bluuebunny/crossref_metadata_2025 huggingface dataset:
Mendelian randomization analysis of smoking behavior and cognitive ability on the Big Five
Authors: Adams Charleen D.
Published: December 2019

Tobacco smoke, a mutagen that can thin the brain’s cortex, might influence the Big Five (neuroticism, conscientiousness, agreeableness, extraversion, and openness). Cognitive ability, however, is a potential confounder, since it is associated with who smokes and with personality. Mendelian randomization (MR), which uses genetic variants as instrumental variables, can be used to probe the causal nature of these factors on personality. Here, MR was used to appraise smoking and cognitive ability on the Big Five and cognitive ability and neuroticism on social disparity. The results seem to suggest that smoking, independent of cognitive ability, leads people to be more neurotic and less extraverted and conscientious. Higher cognitive ability appears to make people less neurotic and more open, when accounting for smoking. Neuroticism appears to increase disparity, and higher cognitive ability appears to decrease it. Smoking may enhance disparity between those of lower and higher cognitive ability by exacerbating personality differences.
Brain-Computer Interface Robotics for Hand Rehabilitation After Stroke: A Systematic Review
Authors: Baniqued Paul Dominick E , Stanyer Emily C , Awais Muhammad , Alazmani Ali , Jackson Andrew E , Mon-Williams Mark A , Mushtaq Faisal , Holt Raymond J
Published: December 2019

Background

Hand rehabilitation is core to helping stroke survivors regain activities of daily living. Recent studies have suggested that the use of electroencephalography-based brain-computer interfaces (BCI) can promote this process. Here, we report the first systematic examination of the literature on the use of BCI-robot systems for the rehabilitation of fine motor skills associated with hand movement and profile these systems from a technical and clinical perspective.

Methods

A search for January 2010-October 2019 articles using Ovid MEDLINE, Embase, PEDro, PsycINFO, IEEE Xplore and Cochrane Library databases was performed. The selection criteria included BCI-hand robotic systems for rehabilitation at different stages of development involving tests on healthy participants or people who have had a stroke. Data fields include those related to study design, participant characteristics, technical specifications of the system, and clinical outcome measures.

Results

30 studies were identified as eligible for qualitative review and among these, 11 studies involved testing a BCI-hand robot on chronic and subacute stroke patients. Statistically significant improvements in motor assessment scores relative to controls were observed for three BCI-hand robot interventions. The degree of robot control for the majority of studies was limited to triggering the device to perform grasping or pinching movements using motor imagery. Most employed a combination of kinaesthetic and visual response via the robotic device and display screen, respectively, to match feedback to motor imagery.

Conclusion

19 out of 30 studies on BCI-robotic systems for hand rehabilitation report systems at prototype or pre-clinical stages of development. Three studies report statistically significant improvements in functional recovery after stroke, but there is a need to develop a standard protocol for assessing technical and clinical outcomes so that the necessary evidence base on efficiency and efficacy can be developed.
A brief report: de novo copy number variants in children with attention deficit hyperactivity disorder
Authors: Martin Joanna , Hosking Grace , Wadon Megan , Agha Sharifah Shameem , Langley Kate , Rees Elliott , Owen Michael J , O’Donovan Michael , Kirov George , Thapar Anita
Published: December 2019

Background

Recent case-control genetic studies of attention deficit hyperactivity disorder (ADHD) have implicated common and rare genetic risk alleles, highlighting the polygenic and complex aetiology of this neurodevelopmental disorder. Studies of other neurodevelopmental disorders, such as autism spectrum disorder (ASD), Tourette disorder, developmental delay/intellectual disability, and schizophrenia indicate that identification of specific risk alleles and additional insights into disorder biology can be gained by studying non-inherited de novo variation. In this study, we aimed to identify large de novo copy number variants (CNVs) in children with ADHD.

Methods

Children with a confirmed diagnosis of ADHD and their parents were genotyped and included in this sample. We used PennCNV to call large (>200kb) CNVs and identified those calls that were present in the proband and absent in both biological parents.

Results

In 305 parent-offspring trios, we detected 14 de novo CNVs in 13 probands, giving a mutation rate of 4.6% and a per individual rate of 4.3%. This rate is higher than published reports in controls and similar to those observed for ASD, schizophrenia and Tourette disorder. We also identified de novo mutations at 4 genomic loci (15q13.1-13.2 duplication, 16p13.11 duplication, 16p12.2 deletion and 22q11.21 duplication) that have previously been implicated in other neurodevelopmental disorders, two of which (16p13.11 and 22q11.21) have also been implicated in case-control ADHD studies.

Conclusions

Our study complements ADHD case-control genomic analyses and demonstrates the need for larger parent-offspring trio genetic studies to gain further insights into the complex aetiology of ADHD.
Hepatitis C Core Antigen test as an alternative for diagnosing HCV infection: mathematical model and cost-effectiveness analysis
Authors: Sadeghimehr Maryam , Keiser Olivia , Negro Francesco , Butsashvili Maia , Shilton Sonjelle , Tskhomelidze Irina , Tsereteli Maia , Bertisch Barbara , Estill Janne
Published: December 2019

Background

The cost and complexity of polymerase chain reaction (PCR) testing is a significant barrier for the diagnosis and treatment of patients infected with hepatitis C virus (HCV). We investigated the cost-effectiveness of various testing strategies using antigen as an alternative to PCR.

Methods

We developed a mathematical model for HCV to estimate the number of newly diagnosed individuals and cases of different stages of liver disease. We compared the following testing strategies: antibody test followed by PCR in case of positive antibody (baseline strategy); antibody test followed by HCV-antigen test (antibody-antigen); antigen test alone; and PCR test alone. We conducted cost-effectiveness analyses considering the costs of HCV testing (of both infected and uninfected individuals) (A1), liver-related complications (A2) and all costs including HCV treatment (A3). The model was parameterized for the country of Georgia, and several sensitivity analyses were conducted to generalize the findings for different settings.

Results

Using the current standard of testing, 89% of infected individuals were detected. Comparatively, antibody-antigen and antigen testing alone detected 86% and 88% of infected individuals, respectively. PCR testing alone detected 91% of the infected individuals with the remaining 9% dying or spontaneously recovering before testing. In analysis A1, antibody-antigen testing was not found to be essentially cheaper compared to the baseline strategy. In analysis A2, strategies using PCR were cheaper than antigen-based strategies. In analysis A3, antibody-antigen testing was the cheapest strategy, followed by the baseline strategy, and PCR testing alone.

Conclusion

Antigen testing, either following a positive antibody test or alone, performed almost as well as the current practice of HCV testing. The cost-effectiveness of these strategies strongly depends on the inclusion of treatment costs.

Lay summary

Core antigen testing is a reliable alternative test for diagnose HCV infection. Antigen-based strategies may be cost-effective, in particular if treatment costs are considered.

Highlights

Strategies using an antigen test to diagnose HCV infection performed reasonably well compared with the traditional antibody- and PCR based approach.

According to our study, antigen test alone missed about 3%, and antibody followed by PCR test 2% of HCV infected individuals.

The maximum difference in quality-adjusted life expectancy across the different strategies of diagnosing HCV was only one month.
ULCERATIVE COLITIS-DERIVED COLONOID CULTURE: A Multi-Mineral-Approach to Improve Barrier Protein Expression
Authors: Aslam Muhammad N , McClintock Shannon D , Attili Durga , Pandya Shailja , Rehman Humza , Nadeem Daniyal M , Jawad-Makki Mohamed Ali H , Rizvi Areeba H , Berner Maliha M , Dame Michael K , Turgeon Danielle Kim , Varani James
Published: December 2019

Background

Recent studies demonstrated that Aquamin®, a calcium-, magnesium-, and multiple trace element-rich natural product, improves barrier structure and function in colonoids obtained from tissue of healthy subjects. The goal of the present study was to determine if the colonic barrier could be improved in tissue from subjects with ulcerative colitis (UC).

Methods

Colonoid cultures were established with tissue from 9 individuals with UC. The colonoids were then incubated for a 2-week period under control conditions (i.e., in culture medium with a final calcium concentration of 0.25 mM) or in the same medium supplemented with Aquamin®to provide 1.5 – 4.5 mM calcium. Effects on differentiation and barrier protein expression were determined using several approaches: phase-contrast & scanning electron microscopy, quantitative histology & immunohistology, mass spectrometry-based proteome assessment and transmission electron microscopy.

Results

Aquamin®-treated colonoids demonstrated a modest up-regulation of tight junctional proteins but stronger induction of adherens junction proteins and desmosomal proteins. Increased desmosomes were seen at the ultrastructural level. Proteomic analysis also demonstrated increased expression of basement membrane proteins and hemidesmosomal components. Proteins expressed at the apical surface (mucins and trefoils) were also increased as were several additional proteins with anti-microbial activity or that modulate inflammation.

Conclusion

A majority of individuals including patients with UC do not reach the recommended daily intake for calcium and other minerals. The findings presented here suggest that adequate mineral intake might improve the colonic barrier.
miRNA profiling in renal carcinoma suggest the existence of a group of pro-angionenic tumors in localized clear cell renal carcinoma
Authors: Trilla-Fuertes Lucía , Miranda Natalia , Castellano Daniel , López-Vacas Rocío , Farfán Tello Carlos A. , de Velasco Guillermo , Villacampa Felipe , López-Camacho Elena , Prado-Vázquez Guillermo , Zapater-Moros Andrea , Espinosa Enrique , Vara Juan Ángel Fresno , Pinto Álvaro , Gámez-Pozo Angelo
Published: December 2019

Renal cell carcinoma comprises a variety of entities, the most common being the clear-cell, papillary and chromophobe subtypes. These subtypes are related to different clinical evolution; however, most therapies have been developed for clear-cell carcinoma and there is not a specific treatment based on different subtypes. In this study, one hundred and sixty-four paraffin samples from primary nephrectomies for localized tumors were analyzed. MiRNAs were isolated and measured by microRNA arrays. Significance Analysis of Microarrays and Consensus Cluster algorithm were used to characterize different renal subtypes. The analyses showed that chromophobe renal tumors are a homogeneous group characterized by an overexpression of miR 1229, miR 10a, miR 182, miR 1208, miR 222, miR 221, miR 891b, miR 629-5p and miR 221-5p. On the other hand, clear cell renal carcinomas presented two different groups inside this histological subtype, with differences in miRNAs that regulate focal adhesion, transcription, apoptosis and angiogenesis processes. Specifically, one of the defined groups had an overexpression of proangiogenic microRNAs miR185, miR126 and miR130a. In conclusion, differences in miRNA expression profiles between histological renal subtypes were established. In addition, clear cell renal carcinomas had different expression of proangiogenic miRNAs. With the emergence of antiangiogenic drugs, these differences could be used as therapeutic targets in the future or as a selection method for tailoring personalized treatments.
Patient-derived ovarian cancer organoids mimic clinical response and exhibit heterogeneous inter- and intrapatient drug responses
Authors: de Witte Chris J. , Valle-Inclan Jose Espejo , Hami Nizar , Lõhmussaar Kadi , Kopper Oded , Vreuls Celien P.H. , Jonges Trudy N. , van Diest Paul , Nguyen Luan , Clevers Hans , Kloosterman Wigard P. , Cuppen Edwin , Snippert Hugo J.G. , Zweemer Ronald P. , Witteveen Petronella O. , Stelloo Ellen
Published: December 2019

Purpose

There remains an unmet need for preclinical models to enable personalized therapy for ovarian cancer (OC) patients. Recently, patient-derived organoid (PDO) cultures of patients with OC have been established that faithfully represent the histopathological features and genomic landscape of the patient tumor. In this study, we evaluate the capacity of OC PDOs to predict clinical drug response and functional consequences of tumor heterogeneity.

Experimental design

36 genomically characterized PDOs from 23 patients with known clinical histories were exposed to chemotherapeutics and targeted drugs.

Results

OC PDOs maintained genomic features of the original tumor lesion and recapitulated patient response to neoadjuvant carboplatin and paclitaxel combination treatment, according to distinct clinical outcomes (histopathological, biochemical and radiological). PDOs displayed inter-as well as intrapatient drug response heterogeneity, which could in part be explained by genetic aberrations. All PDOs were resistant to PARP-inhibitors, in accordance with homologous recombination pathway fidelity and genome-wide mutation context. KRAS, BRAF and NRAS mutation status predicted response to BRAF-inhibitor vemurafenib and pan-HER-inhibitor afatinib, and explained differential response among four PDOs derived from distinct tumor locations of an individual patient. Importantly, PDO drug screening identified sensitivity to at least one drug for the majority of patients (88%).

Conclusions

OC PDOs are a valuable preclinical model system that can provide insights in drug response for individual patients with OC, complementary to genetic testing. Generating PDOs of multiple tumor locations can improve clinical decision making and increase our knowledge on genetic and drug response heterogeneity.
Biological age in UK Biobank: biomarker composition and prediction of mortality, coronary heart disease and hospital admissions
Authors: Chan Mei Sum , Arnold Matthew , Offer Alison , Hammami Imen , Mafham Marion , Armitage Jane , Perera Rafael , Parish Sarah
Published: December 2019

Background

Age is the strongest risk factor for most chronic diseases, and yet individuals may age at different rates biologically. A biological age formed from biomarkers may be a stronger risk factor than chronological age and understanding what factors contribute to it could provide insight into new opportunities for disease prevention.

Methods and findings

Among 480,019 UK Biobank participants aged 40-70 recruited in 2006-2010 and followed up for 6-12 years via linked death registry and secondary care records, a subpopulation of 141,254 (29.4%) non-smoking adults in good health and with no medication use or disease history at baseline were identified. Independent components of 72 biomarkers measured at baseline were characterised by principal component analysis. The Klemera Doubal method (KDM), which derived a weighted sum of biomarker principal components based on the strengths of their linear associations with chronological age, was used to derive sex-specific biological ages in this healthy subpopulation. The proportions of the overall biological and chronological age effects on mortality, coronary heart disease and age-related non-fatal hospital admissions (based on a hospital frailty index) that were explained by biological age were assessed using log-likelihoods of proportional hazards models.

Reduced lung function, reduced kidney function, slower reaction time, lower insulin-like-growth factor 1, lower hand grip strength and higher blood pressure were key contributors to biological age (explaining the highest percentages of its variance) in both men and women, while lower albumin, higher sex hormone-binding globulin and lower muscle mass in men, and higher liver enzymes, blood lipids and HbA1c in women were also important. Across both sexes, a 51-principal component biological age explained 66%, 80% and 63% of the age effects on mortality, coronary heart disease and hospital admissions, respectively. Restricting the biological age to the 12-13 key biomarkers corresponding to the 10 most importantly contributing principal components resulted in little change in these proportions for women, but a reduction to 53%, 63% and 50%, respectively, for men.

Conclusions

This study identified that markers of impaired function in a range of organs account for a substantial proportion of the apparent effect of age on disease and hospital admissions. It supports a broader, multi-system approach to research and prevention of diseases of ageing.
Post-Exertional Malaise in People with Chronic Cancer-Related Fatigue
Authors: Twomey Rosie , Yeung Samuel T. , Wrightson James G. , Millet Guillaume Y. , Culos-Reed S. Nicole
Published: December 2019

Context

Cancer-related fatigue (CRF) is a distressing and persistent sense of tiredness or exhaustion that interferes with usual functioning. Chronic CRF continues for months after curative cancer treatment is complete. Post-exertional malaise (PEM) is a worsening of symptoms after physical or mental activity, with limited investigations in people with chronic CRF.

Objectives

The purpose of this study was to identify and describe self-reported incidences of PEM in people with chronic CRF.

Methods

Participants (n=18) were eligible if they scored ≤34 on the Functional Assessment of Chronic Illness Therapy-Fatigue scale and had a cancer-related onset of fatigue. Participants completed a brief questionnaire to assess PEM over a 6-month time-frame (the DePaul Symptom Questionnaire – Post-Exertional Malaise; DSQ-PEM). In addition, a maximal exercise test was used to investigate self-reported symptom exacerbation (via an open-ended questionnaire) after strenuous physical exertion.

Results

On the DSQ-PEM, three participants met previously defined scoring criteria, which included experiencing moderate to very severe symptoms at least half of the time, worsening of fatigue after minimal effort, plus a recovery duration of >24 h. Content analysis of responses to open-ended questionnaires identified five people who experienced a delayed recovery and symptoms of PEM after maximal exercise.

Conclusion

A subset of people with chronic CRF (up to 33% in this sample) may experience PEM. Exercise specialists and health care professionals working with people with chronic CRF must be aware that PEM may be an issue. Symptom exacerbation after exercise should be monitored, and exercise should be tailored and adapted to limit the potential for harm.

Key message

This study provides preliminary evidence that a subset of people with chronic cancer-related fatigue experience post-exertional malaise.
Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease
Authors: Vallabh Sonia M , Minikel Eric Vallabh , Williams Victoria J , Carlyle Becky C , McManus Alison J , Wennick Chase D , Bolling Anna , Trombetta Bianca A , Urick David , Nobuhara Chloe K , Gerber Jessica , Duddy Holly , Lachmann Ingolf , Stehmann Christiane , Collins Steven J , Blennow Kaj , Zetterberg Henrik , Arnold Steven E
Published: December 2019

BACKGROUND

Fluid biomarkers are important in the development of therapeutics to delay or prevent prion disease, but have not been systematically evaluated in pre-symptomatic individuals at risk for genetic prion disease.

METHODS

We recruited pre-symptomatic individuals with pathogenic mutations in the prion protein gene (PRNP; N=27) and matched controls (N=16), to donate cerebrospinal fluid (CSF) and blood at multiple timepoints to a cohort study at Massachusetts General Hospital. We quantified total prion protein (PrP) and real-time quaking-induced conversion (RT-QuIC) prion seeding activity in CSF, and the neuronal damage markers total tau (T-tau) and neurofilament light chain (NfL) in both CSF and plasma. We compared these markers cross-sectionally between mutation carriers and controls, evaluated short-term test-retest reliability over 2-4 months, and conducted a pilot longitudinal study over 10-20 months for a subset of participants.

FINDINGS

CSF PrP levels were stable on test-retest with a mean coefficient of variation of 7% both over 2-4 months in N=29 participants and over 10-20 months in N=10 participants. RT-QuIC was negative in 22/23 mutation carriers. The sole individual with positive RT-QuIC seeding activity at two study visits had steady CSF PrP levels and slightly increased tau and NfL concentrations compared with others, though still within the normal range, and remained asymptomatic one year later. Overall, tau and NfL showed no significant differences between mutation carriers and controls in either CSF or plasma.

INTERPRETATION

CSF PrP will be interpretable as a pharmacodynamic readout of the effects of a PrP-lowering therapeutic in pre-symptomatic individuals, and may serve as a surrogate biomarker in a “primary prevention” trial paradigm. In contrast, current markers of prion seeding activity and of neuronal damage do not reliably cross-sectionally distinguish mutation carriers from controls, arguing against the feasibility of a “secondary prevention” paradigm in which trials specifically recruit pre-symptomatic participants with prodromal evidence of pathology.
All-cause mortality and causes of death in the Swiss Hepatitis C Cohort Study
Authors: Roelens Maroussia , Bertisch Barbara , Moradpour Darius , Cerny Andreas , Semmo Nasser , Schmid Patrick , Müllhaupt Beat , Clerc Olivier , Semela David , Junker Christoph , Negro Francesco , Keiser Olivia ,   for the Swiss Hepatitis C Cohort Study
Published: December 2019

Background & Aims

With the introduction of direct-acting antiviral agents (DAA), mortality rates and causes of death among persons with hepatitis C virus (HCV) infection are likely to change over time. However, the emergence of such trends may be delayed by the relatively slow progression of chronic hepatitis C. To date, detailed analyses of cause-specific mortality among HCV-infected persons over time remain limited.

Methods

We evaluated changes in causes of death among the Swiss Hepatitis C Cohort Study (SCCS) participants, from 2008 to 2016. We analysed risk factors for all-cause and cause-specific mortality, accounting for changes in treatment, fibrosis stage and use of injectable drugs over time. Mortality ascertainment was completed by linking lost-to-follow-up participants to the Swiss Federal Statistical Office (SFSO) death registry.

Results

We included 4,700 SCCS participants, of whom 478 died between 2008 and 2016. Linkage to the SFSO death registry substantially improved the information on causes of death (from 42% of deaths with unknown cause to 10% after linkage). Leading causes of death were liver failure (crude death rate 4.4/1000 person-years), liver cancer (3.4/1000 p-yrs) and non-liver cancer (2.8/1000 p-yrs), with an increasing proportion of cancer-related deaths over time. Cause-specific analysis showed that persons with sustained virologic response (SVR) were less at risk for liver-related mortality than those never treated or treated unsuccessfully.

Conclusions

Although the expected decrease in mortality is not yet observable, causes of death among HCV-infected persons evolved over time. With the progressive widening of guidelines for DAA use, liver-related mortality is expected to decline in the future. Continued monitoring of cause-specific mortality will remain important to assess the long-term effect of DAA and to design effective interventions.

Lay summary

Leading causes of death among persons with hepatitis C virus (HCV) infection in the Swiss Hepatitis C Cohort study evolved over the past years, with an increasing proportion of cancer-related deaths. The positive impact of new potent anti-HCV drugs on mortality among HCV-infected persons is not yet observable, due to both the slow progression of chronic hepatitis C and the progressive relaxation of guidelines for the use of those new drugs.
Disease progression modeling in Alzheimer’s disease: insights from the shape of cognitive decline
Authors: Raket Lars Lau ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2019

Background

The characterizing symptom of Alzheimer disease (AD) is cognitive deterioration. While much recent work has focused on defining AD as a biological construct, most patients are still diagnosed, staged, and treated based on their cognitive symptoms. But the cognitive capability of a patient at any time throughout this deterioration will not directly reflect the disease state, but rather the effect of the cognitive decline on the patient’s predisease cognitive capability. Patients with high predisease cognitive capabilities tend to score better on cognitive tests relative to patients with low predisease cognitive capabilities at the same disease stage. Thus, a single assessment with a cognitive test is not adequate for determining the stage of an AD patient.

Methods and Findings

I developed a joint statistical model that explicitly modeled disease stage, baseline cognition, and the patients’ individual changes in cognitive ability as latent variables. The developed model takes the form of a nonlinear mixed-effects model. Maximum-likelihood estimation in this model induces a data-driven criterion for separating disease progression and baseline cognition. Applied to data from the Alzheimer’s Disease Neuroimaging Initiative, the model estimated a timeline of cognitive decline in AD that spans approximately 15 years from the earliest subjective cognitive deficits to severe AD dementia. It was demonstrated how direct modeling of latent factors that modify the observed data patterns provide a scaffold for understanding disease progression, biomarkers and treatment effects along the continuous time progression of disease.

Conclusions

The suggested framework enables direct interpretations of factors that modify cognitive decline. The results give new insights to the value of biomarkers for staging patients and suggest alternative explanations for previous findings related to accelerated cognitive decline among highly educated patients and patients on symptomatic treatments.
Clinical validity of expanded carrier screening: evaluating the gene-disease relationship in more than 200 conditions
Authors: Balzotti Marie , Meng Linyan , Muzzey Dale , Taber Katherine Johansen , Beauchamp Kyle ,   Myriad Genetics Curation Team,   Baylor Genetics Curation Team, Mar-Heyming Rebecca , Buckley Bethany , Moyer Krista
Published: December 2019

Objective

Clinical guidelines consider expanded carrier screening (ECS) to be an acceptable method of carrier screening. However, broader guideline support and payer adoption require evidence for associations between the genes on ECS panels and the conditions for which they aim to identify carriers. We applied a standardized framework for evaluation of gene-disease association to assess the clinical validity of conditions screened by ECS panels.

Methods

The ClinGen gene curation framework was used to assess genetic and experimental evidence of associations between 208 genes and conditions screened on two commercial ECS panels. Twenty-one conditions were previously classified by ClinGen, and the remaining 187 were evaluated by curation teams at two laboratories. To ensure consistent application of the framework across the laboratories, concordance was evaluated on a subset of conditions.

Results

All 208 evaluated conditions met the evidence threshold for supporting a gene-disease association. Furthermore, 203 of 208 (98%) achieved the strongest (“Definitive”) level of gene-disease association. All conditions evaluated by both commercial laboratories were similarly classified.

Conclusion

Assessment using the ClinGen standardized framework revealed strong evidence of gene-disease association for conditions on two ECS panels. This result establishes the disease-level clinical validity of the panels considered herein.
OASIS-3: Longitudinal Neuroimaging, Clinical, and Cognitive Dataset for Normal Aging and Alzheimer Disease
Authors: LaMontagne Pamela J. , Benzinger Tammie LS. , Morris John C. , Keefe Sarah , Hornbeck Russ , Xiong Chengjie , Grant Elizabeth , Hassenstab Jason , Moulder Krista , Vlassenko Andrei G. , Raichle Marcus E. , Cruchaga Carlos , Marcus Daniel
Published: December 2019

OASIS-3 is a compilation of MRI and PET imaging and related clinical data for 1098 participants who were collected across several ongoing studies in the Washington University Knight Alzheimer Disease Research Center over the course of 15 years. Participants include 605 cognitively normal adults and 493 individuals at various stages of cognitive decline ranging in age from 42 to 95 years. The OASIS-3 dataset contains over 2000 MR sessions, including multiple structural and functional sequences. PET metabolic and amyloid imaging includes over 1500 raw imaging scans and the accompanying post-processed files from the PET Unified Pipeline (PUP) are also available in OASIS-3. OASIS-3 also contains post-processed imaging data such as volumetric segmentations and PET analyses. Imaging data is accompanied by dementia and APOE status and longitudinal clinical and cognitive outcomes. OASIS-3 is available as an open access data set to the scientific community to answer questions related to healthy aging and dementia.
Blimp-1 in adipose resident Tregs controls adipocyte beiging and obesity
Authors: Beppu Lisa Y. , Qu Xiaoyao , Marrero Giovanni J. , Fooks Allen N. , Frias Adolfo B. , Helfrich Katherine E. , Sipula Ian , Xie Bingxian , Watkins Simon C. , Poholek Amanda C. , Jurczak Michael J. , D’Cruz Louise M.
Published: December 2019

Crosstalk between the immune system and adipocytes is critical for maintaining tissue homeostasis and regulating chronic systemic inflammation during diet-induced obesity (DIO). How visceral adipose tissue resident regulatory T cells (aTregs) signal to adipocytes in the visceral adipose tissue (VAT) is not understood. Here we show that Treg-specific ablation of the transcriptional regulator Blimp-1 resulted in increased insulin sensitivity, decreased body weight and increased Ucp-1 in adipocytes in high fat diet (HFD)-fed mice. Mechanistically, we demonstrate that Blimp-1 drives IL-10 production in Tregs, thus suppressing beiging and energy expenditure in adipocytes. Moreover, IL-10 mRNA expression positively correlated with increasing body weight in humans. These findings reveal a surprising relationship between aTregs and adipocytes in promoting insulin resistance during excessive caloric intake, placing Blimp-1-regulated IL-10 expression by aTregs at a critical juncture in the development of obesity and its associated comorbidities in mice and humans.

Here we show that ablation of Blimp-1 in adipose tissue resident Tregs (aTregs) leads to decreased IL-10 production, resulting in increased Ucp-1 expression and beiging by adipocytes and protection from diet-induced obesity and insulin resistance.
Dual blockade of IL‐4 and IL‐13 with dupilumab, an IL‐4Rα antibody, is required to broadly inhibit type 2 inflammation
Authors: Le Floc’h Audrey , Allinne Jeanne , Nagashima Kirsten , Scott George , Birchard Dylan , Asrat Seblewongel , Bai Yu , Lim Wei Keat , Martin Joel , Huang Tammy , Potocky Terra B. , Kim Jee H. , Rafique Ashique , Papadopoulos Nicholas J. , Stahl Neil , Yancopoulos George D. , Murphy Andrew J. , Sleeman Matthew A. , Orengo Jamie M.
Published: December 2019

Background

Dupilumab, a fully human monoclonal antibody that binds IL‐4Rα and inhibits signaling of both IL‐4 and IL‐13, has shown efficacy across multiple diseases with underlying type 2 signatures and is approved for treatment of asthma, atopic dermatitis, and chronic sinusitis with nasal polyposis. We sought to provide a comprehensive analysis of the redundant and distinct roles of IL‐4 and IL‐13 in type 2 inflammation and report dupilumab mechanisms of action.

Methods

Using primary cell assays and a mouse model of house dust mite–induced asthma, we compared IL‐4 vs IL‐13 vs IL‐4Rα blockers.

Results

Intranasal administration of either IL‐4 or IL‐13 confers an asthma‐like phenotype in mice by inducing immune cell lung infiltration, including eosinophils, increasing cytokine/chemokine expression and mucus production, thus demonstrating redundant functions of these cytokines. We further teased out their respective contributions using human in vitro culture systems. Then, in a mouse asthma model by comparing in head‐to‐head studies, either IL‐4 or IL‐13 inhibition to dual IL‐4/IL‐13 inhibition, we demonstrate that blockade of both IL‐4 and IL‐13 is required to broadly block type 2 inflammation, which translates to protection from allergen‐induced lung function impairment. Notably, only dual IL‐4/IL‐13 blockade prevented eosinophil infiltration into lung tissue without affecting circulating eosinophils, demonstrating that tissue, but not circulating eosinophils, contributes to disease pathology.

Conclusions

Overall, these data support IL‐4 and IL‐13 as key drivers of type 2 inflammation and help provide insight into the therapeutic mechanism of dupilumab, a dual IL‐4/IL‐13 blocker, in multiple type 2 diseases.
Spontaneous progression of experimental peri‐implantitis in augmented and pristine bone: A pre‐clinical in vivo study
Authors: Carcuac Olivier , Abrahamsson Ingemar , Derks Jan , Petzold Max , Berglundh Tord
Published: December 2019

Objective

To examine the progression of experimental peri‐implantitis around different implants placed in augmented and pristine sites.

Materials and Methods

Six labrador dogs were used. Three months after tooth extraction, four implants with different surface modifications were installed on each side of the mandible. A standard osteotomy was applied on one side, while on the contralateral side the osteotomy was modified, resulting in a gap between the implant and the bone wall. The gap was filled with a bone substitute and covered by a resorbable membrane. Three months after implant installation, implants were exposed and healing abutments were connected. Two months later, oral hygiene procedures were abandoned and a cotton ligature was placed in a submarginal position around the neck of all implants and kept in place for 4 weeks. Following ligature removal, plaque formation continued for 6 months (spontaneous progression period). Radiographs were obtained throughout the experiment, and biopsies were collected and prepared for histological evaluation at the end of the spontaneous progression period.

Results

Differences in bone loss during the spontaneous progression period between pristine and augmented sites were small. The size and vertical dimension of the peri‐implantitis lesion were larger at augmented than at pristine sites. Implants with non‐modified surfaces exhibited smaller amounts of bone loss and smaller dimensions of peri‐implantitis lesions than implants with modified surfaces.

Conclusion

Small differences in spontaneous progression of peri‐implantitis were detected between pristine and augmented sites. Implants with modified surfaces exhibited more bone loss and larger lesions than implants with non‐modified surfaces, irrespective of the type of surrounding bone.
Treatment with brentuximab vedotin plus bendamustine in unselected patients with CD30‐positive aggressive lymphomas
Authors: Wagner Sandro M. , Melchardt Thomas , Egle Alexander , Magnes Teresa , Skrabs Cathrin , Staber Philipp , Simonitsch‐Klupp Ingrid , Panny Michael , Lehner Barbara , Greil Richard , Keil Felix , Jäger Ulrich , Sillaber Christian
Published: December 2019

Objectives

A treatment regimen consisting of bendamustine and brentuximab vedotin (BV) has been described as a highly potent salvage therapy and as an effective induction therapy leading to high response rates before autologous stem cell transplantation (ASCT) in patients with classical Hodgkin lymphoma (cHL). In this retrospective analysis, we aimed to assess this therapy's efficacy in unselected patients with cHL and CD30+ peripheral T‐cell lymphoma (PTCL).

Patients and methods

Data of 28 patients with cHL and five patients with PTCL treated with a combination of bendamustine and BV at three Austrian tertiary cancer centers were analyzed.

Results

In patients with cHL, the ORR was 100% (78.6% CR, 21.4% PR). After 17 months median follow‐up, median survival times were not reached; 1‐year PFS was 81.9%, and 1‐year OS was 95.7%. Thirteen eligible patients (46.4%) successfully underwent planned ASCT after salvage therapy with bendamustine and BV and subsequent high‐dose chemotherapy. Three of the five PTCL patients achieved CR, while two did not respond and died during or shortly after therapy.

Conclusion

A combination of bendamustine and BV is an effective salvage and induction therapy before ASCT in patients with relapsed/refractory cHL. Further research is warranted to evaluate the use in patients with PTCL.
High‐dose cyclophosphamide for hard‐to‐treat patients with relapsed or refractory B‐cell non‐Hodgkin's lymphoma, a phase II result
Authors: Michot Jean‐Marie , Annereau Maxime , Danu Alina , Legoupil Clémence , Bertin Louis , Chahine Claude , Achab Nadia , Antosikova Anna , Cerutti Ariane , Rossignol Julien , Ghez David , Willekens Christophe , Dartigues Peggy , Lazarovici Julien , Lemare Francois , Ribrag Vincent
Published: December 2019

Background

High‐dose cyclophosphamide to treat solid refractory tumors demonstrated meaningful activity, while data to treat lymphoma remain scarce. This study aims to assess high‐dose cyclophosphamide to treat relapsed or refractory lymphoma.

Methods

A phase II study included adult patients with relapsed or refractory B‐cell non‐Hodgkin's lymphoma, previously treated by ≥2 prior lines with no other available option of therapy. High‐dose cyclophosphamide was given intravenously 3 g/m2 over two consecutive days and repeated once at 28 days in responding patients. Rituximab 375 mg/m2 intravenously was added in patients not refractory to anti‐CD20 antibody.

Results

Forty‐two patients with median age 65 [56‐70] years were included. Patients had previously received a median of four lines of therapies. Tumor types were diffuse large B‐cell lymphoma (n = 26; 62%), indolent B‐cell non‐Hodgkin lymphoma (n = 10; 24%), or mantle lymphoma (n = 6; 14%). Hematologic and non‐hematologic grade 3‐5 toxicities occurred in 42 (100%) and 18 (43%) of patients, respectively. The overall response rate was 45%.

Conclusion

One to two cycles of high‐dose cyclophosphamide in hard‐to‐treat patients with relapsed or refractory B‐cell non‐Hodgkin lymphoma demonstrated a favorable safety and efficacy profile. This regimen could serve as a bridge to modern cellular therapy with CAR‐T cell.
Predator hunting modes and predator–prey space games
Authors: Luttbeg Barney , Hammond John I. , Brodin Tomas , Sih Andrew
Published: December 2019

Predators and prey are often engaged in a game where their expected fitnesses are affected by their relative spatial distributions. Game models generally predict that when predators and prey move at similar temporal and spatial scales that predators should distribute themselves to match the distribution of the prey's resources and that prey should be relatively uniformly distributed. These predictions should better apply to sit‐and‐pursue and sit‐and‐wait predators, who must anticipate the spatial distributions of their prey, than active predators that search for their prey. We test this with an experiment observing the spatial distributions and estimating the causes of movements between patches for Pacific tree frog tadpoles (Pseudacris regilla), a sit‐and‐pursue dragonfly larvae predator (Rhionaeschna multicolor), and an active salamander larval predator (Ambystoma tigrinum mavortium) when a single species was in the arena and when the prey was with one of the predators. We find that the sit‐and‐pursue predator favors patches with more of the prey's algae resources when the prey is not in the experimental arena and that the prey, when in the arena with this predator, do not favor patches with more resources. We also find that the active predator does not favor patches with more algae and that prey, when with an active predator, continue to favor these higher resource patches. These results suggest that the hunting modes of predators impact their spatial distributions and the spatial distributions of their prey, which has potential to have cascading effects on lower trophic levels.
Kinetic and structural studies of Trypanosoma and Leishmania phosphofructokinases show evolutionary divergence and identify AMP as a switch regulating glycolysis versus gluconeogenesis
Authors: Fernandes Peter M. , Kinkead James , McNae Iain W. , Vásquez‐Valdivieso Monserrat , Wear Martin A. , Michels Paul A. M. , Walkinshaw Malcolm D.
Published: December 2019

Trypanosomatids possess glycosome organelles that contain much of the glycolytic machinery, including phosphofructokinase (PFK). We present kinetic and structural data for PFK from three human pathogenic trypanosomatids, illustrating intriguing differences that may reflect evolutionary adaptations to differing ecological niches. The activity of Leishmania PFK – to a much larger extent than Trypanosoma PFK – is reliant on AMP for activity regulation, with 1 mm AMP increasing the L. infantum PFK (LiPFK) kcat/K0.5F6P value by 10‐fold, compared to only a 1.3‐ and 1.4‐fold increase for T. cruzi and T. brucei PFK, respectively. We also show that Leishmania PFK melts at a significantly lower (> 15 °C) temperature than Trypanosoma PFKs and that addition of either AMP or ATP results in a marked stabilization of the protein. Sequence comparisons of Trypanosoma spp. and Leishmania spp. show that divergence of the two genera involved amino acid substitutions that occur in the enzyme’s ‘reaching arms’ and ‘embracing arms’ that determine tetramer stability. The dramatic effects of AMP on Leishmania activity compared with the Trypanosoma PFKs may be explained by differences between the T‐to‐R equilibria for the two families, with the low‐melting Leishmania PFK favouring the flexible inactive T‐state in the absence of AMP. Sequence comparisons along with the enzymatic and structural data presented here also suggest there was a loss of AMP‐dependent regulation in Trypanosoma species rather than gain of this characteristic in Leishmania species and that AMP acts as a key regulator in Leishmania governing the balance between glycolysis and gluconeogenesis.
The emergence of fatty acids—Aquatic insects as vectors along a productivity gradient
Authors: Scharnweber Kristin , Chaguaceda Fernando , Dalman Erik , Tranvik Lars , Eklöv Peter
Published: December 2019

Aquatic and terrestrial ecosystems differ fundamentally in the abundance of long‐chained polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA; 20:5n‐3), which are produced by aquatic algae, but only in low quantities by terrestrial plants. Aquatic insects, such as Chironomidae (non‐biting midges) feed on algae during their larval stage, making them rich in EPA and therefore high‐quality prey for insectivores after emergence. However, the magnitude of EPA subsidies from aquatic insects may be different among water bodies in response to abiotic (e.g. nutrient load) as well as biotic factors (e.g. food web structure).

To test the predation effects of crucian carp (Carassius carassius), nutrient concentrations, and Chironomidae community composition on the fatty acid export from aquatic ecosystems, we conducted a 25‐day experiment across 20 1,500‐L mesocosms covering a total phosphorus (TP) gradient of 20–1,000 µg/L.

Twice a week, we collected adult emerging Chironomidae and found differences in fatty acid composition in the two most abundant chironomid species emerging from the mesocosms. Two PUFAs, α‐linolenic acid and EPA, contributed to most of the variation in Chironomidae fatty acid content across the nutrient gradient. Whereas the proportions of α‐linolenic acid were positively correlated to the mesocosm TP concentration, we found a negative correlation for the proportions of Chironomidae EPA and mesocosm TP concentration. However, despite lower biomass‐specific EPA content at higher TP, higher biomass of emerging Chironomidae at intermediate TP concentrations resulted in higher total export of PUFAs from water to land.

Predation pressure from carp decreased the biomass of emerging Chironomidae on average 8‐fold. Chironomidae biomass showed a hump‐shaped relationship along the TP‐gradient and was strongly influenced by periphyton biomass.

Export rates of EPA and fatty acids in general responded in a quadratic manner along the nutrient gradient, reaching a maximum value at a TP of 400 µg/L and decreasing thereafter.

These findings highlight that the export of fatty acids from aquatic systems via adult Chironomidae is highly dependent on fish predation pressure, but also the nutrient concentrations of the system.
Follow‐up of need for dental treatment in 126 patients who have received radiation treatment to the head and neck region
Authors: Rinstad Tamara , Bergqvist Birgitta , Mattsson Ulf
Published: December 2019

Objectives

The aim of this study was to evaluate the need for dental treatment, compliance with post‐radiation prophylactic care and incidence of long‐term complications following radiotherapy to the head and neck.

Methods

The study is a retrospective analysis of dental records of patients referred for oral examination before radiation treatment to the head and neck between 2006 and 2016. Data of dental status and need for dental treatment before radiation therapy were used as baseline information. Dental records could be obtained from 126 patients (men n = 74; women n = 52). The mean time from completed radiotherapy to follow‐up was 5.8 years (SD 2.9).

Results

The need for dental treatment was for the majority of patients relatively modest and mainly due to caries and fractures of teeth or fillings, but extensive need for dental treatment was noted in a few patients. One hundred and twenty‐five out of 126 patients had complied with individual post‐radiation prophylactic care programmes provided by the regular caregiver. Ninety‐two out of 126 obtained dental records (73%) described hyposalivation and/or xerostomia. Osteoradionecrosis developed in 11 patients (8.7%), frequently requiring long‐term treatment.

Conclusions

The results indicate that dental status may often be preserved if the patient is given regular information on oral hygiene and complies with prophylactic follow‐up. Individual cases develop serious complications, and dental hygienists and dentists must be observant on early signs of rampant caries, trismus and osteoradionecrosis.