bluuebunny/crossref_metadata_2025_split huggingface dataset:
Simultaneous induction of vasculature and neuronal network formation on a chip reveals a dynamic interrelationship between cell types
Authors: Isosaari Lotta , Vuorenpää Hanna , Yrjänäinen Alma , Kapucu Fikret Emre , Kelloniemi Minna , Pakarinen Toni-Karri , Miettinen Susanna , Narkilahti Susanna 
Published: June 2023

Abstract
Background
Neuronal networks receive and deliver information to regulate bodily functions while the vascular network provides oxygen, nutrients, and signaling molecules to tissues. Neurovascular interactions are vital for both tissue development and maintaining homeostasis in adulthood; these two network systems align and reciprocally communicate with one another. Although communication between network systems has been acknowledged, the lack of relevant in vitro models has hindered research at the mechanistic level. For example, the current used in vitro neurovascular models are typically established to be short-term (≤ 7 days) culture models, and they miss the supporting vascular mural cells.

Methods
In this study, we utilized human induced pluripotent stem cell (hiPSC) -derived neurons, fluorescence tagged human umbilical vein endothelial cells (HUVECs), and either human bone marrow or adipose stem/stromal cells (BMSCs or ASCs) as the mural cell types to create a novel 3D neurovascular network-on-a-chip model. Collagen 1–fibrin matrix was used to establish long-term (≥ 14 days) 3D cell culture in a perfusable microphysiological environment.

Results
Aprotinin-supplemented endothelial cell growth medium-2 (EGM-2) supported the simultaneous formation of neuronal networks, vascular structures, mural cell differentiation, and the stability of the 3D matrix. The formed neuronal and vascular networks were morphologically and functionally characterized. Neuronal networks supported vasculature formation based on direct cell contacts and by dramatically increasing the secretion of angiogenesis-related factors in multicultures in contrast to cocultures without neurons. Both utilized mural cell types supported the formation of neurovascular networks; however, the BMSCs seemed to boost neurovascular networks to greater extent.

Conclusions
Overall, our study provides a novel human neurovascular network model that is applicable for creating in vivo-like tissue models with intrinsic neurovascular interactions. The 3D neurovascular network model on chip forms an initial platform for the development of vascularized and innervated organ-on-chip and further body-on-chip concepts and offers the possibility for mechanistic studies on neurovascular communication both under healthy and in disease conditions.
Disentangling the impact of cerebrospinal fluid formation and neuronal activity on solute clearance from the brain
Authors: Segeroth Martin , Wachsmuth Lydia , Gagel Mathias , Albers Franziska , Hess Andreas , Faber Cornelius 
Published: June 2023

Abstract
Background
Despite recent attention, pathways and mechanisms of fluid transposition in the brain are still a matter of intense discussion and driving forces underlying waste clearance in the brain remain elusive. Consensus exists that net solute transport is a prerequisite for efficient clearance. The individual impact of neuronal activity and cerebrospinal fluid (CSF) formation, which both vary with brain state and anesthesia, remain unclear.

Methods
To separate conditions with high and low neuronal activity and high and low CSF formation, different anesthetic regimens in naive rat were established, using Isoflurane (ISO), Medetomidine (MED), acetazolamide or combinations thereof. With dynamic contrast-enhanced MRI, after application of low molecular weight contrast agent (CA) Gadobutrol to cisterna magna, tracer distribution was monitored as surrogate for solute clearance. Simultaneous fiber-based Ca2+-recordings informed about the state of neuronal activity under different anesthetic regimen. T2-weighted MRI and diffusion-weighted MRI (DWI) provided size of subarachnoidal space and aqueductal flow as surrogates for CSF formation. Finally, a pathway and mechanism-independent two-compartment model was introduced to provide a measure of efficiency for solute clearance from the brain.

Results
Anatomical imaging, DWI and Ca2+-recordings confirmed that conditions with distinct levels of neuronal activity and CSF formation were achieved. A sleep-resembling condition, with reduced neuronal activity and enhanced CSF formation was achieved using ISO+MED and an awake-like condition with high neuronal activity using MED alone. CA distribution in the brain correlated with the rate of CSF formation. The cortical brain state had major influence on tracer diffusion. Under conditions with low neuronal activity, higher diffusivity suggested enlargement of extracellular space, facilitating a deeper permeation of solutes into brain parenchyma. Under conditions with high neuronal activity, diffusion of solutes into parenchyma was hindered and clearance along paravascular pathways facilitated. Exclusively based on the measured time signal curves, the two-compartment model provided net exchange ratios, which were significantly larger for the sleep-resembling condition than for the awake-like condition.

Conclusions
Efficiency of solute clearance in brain changes with alterations in both state of neuronal activity and CSF formation. Our clearance pathway and mechanism agnostic kinetic model informs about net solute transport, solely based on the measured time signal curves. This rather simplifying approach largely accords with preclinical and clinical findings.
Participant retention in paediatric randomised controlled trials published in six major journals 2015–2019: systematic review and meta-analysis
Authors: Gaunt Daisy M. , Papastavrou Brooks Cat , Pedder Hugo , Crawley Esther , Horwood Jeremy , Metcalfe Chris 
Published: June 2023

Abstract
Background
The factors which influence participant retention in paediatric randomised controlled trials are under-researched. Retention may be more challenging due to child developmental stages, involving additional participants, and proxy-reporting of outcomes. This systematic review and meta-analysis explores the factors which may influence retention in paediatric trials.

Methods
Using the MEDLINE database, paediatric randomised controlled trials published between 2015 and 2019 were identified from six general and specialist high-impact factor medical journals. The review outcome was participant retention for each reviewed trial’s primary outcome. Context (e.g. population, disease) and design (e.g. length of trial) factors were extracted. Retention was examined for each context and design factor in turn, with evidence for an association being determined by a univariate random-effects meta-regression analysis.

Results
Ninety-four trials were included, and the median total retention was 0.92 (inter-quartile range 0.83 to 0.98). Higher estimates of retention were seen for trials with five or more follow-up assessments before the primary outcome, those less than 6 months between randomisation and primary outcome, and those that used an inactive data collection method. Trials involving children aged 11 and over had the higher estimated retention compared with those involving younger children. Those trials which did not involve other participants also had higher retention, than those where they were involved. There was also evidence that a trial which used an active or placebo control treatment had higher estimated retention, than treatment-as-usual. Retention increased if at least one engagement method was used. Unlike reviews of trials including all ages of participants, we did not find any association between retention and the number of treatment groups, size of trial, or type of treatment.

Conclusions
Published paediatric RCTs rarely report the use of specific modifiable factors that improve retention. Including multiple, regular follow-ups with participants before the primary outcome may reduce attrition. Retention may be highest when the primary outcome is collected up to 6 months after a participant is recruited. Our findings suggest that qualitative research into improving retention when trials involve multiple participants such as young people, and their caregivers or teachers would be worthwhile. Those designing paediatric trials also need to consider the use of appropriate engagement methods.

Research on Research (RoR) registry
https://ror-hub.org/study/2561
Systemic lupus erythematosus presenting as lupus erythematosus tumidus and lupus nephritis: a case report
Authors: Hajji Meriam , Gorsane Imen , Badrouchi Samaraa , Litaiem Noureddine , Rammeh Soumaya , Ben Hamida Fethi , Abderrahim Ezzeddine 
Published: June 2023

Abstract
Background
Lupus nephritis and lupus erythematosus tumidus (LET) are uncommon manifestations of systemic lupus erythematosus (SLE), and their coexistence as the initial presentation of SLE is exceedingly rare. Here, we report such a case, emphasizing the diagnostic challenges and therapeutic implications of this unusual association.

Case report
A 38-year-old North African woman presented in Nephrology department with a history of lower extremity edema, fatigue, and weight loss of 3 kg in 4 weeks. Physical examination revealed LET lesions on the chest and the Neck. Laboratory investigations showed lymphopenia, low C3 and C4 complement levels, positive antinuclear antibodies, anti-dsDNA antibodies, and anti-SSA/Ro antibodies. Renal function tests showed normal serum creatinine and nephrotic proteinuria. Renal biopsy revealed Class V lupus nephritis. Skin biopsy confirmed the diagnosis of LET, with the presence of lymphohistiocytic infiltrates and dermal mucin. The patient was diagnosed with SLE based on the 2019 EULAR/ACR criteria and treated with prednisone (1 mg/kg/day) and hydroxychloroquine. She showed significant improvement in her cutaneous and renal symptoms at 6 and 12 months follow-up.

Conclusion
The rarity of the coexistence of LET and lupus nephritis as the initial manifestation of SLE, especially in the North African population, underscores the need for further research to elucidate the immunopathogenic mechanisms and prognostic factors associated with this association.
On Orlicz sequence algebras
Authors: Foralewski Paweł , Piszczek Krzysztof 
Published: June 2023

AbstractWe study Orlicz sequence algebras and their properties. In particular, we fully characterize biflat and biprojective Orlicz sequence algebras as well as weakly amenable and approximately (semi-)amenable Orlicz sequence algebras. As a consequence, we show the existence of a wide class of sequence algebras that behave differently—in terms of the amenability properties—from any of the algebras$\ell _{p}, 1\leqslant p\leqslant \infty $ℓp,1⩽p⩽∞.
Non-rigorous versus rigorous home confinement differently impacts mental health, quality of life and behaviors. Which one was better? A cross-sectional study with older Brazilian adults during covid-19 first wave
Authors: Bohn Lucimere , Abdalla Pedro Pugliesi , Gomide Euripedes Barsanulfo Gonçalves , da Silva Leonardo Santos Lopes , dos Santos André Pereira 
Published: June 2023

Abstract
Background
The implementation of social distancing measures during covid-19 influenced health outcomes and population´s behaviors, and its rigidity was very different across countries. We aimed to verify the association between the rigidity of social distancing measures of covid-19 first wave with depression symptoms, quality of life and sleep quality in older adults.

Methods
This is a cross-sectional study including 1023 older adults (90% women; 67.68 ± 5.92 years old) of a community-based program in Fortaleza (Brazil). Dependent variables (depression symptoms, sleep quality, and quality of life) were measured through phone calls along June 2020, during the first covid-19 wave. Confinement rigidity (non-rigorous and rigorous) was considered as independent variable. Sociodemographic characteristics (sex, marital status, scholarity, and ethnicity), number of health conditions, nutritional status, movement behavior (physical activity and sitting time), technological skills, and pet ownership were considered as confounding variables. A binomial logistic regression (odds ratio [OR]) was performed to verify the association of confinement rigidity and depression symptoms, sleep quality, and quality of life, adjusted by confounding variables.

Results
Older adults who adopted a less rigid lockdown had a higher frequency of depression symptoms, worse perception of quality of life, and bad sleep quality (p < 0.001). Confinement rigidity was able to explain the probability of depression symptoms occurrence (OR: 2.067 [95% CI: 1.531–2.791]; p < 0.001), worse quality of life (OR: 1.488 [95% CI: 1.139–1.944]; p < 0.05), and bad sleep quality (OR: 1.839 [95% CI: 1.412–2.395]; p < 0.001). Even adjusted by confounding variables, confinement rigidity was able to explain the poor outcomes analyzed in older adults.

Conclusion
Our findings showed that less rigid lockdown was associated with a superior frequency of depression symptoms, worse sleep quality, and lower perception of quality of life in older adults. Therefore, our study could improve comprehension regarding the impact of social distancing measures rigidity in health-related conditions and in the context of covid-19 and other similar pandemic situations.
Reuse of shipping materials in the intravitreal bevacizumab supply chain: feasibility, cost, and environmental impact
Authors: Vo Loi V. , Mastrorilli Vanessa , Muto Alfonse J. , Emerson Geoffrey G. 
Published: June 2023

Abstract
Background
Intravitreal injections are the most common ophthalmic procedure worldwide and are also a prime opportunity for waste reduction. This study analyzes the feasibility, environmental impact, and cost of reusing shipping materials for intravitreal injection medications, as compared to wasting coolers and cold packs after single-use.

Methods
In this prospective pilot study, shipping materials (cardboard boxes, polystyrene foam coolers, and cold packs) from repackaged bevacizumab delivered to our clinic (500 doses per week) were saved and reused over a 10-week study period. The shipping supplies were photographed and inspected for defects at point of care (Twin Cities, MN), and returned via standard ground shipping to the outsourcing facility (Tonawanda, NY).

Results
Polystyrene foam coolers (n = 3) survived 10 roundtrips between the outsourcing facility and retina clinic (600 mi each way), although wear-and-tear was visible in the form of marks and dents. Cold packs (n = 35) were less durable, lasting 3.1 ± 2.0 roundtrips. Total carbon dioxide equivalent (CO2e) emissions were reduced 43%, by reusing shipping materials (12.88 kgCO2e per 1000 bevacizumab doses), as compared to the standard practice of disposing containers after single-use (22.70 kgCO2e per 1000 bevacizumab doses), and landfill volume was reduced by 89%. Cost savings from reusing containers offset expenses incurred with return shipping and extra handling in the reuse cohort (net savings: $0.52 per 1000 bevacizumab doses).

Conclusions
Reusing shipping supplies can be cost neutral, with less CO2e emissions and reduced landfill. Robust environmental benefit is possible if retina clinics partner with manufacturers to reuse shipping containers.
Updated efficacy and safety of entrectinib in patients (pts) with locally advanced/metastatic NTRK fusion-positive (fp) non-small cell lung cancer (NSCLC).
Authors: Cho Byoung Chul , Chiu Chao-Hua , Massarelli Erminia , Buchschacher Gary L , Goto Koichi , Overbeck Tobias R. , Loong Herbert H. F. , Chee Cheng E. , Garrido Pilar , Heinzmann Sebastian , Bordogna Walter , Zeuner Harald , Osborne Stuart , John Tom 
Published: June 2023

9047 Background: NTRK fusions, encoding for constitutively active oncogenic tropomyosin receptor kinase proteins, are present in many solid tumors, including NSCLC. As central nervous system (CNS) metastases are common in pts with advanced NSCLC, treatments with intracranial efficacy are needed. Entrectinib, a potent CNS-active tyrosine kinase inhibitor, has previously demonstrated efficacy in pts with NTRK-fp NSCLC in an integrated analysis of three phase I/II trials (ALKA-372-001 [EudraCT, 2012-000148–88], STARTRK-1 [NCT02097810], STARTRK-2 [NCT02568267]); objective response rate (ORR) was 63.6% (14/22; data cutoff: August 31 2020). We present updated data for this cohort. Methods: Pts ≥18 years old with locally advanced/metastatic NTRK-fp tumors were enrolled and received 600 mg oral entrectinib until disease progression, toxicity, or death. At Week 4 and then every 8 weeks, tumour response was assessed by blinded independent central review (BICR) per RECIST v1.1. Co-primary endpoints were ORR and duration of response (DoR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), intracranial efficacy, and safety. Enrolment cutoff: July 2 2020; data cutoff: August 2 2021. Results: The efficacy-evaluable population included 31 pts with NTRK-fp NSCLC. Median age was 60.0 years (range 22–88); 26 pts (83.9%) had adenocarcinoma; 11 pts (35.5%) had ≥2 prior lines of systemic therapy; 18 pts (58.1%) were current or former smokers; 15 pts (48.4%) had investigator-assessed baseline CNS metastases. Median survival follow up was 21.8 months (95% CI 19.5–30.2). Entrectinib treatment showed efficacy in pts with NTRK-fp NSCLC, including those with baseline CNS metastases by investigator (Table). In pts with BICR-assessed CNS metastases, intracranial ORR was 60.0% (6/10; 95% CI 26.2–87.8), median intracranial DoR was not estimable (NE), and median intracranial PFS was 8.9 months (95% CI 5.6–NE). In the safety-evaluable population (N=35), most treatment-related adverse events (TRAEs) were Grade 1–2 and non-serious. TRAEs led to dose reduction, interruption and discontinuation in 31.4%, 28.6%, and 5.7% of pts, respectively, and no treatment-related deaths occurred. Conclusions: In line with previously reported data, treatment with entrectinib was associated with deep and durable systemic and intracranial responses in pts with advanced NTRK-fp NSCLC. Clinical trial information: EUCTR 2012-000148-88 , NCT02097810 , NCT02568267 . [Table: see text]
Daratumumab, Cyclophosphamide, Bortezomib, Lenalidomide, and Dexamethasone as Induction and Extended Consolidation Improves Outcome in Ultra-High-Risk Multiple Myeloma
Authors: Kaiser Martin F. , Hall Andrew , Walker Katrina , Sherborne Amy , De Tute Ruth M. , Newnham Nicola , Roberts Sadie , Ingleson Emma , Bowles Kristian , Garg Mamta , Lokare Anand , Messiou Christina , Houlston Richard S. , Jackson Graham , Cook Gordon , Pratt Guy , Owen Roger G. , Drayson Mark T. , Brown Sarah R. , Jenner Matthew W. 
Published: June 2023

PURPOSE The multicenter OPTIMUM (MUKnine) phase II trial investigated daratumumab, low-dose cyclophosphamide, lenalidomide, bortezomib, and dexamethasone (Dara-CVRd) before and after autologous stem-cell transplant (ASCT) in newly diagnosed patients with molecularly defined ultra–high-risk (UHiR) multiple myeloma (NDMM) or plasma cell leukemia (PCL). To provide clinical context, progression-free survival (PFS) and overall survival (OS) were referenced to contemporaneous outcomes seen in patients with UHiR NDMM treated in the recent Myeloma XI (MyeXI) trial. METHODS Transplant-eligible all-comers NDMM patients were profiled for UHiR disease, defined by presence of ≥2 genetic risk markers t(4;14)/t(14;16)/t(14;20), del(1p), gain(1q), and del(17p), and/or SKY92 gene expression risk signature. Patients with UHiR MM/PCL were offered treatment with Dara-CVRd induction, V-augmented ASCT, extended Dara-VR(d) consolidation, and Dara-R maintenance. UHiR patients treated in MyeXI with carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide, or lenalidomide, dexamethasone, and cyclophosphamide, ASCT, and R maintenance or observation were identified by mirrored molecular screening. OPTIMUM PFS at 18 months (PFS18m) was compared against MyeXI using a Bayesian framework, and patients were followed up to the end of consolidation for PFS and OS. RESULTS Of 412 screened NDMM OPTIMUM patients, 103 were identified as UHiR or PCL and subsequently treated on trial with Dara-CVRd; 117 MyeXI patients identified as UHiR formed the external comparator arm, with comparable clinical and molecular characteristics to OPTIMUM. Comparison of PFS18m per Bayesian framework resulted in a 99.5% chance of OPTIMUM being superior to MyeXI. At 30 months' follow-up, PFS was 77% for OPTIMUM versus 39.8% for MyeXI, and OS 83.5% versus 73.5%, respectively. Extended post-ASCT Dara-VRd consolidation therapy was highly deliverable, with limited toxicity. CONCLUSION Our results suggest that Dara-CVRd induction and extended post-ASCT Dara-VRd consolidation markedly improve PFS for UHiR NDMM patients over conventional management, supporting further evaluation of this strategy.
Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer
Authors: Amado Rafael G. , Wolf Michael , Peeters Marc , Van Cutsem Eric , Siena Salvatore , Freeman Daniel J. , Juan Todd , Sikorski Robert , Suggs Sid , Radinsky Robert , Patterson Scott D. , Chang David D. 
Published: June 2023

PURPOSE Panitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials. PATIENTS AND METHODS KRAS mutations were detected using polymerase chain reaction on DNA from tumor sections collected in a phase III mCRC trial comparing panitumumab monotherapy to best supportive care (BSC). We tested whether the effect of panitumumab on progression-free survival (PFS) differed by KRAS status. RESULTS KRAS status was ascertained in 427 (92%) of 463 patients (208 panitumumab, 219 BSC). KRAS mutations were found in 43% of patients. The treatment effect on PFS in the wild-type (WT) KRAS group (hazard ratio [HR], 0.45; 95% CI: 0.34 to 0.59) was significantly greater ( P < .0001) than in the mutant group (HR, 0.99; 95% CI, 0.73 to 1.36). Median PFS in the WT KRAS group was 12.3 weeks for panitumumab and 7.3 weeks for BSC. Response rates to panitumumab were 17% and 0%, for the WT and mutant groups, respectively. WT KRAS patients had longer overall survival (HR, 0.67; 95% CI, 0.55 to 0.82; treatment arms combined). Consistent with longer exposure, more grade III treatment-related toxicities occurred in the WT KRAS group. No significant differences in toxicity were observed between the WT KRAS group and the overall population. CONCLUSION Panitumumab monotherapy efficacy in mCRC is confined to patients with WT KRAS tumors. KRAS status should be considered in selecting patients with mCRC as candidates for panitumumab monotherapy.