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Janet WH Sit,1 Sek Ying Chair,1 Kai Chow Choi,1 Carmen WH Chan,1 Diana TF Lee,1 Aileen WK Chan,1 Jo LK Cheung,1 Siu Wai Tang,2 Po Shan Chan,2 Ruth E Taylor-Piliae3 1The Nethersole School of Nursing, The Chinese University of Hong Kong, Shatin, New Territories, 2Department of Medicine and Rehabilitation, Tung Wah Eastern Hospital, Hong Kong Hospital Authority, Causeway Bay, Hong Kong, People’s Republic of China; 3College of Nursing, The University of Arizona, Tucson, AZ, USA Background: Self-management after a stroke is a challenge because of multifaceted care needs and complex disabling consequences that cause further hindrance to patient participation. A 13-week stroke patient empowerment intervention (Health Empowerment Intervention for Stroke Self-management [HEISS]) was developed to enhance patients’ ability to participate in self-management.Purpose: To examine the effects of the empowerment intervention on stroke patients’ self-efficacy, self-management behavior, and functional recovery.Methods: This is a single-blind randomized controlled trial with stroke survivors assigned to either a control group (CG) receiving usual ambulatory rehabilitation care or the HEISS in addition to usual care (intervention group [IG]). Outcome data were collected at baseline (T0), 1 week (T1), 3 months (T2), and 6 months (T3) postintervention. Data were analyzed on the intention-to-treat principle. The generalized estimating equation model was used to assess the differential change of self-efficacy in illness management, self-management behaviors (cognitive symptom management, communication with physician, medication adherence, and self-blood pressure monitoring), and functional recovery (Barthel and Lawton indices) across time points (baseline = T0, 1 week = T1, 3 months = T2, and 6 months = T3 postintervention) between the two groups.Results: A total of 210 (CG =105, IG =105) Hong Kong Chinese stroke survivors (mean age =69 years, 49% women, 72% ischemic stroke, 89% hemiparesis, and 63% tactile sensory deficit) were enrolled in the study. Those in IG reported better self-efficacy in illness management 3-month (P=0.011) and 6-month (P=0.012) postintervention, along with better self-management behaviors at all follow-up time points (all P0.05). Those in IG had significantly better functional recovery (Barthel, all P

Magnetic flux ropes are structures that are common in the corona of the sun and presumably all stars. They can be thought of as the building blocks of solar structures. They have been observed in Earth's magnetotail and near Mars and Venus. When multiple flux ropes are present magnetic field line reconnection, which converts magnetic energy to other forms, can occur when they collide. The structure of multiple magnetic ropes, the interactions between multiple ropes, and their topological properties such as helicity and writhing have been studied theoretically and in laboratory experiments. Here, we report on spiky potential and magnetic fields associated with the ropes. We show that the potential structures are chaotic for a range of their temporal half-widths and the probability density function (PDF) of their widths resembles the statistical distribution of crumpled paper. The spatial structure of the magnetic spikes is revealed using a correlation counting method. Computer simulation suggests that the potential structures are the nonlinear end result of an instability involving relative drift between ions and electrons.

A seven-year-old girl presented with pain in multiple joints and constitutional symptoms over a period of four months. There were no significant clinical findings apart from joint tenderness. Blood test results did not indicate any specific pathology and initial radiology imaging was normal. Subsequent careful examination of her X-ray images led to an MRI of her left knee, which revealed acute osteonecrotic changes. A following whole-body MRI examination demonstrated multifocal bony lesions. Bone marrow examination conclusively diagnosed acute lymphoblastic leukaemia (ALL). Acute osteonecrosis has classically been described as a complication of treatment in children with ALL and has not been recognised as a presenting feature until recently.

Building upon the job demands–resources (JD-R) theory, this research offers an in-depth exploration of the mechanisms by which idiosyncratic deals (I-deals), such as personalized work arrangements, can enhance academics’ psychological empowerment (PE) and hence affect their work engagement. This study’s purpose was to investigate whether PE mediates the relationships between task and work responsibilities I-deals, flexibility I-deals, and work engagement among academics in higher education and whether the mediating effects are moderated by academics’ internal locus of control. Using an online platform, the survey questionnaire was sent to 650 academics working in higher education. The results reveal that task and work responsibilities I-deals and flexibility I-deals, are positively associated with the academics’ work engagement and that PE mediates those relationships. Additionally, the internal locus of control strengthens the positive relationship between task and work responsibilities I-deals and PE, and it enhances the indirect effect of task and work responsibilities I-deals on academics’ work engagement through PE. Though, this study did not find the moderating effect of internal locus of control on the flexibility I-deals–PE relationship; however, the results indicate that internal locus of control boosts the indirect effect of flexibility I-deals on academics’ work engagement through PE.

An infectious disease is the most apprehensive problem in aquaculture as it can lead to high mortality in aquatic organisms and massive economic loss. Even though significant progress has been accomplished in therapeutic, prevention, and diagnostic using several potential technologies, more robust inventions and breakthroughs should be achieved to control the spread of infectious diseases. MicroRNA (miRNA) is an endogenous small non-coding RNA that post-transcriptionally regulates the protein-coding genes. It involves various biological regulatory mechanisms in organisms such as cell differentiation, proliferation, immune responses, development, apoptosis, and others. Furthermore, an miRNA also acts as a mediator to either regulate host responses or enhance the replication of diseases during infection. Therefore, the emergence of miRNAs could be potential candidates for the establishment of diagnostic tools for numerous infectious diseases. Interestingly, studies have revealed that miRNAs can be used as biomarkers and biosensors to detect diseases, and can also be used to design vaccines to attenuate pathogens. This review provides an overview of miRNA biogenesis and specifically focuses on its regulation during infection in aquatic organisms, especially on the host immune responses and how miRNAs enhance the replication of pathogens in the organism. In addition to that, we explored the potential applications, including diagnostic methods and treatments, that can be employed in the aquaculture industry.

After the outbreak of novel coronavirus (COVID-19) in late December 2019, in an attempt to mitigate its development, the decision to close institutions around the world was made. To continue imparting education and delivering the learning material to their students, many institutions adopted for digital or E-learning. To support those institutions attempting to digitize their learning during this pandemic, the main aim of this study is to examine the students’ accessibility to and success of E-learning portals. Using the DeLone and McLean (D&M) Model, the study explains the differences between female and male students’ accessibility to E-learning portals. This study compares female and male student groups regarding the usage of the E-learning portal in the higher education context. Using an online google survey, the data were collected from 254 students, including males and females. The study utilized PLS-SEM to perform a multi-group analysis examining female and male student groups. The study found a significant and direct relationship of e-service quality with system use and user satisfaction for females and male student groups. System quality also supported the relationship with user satisfaction. The study further revealed a significant and positive relationship between system use and user satisfaction with E-learning portal success for females and male student groups. This study also concluded that insignificant difference exists in using the E-learning portal between female and male student in higher education institutions.

Purpose – The purpose of this paper is to investigate the influence of human resource management (HRM) practices, (recruitment and selection) and organizational performance (OP) through mediation role of ethical climates (ECs) in Nigerian educational agencies. Design/methodology/approach – Quantitative data were collected from 181 educational agencies represented by director of administration; SmartPLS-SEM was used in testing the relationship, as well as testing the mediating effect of ECs. Findings – The results revealed strong support for the mediating role of ECs on the relationship between HRM practice (recruitment and selection) and OP. Research limitations/implications – Policy makers and executives in educational agencies need to consider making appropriate decision in terms of effectively adopt and implement performance-based HRM practices that can encourage and create ethical behavior of employees’ and within organization. Through the adoption and utilization of these practices, educational agencies can enhance OP. Practical implications – This study contributes to the understanding of the relationship between HRM and OP by clarifying a pathway between these variables. This study also generalizes consistent findings on the HRM practices and OP relationship to a different discipline and context, i.e. educational agencies. Originality/value – This study adds to the domain of resource-based view by incorporating EC as a mediator between HRM practices and OP.

Aim. This paper is a report of a study to identify the changes in poststroke quality of life and other clinical issues among older Chinese adults from 1 month to 6 months after stroke and the predictors of poststroke quality of life at 6 months. Background. Stroke survivors are known to suffer from prolonged and multiple impairments leading to a compromised quality of life, but few studies report early predictors for quality of life among older Chinese adults after active rehabilitation has been undertaken during the first 6 months after stroke. Method. A total of 214 patients with first-ever ischaemic stroke were interviewed by a research nurse at 1 month and 188 patients were interviewed again 6 months after hospital admission for stroke. Assessment of quality of life was done using the Modified Rankin Scale for Quality of Life. Changes in and relationships between quality of life and variables in five domains were explored: bio-anatomical, physical, emotional, cognitive, communicative and social support. The data were collected in 2004-2005. Results. Quality of life among two-thirds of participants was unchanged or lower when scores at 1 month and 6 months after stroke were compared. Length of hospital stay after admission for stroke and other 1-month factors - level of worry over current health, cognitive and self-care deficits - were identified as having independent effects on quality of life at 6 months. Conclusion. Clinicians need to observe for early signs of mild cognitive impairments and emotional needs of stroke survivors, as well as to consider longer-term interventions to enhance poststroke quality of life. [ABSTRACT FROM AUTHOR]

Kajian ini menyelidik hubungan antara pengurusan sumber manusia (PSM), budaya organisasi dan prestasi organisasi menerusi pemodelan persamaan struktur. Kajian ini berasaskan reka bentuk tinjauan dan bersifat keratan rentas. Sebanyak 137 soal selidik dikutip daripada organisasi pembuatan di Malaysia dan digunakan dalam analisis statistik. Amalan PSM termasuk pengambilan pekerja, penilaian prestasi, latihan dan pembangunan, ganjaran berasaskan prestasi, pengurusan kerjaya, perkongsian maklumat, dan jaminan pekerjaan. Pemboleh ubah budaya organisasi meliputi penglibatan, koordinasi dan integrasi, komunikasi terbuka, kepercayaan, penambahbaikan, dan kerjasama. Sementara pemboleh ubah prestasi organisasi merangkumi kadar pertumbuhan jualan, hasilan operasi dan hasilan sumber manusia. Hampir 57 peratus daripada varians dalam konstruk budaya organisasi dapat diterangkan oleh konstruk PSM. Sementara kedua-dua konstruk PSM dan budaya organisasi dapat menerangkan kira-kira 68 peratus varians dalam konstruk prestasi organisasi. Model persamaan struktur menunjukkan budaya organisasi berperanan sebagai pengantara dalam hubungan antara PSM dengan prestasi organisasi. Kata kunci: Pengurusan sumber manusia, budaya organisasi, prestasi organisasi, LISREL.

Kajian ini bertujuan meninjau persepsi guru terhadap keadilan penilaian prestasi dari segi keadilan pengagihan dan keadilan prosedur. Di samping itu, kajian ini juga meninjau hubungan antara kedua-dua aspek keadilan penilaian prestasi dan impaknya terhadap pencapaian organisasi sekolah yang diukur melalui motivasi kerja guru dan prestasi akademik sekolah. Tinjauan telah dijalankan ke atas 110 buah sekolah menengah yang dipilih secara rawak daripada senarai sekolah menengah di Kedah dan Perlis. Sebanyak 86 buah sekolah telah mengambil bahagian dalam kajian, iaitu mewakili 78% kadar respon. Analisis korelasi menunjukkan bahawa (a) keadilan prosedur mempunyai korelasi positif yang signifikan dengan keadilan pengagihan; (b) motivasi kerja mempunyai korelasi positif yang signifikan dengan keadilan pengagihan; dan (c) prestasi akademik sekolah mempunyai korelasi positif yang signifikan dengan kedua-dua keadilan prosedur dan pengagihan. Di samping itu, keputusan kajian juga menunjukkan bahawa kedua-dua aspek keadilan mempunyai perhubungan positif yang signifikan dengan prestasi akademik sekolah.

Kajian empirikal ini menggunakan analisis faktor peringkat kedua, untuk menguji sama ada set prinsip-prinsip pengurusan kualiti yang disintesiskan daripada falsafah guru kualiti serta kerangka anugerah kualiti dan system pengurusan kualiti, secara bersama dapat membentuk satu faktor peringkat lebih tinggi yang boleh dinamakan “TQMâ€. Atur cara komputer LISREL 8 (Jöreskog & Sörbom, 1993) telah digunakan untuk menganggar dan menilai kebagusuaian model faktor peringkat kedua yang dikemukakan dengan menggunakan data tinjauan yang diperoleh daripada jabatan pendidikan yang dipilih secara rawak daripada sepuluh buah universiti awam tempatan di Malaysia. Keputusan analisis menunjukkan kesesuaian yang boleh diterima antara model kajian dengan data, dan menyokong kewujudan perhubungan peringkat kedua di antara prinsip-prinsip pengurusan kualiti.

Kajian ini menyelidik hubungan antara prinsip pengurusan kualiti menyeluruh (TQM) dengan hasilan organisasi pendidikan dalam bidang kepuasan hati pelajar dan pencapaian akademik pelajar. Kajian ini menggunakan pendekatan tinjauan dan bersifat keratan rentas. Tinjauan telah dijalankan ke atas 100 buah jabatan pendidikan yang dipilih secara rawak di 10 buah universiti awam tempatan. Sebanyak 85 buah jabatan pendidikan telah mengambil bahagian dalam kajian ini. Saiz sampel ini mewakili hampir 70% daripada populasi jabatan pendidikan. Semua hipotesis telah diuji dengan menggunakan analisis korelasi dan regresi linear. Hasil kajian menyokong semua hipotesis yang dikemukakan, dan ini menyarankan bahawa amalan prinsip-prinsip TQM boleh memanfaatkan organisasi pendidikan. Korelasi Pearson menunjukkan bahawa kesemua prinsip TQM mempunyai korelasi positif yang signifikan dengan pembolehubah utama kepuasan hati pelajar dan pencapaian akademik pelajar. Analisis komponen utama dan regresi linear mudah telah dijalankan untuk mengurangkan kesan multikekolinearan serta menentukan perhubungan antara pembolehubah Keputusan menunjukkan prinsip-prinsip TQM dapat menerangkan peratusan varians yang signifikan.

Objektif artikel ini adalah untuk meneroka saling perhubungan antara prinsip-prinsip Pengurusan Kualiti Menyeluruh (TQM), kepuasan hati staf; kepuasan hati pelajar dan pencapaian akademik pelajar. Elemen-elemen utama bagi pengurusan kualiti dalam konteks pendidikan dihuraikan secara ringkas, dan satu kerangka konseptual diketengahkan untuk menjelaskan saling perhubungan yang dihipotesis antara prinsip-prinsip TQM, kepuasan hati staf (pelanggan dalaman), kepuasan hati pelajar (pelanggan luaran) dan pencapaian akademik pelajar. Penulis merumuskan bahawa prestasi organisasi pendidikan dalam aspek kepuasan hati staf dan pelajar serta pencapaian akademik pelajar merupakan ukuran yang relevan bagi segala usaha penambahbaikan kualiti pendidikan, dan menekankan kepentingan kepuasan hati pelanggan dalaman serta luaran sebagai pengantara dalam perhubungan prinsip-prinsip TQM dengan pencapaian akademik pelajar.

Kajian ini bertujuan menyelidik amalan perekrutan semasa di Malaysia khususnya terhadap jawatan pengurusan. la juga bertujuan untuk meneliti tahap pengetahuan personal dan tahap penggunaan teknik perekrutan. Seterusnya, kajian ini juga meninjau persepsi pengurus sumber manusia tentang keberkesanan teknik perekrutan dalam mendapatkan pekerja yang berkualiti dan yang dapat menunjukkan prestasi kerja yang tinggi. Berdasarkan kepada skor purata, hasil kajian menunjukkan bahawa tahap pengetahuan personal terhadap teknik perekrutan adalah lebih tinggi berbanding dengan tahap penggunaan oleh syarikat. Hasil kajian juga mengesahkan teknik perekrutan tradisional seperti iklan surat khabar, resume dan rujukan pekerja masih popular digunakan.

Smilax glabra Roxb. (SGR) is known for its high nutritional and therapeutic value. However, the frequent appearance of counterfeit products causes confusion and inconsistent quality among SGR varieties. Herein, this study collected the proportion of SGR adulteration and used high-performance liquid chromatography (HPLC) to measure the astilbin content of SGR. Then Fourier-transform near-infrared (FT-NIR) technology, combined with multivariate intelligent algorithms, was used to establish partial least squares regression quantitative models for detecting SGR adulteration and measuring astilbin content, respectively. The method conducted a quantitative analysis of dual indicators through single-spectrum data acquisition (QADS) to comprehensively evaluate the authenticity and superiority of SGR. The coefficients of determination (R 2 ) for both the calibration and prediction sets exceeded 0.96, which successfully leverages FT-NIR combined with multivariate intelligent algorithms to considerably enhance the accuracy and reliability of quantitative models. Overall, this research holds substantial value in the comprehensive quality evaluation in functional health foods., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Drug resistance in cancer therapy is the major reason for poor prognosis. Addressing this clinically unmet issue is important and urgent. In this study, we found that targeting USP24 by the specific USP24 inhibitors, USP24-i and its analogues, dramatically activated autophagy in the interphase and mitotic periods of lung cancer cells by inhibiting E2F4 and TRAF6, respectively. USP24 functional knockout, USP24 C1695A , or targeting USP24 by USP24-i-101 inhibited drug resistance and activated autophagy in gefitinib-induced drug-resistant mice with doxycycline-induced EGFR L858R lung cancer, but this effect was abolished after inhibition of autophagy, indicating that targeting USP24-mediated induction of autophagy is required for inhibition of drug resistance. Genomic instability and PD-L1 levels were increased in drug resistant lung cancer cells and were inhibited by USP24-i-101 treatment or knockdown of USP24. In addition, inhibition of autophagy by bafilomycin-A1 significantly abolished the effect of USP24-i-101 on maintaining genomic integrity, decreasing PD-L1 and inhibiting drug resistance acquired in chemotherapy or targeted therapy. In summary, an increase in the expression of USP24 in cancer cells is beneficial for the induction of drug resistance and targeting USP24 by USP24-i-101 optimized from USP24-i inhibits drug resistance acquired during cancer therapy by increasing PD-L1 protein degradation and genomic stability in an autophagy induction-dependent manner., (© 2024. The Author(s).)

Fluorescence bioimaging with near-infrared II (NIR-II) emissive organic fluorophores has proven to be a viable noninvasive diagnostic technique. However, there is still the need for the development of fluorophores that possess increased stability as well as functionalities that impart stimuli responsiveness. Through strategic design, we can synthesize fluorophores that possess not only NIR-II optical profiles but also pH-sensitivity and the ability to generate heat upon irradiation. In this work, we employ a donor-acceptor-donor (D-A-D) design to synthesize a series of NIR-II fluorophores. Here we use thienothiadiazole (TTD) as the acceptor, 3-hexylthiophene (HexT) as the π-spacer and vary the alkyl amine donor units: N , N -dimethylaniline (DMA), phenylpiperidine (Pip), and phenylmorpholine (Morp). Spectroscopic analysis shows that all three derivatives exhibit emission in the NIR-II region with λ emi max ranging from 1030 to 1075 nm. Upon irradiation, the fluorophores exhibited noticeable heat generation through non-radiative processes. The ability to generate heat indicates that these fluorophores will act as theranostic (combination therapeutic and diagnostic) agents in which simultaneous visualization and treatment can be performed. Additionally, biosensing capabilities were supported by changes in the absorbance properties while under acidic conditions as a result of protonation of the alkyl amine donor units. The fluorophores also show minimal toxicity in a human mammary cell line and with murine red blood cells. Overall, initial results indicate viable NIR-II materials for multiple biomedical applications., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Although FOXP3 + regulatory T cells (Treg) depend on IL-2 produced by other cells for their survival and function, the levels of IL-2 in inflamed tissue are low, making it unclear how Treg access this critical resource. Here, we show that Treg use heparanase (HPSE) to access IL-2 sequestered by heparan sulfate (HS) within the extracellular matrix (ECM) of inflamed central nervous system tissue. HPSE expression distinguishes human and murine Treg from conventional T cells and is regulated by the availability of IL-2. HPSE -/- Treg have impaired stability and function in vivo, including in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Conversely, endowing monoclonal antibody-directed chimeric antigen receptor (mAbCAR) Treg with HPSE enhances their ability to access HS-sequestered IL-2 and their ability to suppress neuroinflammation in vivo. Together, these data identify a role for HPSE and the ECM in immune tolerance, providing new avenues for improving Treg-based therapy of autoimmunity., (© 2024. The Author(s).)

This study explored the preparation process of the placebo of Jiawei Ermiao Granules and evaluated the placebo effect, aiming to provide qualified placebo samples for clinical trials of Jiawei Ermiao Granules and a reference for the preparation and quality evaluation of placebos of traditional Chinese medicine granules. On the basis of the comprehensive analysis results of Jiawei Ermiao Granules, the orthogonal experiment was conducted to optimize the flavoring agents and colorants. After manual evaluation, the placebo formula was determined as dextrin 10 g, Codonopsis Radix extract 5.0 g, bitter melon extract 1.6 g, Mume Fructus extract 0.3 g, stevioside 0.1 g, sucrose octaacetate 0.004 g, indigo 0.004 g, lemon yellow 0.003 1 g, sunset yellow 0.001 8 g, bitter tea powder 0.001 8 g, caramel 0.001 3 g. Pilot trials were conducted on the placebo formula. The simulation effect of placebo was evaluated independently and comparatively, and the objectively evaluated by electronic nose and electronic tongue. The results showed that the independent manual evaluation of the placebo formula had higher error rate, and the placebo and Jiawei Ermiao Granules showed the similarity of 99.61% in the comparative manual evaluation. The smell similarity between the placebo and Jiawei Ermiao Granules was 99.19%, and the electronic tongue test showed little difference in the taste. In conclusion, the placebo prepared in this study shows a high similarity to Jiawei Ermiao Granules, which is not easy to break the blindness when being applied to clinical trials. This study provides a reference for the preparation and quality evaluation and promotes the large-scale production of placebos of traditional Chinese medicine granules, playing a role in improving the persuasiveness and acceptance of the efficacy of traditional Chinese medicines.

Chimeric antigen receptor T cell (CAR-T) therapy has been applied in the treatment of B-cell lymphoma; however, CAR-T manufacturing requires virus- or non-virus-based genetic modification, which causes high manufacturing costs and potential safety concerns. Antibody-cell conjugation (ACC) technology, which originated from bio-orthogonal click chemistry, provides an efficient approach for arming immune cells with cancer-targeting antibodies without genetic modification. Here, we applied ACC technology in Vγ9Vδ2 T (γδ2 T) cells to generate a novel off-the-shelf CD20-targeting cell therapy ACE1831 (rituximab-conjugated γδ2 T cells) against relapsed/refractory B-cell lymphoma. ACE1831 exhibited superior cytotoxicity against B-cell lymphoma cells and rituximab-resistant cells compared to γδ2 T cells without rituximab conjugation. The in vivo xenograft study demonstrated that ACE1831 treatment strongly suppressed the aggressive proliferation of B-cell lymphoma and prolonged the survival of tumor-bearing mice with no observed toxicity. Mass spectrometry analysis indicated that cell activation receptors including the TCR complex, integrins and cytokine receptors were conjugated with rituximab. Intriguingly, the antigen recognition of the ACC-linked antibody/receptor complex stimulated NFAT activation and contributed to ACE1831-mediated cytotoxicity against CD20-expressing cancer cells. This study elucidates the role of the ACC-linked antibody/receptor complex in cytotoxicity and supports the potential of ACE1831 as an off-the-shelf γδ2 cell therapy against relapsed/refractory B-cell lymphoma.

There appear to be huge variations and aberrations in the reported data in COVID-19 2 years now into the pandemic. Conflicting data exist at almost every level and also in the reported epidemiological statistics across different regions. It is becoming clear that COVID-19 is a polymorphic inflammatory spectrum of diseases, and there is a wide range of inflammation-related pathology and symptoms in those infected with the virus. The host's inflammatory response to COVID-19 appears to be determined by genetics, age, immune status, health status and stage of disease. The interplay of these factors may decide the magnitude, duration, types of pathology, symptoms and prognosis in the spectrum of COVID-19 disorders, and whether neuropsychiatric disorders continue to be significant. Early and successful management of inflammation reduces morbidity and mortality in all stages of COVID-19.

A rapid and sensitive approach for the detection of endopeptidases via a new analyte-triggered mutual emancipation of linker-immobilized enzymes (AMELIE) mechanism has been developed and demonstrated using a matrix metallopeptidase, a collagenase, as the model endopeptidase analyte. AMELIE involves an autocatalytic loop created by a pair of selected enzymes immobilized on solid substrates via linkers with specific sites that can be proteolyzed by one another. These bound enzymes are spatially separated so that they cannot act upon their corresponding substrates until the introduction of the target endopeptidase analyte that can also cleave one of the linkers. This triggers the self-sustained loop of enzymatic activities to emancipate all the immobilized enzymes. In this proof of concept, signal transduction was achieved by a colorimetric horseradish peroxidase-tetramethylbenzidine (HRP-TMB-H 2 O 2 ) reaction with HRP that are also being immobilized by one of the linkers. The pair of immobilized enzymes were collagenase and alginate lyase, and they were immobilized by an alginate linker and a short peptide chain containing the amino acid sequence of Leu-Gly-Pro-Ala for collagenase. A detection limit of 2.5 pg collagenase mL -1 with a wide linear range up to 4 orders of magnitude was achieved. The AMELIE biosensor can detect extracellular collagenase in the supernatant of various bacteria cultures, with a sensitivity as low as 10 3 cfu mL -1 of E. coli . AMELIE can readily be adapted to provide the sensitive detection of other endopeptidases., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

The evidential reasoning (ER) rule has been widely applied in the multiple attribute decision making (MADM), which makes the decision-making process transparent and credible by using a belief structure. To improve the ability of the ER rule in dealing with the interval uncertainty, a new interval ER (IER) rule is proposed in this article. The interval uncertainty is described as the interval grade in the new frame of discernment (FoD) to model the local ignorance. It is proved that the IER rule is a generalization of the ER rule. To study the influence of perturbation on the IER rule, the perturbation is first introduced to the belief structure, and the perturbation analysis (PA) is conducted for the IER rule. An optimization model is established to estimate the perturbation threshold, which can measure the effectiveness of the inference result under perturbation. Two numerical examples and a case study are carried out, respectively, to show the implementation process of the proposed IER rule and validate its effectiveness in different decision-making scenarios.

Objective: Vagus nerve stimulation (VNS) plus rehabilitation (Rehab) has shown a potential effect on recovery with a stroke. We systematically synthesised studies examining VNS+Rehab for improving motor function, mental health and activities of daily living (ADL) postintervention and at the end of follow-up in patients with a stroke., Methods: The search was performed in electronic databases EMBASE, Medline, EBSCO, Cochrane Library, PubMed, PsycINFO, CINAHL, CNKI, and WANFANG and three clinical trial registries from inception to February 2022. Randomised controlled trials (RCTs) applied VNS+Rehab in stroke were included., Results: Seven RCTs involving 263 (analysed) participants was included. The effect size of VNS+Rehab over Rehab for motor function was medium postintervention (g=0.432; 95% CI 0.186 to 0.678) and large at the end of follow-up (g=0.840; 95% CI 0.288 to 1.392). No difference was found in the effect of VNS+Rehab over traditional rehabilitation for ADL, mental health or safety outcomes. Subgroup analyses revealed larger effects for patients received taVNS (transcutaneous auricular VNS) devices (at acute/subacute phase of stroke, with lower VNS stimulation frequency or pluses per session, greater VNS on-off time or sessions, higher VNS intervention weekly frequency)., Conclusion: The results suggest VNS+Rehab showed better motor function outcomes in patients after stroke, while no better than Rehab on mental health or ADL. Combinations of phase of stroke, specific parameters of VNS and VNS intervention frequency are key modulators of VNS effects., Trial Registration Number: CRD42022310194., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: A vital role in coronary artery disease is played by Von Willebrand factor (VWF), which serves as a bridge between platelets and the subendothelial matrix after vessel damage. The purpose of the study was to assess the validity of plasma VWF antigen (VWF: Ag) levels as a predictor of clinical outcomes after acute myocardial infarction (AMI)., Methods: Three hundred and seventy-four patients were studied following coronary angiography, including 209 patients suffering from acute myocardial infarction and 165 healthy participants. Coronary angiography was followed by measurement of plasma VWF: Ag levels. Over a 2-year follow-up period, major adverse cardiopulmonary and cerebrovascular events (MACEs) were the primary endpoint. All-cause mortality was investigated as a secondary endpoint., Results: When compared to controls, patients with AMI had mean plasma VWF: Ag levels that were ~1.63 times higher (0.860 ± 0.309 vs. 0.529 ± 0.258 IU/ml; P < 0.001). The plasma VWF: Ag levels were substantially higher in patients who experienced MACEs after myocardial infarction vs. those without MACEs (1.088 ± 0.253 vs. 0.731 ± 0.252 IU/ml; P < 0.001). For predicting long-term MACEs using the optimal cut-off value (0.7884 IU/ml) of VWF: Ag, ROC curve area for VWF: Ag was 0.847, with a sensitivity of 87.2% and a specificity of 66.3% (95%CI: 0.792-0.902; P = 0.001). Two-year follow-up revealed a strong link between higher plasma VWF: Ag levels and long-term MACEs. At the 2-year follow-up, multivariate regression analysis revealed an independent relationship between plasma VWF: Ag levels and MACEs (HR = 6.004, 95%CI: 2.987-12.070)., Conclusion: We found evidence that plasma VWF: Ag levels were independent risk factors for AMI. Meanwhile, higher plasma VWF: Ag levels are associated with long-term MACEs in people with AMI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xier, Zhu, Tang, Kong, Aili, Huojia and Peng.)

Objective: To evaluate the impact of pre-operative contrast-enhanced mammography (CEM) in breast cancer patients with dense breasts., Methods: We conducted a retrospective review of 232 histologically proven breast cancers in 200 women (mean age: 53.4 years ± 10.2) who underwent pre-surgical CEM imaging across two Asian institutions (Singapore and Taiwan). Majority (95.5%) of patients had dense breast tissue (BI-RADS category C or D). Surgical decision was recorded in a simulated blinded multi-disciplinary team setting on two separate scenarios: (i) pre-CEM setting with standard imaging, and clinical and histopathological results; and (ii) post-CEM setting with new imaging and corresponding histological findings from CEM. Alterations in surgical plan (if any) because of CEM imaging were recorded. Predictors CEM of patients who benefitted from surgical plan alterations were evaluated using logistic regression., Results: CEM resulted in altered surgical plans in 36 (18%) of 200 patients in this study. CEM discovered clinically significant larger tumor size or extent in 24 (12%) patients and additional tumors in 12 (6%) patients. CEM also detected additional benign/false-positive lesions in 13 (6.5%) of the 200 patients. Significant predictors of patients who benefitted from surgical alterations found on multivariate analysis were pre-CEM surgical decision for upfront breast conservation (OR, 7.7; 95% CI, 1.9-32.1; p = 0.005), architectural distortion on mammograms (OR, 7.6; 95% CI, 1.3-42.9; p = .022), and tumor size of ≥ 1.5 cm (OR, 1.5; 95% CI, 1.0-2.2; p = .034)., Conclusion: CEM is an effective imaging technique for pre-surgical planning for Asian breast cancer patients with dense breasts., Key Points: • CEM significantly altered surgical plans in 18% (nearly 1 in 5) of this Asian study cohort with dense breasts. • Significant patient and imaging predictors for surgical plan alteration include (i) patients considered for upfront breast-conserving surgery; (ii) architectural distortion lesions; and (iii) tumor size of ≥ 1.5 cm. • Additional false-positive/benign lesions detected through CEM were uncommon, affecting only 6.5% of the study cohort., (© 2022. The Author(s).)

Graft-versus-host disease (GvHD) is a major complication after allogeneic hematopoietic cell transplantation (HCT). Current strategies to prevent GvHD with immunosuppressive drugs carry significant morbidity and may affect the graft-versus-tumor (GVT) effect. Inflammatory bowel disease (IBD) is an intestinal inflammatory condition that affects more than 2 million people in the United States. Current strategies to prevent colitis with immunosuppressive drugs carry significant morbidity. Recently, Repulsive Guidance Molecule b (RGMb) has been identified as part of a signaling hub with neogenin and BMP receptors in mice and humans. In addition, RGMb binds BMP-2/4 in mice and humans as well as PD-L2 in mice. RGMb is expressed in the gut epithelium and by antigen presenting cells, and we found significantly increased expression in mouse small intestine after total body irradiation HCT conditioning. We hypothesized that RGMb may play a role in GvHD and IBD pathogenesis by contributing to mucosal inflammation. Using major-mismatched HCT mouse models, treatment with an anti-RGMb monoclonal antibody (mAb) that blocks the interaction with BMP-2/4 and neogenin prevented GvHD and improved survival compared to isotype control (75% versus 30% survival at 60 days after transplantation). The GVT effect was retained in tumor models. Using an inflammatory bowel disease dextran sulfate sodium model, treatment with anti-RGMb blocking monoclonal antibody but not isotype control prevented colitis and improved survival compared to control (73% versus 33% at 21 days after treatment) restoring gut homeostasis. Anti-RGMb mAb (9D1) treatment decreased IFN-γ and significantly increased IL-5 and IL-10 in the gut of the treated mice compared to the isotype control treated mice., Competing Interests: EM, RD, and GF are co-founders and equity holders in Triursus Therapeutics. EM is a co-founder of GigaGen, Inc. GF has patents/pending royalties on the PD-1/PD-L1 pathway from Roche, Merck MSD, Bristol-Myers-Squibb, Merck KGA, Boehringer-Ingelheim, AstraZeneca, Dako, Leica, Mayo Clinic, and Novartis. GF has served on advisory boards for Roche, Bristol-Myers-Squibb, Xios, Origimed, Triursus, iTeos, NextPoint, IgM, Jubilant, GV20, Geode, IOME, and Invaria. GF has equity in Nextpoint, Xios, iTeos, IgM, GV20, Trillium, Invaria, and is a co-founder and equity holder in Triursus. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pérez-Cruz, Iliopoulou, Hsu, Wu, Erkers, Swaminathan, Tang, Bader, Kambham, Xie, Dekruyff, Freeman and Meyer.)

A 50-year-old woman with no past medical history presented with a left anterior chest wall mass that was clinically soft, mobile, and non-tender. A targeted ultrasound (US) showed findings suggestive of a lipoma. However, focal "mass-like" nodules seen within the inferior portion suggested malignant transformation of a lipomatous lesion called for cross sectional imaging, such as MRI or invasive biopsy or excision for histological confirmation. A T1-weighted image demonstrated a large lipoma that has a central fat-containing region surrounded by an irregular hypointense rim in the inferior portion, confirming the benignity of the lipoma. An ultrasound-guided photoacoustic imaging (PA) of the excised specimen to derive the biochemical distribution demonstrated the "mass-like" hypoechoic regions on US as fat-containing, suggestive of benignity of lesion, rather than fat-replacing suggestive of malignancy. The case showed the potential of PA as an adjunct to US in improving the diagnostic confidence in lesion characterization.

Objective: To determine IgG antibody levels of measles, rubella, mumps in healthy population in Shanghai from 2010 to 2020 and analyze the trend of antibody changes in different age groups. Methods: 10 828 healthy people without measles, rubella and mumps in Shanghai were included in the study from 2010 to 2020. Serum samples were collected from 12 age groups, and the serum IgG antibody of measles, rubella and mumps were detected by ELISA. The difference of antibody positive rates and antibody levels were analyzed. Results: The median age M ( Q 1 , Q 3 ) of 10 828 objects were 8 years old (9 months old, 20 years old). Males accounted for 48.34% (5 234/10 828) and females accounted for 50.92% (5 514/10 828). Unknown gender information accounted for 0.74% (80/10 828), and 27.03% (2 927/10 828) of participants had unknown MMR immunization history. The total positive rates of measles, rubella and mumps IgG antibody were 76.78%, 64.46% and 64.29% and their GMCs were 541.45 mIU/ml, 31.76 IU/ml and 133.73 U/ml respectively. There were significant differences in serum IgG antibody GMC of measles, rubella and mumps in each year ( F measles =180.74, P <0.001; F rubella =189.95, P <0.001; F mumps =122.40, P <0.001). The positive rate of measles antibody was higher than that of rubella and mumps, and the difference was statistically significant (χ²=518.09, P <0.001). Conclusion: The level of measles IgG antibody in healthy people in Shanghai is higher, while the level of rubella and mumps IgG antibody is slightly lower.

This study aimed to explore the triterpenic acid components in leaves of Ilex hainanensis. Alkaline water extraction, macroporous resin adsorption, and high performance liquid chromatography were used to separate and purify the triterpenic acid components in leaves of I. hainanensis. The physical and chemical property analysis, MS, NMR spectroscopy, and literature comparison were performed to identify the structures, and a new triterpene acid compound was discovered:(3S, 4R, 5R, 8R, 9R, 10R, 14S, 17S, 18S, 19R)-3,19-dihydroxyursa-12,20(30)-diene-24,28-dioic-acid, and named ilexhainanin F. In addition, according to its structural characteristics, the ~(19)F-NMR Mosher method was further employed to study its absolute configuration. By comparison of the ~(19)F-NMR chemical shifts of Mosher esters, it was determined that the absolute configuration of the 3-position chiral center of the compound was the S configuration.

Evidential reasoning (ER) rule has been widely used in dealing with uncertainty. As an important parameter to measure the inherent property of evidence, the evidence reliability makes the ER rule constitute a generalized reasoning framework. In current research of the ER rule, the evidence reliability tends to be expressed in the form of quantitative value by certain methods or expert knowledge. The single quantitative value lacks the ability to describe the statistical property of reliability, which leads to unreasonable results. In this article, a new ER rule with continuous probability distribution of reliability denoted by ERr-CR is proposed. The combination of two pieces of evidence is discussed in detail, where the reliability is profiled as random variables with specific probability distribution. To characterize the output of ERr-CR, a novel concept of expectation of the expected utility is proposed. In addition, the ERr-CR is expanded to multiple pieces of evidence to show its universality. Further, the basic performances of the ERr-CR are explored to illustrate the rationality. Moreover, a case study of safety assessment of natural gas storage tanks (NGSTs) is conducted to show the potential applications of ERr-CR, which makes the proposed method more practical.

To date, studies which utilized ultrasound (US) and optoacoustic tomography (OT) fusion (US-OT) in biochemical differentiation of malignant and benign breast conditions have relied on limited biochemical data such as oxyhaemoglobin (OH) and deoxyhaemoglobin (DH) only. There has been no data of the largest biochemical components of breast fibroglandular tissue: lipid and collagen. Here, the authors believe the ability to image collagen and lipids within the breast tissue could serve as an important milestone in breast US-OT imaging with many potential downstream clinical applications. Hence, we would like to present the first-in-human US-OT demonstration of lipid and collagen differentiation in an excised breast tissue from a 38-year-old female., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Goh Yonggeng has patent #IBB-016 issued to Licensee., (© 2022 Published by Elsevier GmbH.)

Long COVID refers to the lingering symptoms which persist or appear after the acute illness. The dominant long COVID symptoms in the two years since the pandemic began (2020-2021) have been depression, anxiety, fatigue, concentration and cognitive impairments with few reports of psychosis. Whether other symptoms will appear later on is not yet known. For example, dopamine-dependent movement disorders generally take many years before first symptoms are seen. Post-stroke depression and anxiety may explain many of the early long COVID cases. Hemorrhagic, hypoxic and inflammatory damages of the central nervous system, unresolved systematic inflammation, metabolic impairment, cerebral vascular accidents such as stroke, hypoxia from pulmonary damages and fibrotic changes are among the major causes of long COVID. Glucose metabolic and hypoxic brain issues likely predispose subjects with pre-existing diabetes, cardiovascular or lung problems to long COVID as well. Preliminary data suggest that psychotropic medications may not be a danger but could instead be beneficial in combating COVID-19 infection. The same is true for diabetes medications such as metformin. Thus, a focus on sigma-1 receptor ligands and glucose metabolism is expected to be useful for new drug development as well as the repurposing of current drugs. The reported protective effects of psychotropics and antihistamines against COVID-19, the earlier reports of reduced number of sigma-1 receptors in post-mortem schizophrenic brains, with many antidepressant and antipsychotic drugs being antihistamines with significant affinity for the sigma-1 receptor, support the role of sigma and histamine receptors in neuroinflammation and viral infections. Literature and data in all these areas are accumulating at a fast rate. We reviewed and discussed the relevant and important literature.

Background: The hypothesis that breast cancer (BC) susceptibility variants are linked to chemotherapy-induced toxicity has been previously explored. Here, we investigated the association between a validated 313-marker-based BC polygenic risk score (PRS) and chemotherapy-induced neutropenia without fever and febrile neutropenia (FNc) in Asian BC patients., Methods: This observational case-control study of Asian BC patients treated with chemotherapy included 161 FNc patients, 219 neutropenia patients, and 936 patients who did not develop neutropenia. A continuous PRS was calculated by summing weighted risk alleles associated with overall, estrogen receptor- (ER-) positive, and ER-negative BC risk. PRS distributions neutropenia or FNc cases were compared to controls who did not develop neutropenia using two-sample t -tests. Odds ratios (OR) and corresponding 95% confidence intervals were estimated for the associations between PRS (quartiles and per standard deviation (SD) increase) and neutropenia-related outcomes compared to controls., Results: PRS distributions were not significantly different in any of the comparisons. Higher PRS overall quartiles were negatively correlated with neutropenia or FNc. However, the associations were not statistically significant (PRS per SD increase OR neutropenia: 0.91 [0.79-1.06]; FNc: 0.87 [0.73-1.03]). No dose-dependent trend was observed for the ER-positive weighted PRS (PRS ER-pos ) and ER-negative weighted PRS (PRS ER-neg )., Conclusion: BC PRS was not strongly associated with chemotherapy-induced neutropenia or FNc.

Background: Breast cancers are heterogeneous with variable clinical courses and treatment responses., Objective: We sought to evaluate dynamic changes in the molecular landscape of HER2-negative tumors treated with chemotherapy and anti-angiogenic agents., Patients and Methods: Newly diagnosed HER2-negative breast cancer patients received low-dose sunitinib or bevacizumab prior to four 2-weekly cycles of dose-dense doxorubicin and cyclophosphamide. Tumor biopsies were obtained at baseline, after 2 weeks and after 8 weeks of chemotherapy. Next-generation sequencing was performed to assess for single nucleotide variants (SNVs) and copy number alterations (CNAs) of 440 cancer-related genes (ACTOnco ® ). Observed genomic changes were correlated with the Miller-Payne histological response to treatment., Results: Thirty-four patients received sunitinib and 18 received bevacizumab. In total, 77% were hormone receptor positive (HER2-/HR+) and 23% were triple negative breast cancers (TNBC). New therapy-induced mutations were infrequent, occurring only in 13%, and appeared early after a single cycle of treatment. Seventy-two percent developed changes in the variant allele frequency (VAF) of pathogenic SNVs; the majority (51%) of these changes occurred early at 2 weeks and were sustained for 8 weeks. Changes in VAF of SNVs were most commonly seen in the PI3K/mTOR/AKT pathway; 13% developed changes in pathogenic mutations, which potentially confer sensitivity to PIK3CA inhibitors. Tumors with poor Miller-Payne response to treatment were less likely to experience changes in VAF of SNVs compared with those with good response (50% [7/14] vs 15% [4/24] had no changes observed at any timepoint, p = 0.029)., Conclusions: Serial molecular profiling identifies early therapy-induced genomic alterations, which may guide future selection of targeted therapies in breast cancer patients who progress after standard chemotherapy., Clinical Trial Registration: ClinicalTrials.gov: NCT02790580 (first posted June 6, 2016)., (© 2022. The Author(s).)

In current studies of safety assessment for complex systems with the evidential reasoning (ER) rule, the evidence reliability is generally given by experts, which makes the observation data by sensors ignored. However, sensors are inevitably affected by such various uncertainties as perturbations in engineering practice, which can reduce their quality and tracking ability. As such, the observation data may become unreliable, and the modeling accuracy of the ER rule is decreased. In this article, a new ER rule-based safety assessment method with sensor reliability for complex systems is proposed, where sensor reliability and perturbation are considered. The coefficient of the variation-based weighting (CVBW) method is employed to obtain sensor weight. The sensor reliability is calculated by static reliability and dynamic reliability, which are determined by experts and the distance-based method, respectively. The perturbation is quantified as a bounded parameter defined as the perturbation factor, which is used to describe uncertainties and aggregate static reliability and dynamic reliability. The performance analysis of safety assessment is conducted to demonstrate the rationality of perturbation and position poor sensors, followed by a safety assessment algorithm. A case study is carried out to validate the effectiveness of the proposed method.

Background: Family history, and genetic and non-genetic risk factors can stratify women according to their individual risk of developing breast cancer. The extent of overlap between these risk predictors is not clear., Methods: In this case-only analysis involving 7600 Asian breast cancer patients diagnosed between age 30 and 75 years, we examined identification of high-risk patients based on positive family history, the Gail model 5-year absolute risk [5yAR] above 1.3%, breast cancer predisposition genes (protein-truncating variants [PTV] in ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, or TP53), and polygenic risk score (PRS) 5yAR above 1.3%., Results: Correlation between 5yAR (at age of diagnosis) predicted by PRS and the Gail model was low (r=0.27). Fifty-three percent of breast cancer patients (n=4041) were considered high risk by one or more classification criteria. Positive family history, PTV carriership, PRS, or the Gail model identified 1247 (16%), 385 (5%), 2774 (36%), and 1592 (21%) patients who were considered at high risk, respectively. In a subset of 3227 women aged below 50 years, the four models studied identified 470 (15%), 213 (7%), 769 (24%), and 325 (10%) unique patients who were considered at high risk, respectively. For younger women, PRS and PTVs together identified 745 (59% of 1276) high-risk individuals who were not identified by the Gail model or family history., Conclusions: Family history and genetic and non-genetic risk stratification tools have the potential to complement one another to identify women at high risk., (© 2022. The Author(s).)

Many patients under treatment for mood disorders, in particular patients with bipolar mood disorders, experience episodes of mood switching from one state to another. Various hypotheses have been proposed to explain the mechanism of mood switching, spontaneously or induced by drug treatment. Animal models have also been used to test the role of psychotropic drugs in the switching of mood states. We examine the possible relationship between the pharmacology of psychotropic drugs and their reported incidents of induced mood switching, with reference to the various hypotheses of mechanisms of mood switching.

Key Message: Cytochimera potato plants, which mixed with diploid and tetraploid cells, could cause the highest and significantly increased biomass yield than the polyploid and diploid potato plants. Polyploidization is an important approach in crop breeding for agronomic trait improvement, especially for biomass production. Cytochimera contains two or more mixed cells with different levels of ploidy, which is considered a failure in whole genome duplication. Using colchicine treatment with diploid (Dip) potato (Solanum chacoense) plantlets, this study generated tetraploid (Tet) and cytochimera (Cyt) lines, which, respectively, contained complete and partial cells with genome duplication. Compared to the Dip potato, we observed remarkably enhanced plant growth and biomass yields in Tet and Cyt lines. Notably, the Cyt potato straw, which was generated from incomplete genome doubling, was of significantly higher biomass yield than that of the Tet with a distinctively altered cell wall composition. Meanwhile, we observed that one layer of the tetraploid cells (about 30%) in Cyt plants was sufficient to trigger a gene expression pattern similar to that of Tet, suggesting that the biomass dominance of Cyt may be related to the proportion of different ploidy cells. Further genome-wide analyses of co-expression networks indicated that down-regulation (against Dip) of spliceosomal-related transcripts might lead to differential alternative splicing for specifically improved agronomic traits such as plant growth, biomass yield, and lignocellulose composition in Tet and Cyt plants. In addition, this work examined that the genome of Cyt line was relatively stable after years of asexual reproduction. Hence, this study has demonstrated that incomplete genome doubling is a promising strategy to maximize biomass production in potatoes and beyond., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Tumor angiogenesis controlled predominantly by vascular endothelial growth factor and its receptor (VEGF-VEGFR) interaction plays a key role in the growth and propagation of cancer cells. However, the newly formed network of blood vessels is disorganized and leaky. Pre-treatment with anti-angiogenic agents can "normalize" the tumor vasculature allowing effective intra-tumoral delivery of standard chemotherapy. Immunohistochemistry (IHC) analysis was applied to investigate and compare the vascular normalization and anti-angiogenic effects of two commonly used anti-angiogenic agents, Sunitinib and Bevacizumab, administered prior to chemotherapy in HER2-negative breast cancer patients., Methods: This prospective clinical trial enrolled 38 patients into a sunitinib cohort and 24 into a bevacizumab cohort. All received 4 cycles of doxorubicin/cyclophosphamide chemotherapy and pre-treatment with either sunitinib or bevacizumab. Tumor biopsies were obtained at baseline, after cycle 1 (C1) and cycle 4 (C4) of chemotherapy. IHC was performed to assess the tumor vascular normalization index (VNI), lymphatic vessel density (LVD), Ki67 proliferation index and expression of tumor VEGFR2., Results: In comparison to Bevacizumab, Sunitinib led to a significant increase in VNI post-C1 and C4 (p < 0.001 and 0.001) along with decrease in LVD post-C1 (p = 0.017). Both drugs when combined with chemotherapy resulted in significant decline in tumor proliferation after C1 and C4 (baseline vs post-C4 Ki67 index p = 0.006 for Sunitinib vs p = 0.021 for Bevacizumab). Bevacizumab resulted in a significant decrease in VEGFR2 expression post-C1 (p = 0.004)., Conclusion: Sunitinib, in comparison to Bevacizumab showed a greater effect on tumor vessel modulation and lymphangiogenesis suggesting that its administration prior to chemotherapy might result in improved drug delivery., Trial Registry: ClinicalTrials.gov: NCT02790580 (first posted June 6, 2016)., (© 2021. The Author(s).)