bluuebunny/crossref_metadata_2025 huggingface dataset:
Qualitative analysis of the impact of the SARS-CoV-2 pandemic response on paediatric health services in North of Scotland and North of England
Authors: Gadsby Erica W , Christie-de Jong Floor , Bhopal Sunil , Corlett Heather , Turner Stephen
Published: February 2022

Objective

To capture the extent and impact of changes in the delivery of child health services in the UK, resulting from the SARS-CoV-2 pandemic response, from the perspectives of a range of child healthcare providers.

Setting

National Health Service commissioned/delivered healthcare services in two regional settings in the UK: North of Scotland (NOS) and North East and North Cumbria (NENC) in England.

Participants

Purposive sample of 39 child healthcare professionals including paediatricians, community/specialist nurses, allied health professionals and mental health professionals, from across the two regions (22 in NOS, 17 in NENC).

Methods

Semistructured qualitative interviews conducted via telephone between June and October 2020, fully transcribed and analysed in NVivo V.11 using thematic analysis.

Results

Extensive changes across a range of paediatric services were rapidly implemented to support the pandemic response and ongoing healthcare delivery. New ways of working emerged, principally to control the spread of the virus. Keeping users and their families out of hospital was an urgent driver for change. The changes had considerable impact on the health and well-being of staff with many experiencing radical changes to their working conditions and roles. However, there were some positive changes noted: some practitioners felt empowered and listened to by decision makers; some of the usual bureaucratic barriers to change were lifted; staff saw improved collaboration and joint working across the system; and some new ways of working were seen to be more efficient. Interviewees perceived the implications for children and their families to be profound, particularly with regard to self-care, relationships with practitioners and timely access to services.

Conclusions

Despite the challenges experienced by staff, the pandemic provided an opportunity for positive, lasting change. It is vital to capitalise on this opportunity to benefit patient outcomes and to ‘build back’ services in a more sustainable way.
Rationally targeted anti-VISTA antibody that blockades the C-C’ loop region can reverse VISTA immune suppression and remodel the immune microenvironment to potently inhibit tumor growth in an Fc independent manner
Authors: Thakkar Dipti , Paliwal Shalini , Dharmadhikari Bhushan , Guan Siyu , Liu Lillian , Kar Shreya , Tulsian Nikhil K , Gruber Joshua J , DiMascio Leah , Paszkiewicz Konrad H , Ingram Piers J , D Boyd-Kirkup Jerome
Published: February 2022

Background

Despite significant progress in cancer immunotherapy in recent years, resistance to existing immune checkpoint therapies (ICT) is common. V-domain Ig suppressor of T cell activation (VISTA), a predominantly myeloid immune checkpoint regulator, represents a promising therapeutic target due to its role in suppressing proinflammatory antitumor responses in myeloid-enriched tumor microenvironments. However, uncertainty around the cognate VISTA ligand has made the development of effective anti-VISTA antibodies challenging. The expression of VISTA on normal immune cell subtypes argues for a neutralizing non-depleting antibody, however, previous reported anti-VISTA antibodies use IgG1 Fc isotypes that deplete VISTA+ cells by antibody dependent cellular cytotoxicity/complement dependent cytotoxicity and these antibodies have shown fast serum clearance and immune toxicities.

Method

Here we used a rational antibody discovery approach to develop the first Fc-independent anti-VISTA antibody, HMBD-002, that binds a computationally predicted functional epitope within the C-C-loop, distinct from other known anti-VISTA antibodies. This epitope is species-conserved allowing robust in vitro and in vivo testing of HMBD-002 in human and murine models of immune activation and cancer including humanized mouse models.

Results

We demonstrate here that blockade by HMBD-002 inhibits VISTA binding to potential partners, including V-Set and Immunoglobulin domain containing 3, to reduce myeloid-derived suppression of T cell activity and prevent neutrophil migration. Analysis of immune cell milieu suggests that HMBD-002 treatment stimulates a proinflammatory phenotype characterized by a Th1/Th17 response, recapitulating a phenotype previously noted in VISTA knockout models. This mechanism of action is further supported by immune-competent syngenic and humanized mouse models of colorectal, breast and lung cancer where neutralizing VISTA, without depleting VISTA expressing cells, significantly inhibited tumor growth while decreasing infiltration of suppressive myeloid cells and increasing T cell activity. Finally, we did not observe either the fast serum clearance or immune toxicities that have been reported for IgG1 antibodies.

Conclusion

In conclusion, we have shown that VISTA-induced immune suppression can be reversed by blockade of the functional C-C’ loop region of VISTA with a first-in-class rationally targeted and non-depleting IgG4 isotype anti-VISTA antibody, HMBD-002. This antibody represents a highly promising novel therapy in the VISTA-suppressed ICT non-responder population.
Soluble PD-L1 as an early marker of progressive disease on nivolumab
Authors: Mahoney Kathleen M , Ross-Macdonald Petra , Yuan Long , Song Linan , Veras Eliseo , Wind-Rotolo Megan , McDermott David F , Stephen Hodi F , Choueiri Toni K , Freeman Gordon J
Published: February 2022

Background

Soluble PD-L1 (sPD-L1) has been associated with worse prognosis in numerous solid tumors. We determined sPD-L1 levels before and during nivolumab treatment in two prospective clinical trials of metastatic clear cell renal cell carcinoma (RCC) and melanoma patients, and investigated its relationship to clinical factors, biomarkers, and outcome.

Methods

Using a new Single Molecule Array assay, serum sPD-L1 level were determined in RCC (CheckMate 009, n=91) and melanoma (CheckMate 038-Part 1, n=78) prior to, and at two time points on treatment. Gene expression data was obtained from biopsies taken prior to, and at day 28 on treatment. Results were integrated with clinical variables, tumor PD-L1 status from immuno-histochemistry, and genomic mutation status.

Results

In RCC patients, sPD-L1 levels were higher in patients with progressive disease as their best response. For both RCC and melanoma patients, progressive or stable disease was associated with an increase in sPD-L1 on nivolumab therapy, whereas mean sPD-L1 levels did not change or declined in patients with objective responses. By categorizing RCC patients into transcriptomic molecular subtypes, we identified a subgroup where the associations between sPD-L1 and progressive disease were particularly evident. In baseline biopsies, we identified six biological processes that were associated with sPD-L1 level in both RCC and melanoma: higher sPD-L1 is associated with lower tumor expression of the Hallmark gene sets ‘hypoxia’, ‘fatty acid metabolism’, ‘glycolysis’, ‘MTORC1 signaling’ and ‘androgen response’, and with higher expression of ‘KRAS signaling_Down’.

Conclusion

Baseline and on-therapy sPD-L1 levels in RCC have the potential to predict progressive disease on PD-1 inhibitor nivolumab. In a hypothesis-generating analysis of tumor gene expression, high baseline sPD-L1 is associated with a tumor metabolic state reflecting potentially targetable processes in both melanoma and RCC. In both trials, we observed associations between change in sPD-L1 on treatment and outcome metrics. sPD-L1 levels may further refine a nivolumab-refractory subtype of RCC within transcriptionally based subtypes of RCC.
Reductions in circulating B cell subsets and immunoglobulin G levels with long-term belimumab treatment in patients with SLE
Authors: Struemper Herbert , Kurtinecz Milena , Edwards Lisa , Freimuth William W , Roth David A , Stohl William
Published: February 2022

Objective

To examine the long-term changes in circulating B cell subsets and IgG levels at 5+ years of continuous belimumab treatment and their correlations with efficacy and safety measures.

Methods

This was a post hoc analysis of a continuation study (BEL112233;NCT00724867) of eligible US patients who completed the 76-week BLISS-76 Study (BEL110751;NCT00410384), with up to eight calendar-years of follow-up and median (IQR) belimumab exposure of 310 (209, 364) weeks. From week 76, patients initially randomised to intravenous belimumab 1 mg/kg or 10 mg/kg every 4 weeks in BLISS-76 continued to receive the same dose in the continuation study, while those initially randomised to placebo received belimumab 10 mg/kg intravenous every 4 weeks during continuation. All patients continued to receive standard SLE therapy. Biomarker data were collected, and the effects on baseline and early changes (weeks 0–24 after starting belimumab) from baseline in biomarkers on SLE Responder Index (SRI-4) and infection rate were evaluated.

Results

Of the 819 patients from BLISS-76, 268 self-selecting patients entered BEL112233. Compared with baseline, B cell subset counts decreased by 40%–99% after 312 weeks (6 years), and serum IgG levels decreased by 28% after 284 weeks. Higher baseline naïve B cell counts were associated with greater SRI-4 response rates (p<0.05), whereas higher baseline SLE subset plasma and short-lived plasma B cell counts were associated with lower SRI-4 response rates (p<0.05). Elevated baseline IgG levels were associated with increased infection rates over the treatment period (p<0.05), and early greater decreases in IgG levels were associated with higher SRI-4 response rates (p<0.05).

Conclusions

Belimumab treatment up to 312 weeks (6 years) resulted in substantial decreases in several circulating B cell subsets and IgG levels. Higher baseline naïve B cell counts and IgG levels were associated with improved SRI-4 response and increased infection rates, respectively.
Safety, patient acceptance and diagnostic accuracy of ultrasound core needle biopsy of parotid or submandibular glands in primary Sjögren’s syndrome with suspected salivary gland lymphoma
Authors: Giovannini Ivan , Lorenzon Michele , Manfrè Valeria , Zandonella Callegher Sara , Pegolo Enrico , Zuiani Chiara , Girometti Rossano , Hocevar Alojzija , Dejaco Christian , Quartuccio Luca , De Vita Salvatore , Zabotti Alen
Published: February 2022

Background

Enlargement of the major salivary glands (SGs) is a major risk factor for B-cell lymphoma among patients with primary Sjögren’s syndrome (pSS). Ultrasound-guided core needle biopsy (US-guided CNB) could be a novel technique to manage SG enlargement among patients with pSS.

Objective

Accordingly, this study’s main aim was to evaluate the safety, patient tolerance and diagnostic accuracy of US-guided CNB procedure for patients with pSS with major SG enlargement.

Methods

Patients with clinical diagnosis of pSS and a clinical indication for SG biopsy consecutively underwent US-guided CNB between September 2019 and June 2021. These patients were evaluated clinically 1, 2 and 12 weeks after US-guided CNB. Patients were asked to complete a questionnaire about postprocedural complications as well as periprocedural pain, using the Visual Analogue Scale. Complications were categorised as transient (<12 weeks) or persistent (≥12 weeks).

Results

US-guided CNB was performed on 30 major salivary glands (22 parotid glands and 8 submandibular glands). The procedure was well tolerated. Transient complications—such as haematoma, swelling—were observed among 43% of patients, and mean periprocedural pain was low. However, no persistent complications were reported during the study’s follow-up period.

Conclusion

US-guided CNB represents a novel approach for the management of patients with pSS with SG enlargement. The procedure showed remarkable patient safety and tolerance, allowing adequate glandular sampling and a definite diagnosis for almost all participating patients without long-term complications.
Bermudan option pricing by quantum amplitude estimation and Chebyshev interpolation
Authors: Miyamoto Koichi
Published: February 2022

Pricing of financial derivatives, in particular early exercisable options such as Bermudan options, is an important but heavy numerical task in financial institutions, and its speed-up will provide a large business impact. Recently, applications of quantum computing to financial problems have been started to be investigated. In this paper, we first propose a quantum algorithm for Bermudan option pricing. This method performs the approximation of the continuation value, which is a crucial part of Bermudan option pricing, by Chebyshev interpolation, using the values at interpolation nodes estimated by quantum amplitude estimation. In this method, the number of calls to the oracle to generate underlying asset price paths scales as $\widetilde{O}(\epsilon ^{-1})$

O
˜

(

ϵ

−
1

)
, where ϵ is the error tolerance of the option price. This means the quadratic speed-up compared with classical Monte Carlo-based methods such as least-squares Monte Carlo, in which the oracle call number is $\widetilde{O}(\epsilon ^{-2})$

O
˜

(

ϵ

−
2

)
.
Selection of Optimal Thresholds in Multi-Level Thresholding Using Multi-Objective Emperor Penguin Optimization for Precise Segmentation of Mammogram Images
Authors: Subasree S. , Sakthivel N. K. , Balasaraswathi V. R. , Tyagi Amit Kumar
Published: February 2022

In medical image examination, image segmentation is the broadly used method. Currently, the efficient segmentation of mammogram images is the main challenge. Many methods were presented for segmenting the mammogram images, but the results are not satisfactory. In this paper, an efficient segmentation of mammogram images-based Multilevel Thresholding (MLT) method is proposed. Initially, the preprocessing step is executed for eliminating the unnecessary noises. For gaining the useful features from the mammogram images, mammogram image segmentation is carried out using multilevel thresholding method. In this paper, a novel Multi-Objective Emperor Penguin Optimization (MOEPO) algorithm is proposed for searching the multilevel greatest thresholds that segment the images into background and objects. The objective functions of the MLT are Otsu’s method, Kapur and Tsallis entropy. The effectiveness of the proposed method is analyzed using several performances evaluating metrics, like PSNR, FSIM and SSIM. The experimental outcomes show that the performance of the proposed technique is superior to other state-of-the-art methods. The proposed technique is likened to three existing models, viz. ScPSO-MT, Double Threshold and IWO-SUSAN. The SSIM of the proposed technique is 24.99%, 27.83% and 26.95% better than ScPSO-MT, Double Threshold and IWO-SUSAN existing approaches. The PSNR of the proposed technique is 25.27%, 40% and 50.74% better than ScPSO-MT, Double Threshold and IWO-SUSAN approaches. The FSIM of the proposed technique is 28.57%, 34.12% and 34.12% better than ScPSO-MT, Double Threshold and IWO-SUSAN methods.
Structural reflection, shrewd cardinals and the size of the continuum
Authors: Lücke Philipp
Published: February 2022

Motivated by results of Bagaria, Magidor and Väänänen, we study characterizations of large cardinal properties through reflection principles for classes of structures. More specifically, we aim to characterize notions from the lower end of the large cardinal hierarchy through the principle [Formula: see text] introduced by Bagaria and Väänänen. Our results isolate a narrow interval in the large cardinal hierarchy that is bounded from below by total indescribability and from above by subtleness, and contains all large cardinals that can be characterized through the validity of the principle [Formula: see text] for all classes of structures defined by formulas in a fixed level of the Lévy hierarchy. Moreover, it turns out that no property that can be characterized through this principle can provably imply strong inaccessibility. The proofs of these results rely heavily on the notion of shrewd cardinals, introduced by Rathjen in a proof-theoretic context, and embedding characterizations of these cardinals that resembles Magidor’s classical characterization of supercompactness. In addition, we show that several important weak large cardinal properties, like weak inaccessibility, weak Mahloness or weak [Formula: see text]-indescribability, can be canonically characterized through localized versions of the principle [Formula: see text]. Finally, the techniques developed in the proofs of these characterizations also allow us to show that Hamkin’s weakly compact embedding property is equivalent to Lévy’s notion of weak [Formula: see text]-indescribability.
A Hybrid SDN Architecture for IDS Using Bio-Inspired Optimization Techniques
Authors: Saritha A. , Ramasubba Reddy B. , Suresh Babu A.
Published: February 2022

Software-defined networking (SDN) is a networking paradigm of subsequent generation where various network components are used by a centralized controller that allows reliability in network system configuration, execution of policy decisions, and management via a primary programmable network infrastructure unit. SDN is known to deny DDoS attacks despite the default security protocols. State-of-the-art researches have shown that SDN intrusion is possible in diverse layers of its generalized architecture. Addressing this problem, this work presents an optimized intrusion detection system for SDN to mitigate the effect of DDoS attacks. This article’s main contribution comprises the development of a voting strategy-based ensemble classifier, which is established based on bio-inspired particle swarm optimization and salp swarm optimization in the context of optimized classification of DDoS attack-prone traffic SDN. Experimental analysis of the proposed SDN-IDS depicts that the proposed strategy outperforms existing classifiers in terms of accuracy.
Are We Skillful or Just Lucky? Interpreting the Possible Histories of Vulnerability Disclosures
Authors: Householder Allen D. , Spring Jonathan
Published: February 2022

Coordinated Vulnerability Disclosure (CVD) stands as a consensus response to the persistent fact of vulnerable software, yet few performance indicators have been proposed to measure its efficacy at the broadest scales. In this article, we seek to fill that gap. We begin by deriving a model of all possible CVD histories from first principles, organizing those histories into a partial ordering based on a set of desired criteria. We then compute a baseline expectation for the frequency of each desired criteria and propose a new set of performance indicators to measure the efficacy of CVD practices based on the differentiation of skill and luck in observation data. As a proof of concept, we apply these indicators to a variety of longitudinal observations of CVD practice and find evidence of significant skill to be prevalent. We conclude with reflections on how this model and its accompanying performance indicators could be used by various stakeholders (vendors, system owners, coordinators, and governments) to interpret the quality of their CVD practices.
Hydrogen Evolution at Conjugated Polymer Nanoparticle Electrodes
Authors: Fortin Patrick , Holdcroft Steven
Published: February 2022

Currently, there is a global effort being made to reduce greenhouse gas emissions through the implementation of renewable energies. An attractive alternative to fossil fuels is hydrogen, as it can be stored, transported and used as on demand as a liquid fuel while producing only water vapor as a by-product. The production of hydrogen can be attained through the photoelectrochemical splitting of water into hydrogen and oxygen, representing a sustainable, carbon neutral method of hydrogen generation. Our research focuses on the use of conjugated polymers, namely poly(3-hexylthiophene) (P3HT), as photocathode materials to convert solar energy into hydrogen. Using phenyl-C61-butryic acid methyl ester (PCBM) as an electron acceptor to effectively separate the photogenerated electron-hole pair within the semiconducting polymer, we can take advantage of these separated charges to perform electrochemical reactions at the polymer/electrolyte interface. This work investigates the preparation of nanostructured organic thin films from P3HT:PCBM nanoparticles and their characterization as photoelectrodes for photoelectrochemical hydrogen evolution. The morphology and optoelectronic properties of the nanostructured photocathodes are compared with conventional, solution-cast thin films of P3HT:PCBM. The nanostructured photoelectrodes provide increased surface area compared with solution-cast films, as well as greater control of the nanoscale morphology within each nanoparticle, leading to enhanced P3HT:PCBM phase segregation. The photo-assisted deposition of platinum nanoparticles as hydrogen evolution reaction (HER) catalysts onto the nanostructured P3HT:PCBM photocathodes facilitates the photoreduction of protons to H2.
Circulating hsa-let-7e-5p and hsa-miR-125a-5p as Possible Biomarkers in the Diagnosis of Major Depression and Bipolar Disorders
Authors: Gecys Dovydas , Dambrauskiene Kristina , Simonyte Sandrita , Patamsyte Vaiva , Vilkeviciute Alvita , Musneckis Algirdas , Butkute-Sliuoziene Kristina , Lesauskaite Vaiva , Zemaitis Lukas , Usaite Deimante , Adomaitiene Virginija
Published: February 2022

Background. Evidence shows that microRNAs (miRNAs) could play a key role in the homeostasis and development of major depressive disorder and bipolar disorder. The present study is aimed at investigating the changes in circulating miRNA expression profiles in a plasma of patients suffering from major depressive disorder (MDD) and bipolar disorder (BD) to distinguish and evaluate these molecules as biomarkers for mood disorders. Methods. A study enrolled a total of 184 subjects: 74 controls, 84 MDD patients, and 26 BD patients. Small RNA sequencing revealed 11 deregulated circulating miRNAs in MDD and BD plasma, of which expression of 5, hsa-miR-139-3p, miRNAs hsa-let-7e-5p, hsa-let-7f-5p, hsa-miR-125a-5p, and hsa-miR-483-5p, were further verified using qPCR. miRNA gene expression data was evaluated alongside the data from clinical assessment questionnaires. Results. hsa-let-7e-5p and hsa-miR-125a-5p were both confirmed upregulated: 0.75-fold and 0.25-fold, respectively, in the MDD group as well as 1.36-fold and 0.68-fold in the BD group. Receiver operating curve (ROC) analysis showed mediocre diagnostic sensitivity and specificity of both hsa-let-7e-5p and hsa-miR-125a-5p with approximate area under the curve (AOC) of 0.66. ROC analysis of combined miRNA and clinical assessment data showed that hsa-let-7e-5p and hsa-miR-125a-5p testing could improve MDD and BD diagnostic accuracy by approximately 10%. Conclusions. Circulating hsa-let-7e-5 and hsa-miR-125a-5p could serve as additional peripheral biomarkers for mood disorders; however, suicidal ideation remains the major diagnostic factor for MDD and BD.
An Analysis of Maxillary Anterior Teeth Crown Width‐Height Ratios: A Photographic, Three‐Dimensional, and Standardized Plaster Model’s Study
Authors: Ahmed Naseer , Halim Mohamad Syahrizal , Aslam Ayesha , Ghani Zuryati Ab , Safdar Jawad , Alam Mohammad Khursheed
Published: February 2022

Objective. To analyze the width and height ratios of maxillary anterior teeth at different crown levels through photographs, 3D, and plaster dental model techniques in a subset of the Pakistani population. Material and Methods. This clinical study consisted of 230 participants. The maxillary impression, standardized photographs, and models were constructed for crown width and height analysis. The SPSS version 25 was used for statistical analysis. Descriptive statistics were carried out for mean, standard deviation, and percentage calculation of teeth width and height, gender, and age of participants. Paired t‐test analysis was carried out to compare the dependent variables (teeth size, width, and height ratios) with independent variables (techniques applied, side disparity). A p value of ≤ 0.05 was considered statistically significant. Results. The mean width and height of maxillary anterior teeth obtained through photographs, 3D, and plater models were statistically different. The 3D dental model analysis showed reliable and accurate results. The mean width and height ratio of teeth were different on both sides of the arch. There was a significant difference (p = 0.001) in crown width‐height ratios at different crown levels. Conclusion. The width and height ratios in the studied population were different at various crown levels. The dimensions of teeth varied from the incisal to the cervical part of the crown. Hence, rather than relying on a single, fixed ratio of 78% to 80% suggested by researchers for anterior teeth, the clinician should adopt different crown width‐height ratios to restore teeth with the optimum esthetic outcome.
Boundedness for the Modified Fractional Integral Operator from Mixed Morrey Spaces to the Bounded Mean Oscillation Space and Lipschitz Spaces
Authors: Wei Mingquan , Sun Lanyin
Published: February 2022

In this paper, we establish the boundedness of the modified fractional integral operator from mixed Morrey spaces to the bounded mean oscillation space and Lipschitz spaces, respectively.
Retinal Surface Macrophage Changes in Thyroid Eye Disease before and after Treatment with Teprotumumab
Authors: Otero-Marquez Oscar , Fayad Mona , Pinhas Alexander , Chui Toco Y. P. , Rosen Richard B. , Reddy Harsha S.
Published: February 2022

Retinal surface macrophages play key roles in the regulation of immune response, maintenance of vitreous clarity, and tissue repair. We examined the variation of parafoveal surface macrophages in a thyroid eye disease (TED) patient before and after treatment with teprotumumab (Tepezza, Horizon therapeutics). Pre- and posttreatment parafoveal surface macrophages were imaged using clinical en face OCT, and their density was assessed using a novel cell density mapping technique. Pretreatment, surface macrophage cell density was high. Macrophages had a nonuniform spatial distribution, and their appearance was round with few protrusions, consistent with an “activated” state. Posttreatment, cell density decreased. The macrophages were regularly spaced and had a ramified appearance and filopodia-like processes, consistent with a “quiescent” state. Surface macrophage density decreased as the Clinical Activity Score (CAS) decreased with teprotumumab treatment, suggesting a potential association of these cells with an underlying intraocular and retinal inflammatory process previously not described in TED.
Active Soil Pressure of Unsaturated Soil under Rainfall Conditions
Authors: Hu Qizhi , Li Yugang
Published: February 2022

To study the change in unsaturated active earth pressure under rainfall conditions, based on the thin layer element method and shear strength formula of unsaturated soil, Iverson analysis was used to improve the traditional Coulomb earth pressure theory, and the active earth pressure formula of unsaturated soil considering the change in matric suction was derived under rainfall infiltration conditions. The results show that the active soil pressure of unsaturated soil considering rainfall is greater than that without rainfall. With the continuous occurrence of rainfall infiltration, the active soil pressure of unsaturated soil first increases, then decreases and finally tends to be stable. The above phenomenon is caused by the change in matric suction during rainfall infiltration.
Eco‐Friendly Synthesis of Carbon Nanoparticles by Laser Ablation in Water and Evaluation of Their Antibacterial Activity
Authors: AlMalki Faizah A. , Khashan Khawla S. , Jabir Majid S. , Hadi Aseel A. , Sulaiman Ghassan M. , Abdulameer Farah A. , Albukhaty Salim , Al-Karagoly Hassan , Albaqami Jawaher
Published: February 2022

Carbon nanomaterials are ground‐breaking two‐dimensional materials with a wide range of applications because of their unique properties, which include excellent optical, electrical, thermal, and mechanical capabilities; biocompatibility; and inexpensive large‐scale production costs. In this study, carbon nanostructural materials (CNMs) were effectively generated using a pulsed laser ablation method on a graphite target immersed in deionized water, and their cytotoxicity and antibacterial activities were evaluated. Lasing pulse duration, ns (1064 nm) with different laser energies (60‐220 mJ), was employed for irradiating the target. The formation of CNMs was analyzed using Fourier transform infrared spectroscopy, which demonstrated that C–H, C–C, C–O, and C=C bonds were successfully formed. TEM micrographs observed CNM formation with a spherical shape and size ranging from 20 to 90 nm. The absorbance was measured using UV‐Vis spectroscopy; it increased with increasing laser energy showing two broad shoulders around 210 and 305 nm. Thereafter, the antibacterial activity was tested against Escherichia coli and Staphylococcus aureus using the agar method. The results indicated that CNMs fabricated at laser energy 220 mJ have the highest activity against both strains and have presented inhibition zone (IZ) of about 34 ± 1.0 mm in S. aureus and 31 ± 1.5 mm for E. coli. A comparison with CNMs prepared at 160 mJ showed an IZ of 14 mm for S. aureus and of 12 mm for E. coli due to synergistic impact, while the cellular material release analysis displayed increased release with respect to the time of exposure due to inhibition of bacterial growth.
Comparison of Different Machine Learning Models in Prediction of Postirradiation Recurrence in Prostate Carcinoma Patients
Authors: Marinkovic Mladen , Popovic Marina , Stojanovic-Rundic Suzana , Nikolic Milos , Cavic Milena , Gavrilovic Dusica , Teodorovic Dusan , Mitrovic Nenad , Mijatovic Teodorovic Ljiljana
Published: February 2022

After primary treatment of localized prostate carcinoma (PC), up to a third of patients have disease recurrence. Different predictive models have already been used either for initial stratification of PC patients or to predict disease recurrence. Recently, artificial intelligence has been introduced in the diagnosis and management of PC with a potential to revolutionize this field. The aim of this study was to analyze machine learning (ML) classifiers in order to predict disease progression in the moment of prostate‐specific antigen (PSA) elevation during follow‐up. The study cohort consisted of 109 PC patients treated with external beam radiotherapy alone or in combination with androgen deprivation therapy. We developed and evaluated the performance of two ML algorithms based on artificial neural networks (ANN) and naïve Bayes (NB). Of all patients, 72.5% was randomly selected for a training set while the remaining patients were used for testing of the models. The presence/absence of disease progression was defined as the output variable. The input variables for models were conducted from the univariate analysis preformed among two groups of patients in the training set. They included two pretreatment variables (UICC stage and Gleason’s score risk group) and five posttreatment variables (nadir PSA, time to nadir PSA, PSA doubling time, PSA velocity, and PSA in the moment of disease reevaluation). The area under the receiver operating characteristic curve, sensitivity, specificity, positive predictive value, negative predictive value, and predictive accuracy was calculated to test the models’ performance. The results showed that specificity was similar for both models, while NB achieved better sensitivity then ANN (100.0% versus 94.4%). The ANN showed an accuracy of 93.3%, and the matching for NB model was 96.7%. In this study, ML classifiers have shown potential for application in routine clinical practice during follow‐up when disease progression was suspected.
Multiple Venous Thromboembolism Pharmacologic Agents Are Associated with an Increased Risk for Early Postoperative Complications following a Total Joint Arthroplasty
Authors: Shaw Jonathan H. , Wesemann Luke D. , Kadri Omar M. , Les Clifford M. , North Wayne T. , Charters Michael A.
Published: February 2022

The purpose of this study was to determine the effect that concurrent venous thromboembolism (VTE) medications had on early outcomes following primary total joint arthroplasty (TJA). 2653 total knee and hip arthroplasties were reviewed at a tertiary medical center. The study performed a multivariable comparison of outcomes in patients on 2 or more VTE medications, as well as a logistic regression on outcomes following each addition of a VTE medication postoperatively (number of VTE medications was 1–4). Controlling for gender, age, body mass index, and preoperative American Society of Anesthesiologists score throughout the analysis, patients who received 2 or more VTE prophylaxis medications had increased LOS (

p
<
0.001

), transfusions (

p
<
0.001

), emergency department visits (

p
=
0.001

), readmissions (

p
<
0.001

), 90dPOE (

p
<
0.001

), and PE (

p
<
0.001

). Every additional postoperative VTE medication incrementally increased the risk for longer LOS (

p
<
0.001

), transfusions (

p
<
0.001

), 90dPOE (

p
<
0.001

), deep vein thrombosis (

p
=
0.049

), PE (

p
<
0.001

), emergency department visits (

p
=
0.005

), and readmission (

p
=
0.010

). Patients on multiple VTE medications following TJA demonstrate significantly poorer outcomes. The current study’s findings caution the use of multiple VTE medications whenever possible immediately following a TJA.
Cytokine Changes in the Aqueous Humor in Rubella-Related Fuchs Heterochromic Iridocyclitis
Authors: Mao Yi , Lin Sijie , Zhu Chengfang , Liu Xiaodong , Wu Huping , Ou Shangkun
Published: February 2022

This retrospective study is aimed at determining the correlation between cytokine levels and virus status in the aqueous humor of 38 patients with Fuchs heterochromic iridocyclitis (FHI) with/without a viral presence between May 2017 and January 2020. The levels of cytokines were analyzed in the groups with and without virus-related FHI. Among the patients, 50% had rubella virus, 5.26% had cytomegalovirus, and 2.63% had herpes simplex virus infections. The expression of interleukin-6 (IL-6) and IL-8 was significantly higher, and that of basic fibroblast growth factor (bFGF) was significantly lower in the virus-positive group than in the virus-negative group (

P
=
0.015

,

P
=
0.001

, and

P
=
0.001

, respectively). Although there was no significant difference in the mean expression of vascular cell adhesion protein 1 (VCAM-1), IL-10, and vascular endothelial growth factor (VEGF), that of VCAM-1 and IL-10 was higher (

M
=
1338

and

M
=
1390

, respectively;

M
=
6.225

and 10.600, respectively) and that of VEGF was lower (

M
=
134.5

and

M
=
38.70

, respectively) in the virus-positive group than in the virus-negative group. Similar findings were observed for the expressions of IL-6, IL-8, and bFGF in the rubella-positive and rubella-negative groups. Viral presence was highly related to FHI, especially that of the rubella virus. High levels of inflammatory cytokines and low levels of neovascularization-related factors are involved in rubella-related FHI. These study findings could be helpful in the diagnosis and treatment of FHI.
Influence of Periodontitis, Implant, and Prosthesis Characteristics on the Peri-Implant Status: A Cross-Sectional Study
Authors: Papalou Ioanna , Vagia Panagiota , Cakir Ahmet , Tenenbaum Henri , Huck Olivier , Davideau Jean-Luc
Published: February 2022

Background. The association between peri-implant diseases and the periodontal, implant, and prosthesis characteristics has been characterized in various ways. Purpose. The aim of this study was to evaluate the link between the peri-implant and periodontal status and the influence of implant and prosthesis parameters during implant follow-up. Materials and Methods. One hundred and seven patients with a total of 310 implants that had at least one year of function who were attending periodontal and implant maintenance at a university clinic setting were included in this cross-sectional study. The demographic, periodontal, peri-implant tissue, implant, and prosthesis parameters were recorded. A pocket depth > 4 mm with bleeding on probing defined periodontal/peri-implant soft tissue diseased sites. Analyses were performed at the patient and implant levels using univariable and multivariable mixed regression analysis. Results. The mean implant follow-up was 7.22 years. At the patient level, the bleeding on probing and pocket depth measurements were more pronounced around the implant than around the teeth. The opposite was observed for plaque and the clinical attachment levels. At the implant level, multivariable analysis showed that the periodontal and corresponding peri-implant tissue parameters, such as diseased sites, were closely related. The implant location, bone level, and number were selectively associated with the implant bone level, while cemented retention and emergence restoration profile influenced the implant pocket depth. Conclusions. The present study suggested that clinical peri-implant and periodontal soft tissue statuses were different, which could be a consequence of the initial implant and prosthesis healing process. However, during implant follow-up, the peri-implant parameters were predominantly associated with their corresponding periodontal parameters regardless of an association with the implant and prosthesis characteristics. This trial is registered with ClinicalTrials.gov ID: NCT03841656.
Linking a Trio of Molecular Features in Clear-Cell Renal Cell Carcinoma
Authors: Labaki Chris , Van Allen Eliezer M. , Choueiri Toni K.
Published: February 2022

Clear-cell renal cell carcinoma exhibits unique molecular features, some of which are associated with the response to immunotherapy. However, the interactions between different genomic entities remains incompletely understood. In this issue, Zhou and colleagues show that PBRM1 inactivation is associated with increased expression of specific human endogenous retroviruses and identify HIF1/2A transcriptional activity as an important mediator of this interaction, helping uncover the interplay between some of the key molecular traits of this disease.

See related article by Zhou et al., p. 285 (3).
Sexually Dimorphic Properties in Meiotic Chromosome
Authors: Ishiguro Kei-Ichiro
Published: February 2022

Background:Meiosis is a crucial process for germ cell development. It consists of 1 round of DNA replication followed by 2 rounds of chromosome segregation, producing haploid gametes from diploid cells. During meiotic prophase, chromosomes are organized into axis-loop structures, which underlie meiosis-specific events such as meiotic recombination and homolog synapsis. Meiosis-specific cohesin plays a pivotal role in establishing higher-order chromosome architecture and regulating chromosome dynamics. Summary: Notably, sexually dimorphic properties of chromosome architecture are prominent during meiotic prophase, despite the same axial proteins being conserved between male and female. The difference in chromosome structure between the sexes gives sexual differences in the regulation of meiotic recombination and crossover distribution. Key Messages: This review mainly focuses on the sexual differences of meiosis from the viewpoint of chromosome structure in mammals, elucidating the differences in meiotic recombination and homolog synapsis between the sexes.
Post-Immunotherapy Robotic-Assisted Resection for Primary Anorectal Melanoma: A Case Report
Authors: Tsutsui Keita , Ogata Dai , Tsukamoto Shunsuke , Moritani Konosuke , Mori Taisuke , Namikawa Kenjiro , Takahashi Akira , Kanemitsu Yukihide , Yamazaki Naoya
Published: February 2022

Anorectal malignant melanoma (AMM) is a rare and aggressive neoplasm. Here, we report a case of AMM that was treated with robotic-assisted abdominoperineal resection (APR) after immunotherapy. A 68-year-old Japanese woman presented at our hospital because of diagnosis AMM. Computed tomography revealed a mass in the lower anorectal region and enlarged perirectal lymph nodes, but showed no evidence of distant metastases. We determined that radical resection would be difficult; therefore, the patient received immunotherapy with pembrolizumab for nine cycles. The size of pararectal lymph nodes was reduced, and the patient subsequently underwent robot-assisted APR and lymph node dissection. Histopathological examination showed spindle-shaped atypical melanocytes with acidophilic changes indicative of tumor cell necrosis in the rectal mucosa. We found no viable tumor cells in all 48 lymph nodes that were resected, and resection margins were tumor free. The patient was able to complete 15 cycles of adjuvant immunotherapy with pembrolizumab and remained relapse free at the 2-year postoperative follow-up. The present case showed that combination of complete surgical resection and immunotherapy is expected to improve outcomes in AMM patients if immunotherapy is effective.
Genetic Analysis of a Family with Multiple Incidences of Prostate Cancer
Authors: Feng Ninghan , Liu Fengping , Xu Xinyu , Wang Yang , Sheng Qingsong , Zhu Kuichun
Published: February 2022

A family with multiple members diagnosed with prostate cancer was identified, and genetic variants were analyzed. Three brothers were diagnosed with prostate cancer. Germline variants in BRCA1, BRCA2, TINF2, and CD19 were found through next-generation DNA sequencing using a hereditary cancer panel. The BRCA1 G275D variant was present in patients, but absent in the healthy member. An ELAC2 variant was found in 1 patient. Several mutations were predicted to be deleterious by a set of computation programs. Multiple gene mutations might contribute to the overall predisposition to prostate cancer in the family. Even in cases with potentially deleterious variants in BRCA1 or BRCA2, there could be diverse clinical manifestations.
Primary Sclerosing Cholangitis Complicated with Aphthoid Colitis Difficult to Diagnose from IgG4-Related Sclerosing Cholangitis
Authors: Imai Jin , Ichikawa Hitoshi , Kaneko Motoki , Ito Hiroyuki , Takashimizu Shinji , Shirai Takayuki , Tajiri Takuma , Watanabe Norihito , Suzuki Hidekazu
Published: February 2022

A 19-year-old man visited our hospital because of diarrhea and blood and liver dysfunction. Magnetic and endoscopic retrograde cholangiography revealed diffuse narrowing of the common biliary tract and intrahepatic biliary tract. A biopsy specimen from the narrowed area of the common biliary tract revealed IgG4-related sclerosing cholangitis (IgG4-SC). Colonoscopy showed multiple aphthoid colitis. He was treated with corticosteroids, and the levels of hepatobiliary enzymes, IgG, and IgG4 gradually decreased. This is an extremely rare case of colitis in which the patient had a phenotype of sclerosing cholangitis similar to IgG4-SC, which was finally diagnosed as primary sclerosing cholangitis.
Intra-Articular Proximal Phalanx Osteotomy Using a Three-Dimensional Printed Template: A Case Report
Authors: Tan Yuhan , Vissers Gino , Vanmierlo Bert , Goubau Jean
Published: February 2022

Malunion of an intra-articular fracture of the metacarpophalangeal joint can cause a dramatic effect, decreasing mobility and strength. For small joints, surgical options are often drastic; joint arthroplasty or arthrodesis. However, in cases of preserved joint space, an intra-articular osteotomy can be proposed. In order to improve preoperative planning, considering the small size of the articular surface and the importance of a precise osteotomy plane, we used a preoperative three-dimensional printed template to perform the intra-articular opening wedge osteotomy. This was followed by plate and screw osteosynthesis after adding a freeze-dried allograft to the created defect. The outcome at 1-year follow-up was more than satisfactory, with a normal range of motion and a restored, painless grip strength. A three-dimensional printed template is a useful, accurate, and efficient method to correct malunion of intra-articular fractures of the base of the proximal phalanx at the metacarpophalangeal joint.
Cost-Effectiveness of a Sublingual Bacterial Vaccine for the Prophylaxis of Recurrent Urinary Tract Infections
Authors: Carrión-López Pedro , Martínez-Ruiz Jesus , Giménez-Bachs José Miguel , Fernández-Anguita Pedro Jesús , Díaz de Mera-Sánchez Migallón Inmaculada , Legido-Gómez Oscar , Rico-Marco Saúl , Lorenzo-Sánchez Marta Victoria , Salinas-Sánchez Antonio Santiago
Published: February 2022

Introduction: Recurrent urinary tract infections (rUTIs) affect 5–10% of women, resulting in an enormous healthcare and society burden. Uromune® is a polybacterial sublingual vaccine with an excellent clinical benefit in rUTI prophylaxis. This study assesses the impact of sublingual vaccination on healthcare resource use and expenditures associated with this pathology. Methods: A quasi-experimental, pretest-posttest, single center study including women with rUTI and vaccinated with Uromune® in real-life clinical practice was performed. Variables were the need of healthcare resources, collected prospectively during two follow-up years, and the rUTI-associated expenditure, calculated using the micro-costing methodology; these were compared before and after vaccination. Results: A total of 166 women {mean (standard deviation [SD]) urinary tract infection episodes/year 6.19 (2.15)} were included. After vaccination, annual consultations with a primary care physician (PCP) (43.9%), emergency room visits (71.8%), urinary analysis (90.0%), and ultrasound exams (35.6%) decreased compared to pre-vaccination (all p < 0.001). Per patient consumption in antibiotics, PCP consultations, emergency room visits, and complementary exams significantly decreased (all p < 0.02), resulting in a reduction in healthcare expenditure per patient/year from mean (SD) 1,001.1 (655.0) to 497.1 (444.4) EUR. Conclusion: Sublingual bacterial vaccination with Uromune® decreased healthcare resource use and associated expenditure in women with rUTI, representing an optimal strategy to reduce rUTI-associated healthcare and economic burden.
Comprehensive Genomic Profiling for Therapeutic Decision and Identification of Gene Mutation in Uterine Endometrial Dedifferentiated Carcinoma
Authors: Taira Yusuke , Shimoji Yuko , Arakaki Yoshihisa , Nakamoto Tomoko , Kudaka Wataru , Aoki Yoichi
Published: February 2022

Endometrial dedifferentiated carcinoma is a new concept among endometrial malignancies, is rare, and has a poor prognosis as it is discovered in advanced stages and has no established treatment. It has higher rates of gene mutations, such as mismatch repair, than general endometrial cancer and has been associated with Lynch syndrome. However, due to its heterogeneity, case-by-case searches are needed. Comprehensive genomic profiling by Foundation One® CDx can comprehensively identify over 300 gene mutations via a next-generation sequencer and can evaluate biomarkers, such as the microsatellite status and tumor mutation burden. Therefore, it may be beneficial in identifying therapeutic targets and drugs for diseases whose treatment has not been established. In this case, 13 therapies, including immune checkpoint inhibitor therapy for microsatellite instability-High and 40 clinical trials for several gene mutations might be beneficial. We report a case of endometrial dedifferentiated carcinoma for which Foundation One® CDx gene profiling was used to propose treatment.