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  • 1
    Online Resource
    Online Resource
    Genetic Variation in ABCC4 and CFTR and Acute Pancreatitis during Treatment of Pediatric Acute Lymphoblastic Leukemia
    MDPI AG ; 2021
    In:  Journal of Clinical Medicine Vol. 10, No. 21 ( 2021-10-20), p. 4815-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 10, No. 21 ( 2021-10-20), p. 4815-
    Abstract: Background: Acute pancreatitis (AP) is a serious, mechanistically not entirely resolved side effect of L-asparaginase-containing treatment for acute lymphoblastic leukemia (ALL). To find new candidate variations for AP, we conducted a genome-wide association study (GWAS). Methods: In all, 1,004,623 single-nucleotide variants (SNVs) were analyzed in 51 pediatric ALL patients with AP (cases) and 1388 patients without AP (controls). Replication used independent patients. Results: The top-ranked SNV (rs4148513) was located within the ABCC4 gene (odds ratio (OR) 84.1; p = 1.04 × 10−14). Independent replication of our 20 top SNVs was not supportive of initial results, partly because rare variants were neither present in cases nor present in controls. However, results of combined analysis (GWAS and replication cohorts) remained significant (e.g., rs4148513; OR = 47.2; p = 7.31 × 10−9). Subsequently, we sequenced the entire ABCC4 gene and its close relative, the cystic fibrosis associated CFTR gene, a strong AP candidate gene, in 48 cases and 47 controls. Six AP-associated variants in ABCC4 and one variant in CFTR were detected. Replication confirmed the six ABCC4 variants but not the CFTR variant. Conclusions: Genetic variation within the ABCC4 gene was associated with AP during the treatment of ALL. No association of AP with CFTR was observed. Larger international studies are necessary to more conclusively assess the risk of rare clinical phenotypes.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm10214815
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2662592-1
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  • 2
    Online Resource
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    Retinal Vascular Occlusion after COVID-19 Vaccination: More Coincidence than Causal Relationship? Data from a Retrospective Multicentre Study
    MDPI AG ; 2022
    In:  Journal of Clinical Medicine Vol. 11, No. 17 ( 2022-08-30), p. 5101-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 11, No. 17 ( 2022-08-30), p. 5101-
    Abstract: Background: To investigate whether vaccination against SARS-CoV-2 is associated with the onset of retinal vascular occlusive disease (RVOD). Methods: In this multicentre study, data from patients with central and branch retinal vein occlusion (CRVO and BRVO), central and branch retinal artery occlusion (CRAO and BRAO), and anterior ischaemic optic neuropathy (AION) were retrospectively collected during a 2-month index period (1 June–31 July 2021) according to a defined protocol. The relation to any previous vaccination was documented for the consecutive case series. Numbers of RVOD and COVID-19 vaccination were investigated in a case-by-case analysis. A case–control study using age- and sex-matched controls from the general population (study participants from the Gutenberg Health Study) and an adjusted conditional logistic regression analysis was conducted. Results: Four hundred and twenty-one subjects presenting during the index period (61 days) were enrolled: one hundred and twenty-one patients with CRVO, seventy-five with BRVO, fifty-six with CRAO, sixty-five with BRAO, and one hundred and four with AION. Three hundred and thirty-two (78.9%) patients had been vaccinated before the onset of RVOD. The vaccines given were BNT162b2/BioNTech/Pfizer (n = 221), followed by ChadOx1/AstraZeneca (n = 57), mRNA-1273/Moderna (n = 21), and Ad26.COV2.S/Johnson & Johnson (n = 11; unknown n = 22). Our case–control analysis integrating population-based data from the GHS yielded no evidence of an increased risk after COVID-19 vaccination (OR = 0.93; 95% CI: 0.60–1.45, p = 0.75) in connection with a vaccination within a 4-week window. Conclusions: To date, there has been no evidence of any association between SARS-CoV-2 vaccination and a higher RVOD risk.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm11175101
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2662592-1
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  • 3
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    Serum and Urinary Soluble α-Klotho as Markers of Kidney and Vascular Impairment
    MDPI AG ; 2023
    In:  Nutrients Vol. 15, No. 6 ( 2023-03-18), p. 1470-
    Details
    In: Nutrients, MDPI AG, Vol. 15, No. 6 ( 2023-03-18), p. 1470-
    Abstract: This study was designed to investigate the controversy on the potential role of sKlotho as an early biomarker in Chronic Kidney Disease–Mineral Bone Disorder (CKD-MBD), to assess whether sKlotho is a reliable marker of kidney α-Klotho, to deepen the effects of sKlotho on vascular smooth muscle cells (VSMCs) osteogenic differentiation and to evaluate the role of autophagy in this process. Experimental studies were conducted in CKD mice fed a normal phosphorus (CKD+NP) or high phosphorus (CKD+HP) diet for 14 weeks. The patients’ study was performed in CKD stages 2–5 and in vitro studies which used VSMCs exposed to non-calcifying medium or calcifying medium with or without sKlotho. The CKD experimental model showed that the CKD+HP group reached the highest serum PTH, P and FGF23 levels, but the lowest serum and urinary sKlotho levels. In addition, a positive correlation between serum sKlotho and kidney α-Klotho was found. CKD mice showed aortic osteogenic differentiation, together with increased autophagy. The human CKD study showed that the decline in serum sKlotho is previous to the rise in FGF23. In addition, both serum sKlotho and FGF23 levels correlated with kidney function. Finally, in VSMCs, the addition of sKlotho prevented osteogenic differentiation and induced autophagy. It can be concluded that serum sKlotho was the earliest CKD-MBD biomarker, a reliable indicator of kidney α-Klotho and that might protect against osteogenic differentiation by increasing autophagy. Nevertheless, further studies are needed to investigate the mechanisms of this possible protective effect.
    Type of Medium: Online Resource
    ISSN: 2072-6643
    URL: Article
    DOI: 10.3390/nu15061470
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2518386-2
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  • 4
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    Epidemiology of the Rhinovirus (RV) in African and Southeast Asian Children: A Case-Control Pneumonia Etiology Study
    MDPI AG ; 2021
    In:  Viruses Vol. 13, No. 7 ( 2021-06-27), p. 1249-
    Details
    In: Viruses, MDPI AG, Vol. 13, No. 7 ( 2021-06-27), p. 1249-
    Abstract: Rhinovirus (RV) is commonly detected in asymptomatic children; hence, its pathogenicity during childhood pneumonia remains controversial. We evaluated RV epidemiology in HIV-uninfected children hospitalized with clinical pneumonia and among community controls. PERCH was a case-control study that enrolled children (1–59 months) hospitalized with severe and very severe pneumonia per World Health Organization clinical criteria and age-frequency-matched community controls in seven countries. Nasopharyngeal/oropharyngeal swabs were collected for all participants, combined, and tested for RV and 18 other respiratory viruses using the Fast Track multiplex real-time PCR assay. RV detection was more common among cases (24%) than controls (21%) (aOR = 1.5, 95%CI:1.3–1.6). This association was driven by the children aged 12–59 months, where 28% of cases vs. 18% of controls were RV-positive (aOR = 2.1, 95%CI:1.8–2.5). Wheezing was 1.8-fold (aOR 95%CI:1.4–2.2) more prevalent among pneumonia cases who were RV-positive vs. RV-negative. Of the RV-positive cases, 13% had a higher probability ( 〉 75%) that RV was the cause of their pneumonia based on the PERCH integrated etiology analysis; 99% of these cases occurred in children over 12 months in Bangladesh. RV was commonly identified in both cases and controls and was significantly associated with severe pneumonia status among children over 12 months of age, particularly those in Bangladesh. RV-positive pneumonia was associated with wheezing.
    Type of Medium: Online Resource
    ISSN: 1999-4915
    URL: Article
    DOI: 10.3390/v13071249
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2516098-9
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  • 5
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    Online Resource
    Modeling Coding Intensity of Procedures in a U.S. Population-Based Hip/Knee Arthroplasty Inpatient Cohort Adjusting for Patient- and Facility-Level Characteristics
    MDPI AG ; 2022
    In:  Healthcare Vol. 10, No. 8 ( 2022-07-23), p. 1368-
    Details
    In: Healthcare, MDPI AG, Vol. 10, No. 8 ( 2022-07-23), p. 1368-
    Abstract: Variations in procedure coding intensity, defined as excess coding of procedures versus industry (instead of clinical) standards, can result in differentials in quality of care for patients and have additional implications for facilities and payors. The literature regarding coding intensity of procedures is limited, with a need for risk-adjusted methods that help identify over- and under-coding using commonly available data, such as administrative claims. Risk-adjusted metrics are needed for quality control and enhancement. We propose a two-step approach to risk adjustment, using a zero-inflated Poisson model, applied to a hip-knee arthroplasty cohort discharged during 2019 (n = 313,477) for patient-level risk adjustment, and a potential additional layer for adjustment based on facility-level characteristics, when desired. A 21.41% reduction in root-mean-square error was achieved upon risk adjustment for patient-level factors alone. Furthermore, we identified facilities that over- and under-code versus industry coding expectations, adjusting for both patient-level and facility-level factors. Excess coding intensity was found to vary across multiple levels: (1) geographically across U.S. Census regional divisions; (2) temporally with marked seasonal components; (3) by facility, with some facilities largely departing from industry standards, even after adjusting for both patient- and facility-level characteristics. Our proposed method is simple to implement, generalizable, it can be used across cohorts with different sets of information available, and it is not limited by the accessibility and sparsity of electronic health records. By identifying potential over- and under-coding of procedures, quality control personnel can explore and assess internal needs for enhancements in their health delivery services and monitor subsequent quality improvements.
    Type of Medium: Online Resource
    ISSN: 2227-9032
    URL: Article
    DOI: 10.3390/healthcare10081368
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2721009-1
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  • 6
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    Online Resource
    High Specificity of BCL11B and GLG1 for EWSR1-FLI1 and EWSR1-ERG Positive Ewing Sarcoma
    MDPI AG ; 2020
    In:  Cancers Vol. 12, No. 3 ( 2020-03-10), p. 644-
    Details
    In: Cancers, MDPI AG, Vol. 12, No. 3 ( 2020-03-10), p. 644-
    Abstract: Ewing sarcoma (EwS) is an aggressive cancer displaying an undifferentiated small-round-cell histomorphology that can be easily confused with a broad spectrum of differential diagnoses. Using comparative transcriptomics and immunohistochemistry (IHC), we previously identified BCL11B and GLG1 as potential specific auxiliary IHC markers for EWSR1-FLI1-positive EwS. Herein, we aimed at validating the specificity of both markers in a far larger and independent cohort of EwS (including EWSR1-ERG-positive cases) and differential diagnoses. Furthermore, we evaluated their intra-tumoral expression heterogeneity. Thus, we stained tissue microarrays from 133 molecularly confirmed EwS cases and 320 samples from morphological mimics, as well as a series of patient-derived xenograft (PDX) models for BCL11B, GLG1, and CD99, and systematically assessed the immunoreactivity and optimal cut-offs for each marker. These analyses demonstrated that high BCL11B and/or GLG1 immunoreactivity in CD99-positive cases had a specificity of 97.5% and an accuracy of 87.4% for diagnosing EwS solely by IHC, and that the markers were expressed by EWSR1-ERG-positive EwS. Only little intra-tumoral heterogeneity in immunoreactivity was observed for differential diagnoses. These results indicate that BCL11B and GLG1 may help as specific auxiliary IHC markers in diagnosing EwS in conjunction with CD99, especially if confirmatory molecular diagnostics are not available.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers12030644
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2527080-1
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  • 7
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    Centralised RECIST Assessment and Clinical Outcomes with Lenvatinib Monotherapy in Recurrent and Metastatic Adenoid Cystic Carcinoma
    MDPI AG ; 2021
    In:  Cancers Vol. 13, No. 17 ( 2021-08-27), p. 4336-
    Details
    In: Cancers, MDPI AG, Vol. 13, No. 17 ( 2021-08-27), p. 4336-
    Abstract: Adenoid cystic carcinoma (ACC) is a rare cancer of secretory glands. Recurrent or metastatic (R/M) ACC is generally considered resistant to cytotoxic chemotherapy. Recent phase II studies have reported improved objective response rates (ORR) with the use of the multi-kinase inhibitor lenvatinib. We sought to evaluate real-world experience of R/M ACC patients treated with lenvatinib monotherapy within the UK National Health Service (NHS) to determine the response rates by Response Evaluation Criteria of Solid Tumour (RECIST) and clinical outcomes. Twenty-three R/M ACC patients from eleven cancer centres were included. All treatment assessments for clinical decision making related to drug therapy were undertaken at the local oncology centre. Central radiology review was performed by an independent clinical trial radiologist and blinded to the clinical decision making. In contrast to previously reported ORR of 12–15%, complete or partial response was not observed in any patients. Eleven patients (52.4%) had stable disease and 5 patients (23.8%) had progression of disease as the best overall response. The median time on treatment was 4 months and the median survival from discontinuation was 1 month. The median PFS and OS from treatment initiation were 4.5 months and 12 months respectively. Multicentre collaborative studies such as this are required to evaluate rare cancers with no recommended standard of care therapy and variable disease courses.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers13174336
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527080-1
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  • 8
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    Online Resource
    A Randomised Control Trial Investigating the Efficacy of the MapMe Intervention on Parental Ability to Correctly Categorise Overweight in Their Child and the Impact on Child BMI Z-Score Change at 1 Year
    MDPI AG ; 2023
    In:  Children Vol. 10, No. 9 ( 2023-09-21), p. 1577-
    Details
    In: Children, MDPI AG, Vol. 10, No. 9 ( 2023-09-21), p. 1577-
    Abstract: Research suggests parental ability to recognise when their child has overweight is limited. It is hypothesised that recognition of child overweight/obesity is fundamental to its prevention, acting as a potential barrier to parental action to improve their child’s health-related behaviours and/or help seeking. The purpose of this study was to investigate the efficacy of an intervention (MapMe) to improve parental ability to correctly categorise their child as having overweight one-month post-intervention, and reduce child body mass index (BMI) z-score 12 months post-intervention. MapMe consists of body image scales of known child BMI and information on the consequences of childhood overweight, associated health-related behaviours and sources of support. We conducted a three-arm (paper-based MapMe, web-based MapMe and control) randomised control trial in fifteen English local authority areas with parents/guardians of 4–5- and 10–11-year-old children. Parental categorisation of child weight status was assessed using the question ‘How would you describe your child’s weight at the moment?’ Response options were: underweight, healthy weight, overweight, and very overweight. Child weight status and BMI z-scores were calculated using objectively measured height and weight data and UK90 clinical thresholds. There was no difference in the percentage of parents correctly categorising their child as having overweight/very overweight (n = 264: 41% control, 48% web-based, and 43% paper-based, p = 0.646). BMI z-scores were significantly reduced for the intervention group at 12 months post-intervention compared to controls (n = 338, mean difference in BMI z-score change −0.11 (95% CI −0.202 to −0.020, p = 0.017). MapMe was associated with a decrease in BMI z-score 12 months post-intervention, although there was no direct evidence of improved parental ability to correctly categorise child overweight status. Further work is needed to replicate these findings in a larger sample of children, investigate mechanisms of action, and determine the use of MapMe as a public health initiative.
    Type of Medium: Online Resource
    ISSN: 2227-9067
    URL: Article
    DOI: 10.3390/children10091577
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2732685-8
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  • 9
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    Extra Virgin Olive Oil Contains a Phenolic Inhibitor of the Histone Demethylase LSD1/KDM1A
    MDPI AG ; 2019
    In:  Nutrients Vol. 11, No. 7 ( 2019-07-19), p. 1656-
    Details
    In: Nutrients, MDPI AG, Vol. 11, No. 7 ( 2019-07-19), p. 1656-
    Abstract: The lysine-specific histone demethylase 1A (LSD1) also known as lysine (K)-specific demethylase 1A (KDM1A) is a central epigenetic regulator of metabolic reprogramming in obesity-associated diseases, neurological disorders, and cancer. Here, we evaluated the ability of oleacein, a biophenol secoiridoid naturally present in extra virgin olive oil (EVOO), to target LSD1. Molecular docking and dynamic simulation approaches revealed that oleacein could target the binding site of the LSD1 cofactor flavin adenosine dinucleotide with high affinity and at low concentrations. At higher concentrations, oleacein was predicted to target the interaction of LSD1 with histone H3 and the LSD1 co-repressor (RCOR1/CoREST), likely disturbing the anchorage of LSD1 to chromatin. AlphaScreen-based in vitro assays confirmed the ability of oleacein to act as a direct inhibitor of recombinant LSD1, with an IC50 as low as 2.5 μmol/L. Further, oleacein fully suppressed the expression of the transcription factor SOX2 (SEX determining Region Y-box 2) in cancer stem-like and induced pluripotent stem (iPS) cells, which specifically occurs under the control of an LSD1-targeted distal enhancer. Conversely, oleacein failed to modify ectopic SOX2 overexpression driven by a constitutive promoter. Overall, our findings provide the first evidence that EVOO contains a naturally occurring phenolic inhibitor of LSD1, and support the use of oleacein as a template to design new secoiridoid-based LSD1 inhibitors.
    Type of Medium: Online Resource
    ISSN: 2072-6643
    URL: Article
    DOI: 10.3390/nu11071656
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2518386-2
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  • 10
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    Design and Optimization of a Monkeypox virus Specific Serological Assay
    MDPI AG ; 2023
    In:  Pathogens Vol. 12, No. 3 ( 2023-03-01), p. 396-
    Details
    In: Pathogens, MDPI AG, Vol. 12, No. 3 ( 2023-03-01), p. 396-
    Abstract: Monkeypox virus (MPXV), a member of the Orthopoxvirus (OPXV) genus, is a zoonotic virus, endemic to central and western Africa that can cause smallpox-like symptoms in humans with fatal outcomes in up to 15% of patients. The incidence of MPXV infections in the Democratic Republic of the Congo, where the majority of cases have occurred historically, has been estimated to have increased as much as 20-fold since the end of smallpox vaccination in 1980. Considering the risk global travel carries for future disease outbreaks, accurate epidemiological surveillance of MPXV is warranted as demonstrated by the recent Mpox outbreak, where the majority of cases were occurring in non-endemic areas. Serological differentiation between childhood vaccination and recent infection with MPXV or other OPXVs is difficult due to the high level of conservation within OPXV proteins. Here, a peptide-based serological assay was developed to specifically detect exposure to MPXV. A comparative analysis of immunogenic proteins across human OPXVs identified a large subset of proteins that could potentially be specifically recognized in response to a MPXV infection. Peptides were chosen based upon MPXV sequence specificity and predicted immunogenicity. Peptides individually and combined were screened in an ELISA against serum from well-characterized Mpox outbreaks, vaccinee sera, and smallpox sera collected prior to eradication. One peptide combination was successful with ~86% sensitivity and ~90% specificity. The performance of the assay was assessed against the OPXV IgG ELISA in the context of a serosurvey by retrospectively screening a set of serum specimens from the region in Ghana believed to have harbored the MPXV-infected rodents involved in the 2003 United States outbreak.
    Type of Medium: Online Resource
    ISSN: 2076-0817
    URL: Article
    DOI: 10.3390/pathogens12030396
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2695572-6
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