spearman r = 0.49, P = 0.03). Choline, a putative neuroinflammatory 1H-MRS-assessed metabolite elevated in fibromyalgia and associated with pain interference, may be linked with astrogliosis in these patients.
Extracorporeal shock-wave lithotripsy: is it still valid in the era of robotic endourology? Can it be more efficient?
Authors: Rassweiler Jens , Rieker Phillip , Rassweiler-Seyfried Marie-Claire
Published: January 2020

Purpose of review

The aim of the article is to evaluate the actual role of extracorporeal shock-wave lithotripsy (ESWL) in the management of urolithiasis based on the new developments of flexible ureterorenoscopy (FURS) and percutaneous nephrolithotomy (PCNL).

Recent findings

In Western Europe, there is a significant change of techniques used for treatment of renal stones with an increase of FURS and a decrease of ESWL. The reasons for this include the change of indications, technical improvement of the endourologic armamentarium, including robotic assistance. Mostly relevant is the introduction of digital reusable and single-use flexible ureterorenoscopes, whereas micro-PCNL has been abandoned. Some companies have stopped production of lithotripters and novel ideas to improve the efficacy of shock waves have not been implemented in the actual systems. Promising shock-wave technologies include the use of burst-shock-wave lithotripsy (SWL) or high-frequent ESWL. The main advantage would be the very fast pulverization of the stone as shown in in-vitro models.

The role of ESWL in the management of urolithiasis is decreasing, whereas FURS is constantly progressing. Quality and safety of intracorporeal shock-wave lithotripsy using holmium:YAG-laser under endoscopic control clearly outweighs the advantages of noninvasive ESWL. To regain ground, new technologies like burst-SWL or high-frequent ESWL have to be implemented in new systems.
Simulation and Active Learning Decreases Training Time of an Emergency Triage Assessment and Treatment Course in Pilot Study in Malawi
Authors: Sigalet Elaine L. , Lufesi Norman , Dubrowski Adam , Haji Faizal , Khan Rabia , Grant David , Weinstock Peter , Wishart Ian , Molyneux Elizabeth , Kissoon Niranjan
Published: January 2020

Objectives

The aim of the Emergency Triage Assessment and Treatment (ETAT) plus trauma course is to improve the quality of care provided to infants and children younger than 5 years. The curriculum was revised and shortened from 5 to 2.5 days by enhancing simulation and active learning opportunities. The aim of this study was to examine the feasibility and value of the new short-form ETAT course by assessing postcourse knowledge and satisfaction.

Methods

We delivered the short-form ETAT course to a group of interdisciplinary health workers in Malawi. Precourse and postcourse knowledge was assessed using a standardized 20 questions short answer test used previously in the 5-day courses. A 13-statement survey with 2 open-ended questions was used to examine participant satisfaction.

Results

Participants' postcourse knowledge improved significantly (P < 0.001) after the shorter ETAT course. Participants reported high levels of satisfaction with the short-form ETAT.

Conclusions

Simulation and other active learning strategies reduced training time by 50% in the short-form ETAT course. Participants with and without previous ETAT training improved their knowledge after participating in the short-form ETAT course. Reduced training time is beneficial in settings already burdened by scarce human resources, may facilitate better access to in-service training, and build capacity while conserving resources in low-resource settings.
Managing and preventing exacerbation of bronchiectasis
Authors: Abo-Leyah Hani , Chalmers James D.
Published: January 2020

Purpose of review

Pulmonary exacerbations are key events in the natural history of bronchiectasis given their impact on quality of life, prognosis, and their contribution to healthcare costs. Preventing and managing exacerbations is a priority for clinicians and in this review, we discuss measures that should be utilized to achieve this aim.

Recent findings

Experts have proposed a focus on phenotyping and endotyping the bronchiectasis population to overcome the heterogeneity of this condition. Recent large studies of inhaled antibiotics and smaller studies of macrolides, which included exacerbation measures as their primary outcomes, have drawn further attention to this issue.

Exacerbations are currently treated with prolonged antibiotic treatment (10–14 days). Prevention of exacerbations requires a multidisciplinary approach which includes optimising airway clearance and treating underlying conditions. Patients who continue to experience exacerbations despite these measures may be offered chronic macrolide therapy or additional therapies based on identified treatable traits.
Hepatitis C Virus Infection in Pregnancy
Authors: Altınbas Sibel , Holmes Jacinta A. , Altınbas Akif
Published: January 2020

Parenteral transmission is the major route of hepatitis C virus transmission in adults; however, vertical transmission is most common in children. There are several factors that have been shown to be associated with vertical transmission of hepatitis C virus, including hepatitis C virus RNA, human immunodeficiency virus coinfection, and peripheral blood mononuclear cell infection. As there is no effective vaccine to prevent hepatitis C virus infection, and there are no human data describing the safety of the new direct acting antiviral agents in pregnancy, the only preventive strategy for vertical transmission is to treat the hepatitis C virus infection before becoming pregnant. Direct acting antiviral agents are interferon-free, and many are also ribavirin-free. Based on animal studies, sofosbuvir plus ledipasvir may be the best safety profile during pregnancy for now; however, it is too early to recommend treating hepatitis C virus-infected pregnant women with these direct acting antiviral agents currently.
Effect of Short Message Service Use on Bowel Preparation Quality in Patients Undergoing Colonoscopy
Authors: Kızılcık Özkan Zeynep , Ünver Seher , Yıldız Fındık Ümmü , Albayrak Doğan , Fidan Şükriye
Published: January 2020

This study aimed to determine the effect of SMS use on the bowel preparation quality and satisfaction in patients who underwent colonoscopy. This study was conducted as an experimental-control study with 200 patients who had received colonoscopy in the endoscopy unit of a university hospital in Eastern Thrace of Turkey between December 1, 2016, and June 30, 2017. All patients received a standard bowel preparation. The SMS was sent in addition to the standard bowel preparation to patients in an SMS group. In the SMS group, patients were informed about the standard bowel preparation practices via SMS 3 days before colonoscopy. “Patient identification,” “bowel preparation quality,” and “patient satisfaction” forms were used for data collection. Chi-square and independent sample t tests were used in data analysis. The average age of the participants was 57.57 ± 12.37 years, and it was determined that most of the participants were male (64.5%) and had colonoscopy experience (55%). The bowel preparation quality was significantly higher in the SMS group than in the no-SMS group (p = .044), and most patients (91%) were “very satisfied” with being informed via SMS. Sending SMS about bowel preparation practices to colonoscopy patients improves bowel preparation quality and patient satisfaction. Integrating SMS into standard care may help patients manage the bowel preparation process.
Climate change and intensive land use reduce soil animal biomass through dissimilar pathways
Authors: Yin Rui , Siebert Julia , Eisenhauer Nico , Schädler Martin
Published: January 2020

Global change drivers, such as climate and land use, may profoundly influence body size, density, and biomass of organisms. It is still poorly understood how these concurrent drivers interact in affecting ecological communities. We present results of an experimental field study assessing the interactive effects of climate change and land-use intensification on body size, density, and biomass of soil microarthropods. We found that both climate change and intensive land use decreased their total biomass. Strikingly, this reduction was realized via two dissimilar pathways: climate change reduced mean body size, while intensive land use decreased population size. These findings highlight that two of the most pervasive global change drivers operate via different pathways when decreasing soil animal biomass. These shifts in soil communities may threaten essential ecosystem functions like organic matter turnover and nutrient cycling in future ecosystems.

Significance

Many important ecosystem functions are determined by the biomass of soil animal, however, how their biomass may respond to climate change and land-use intensification still remains unknown. We conducted a large field study to investigate the potential interaction between these two pervasive global change drivers, and disentangle the pathways where they contribute to the changes in soil animal biomass. Our findings are exceptionally novel by showing detrimental, but largely independent, effects of climate change and land-use intensity on soil animal biomass, and that these independent effects can be explained by two dissimilar pathways: climate change reduced mean body size, while intensive land use decreased population size. Notably, consistent climate change effects under different land-use regimes suggest that (1) the identified pathways may apply to a wide range of environmental conditions, and (2) current extensive land-use regimes do not mitigate detrimental climate change effects on ecosystems.
Seasonally Variant Gene Expression in Full-Term Human Placenta
Authors: Clarkson-Townsend Danielle A. , Kennedy Elizabeth , Everson Todd M. , Deyssenroth Maya A. , Burt Amber A. , Hao Ke , Chen Jia , Pardue Machelle , Marsit Carmen J.
Published: January 2020

Seasonal exposures influence human health and development. The placenta, as a mediator of the maternal and fetal systems and a regulator of development, is an ideal tissue to understand the biological pathways underlying relationships between season of birth and later life health outcomes. Here, we conducted a transcriptome-wide association study of season of birth in full-term human placental tissue to evaluate whether the placenta may be influenced by seasonal cues. Of the analyzed transcripts, 583 displayed differential expression between summer and winter births (FDR q<0.05); among these, BHLHE40, MIR210HG, and HILPDA had increased expression among winter births (Bonferroni p<0.05). Enrichment analyses of the seasonally variant genes between summer and winter births indicated over-representation of transcription factors HIF1A, VDR, and CLOCK, among others, and of GO term pathways related to ribosomal activity and infection. Additionally, a cosinor analysis found rhythmic expression for approximately 11.9% of all 17,664 analyzed placental transcripts. These results suggest that the placenta responds to seasonal cues and add to the growing body of evidence that the placenta acts as a peripheral clock, which may provide a molecular explanation for the extensive associations between season of birth and health outcomes.
Primary care consultation length by deprivation and multimorbidity in England
Authors: Gopfert Anya , Deeny Sarah , Fisher Rebecca , Stafford Mai
Published: January 2020

Background

Longer GP consultations are recommended as one way of improving care for people with multimorbidity. In Scotland, multimorbid patients in deprived areas do not have had longer consultations though their counterparts in the least deprived areas do. This example of the inverse care law has not been examined in England.

Aim

To assess GP consultation length by socioeconomic deprivation and multimorbidity.

Design and Setting

Random sample of 1.2 million consultations from 1st April 2014-31st March 2016 for 185,755 adults in England drawn from the Clinical Practice Research Datalink.

Method

Consultation duration was derived from time of opening and closing the patient’s electronic record. Mean duration was estimated by multimorbidity level and type, adjusted for number of consultations and other patient and staff characteristics and patient and practice random effects.

Results

Consultations lasted 10.9 minutes and mean duration increased with number of conditions. Patients with 6+ conditions had 0.9 (95% CI 0.8, 1.0) minutes longer than those with none. Patients with both mental and physical health condition had 0.5 (95% CI 0.4, 0.5) minutes longer than non-multimorbid patients. However, consultations were 0.5 (95% CI 0.4, 0.5) minutes shorter in the most compared with the least deprived fifth of areas at all levels of multimorbidity.

Conclusion

GPs in England spend longer with patients who have more conditions but at all multimorbidity levels, those in deprived areas have less time per GP consultation. Research is needed to assess the impact of consultation length on patient and system outcomes for people with multimorbidity.
Contrasting Effects of Western vs. Mediterranean Diets on Monocyte Inflammatory Gene Expression and Social Behavior in a Primate Model
Authors: Johnson Corbin S.C. , Shively Carol A. , Michalson Kristofer T. , Lea Amanda J. , DeBo Ryne J. , Howard Timothy D. , Hawkins Gregory A. , Appt Susan E. , Liu Yongmei , McCall Charles E. , Herrington David M. , Ip Edward H. , Register Thomas C. , Snyder-Mackler Noah
Published: January 2020

Dietary changes associated with industrialization substantially increase the prevalence of chronic diseases, such as obesity, type II diabetes, and cardiovascular disease, which are major contributors to the public health burden. The high prevalence of these chronic diseases is often attributed to an “evolutionary mismatch,” between human physiology and modern nutritional environments. In support of this idea, Western diets enriched with foods that were scarce throughout human evolutionary history (e.g., simple sugars and saturated fats) promote inflammation and disease relative to diets more akin to hunter-gatherer diets, such as a Mediterranean diet; however, the mechanisms linking dietary mismatch to inflammation and chronic disease are poorly understood. We used a macaque model and whole diet manipulations to evaluate one possible mechanism – inflammatory polarization of monocytes – that potentially leads to this evolutionary mismatch. After consuming a Western- or Mediterranean-like diet for 15 months, monocytes from Western diet consumers exhibited a more proinflammatory phenotype, with 40% of their genes differentially expressed (FDR<0.05). Compared to the Mediterranean diet, the Western diet shifted the co-expression of 445 gene pairs, including small RNAs and transcription factors associated with metabolism and adiposity in humans, and dramatically altered animal behavior. For example, Western-fed individuals were more anxious and less socially integrated compared to the Mediterranean-fed subjects. These behavioral changes were also associated with some of the effects of diet on gene expression, suggesting an interaction between diet, central nervous system activity, and monocyte gene expression. The results of this study provide new insights into evolutionary mismatch at the molecular level and uncover new pathways through which Western diets generate inflammation and disease.
Are skyline plot-based demographic estimates overly dependent on smoothing prior assumptions?
Authors: Parag Kris V , Pybus Oliver G , Wu Chieh-Hsi
Published: January 2020

In Bayesian phylogenetics, the coalescent process provides an informative framework for inferring changes in the effective size of a population from a phylogeny (or tree) of sequences sampled from that population. Popular coalescent inference approaches such as theBayesian Skyline Plot, SkyrideandSkygridall model these population size changes with a discontinuous, piecewise-constant function but then apply a smoothing prior to ensure that their posterior population size estimates transition gradually with time. These prior distributions implicitly encode extra population size information that is not available from the observed coalescent data i.e., the tree. Here we present a novel statistic, Ω, to quantify and disaggregate the relative contributions of the coalescent data and prior assumptions to the resulting posterior estimate precision. Our statistic also measures the additional mutual information introduced by such priors. Using Ω we show that, because it is surprisingly easy to over-parametrise piecewise-constant population models, common smoothing priors can lead to overconfident and potentially misleading inference, even under robust experimental designs. We propose Ω as a useful tool for detecting when effective population size estimates are overly reliant on prior assumptions and for improving quantification of the uncertainty in those estimates.
Layer-specific inhibitory microcircuits of layer 6 interneurons in rat prefrontal cortex
Authors: Ding Chao , Emmenegger Vishalini , Schaffrath Kim , Feldmeyer Dirk
Published: January 2020

GABAergic interneurons in different cortical areas play important roles in diverse higher order cognitive functions. The heterogeneity of interneurons is well characterized in different sensory cortices, in particular in primary somatosensory and visual cortex. However, the structural and functional properties of the medial prefrontal cortex (mPFC) interneurons have received less attention. In this study, a cluster analysis based on axonal projection patterns revealed four distinct clusters of L6 interneurons in rat mPFC: Cluster 1 interneurons showed axonal projections similar to Martinotti-like cells extending to layer 1, cluster 2 displayed translaminar projections mostly to layer 5, cluster 3 interneuron axons were confined to the layer 6, whereas those of cluster 4 interneurons extend also into the white matter. Correlations were found between neuron location and axonal distribution in all clusters. Moreover, all cluster 1 L6 interneurons showed a monotonically adapting firing pattern with an initial high-frequency burst. All cluster 2 interneurons were fast-spiking, while neurons in cluster 3 and 4 showed heterogeneous firing patterns. Our data suggest that L6 interneurons that have distinct morphological and physiological characteristics are likely to innervate different targets in mPFC thus play differential roles in the L6 microcircuitry and in mPFC-associated functions.
The first eukaryotic kinome tree illuminates the dynamic history of present-day kinases
Authors: van Wijk Leny M. , Snel Berend
Published: January 2020

Eukaryotic Protein Kinases (ePKs) are essential for eukaryotic cell signalling. Several phylogenetic trees of the ePK repertoire of single eukaryotes have been published, including the human kinome tree. However, a eukaryote-wide kinome tree was missing due to the large number of kinases in eukaryotes. Using a pipeline that overcomes this problem, we present here the first eukaryotic kinome tree. The tree reveals that the Last Eukaryotic Common Ancestor (LECA) possessed at least 92 ePKs, much more than previously thought. The retention of these LECA ePKs in present-day species is highly variable. Fourteen human kinases with unresolved placement in the human kinome tree were found to originate from three known ePK superfamilies. Further analysis of ePK superfamilies shows that they exhibit markedly diverse evolutionary dynamics between the LECA and present-day eukaryotes. The eukaryotic kinome tree thus unveils the evolutionary history of ePKs, but the tree also enables the transfer of functional information between related kinases.
Probiotics for the prevention of antibiotic-associated adverse events in children – a systematic review to inform development of a core outcome set
Authors: Łukasik Jan , Guo Qin , Boulos Leah , Szajewska Hania , Johnston Bradley C.
Published: January 2020

Introduction

Routine use of probiotics during antibiotic therapy in children remains a subject of discussion. To facilitate synthesis of individual study results and guideline formulation, it is important to assess predefined, similar, and clinically important outcomes. Core outcome sets are a proposed solution for this issue. Aim of this review was to document choice, design, and heterogeneity of outcomes in studies that assessed the effects of probiotics used for the prevention of antibiotic-associated adverse events in children.

Methods

A systematic literature search covering three major databases was performed. Trials that evaluated oral probiotics’ use concomitant with antibiotic therapy in children were included. Data on outcome definitions, measurement instruments, and follow-up were extracted. The outcomes were assigned to predefined core areas and domains. Data were analyzed descriptively.

Results

Thirty-six trials were included in this review. Diarrhea, the most commonly reported outcome, had diagnostic criteria clearly defined only in 20 trials. In total, sixteen different definitions of diarrhea were identified. Diarrhea duration, severity and etiology were reported in 8, 4 and 6 studies, respectively. Nineteen studies assessed gastrointestinal symptoms other than diarrhea. Seven studies reported outcomes related to resource use or the economic impact of the intervention. Only 2 studies assessed outcomes related to life impact. None of the studies predefined adverse events of probiotic use.

Conclusions

Identified outcomes were characterized by substantial heterogeneity. Majority of outcomes were not designed to evaluate endpoints of real-life relevance. Results from this review suggest the need for a new core outcome set consisting of outcomes important for decision-making.
Implicit food odour priming effects on reactivity and inhibitory control towards foods
Authors: Mas Marine , Brindisi Marie-Claude , Chabanet Claire , Chambaron Stéphanie
Published: January 2020

The food environment can interact with cognitive processing and influence eating behaviour. Our objective was to characterize the impact of implicit olfactory priming on inhibitory control towards food, in groups with different weight status. Ninety-two adults completed a modified Affective Shifting Task: they had to detect target stimuli and ignore distractor stimuli while being primed with non-attentively perceived odours. We measured reactivity and inhibitory control towards food pictures. Priming effects were observed on reactivity: participants with overweight and obesity were slower when primed with pear and pound cake odour respectively. Common inhibitory control patterns toward foods were observed between groups. We suggest that non-attentively perceived food cues influence bottom-up processing by activating distinguished mental representations according to weight status. Also, our data show that cognitive load influences inhibitory control toward foods. Those results contribute to understanding how the environment can influence eating behaviour in individuals with obesity.
MazeMaster: an open-source Python-based software package for controlling virtual reality experiments
Authors: Bexter Alexander , Kampa Björn M.
Published: January 2020

Abstract

In the last 15 years, virtual realities have revolutionized behavior experiments in particular for rodents. In combination with treadmills, running wheels, or air-floating balls, the implementation of a virtual reality (VR) provides not only the opportunity to simultaneously explore behavior and neuronal activity in head-fixed animals under nearly natural conditions, but also allows full control over the visual sensory input presented to the animal. Furthermore, VRs can be combined with other sensory modalities such as auditory, tactile or olfactory stimuli. Despite the power of using VRs in animal experiments, available software packages are very limited, expensive and lack the required flexibility to design appropriate behavior and neurophysiology experiments. For this reason, we have developed the versatile, adaptable and easy to use VR environmentMazeMaster, an open-source, Python-based software package for controlling virtual reality setups and behavior experiments. The software package includes a graphical user interface (GUI) and can be integrated into standard electrophysiology and imaging setups even by non-programmers. Ready-made behavioral experiments such as multisensory discrimination in T-mazes are already implemented including full control for reward supply and bias correction. For more individual setup designs, the modularity ofMazeMasterallows more programming-affine users to extend the software with potentially missing features. WithMazeMaster, we offer a free and easy-to-use VR controller that will facilitate the implementation of VR setups in scientific laboratories. In addition,MazeMasterallows the design and control of common head-fixed rodent behavior paradigms with extensive acquisition of meta-data required for reproducible VR experiments. TheMazeMasterVR package, therefore, offers a collaboration tool for reproducible research within and across neuroscience laboratories according to the FAIR principles.
Polymorphisms in immunoglobulin heavy chain variable genes and their upstream regions
Authors: Mikocziova Ivana , Gidoni Moriah , Lindeman Ida , Peres Ayelet , Snir Omri , Yaari Gur , Sollid Ludvig M.
Published: January 2020

Germline variations in immunoglobulin genes influence the repertoire of B cell receptors and antibodies, and such polymorphisms may impact disease susceptibility. However, the knowledge of the genomic variation of the immunoglobulin loci is scarce. Here, we report 25 novel germlineIGHValleles as inferred from rearranged naïve B cell cDNA repertoires of 98 individuals. Thirteen novel alleles were selected for validation, out of which ten were successfully confirmed by targeted amplification and Sanger sequencing of non-B cell DNA. Moreover, we detected a high degree of variability upstream of the V-region in the 5’UTR, leader 1, and leader 2 sequences, and found that identical V-region alleles can differ in upstream sequences. Thus, we have identified a large genetic variation not only in the V-region but also in the upstream sequences ofIGHVgenes. Our findings challenge current approaches used for annotating immunoglobulin repertoire sequencing data.
PathWalks: Identifying pathway communities using a disease-related map of integrated information
Authors: Karatzas Evangelos , Zachariou Margarita , Bourdakou Marilena , Minadakis George , Oulas Anastasios , Kolios George , Delis Alex , Spyrou George M.
Published: January 2020

Understanding disease underlying biological mechanisms and respective interactions remains an elusive, time consuming and costly task. The realization of computational methodologies that can propose pathway/mechanism communities and reveal respective relationships can be of great value as it can help expedite the process of identifying how perturbations in a single pathway can affect other pathways.

Random walks is a stochastic approach that can be used for both efficient discovery of strong connections and identification of communities formed in networks. The approach has grown in popularity as it efficiently exposes key network components and reveals strong interactions among genes, proteins, metabolites, pathways and drugs. Using random walks in biology, we need to overcome two key challenges: 1) construct disease-specific biological networks by integrating information from available data sources as they become available, and 2) provide guidance to the walker so as it can follow plausible trajectories that comply with inherent biological constraints.

In this work, we present a methodology called PathWalks, where a random walker crosses a pathway-to-pathway network under the guidance of a disease-related map. The latter is a gene network that we construct by integrating multi-source information regarding a specific disease. The most frequent trajectories highlight communities of pathways that are expected to be strongly related to the disease under study. We present maps forAlzheimer’s DiseaseandIdiopathic Pulmonary Fibrosisand we use them as case-studies for identifying pathway communities through the application of PathWalks.

In the case ofAlzheimer’s Disease, the most visited pathways are the “Alzheimer’s disease” and the “Calcium signaling” pathways which have indeed the strongest association withAlzheimer’s Disease. Interestingly however, in the top-20 visited pathways we identify the “Kaposi sarcoma-associated herpesvirus infection” (HHV-8) and the “Human papillomavirus infection” (HPV) pathways suggesting that viruses may be involved in the development and progression ofAlzheimer’s. Similarly, most of the highlighted pathways inIdiopathic Pulmonary Fibrosisare backed by the bibliography. We establish that “MAPK signaling” and “Cytokine-cytokine receptor interaction” pathways are the most visited. However, the “NOD receptor signaling” pathway is also in the top-40 edges. InIdiopathic Pulmonary Fibrosissamples, increased NOD receptor signaling has been associated with augmented concentrations of certain strains of Streptococcus. Additional experimental evidence is required however to further explore and ascertain the above indications.