bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of masks, testing and contact tracing in preventing COVID-19 resurgences: a case study from New South Wales, Australia
Authors: Stuart Robyn M , Abeysuriya Romesh G , Kerr Cliff C , Mistry Dina , Klein Dan J , Gray Richard T , Hellard Margaret , Scott Nick 
Published: April 2021

ObjectivesThe early stages of the COVID-19 pandemic illustrated that SARS-CoV-2, the virus that causes the disease, has the potential to spread exponentially. Therefore, as long as a substantial proportion of the population remains susceptible to infection, the potential for new epidemic waves persists even in settings with low numbers of active COVID-19 infections, unless sufficient countermeasures are in place. We aim to quantify vulnerability to resurgences in COVID-19 transmission under variations in the levels of testing, tracing and mask usage.SettingThe Australian state of New South Wales (NSW), a setting with prolonged low transmission, high mobility, non-universal mask usage and a well-functioning test-and-trace system.ParticipantsNone (simulation study).ResultsWe find that the relative impact of masks is greatest when testing and tracing rates are lower and vice versa. Scenarios with very high testing rates (90% of people with symptoms, plus 90% of people with a known history of contact with a confirmed case) were estimated to lead to a robustly controlled epidemic. However, across comparable levels of mask uptake and contact tracing, the number of infections over this period was projected to be 2–3 times higher if the testing rate was 80% instead of 90%, 8–12 times higher if the testing rate was 65% or 30–50 times higher with a 50% testing rate. In reality, NSW diagnosed 254 locally acquired cases over this period, an outcome that had a moderate probability in the model (10%–18%) assuming low mask uptake (0%–25%), even in the presence of extremely high testing (90%) and near-perfect community contact tracing (75%–100%), and a considerably higher probability if testing or tracing were at lower levels.ConclusionsOur work suggests that testing, tracing and masks can all be effective means of controlling transmission. A multifaceted strategy that combines all three, alongside continued hygiene and distancing protocols, is likely to be the most robust means of controlling transmission of SARS-CoV-2.
Conducting an ongoing HIV clinical trial during the COVID-19 pandemic in Uganda: a qualitative study of research team and participants’ experiences and lessons learnt
Authors: Muwanguzi Patience A , Kutyabami Paul , Osingada Charles Peter , Nasuuna Esther M , Kitutu Freddy Eric , Ngabirano Tom Denis , Nankumbi Joyce , Muhindo Richard , Kabiri Lydia , Namutebi Mariam , Nabunya Racheal , Kiwanuka Noah , Sewankambo Nelson 
Published: April 2021

ObjectiveTo explore the experiences and lessons learnt by the study team and participants of the Workplace-based HIV self-testing among Men trial during the COVID-19 pandemic in Uganda.DesignAn explorative qualitative study comprising two virtual focus group discussions (FGDs) with 12 trial team members and 32 in-depth participant interviews (N=44). Data were collected via telephone calls for in-depth interviews or Zoom for FGDs and manually analysed by inductive content analysis.SettingFourteen private security companies in two Uganda districts.ParticipantsMembers of the clinical trial study team, and men working in private security companies who undertook workplace-based HIV testing.ResultsThe key themes for participants experiences were: ‘challenges in accessing HIV treatment and care, and prevention services’, ‘misinformation’ and ‘difficulty participating in research activities’. The effects on HIV treatment and prevention resulted from; repercussions of the COVID-19 restrictions, participants fear of coinfection and negative experiences at health facilities. The difficulty in participating in research activities arose from: fear of infection with COVID-19 for the participants who tested HIV negative, transport difficulties, limited post-test psychosocial support and lack of support to initiate pre-exposure prophylaxis. The key study team reflections focused on the management of the clinical trial, effects of the local regulations and government policies and the need to adhere to ethical principles of research.ConclusionsFindings highlight the need to organise different forms of HIV support for persons living with HIV during a pandemic. Additionally, the national research regulators and ethics committees or review boards are strongly urged to develop policies and guidelines for the continuity of research and clinical trials in the event of future shocks. Furthermore, this study calls on the appropriate government agencies to ensure public and researchers’ preparedness through continuing education and support.Trial registration numberClinicaltrials.gov NCT04164433; Pre-results.
Protocol for The Toxin Study: Understanding clinical and patient reported response of children and young people with cerebral palsy to intramuscular lower limb Botulinum neurotoxin-A injections, exploring all domains of the ICF. A pragmatic longitudinal observational study using a prospective one-group repeated measures design
Authors: Katchburian Lesley R , Oulton Kate , Main Eleanor , Morris Christopher , Carr Lucinda J 
Published: April 2021

IntroductionBotulinum neurotoxin-A (BoNT-A) is an accepted treatment modality for the management of hypertonia in children and young people with cerebral palsy (CYPwCP). Nevertheless, there are concerns about the long-term effects of BoNT-A, with a lack of consensus regarding the most meaningful outcome measures to guide its use. Most evidence to date is based on short-term outcomes, related to changes at impairment level (restrictions of body functions and structures), rather than changes in adaptive skills (enabling both activity and participation). The proposed study aims to evaluate clinical and patient reported outcomes in ambulant CYPwCP receiving lower limb BoNT-A injections over a 12-month period within all domains of the WHO’s International Classification of Functioning, Disability and Health and health-related quality of life (HRQoL).Methods and analysisThis pragmatic prospective longitudinal observational study will use a one-group repeated measures design. Sixty CYPwCP, classified as Gross Motor Function Classification System (GMFCS) levels I–III, aged between 4 and 18 years, will be recruited from an established movement disorder service in London, UK. Standardised clinical and patient reported outcome measures within all ICF domains; body structures and function, activity (including quality of movement), goal attainment, participation and HRQoL, will be collected preinjection and at 6 weeks, 6 months and up to 12 months postinjection. A representative subgroup of children and carers will participate in a qualitative component of the study, exploring how their experience of BoNT-A treatment relates to clinical outcome measures.Ethics and disseminationCentral London Research Ethics Committee has granted ethics approval (#IRAS 211617 #REC 17/LO/0579). Findings will be disseminated in peer-reviewed publications, conferences and via networks to participants and relevant stakeholders using a variety of accessible formats including social media.
Diagnosis of coeliac disease by flow cytometry of intraepithelial lymphocytes: a new ‘gold’ standard?
Authors: Basu Kaninika , Creasey Hannah , Bruggemann Nina , Stevens Jennifer , Bloxham David , Woodward Jeremy Mark 
Published: April 2021

ObjectiveThe analysis of intraepithelial lymphocytes (IELs) by flow cytometry of duodenal biopsies—the ‘IEL’ lymphogram—has been proposed as a diagnostic test for coeliac disease. However, its clinical applicability has been limited due to variability in methods and definitions. This study set out to define useful parameters for the application of the IEL lymphogram to the diagnosis of coeliac disease.DesignFlow cytometry was performed on 117 sets of duodenal biopsies in 107 adult patients with active coeliac disease, long-term coeliac disease on a gluten free diet and a control group. The initial 95 samples were used for hypothesis generation for the subsequent samples comprising 12 patients with coeliac disease and 10 controls.ResultsRather than using single linear cut-offs for CD3 and T-cell receptor γδ (TCRγδ)+ve IELs, a discriminant function was identified as %CD3+ve IELs+2x(%TCRγδ+IELs)>100. This differentiated coeliac disease from control biopsies in the hypothesis generating group. These results were replicated in the validation group and found to be independent of histology in patients on long-term gluten free diet up to 12 years (combined sensitivity, 98.5%; specificity, 97.7%).ConclusionsFlow cytometric analysis of IELs is a highly sensitive and specific adjunct to serology and histological examination for the diagnosis of coeliac disease, even in individuals with coeliac disease following a gluten free diet who exhibit normal duodenal histology.
Personalised virtual gene panels reduce interpretation workload and maintain diagnostic rates of proband-only clinical exome sequencing for rare disorders
Authors: Molina-Ramírez Leslie Patricia , Kyle Claire , Ellingford Jamie M , Wright Ronnie , Taylor Algy , Bhaskar Sanjeev S , Campbell Christopher , Jackson Harriet , Fairclough Adele , Rousseau Abigail , Burghel George J , Dutton Laura , Banka Siddharth , Briggs Tracy A , Clayton-Smith Jill , Douzgou Sofia , Jones Elizabeth A , Kingston Helen M , Kerr Bronwyn , Ealing John , Somarathi Suresh , Chandler Kate E , Stuart Helen M , Burkitt-Wright Emma MM , Newman William G , Bruce Iain A , Black Graeme C , Gokhale David 
Published: April 2021

PurposeThe increased adoption of genomic strategies in the clinic makes it imperative for diagnostic laboratories to improve the efficiency of variant interpretation. Clinical exome sequencing (CES) is becoming a valuable diagnostic tool, capable of meeting the diagnostic demand imposed by the vast array of different rare monogenic disorders. We have assessed a clinician-led and phenotype-based approach for virtual gene panel generation for analysis of targeted CES in patients with rare disease in a single institution.MethodsRetrospective survey of 400 consecutive cases presumed by clinicians to have rare monogenic disorders, referred on singleton basis for targeted CES. We evaluated diagnostic yield and variant workload to characterise the usefulness of a clinician-led approach for generation of virtual gene panels that can incorporate up to three different phenotype-driven gene selection methods.ResultsAbnormalities of the nervous system (54.5%), including intellectual disability, head and neck (19%), skeletal system (16%), ear (15%) and eye (15%) were the most common clinical features reported in referrals. Combined phenotype-driven strategies for virtual gene panel generation were used in 57% of cases. On average, 7.3 variants (median=5) per case were retained for clinical interpretation. The overall diagnostic rate of proband-only CES using personalised phenotype-driven virtual gene panels was 24%.ConclusionsOur results show that personalised virtual gene panels are a cost-effective approach for variant analysis of CES, maintaining diagnostic yield and optimising the use of resources for clinical genomic sequencing in the clinic.
Randomised study of PF-06410293, an adalimumab (ADL) biosimilar, compared with reference ADL for the treatment of active rheumatoid arthritis: results from weeks 26–52, including a treatment switch from reference ADL to PF-06410293
Authors: Fleischmann Roy M , Alvarez Daniel F , Bock Amy E , Cronenberger Carol , Vranic Ivana , Zhang Wuyan , Alten Rieke 
Published: April 2021

ObjectiveTo investigate the efficacy, safety, immunogenicity and pharmacokinetics of biosimilar adalimumab (ADL) PF-06410293 (ADL-PF; adalimumab-afzb) versus EU-sourced reference ADL (ADL-EU) in patients with active rheumatoid arthritis (RA) on longer-term treatment and after being switched from ADL-EU to ADL-PF.MethodsIn this multinational, double-blind study, patients with active RA were initially randomised to ADL-PF or ADL-EU for 26 weeks (treatment period (TP) 1). At the start of TP2 (weeks 26–52), patients in the ADL-EU arm were blindly re-randomised 1:1 to remain on ADL-EU (ADL-EU/ADL-EU; n=135) or switched to ADL-PF (ADL-EU/ADL-PF; n=134); patients receiving ADL-PF continued blinded treatment (ADL-PF/ADL-PF; n=283).ResultsThe American College of Rheumatology 20% improvement (ACR20) response rates were comparable between treatment groups at all visits during TP2. At week 52, ACR20 response rates were 82.7% (ADL-PF/ADL-PF), 79.3% (ADL-EU/ADL-EU) and 84.3% (ADL-EU/ADL-PF). Other measures of deep response (ACR50/70, ACR/EULAR-defined remission, EULAR good response, and Disease Activity Score in 28 Joints Based on High-Sensitivity C-Reactive Protein <2.6) and Health Assessment Questionnaire−Disability Index were maintained over TP2 and comparable between groups. Treatment-emergent adverse events were reported in 43.5% (ADL-PF/ADL-PF), 44.4% (ADL-EU/ADL-EU) and 38.3% (ADL-EU/ADL-PF) of patients; there were no clinically meaningful differences in the safety profiles between groups. The percentage of patients who were antidrug antibody positive was comparable overall among ADL-PF/ADL-PF (47.3%), ADL-EU/ADL-EU (54.1%) and ADL-EU/ADL-PF (45.9%).ConclusionsThe similar efficacy, safety, immunogenicity and pharmacokinetics of ADL-PF and ADL-EU, maintained up to week 52, were unaffected by blinded treatment switch from ADL-EU to ADL-PF at week 26.Trial registration numberClinicalTrials.gov identifier:NCT02480153; EudraCT number: 2014-000352-29.
Sphingosine kinase 1 regulates lysyl oxidase through STAT3 in hyperoxia-mediated neonatal lung injury
Authors: Ha Alison W , Bai Tao , Ebenezer David L , Sethi Tanvi , Sudhadevi Tara , Mangio Lizar Ace , Garzon Steven , Pryhuber Gloria S , Natarajan Viswanathan , Harijith Anantha 
Published: April 2021

IntroductionNeonatal lung injury as a consequence of hyperoxia (HO) therapy and ventilator care contribute to the development of bronchopulmonary dysplasia (BPD). Increased expression and activity of lysyl oxidase (LOX), a key enzyme that cross-links collagen, was associated with increased sphingosine kinase 1 (SPHK1) in human BPD. We, therefore, examined closely the link between LOX and SPHK1 in BPD.MethodThe enzyme expression of SPHK1 and LOX were assessed in lung tissues of human BPD using immunohistochemistry and quantified (Halo). In vivo studies were based on Sphk1−/− and matched wild type (WT) neonatal mice exposed to HO while treated with PF543, an inhibitor of SPHK1. In vitro mechanistic studies used human lung microvascular endothelial cells (HLMVECs).ResultsBoth SPHK1 and LOX expressions were increased in lungs of patients with BPD. Tracheal aspirates from patients with BPD had increased LOX, correlating with sphingosine-1-phosphate (S1P) levels. HO-induced increase of LOX in lungs were attenuated in both Sphk1−/− and PF543-treated WT mice, accompanied by reduced collagen staining (sirius red). PF543 reduced LOX activity in both bronchoalveolar lavage fluid and supernatant of HLMVECs following HO. In silico analysis revealed STAT3 as a potential transcriptional regulator of LOX. In HLMVECs, following HO, ChIP assay confirmed increased STAT3 binding to LOX promoter. SPHK1 inhibition reduced phosphorylation of STAT3. Antibody to S1P and siRNA against SPNS2, S1P receptor 1 (S1P1) and STAT3 reduced LOX expression.ConclusionHO-induced SPHK1/S1P signalling axis plays a critical role in transcriptional regulation of LOX expression via SPNS2, S1P1 and STAT3 in lung endothelium.
Realizing high-efficiency low frequency sound absorption of underwater meta-structures by acoustic siphon effect
Authors: Wang Li Bo , Ma Cheng Zhi , Wu Jiu Hui , Liu Chong Rui 
Published: April 2021

The underwater acoustic siphon effect is proposed in this work, which aims to reveal the basic physical mechanism of high-efficiency sound absorption in meta-structures composed of multiple detuned units. Furthermore, the influence of the area ratio on the underwater acoustic siphon effect is then investigated by finite element simulation (FES) and theoretical calculation. On this basis, a meta-structure with the maximum absorption coefficient of almost 100% and average absorption coefficient of 80% at 600–1400 Hz is achieved. The underwater acoustic siphon effect could provide a better understanding of high-efficiency sound absorption and offer a new perspective in controlling underwater noises.
TipTap: Approximate Mining of Frequent
k
-Subgraph Patterns in Evolving Graphs
Authors: Nasir Muhammad Anis Uddin , Aslay Cigdem , Morales Gianmarco De Francisci , Riondato Matteo 
Published: April 2021

“Perhaps he could dance first and think afterwards, if it isn’t too much to ask him.”

S. Beckett,
Waiting for Godot

Given a labeled graph, the collection of
k
-vertex induced connected subgraph patterns that appear in the graph more frequently than a user-specified minimum threshold provides a compact summary of the characteristics of the graph, and finds applications ranging from biology to network science. However, finding these patterns is challenging, even more so for dynamic graphs that evolve over time, due to the streaming nature of the input and the exponential time complexity of the problem.

We study this task in both incremental and fully-dynamic streaming settings, where arbitrary edges can be added or removed from the graph. We present
TipTap
, a suite of algorithms to compute high-quality approximations of the frequent
k
-vertex subgraphs w.r.t. a given threshold, at any time (i.e., point of the stream), with high probability. In contrast to existing state-of-the-art solutions that require iterating over the entire set of subgraphs in the vicinity of the updated edge,
TipTap
operates by efficiently maintaining a uniform sample of connected
k
-vertex subgraphs, thanks to an optimized neighborhood-exploration procedure. We provide a theoretical analysis of the proposed algorithms in terms of their unbiasedness and of the sample size needed to obtain a desired approximation quality. Our analysis relies on sample-complexity bounds that use Vapnik–Chervonenkis dimension, a key concept from statistical learning theory, which allows us to derive a sufficient sample size that is independent from the size of the graph. The results of our empirical evaluation demonstrates that
TipTap
returns high-quality results more efficiently and accurately than existing baselines.
Bone Marrow Mesenchymal Stromal Cells Can Render Multiple Myeloma Cells Resistant to Cytotoxic Machinery of CAR T Cells through Inhibition of Apoptosis
Authors: Holthof Lisa C. , van der Schans Jort J. , Katsarou Afroditi , Poels Renée , Gelderloos Anne T. , Drent Esther , van Hal-van Veen Susan E. , Li Fengzhi , Zweegman Sonja , van de Donk Niels W.C.J. , Themeli Maria , Groen Richard W.J. , Mutis Tuna 
Published: April 2021

Abstract

Purpose:
The microenvironment of multiple myeloma (MM) can critically impair therapy outcome, including immunotherapies. In this context, we have earlier demonstrated that bone marrow mesenchymal stromal cells (BMMSC) protect MM cells against the lytic machinery of MM-reactive cytotoxic T cells (CTL) and daratumumab-redirected natural killer (NK) cells through the upregulation of antiapoptotic proteins Survivin and Mcl-1 in MM cells. Here, we investigated the significance of this mode of immune escape on T cells engineered to express chimeric antigen receptors (CAR T cells).

Experimental Design:
We tested the cytolytic ability of a panel of 10 BCMA-, CD38-, and CD138-specific CAR T cells with different affinities against a model MM cell line and against patient-derived MM cells in the presence versus absence of BMMSCs.

Results:
Although BMMSCs hardly protected MM cells from lysis by high-affinity, strongly lytic BCMA- and CD38-CAR T cells, they significantly protected against lower affinity, moderately lytic BCMA-, CD38-, and CD138-specific CAR T cells in a cell–cell contact-dependent manner. Overall, there was a remarkable inverse correlation between the protective ability of BMMSCs and the lytic activity of all CAR T cells, which was dependent on CAR affinity and type of costimulation. Furthermore, BMMSC-mediated resistance against CAR T cells was effectively modulated by FL118, an inhibitor of antiapoptotic proteins Survivin, Mcl-1, and XIAP.

Conclusions:
These results extend our findings on the negative impact of the microenvironment against immunotherapies and suggest that outcome of CAR T cell or conventional CTL therapies could benefit from inhibition of antiapoptotic proteins upregulated in MM cells through BMMSC interactions.
Lutetium-177-PSMA-617 in Low-Volume Hormone-Sensitive Metastatic Prostate Cancer: A Prospective Pilot Study
Authors: Privé Bastiaan M. , Peters Steffie M.B. , Muselaers Constantijn H.J. , van Oort Inge M. , Janssen Marcel J.R. , Sedelaar J.P. Michiel , Konijnenberg Mark W. , Zámecnik Patrik , Uijen Maike J.M. , Schilham Melline G.M. , Eek Annemarie , Scheenen Tom W.J. , Verzijlbergen J. Fred , Gerritsen Winald R. , Mehra Niven , Kerkmeijer Linda G.W. , Smeenk Robert J. , Somford Diederik M. , van Basten Jean-Paul A. , Heskamp Sandra , Barentsz Jelle O. , Gotthardt Martin , Witjes J. Alfred , Nagarajah James 
Published: April 2021

Abstract

Purpose:
[177Lu]Lu-PSMA-617 radioligand therapy (177Lu-PSMA) is a novel treatment for metastatic castration-resistant prostate cancer (mCRPC), which could also be applied to patients with metastatic hormone-sensitive prostate cancer (mHSPC) with PSMA expression. In this prospective study (NCT03828838), we analyzed toxicity, radiation doses, and treatment effect of 177Lu-PSMA in pateints with low-volume mHSPC.

Patients and Methods:
Ten progressive patients with mHSPC following local treatment, with a maximum of ten metastatic lesions on [68Ga]Ga-PSMA-11 PET/diagnostic-CT imaging (PSMA-PET) and serum PSA doubling time &lt;6 months received two cycles of 177Lu-PSMA. Whole-body single-photon emission CT/CT (SPECT/CT) and blood dosimetry was performed to calculate doses to the tumors and organs at risk (OAR). Adverse events (AE), laboratory values (monitoring response and toxicity), and quality of life were monitored until week 24 after cycle 2, the end of study (EOS). All patients underwent PSMA-PET at screening, 8 weeks after cycle 1, 12 weeks after cycle 2, and at EOS.

Results:
All patients received two cycles of 177Lu-PSMA without complications. No treatment-related grade III–IV adverse events were observed. According to dosimetry, none of the OAR reached threshold doses for radiation-related toxicity. Moreover, all target lesions received a higher radiation dose than the OAR. All 10 patients showed altered PSA kinetics, postponed androgen deprivation therapy, and maintained good quality of life. Half of the patients showed a PSA response of more than 50%. One patient had a complete response on PSMA-PET imaging until EOS and two others had only minimal residual disease.

Conclusions:
177Lu-PSMA appeared to be a feasible and safe treatment modality in patients with low-volume mHSPC.