bluuebunny/crossref_metadata_2025 huggingface dataset:
FOXC2 controls adult lymphatic endothelial specialization, function, and gut lymphatic barrier preventing multiorgan failure
Authors: González-Loyola Alejandra , Bovay Esther , Kim Jaeryung , Lozano Tania Wyss , Sabine Amélie , Renevey Francois , Arroz-Madeira Silvia , Rapin Alexis , Wypych Tomasz P. , Rota Giorgia , Durot Stephan , Velin Dominique , Marsland Benjamin , Guarda Greta , Delorenzi Mauro , Zamboni Nicola , Luther Sanjiv A. , Petrova Tatiana V.
Published: July 2021

Foxc2sustains adult lymphatic vascular specialization and coordinates organ-specific lymph flow, gut microbiota, and inflammation.
Epetraborole Is Active against Mycobacterium abscessus
Authors: Ganapathy Uday S. , Gengenbacher Martin , Dick Thomas
Published: July 2021

Benzoxaboroles are a new class of leucyl-tRNA synthetase inhibitors. We recently reported that the antitubercular 4-halogenated benzoxaboroles are active against
Mycobacterium abscessus
.
Fasting hypoglycaemia secondary to carnitine deficiency: a late consequence of gastric bypass
Authors: Chen Xin , Kimura Brad , Nagelberg Jodi , McCowen Karen C
Published: July 2021

Twelve years following gastric bypass surgery, a cachectic 69-year-old woman presented with both fasting and postprandial hypoglycaemia. Postprandial symptoms were relieved by dietary modification and acarbose, as is common in such cases. During a supervised fast, symptomatic hypoglycaemia occurred. Concurrent laboratory testing showed suppression of plasma insulin, c-peptide, proinsulin and insulin-like growth factor II. However, beta-hydroxybutyrate was also low, surprising given insulin deficiency. Elevated plasma free fatty acid (FFA) concentrations suggested that lipolysis was not impaired, making cachexia/malnutrition a less likely cause of hypoglycaemia. The apparent diagnosis was failure to counter-regulate—subsequent plasma carnitine measurements showed carnitine deficiency which presumably prevented FFA transport across mitochondrial membranes for ketogenesis. Repletion with high-dose oral carnitine supplements effected resolution of fasting hypoglycaemia.
Primary cam morphology; bump, burden or bog-standard? A concept analysis
Authors: Dijkstra H Paul , Ardern Clare L , Serner Andreas , Mosler Andrea Britt , Weir Adam , Roberts Nia Wyn , Mc Auliffe Sean , Oke Jason L , Khan Karim M , Clarke Mike , Glyn-Jones Siôn
Published: July 2021

Background

Cam morphology, a distinct bony morphology of the hip, is prevalent in many athletes, and a risk factor for hip-related pain and osteoarthritis. Secondary cam morphology, due to existing or previous hip disease (eg, Legg-Calve-Perthes disease), is well-described. Cam morphology not clearly associated with a disease is a challenging concept for clinicians, scientists and patients. We propose this morphology, which likely develops during skeletal maturation as a physiological response to load, should be referred to asprimarycam morphology. The aim of this study was to introduce and clarify the concept ofprimarycam morphology.

Design

We conducted a concept analysis of primary cam morphology using articles that reported risk factors associated with primary cam morphology; we excluded articles on secondary cam morphology. The concept analysis method is a rigorous eight-step process designed to clarify complex ‘concepts’; the end product is a precise definition that supports the theoretical basis of the chosen concept.

Results

We propose five defining attributes of primary cam morphology—tissue type, size, site, shape and ownership—in a new conceptual and operational definition. Primary cam morphology is a cartilage or bony prominence (bump) of varying size at the femoral head-neck junction, which changes the shape of the femoral head from spherical to aspherical. It often occurs in asymptomatic male athletes in both hips. The cartilage or bone alpha angle (calculated from radiographs, CT or MRI) is the most common method to measure cam morphology. We found inconsistent reporting of primary cam morphology taxonomy, terminology, and how the morphology is operationalised.

Conclusion

We introduce and clarify primary cam morphology, and propose a new conceptual and operational definition. Several elements of the concept of primary cam morphology remain unclear and contested. Experts need to agree on the new taxonomy, terminology and definition that better reflect the primary cam morphology landscape—a bog-standard bump in most athletic hips, and a possible hip disease burden in a selected few.
What do users think of the UK’s three COVID-19 contact-tracing apps? A comparative analysis
Authors: Garousi Vahid , Cutting David
Published: July 2021

Objectives

Our goal was to gain insights into the user reviews of the three COVID-19 contact-tracing mobile apps, developed for the different regions of the UK: ‘NHS COVID-19’ for England and Wales, ‘StopCOVID NI’ for Northern Ireland and ‘Protect Scotland’ for Scotland. Our two research questions are (1) what are the users’ experience and satisfaction levels with the three apps? and (2) what are the main issues (problems) that users have reported about the apps?

Methods

We assess the popularity of the apps and end users’ perceptions based on user reviews in app stores. We conduct three types of analysis (data mining, sentiment analysis and topic modelling) to derive insights from the combined set of 25 583 user reviews of the aforementioned three apps (submitted by users until the end of 2020).

Results

Results show that end users have been generally dissatisfied with the apps under study, except the Scottish app. Some of the major issues that users have reported are high battery drainage and doubts on whether apps are really working.

Discussion

Towards the end of 2020, the much-awaited COVID-19 vaccines started to be available, but still, analysing the users’ feedback and technical issues of these apps, in retrospective, is valuable to learn the right lessons to be ready for similar circumstances in future.

Conclusion

Our results show that more work is needed by the stakeholders behind the apps (eg, apps’ software engineering teams, public-health experts and decision makers) to improve the software quality and, as a result, the public adoption of these apps. For example, they should be designed to be as simple as possible to operate (need for usability).
eHealth intervention to manage symptoms for patients with cancer on immunotherapy (SOFIA): a study protocol for a randomised controlled external pilot trial
Authors: Sauer Christina , Krauß Jürgen , Jäger Dirk , Zschäbitz Stefanie , Haag Georg Martin , Walle Thomas , Sauer Simeon , Kiermeier Senta , Friederich Hans-Christoph , Maatouk Imad
Published: July 2021

Introduction

Immune checkpoint therapy (ICT) is associated with a distinct pattern of immune-related adverse events (irAEs) caused by inadvertently redirecting immune responses to healthy tissues. IrAEs can occur at any time; however, in most cases, they arise during the first 14 weeks of the beginning of immune checkpoint blockade. In many cases, immunotherapy must be discontinued due to irAEs. Early detection of irAEs triggers the temporary withholding of ICT or initiation of short-term immunosuppressive treatment, is crucial in preventing further aggravation of irAEs and enables safe re-exposure to ICT. This prospective study aims to evaluate the feasibility of an eHealth intervention for patients under immunotherapy (managingsymptomsof immunotherapy, SOFIA). The SOFIA-App consists of two components: SOFIA-Monitoring, a tool to rate patient-reported outcomes (PROs) including irAEs, and SOFIA-Coaching, which provides important information about cancer-specific and immunotherapy-specific topics and the counselling services of the National Centre for Tumour Diseases (NCT) Heidelberg.

Methods and analysis

We outlined a patient-level two-arm randomised controlled pilot trial of the intervention (SOFIA) versus no-SOFIA for patients with cancer beginning an immunotherapy, aged ≥18 years, recruited from the NCT, Heidelberg. Feasibility outcomes include: recruitment rate; drop-out rate; reasons for refusal and drop-out; willingness to be randomised, utilisation rate of SOFIA-Monitoring and utilisation time of SOFIA-Coaching, physicians utilisation rate of the PROs; feasibility of the proposed outcome measures and optimal sample size estimation. The clinical outcomes are measures of quality of life, psychosocial symptoms, self-efficacy, physician-patient communication and medical process data, which are assessed at the beginning of the intervention, postintervention and at 6-month follow-up.

Ethics and dissemination

This trial protocol was approved by the Ethical Committee of Heidelberg University, Germany (Reference, S-581/2018).

Trial registration number

We registered the study in the German Clinical Trial Register (Reference: DRKS00021064). Findings will be disseminated broadly via peer-reviewed empirical journals, articles and conference presentations.
Competing-risks nomogram for predicting cancer-specific death in upper tract urothelial carcinoma: a population-based analysis
Authors: Li Chengzhuo , Han Didi , Huang Qiao , Xu Fengshuo , Zheng Shuai , Li Xiang , Zhao Fanfan , Feng Xiaojie , Lyu Jun
Published: July 2021

Objective

This study aimed to use a competing-risks model to establish a nomogram to accurately analyse the prognostic factors for upper tract urothelial carcinoma (UTUC) cancer-specific death (CSD).

Design

Retrospective observational cohort study.

Setting

The programme has yielded a database of all patients with cancer in 18 defined geographical regions of the USA.

Participants

We selected patients with UTUC from the latest edition of the Surveillance, Epidemiology, and End Results database from 1975 to 2016. After excluding patients with unknown histological grade, tumour size and lymph node status, 2576 patients were finally selected.

Primary and secondary outcome measures

We used the Fine-Gray proportional subdistribution hazards model for multivariate analysis and compared the results with cause-specific hazards model. We finally constructed a nomogram for 3-year, 5-year and 8-year CSD rates and tested these rates in a validation cohort.

Results

The proportional subdistribution hazards model showed that sex, tumour size, distant metastasis, surgery status, number of lymph nodes positive (LNP) and lymph nodes ratio (LNR) were independent prognostic factors for CSD. All significant factors associated with CSD were included in the nomogram. The 3-year, 5-year and 8-year concordance indexes were 0.719, 0.702 and 0.692 in the training cohort and 0.701, 0.675 and 0.668 in the validation cohort, respectively.

Conclusions

The competing-risks model showed that sex, tumour size, distant metastasis, surgery status, LNP and LNR were associated with CSD. The nomogram predicts the probability of CSD in patients with UTUC at 3, 5 and 8 years, which may help clinicians in predicting survival probabilities in individual patients.
Cost effectiveness of ramipril treatment for cardiovascular risk reduction
Authors: Malik I S , Bhatia V K , Kooner J S
Published: July 2021

OBJECTIVE

To assess the cost effectiveness of ramipril treatment in patients at low, medium, and high risk of cardiovascular death.

DESIGN

Population based cost effectiveness analysis from the perspective of the health care provider in the UK. Effectiveness was modelled using data from the HOPE (heart outcome prevention evaluation) trial. The life table method was used to predict mortality in a medium risk cohort, as in the HOPE trial (2.44% annual mortality), and in low and high risk groups (1% and 4.5% annual mortality, respectively).

SETTING

UK population using 1998 government actuary department data.

MAIN OUTCOME MEASURE

Cost per life year gained at five years and lifetime treatment with ramipril.

RESULTS

Cost effectiveness was £36 600, £13 600, and £4000 per life year gained at five years and £5300, £1900, and £100 per life year gained at 20 years (lifetime treatment) in low, medium, and high risk groups, respectively. Cost effectiveness at 20 years remained well below that of haemodialysis (£25 000 per life year gained) over a range of potential drug costs and savings. Treatment of the HOPE population would cost the UK National Health Service (NHS) an additional £360 million but would prevent 12 000 deaths per annum.

CONCLUSIONS

Ramipril is cost effective treatment for cardiovascular risk reduction in patients at medium, high, and low pretreatment risk, with a cost effectiveness comparable with the use of statins. Implementation of ramipril treatment in a medium risk population would result in a major reduction in cardiovascular deaths but would increase annual NHS spending by £360 million.
Correlation between high frequency intravascular ultrasound and histomorphology in human coronary arteries
Authors: Prati F , Arbustini E , Labellarte A , Dal Bello B , Sommariva L , Mallus M T , Pagano A , Boccanelli A
Published: July 2021

OBJECTIVE

To test the efficacy of high frequency intravascular ultrasound (IVUS) transducers in identifying lipid/necrotic pools in atherosclerotic plaques.

METHODS

40 MHz transducers were used for in vitro IVUS assessment of 12 arterial segments (10 coronary and two carotid arteries, dissected from five different necropsy cases). IVUS acquisition was performed at 0.5 mm/s after ligature of the branching points to generate a closed system. Lipid/necrotic areas were defined by IVUS as large echolucent intraplaque areas surrounded by tissue with higher echodensity. To obtain histopathological sections corresponding to IVUS cross sections, vessels were divided into consecutive 3 mm long segments using the most distal recorded IVUS image as the starting reference. Samples were then fixed with 10% buffered formalin, processed for histopathological study, serially cut, and stained using the Movat pentacrome method.

RESULTS

122 sections were analysed. Lipid pools were observed by histology in 30 sections (25%). IVUS revealed the presence of lipid pools in 19 of these sections (16%; sensitivity 65%, specificity 95%).

CONCLUSIONS

In vitro assessment of lipid/necrotic pools with high frequency transducers was achieved with good accuracy. This opens new perspectives for future IVUS characterisation of atherosclerotic plaques.
Increased concentrations of inflammatory mediators in unstable angina: correlation with serum troponin T
Authors: Mazzone A , De Servi S , Mazzucchelli I , Bossi I , Ottini E , Vezzoli M , Meloni F , Lotzinker M , Mariani G
Published: July 2021

OBJECTIVE

To measure plasma interferon γ, monocyte chemotactic protein-1 (MCP-1), and interleukin 6 and to assess their correlation with cardiac troponin T in unstable angina.

DESIGN

Blood sampling in patients undergoing coronary arteriography for known or suspected ischaemic heart disease.

PATIENTS

76 patients divided in three groups: 29 with unstable angina (group 1), 28 with stable angina (group 2), and 19 without ischaemic heart disease and with angiographically normal coronary arteries (group 3).

MAIN OUTCOME MEASURES

Plasma interleukin 6, interferon γ, MCP-1, and troponin T in the three groups of patients.

RESULTS

Interleukin 6 was increased in group 1 (median 2.19 (range 0.53–50.84) pg/ml) compared with the control group (1.62 (0.79–3.98) pg/ml) (p < 0.005), whereas interferon γ was higher in group 1 (range 0–5.51 pg/ml) than in the other two groups (range 0–0.74 pg/ml and 0–0.37 pg/ml; p < 0.005 and p < 0.001, respectively). Patients with unstable angina (group 1) and positive troponin T had higher concentrations of interferon γ than those with negative troponin T (0–5.51 pg/mlv 0–0.60 pg/ml, p < 0.001). Plasma MCP-1 was also higher in group 1 (median 267 (range 6–8670) pg/ml) than in the other two groups (134 (19–890) pg/ml and 84.5 (5–325) pg/ml; p < 0.005 and p < 0.001, respectively), and among group 1 patients with a positive troponin T assay than in those with normal troponin T (531 (14.5–8670) pg/mlv 69 (6–3333) pg/ml; p < 0.01). There was no difference in plasma interleukin 6 in group 1 patients between those with and without raised troponin T.

CONCLUSIONS

The inflammatory cytokines interferon γ and MCP-1 are increased in patients with unstable angina, particularly in those with raised concentrations of troponin T, suggesting that they are probably related to myocardial cell damage or to plaque rupture and thrombus formation.
Management and outcome of cardiogenic shock complicating acute myocardial infarction in hospitals with and without on-site catheterisation facilities
Authors: Barbash I M , Behar S , Battler A , Hasdai D , Boyko V , Gottlieb S , Leor J
Published: July 2021

OBJECTIVE

To determine whether the availability of on-site catheterisation and revascularisation facilities influenced hospital management and outcome of patients with acute myocardial infarction complicated by cardiogenic shock.

METHODS

Patients with acute myocardial infarction were enrolled prospectively in four nationwide surveys during 1992, 1994, 1996, and 1998. The characteristics, management, and outcome of patients with cardiogenic shock were compared between hospitals with on-site catheterisation facilities (group 1; 18 hospitals) and without such facilities (group 2; 8 hospitals).

RESULTS

Of 5351 patients with acute myocardial infarction, 254 (4.7%) developed cardiogenic shock. Group 1 patients (n = 186 of 3854; 4.6%) were younger (mean (SD) age, 69.6 (12) v 73.7 (10) years, p = 0.006) and had a lower proportion of women (36% v 52%, p = 0.03) than group 2 (n = 68 of 1243; 5.2%). There was no difference in other characteristics including the use of thrombolysis. Group 1 patients more often underwent coronary angiography (26%v 4%, p < 0.001), angioplasty (21%v 4%, p = 0.002), and intra-aortic balloon counterpulsation (28% v 4%, p < 0.001). Seven day mortality was lower among group 1 than among group 2 patients (61% v 77%, p = 0.02), even after age and sex adjustment (odds ratio (OR) 0.54; 95% confidence interval (CI) 0.28 to 1.02). This outcome benefit persisted at 30 days (74%v 88%, p = 0.01; OR 0.45, 95% CI 0.18 to 0.98), and at 6 months (80% v 90%, p = 0.06; OR 0.57, 95% CI 0.22 to 1.33).

CONCLUSIONS

The greater use of invasive and interventional procedures in hospitals with catheterisation facilities is associated with improved survival of patients with acute myocardial infarction complicated by cardiogenic shock. Immediate availability of invasive care facilities will improve the outcome of cardiogenic shock in the community setting.
Prevalence of asymptomatic ST segment elevation in right precordial leads with right bundle branch block (Brugada-type ST shift) among the general Japanese population
Authors: Furuhashi M , Uno K , Tsuchihashi K , Nagahara D , Hyakukoku M , Ohtomo T , Satoh S , Nishimiya T , Shimamoto K
Published: July 2021

OBJECTIVE

To examine the modality and morbidity of asymptomatic ST segment elevation in leads V1 to V3 with right bundle branch block (Brugada-type ST shift).

METHODS

8612 Japanese subjects (5987 men and 2625 women, mean age 49.2 years) who underwent a health check up in 1997 were investigated. Those with Brugada-type ST shift underwent the following further examinations over a two year period after the initial check up: ECG, echocardiogram, 24 hour Holter monitoring, treadmill exercise testing, signal averaged ECG, and slow kinetic sodium channel blocker loading test (cibenzoline, 1.4 mg/kg).

RESULTS

Asymptomatic Brugada-type ST shift was found in 12 of 8612 (0.14%) subjects. Eleven of these 12 subjects were followed up. Follow up ECG exhibited persistent Brugada-type ST shift in seven of 11 (63.6%) subjects. ST shift was transformed from a saddle back to a coved type in three subjects. None of the subjects had morphological abnormalities or abnormal tachyarrhythmias. Positive late potentials were found in seven of 11 (63.6%) subjects. Augmentation of ST shift was shown by both submaximal exercise and drug administration in one of the 11 subjects (9.1%).

CONCLUSIONS

Asymptomatic subjects with Brugada-type ST shift were not unusual, at a rate of 0.14% in the general Japanese population. Almost all of the subjects had some abnormalities in non-invasive secondary examinations. Additional and prospective studies are needed to confirm the clinical significance and the prognosis of asymptomatic Brugada-type ST shift.
Uncomplicated moderate coronary artery dissections after balloon angioplasty: good outcome without stenting
Authors: Albertal M , Van Langenhove G , Regar E , Kay I P , Foley D , Sianos G , Kozuma K , Beijsterveldt T , Carlier S G , Belardi J A , Boersma E , Sousa J E , de Bruyne B , Serruys P W
Published: July 2021

OBJECTIVE

To study the relation between moderate coronary dissections, coronary flow velocity reserve (CFVR), and long term outcome.

METHODS

523 patients undergoing balloon angioplasty and sequential intracoronary Doppler measurements were examined as part of the DEBATE II trial (Doppler endpoints balloon angioplasty trial Europe). After successful balloon angioplasty, patients were randomised to stenting or no further treatment. Dissections were graded at the core laboratory by two observers and divided into four categories: none, mild (type A-B), moderate (type C), severe (types D to F). Patients with severe dissections (n = 128) or without available reference vessel CFVR (n = 139) were excluded. The remaining 256 patients were divided into two groups according to the presence (group A, n = 45) or absence (group B, n = 211) of moderate dissection.

RESULTS

Following balloon angioplasty, there was no difference in CFVR between the two groups. At 12 months follow up, a higher rate of major adverse cardiac events was observed overall in group A than in group B (10 (22%)v 23 (11%), p = 0.041). However, the risk of major adverse events was similar in the subgroups receiving balloon angioplasty (group A, 6 (19%) v group B, 16 (16%), NS). Among group A patients, the adverse events risk was greater in those randomised to stenting (odds ratios 6.603v 1.197, p = 0.046), whereas there was no difference in risk if the group was analysed according to whether the CFVR was < 2.5 or ⩾ 2.5 after balloon angioplasty.

CONCLUSIONS

Moderate dissections left untreated result in no increased risk of major adverse cardiac events. Additional stenting does not improve the long term outcome.
Exposure to unhealthy food and beverage advertising during the school commute in Australia
Authors: Trapp Gina , Hooper Paula , Thornton Lukar E , Kennington Kelly , Sartori Ainslie , Wickens Nicole , Billingham Wesley
Published: July 2021

Background

Food marketing exposure has the potential to influence children’s dietary behaviours and health status, however, few studies have identified how ‘obesogenic’ the outdoor food marketing environment is along public transport (bus and/or train) or walking routes that children take to school.

Methods

Audits of all outdoor advertisements present along likely train, bus and walking routes to 24 secondary schools (ie, 3 routes per school, 72 routes total) were conducted in Perth, Western Australia (WA). The size, content, type and setting of each advertisement were recorded in accordance with the International Network for Food and Obesity/non-communicable diseases Research, Monitoring and Action Support protocol for monitoring outdoor advertising.

Results

Of the 4016 total advertisements observed, almost half were for food (n=1754, 44%) and of these, 80% (n=1397) advertised discretionary (non-core) foods, and 8% (n=138) advertised healthy (core) foods. On average, commuting to school by train, bus and walking exposed Perth schoolchildren to 37.1, 22 and 4.5 discretionary (non-core) food ads per one-way trip to school, respectively.

Conclusions

Children living in Perth, WA experience a high level of exposure to unhealthy outdoor food advertisements during the school commute. Policies which restrict the placement and content of outdoor advertising, could be a useful strategy in the fight against childhood obesity.
Tumor rejection inCblb−/−mice depends on IL-9 and Th9 cells
Authors: Schanz Oliver , Cornez Isabelle , Yajnanarayana Sowmya Parampalli , David Friederike Sophie , Peer Sebastian , Gruber Thomas , Krawitz Peter , Brossart Peter , Heine Annkristin , Landsberg Jenny , Baier Gottfried , Wolf Dominik
Published: July 2021

Background

Casitas B lymphoma-b (Cbl-b) is a central negative regulator of cytotoxic T and natural killer (NK) cells and functions as an intracellular checkpoint in cancer. In particular, Th9 cells support mast cell activation, promote dendritic cell recruitment, enhance the cytolytic function of cytotoxic T lymphocytes and NK cells, and directly kill tumor cells, thereby contributing to tumor immunity. However, the role of Cbl-b in the differentiation and antitumor function of Th9 cells is not sufficiently resolved.

Methods

UsingCblb−/−mice, we investigated the effect of knocking outCblbon the differentiation process and function of different T helper cell subsets, focusing on regulatory T cell (Treg) and Th9 cells. We applied single-cell RNA (scRNA) sequencing ofin vitrodifferentiated Th9 cells to understand how Cbl-b shapes the transcriptome and regulates the differentiation and function of Th9 cells. We transferred tumor-model antigen-specificCblb−/−Th9 cells into melanoma-bearing mice and assessed tumor controlin vivo. In addition, we blocked interleukin (IL)-9 in melanoma cell-exposedCblb−/−mice to investigate the role of IL-9 in tumor immunity.

Results

Here, we provide experimental evidence that Cbl-b acts as a rheostat favoring Tregs at the expense of Th9 cell differentiation.Cblb−/−Th9 cells exert superior antitumor activity leading to improved melanoma controlin vivo. Accordingly, blocking IL-9 in melanoma cell-exposedCblb−/−mice reversed their tumor rejection phenotype. Furthermore, scRNA sequencing of in vitro differentiated Th9 cells from naïve T cells isolated from wildtype andCblb−/−animals revealed a transcriptomic basis for increased Th9 cell differentiation.

Conclusion

We established IL-9 and Th9 cells as key antitumor executers inCblb−/−animals. This knowledge may be helpful for the future improvement of adoptive T cell therapies in cancer.
Novel germline variant in the histone demethylase and transcription regulator KDM4C induces a multi-cancer phenotype
Authors: Katainen Riku , Donner Iikki , Räisänen Maritta , Berta Davide , Kuosmanen Anna , Kaasinen Eevi , Hietala Marja , Aaltonen Lauri A
Published: July 2021

Background

Genes involved in epigenetic regulation are central for chromatin structure and gene expression. Specific mutations in these might promote carcinogenesis in several tissue types.

Methods

We used exome, whole-genome and Sanger sequencing to detect rare variants shared by seven affected individuals in a striking early-onset multi-cancer family. The only variant that segregated with malignancy resided in a histone demethylase KDM4C. Consequently, we went on to study the epigenetic landscape of the mutation carriers with ATAC, ChIP (chromatin immunoprecipitation) and RNA-sequencing from lymphoblastoid cell lines to identify possible pathogenic effects.

Results

A novel variant in KDM4C, encoding a H3K9me3 histone demethylase and transcription regulator, was found to segregate with malignancy in the family. Based on Roadmap Epigenomics Project data, differentially accessible chromatin regions between the variant carriers and controls enrich to normally H3K9me3-marked chromatin. We could not detect a difference in global H3K9 trimethylation levels. However, carriers of the variant seemed to have more trimethylated H3K9 at transcription start sites. Pathway analyses of ChIP-seq and differential gene expression data suggested that genes regulated through KDM4C interaction partner EZH2 and its interaction partner PLZF are aberrantly expressed in mutation carriers.

Conclusions

The apparent dysregulation of H3K9 trimethylation and KDM4C-associated genes in lymphoblastoid cells supports the hypothesis that the KDM4C variant is causative of the multi-cancer susceptibility in the family. As the variant is ultrarare, located in the conserved catalytic JmjC domain and predicted pathogenic by the majority of available in silico tools, further studies on the role of KDM4C in cancer predisposition are warranted.
2 Personalized closed-loop neurostimulation for depression
Authors: Scangos Katherine
Published: July 2021

Major depression (MDD) is a common psychiatric condition and a leading cause of disability worldwide. While psychotherapy and pharmacotherapy are effective treatments for the majority of people, a substantial number of patients remain refractory to all available treatments. Neuromodulation such as deep brain stimulation (DBS), is a promising solution for these people. However, results from randomized controlled trials of DBS for depression have been inconsistent, suggesting novel strategies for neuromodulation are needed. One such strategy is personalized closed- loop neurostimulation. It addresses the challenge posed by the etiological and diagnostic heterogeneity of depression. Personalized closed-loop neurostimulation involves individualized target selection, customized biomarker driven stimulation, and continuous neural sensing so that treatment is both spatially and temporally individualized.
#3041 High prevalence of lifetime depressive symptoms in patients referred for clinical amyloid-PET: a retrospective study
Authors: Fitzgerald Anna , Loreto Flavia , Golemme Mara , Win Zarni , Patel Neva , Carswell Christopher , Perry Richard , Malhotra Paresh
Published: July 2021

Objectives/Aims

Depression has been reported as a possible risk factor for Alzheimer’s Disease, but also as one of the clinical features of Alzheimer’s as well as other dementias. Further, depression has long been associated with cognitive impairment in the absence of neurodegeneration (Connors et al. 2018). Here we sought to ascertain the prevalence of clinical depression in patients meeting widely accepted Appropriate Use Criteria for Amyloid PET Imaging (API). We examined the prevalence of lifetime depression in patients undergoing clinical API in a real-world clinical setting and compared our findings with population data from community-dwelling older adults. We also examined whether rates of depression were higher in amyloid positive or negative groups.

Methods

One-hundred-and-eighty-five older adults (mean age 67.079.37, 49% females) underwent diagnostic workup, including API, at the Imperial Memory Clinic between January 2017 and June 2019. API was performed in line with appropriate use criteria after multidisciplinary team discussion. History of depressive symptoms and features of depression were evaluated through a review of hospital records and clinical correspondence. Patients were defined as having a history of depression if there was evidence of previous or current depressive symptoms and/or of a formal diagnosis of depression in their clinical records.

Results

Based on visual reads, 83 individuals had positive Amyloid-PET scans and 102 were negative. Overall, 102 (55%) patients(mean age=66.758.99, 56% females) had a history of lifetime depressive symptoms, compared with just 12 and 19% of elderly individuals in the general population (McDougall et al. 2007; Biddulph et al. 2014). Of the 92 patients for whom further information regarding depression onset were available, 54 (58.7%) had early symptom onset (age <60), and 38 (41.3%) had late symptom onset (age ≥s60). At the time of the clinical assessment at the Imperial Memory Clinic, 71 of those 102 (69.6%) were on active treatment for depression. Finally, depression was not associated with amyloid status (χ2(1) =1.12p=.26), with 42 (41.2%) amyloid-positive and 60 (58.8%) amyloid-negative patients reporting a history of depression.

Conclusions

Over half of patients with suspected cognitive impairment and meeting appropriate use criteria for clinical API had a history of depression, regardless of amyloid status. Depression is an important but incompletely understood factor in referral for evaluation with Amyloid-PET.
#3125 Novel framework for neurocognitive COVID-19 assessment
Authors: Mathur Jai , Carson Alan
Published: July 2021

Background

The neurotrophic effects of Covid-19 are becoming increasingly recognized, with altered mental state now being the second most common presenting complaint insert numbers. A key question is whether this has long term consequences. Cognitive problems are commonly reported in patients 3 months after acute infection as part of the so called Long-Covid syndrome. However, the underlying cause is not well understood. Candidate explanations include legacy from encephalitis and stroke; however, other complications such as the sequelae, delirium, remain underexplored. Furthermore, little consideration has been given to functional cognitive disorders and the cognitive consequences of depression, anxiety and fatigue.

Aims

We propose a structured approach to clinical assessment for clinicians reviewing late cognitive complaints after COVID 19.

Methods

We created our own unique framework for neurocognitive Covid assessment based upon a review of the literature.

Results

Covid status- Any positive test. If not review of core symptoms such as breathlessness, headache, anosmia, nasal obstruction, cough, myalgia, or gustatory dysfunction; duration, extent of exposure to Covid confirmed cases. Consider rapid antibody testing.

Neuropsychiatric history- Part 1 symptoms at onset- in particular disruptions of consciousness and altered mental state. Acute memory impairment, anterograde/retrograde and with/without a temporal gradient. neurocognitive function. ITU admission and oxygen requirements.

Part 2 Current cognitive and mental state- in addition to standard history seek evidence of internal inconsistency of memory symptoms and attentional dysregulation. Has social cognition and meta-cognition been affected. Note attribution bias i.e. no Im not depressed, I cant enjoy anything because of my symptoms

Background history- subtle suggestion of neurodegeneration and depression, anxiety and functional symptoms should be explored.

MRI findings- signal changes in the medial temporal lobe, nonconfluent multifocal white matter hyperintense lesions, and isolated white matter microhemorrhages.

Novel biomarkers IL-6, MCP-1, and IP-10.

Conclusion

Cognitive symptoms are common after confirmed and assumed COVID exposure. We propose a framework for neuropsychiatric assessment and the use of adjuvant imaging and potential biomarkers.
4 Brain computer interface for paralysis
Authors: Hochberg Leigh R
Published: July 2021

Intracortically-based Brain-Computer Interfaces (iBCIs) are poised to revolutionize our ability to restore lost neurologic functions. By recording high resolution neural activity from the brain, the intention to move ones hand can be detected and decoded in real- time, potentially providing people with motor neuron disease (ALS), stroke, or spinal cord injury with restored or maintained ability to control communication devices, assistive technologies, and their own limbs. iBCIs also are central to the development of closed-loop neuromodulation systems, with great potential to serve people with neuropsychiatric disorders. A multi-site pilot clinical trial of the investigational BrainGate system is assessing the feasibility of people with tetraplegia controlling a computer cursor and other devices simply by imagining the movement of their own arm or hand. This presentation will review some of the recent progress made in iBCIs, the information that can be decoded from ensembles of cortical or subcortical neurons in real-time, and the challenges and opportunities for restorative neurotechnologies in research and clinical practice.
9 When the spark goes out: the neurology of apathy and motivation
Authors: Husain Masud
Published: July 2021

Disorders of motivation are common across brain disorders. Clinicians frequently encounter pathological apathy across a range of conditions, including many neurodegenerative conditions such as small cerebrovascular disease, Parkinsons and Alzheimers disease. It is now becoming understood that apathy has a poor prognosis for long-term functional and cognitive outcome. Unfortunately, we understand very little about the mechanisms underlying the syndrome.

In this talk, I shall put forward a conceptual framework with which we can begin to understand apathy by considering the processes that normally underlie motivated, goal- directed behavior. In particular Ill focus on the ability to generate options for behavior and effort-based decision making for rewards. Recent studies of the latter have been particularly revealing in both healthy people and neurological patient populations.

Several lines of evidence suggest that when we make decisions about how much effort we might invest in actions, we weigh up the costs involved for the potential rewards to be obtained. Functional imaging in healthy people reveals both medial frontal and basal ganglia involvement when individuals make such decisions. In patients with apathy, this evaluation is altered. Apathetic patients show blunted sensitivity to rewards and less inclination to invest effort for low rewards than healthy individuals. Some evidence shows that these factors can be improved by dopaminergic medication. The findings support the view that it might be possible to provide a mechanistic account of the syndrome of apathy which might lead to treatments for the disorder.
Relationship between flood severity and risk of hospitalisation in the Mekong River Delta of Vietnam
Authors: Phung Dung T , Warren Joshua L , Chu Cordia Ming-Yeuk , Dubrow Robert
Published: July 2021

Objective

To examine the relationship between flood severity and risk of hospitalisation in the Vietnam Mekong River Delta (MRD).

Methods

We obtained data on hospitalisations and hydro-meteorological factors during 2011–2014 for seven MRD provinces. We classified each day into a flood-season exposure period: the 2011 extreme annual flood (EAF); 2012–2014 routine annual floods (RAF); dry season and non-flood wet season (reference period). We used province-specific Poisson regression models to calculate hospitalisation incidence rate ratios (IRRs). We pooled IRRs across provinces using random-effects meta-analysis.

Results

During the EAF, non-external cause hospitalisations increased 7.2% (95% CI 3.2% to 11.4%); infectious disease hospitalisations increased 16.4% (4.3% to 29.8%) and respiratory disease hospitalisations increased 25.5% (15.5% to 36.4%). During the RAF, respiratory disease hospitalisations increased 8.2% (3.2% to 13.5%). During the dry season, hospitalisations decreased for non-external causes and for each specific cause except injuries.

Conclusions

We observed a gradient of decreasing risk of hospitalisation from EAF to RAF/non-flood wet season to dry season. Adaptation measures should be strengthened to prepare for the increased probability of more frequent extreme floods in the future, driven by climate change.
Nitrogen dioxide exposure from domestic gas cooking and airway response in asthmatic women
Authors: Ng T P , Seet C S R , Tan W C , Foo S C
Published: July 2021

BACKGROUND

Previous studies have not found a consistent association between exposure to domestic cooking using gas appliances and exacerbation of asthma. We investigated the immediate airflow response to acute exposure from single episodes of gas cooking, and peak airflow variability from continued exposure to repeated episodes of gas cooking in a group of non-smoking asthmatic women.

METHODS

Sixteen adult non-smoking women with mild to severe persistent asthma were studied. The acute short term level of nitrogen dioxide (NO2) during gas cooking episodes and the mean exposure to NO2from repeated gas cooking episodes were measured over a 2 week period, as well as proxy measures of frequency of cooking on each day and the length of time spent cooking each day. Their asthma status was monitored using peak expiratory flow rates (PEFR) before and after cooking, 2 week self-recorded serial readings of PEFR, respiratory symptom severity score, and use of rescue bronchodilators for acute asthma attacks.

RESULTS

Cooking was significantly associated with an immediate mean fall in PEFR of 3.4% (p=0.015, pairedttest). The acute short term NO2level during cooking was significantly correlated with the fall in PEFR (r=–0.579; p=0.019). The frequency of cooking over a 2 week period was positively correlated with the mean exposure to NO2(r=0.529; p=0.042). Continued exposure to NO2over a 2 week period was associated significantly with increased frequency of rescue bronchodilator usage for asthma attacks (r=0.597; p=0.031). However, it was negatively associated with PEFR variability (r=–0.512; p=0.051) and respiratory symptom severity score (r= –0.567; p=0.043), probably due to the masking effects of bronchodilator treatment.

CONCLUSIONS

Acute short term exposure to NO2from single episodes of gas cooking is associated with immediate airflow limitation. Continued exposure from repeated episodes of gas cooking in asthmatic women is associated with greater use of rescue bronchodilators.
Bedside tracer gas technique accurately predicts outcome in aspiration of spontaneous pneumothorax
Authors: Kiely D G , Ansari S , Davey W A , Mahadevan V , Taylor G J , Seaton D
Published: July 2021

BACKGROUND

There is no technique in general use that reliably predicts the outcome of manual aspiration of spontaneous pneumothorax. We have hypothesised that the absence of a pleural leak at the time of aspiration will identify a group of patients in whom immediate discharge is unlikely to be complicated by early lung re-collapse and have tested this hypothesis by using a simple bedside tracer gas technique.

METHODS

Eighty four episodes of primary spontaneous pneumothorax and 35 episodes of secondary spontaneous pneumothorax were studied prospectively. Patients breathed air containing a tracer (propellant gas from a pressurised metered dose inhaler) while the pneumothorax was aspirated percutaneously. Tracer gas in the aspirate was detected at the bedside using a portable flame ioniser and episodes were categorised as tracer gas positive (>1 part per million of tracer gas) or negative. The presence of tracer gas was taken to imply a persistent pleural leak. Failure of manual aspiration and the need for a further intervention was based on chest radiographic appearances showing either failure of the lung to re-expand or re-collapse following initial re-expansion.

RESULTS

A negative tracer gas test alone implied that manual aspiration would be successful in the treatment of 93% of episodes of primary spontaneous pneumothorax (p<0.001) and in 86% of episodes of secondary spontaneous pneumothorax (p=0.01). A positive test implied that manual aspiration would either fail to re-expand the lung or that early re-collapse would occur despite initial re-expansion in 66% of episodes of primary spontaneous pneumothorax and 71% of episodes of secondary spontaneous pneumothorax. Lung re-inflation on the chest radiograph taken immediately after aspiration was a poor predictor of successful aspiration, with lung re-collapse occurring in 34% of episodes by the following day such that a further intervention was required.

CONCLUSIONS

National guidelines currently recommend immediate discharge of patients with primary spontaneous pneumothorax based primarily on the outcome of the post-aspiration chest radiograph which we have shown to be a poor predictor of early lung re-collapse. Using a simple bedside test in combination with the post-aspiration chest radiograph, we can predict with high accuracy the success of aspiration in achieving sustained lung re-inflation, thereby identifying patients with primary spontaneous pneumothorax who can be safely and immediately discharged home and those who should be observed overnight because of a significant risk of re-collapse, with an estimated re-admission rate of 1%.
Anti-Pseudomonas aeruginosa antibody detection in patients with bronchiectasis without cystic fibrosis
Authors: Caballero E , Drobnic M-E , Pérez M-T , Manresa J-M , Ferrer A , Orriols R
Published: July 2021

BACKGROUND

Pseudomonas aeruginosa is a frequent cause of infection in patients with bronchiectasis. Differentiation between non-infected patients and those with different degrees of P aeruginosainfection could influence the management and prognosis of these patients. The diagnostic usefulness of serum IgG antibodies againstP aeruginosa outer membrane proteins was determined in patients with bronchiectasis without cystic fibrosis.

METHODS

Fifty six patients were classified according to sputum culture into three groups: group A (n=18) with no P aeruginosain any sample; group B (n=18) with P aeruginosa alternating with other microorganisms; and group C (n=20) with P aeruginosa in all sputum samples. Each patient had at least three sputum cultures in the 6 months prior to serum collection. Detection of antibodies was performed by Western blot and their presence against 20 protein bands (10–121 kd) was assessed.

RESULTS

Antibodies to more than four bands in total or to five individual bands (36, 26, 22, 20 or 18 kd) differentiated group B from group A, while antibodies to a total of more than eight bands or to 10 individual bands (104, 69, 63, 56, 50, 44, 30, 25, 22, 13 kd) differentiated group C from group B. When discordant results between the total number of bands and the frequency of P aeruginosa isolation were obtained, the follow up of patients suggested that the former, in most cases, predicted chronic P aeruginosacolonisation.

CONCLUSION

In patients with bronchiectasis the degree of P aeruginosa infection can be determined by the number and type of outer membrane protein bands indicating which serum antibodies are present.
Effects of one dark septate endophytic fungal and two Helotiales strains on the growth of plane-leaved willow (Salix planifolia) cuttings on iron ore waste rock
Authors: Jean Roudy , Khasa Damase Phambu , Boudreau Stéphane
Published: July 2021

Plants maintain beneficial mutualistic relationships with the mycobiont communities found in their rhizosphere, leading to an increase in plant productivity and health. In nutrient-depleted substrates like mine tailings, mycobiont inoculation is often recommended to help restore a successful plant cover. Our 15-week greenhouse experiment aimed to assess the individual effects of a dark septate endophyte (Phialocephala fortinii C.J.K. Wang & H.E. Wilcox #4 (KX611529)) and two Helotiales strains (Rhizoscyphus ericae (D.J. Read) W.Y. Zhuang & Korf #22 (EU221877) and Meliniomyces sp. #1 (KT275679)) on the growth of plane-leaved willow (Salix planifolia Pursh) cuttings on sterilized and unsterilized waste rock. Rhizoscyphus ericae increased shoot biomass of cuttings on sterilized waste rock, whereas Meliniomyces sp. had a positive effect on cuttings grown on unsterilized waste rock. However, P. fortinii strain had no effect on the survival rate, shoot production, and biomass production of S. planifolia cuttings. This study demonstrates that controlled inoculation with ecologically well-adapted mycobionts could promote plant establishment and productivity on abandoned waste rock and could be an efficient and integrated biotechnological approach for ecological restoration of Canadian mining boreal ecosystems.