Medicine (Austin & Northern Health) - Research Publications

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    Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis.
    Hudson, J ; Cruickshank, M ; Quinton, R ; Aucott, L ; Aceves-Martins, M ; Gillies, K ; Bhasin, S ; Snyder, PJ ; Ellenberg, SS ; Grossmann, M ; Travison, TG ; Gianatti, EJ ; van der Schouw, YT ; Emmelot-Vonk, MH ; Giltay, EJ ; Hackett, G ; Ramachandran, S ; Svartberg, J ; Hildreth, KL ; Groti Antonic, K ; Brock, GB ; Tenover, JL ; Tan, HM ; Kong, CHC ; Tan, WS ; Marks, LS ; Ross, RJ ; Schwartz, RS ; Manson, P ; Roberts, S ; Andersen, MS ; Magnussen, LV ; Hernández, R ; Oliver, N ; Wu, F ; Dhillo, WS ; Bhattacharya, S ; Brazzelli, M ; Jayasena, CN (Elsevier BV, 2022-06)
    BACKGROUND: Testosterone is the standard treatment for male hypogonadism, but there is uncertainty about its cardiovascular safety due to inconsistent findings. We aimed to provide the most extensive individual participant dataset (IPD) of testosterone trials available, to analyse subtypes of all cardiovascular events observed during treatment, and to investigate the effect of incorporating data from trials that did not provide IPD. METHODS: We did a systematic review and meta-analysis of randomised controlled trials including IPD. We searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Epub Ahead of Print, Embase, Science Citation Index, the Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, and Database of Abstracts of Review of Effects for literature from 1992 onwards (date of search, Aug 27, 2018). The following inclusion criteria were applied: (1) men aged 18 years and older with a screening testosterone concentration of 12 nmol/L (350 ng/dL) or less; (2) the intervention of interest was treatment with any testosterone formulation, dose frequency, and route of administration, for a minimum duration of 3 months; (3) a comparator of placebo treatment; and (4) studies assessing the pre-specified primary or secondary outcomes of interest. Details of study design, interventions, participants, and outcome measures were extracted from published articles and anonymised IPD was requested from investigators of all identified trials. Primary outcomes were mortality, cardiovascular, and cerebrovascular events at any time during follow-up. The risk of bias was assessed using the Cochrane Risk of Bias tool. We did a one-stage meta-analysis using IPD, and a two-stage meta-analysis integrating IPD with data from studies not providing IPD. The study is registered with PROSPERO, CRD42018111005. FINDINGS: 9871 citations were identified through database searches and after exclusion of duplicates and of irrelevant citations, 225 study reports were retrieved for full-text screening. 116 studies were subsequently excluded for not meeting the inclusion criteria in terms of study design and characteristics of intervention, and 35 primary studies (5601 participants, mean age 65 years, [SD 11]) reported in 109 peer-reviewed publications were deemed suitable for inclusion. Of these, 17 studies (49%) provided IPD (3431 participants, mean duration 9·5 months) from nine different countries while 18 did not provide IPD data. Risk of bias was judged to be low in most IPD studies (71%). Fewer deaths occurred with testosterone treatment (six [0·4%] of 1621) than placebo (12 [0·8%] of 1537) without significant differences between groups (odds ratio [OR] 0·46 [95% CI 0·17-1·24]; p=0·13). Cardiovascular risk was similar during testosterone treatment (120 [7·5%] of 1601 events) and placebo treatment (110 [7·2%] of 1519 events; OR 1·07 [95% CI 0·81-1·42]; p=0·62). Frequently occurring cardiovascular events included arrhythmia (52 of 166 vs 47 of 176), coronary heart disease (33 of 166 vs 33 of 176), heart failure (22 of 166 vs 28 of 176), and myocardial infarction (10 of 166 vs 16 of 176). Overall, patient age (interaction 0·97 [99% CI 0·92-1·03]; p=0·17), baseline testosterone (interaction 0·97 [0·82-1·15]; p=0·69), smoking status (interaction 1·68 [0·41-6·88]; p=0.35), or diabetes status (interaction 2·08 [0·89-4·82; p=0·025) were not associated with cardiovascular risk. INTERPRETATION: We found no evidence that testosterone increased short-term to medium-term cardiovascular risks in men with hypogonadism, but there is a paucity of data evaluating its long-term safety. Long-term data are needed to fully evaluate the safety of testosterone. FUNDING: National Institute for Health Research Health Technology Assessment Programme.
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    Loss-of-function variants in the KCNQ5 gene are implicated in genetic generalized epilepsies
    Krueger, J ; Schubert, J ; Kegele, J ; Labalme, A ; Mao, M ; Heighway, J ; Seebohm, G ; Yan, P ; Koko, M ; Aslan-Kara, K ; Caglayan, H ; Steinhoff, BJ ; Weber, YG ; Keo-Kosal, P ; Berkovic, SF ; Hildebrand, MS ; Petrou, S ; Krause, R ; May, P ; Lesca, G ; Maljevic, S ; Lerche, H (ELSEVIER, 2022-10-01)
    BACKGROUND: De novo missense variants in KCNQ5, encoding the voltage-gated K+ channel KV7.5, have been described to cause developmental and epileptic encephalopathy (DEE) or intellectual disability (ID). We set out to identify disease-related KCNQ5 variants in genetic generalized epilepsy (GGE) and their underlying mechanisms. METHODS: 1292 families with GGE were studied by next-generation sequencing. Whole-cell patch-clamp recordings, biotinylation and phospholipid overlay assays were performed in mammalian cells combined with homology modelling. FINDINGS: We identified three deleterious heterozygous missense variants, one truncation and one splice site alteration in five independent families with GGE with predominant absence seizures; two variants were also associated with mild to moderate ID. All missense variants displayed a strongly decreased current density indicating a loss-of-function (LOF). When mutant channels were co-expressed with wild-type (WT) KV7.5 or KV7.5 and KV7.3 channels, three variants also revealed a significant dominant-negative effect on WT channels. Other gating parameters were unchanged. Biotinylation assays indicated a normal surface expression of the variants. The R359C variant altered PI(4,5)P2-interaction. INTERPRETATION: Our study identified deleterious KCNQ5 variants in GGE, partially combined with mild to moderate ID. The disease mechanism is a LOF partially with dominant-negative effects through functional deficits. LOF of KV7.5 channels will reduce the M-current, likely resulting in increased excitability of KV7.5-expressing neurons. Further studies on network level are necessary to understand which circuits are affected and how this induces generalized seizures. FUNDING: DFG/FNR Research Unit FOR-2715 (Germany/Luxemburg), BMBF rare disease network Treat-ION (Germany), foundation 'no epilep' (Germany).
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    Intent among Parents to Vaccinate Children before Pediatric COVID-19 Vaccine Recommendations, Minnesota and Los Angeles County, California-May-September 2021.
    Suvada, KA ; Quan, SF ; Weaver, MD ; Sreedhara, M ; Czeisler, MÉ ; Como-Sabetti, K ; Lynfield, R ; Grounder, P ; Traub, E ; Amoon, A ; Ladva, CN ; Howard, ME ; Czeisler, CA ; Rajaratnam, SMW ; Ekwueme, DU ; Flannery, B ; Lane, RI (MDPI AG, 2022-09-01)
    Objectives: This study assessed the associations between parent intent to have their child receive the COVID-19 vaccination, and demographic factors and various child activities, including attendance at in-person education or childcare. Methods: Persons undergoing COVID-19 testing residing in Minnesota and Los Angeles County, California with children aged <12 years completed anonymous internet-based surveys between 10 May and 6 September 2021 to assess factors associated with intention to vaccinate their child. Factors influencing the parents' decision to have their child attend in-person school or childcare were examined. Estimated adjusted odds rations (AORs, 95% CI) were computed between parents' intentions regarding children's COVID-19 vaccination and participation in school and extra-curricular activities using multinomial logistic regression. Results: Compared to parents intending to vaccinate their children (n = 4686 [77.2%]), those undecided (n = 874 [14.4%]) or without intention to vaccinate (n = 508 [8.4%]) tended to be younger, non-White, less educated, and themselves not vaccinated against COVID-19. Their children more commonly participated in sports (aOR:1.51 1.17-1.95) and in-person faith or community activities (aOR:4.71 3.62-6.11). A greater proportion of parents without intention to vaccinate (52.5%) indicated that they required no more information to make their decision in comparison to undecided parents (13.2%). They further indicated that additional information regarding vaccine safety and effectiveness would influence their decision. COVID-19 mitigation measures were the most common factors influencing parents' decision to have their child attend in-person class or childcare. Conclusions: Several demographic and socioeconomic factors are associated with parents' decision whether to vaccinate their <12-year-old children for COVID-19. Child participation in in-person activities was associated with parents' intentions not to vaccinate. Tailored communications may be useful to inform parents' decisions regarding the safety and effectiveness of vaccination.
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    Improvement of the Fatigue Resistance of Super Duplex Stainless-Steel (SDSS) Components Fabricated by Wire Arc Additive Manufacturing (WAAM)
    Sales, A ; Kotousov, A ; Perilli, E ; Yin, L (MDPI AG, 2022-09-01)
    This study aimed to improve the overall fatigue properties of WAAM-produced SDSS by changing the interpass temperatures. Micro-computed tomography was used to quantitatively characterise the internal defects, such as porosity, in large-volume WAAM-fabricated SDSS materials. An increase in the interpass temperature led to a reduction in the ferrite phase balance by up to 20%. The fatigue anisotropy was still evident, but the fatigue limit in the weakest (transverse) direction was increased to 250 MPa or by approximately 40%. Meanwhile, the increased interpass temperature had no significant effect on fatigue resistance in the longitudinal direction. This study suggests that the interpass temperature can be critical for both achieving isotropic mechanical properties and increasing fatigue life of structural components fabricated with the WAAM method.
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    Plasma Angiotensin Converting Enzyme 2 (ACE2) Activity in Healthy Controls and Patients with Cardiovascular Risk Factors and/or Disease
    Lim, HY ; Patel, SK ; Huang, P ; Tacey, M ; Choy, KW ; Wang, J ; Donnan, G ; Nandurkar, HH ; Ho, P ; Burrell, LM (MDPI, 2022-09-01)
    Angiotensin converting enzyme 2 (ACE2) is an endogenous negative regulator of the renin-angiotensin system, a key factor in the development of cardiovascular disease (CVD). ACE2 is also used by SARS-CoV-2 for host cell entry. Given that COVID-19 is associated with hypercoagulability, it is timely to explore the potential relationship between plasma ACE2 activity and the coagulation profile. In this cross-sectional study, ACE2 activity and global coagulation assays (GCA) including thromboelastography, thrombin, and fibrin generation were measured in adult healthy controls (n = 123; mean age 41 ± 17 years; 35% male) and in patients with cardiovascular risk factors and/or disease (n = 258; mean age 65 ± 14 years; 55% male). ACE2 activity was significantly lower in controls compared to patients with cardiovascular risk factors and/or disease (median 0.10 (0.02, 3.33) vs. 5.99 (1.95, 10.37) pmol/mL/min, p < 0.001). Of the healthy controls, 48% had undetectable ACE2 activity. Controls with detectable ACE2 had lower maximum amplitude (p < 0.001). In patients with cardiovascular risk factors and/or disease, those in the 3rd tertile were older and male (p = 0.002), with a higher Framingham grade and increased number of cardiovascular risk factors (p < 0.001). In conclusion, plasma ACE2 activity is undetectable to very low in young healthy controls with minimal clinically relevant associations to GCA. Patients with cardiovascular risk factors and/or disease have increased plasma ACE2 activity, suggesting that it may be an important biomarker of endothelial dysfunction and atherosclerosis.
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    Nova1 or Bim Deficiency in Pancreatic β-Cells Does Not Alter Multiple Low-Dose Streptozotocin-Induced Diabetes and Diet-Induced Obesity in Mice.
    Brahma, MK ; Xiao, P ; Popa, M ; Negueruela, J ; Vandenbempt, V ; Demine, S ; Cardozo, AK ; Gurzov, EN (MDPI AG, 2022-09-18)
    The loss of functional pancreatic β-cell mass is an important hallmark of both type 1 and type 2 diabetes. The RNA-binding protein NOVA1 is expressed in human and rodent pancreatic β-cells. Previous in vitro studies indicated that NOVA1 is necessary for glucose-stimulated insulin secretion and its deficiency-enhanced cytokine-induced apoptosis. Moreover, Bim, a proapoptotic protein, is differentially spliced and potentiates apoptosis in NOVA1-deficient β-cells in culture. We generated two novel mouse models by Cre-Lox technology lacking Nova1 (βNova1-/-) or Bim (βBim-/-) in β-cells. To test the impact of Nova1 or Bim deletion on β-cell function, mice were subjected to multiple low-dose streptozotocin (MLD-STZ)-induced diabetes or high-fat diet-induced insulin resistance. β-cell-specific Nova1 or Bim deficiency failed to affect diabetes development in response to MLD-STZ-induced β-cell dysfunction and death evidenced by unaltered blood glucose levels and pancreatic insulin content. In addition, body composition, glucose and insulin tolerance test, and pancreatic insulin content were indistinguishable between control and βNova1-/- or βBim-/- mice on a high fat diet. Thus, Nova1 or Bim deletion in β-cells does not impact on glucose homeostasis or diabetes development in mice. Together, these data argue against an in vivo role for the Nova1-Bim axis in β-cells.
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    High-Throughput Human Complement C3 N-Glycoprofiling Identifies Markers of Early Onset Type 1 Diabetes Mellitus in Children.
    Šoić, D ; Keser, T ; Štambuk, J ; Kifer, D ; Pociot, F ; Lauc, G ; Morahan, G ; Novokmet, M ; Gornik, O (Elsevier BV, 2022-10)
    Recently, it was shown that children at the onset of type 1 diabetes (T1D) have a higher proportion of oligomannose glycans in their total plasma protein N-glycome compared to their healthy siblings. The most abundant complement component, glycoprotein C3, contains two N-glycosylation sites occupied exclusively by this type of glycans. Furthermore, complement system, as well as C3, was previously associated with T1D. It is also known that changes in glycosylation can modulate inflammatory responses, so our aim was to characterize the glycosylation profile of C3 in T1D. For this purpose, we developed a novel high-throughput workflow for human C3 concanavalin A lectin affinity enrichment and subsequent LC-MS glycopeptide analysis which enables protein-specific N-glycosylation profiling. From the Danish Childhood Diabetes Register, plasma samples of 61 children/adolescents newly diagnosed with T1D and 84 of their unaffected siblings were C3 N-glycoprofiled. Significant changes of C3 N-glycan profiles were found. T1D was associated with an increase in the proportion of unprocessed glycan structures with more mannose units. A regression model including C3 N-glycans showed notable discriminative power between children with early onset T1D and their healthy siblings with area under curve of 0.879. This study confirmed our previous findings of plasma high-mannose glycan changes in a cohort of recent onset T1D cases, suggesting the involvement of C3 N-glycome in T1D development. Our C3 glycan-based discriminative model could be valuable in assessment of T1D risk in children.
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    On-Line Solid Phase Extraction High Performance Liquid Chromatography Method Coupled With Tandem Mass Spectrometry for the Therapeutic Monitoring of Cannabidiol and 7-Hydroxy-cannabidiol in Human Serum and Saliva
    Franco, V ; Palmisani, M ; Marchiselli, R ; Crema, F ; Fattore, C ; De Giorgis, V ; Varesio, C ; Rota, P ; Dibari, VF ; Perucca, E (FRONTIERS MEDIA SA, 2022-06-22)
    Cannabidiol is a novel antiseizure medication approved in Europe and the US for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome and tuberous sclerosis complex. We describe in this article a new and simple liquid chromatography-mass spectrometry method (LC-MS/MS) for the determination of cannabidiol and its active metabolite 7-hydroxy-cannabidiol in microvolumes of serum and saliva (50 μl), to be used as a tool for therapeutic drug monitoring (TDM) and pharmacokinetic studies. After on-line solid phase extraction cannabidiol, 7-hydroxy-cannabidiol and the internal standard cannabidiol-d3 are separated on a monolithic C18 column under gradient conditions. Calibration curves are linear within the validated concentration range (10-1,000 ng/ml for cannabidiol and 5-500 ng/ml for 7-hydroxy-cannabidiol). The method is accurate (intraday and interday accuracy within 94-112% for cannabidiol, 91-109% for 7-hydroxy-cannabidiol), precise (intraday and interday precision <11.6% for cannabidiol and <11.7% for 7- hydroxy-cannabidiol) and sensitive, with a LOQ of 2.5 ng/ml for cannabidiol and 5 ng/ml for 7-hydroxy-cannabidiol. The stability of the analytes was confirmed under different storage conditions. Extraction recoveries were in the range of 81-129% for cannabidiol and 100-113% for 7-hydroxy-cannabidiol. The applicability of the method to TDM was demonstrated by analysis of human serum and saliva samples obtained from patients with epilepsy treated with cannabidiol.
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    A cohort study of the efficacy and safety of immune checkpoint inhibitors plus anlotinib versus immune checkpoint inhibitors alone as the treatment of advanced non-small cell lung cancer in the real world.
    Shi, Y ; Ji, M ; Jiang, Y ; Yin, R ; Wang, Z ; Li, H ; Wang, S ; He, K ; Ma, Y ; Wang, Z ; Lu, J ; Shi, M ; Shen, B ; Zhou, G ; Leong, TL ; Wang, X ; Chen, C ; Feng, J (AME Publishing Company, 2022-06)
    BACKGROUND: Anlotinib is a new multi-target tyrosine kinase inhibitor (TKI) and has been shown to have antitumor effects and synergistic antitumor effects with immunotherapy only in animal studies and in the 2nd-line treatment in small clinical trials. A real-world study with large sample to compare the efficacy and safety of anlotinib plus immune checkpoint inhibitors (ICIs) with ICIs alone in the multiline treatment of advanced non-small cell lung cancer (NSCLC) was urgently needed. METHODS: The data of 535 advanced NSCLC patients were collected from January 1, 2018, to December 31, 2021. The patients were divided into 2 groups: (I) ICI monotherapy (230 patients); (II) ICI + anlotinib (305 patients). After propensity-score matching (PSM) to reduce the effects of biases and confounding variables, the progression-free survival time (PFS), occurrence of adverse events, disease control rate (DCR), and objective response rate (ORR) of the 2 groups were compared. The effects of clinical factors, including age, gender, gene mutations, tumor proportion score, metastases, and combined radiotherapy, were also analyzed. RESULTS: After PSM, the baseline clinical characteristics were well balanced and the 2 group had a good comparability. Patients in the ICI + anlotinib group had significantly longer median PFS in both the 2nd-line treatment (7.73 vs. 4.70 months; P=0.003) and 3rd-line treatment (5.90 vs. 3.37 months; P=0.020), but the difference lacked statistical significance in the 1st-line treatment (8.40 vs. 5.20 months; P=0.229). The overall median PFS of patients in the ICI + anlotinib group was also much longer than that of patients in the ICI monotherapy group (6.37 vs. 3.90 months; P<0.001). The ICI + anlotinib group also tended to have a higher DCR, a higher ORR, and a higher probability of severe adverse drug reactions during the treatment than the ICI monotherapy group, but the differences were not statistically significant. Combining ICI + anlotinib could improve the outcomes of patients with bone metastasis. CONCLUSIONS: Anlotinib + ICI therapy could have greater efficacy in the treatment of advanced NSCLC patients than ICI monotherapy. The probability of adverse events might increase in the combined treatment, but could be controlled.
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    Epidemiology and outcomes of primary sclerosing cholangitis: an Australian multicentre retrospective cohort study
    Tan, N ; Ngu, N ; Worland, T ; Lee, T ; Abrahams, T ; Pandya, K ; Freeman, E ; Hannah, N ; Gazelakis, K ; Madden, RG ; Lynch, KD ; Valaydon, Z ; Sood, S ; Dev, A ; Bell, S ; Thompson, A ; Ding, J ; Nicoll, AJ ; Liu, K ; Gow, P ; Lubel, J ; Kemp, W ; Roberts, SK ; Majeed, A (SPRINGER, 2022-06-03)
    BACKGROUND AND AIMS: Little is known regarding the epidemiology and outcomes of patients with primary sclerosing cholangitis (PSC) in Australia. We, therefore, evaluated the epidemiology and clinical outcomes of PSC in a large cohort of Australian patients and compared these to the general population. METHODS: We conducted a multicentre, retrospective cohort study of PSC patients at nine tertiary liver centers across three Australian states, including two liver transplant centers. RESULTS: A total of 413 PSC patients with 3,285 person-years of follow-up were included. Three hundred and seventy-one (90%) patients had large duct PSC and 294 (71%) had associated inflammatory bowel disease. A total of 168 (41%) patients developed cirrhosis (including 34 at the time of PSC diagnosis) after a median of 15.8 (95% CI 12.4, NA) years. The composite endpoint of death or liver transplantation occurred in 49 (12%) and 78 (19%) patients, respectively, with a median transplant-free survival of 13.4 (95% CI 12.2-15) years. Compared to the general population, PSC accounted for a 240-fold increased risk of development of cholangiocarcinoma (CCA) and CCA-related death. CCA risk was increased with older age of PSC diagnosis, presence of dominant stricture and colectomy. Compared to same-aged counterparts in the general population, PSC patients who were diagnosed at an older age or with longer disease duration had reduced relative survival. CONCLUSION: In this large retrospective cohort study of PSC patients in Australia, increased age and time from diagnosis was associated with increased mortality and morbidity particularly from CCA and development of cirrhosis, necessitating need for liver transplant.