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This article focuses on problems faced by Australian shareholders in a takeover situation. The problems include determining the value of the consideration offered by the bidding party, establishing when the consideration will be paid, and understanding the regulations, procedures and practices involved in takeover bids. Two features of a takeover offer are usually of interest to all shareholders: they wish to know the price offered for their shares, and should the offer be accepted, they wish to know when the consideration will be received. Valuation of the offer is a simple procedure when the consideration proposed consists entirely of cash. But when it consists of shares in the offeror company, or a combination of cash and shares, shareholders are placed in the situation of having to value both sets of shares in order to evaluate the offer. It is unlikely, of course, that shareholders would accept any value imputed to the shares by the offer or without evidence to support such an opinion. In any case, an independent valuation is available for shares in a listed company.

This article discusses the factors influencing the outcome of take-over offers of shareholders. The factors considered are the premium included in the offer price in relation to re-offer prices, disclosed net tangible asset backing per share and the reaction of the directors of the offeree company to a take-over offer. No clear relationship was found that existed between the size of premiums included in the offer price and the outcome of the offers. The support of, or opposition to, a take-over offer by the directors of an offeree does not influence the outcome.

How an economically affordable, environmentally effective and socially acceptable municipal solid waste management system can be developed is currently unclear. Considerable research has been carried out onthe practical aspects of municipal waste management (i.e. transport,treatment and disposal) and how citizens feel about source separation, recycling, incineration and landfill but the perspective of the waste manager within the context of long term planning is often ignored. In this study, waste managers from 11 different leading-edge European municipal solid waste programs in nine different countries were interviewed. The economic, social, political, environmental, legal and technical factors of their specific programs were explored and analyzed. The transition of municipal solid waste management to urban resources management was observed and key `system drivers' for more sustainable waste management practices were identified. Programs visited were: Brescia (I), Copenhagen (DK), Hampshire (UK), Helsinki (FI), Lahn-Dill-Kreis (D), Malmo (SE), Pamplona (E), Prato (I), Saarbrucken (D), Vienna (A), and Zurich (CH). [ABSTRACT FROM AUTHOR]

Introduction: Duchenne muscular dystrophy (DMD) is a rare, progressive, debilitating neuromuscular disease. The early childhood onset and debilitating nature of the disease necessitate decades of caretaking for most patients. Caregivers have a critical role in evaluating patients' physical functioning and/or response to treatment. Using DMD-specific caregiver-reported scales, the impact of delandistrogene moxeparvovec gene therapy on caregivers' perceived change in patient disease status or severity was evaluated using the Caregiver Global Impression of Change and Severity (CaGI-C and CaGI-S, respectively)., Methods: In the Phase 3 randomized, double-blind, placebo-controlled trial (EMBARK; NCT05096221), the CaGI-C at week 52 and change from baseline to week 52 in CaGI-S were evaluated in a post hoc analysis. The CaGI-C assesses caregivers' impressions of change in DMD symptoms, physical ability, ability to perform daily activities, and overall health. The CaGI-S evaluates current severity of DMD symptoms, physical ability, ability to perform activities of daily living, and overall health. Data were evaluated using multi-domain responder index (MDRI) and ordinal regression analyses., Results: MDRI analyses across all four CaGI-C items yielded a treatment difference of 1.7 (95% confidence interval [CI]: 0.90-2.5) favoring delandistrogene moxeparvovec; a treatment difference of 1.1 (95% CI 0.30-1.9) was observed for the CaGI-S favoring delandistrogene moxeparvovec. After adjusting for age, ordinal regression analysis showed a nominally significant increase in the odds of achieving a better rating for delandistrogene moxeparvovec-treated patients on all four CaGI-C items (≥ 3.8-fold increase). After adjusting for baseline severity and age, ordinal regression analysis showed a nominally significant increase in the odds of improvement on all four CaGI-S items (≥ 2.2-fold increase)., Conclusion: These exploratory findings captured by caregiver-reported outcomes add to the totality of evidence that supports the clinical benefits of delandistrogene moxeparvovec for patients with DMD., Trial Registration Number: ClinicalTrials.gov identifier, NCT05096221., Competing Interests: Declarations. Conflict of Interest: Jacob S. Elkins, Sai Dharmarajan, Katherine Gooch, Ivana Audhya: Employees of Sarepta Therapeutics, Inc., and may hold stock/options in the company. Teofil Ciobanu: Employee of F. Hoffmann-La Roche Ltd. Claire J. Lansdall: Employee of F. Hoffmann-La Roche Ltd. and shareholder of F. Hoffmann-La Roche Ltd. Alexander P. Murphy: Employee of Roche Products UK and may hold shares in F. Hoffmann-La Roche Ltd. Fiona McDougall: Employee of Genentech, Inc.and shareholder of F. Hoffmann-La Roche Ltd. Craig M. McDonald: Reports grants from Capricor Therapeutics, Catabasis, Edgewise Therapeutics, Epirium Bio, Italfarmaco, Pfizer, PTC Therapeutics, Santhera Pharmaceuticals, Sarepta Therapeutics; and has a consultancy/advisory role with Biomarin, Capricor Therapeutics, Catalyst, Edgewise Therapeutics, Italfarmaco, PTC Therapeutics, F. Hoffmann-La Roche Ltd, Santhera Pharmaceuticals and Sarepta Therapeutics. He has received honoraria from PTC Therapeutics and Sarepta Therapeutics. Eugenio M. Mercuri: Reports receiving fees from AveXis, Biogen, and F. Hoffmann-La Roche Ltd. Ethical Approval: EMBARK was conducted in accordance with the provisions of the Declaration of Helsinki and Good Clinical Practice guidelines. Trial protocol and all amendments were approved by an institutional review board and ethics committee at each site. The full list of institutional review boards and ethics committees is available in the Supplementary Information. Informed consent, including consent to publish, was obtained from parent(s)/legal guardian(s), and patients’ assent was obtained when indicated., (© 2024. The Author(s).)

Introduction: Consensus definitions of meaningful within-patient change (MWPC) on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) are needed. Existing estimates use clinician-rated anchors in clinically diagnosed Alzheimer's disease (AD) populations. Incorporating the care partner perspective offers important insights, and evaluating biomarker-confirmed cohorts aligns estimates with ongoing trials., Methods: Anchor-based analyses were conducted to evaluate MWPC on the CDR-SB in early AD (Tauriel; NCT03289143) using Caregiver Global Impression of Change in memory or daily activities., Results: Across time points and anchors, mean CDR-SB changes associated with the "somewhat worse" category ranged from 1.50 to 2.12 in early AD, 1.07 to 2.06 in mild cognitive impairment-AD, and 1.79 to 2.25 in mild AD., Discussion: The proposed ranges are appropriate to define meaningful progression on the CDR-SB in similar cohorts and support the interpretation of treatment benefit through MWPC analyses. Thresholds should be calibrated to the context of use; lower/higher thresholds may be applicable in studies of earlier/later disease over shorter/longer durations., Highlights: Within-patient CDR-SB change thresholds are provided using caregiver-rated anchors. 1.5 to 2.5 points may be an appropriate range in early AD trials of similar durations. Cumulative distribution function plots illustrate the benefit of a given treatment. When selecting thresholds, the target population and study design should be considered., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Enteropathogenic Escherichia coli (EPEC) is an important cause of diarrhoeal disease in human infants. EPEC strains are defined by the presence of specific virulence factors including intimin (encoded by the eae gene) and bundle forming pili (Bfp). Bfp is encoded by the bfp operon and includes the bfpA gene for the major pilus subunit. By definition, Bfp are only present in typical EPEC (tEPEC), for which, humans are considered to be the only known natural host. This study detected tEPEC in faecal samples from a wild Australian fruit bat species, the grey-headed flying-fox (Pteropus poliocephalus). Whole genome sequencing of 61 E. coli isolates from flying-foxes revealed that 21.3 % (95%CI: 13 %-33 %) were tEPEC. Phylogenetic analyses showed flying-fox tEPEC shared evolutionary lineages with human EPEC, but were predominantly novel sequence types (9 of 13) and typically harboured novel bfpA variants (11 of 13). HEp-2 cell adhesion assays showed adherence to human-derived epithelial cells by all 13 flying-fox tEPEC, indicating that they all carried functional Bfp. Using an EPEC-specific duplex PCR, it was determined that tEPEC comprised 17.4 % (95%CI: 13 %-22 %) of 270 flying-fox E. coli isolates. Furthermore, a tEPEC-specific multiplex PCR detected the eae and bfpA virulence genes in 18.0 % (95%CI: 8.0 %-33.7 %) of 506 flying-fox faecal DNA samples, with occurrences ranging from 1.3 % to 87.0 % across five geographic areas sampled over a four-year period. The identification of six novel tEPEC sequence types and five novel bfpA variants suggests flying-foxes carry bat-specific tEPEC lineages. However, their close relationship with human EPEC and functional Bfp, indicates that flying-fox tEPEC have zoonotic potential and that dissemination of flying-fox tEPEC into urban environments may pose a public health risk. The consistent detection of tEPEC in flying-foxes over extensive geographical and temporal scales indicates that both wild grey-headed flying-foxes and humans should be regarded as natural tEPEC hosts., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

In evaluating the clinical benefit of new therapeutic interventions, it is critical that the treatment outcomes assessed reflect aspects of health that are clinically important and meaningful to patients. Performance outcome (PerfO) assessments are measurements based on standardized tasks actively undertaken by a patient that reflect physical, cognitive, sensory, and other functional skills that bring meaning to people's lives. PerfO assessments can have substantial value as drug development tools when the concepts of interest being measured best suit task performance and in cases where patients may be limited in their capacity for self-report. In their development, selection, and modification, including the evaluation and documentation of validity, reliability, usability, and interpretability, the good practice recommendations established for other clinical outcome assessment types should continue to be followed, with concept elicitation as a critical foundation. In addition, the importance of standardization, and the need to ensure feasibility and safety, as well as their utility in patient groups, such as pediatric populations, or those with cognitive and psychiatric challenges, may enhance the need for structured pilot evaluations, additional cognitive interviewing, and evaluation of quantitative data, such as that which would support concept confirmation or provide ecological evidence and other forms of construct evidence within a unitary approach to validity. The opportunity for PerfO assessments to inform key areas of clinical benefit is substantial and establishing good practices in their selection or development, validation, and implementation, as well as how they reflect meaningful aspects of health is critical to ensuring high standards and in furthering patient-focused drug development., (Copyright © 2023. Published by Elsevier Inc.)

Background: Angelman syndrome (AS) is a rare, heterogenous neurogenetic condition, which significantly impacts the lives of people with AS and their families. Valid and reliable measures reporting key symptoms and functional impairments of AS are required to support development of patient-centered therapies. We describe the development of clinician- and caregiver-reported, AS-specific Global Impression scales for incorporation into clinical trials. Best practice US Food and Drug Administration guidance for measure development was followed with input from expert clinicians, patient advocates, and caregivers during content generation and refinement., Results: Initial measurement domains for the Symptoms of AS-Clinician Global Impression (SAS-CGI) and the Caregiver-reported AS Scale (CASS) were identified from a conceptual disease model of AS symptoms and impacts, derived from interviews with caregivers and clinicians. Two rounds of cognitive debriefing (CD) interviews were performed; clinicians debriefed the SAS-CGI, with patient advocates and caregivers debriefing the CASS to ensure relevance and comprehension. Feedback was used to refine items and ensure wording was age-appropriate and captured AS-specific symptoms, as well as associated impacts and functional impairments. The SAS-CGI and CASS capture global assessments of seizures, sleep, maladaptive behaviors, expressive communication, fine and gross motor skills, cognition, and self-care, which were determined by clinicians, patient advocates, and caregivers to be the most challenging aspects of AS. Additionally, the measures include items for assessing overall AS symptoms and the meaningfulness of any change. In addition to ratings for severity, impact, and change, a notes field was included in the SAS-CGI to provide the rationale for the chosen rating. CD interviews confirmed the measures covered key concepts of AS from the perspective of clinicians and caregivers, and demonstrated that the measures' instructions, items, and response options were clear and appropriate. Interview feedback informed adjustments to the wording of the instructions and the items., Conclusions: The SAS-CGI and CASS were designed to capture multiple AS symptoms, reflecting the heterogeneity and complexity of AS in children 1 to 12 years old. These clinical outcome assessments have been incorporated into AS clinical studies, which will allow for the evaluation of their psychometric properties and inform further refinements if needed., (© 2023. The Author(s).)

The emergence of antimicrobial-resistant Escherichia coli in wildlife is concerning-especially resistance to clinically important beta-lactam antibiotics. Wildlife in closer proximity to humans, including in captivity and in rescue/rehabilitation centres, typically have a higher prevalence of antimicrobial-resistant E. coli compared to their free-living counterparts. Each year, several thousand Australian fruit bat pups, including the grey-headed flying fox (GHFF; Pteropus poliocephalus) , require rescuing and are taken into care by wildlife rescue and rehabilitation groups. To determine the prevalence of beta-lactam-resistant E. coli in rescued GHFF pups from South Australia, faecal samples were collected from 53 pups in care. A combination of selective culture, PCR, antimicrobial susceptibility testing, whole-genome sequencing, and phylogenetic analysis was used to identify and genetically characterise beta-lactam-resistant E. coli isolates. The prevalence of amoxicillin-, amoxicillin-plus-clavulanic-acid-, and cephalosporin-resistant E. coli in the 53 pups was 77.4% ( n = 41), 24.5% ( n = 13), and 11.3% ( n = 6), respectively. GHFF beta-lactam-resistant E. coli also carried resistance genes to aminoglycosides, trimethoprim plus sulphonamide, and tetracyclines in 37.7% ( n = 20), 35.8% ( n = 19), and 26.4% ( n = 14) of the 53 GHFF pups, respectively, and 50.9% ( n = 27) of pups carried multidrug-resistant E. coli . Twelve E. coli strain types were identified from the 53 pups, with six strains having extraintestinal pathogenic traits, indicating that they have the potential to cause blood, lung, or wound infections in GHFFs. Two lineages- E. coli ST963 and ST58 O8:H25-were associated with human extraintestinal infections. Phylogenetic analyses determined that all 12 strains were lineages associated with humans and/or domestic animals. This study demonstrates high transmission of anthropogenic-associated beta-lactam-resistant E. coli to GHFF pups entering care. Importantly, we identified potential health risks to GHFF pups and zoonotic risks for their carers, highlighting the need for improved antibiotic stewardship and biosafety measures for GHFF pups entering care.

The rapid emergence of antimicrobial resistance (AMR) is a major concern for wildlife and ecosystem health globally. Genetic determinants of AMR have become indicators of anthropogenic pollution due to their greater association with humans and rarer presence in environments less affected by humans. The objective of this study was to determine the distribution and frequency of the class 1 integron, a genetic determinant of AMR, in both the faecal microbiome and in Escherichia coli isolated from neonates of three pinniped species. Australian sea lion (Neophoca cinerea), Australian fur seal (Arctocephalus pusillus doriferus) and long-nosed fur seal (Arctocephalus forsteri) pups from eight breeding colonies along the Southern Australian coast were sampled between 2016-2019. DNA from faecal samples (n = 309) and from E. coli (n = 795) isolated from 884 faecal samples were analysed for class 1 integrons using PCRs targeting the conserved integrase gene (intI) and the gene cassette array. Class 1 integrons were detected in A. p. doriferus and N. cinerea pups sampled at seven of the eight breeding colonies investigated in 4.85% of faecal samples (n = 15) and 4.52% of E. coli isolates (n = 36). Integrons were not detected in any A. forsteri samples. DNA sequencing of the class 1 integron gene cassette array identified diverse genes conferring resistance to four antibiotic classes. The relationship between class 1 integron carriage and the concentration of five trace elements and heavy metals was also investigated, finding no significant association. The results of this study add to the growing evidence of the extent to which antimicrobial resistant bacteria are polluting the marine environment. As AMR determinants are frequently associated with bacterial pathogens, their occurrence suggests that these pinniped species are vulnerable to potential health risks. The implications for individual and population health as a consequence of AMR carriage is a critical component of ongoing health investigations., Competing Interests: The authors have declared that no competing interests exist.