bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stability and safety key factors of the oncolytic protoparvovirus H-1 from manufacturing to human application
Authors: Frehtman Veronika , Wohlfarth Daniel , Müller Marcus , Krebs Ottheinz , Leuchs Barbara 
Published: May 2023

Abstract
The oncolytic rodent protoparvovirus H-1PV has been successfully used in phase I/II clinical trials to treat recurrent glioblastoma multiforme and pancreatic cancer. The present work focuses on the stability and environmental safety of the H-1PV drug product from production up to its use in patients. We identified hold-steps in manufacturing for up to 3 months and showed 7-years stability for the optimal product formulation. Stress testing via UV, temperature, and pH also determined that the drug product is stable. De- and rehydration for lyophilization simulation are possible without infectious virus loss. Furthermore, we prove in-use stability for 4 days at room temperature and show no virus adsorption to injection devices, guaranteeing the correct administration dose. Iodixanol in the formulation, resulting in high viscosity, protects H-1PV against UV and some disinfectants. Nonetheless, H-1PV is depleted with rapid heat deactivation, autoclavation, and nanofiltration. Assessment of chemical disinfectants that are currently recommended by the Robert Koch-Institute demonstrated that ethanol-based hand disinfectants are not effective; however, aldehyde-based disinfectants for surfaces and instruments demonstrate sufficient H-1PV deactivation in aqueous formulations by 4 to 6 log10. With these results, we could establish a specific hygiene plan for all involved facilities from manufacturing to patient application. Overall, using 48% Iodixanol in Visipaque/Ringer as a drug formulation stabilizes H-1PV infectivity over years and protects against virus loss from short-term UV, low pH, and temperature exposure.

Key points
• Optimal formulation of drug product protects the H-1PV protoparvovirus against UV, temperatures up to 50 °C, and low pH (> 1.25), stabilizing the virus during manufacturing, storage, transport, and application.
• H-1PV is stable during in-use and does not adsorb to injection devices during patient administration.
• Hygiene plan for H-1PV with physicochemical methods has been established.
Sequential CAR T cell and targeted alpha immunotherapy in disseminated multiple myeloma
Authors: Awuah Dennis , Minnix Megan , Caserta Enrico , Tandoh Theophilus , Adhikarla Vikram , Poku Erasmus , Rockne Russell , Pichiorri Flavia , Shively John E. , Wang Xiuli 
Published: May 2023

AbstractMultiple myeloma (MM) is still an incurable disorder despite improved antibody and cellular therapies against different MM antigens. Single targeted antigens have so far been ineffective against MM with most patients relapsing after initial response. Hence, sequential immunotherapies directed at different targets are expected to perform better than monotherapy alone. Here, we optimized and established in preclinical studies the therapeutic rationale of using targeted alpha therapy (TAT) directed against CD38 antigen (225Ac-DOTA-daratumumab) with CAR T cell therapy directed at CS1 antigen in a systemic MM model. The sequential therapies compared CAR T therapy followed by TAT to TAT followed by CAR T therapy. CAR T cell monotherapy increased median survival from 49 days (d) in untreated controls to 71d with a modest improvement to 89d for 3.7 kBq of TAT given 14d later. When CAR T was followed by 7.4 kBq of TAT 29d later, sequential therapy increased median survival from 47d in untreated controls to 106d, compared to 68d for CAR T monotherapy. When CAR T therapy was followed by untargeted alpha immunotherapy using 7.4 kBq of 225Ac-DOTA-trastuzumab (anti-HER2) antibody 29d later, there was only a slight improvement in response over CAR T monotherapy demonstrating the role of tumor targeting. TAT (7.4 kBq) followed by CAR T therapy was also effective when CAR T therapy was delayed for 21d vs 14d or 28d post TAT, highlighting the importance of timing sequential therapies. Sequential targeted therapies using CS1 CAR T or 225Ac-DOTA-CD38 TAT in either order shows promise over monotherapies alone.
Risk Factors for Postoperative Complications Following Resection of Colorectal Liver Metastases and the Impact on Long‐Term Survival: A Population‐Based National Cohort Study
Authors: Scherman Peter , Syk Ingvar , Holmberg Erik , Naredi Peter , Rizell Magnus 
Published: May 2023

AbstractBackgroundPostoperative complications (POCs) following resection of colorectal liver metastases (CRLM) are common. The objective of this study was to evaluate risk factors for developing complications and their impact on survival considering prognostic factors of the primary tumor, metastatic pattern and treatment in a well‐defined national cohort.MethodsPatients treated with resection for CRLM that was also radically resected for their primary colorectal cancer (diagnosed in 2009–2013) were identified in Swedish national registers. Liver resections were categorized according to extent of surgery (Category I–IV). Risk factors for developing POCs as well as prognostic impact of POCs were evaluated in multivariable analyses. A subgroup analysis of minor resections was performed to evaluate POCs after laparoscopic surgery.ResultsPOCs were registered for 24% (276/1144) of all patients after CRLM resection. Major resection was a risk factor for POCs in multivariable analysis (IRR 1.76; P = 0.001). Comparing laparoscopic and open resections in the subgroup analysis of small resections, 6% (4/68) in the laparoscopic group developed POCs compared to 18% (51/289) after open resection (IRR 0.32; P = 0.024). POCs were associated with a 27% increased excess mortality rate (EMRR 1.27; P = 0.044). However, primary tumor characteristics, tumor burden in the liver, extrahepatic spread, extent of liver resection and radicality had higher impact on survival.ConclusionMinimal invasive resections were associated with a decreased risk of POCs following resection of CRLM which should be considered in surgical strategy. Postoperative complications were associated with a moderate risk for inferior survival.
Fully Robotic Side‐to‐Side Linear‐Stapled Anastomosis During Robotic Ivor Lewis Esophagectomy
Authors: Guerra Francesco , Tribuzi Angela , Giuliani Giuseppe , Di Marino Michele , Coratti Andrea 
Published: May 2023

AbstractBackgroundThe adoption of robotic surgery for esophageal cancer has been expanding rapidly over the recent years. In the setting of two‐field esophagectomy, different techniques exist for intrathoracic esophagogastric anastomosis, although the superiority of one over another has not been clearly demonstrated. Potential benefits in terms of anastomotic leakage and stenosis have been reported in association with a linear‐stapled anastomosis as compared to the more widespread techniques of circular mechanical and hand‐sewn reconstructions, however, there is still limited reported evidence on its application to robotic surgery. We here report our fully robotic technique of side‐to‐side, semi‐mechanical anastomosis.MethodsAll consecutive patients undergoing fully robotic esophagectomy featuring intrathoracic side‐to‐side stapled anastomosis by a single surgical team were included in this analysis. Operative technique is detailed, and perioperative data are assessed.ResultsA total of 49 patients were included. There were no intraoperative complications and no conversion occurred. The rate of overall postoperative morbidity was 25, 14% being the relative rate of major complications. With anastomotic‐related morbidity in particular, one patient developed minor anastomotic leakage.ConclusionsOur experience demonstrates that a linear, side‐to‐side fully robotic stapled anastomosis can be created with a high technical success and minimal incidence of anastomosis‐related morbidity.
Outpatient Non‐operative Management of Uncomplicated Acute Appendicitis: A Non‐inferiority Study
Authors: Ceresoli Marco , Fumagalli Chiara , Fugazzola Paola , Zanini Nicola , Magnone Stefano , Ravasi Michela , Bonalumi Jacopo , Morezzi Daniele , Bova Raffaele , Sargenti Benedetta , Schiavone Luca , Lucianetti Alessandro , Catena Fausto , Ansaloni Luca , Braga Marco 
Published: May 2023

AbstractIntroductionNon‐operative management (NOM) of uncomplicated acute appendicitis is a well‐established alternative to upfront surgery. The administration of intravenous broad‐spectrum antibiotics is usually performed in hospital, and only one study described outpatient NOM. The aim of this multicentre retrospective non‐inferiority study was to evaluate both safety and non‐inferiority of outpatient compared to inpatient NOM in uncomplicated acute appendicitis.MethodsThe study included 668 consecutive patients with uncomplicated acute appendicitis. Patients were treated according to the surgeon’s preference: 364 upfront appendectomy, 157 inpatient NOM (inNOM), and 147 outpatient NOM (outNOM). The primary endpoint was the 30‐day appendectomy rate, with a non‐inferiority limit of 5%. Secondary endpoints were negative appendectomy rate, 30‐day unplanned emergency department (ED) visits, and length of stay.Results30‐day appendectomies were 16 (10.9%) in the outNOM group and 23 (14.6%) in the inNOM group (p = 0.327). OutNOM was non‐inferior to inNOM with a risk difference of—3.80% 97.5% CI (− 12.57; 4.97). No difference was found between inNOM and outNOM groups for the number of complicated appendicitis (3 vs. 5) and negative appendectomy (1 vs. 0). Twenty‐six (17.7%) outNOM patients required an unplanned ED visit after a median of 1 (1–4) days. In the outNOM group, the mean cumulative in‐hospital stay was 0.89 (1.94) days compared with 3.94 (2.17) days in the inNOM group (p < 0.001).ConclusionsOutpatient NOM was non‐inferior to inpatient NOM with regard to the 30‐day appendectomy rate, while a shorter hospital stay was found in the outNOM group. Further, studies are required to confirm these findings.
Impact of sex on the efficacy of immune checkpoint inhibitors in kidney and urothelial cancers: a systematic review and meta-analysis
Authors: Yanagisawa Takafumi , Kawada Tatsushi , Quhal Fahad , Bekku Kensuke , Laukhtina Ekaterina , Rajwa Pawel , von Deimling Markus , Majdoub Muhammad , Chlosta Marcin , Pradere Benjamin , Mori Keiichiro , Kimura Takahiro , Schmidinger Manuela , Karakiewicz Pierre I. , Shariat Shahrokh F. 
Published: May 2023

Abstract
Purpose
To analyze and summarize the efficacy of immune checkpoint inhibitor (ICI) alone or in combination therapy for renal cell carcinoma (RCC) and urothelial carcinoma (UC) stratified by sex.

Methods
Three databases were queried in October 2022 for randomized controlled trials (RCTs) analyzing RCC and UC patients treated with ICIs. We analyzed the association between sex and the efficacy of ICIs in RCC and UC patients across several clinical settings. The outcomes of interest were overall survival (OS) and progression-free survival for the metastatic setting and disease-free survival (DFS) for the adjuvant setting.

Results
Overall, 16 RCTs were included for meta-analyses and network meta-analyses. In the first-line treatment of metastatic RCC (mRCC) and UC (mUC) patients, ICI-based combination therapies significantly improved OS compared to the current standard of care, regardless of sex. Adjuvant ICI monotherapy reduced the risk of disease recurrence in female patients with locally advanced RCC (pooled hazard ratio [HR]: 0.71, 95% confidence interval [CI] 0.55–0.93) but not in male patients, and, conversely, in male patients with muscle-invasive UC (pooled HR: 0.80, 95%CI 0.68–0.94) but not in female patients. Treatment ranking analyses in the first-line treatment of mRCC and mUC showed different results between sexes. Of note, regarding adjuvant treatment for RCC, pembrolizumab (99%) had the highest likelihood of improved DFS in males, whereas atezolizumab (84%) in females.

Conclusions
OS benefit of first-line ICI-based combination therapy was seen in mRCC and mUC patients regardless of sex. Sex-based recommendations for ICI-based regimens according to the clinical setting may help guide clinical decision-making.
On the characterization of bias errors in defocusing-based 3D particle tracking velocimetry for microfluidics
Authors: Coutinho Gonçalo , Moita Ana , Ribeiro Ana , Moreira António , Rossi Massimiliano 
Published: May 2023

AbstractIn this work, we provide a systematic theoretical and experimental characterization of bias errors in defocusing particle tracking (DPT) methods based on a single calibration function, with respect to microfluidic applications, in which it is not possible to use calibration targets inside the measurement volume. This approach is widely used in microfluidic experiments, but bias errors are often neglected and to date only few works reported empirical procedures to compensate for that. A systematic characterization of the impact of such error in DPT measurements is still lacking. We show that the field curvature aberration and the refractive index mismatch are the main sources of bias error in these applications. We present a correction methodology for the bias error based on the determination of a reference surface, and in addition we propose a procedure based on a reference measurement of a Poiseuille flow to determine the reference surface on microfluidic channels with constant cross section. We discuss the impact of the refractive index mismatch and how to correctly compensate for it. We validated our methodology and quantified the bias errors on 10 different experimental setups, using different working fluids, materials, geometries, and microscope objective lenses ranging from 5$$\times$$
×
to 40$$\times$$
×
magnification. Our results indicate that the impact of this type of bias errors is in general not predictable and must be evaluated case by case. The proposed methodology allows to estimate and minimize the bias error in most microfluidic setups and is suitable for any single-camera DPT approach.
Separation control with elliptical air-jet vortex generators
Authors: Ramaswamy Deepak Prem , Schreyer Anne-Marie 
Published: May 2023

AbstractThe flow organisation of air-jet vortex generators (AJVGs) of elliptical cross sections and their control effectiveness on a$$24^{\circ }$$24∘-compression-ramp-induced shock-wave/boundary-layer interaction was analysed on the basis of experiments at$$M_{\infty } = 2.52$$M∞=2.52and$$Re_{\theta _c} = 8225$$Reθc=8225. We investigated a circular orifice and two elliptical orifices of aspect ratios 0.5 and 2; all characterised by the same hydraulic diameter. Measurements of separation lengths from oil-flow visualisation and PIV reveal that elliptical AJVGs achieve a$$25\%$$25%reduction in total separation length, which constitutes a strong improvement over the$$17\%$$17%reduction achieved with the commonly used circular AJVGs. The jet-induced structures from elliptical AJVGs penetrate on average$$25\%$$25%farther into the boundary layer. However, the lateral spread is limited to a maximum value equal to the inter-jet spacing in the control array, which highlights the onset of jet/jet interactions between adjacent jets in the array. A consequence of these interactions is better flow entrainment for the elliptical cases, as observed in the mean boundary-layer velocity profiles and an improved turbulent mixing (indicated by an increase in Reynolds-shear-stress magnitude).
Computational framework for complex flow and transport in heterogeneous porous media
Authors: Icardi Matteo , Pescimoro Eugenio , Municchi Federico , Hidalgo Juan J. 
Published: May 2023

AbstractWe present a flexible scalable open-source computational framework, named , based on the finite-volume library OpenFOAM®, for flow and transport problems in highly heterogeneous geological media and other porous materials. The framework combines geostatistical pre- and post-processing tools with specialised partial differential equations solvers. Random fields, for permeability and other physical properties, are generated by means of continuous or thresholded Gaussian random fields with various covariance/variogram functions. The generation process is based on an explicit spectral Fourier decomposition of the field which, although more computationally intensive than Fast Fourier Transform methods, allows a more flexible choice of statistical parameters and can be used for general geometries and grids. Flow and transport equations are solved for single-phase and variable density problems, with and without the Boussinesq approximation, and for a wide range of density, viscosity, and dispersion models, including dual-continuum (dual permeability or dual porosity) formulations. The mathematical models are here presented in details and the numerical strategies to deal with heterogeneities, equation coupling, and boundary conditions are discussed and benchmarked for the heterogeneous Henry and Horton–Rogers–Lapwood problems, and other test cases. We show that our framework is capable of dealing with large permeability variances, viscous instabilities, and large-scale three-dimensional transport problems.
COVID-19- Experiences and support needs of children and young people with Hydrocephalus and parents in the United Kingdom
Authors: Collaço Nicole , Campion Anna , McNicholas Roisin , Darlington Anne-Sophie 
Published: May 2023

Abstract
Purpose
Little is known about the impact of COVID-19 on children and young people (CYP) with hydrocephalus and their families. This study explored the experiences and support needs of CYP with hydrocephalus and parents who have a child with hydrocephalus during the COVID-19 pandemic.

Methods
CYP with hydrocephalus and parents of CYP with hydrocephalus in the United Kingdom completed an online survey with open and closed questions exploring experiences, information, support needs and decision making processes. Qualitative thematic content analysis and descriptive quantitative analyses were undertaken.

Results
CYP aged 12-32 years (n=25) and parents of CYP aged 0-20 years (n=69) responded. Parents (63.5%) and CYP (40.9%) worried about the virus, and both were vigilant for virus symptoms (86.5% and 57.1%). Parents (71.2%) and CYP (59.1%) worried about their child/feeling more isolated during the virus outbreak. Parents felt concerned about having to take their child to hospital with a suspected shunt problem during the virus outbreak (64.0%). Qualitative findings reported the following themes: (1) Healthcare and treatment provision: delays and challenges to access and availability of care (2) Impact of COVID-19/lockdown on daily lives and routines, and (3) Provision of information and support for parents and CYP with hydrocephalus.

Conclusion
The impact of COVID-19 and national measures to control the spread of the virus- no contact with anyone outside the household significantly impacted the daily lives and routines of CYP with hydrocephalus and parents. Social engagements were missed, families faced challenges to their work life, education and access to health care and support, which subsequently contributed negatively to their mental wellbeing. CYP and parents highlighted a need for clear, timely and targeted information to address their concerns.
Atlantic decadal-to-bidecadal variability in a version of the Kiel Climate Model
Authors: Sun Jing , Latif Mojib , Park Wonsun 
Published: May 2023

AbstractAtlantic decadal-to-bidecadal variability (ADV) is described from a multimillennial control integration of a version of the Kiel Climate Model (KCM). The KCM’s ADV is the second most energetic mode of long-term North Atlantic variability in that simulation, whereas the Atlantic multidecadal variability (AMV) is the leading mode that has been described in a previous study. The KCM’s ADV can be regarded as a mixed oceanic gyre-overturning circulation mode that is forced by the North Atlantic Oscillation. The extratropical North Atlantic sea surface temperature (SST) anomalies associated with the model’s ADV initially exhibit a tripolar structure in the meridional direction, which is linked to the gyre circulation. After some years, the SST-anomaly pattern turns into a monopolar pattern located in the subpolar North Atlantic. This transition is related to the overturning circulation. The AMV and the ADV co-exist and share some similarities. Both modes of variability rely on the upper-ocean heat transport into the subpolar North Atlantic. They differ in the importance of the gyre and overturning circulations. In the ADV, gyre and overturning-heat transports into the subpolar North Atlantic are equally important in contrast to the AMV where the overturning contribution dominates.
Robot-assisted laparoscopic varicocelectomy in a pediatric population
Authors: Reinhardt Susanne , Thorup Jorgen , Joergensen Peter Hjorth , Fode Mikkel 
Published: May 2023

Abstract
Purpose
To present our experience with robot-assisted laparoscopic varicocelectomy in a pediatric population.

Methods
We reviewed 49 consecutive cases performed by the same experienced surgeon. One-to-four veins were ligated at the internal ring of the inguinal canal, while the testicular artery and lymphatics were spared. Information on patient characteristics, surgical time, complications, and recurrences were collected.

Results
Median patient age was 14 (range 10–17) years. Forty-eight had left-sided varicoceles and one had a bilateral varicocele. Forty-five were grade 3. All patients were referred due to discomfort/pain and 20 also had reduced testicular size. The median operating time from skin incision was 48 min (31–89 min) and the median console time was 18 min (7–55 min). Forty-seven patients were discharged the same day. Two patients experienced pain and problems urinating, respectively. These issues had resolved by the first post-operative day. There were no other complications, but at 6 months, eight recurrences were noted (16%). Scrotal complaints had subsided in all patients. Catch-up growth of the affected testicles was seen in 19/20 cases.

Conclusion
Robot-assisted laparoscopic varicocelectomy is feasible and safe in a pediatric population but with a relatively high recurrence rate.
A machine learning method for distinguishing detrital zircon provenance
Authors: Zhong S. H. , Liu Y. , Li S. Z. , Bindeman I. N. , Cawood P. A. , Seltmann R. , Niu J. H. , Guo G. H. , Liu J. Q. 
Published: May 2023

AbstractZircon geochemistry provides a sensitive monitor of its parental magma composition. However, due to the complexity of the uptake of trace elements during zircon growth, identifying source magmas remains challenging, particularly for detrital grains whose petrological context is lost. We use a machine learning-based approach to explore the classifiers for zircon provenance, based on 3794 published, high-quality zircon trace element analyses compiled from I-, S-, and A-type granites. Three supervised machine learning algorithms, namely, Support Vector Machine (SVM), Random Forest (RF), and Multilayer Perceptron (MLP) were used and trained with 11 features, including 7 trace elements (Ce, Eu, Ho, Nb, Ta, Th, and U) and 4 derived trace element ratios (Th/U, U/Yb, Ce/Ce*, and Eu/Eu*). Our results show that all three trained machine learning methods perform very well with accuracy varying from 0.86 to 0.89, and that input–output relationships captured by different ML methods are nearly consistent and can be explained by the known petrological processes. The application of our trained machine learning classifiers to detrital zircon studies will enhance the interpretability of zircon assemblages of different origins. It also helps develop interpretations, approaches, and tools that will benefit, for example, the study of continental crust evolution and mineral exploration.