Minerva Elements Records

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Universal genetic testing for women with newly diagnosed breast cancer in the context of multidisciplinary team care

De Silva, DL ; Stafford, L ; Skandarajah, AR ; Sinclair, M ; Devereux, L ; Hogg, K ; Kentwell, M ; Park, A ; Lal, L ; Zethoven, M ; Jayawardana, MW ; Chan, F ; Butow, PN ; James, PA ; Mann, GB ; Campbell, IG ; Lindeman, GJ (WILEY, 2023-04-02)

OBJECTIVE: To determine the feasibility of universal genetic testing of women with newly diagnosed breast cancer, to estimate the incidence of pathogenic gene variants and their impact on patient management, and to evaluate patient and clinician acceptance of universal testing. DESIGN, SETTING, PARTICIPANTS: Prospective study of women with invasive or high grade in situ breast cancer and unknown germline status discussed at the Parkville Breast Service (Melbourne) multidisciplinary team meeting. Women were recruited to the pilot (12 June 2020 - 22 March 2021) and expansion phases (17 October 2021 - 8 November 2022) of the Mutational Assessment of newly diagnosed breast cancer using Germline and tumour genomICs (MAGIC) study. MAIN OUTCOME MEASURES: Germline testing by DNA sequencing, filtered for nineteen hereditary breast and ovarian cancer genes that could be classified as actionable; only pathogenic variants were reported. Surveys before and after genetic testing assessed pilot phase participants' perceptions of genetic testing, and psychological distress and cancer-specific worry. A separate survey assessed clinicians' views on universal testing. RESULTS: Pathogenic germline variants were identified in 31 of 474 expanded study phase participants (6.5%), including 28 of 429 women with invasive breast cancer (6.5%). Eighteen of the 31 did not meet current genetic testing eligibility guidelines (probability of a germline pathogenic variant ≥ 10%, based on CanRisk, or Manchester score ≥ 15). Clinical management was changed for 24 of 31 women after identification of a pathogenic variant. Including 68 further women who underwent genetic testing outside the study, 44 of 542 women carried pathogenic variants (8.1%). Acceptance of universal testing was high among both patients (90 of 103, 87%) and clinicians; no decision regret or adverse impact on psychological distress or cancer-specific worry were reported. CONCLUSION: Universal genetic testing following the diagnosis of breast cancer detects clinically significant germline pathogenic variants that might otherwise be missed because of testing guidelines. Routine testing and reporting of pathogenic variants is feasible and acceptable for both patients and clinicians.
Inward foreign investment screening targets China: interdisciplinary perspectives*

McCalman, P ; Puzzello, L ; Voon, T ; Walter, A (Edward Elgar Publishing, 2023-06-28)

Screening of inward foreign investment in numerous countries worldwide has heightened in recent years for a range of reasons, one of which is the volume of Chinese outward investment. Moulding screening policies around concerns about Chinese investment has been a common pattern, particularly among developed countries and allies of the United States. The application of screening measures to Chinese investments in particular is also seen in recent practice in numerous countries. These developments create potential inconsistencies with international investment law, at least for those countries with an international investment agreement with China. The 2020 arbitral award in Global Telecom v Canada shows that even a provision that explicitly excludes investment screening decisions from a bilateral investment treaty may not apply to prevent all related investment treaty claims. The increased use of screening as a policy tool, with respect to China and otherwise, also raises questions about economic rationale and impact. Put simply, blocking a foreign investment proposal may have negative effects on shareholders, jobs and the economy itself, while even the existence of a restrictive screening regime and the threat of the imposition of conditions on a deal may dampen the appeal for foreign investors.
Selective transduction and photoinhibition of pre-Bötzinger neurons that project to the facial nucleus in rats affect the nasofacial activity.

Melo, MR ; Wykes, AD ; Connelly, AA ; Bassi, JK ; Cheung, SD ; McDougall, SJ ; Menuet, C ; Bathgate, RAD ; Allen, AM (eLife Sciences Publications, Ltd, 2023-09-29)

The preBötzinger Complex (preBötC), a key primary generator of the inspiratory breathing rhythm, contains neurons that project directly to facial nucleus (7n) motoneurons to coordinate orofacial and nasofacial activity. To further understand the identity of 7n-projecting preBötC neurons, we used a combination of optogenetic viral transgenic approaches to demonstrate that selective photoinhibition of these neurons affects mystacial pad activity, with minimal effects on breathing. These effects are altered by the type of anesthetic employed and also between anesthetised and conscious states. The population of 7n-projecting preBötC neurons we transduced consisted of both excitatory and inhibitory neurons that also send collaterals to multiple brainstem nuclei involved with the regulation of autonomic activity. We show that modulation of subgroups of preBötC neurons, based on their axonal projections, is a useful strategy to improve our understanding of the mechanisms that coordinate and integrate breathing with different motor and physiological behaviours. This is of fundamental importance, given that abnormal respiratory modulation of autonomic activity and orofacial behaviours have been associated with the development and progression of diseases.
Global diversity and antimicrobial resistance of typhoid fever pathogens: Insights from a meta-analysis of 13,000 Salmonella Typhi genomes.

Carey, ME ; Dyson, ZA ; Ingle, DJ ; Amir, A ; Aworh, MK ; Chattaway, MA ; Chew, KL ; Crump, JA ; Feasey, NA ; Howden, BP ; Keddy, KH ; Maes, M ; Parry, CM ; Van Puyvelde, S ; Webb, HE ; Afolayan, AO ; Alexander, AP ; Anandan, S ; Andrews, JR ; Ashton, PM ; Basnyat, B ; Bavdekar, A ; Bogoch, II ; Clemens, JD ; da Silva, KE ; De, A ; de Ligt, J ; Diaz Guevara, PL ; Dolecek, C ; Dutta, S ; Ehlers, MM ; Francois Watkins, L ; Garrett, DO ; Godbole, G ; Gordon, MA ; Greenhill, AR ; Griffin, C ; Gupta, M ; Hendriksen, RS ; Heyderman, RS ; Hooda, Y ; Hormazabal, JC ; Ikhimiukor, OO ; Iqbal, J ; Jacob, JJ ; Jenkins, C ; Jinka, DR ; John, J ; Kang, G ; Kanteh, A ; Kapil, A ; Karkey, A ; Kariuki, S ; Kingsley, RA ; Koshy, RM ; Lauer, AC ; Levine, MM ; Lingegowda, RK ; Luby, SP ; Mackenzie, GA ; Mashe, T ; Msefula, C ; Mutreja, A ; Nagaraj, G ; Nagaraj, S ; Nair, S ; Naseri, TK ; Nimarota-Brown, S ; Njamkepo, E ; Okeke, IN ; Perumal, SPB ; Pollard, AJ ; Pragasam, AK ; Qadri, F ; Qamar, FN ; Rahman, SIA ; Rambocus, SD ; Rasko, DA ; Ray, P ; Robins-Browne, R ; Rongsen-Chandola, T ; Rutanga, JP ; Saha, SK ; Saha, S ; Saigal, K ; Sajib, MSI ; Seidman, JC ; Shakya, J ; Shamanna, V ; Shastri, J ; Shrestha, R ; Sia, S ; Sikorski, MJ ; Singh, A ; Smith, AM ; Tagg, KA ; Tamrakar, D ; Tanmoy, AM ; Thomas, M ; Thomas, MS ; Thomsen, R ; Thomson, NR ; Tupua, S ; Vaidya, K ; Valcanis, M ; Veeraraghavan, B ; Weill, F-X ; Wright, J ; Dougan, G ; Argimón, S ; Keane, JA ; Aanensen, DM ; Baker, S ; Holt, KE ; Global Typhoid Genomics Consortium Group Authorship, (eLife Sciences Publications, Ltd, 2023-09-12)

BACKGROUND: The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000). METHODS: This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch. RESULTS: Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal 'sentinel' surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. CONCLUSIONS: The consortium's aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies. FUNDING: No specific funding was awarded for this meta-analysis. Coordinators were supported by fellowships from the European Union (ZAD received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 845681), the Wellcome Trust (SB, Wellcome Trust Senior Fellowship), and the National Health and Medical Research Council (DJI is supported by an NHMRC Investigator Grant [GNT1195210]).
Does Post-traumatic Stress Disorder Impact Treatment Outcomes within a Randomised Controlled Trial of Mitochondrial Agents for Bipolar Depression?

Russell, SE ; Wrobel, AL ; Ashton, MM ; Turner, A ; Mohebbi, M ; Berk, M ; Cotton, S ; Dodd, S ; Ng, CH ; Malhi, GS ; Dean, OM (KOREAN COLL NEUROPSYCHOPHARMACOLOGY, 2023-08)

OBJECTIVE: Bipolar disorder often co-occurs with post-traumatic stress disorder, yet few studies have investigated the impact of post-traumatic stress disorder in bipolar disorder on treatment outcomes. The aim of this sub-analysis was to explore symptoms and functioning outcomes between those with bipolar disorder alone and those with comorbid bipolar disorder and post-traumatic stress disorder. METHODS: Participants (n = 148) with bipolar depression were randomised to: (i) N-acetylcysteine alone; (ii) a combination of nutraceuticals; (iii) or placebo (in addition to treatment as usual) for 16 weeks (＋4 weeks discontinuation). Differences between bipolar disorder and comorbid bipolar disorder and post-traumatic stress disorder on symptoms and functioning at five timepoints, as well as on the rate of change from baseline to week 16 and baseline to week 20, were examined. RESULTS: There were no baseline differences between bipolar disorder alone and comorbid bipolar disorder and post-traumatic stress disorder apart from the bipolar disorder alone group being significantly more likely to be married (p = 0.01). There were also no significant differences between bipolar disorder alone and comorbid bipolar disorder and post-traumatic stress disorder on symptoms and functioning. CONCLUSION: There were no differences in clinical outcomes over time within the context of an adjunctive randomised controlled trial between those with bipolar disorder alone compared to those with comorbid bipolar disorder and post-traumatic stress disorder. However, differences in psychosocial factors may provide targets for areas of specific support for people with comorbid bipolar disorder and post-traumatic stress disorder.
The evolutionary mechanism of non-carbapenemase carbapenem-resistant phenotypes in Klebsiella spp

Rosas, NC ; Wilksch, J ; Barber, J ; Li, J ; Wang, Y ; Sun, Z ; Rocker, A ; Webb, CT ; Perlaza-Jimenez, L ; Stubenrauch, CJ ; Dhanasekaran, V ; Song, J ; Taiaroa, G ; Davies, M ; Strugnell, RA ; Bao, Q ; Zhou, T ; McDonald, MJ ; Lithgow, T (eLIFE SCIENCES PUBL LTD, 2023-07-06)

Antibiotic resistance is driven by selection, but the degree to which a bacterial strain's evolutionary history shapes the mechanism and strength of resistance remains an open question. Here, we reconstruct the genetic and evolutionary mechanisms of carbapenem resistance in a clinical isolate of Klebsiella quasipneumoniae. A combination of short- and long-read sequencing, machine learning, and genetic and enzymatic analyses established that this carbapenem-resistant strain carries no carbapenemase-encoding genes. Genetic reconstruction of the resistance phenotype confirmed that two distinct genetic loci are necessary in order for the strain to acquire carbapenem resistance. Experimental evolution of the carbapenem-resistant strains in growth conditions without the antibiotic revealed that both loci confer a significant cost and are readily lost by de novo mutations resulting in the rapid evolution of a carbapenem-sensitive phenotype. To explain how carbapenem resistance evolves via multiple, low-fitness single-locus intermediates, we hypothesised that one of these loci had previously conferred adaptation to another antibiotic. Fitness assays in a range of drug concentrations show how selection in the antibiotic ceftazidime can select for one gene (blaDHA-1) potentiating the evolution of carbapenem resistance by a single mutation in a second gene (ompK36). These results show how a patient's treatment history might shape the evolution of antibiotic resistance and could explain the genetic basis of carbapenem-resistance found in many enteric-pathogens.
Current and emerging medications for the management of obesity in adults.

Walmsley, R ; Sumithran, P (Wiley, 2023-08-21)
The characteristics of SARS-CoV-2-positive children in Australian hospitals: a PREDICT network study.

Ibrahim, L ; Wilson, C ; Tham, D ; Corden, M ; Jani, S ; Zhang, M ; Kochar, A ; Tan, KF ; George, S ; Phillips, NT ; Buntine, P ; Robins-Browne, K ; Chong, V ; Georgeson, T ; Lithgow, A ; Davidson, S ; O'Brien, S ; Tran, V ; Babl, FE (Wiley, 2023-06-05)

OBJECTIVES: To examine the clinical characteristics and short term outcomes for children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections who presented to Australian hospitals during 2020 and 2021. DESIGN, SETTING: Retrospective case review study in nineteen hospitals of the Paediatric Research in Emergency Departments International Collaborative (PREDICT) network from all Australian states and territories, including seven major paediatric tertiary centres and eight Victorian hospitals. PARTICIPANTS: SARS-CoV-2-positive people under 18 years of age who attended emergency departments or were admitted to hospital during 1 February 2020 - 31 December 2021. MAIN OUTCOME MEASURES: Epidemiological and clinical characteristics, by hospital care type (emergency department [ED] or inpatient care). RESULTS: A total of 1193 SARS-CoV-2-positive children and adolescents (527 girls, 44%) attended the participating hospitals (107 in 2020, 1086 in 2021). Their median age was 3.8 years (interquartile range [IQR], 0.8-11.4 years); 63 were Aboriginal or Torres Strait Islander people (5%). Other medical conditions were recorded for 293 children (25%), including asthma (86, 7%) and premature birth (68, 6%). Medical interventions were not required during 795 of 1181 ED presentations (67%); children were discharged directly home in 764 cases (65%) and admitted to hospital in 282 (24%; sixteen to intensive care units). The 384 admissions to hospital (including 102 direct admissions) of 341 children (25 infants under one month of age) included 23 to intensive care (6%); the median length of stay was three days (IQR, 1-9 days). Medical interventions were not required during 261 admissions (68%); 44 children received respiratory support (11%) and 21 COVID-19-specific treatments, including antiviral and biologic agents (5%). Being under three months of age (v one year to less than six years: odds ratio [OR], 2.6; 95% confidence interval [CI], 1.7-4.0) and pre-existing medical conditions (OR, 2.5; 95% CI, 1.9-3.2) were the major predictors of hospital admission. Two children died, including one without a known pre-existing medical condition. CONCLUSION: During 2020 and 2021, most SARS-CoV-2-positive children and adolescents who presented to participating hospitals could be managed as outpatients. Outcomes were generally good, including for those admitted to hospital.
Early Results from GLASS-JWST. XVIII. A First Morphological Atlas of the 1 < z < 5 Universe in the Rest-frame Optical

Jacobs, C ; Glazebrook, K ; Calabro, A ; Treu, T ; Nannayakkara, T ; Jones, T ; Merlin, E ; Abraham, R ; Stevens, ARH ; Vulcani, B ; Yang, L ; Bonchi, A ; Boyett, K ; Bradac, M ; Castellano, M ; Fontana, A ; Marchesini, D ; Malkan, M ; Mason, C ; Morishita, T ; Paris, D ; Santini, P ; Trenti, M ; Wang, X (IOP Publishing Ltd, 2023-05-01)

Abstract We present a rest-frame optical morphological analysis of galaxies observed with the NIRCam imager on the James Webb Space Telescope (JWST) as part of the GLASS-JWST Early Release Science program. We select 388 sources at redshifts 0.8 < z < 5.4 and use the seven 0.9–5 μm NIRCam filters to generate rest-frame gri composite color images, and conduct visual morphological classification. Compared to Hubble Space Telescope (HST)–based work we find a higher incidence of disks and bulges than expected at z > 1.5, revealed by rest-frame optical imaging. We detect 123 clear disks (58 at z > 1.5) of which 76 have bulges. No evolution of bulge fraction with redshift is evident: 61% at z < 2 (N = 110) versus 60% at z ≥ 2 (N = 13). A stellar mass dependence is evident, with bulges visible in 80% of all disk galaxies with mass >109.5 M ⊙ (N = 41) but only 52% at M < 109.5 M ⊙ (N = 82). We supplement visual morphologies with nonparametric measurements of Gini and asymmetry coefficients in the rest-frame i band. Our sources are more asymmetric than local galaxies, with slightly higher Gini values. When compared to high-z rest-frame ultraviolet measurements with HST, JWST shows more regular morphological types such as disks, bulges, and spiral arms at z > 1.5, with smoother (i.e., lower Gini) and more symmetrical light distributions.
Conversion of Upper-Limb Inertial Measurement Unit Data to Joint Angles: A Systematic Review.

Fang, Z ; Woodford, S ; Senanayake, D ; Ackland, D (MDPI AG, 2023-07-19)

Inertial measurement units (IMUs) have become the mainstay in human motion evaluation outside of the laboratory; however, quantification of 3-dimensional upper limb motion using IMUs remains challenging. The objective of this systematic review is twofold. Firstly, to evaluate computational methods used to convert IMU data to joint angles in the upper limb, including for the scapulothoracic, humerothoracic, glenohumeral, and elbow joints; and secondly, to quantify the accuracy of these approaches when compared to optoelectronic motion analysis. Fifty-two studies were included. Maximum joint motion measurement accuracy from IMUs was achieved using Euler angle decomposition and Kalman-based filters. This resulted in differences between IMU and optoelectronic motion analysis of 4° across all degrees of freedom of humerothoracic movement. Higher accuracy has been achieved at the elbow joint with functional joint axis calibration tasks and the use of kinematic constraints on gyroscope data, resulting in RMS errors between IMU and optoelectronic motion for flexion-extension as low as 2°. For the glenohumeral joint, 3D joint motion has been described with RMS errors of 6° and higher. In contrast, scapulothoracic joint motion tracking yielded RMS errors in excess of 10° in the protraction-retraction and anterior-posterior tilt direction. The findings of this study demonstrate high-quality 3D humerothoracic and elbow joint motion measurement capability using IMUs and underscore the challenges of skin motion artifacts in scapulothoracic and glenohumeral joint motion analysis. Future studies ought to implement functional joint axis calibrations, and IMU-based scapula locators to address skin motion artifacts at the scapula, and explore the use of artificial neural networks and data-driven approaches to directly convert IMU data to joint angles.

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