bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigating associated factors of primary and specialist health care utilization among people with selected nationalities: results of a multilingual survey in two German federal states
Authors: Loer Anne-Kathrin M. , Koschollek Carmen , Hövener Claudia
Published: August 2022

Background

Approximately every fourth person in Germany has a migration background. Health research on the use of primary and specialist health care in this group is still scarce. Few studies have suggested a difference in the use of primary and specialist health care among people with a migration background. Potential resources and barriers to health care access should be investigated as they are critical to health equity. This study investigates associated sociodemographic, migration-sensitive, and health-related factors of primary and specialist health care utilization among people with a migration background as defined by nationality.

Methods

Analyses are based on data from a feasibility study of the project “Improving Health Monitoring in Migrant Populations” (IMIRA), conducted by the Robert Koch Institute. The sample (n = 1055) included persons with Croatian, Polish, Romanian, Syrian, and Turkish nationalities living in the federal states of Berlin and Brandenburg, Germany. Descriptive and bivariate analyses as well as multiple binary logistic regression analyses were carried out to assess sociodemographic (sex, age, socioeconomic position), health-related (self-rated health), and migration-sensitive factors (duration of residence in Germany, residence status, German language proficiency) associated with the use of primary and specialist health care services in the past 12 months.

Results

Of the total study population, 79.62% visited a general practitioner and 59.53% a specialized physician in the past 12 months. Participants who were female sex, aged 65 and older, and with moderate/poor/very poor self-rated health had higher odds of visiting a general practitioner and a specialized physician, with the strongest impact from self-rated health. After controlling for sociodemographic and health-related factors, duration of residence in Germany and residence status were associated with primary but not with specialist health care utilization.

Conclusions

Our results suggest that migration-sensitive characteristics, such as duration of residence, should be considered in a differentiated manner in health services research to gain detailed insights into health care utilization and its potential barriers among the heterogenous group of people with a migration background. Further research needs to be done to evaluate how to get people into contact with a general practitioner.
Expanding the genetic and clinical characteristics of Protocadherin 19 gene mutations
Authors: Dell’Isola Giovanni Battista , Mencaroni Elisabetta , Fattorusso Antonella , Tascini Giorgia , Prontera Paolo , Imperatore Valentina , Di Cara Giuseppe , Striano Pasquale , Verrotti Alberto
Published: August 2022

Background

PCDH19-related epilepsy is a rare X-linked type of epilepsy caused by genomic variants of the Protocadherin 19 (PCDH19) gene. The clinical characteristics of PCDH19-related epilepsy are epileptic and non-epileptic symptoms with highly variable severity among patients.

Case presentation

We present a case of a 4-year old female with PCDH19-related epilepsycaused by new variants in the PCDH19 gene. Our patient was admitted for the first time at the age of 12 months for seizure clusters arising under condition of apyrexia. The electroencephalography (EEG) showed frontal paroxysmal activity. The genetic analysis identified the two variants c.1006G > A (p.Val336Met) and c.1014C > A (p.Asp338Glu) in the gene PCDH19. The patient was treated with Carbamazepine and Clonazepam achieving the disappearance of seizures. During the follow-up, the neurological examination was persistently normal with neither cognitive impairment nor behavior disturbances. From 2 years of age EEG controls were persistently normal.

Conclusion

This patient presents two novel variants of the PCDH19 gene associated with a mild form of epilepsy with normal cognitive development with an apparently better prognosis. According to our experience, the dual therapy with Carbamazepine and Clonazepam has led to a good control of seizures.
“We should be at the table together from the beginning”: perspectives on partnership from stakeholders at four research institutions in sub-Saharan Africa
Authors: Voller Shirine , Chitalu Chama-Chiliba Miriam , Nyondo-Mipando Alinane Linda , Opobo Timothy , Bangirana Clare Ahabwe , Thorogood Nicki , Schellenberg Joanna , Chi Primus
Published: August 2022

Background

Global health research partnerships have been scrutinised for how they operate and criticised for perpetuating inequities. Guidance to inform fair partnership practice has proliferated and the movement to decolonise global health has added momentum for change. In light of this evolving context, we sought in this study to document contemporary experiences of partnership from the perspective of stakeholders in four sub-Saharan African research institutions.

Methods

We conducted qualitative interviews with 20 stakeholders at research institutions in four countries in anglophone eastern and southern Africa. Interview questions were informed by published guidance on equitable research partnerships. Data was analysed through an iterative process of inductive and deductive coding, supported by NVivo software.

Results

Early-career, mid-career and senior researchers and research administrators from four sub-Saharan African research institutions described wide-ranging experiences of partnership with high-income country collaborators. Existing guidelines for partnership provided good coverage of issues that participants described as being the key determinants of a healthy partnership, including mutual respect, role clarity and early involvement of all partners. However, there was almost no mention of guidelines being used to inform partnership practice. Participants considered the key benefits of partnership to be capacity strengthening and access to research funding. Meanwhile, participants continued to experience a range of well-documented inequities, including exclusion from agenda setting, study design, data analysis and authorship; and relationships that were exploitative and dominated by high-income country partners’ interests. Participants also reported emerging issues where their institution had been the prime recipient of funds. These included high-income country partners being unwilling to accept a subordinate role and failing to comply with reporting requirements.

Conclusions

Insights from stakeholders in four sub-Saharan African research institutions suggest that contemporary global health research partnerships generate considerable benefits but continue to exhibit longstanding inequities and reveal emerging tensions. Our findings suggest that long-term support targeted towards institutions and national research systems remains essential to fulfil the potential of research led from sub-Saharan Africa. High-income country stakeholders need to find new roles in partnerships and stakeholders from sub-Saharan Africa must continue to tackle challenges presented by the resource-constrained contexts in which they commonly operate.
Expression profile and prognostic value of CXCR family members in head and neck squamous cell carcinoma
Authors: Shen Yiming , Zhou Chongchang , Cao Yujie , Li Qun , Deng Hongxia , Gu Shanshan , Wu Yidong , Shen Zhisen
Published: August 2022

Background

CXC chemokine receptor gene family consists of seven well-established members which are broadly involved in biological functions of various cancers. Currently, limited studies have shed light on the expression profile of CXCR family members (CXCRs), as well as their prognostic value, in head and neck squamous cells carcinoma (HNSCC).

Methods

The data for this study were retrieved from the Cancer Genome Atlas database and other publicly available databases, including gene expression, methylation profiles, clinical information, immunological features, and prognoses. The expression pattern and prognostic values of CXCRs were identified, and the potential mechanism underlying CXCRs function in HNSCC was investigated by gene set enrichment analysis (GSEA).

Results

CXCRs were differentially expressed in HNSCC. As shown by Kaplan–Meier analysis, high CXCR3-6 expression was significantly associated with better prognostic outcomes of HNSCC patients, including overall survival and progression-free survival. According to the results of univariate and multivariate Cox proportional risk regression analysis, it was demonstrated that upregulation of CXCR3-6 was an independent factor for better prognosis, while the two other clinical features, age and stage, were factors for worse prognosis. A significant positive correlation between CXCR3-6 and tumor-infiltrated immune cells was revealed by results from Tumor Immune Estimation Resource and CIBERSORT analysis database. The main involvement of CXCRs in immune and inflammatory responses was further confirmed by GSEA.

Conclusions

Overall, this study provided a rationale for targeting CXCRs as a promising therapeutic strategy of HNSCC.
Testing P2Y12 platelet inhibitors generics beyond bioequivalence: a parallel single-blinded randomized trial
Authors: Zarif Bassem , Soliman Lamyaa , Sabry Nirmeen A. , Said Eman
Published: August 2022

Cardiovascular diseases are the leading cause of death worldwide. Ticagrelor is an oral antiplatelet drug used in acute coronary syndrome. Although generic drugs are approved for their bioequivalence to the original product, they are not necessarily to be therapeutically equivalent. This study was conducted to prove the efficacy and safety of ticagrelor generically named Ticaloguard® compared to its brand Brilique® in healthy volunteers. A loading dose of 180 mg ticagrelor named Brilique® or Ticaloguard® followed by a 90 mg twice daily regimen as maintenance dose was given to 14 and 15 volunteers in Tica and Brili groups, respectively. The platelet aggregation on the ADP agonist was assessed at baseline and repeated 1 h and 3 h after the loading dose, on day 4 (after reaching steady-state), 12 and 24 h after discontinuation of the antiplatelet drug. Adverse effects from trial medications were noted by direct questions. It was shown that generic Ticaloguard® provides a similar therapeutic effect and safety as its branded Brilique® (p > 0.05). This will permit safe and trusted use of the generic Ticaloguard® when treating it in the same manner as Brilique®. Testing generic drug effects rather than simple bioequivalency, especially for drugs that are used in critical life-threatening situations, is crucial. We advocate applying this form of a clinical trial to test surrogate clinical efficacy for generics used in critical indications before having real-world data whenever possible.
Novel neoplasms associated with syndromic pediatric medulloblastoma: integrated pathway delineation for personalized therapy
Authors: Georgescu Maria-Magdalena , Whipple Stephen G. , Notarianni Christina M.
Published: August 2022

Medulloblastoma is the most common pediatric embryonal brain tumor, and may occur in cancer predisposition syndromes. We describe novel associations of medulloblastoma with atypical prolactinoma and dural high-grade sarcoma in Li-Fraumeni syndrome (LFS), and epidural desmoid fibromatosis in familial adenomatous polyposis (FAP)/Turcot syndrome. Genomic analysis showing XRCC3 alterations suggested radiotherapy as contributing factor to the progression of LFS-associated medulloblastoma, and demonstrated different mechanisms of APC inactivation in the FAP-associated tumors. The integrated genomic-transcriptomic analysis uncovered the growth pathways driving tumorigenesis, including the prolactin-prolactin receptor (PRLR) autocrine loop and Shh pathway in the LFS-associated prolactinoma and medulloblastoma, respectively, the Wnt pathway in both FAP-associated neoplasms, and the TGFβ and Hippo pathways in the soft tissue tumors, regardless of germline predisposition. In addition, the comparative analysis of paired syndromic neoplasms revealed several growth pathways susceptible to therapeutic intervention by PARP, PRLR, and selective receptor tyrosine kinase (RTK) inhibitors. These could target the defective DNA damage repair in the LFS-associated medulloblastoma, the prolactin autocrine loop in the atypical prolactinoma, the EPHA3/7 and ALK overexpression in the FAP-associated medulloblastoma, and the multi-RTK upregulation in the soft tissue neoplasms. This study presents the spatiotemporal evolution of novel neoplastic associations in syndromic medulloblastoma, and discusses the post-radiotherapy risk for secondary malignancies in syndromic pediatric patients, with important implications for the biology, diagnosis, and therapy of these tumors.
Astrocytic and microglial cells as the modulators of neuroinflammation in Alzheimer’s disease
Authors: Singh Deepali
Published: August 2022

Neuroinflammation is instigated by the misfiring of immune cells in the central nervous system (CNS) involving microglia and astrocytes as key cell-types. Neuroinflammation is a consequence of CNS injury, infection, toxicity, or autoimmunity. It is favorable as well as a detrimental process for neurodevelopment and associated processes. Transient activation of inflammatory response involving release of cytokines and growth factors positively affects the development and post-injury tissue. However, chronic or uncontrolled inflammatory responses may lead to various neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis, and multiple sclerosis. These diseases have variable clinical and pathological features, but are underlaid by the aggregation of misfolded proteins with a cytotoxic effect. Notably, abnormal activation of glial cells could mediate neuroinflammation, leading to the neurodegenerative condition. Microglia, a type of glial cell, a resident immune cell, form the forefront defense of the CNS immune system. Dysfunctional microglia and astrocyte, a different kind of glial cell with homeostatic function, impairs the protein aggregate (amyloid-beta plaque) clearance in AD. Studies have shown that microglia and astrocytes undergo alterations in their genetic profile, cellular and molecular responses, and thus promote dysfunctional immune cross-talk in AD. Hence, targeting microglia and astrocytes-driven molecular pathways could resolve the particular layers of neuroinflammation and set a reliable therapeutic intervention in AD progression.
Role of aging in Blood–Brain Barrier dysfunction and susceptibility to SARS-CoV-2 infection: impacts on neurological symptoms of COVID-19
Authors: Adesse Daniel , Gladulich Luis , Alvarez-Rosa Liandra , Siqueira Michele , Marcos Anne Caroline , Heider Marialice , Motta Caroline Soares , Torices Silvia , Toborek Michal , Stipursky Joice
Published: August 2022

COVID-19, which is caused by Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2), has resulted in devastating morbidity and mortality worldwide due to lethal pneumonia and respiratory distress. In addition, the central nervous system (CNS) is well documented to be a target of SARS-CoV-2, and studies detected SARS-CoV-2 in the brain and the cerebrospinal fluid of COVID-19 patients. The blood–brain barrier (BBB) was suggested to be the major route of SARS-CoV-2 infection of the brain. Functionally, the BBB is created by an interactome between endothelial cells, pericytes, astrocytes, microglia, and neurons, which form the neurovascular units (NVU). However, at present, the interactions of SARS-CoV-2 with the NVU and the outcomes of this process are largely unknown. Moreover, age was described as one of the most prominent risk factors for hospitalization and deaths, along with other comorbidities such as diabetes and co-infections. This review will discuss the impact of SARS-CoV-2 on the NVU, the expression profile of SARS-CoV-2 receptors in the different cell types of the CNS and the possible role of aging in the neurological outcomes of COVID-19. A special emphasis will be placed on mitochondrial functions because dysfunctional mitochondria are also a strong inducer of inflammatory reactions and the “cytokine storm” associated with SARS-CoV-2 infection. Finally, we will discuss possible drug therapies to treat neural endothelial function in aged patients, and, thus, alleviate the neurological symptoms associated with COVID-19.
Immune checkpoint modulators in cancer immunotherapy: recent advances and emerging concepts
Authors: Wang Yuchen , Zhang Hao , Liu Chao , Wang Zeyu , Wu Wantao , Zhang Nan , Zhang Longbo , Hu Jason , Luo Peng , Zhang Jian , Liu Zaoqu , Peng Yun , Liu Zhixiong , Tang Lanhua , Cheng Quan
Published: August 2022

The discovery of immune checkpoint inhibitors (ICIs) has now been universally acknowledged as a significant breakthrough in tumor therapy after the targeted treatment of checkpoint molecules: anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) on several cancer types achieved satisfying results. However, there are still quite a lot of patients suffering from severe side effects and ineffective treatment outcomes. Although the current ICI therapy is far from satisfying, a series of novel immune checkpoint molecules with remarkable preclinical and clinical benefits are being widely investigated, like the V-domain Ig suppressor of T cell activation (VISTA), which can also be called PD-1 homolog (PD-1H), and ectonucleotidases: CD39, CD73, and CD38, which belong to the ribosyl cyclase family, etc. In this review, we systematically summarized and discussed these molecules' biological structures, molecular features, and the corresponding targeted drugs, aiming to help the in-depth understanding of immune checkpoint molecules and promote the clinical practice of ICI therapy.
Targeting macrophages in hematological malignancies: recent advances and future directions
Authors: Li Wei , Wang Fang , Guo Rongqun , Bian Zhilei , Song Yongping
Published: August 2022

Emerging evidence indicates that the detection and clearance of cancer cells via phagocytosis induced by innate immune checkpoints play significant roles in tumor-mediated immune escape. The most well-described innate immune checkpoints are the “don’t eat me” signals, including the CD47/signal regulatory protein α axis (SIRPα), PD-1/PD-L1 axis, CD24/SIGLEC-10 axis, and MHC-I/LILRB1 axis. Molecules have been developed to block these pathways and enhance the phagocytic activity against tumors. Several clinical studies have investigated the safety and efficacy of CD47 blockades, either alone or in combination with existing therapy in hematological malignancies, including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and lymphoma. However, only a minority of patients have significant responses to these treatments alone. Combining CD47 blockades with other treatment modalities are in clinical studies, with early results suggesting a synergistic therapeutic effect. Targeting macrophages with bispecific antibodies are being explored in blood cancer therapy. Furthermore, reprogramming of pro-tumor macrophages to anti-tumor macrophages, and CAR macrophages (CAR-M) demonstrate anti-tumor activities. In this review, we elucidated distinct types of macrophage-targeted strategies in hematological malignancies, from preclinical experiments to clinical trials, and outlined potential therapeutic approaches being developed.
Triple MAPK inhibition salvaged a relapsed post-BCMA CAR-T cell therapy multiple myeloma patient with a BRAF V600E subclonal mutation
Authors: Elnaggar Muhammad , Agte Sarita , Restrepo Paula , Ram Meghana , Melnekoff David , Adamopoulos Christos , Stevens Mark M. , Kappes Katerina , Leshchenko Violetta , Verina Daniel , Jagannath Sundar , Poulikakos Poulikos I. , Parekh Samir , Laganà Alessandro
Published: August 2022

Background

Multiple Myeloma (MM) is a progressive plasma cell neoplasm characterized by heterogeneous clonal expansion. Despite promising response rates achieved with anti-BCMA CAR-T cell therapy, patients may still relapse and there are currently no clear therapeutic options in post-CAR-T settings. In this report, we present a case of a post-BCMA CAR-T relapsed/refractory (RR) MM patient with skin extramedullary disease (EMD) in which a novel MAPK inhibition combinatorial strategy was implemented based on next-generation sequencing and in vitro experiments.

Case presentation

A 61-year-old male with penta-refractory MM penta- (IgA lambda), ISS stage 3 with hyperdiploidy, gain of 1q21 and del13 was treated with anti-BCMA CAR-T cell therapy, achieving a best response of VGPR. He progressed after 6 months and was salvaged for a short period with autologous stem cell transplantation. Eventually, he progressed with extramedullary disease manifested as subcutaneous nodules. Based on whole-exome sequencing, we identified a BRAF (V600E) dominant subclone in both bone marrow and cutaneous plasmacytoma. Following in vitro experiments, and according to our previous studies, we implemented a triple MAPK inhibition strategy under which the patient achieved a very good partial response for 110 days, which allowed to bridge him to subsequent clinical trials and eventually achieve a stringent complete response (sCR).

Conclusion

Here, we show the applicability, effectiveness, and tolerability the triple MAPK inhibition strategy in the context of post-BCMA CAR-T failure in specific subset of patients. The triple therapy could bridge our hospice bound RRMM patient with BRAF (V600E) to further therapeutic options where sCR was achieved. We will further evaluate triple MAPK inhibition in patients with BRAF V600E in a precision medicine clinical trial launching soon.
YTHDC1 is downregulated by the YY1/HDAC2 complex and controls the sensitivity of ccRCC to sunitinib by targeting the ANXA1-MAPK pathway
Authors: Li Wei , Ye Kun , Li Xurui , Liu Xinlin , Peng Mou , Chen Fang , Xiong Wei , Wang Yinhuai , Zhu Liang
Published: August 2022

Background

Tyrosine kinase inhibitors (TKIs) such as sunitinib are multitarget antiangiogenic agents in clear cell renal cell carcinoma (ccRCC). They are widely used in the treatment of advanced/metastatic renal cancer. However, resistance to TKIs is common in the clinic, particularly after long-term treatment. YTHDC1 is the main nuclear reader protein that binds with m6A to regulate the splicing, export and stability of mRNA. However, the specific role and corresponding mechanism of YTHDC1 in renal cancer cells are still unclear.

Methods

The Cancer Genome Atlas (TCGA) dataset was used to study the expression of YTHDC1 in ccRCC. Cell counting kit-8 (CCK-8), wound healing, Transwell and xenograft assays were applied to explore the biological function of YTHDC1 in ccRCC. Western blot, quantitative real time PCR (RT‒qPCR), RNA immunoprecipitation PCR (RIP-qPCR), methylated RIP-qPCR (MeRIP-qPCR) and RNA sequencing (RNA-seq) analyses were applied to study the YY1/HDAC2/YTHDC1/ANXA1 axis in renal cancer cells. The CCK-8 assay and xenograft assay were used to study the role of YTHDC1 in determining the sensitivity of ccRCC to sunitinib.

Results

Our results demonstrated that YTHDC1 is downregulated in ccRCC tissues compared with normal tissues. Low expression of YTHDC1 is associated with a poor prognosis in patients with ccRCC. Subsequently, we showed that YTHDC1 inhibits the progression of renal cancer cells via downregulation of the ANXA1/MAPK pathways. Moreover, we also showed that the YTHDC1/ANXA1 axis modulates the sensitivity of tyrosine kinase inhibitors. We then revealed that HDAC2 inhibitors resensitize ccRCC to tyrosine kinase inhibitors through the YY1/HDAC2 complex. We have identified a novel YY1/HDAC2/YTHDC1/ANXA1 axis modulating the progression and chemosensitivity of ccRCC.

Conclusion

We identified a novel YY1/HDAC2/YTHDC1/ANXA1 axis modulating the progression and chemosensitivity of ccRCC.
HORNBILL: a phase I/IIa trial examining the safety, tolerability and early response of BI 764524 in patients with diabetic retinopathy and diabetic macular ischaemia—rationale, study design and protocol
Authors: Chong Victor , Nguyen Quan Dong , Sepah Yasir , Giani Andrea , Pearce Elizabeth
Published: August 2022

Background

Diabetic macular ischaemia (DMI) is a complication of diabetic retinopathy that leads to irreversible vision loss. DMI is characterised by reduced retinal vessel density and enlargement of the foveal avascular zone (FAZ). Despite its clinical burden, there is no formal consensus on the definition of DMI, and no approved treatment. Semaphorin 3A (Sema3A) is an axonal guidance molecule that blocks revascularisation of the ischaemic retina. Sema3A modulation is therefore a promising mechanism of action for the treatment of ischaemic eye diseases. BI 764524 is an intravitreal anti-Sema3A ischaemia modulator agent.

Methods

HORNBILL (NCT04424290) is a phase I/IIa trial comprising a non-randomised, open-label, single rising dose (SRD) part and a randomised, masked, sham-controlled multiple dose (MD) part to investigate the safety, tolerability and early biological response of ischaemia modulator BI 764524 in adults (≥18 years) with DMI. DMI will be defined using optical coherence tomography angiography (OCTA) as either any degree of disruption in the retinal vascularity (SRD) or a FAZ of ≥0.5 mm2 (MD). Subjects in the SRD part will receive 0.5, 1.0 or 2.5 mg of BI 764524; the maximum tolerated dose will then be used in the MD part. A minimum of 12 subjects will be enrolled into the SRD part; planned enrollment is 30 for the MD part. The primary endpoint of the SRD part is the number of subjects with dose-limiting adverse events (AEs) until day 8. The primary endpoint of the MD part is the number of subjects with drug-related AEs from baseline to end of study, and secondary endpoints include change from baseline in the size of the FAZ, best-corrected visual acuity and central retinal thickness.

Discussion

DMI is a poorly defined condition with no treatment options. HORNBILL is the first clinical trial to assess a treatment for DMI and to use OCTA as a means to define and examine DMI. The OCTA data generated in this trial could form the basis of formal diagnostic criteria for DMI. Furthermore, the novel mechanism of action (Sema3A modulation) explored in this trial has the potential to revolutionise the treatment landscape for patients with DMI.

Trial registration

ClinicalTrials.govNCT04424290; EudraCT 2019-004432-28. Registered on 9 June 2020
Comparison of explanatory and pragmatic design choices in a cluster-randomized hypertension trial: effects on enrollment, participant characteristics, and adherence
Authors: Margolis Karen L. , Crain A. Lauren , Green Beverly B. , O’Connor Patrick J. , Solberg Leif I. , Beran MarySue , Bergdall Anna R. , Pawloski Pamala A. , Ziegenfuss Jeanette Y. , JaKa Meghan M. , Appana Deepika , Sharma Rashmi , Kodet Amy J. , Trower Nicole K. , Rehrauer Daniel J. , McKinney Zeke , Norton Christine K. , Haugen Patricia , Anderson Jeffrey P. , Crabtree Benjamin F. , Norman Sarah K. , Sperl-Hillen JoAnn M.
Published: August 2022

Background

Explanatory trials are designed to assess intervention efficacy under ideal conditions, while pragmatic trials are designed to assess whether research-proven interventions are effective in “real-world” settings without substantial research support.

Methods

We compared two trials (Hyperlink 1 and 3) that tested a pharmacist-led telehealth intervention in adults with uncontrolled hypertension. We applied PRagmatic Explanatory Continuum Indicator Summary-2 (PRECIS-2) scores to describe differences in the way these studies were designed and enrolled study-eligible participants, and the effect of these differences on participant characteristics and adherence to study interventions.

Results

PRECIS-2 scores demonstrated that Hyperlink 1 was more explanatory and Hyperlink 3 more pragmatic. Recruitment for Hyperlink 1 was conducted by study staff, and 2.9% of potentially eligible patients enrolled. Enrollees were older, and more likely to be male and White than non-enrollees. Study staff scheduled the initial pharmacist visit and adherence to attending this visit was 98%. Conversely for Hyperlink 3, recruitment was conducted by clinic staff at routine encounters and 81% of eligible patients enrolled. Enrollees were younger, and less likely to be male and White than non-enrollees. Study staff did not assist with scheduling the initial pharmacist visit and adherence to attending this visit was only 27%. Compared to Hyperlink 1, patients in Hyperlink 3 were more likely to be female, and Asian or Black, had lower socioeconomic indicators, and were more likely to have comorbidities. Owing to a lower BP for eligibility in Hyperlink 1 (>140/90 mm Hg) than in Hyperlink 3 (>150/95 mm Hg), mean baseline BP was 148/85 mm Hg in Hyperlink 1 and 158/92 mm Hg in Hyperlink 3.

Conclusion

The pragmatic design features of Hyperlink 3 substantially increased enrollment of study-eligible patients and of those traditionally under-represented in clinical trials (women, minorities, and patients with less education and lower income), and demonstrated that identification and enrollment of a high proportion of study-eligible subjects could be done by usual primary care clinic staff. However, the trade-off was much lower adherence to the telehealth intervention than in Hyperlink 1, which is likely to reflect uptake under real-word conditions and substantially dilute intervention effect on BP.

Trial registration

The Hyperlink 1 study (NCT00781365) and the Hyperlink 3 study (NCT02996565) are registered at ClinicalTrials.gov.
Design, synthesis, anticancer evaluation and docking studies of novel 2-(1-isonicotinoyl-3-phenyl-1H-pyrazol-4-yl)-3-phenylthiazolidin-4-one derivatives as Aurora-A kinase inhibitors
Authors: Beniwal Meenu , Jain Neelam , Jain Sandeep , Aggarwal Navidha
Published: August 2022

Introduction

Aurora-A kinase is associated with the Aurora kinase family which has been considered a striking anticancer target for the treatment of human cancers.

Objective

To design, synthesize, anticancer evaluation, and docking studies of novel 2-(1-isonicotinoyl-3-phenyl-1H-pyrazol-4-yl)-3-phenylthiazolidin-4-one derivatives as Aurora-A Kinase inhibitors.

Method

A total of 21 Pyrazole derivativesP (1–21)were synthesized by using the Vilsmeier Haack reagent which was characterized by FT-IR,1H NMR,13C NMR, and Mass spectroscopy. The synthesized derivatives were evaluated for their potential in vitro anticancer activity by MTT assay and Aurora-A kinase inhibition assay.

Results

The cytotoxicity assay (MTT assay) showed that compoundP-6exhibited potent cytotoxicity (IC50 = 0.37–0.44 μM) against two cancer (HCT 116 and MCF-7) cell lines, which were comparable to the standard compound, VX-680. CompoundP-6also showed inhibition of Aurora-A kinase with an IC50value of 0.11 ± 0.03 µM. A Docking study was done to compoundP-6andP-20into the active site of Aurora A kinase, in order to get the probable binding model for further study.

Conclusion

A series of 21 novel pyrazole derivativesP(1–21)were designed, synthesized, in vitro anticancer evaluation, and docking studies for Aurora A kinase inhibition. The results established thatP-6is a prospective aspirant for the development of anticancer agents targeting Aurora-A kinase.
A statistical calibration tool for methods used to sample outdoor-biting mosquitoes
Authors: Ngowo Halfan S. , Limwagu Alex J. , Ferguson Heather M. , Matthiopoulos Jason , Okumu Fredros O. , Nelli Luca
Published: August 2022

Background

Improved methods for sampling outdoor-biting mosquitoes are urgently needed to improve surveillance of vector-borne diseases. Such tools could potentially replace the human landing catch (HLC), which, despite being the most direct option for measuring human exposures, raises significant ethical and logistical concerns. Several alternatives are under development, but detailed evaluation still requires common frameworks for calibration relative to HLC. The aim of this study was to develop and validate a statistical framework for predicting human-biting rates from different exposure-free alternatives.

Methods

We obtained mosquito abundance data (Anopheles arabiensis, Anopheles funestus and Culex spp.) from a year-long Tanzanian study comparing six outdoor traps [Suna Trap (SUN), BG Sentinel (BGS), M-Trap (MTR), M-Trap + CDC (MTRC), Ifakara Tent Trap-C (ITT-C) and Mosquito Magnet-X Trap (MMX)] and HLC. Generalised linear models were developed within a Bayesian framework to investigate associations between the traps and HLC, taking intra- and inter-specific density dependence into account. The best model was used to create a calibration tool for predicting HLC-equivalents.

Results

For An. arabiensis, SUN catches had the strongest correlation with HLC (R2 = 19.4), followed by BGS (R2 = 17.2) and MTRC (R2 = 13.1) catches. The least correlated catch was MMX (R2 = 2.5). For An. funestus, BGS had the strongest correlation with the HLC (R2 = 53.4), followed by MTRC (R2 = 37.4) and MTR (R2 = 37.4). For Culex mosquitoes, the traps most highly correlated with the HLC were MTR (R2 = 45.4) and MTRC (R2 = 44.2). Density dependence, both between and within species, influenced the performance of only BGS traps. An interactive Shiny App calibration tool was developed for this and similar applications.

Conclusion

We successfully developed a calibration tool to assess the performance of different traps for assessing outdoor-biting risk, and established a valuable framework for estimating human exposures based on the trap catches. The performance of candidate traps varied between mosquito taxa; thus, there was no single optimum. Although all the traps tested underestimated the HLC-derived exposures, it was possible to mathematically define their representativeness of the true biting risk, with or without density dependence. The results of this study emphasise the need to aim for a consistent and representative sampling approach, as opposed to simply seeking traps that catch the most mosquitoes.

Graphical Abstract
A systematic method for comparing multimorbidity in national surveys
Authors: Roomaney Rifqah Abeeda , van Wyk Brian , Pillay-van Wyk Victoria
Published: August 2022

Objective

Due to gaps in the literature, we developed a systematic method to assess multimorbidity using national surveys. The objectives of this study were thus to identify methods used to define and measure multimorbidity, to create a pre-defined list of disease conditions, to identify potential national surveys to include, to select disease conditions for each survey, and to analyse and compare the survey findings.

Results

We used the count method to define multimorbidity. We created a pre-defined list of disease conditions by examining international literature and using local data on the burden of disease. We assessed national surveys, reporting on more than one disease condition in people 15 years and older, for inclusion. For each survey, the prevalence of multimorbidity was calculated, the disease patterns among the multimorbid population were assessed using a latent class analysis and logistic regression was used to identify sociodemographic and behavioural factors associated with multimorbidity. The prevalence of multimorbidity varied for each survey from 2.7 to 20.7%. We used a systematic and transparent method to interrogate multimorbidity in national surveys. While the prevalence in each survey differs, they collectively indicate that multimorbidity increases in older age groups and tends to be higher among women.
Enhanced CT-based radiomics predicts pathological complete response after neoadjuvant chemotherapy for advanced adenocarcinoma of the esophagogastric junction: a two-center study
Authors: Huang Wenpeng , Li Liming , Liu Siyun , Chen Yunjin , Liu Chenchen , Han Yijing , Wang Fang , Zhan Pengchao , Zhao Huiping , Li Jing , Gao Jianbo
Published: August 2022

Purpose

This study aimed to develop and validate CT-based models to predict pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) for advanced adenocarcinoma of the esophagogastric junction (AEG).

Methods

Pre-NAC clinical and imaging data of AEG patients who underwent surgical resection after preoperative-NAC at two centers were retrospectively collected from November 2014 to September 2020. The dataset included training (n = 60) and external validation groups (n = 32). Three models, including CT-based radiomics, clinical and radiomics–clinical combined models, were established to differentiate pCR (tumor regression grade (TRG) = grade 0) and nonpCR (TRG = grade 1–3) patients. For the radiomics model, tumor-region-based radiomics features in the arterial and venous phases were extracted and selected. The naïve Bayes classifier was used to establish arterial- and venous-phase radiomics models. The selected candidate clinical factors were used to establish a clinical model, which was further incorporated into the radiomics–clinical combined model. ROC analysis, calibration and decision curves were used to assess the model performance.

Results

For the radiomics model, the AUC values obtained using the venous data were higher than those obtained using the arterial data (training: 0.751 vs. 0.736; validation: 0.768 vs. 0.750). Borrmann typing, tumor thickness and degree of differentiation were utilized to establish the clinical model (AUC-training: 0.753; AUC-validation: 0.848). The combination of arterial- and venous-phase radiomics and clinical factors further improved the discriminatory performance of the model (AUC-training: 0.838; AUC-validation: 0.902). The decision curve reflects the higher net benefit of the combined model.

Conclusion

The combination of CT imaging and clinical factors pre-NAC for advanced AEG could help stratify potential responsiveness to NAC.
Multirate DAE-simulation and its application in system simulation software for the development of electric vehicles
Authors: Kolmbauer Michael , Offner Günter , Pfau Ralf Uwe , Pöchtrager Bernhard
Published: August 2022

This work is devoted to the efficient simulation of large multi-physical networks stemming from automated modelling processes in system simulation software. The simulation of hybrid, battery and fuel cell electric vehicle applications requires the coupling of electrical, mechanical, fluid, and thermal networks. Each network is established by combining the connection structure of a graph with physical equations of elementary components and resulting in a DAE (differential algebraic equation). To speed up the simulation a non-iterative multirate time integration co-simulation method for the system of coupled DAEs is established. The power of the multirate method is shown via two representative examples of battery powered electric vehicle with a cooling system for the battery pack and a three phase inverter with a cooling system. This work is an extended version of (Kolmbauer et al. in Scientific Computing in Electrical Engineering (SCEE 2020), Springer, Cham, pp. 231–240, 2021).
The DHAV-1 protein VP1 interacts with PI3KC3 to induce autophagy through the PI3KC3 complex
Authors: Li Juan , Wang Mingshu , Zhou Shan , Cheng Anchun , Ou Xuming , Sun Di , Wu Ying , Yang Qiao , Gao Qun , Huang Juan , Tian Bin , Mao Sai , Zhang Shaqiu , Zhao Xinxin , Jia Renyong , Liu Mafeng , Zhu Dekang , Chen Shun , Liu Yunya , Yu Yanling , Zhang Ling , Pan Leichang
Published: August 2022

Duck hepatitis A virus type 1 (DHAV-1) is one of the main pathogens responsible for death in ducklings. Autophagy is a catabolic process that maintains cellular homeostasis, and the PI3KC3 protein plays an important role in the initiation of autophagy. DHAV-1 infection induces autophagy in duck embryo fibroblasts (DEFs) but the molecular mechanism between it and autophagy has not been reported. First, we determined that DHAV-1 infection induces autophagy in DEFs and that autophagy induction is dependent on the integrity of viral proteins by infecting DEFs with UV-inactivated or heat-inactivated DHAV-1. Then, in experiments using the pharmacological autophagy inducer rapamycin and the autophagy inhibitor chloroquine, autophagy inhibition was shown to reduce intracellular and extracellular DHAV-1 genome copies and viral titres. These results suggest that autophagy activated by DHAV-1 infection in DEFs affects DHAV-1 proliferation and extracellular release. Next, we screened the autophagy-inducing effects of the DHAV-1 structural proteins VP0, VP3, and VP1 and found that all DHAV-1 structural proteins could induce autophagy in DEFs but not the full autophagic flux. Finally, we found that VP1 promotes protein expression of PI3KC3 and Beclin1 by western blot experiments and that VP1 interacts with PI3KC3 by co-immunoprecipitation experiments; moreover, 3-MA-induced knockdown of PI3KC3 inhibited VP1 protein-induced autophagy in DEFs. In conclusion, the DHAV-1 structural protein VP1 regulates the PI3KC3 complex by interacting with PI3KC3 to induce autophagy in DEFs.
Feasibility and preliminary efficacy of tantalum components in the management of acetabular reconstruction following periacetabular oncologic resection in primary malignancies
Authors: Zan Pengfei , Ma Xiaojun , Wang Hongsheng , Cai Zhengdong , Shen Jiakang , Sun Wei
Published: August 2022

Background

The aim of the study was to investigate the feasibility and preliminary efficacy of tantalum components utility in the reconstruction of acetabular defects following periacetabular oncologic resection of primary malignancies.

Methods

We prospectively collected a consecutive of 15 cases that were treated with tantalum components for acetabular reconstruction after periacetabular oncologic resection from January 2018 to December 2018. The cohort included 8 male and 7 female patients, with a mean age of 47.6 years (range, 33 to 67 years). Pathology types: chondrosarcoma (n = 9), malignant bone giant cell tumor (n = 3) and osteosarcoma (n = 3). Clinical outcomes, functional and radiographic results were recorded in detail for analysis.

Results

Patients received planned oncologic resection and tantalum components reconstruction without casualty; they were followed up with a mean of 39.7 months (35–45 months). The mean operation time was 4.0 h (3.0–6.0 h), and the mean blood loss was 1260 ml (800–2200 ml). Functional outcomes were assessed by MSTS-93 scale, with an average of 21.8 (12.0–26.0 scores), among which 3 cases were excellent, 11 were good and 1 was fair. The mean Harris Hip Score was 79.1scores (46.0–92.0 scores) at 1-year follow-up postoperatively. 3(3/15, 20.0%) cases experienced postoperative complications: 2 cases with hip dislocation received closed reduction under general anesthesia and were fixed with hip joint abduction braces for 6 weeks; one case had a superficial infection and received debridement with a delayed wound healing. Oncologic prognosis: one case relapsed at 8-month follow-up and received hemi-pelvic amputation; and another osteosarcoma patient experienced relapse with pulmonary metastasis and received further chemotherapy. No prosthetic loosening, displacement or fracture occurred during the follow-up period.

Conclusion

Preliminary results suggested that the use of tantalum components in the management of acetabular reconstruction following periacetabular oncologic resection provided reasonable improvement on functional outcomes and early stability of the prostheses. Porous tantalum components are conducive to bony ingrowth, which is a potential alternative to various existing reconstruction techniques to achieve better functional outcomes.
Social networking and risk attitudes nexus: implication for technology adoption among smallholder cassava farmers in Ghana
Authors: Dadzie Samuel K. N. , Ndebugri Joseph , Inkoom Emmanuel W. , Akuamoah-Boateng Samuel
Published: August 2022

Background

Theoretically, social climate and social networking which may affect attitudes, motivations, and readiness towards quality improvement and rewards, influence the adoption decision process by possibly modifying the risk behaviour/attitudes of individuals. Thus for effective promotion of agricultural technologies among farmers in Africa, it is necessary to understand the social context within which risk attitudes are formed and social participation decisions are made. The study, therefore, employed the recursive bivariate endogenous switching probit model to examine how risk attitudes of farmers are shaped through social interactions in the information and communication networks of farmers to influence their technology adoption decisions. Here, the empirical application was done with the contextual case of agriculture intensification technologies in the Root and Tuber Improvement and Marketing Programme (RTIMP) introduced to smallholder cassava farmers in Ghana. This paper makes a contribution to recent advances in the empirical analysis of impact where anticipated problems posed by unobserved confounders are accounted for. This was possible since the approach used allows for the estimation of the treatment effect of endogenous risk attitude variable of interest on farmers’ adoption decisions.

Results

The study found that the effectiveness and usefulness of social interactions as well as a high degree of trust by cassava farmers in their social networks have higher tendencies to lower the degree of risk aversion behaviour of the farmers to significantly influence RTIMP Technologies adoption decisions positively. The ATE estimate confirms that there has been a significant increase of 38% probability in the likelihood of adopting agricultural intensification technologies in the RTIMP attributable to the non-risk aversion attitudes of cassava farmers. The cassava farmers’ risk attitudes were found to be significantly influenced by the effectiveness and usefulness of social interactions, and a high degree of trust as well as age, frequency of extension services, access to credit, and revenue.

Conclusion

By implication, attempts to introduce innovations to improve agricultural commodities value chains that target farmers must pay particular attention to the information and communication network to ensure the effectiveness and usefulness of information dissemination to farmers in an honest manner, so as to build trust; which will go a long way to reduce doubts and uncertainties (function of risk aversion). This will help achieve higher innovation adoption impacts thereby resulting in attaining the overall deliverable objectives of agricultural innovations.