A Comparative Account of Institutional Approaches to Addressing Campus-Based Sexual Violence in Australia and Aotearoa New Zealand.

Sexual violence is prevalent on university campuses globally. In this article, we report a qualitative insider research study examining practices for addressing sexual violence at four universities across Australia and Aotearoa New Zealand. We collected, analysed, and synthesised descriptive information about the practices at each institution. We found unique institutional approaches that nonetheless share some commonalities, yieldingseveral themes that are central to practice. In reflecting on our findings, we conclude with an outline of critical considerations and a call to action for future efforts to address campus-based sexual violence, particularly as this field remains underdeveloped across Australia and Aotearoa New Zealand.

Evidence for early domestic yak, taurine cattle, and their hybrids on the Tibetan Plateau.

Domestic yak, cattle, and their hybrids are fundamental to herder survival at high altitudes on the Tibetan Plateau. However, little is known about their history. Bos remains are uncommon in this region, and ancient domestic yak have not been securely identified. To identify Bos taxa and investigate their initial management, we conducted zooarchaeological analyses of 193 Bos specimens and sequenced five nuclear genomes from recently excavated assemblages at Bangga. Morphological data indicated that more cattle than yak were present. Ancient mitochondrial DNA and nuclear genome sequences identified taurine cattle and provided evidence for domestic yak and yak-cattle hybridization ~2500 years ago. Reliance on diverse Bos species and their hybrid has increased cattle adaptation and herder resilience to plateau conditions. Ancient cattle and yak at Bangga were closely related to contemporary livestock, indicating early herder legacies and the continuity of cattle and yak husbandry on the Tibetan Plateau.

"Crack on": a qualitative study of care home managers experiences and responses to system-led setbacks during the crisis of the COVID-19 Pandemic in England.

OBJECTIVES: To explore care home managers' experiences of systems working with various organisations, including statutory, third sector and private, during the second wave of the COVID-19 pandemic from Sept 2020 to April 2021 DESIGN: An exploratory qualitative interview study using a systems theory approach focussing on the intersections of relationship interdependencies with other organisations. SETTING: Conducted remotely with care home managers and key advisors who had worked since the start of the pandemic in/with care homes for older people across the East Midlands, UK. PARTICIPANTS: 8 care home managers and 2 end-of-life advisors who participated during the second wave of the pandemic from Sept 2020. A total of 18 care home managers participated in the wider study from April 2020 to April 2021 RESULTS: Four organisational relationship interdependencies were identified: care practices, resources governance and wise working. Managers identified changes in their care practices as a shift towards the normalisation of care, with an emphasis on navigating pandemic restrictions to fit the context. Resources such as staffing, clinical reviews, pharmaceutical and equipment supplies were challenged, leading to a sense of precarity and tension. National polices and local guidance were fragmented, complex and disconnected from the reality of managing a care home. As a response a highly pragmatic reflexive style of management was identified which encompassed the use of mastery to navigate and in some cases circumvent official systems and mandates. Managers' experience of persistent and multiple setbacks were viewed as negative and confirmed their views that care homes as a sector ere marginalised by policy makers and statutory bodies. CONCLUSIONS: Interactions with various organisations shaped the ways in which care home managers responded to and sought to maximise residents and staff well-being. Some relationships dissolved over time, such as when local business and schools returned to normal obligations. Other newly formed relationships became more robust including those with other care home managers, families, and hospices. Significantly, most managers viewed their relationship with local authority and national statutory bodies as detrimental to effective working, leading to a sense of increased mistrust and ambiguity. Respect, recognition and meaningful collaboration with the care home sector should underpin any future attempts to introduce practice change in the sector.

Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation.

Amyotrophic lateral sclerosis (ALS) is a devastating disease caused by degeneration of motor neurons. As with all major neurodegenerative disorders, development of disease-modifying therapies has proven challenging for multiple reasons. Nevertheless, ALS is one of the few neurodegenerative diseases for which disease-modifying therapies are approved. Significant discoveries and advances have been made in ALS preclinical models, genetics, pathology, biomarkers, imaging and clinical readouts over the last 10-15 years. At the same time, novel therapeutic paradigms are being applied in areas of high unmet medical need, including neurodegenerative disorders. These developments have evolved our knowledge base, allowing identification of targeted candidate therapies for ALS with diverse mechanisms of action. In this Review, we discuss how this advanced knowledge, aligned with new approaches, can enable effective translation of therapeutic agents from preclinical studies through to clinical benefit for patients with ALS. We anticipate that this approach in ALS will also positively impact the field of drug discovery for neurodegenerative disorders more broadly.

Automatic Assessment of the Type and Intensity of Agitated Hand Movements.

With increasing numbers of people living with dementia, there is growing interest in the automatic monitoring of agitation. Current assessments rely on carer observations within a framework of behavioural scales. Automatic monitoring of agitation can supplement existing assessments, providing carers and clinicians with a greater understanding of the causes and extent of agitation. Despite agitation frequently manifesting in repetitive hand movements, the automatic assessment of repetitive hand movements remains a sparsely researched field. Monitoring hand movements is problematic due to the subtle differences between different types of hand movements and variations in how they can be carried out; the lack of training data creates additional challenges. This paper proposes a novel approach to assess the type and intensity of repetitive hand movements using skeletal model data derived from video. We introduce a video-based dataset of five repetitive hand movements symptomatic of agitation. Using skeletal keypoint locations extracted from video, we demonstrate a system to recognise repetitive hand movements using discriminative poses. By first learning characteristics of the movement, our system can accurately identify changes in the intensity of repetitive movements. Wide inter-subject variation in agitated behaviours suggests the benefit of personalising the recognition model with some end-user information. Our results suggest that data captured using a single conventional RGB video camera can be used to automatically monitor agitated hand movements of sedentary patients.

From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease.

Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936-a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.

Targeting impaired adult hippocampal neurogenesis in ageing by leveraging intrinsic mechanisms regulating Neural Stem Cell activity.

Deficits in adult neurogenesis may contribute to the aetiology of many neurodevelopmental, psychiatric and neurodegenerative diseases. Genetic ablation of neurogenesis provides proof of concept that adult neurogenesis is required to sustain complex and dynamic cognitive functions, such as learning and memory, mostly by providing a high degree of plasticity to neuronal circuits. In addition, adult neurogenesis is reactive to external stimuli and the environment making it particularly susceptible to impairment and consequently contributing to comorbidity. In the human brain, the dentate gyrus of the hippocampus is the main active source of neural stem cells that generate granule neurons throughout life. The regulation and preservation of the pool of neural stem cells is central to ensure continuous and healthy adult hippocampal neurogenesis (AHN). Recent advances in genetic and metabolic profiling alongside development of more predictive animal models have contributed to the development of new concepts and the emergence of molecular mechanisms that could pave the way to the implementation of new therapeutic strategies to treat neurological diseases. In this review, we discuss emerging molecular mechanisms underlying AHN that could be embraced in drug discovery to generate novel concepts and targets to treat diseases of ageing including neurodegeneration. To support this, we review cellular and molecular mechanisms that have recently been identified to assess how AHN is sustained throughout life and how AHN is associated with diseases. We also provide an outlook on strategies for developing correlated biomarkers that may accelerate the translation of pre-clinical and clinical data and review clinical trials for which modulation of AHN is part of the therapeutic strategy.

Safety, pharmacokinetics and exploratory pro-cognitive effects of HTL0018318, a selective M1 receptor agonist, in healthy younger adult and elderly subjects: a multiple ascending dose study.

BACKGROUND: The cholinergic system and M1 receptor remain an important target for symptomatic treatment of cognitive dysfunction. The selective M1 receptor partial agonist HTL0018318 is under development for the symptomatic treatment of Dementia's including Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). We investigated the safety, tolerability, pharmacokinetics and exploratory pharmacodynamics of multiple doses of HTL0018318 in healthy younger adults and elderly subjects. METHODS: This randomised, double blind, placebo-controlled study was performed, investigating oral doses of 15-35 mg/day HTL0018318 or placebo in 7 cohorts of healthy younger adult (n = 36; 3 cohorts) and elderly (n = 50; 4 cohorts) subjects. Safety, tolerability and pharmacokinetic measurements were performed. Pharmacodynamics were assessed using a battery of neurocognitive tasks and electrophysiological biomarkers of synaptic and cognitive functions. RESULTS: HTL0018318 was generally well-tolerated in multiple doses up to 35 mg/day and were associated with mild or moderate cholinergic adverse events. There were modest increases in blood pressure and pulse rate when compared to placebo-treated subjects, with tendency for the blood pressure increase to attenuate with repeated dosing. There were no clinically significant observations or changes in blood and urine laboratory measures of safety or abnormalities in the ECGs and 24-h Holter assessments. HTL0018318 plasma exposure was dose-proportional over the range 15-35 mg. Maximum plasma concentrations were achieved after 1-2 h. The apparent terminal half-life of HTL0018318 was 16.1 h (± 4.61) in younger adult subjects and 14.3 h (± 2.78) in elderly subjects at steady state. HTL0018318 over the 10 days of treatment had significant effects on tests of short-term (working) memory (n-back) and learning (Milner maze) with moderate to large effect sizes. CONCLUSION: Multiple doses of HTL0018138 showed well-characterised pharmacokinetics and were safe and generally well-tolerated in the dose range studied. Pro-cognitive effects on short-term memory and learning were demonstrated across the dose range. These data provide encouraging data in support of the development of HTL0018138 for cognitive dysfunction in AD and DLB. TRIAL REGISTRATION: Netherlands Trial Register identifier NTR5781 . Registered on 22 March 2016.

Safety, pharmacokinetics and pharmacodynamics of HTL0009936, a selective muscarinic M1 -acetylcholine receptor agonist: A randomized cross-over trial.

AIMS: HTL0009936 is a selective M1 muscarinic receptor agonist in development for cognitive dysfunction in Alzheimer's disease. Safety, tolerability and pharmacokinetics and exploratory pharmacodynamic effects of HTL0009936 administered by continuous IV infusion at steady state were investigated in elderly subjects with below average cognitive functioning (BACF). METHODS: Part A was a four-treatment open label sequential study in healthy elderly investigating 10-83 mg HTL0009936 (IV) and a 24 mg HTL0009936 single oral dose. Part B was a five-treatment randomized, double-blind, placebo and physostigmine controlled cross-over study with IV HTL0009936 in elderly subjects with BACF. Pharmacodynamic assessments were performed using neurocognitive and electrophysiological tests. RESULTS: Pharmacokinetics of HTL0009936 showed dose-proportional increases in exposure with a mean half-life of 2.4 hours. HTL0009936 was well-tolerated with transient dose-related adverse events (AEs). Small increases in mean systolic blood pressure of 7.12 mmHg (95% CI [3.99-10.24]) and in diastolic of 5.32 mmHg (95% CI [3.18-7.47]) were noted at the highest dose in part B. Overall, there was suggestive, but no definitive, positive or negative pharmacodynamic effects. Statistically significant effects were observed on P300 with HTL0009936 and adaptive tracking with physostigmine. CONCLUSIONS: HTL0009936 showed well-characterized pharmacokinetics and single doses were safe and generally well-tolerated in healthy elderly subjects. Due to physostigmine tolerability issues and subject burden, the study design was changed and some pharmacodynamic assessments (neurocognitive) were performed at suboptimal drug exposures. Therefore no clear conclusions can be made on pharmacodynamic effects of HTL0009936, although an effect on P300 is suggestive of central target engagement.

Care homes, their communities, and resilience in the face of the COVID-19 pandemic: interim findings from a qualitative study.

BACKGROUND: From late February 2020, English care homes rapidly adapted their practices in response to the COVID-19 pandemic. In addition to accommodating new guidelines and policies, staff had to adjust to rapid reconfiguration of services external to the home that they would normally depend upon for support. This study examined the complex interdependencies of support as staff responded to COVID-19. The aim was to inform more effective responses to the ongoing pandemic, and to improve understanding of how to work with care home staff and organisations after the pandemic has passed. METHODS: Ten managers of registered care homes in the East Midlands of England were interviewed by videoconference or phone about their experiences of the crisis from a structured organisational perspective. Analysis used an adapted organisational framework analysis approach with a focus on social ties and interdependencies between organisations and individuals. RESULTS: Three key groups of interdependencies were identified: care processes and practice; resources; and governance. Care home staff had to deliver care in innovative ways, making high stakes decisions in circumstances defined by: fluid ties to organisations outside the care home; multiple, sometimes conflicting, sources of expertise and information; and a sense of deprioritisation by authorities. Organisational responses to the pandemic by central government resulted in resource constraints and additional work, and sometimes impaired the ability of staff and managers to make decisions. Local communities, including businesses, third-sector organisations and individuals, were key in helping care homes overcome challenges. Care homes, rather than competing, were found to work together to provide mutual support. Resilience in the system was a consequence of dedicated and resourceful staff using existing local networks, or forging new ones, to overcome barriers to care. CONCLUSIONS: This study identified how interdependency between care home organisations, the surrounding community, and key statutory and non-statutory organisations beyond their locality, shaped decision making and care delivery during the pandemic. Recognising these interdependencies, and the expertise shown by care home managers and staff as they navigate them, is key to providing effective healthcare in care homes as the pandemic progresses, and as the sector recovers afterwards.

SEeking AnsweRs for Care Homes during the COVID-19 pandemic (COVID SEARCH).

The care and support of older people residing in long-term care facilities during the COVID-19 pandemic has created new and unanticipated uncertainties for staff. In this short report, we present our analyses of the uncertainties of care home managers and staff expressed in a self-formed closed WhatsApp™ discussion group during the first stages of the pandemic in the UK. We categorised their wide-ranging questions to understand what information would address these uncertainties and provide support. We have been able to demonstrate that almost one-third of these uncertainties could have been tackled immediately through timely, responsive and unambiguous fact-based guidance. The other uncertainties require appraisal, synthesis and summary of existing evidence, commissioning or provision of a sector- informed research agenda for medium to long term. The questions represent wider internationally relevant care home pandemic-related uncertainties.

First-in-man study to investigate safety, pharmacokinetics and exploratory pharmacodynamics of HTL0018318, a novel M1 -receptor partial agonist for the treatment of dementias.

AIMS: HTL0018318 is a selective M1 receptor partial agonist currently under development for the symptomatic treatment of cognitive and behavioural symptoms in Alzheimer's disease and other dementias. We investigated safety, tolerability, pharmacokinetics and exploratory pharmacodynamics (PD) of HTL0018318 following single ascending doses. METHODS: This randomized, double-blind, placebo-controlled study in 40 healthy younger adult and 57 healthy elderly subjects, investigated oral doses of 1-35 mg HTL0018318. Pharmacodynamic assessments were performed using a battery of neurocognitive tasks and electrophysiological measurements. Cerebrospinal fluid concentrations of HTL0018318 and food effects on pharmacokinetics of HTL0018318 were investigated in an open label and partial cross-over design in 14 healthy subjects. RESULTS: Pharmacokinetics of HTL0018318 were well-characterized showing dose proportional increases in exposure from 1-35 mg. Single doses of HTL0018318 were associated with mild dose-related adverse events of low incidence in both younger adult and elderly subjects. The most frequently reported cholinergic AEs included hyperhidrosis and increases in blood pressure up to 10.3 mmHg in younger adults (95% CI [4.2-16.3], 35-mg dose) and up to 11.9 mmHg in elderly subjects (95% CI [4.9-18.9], 15-mg dose). There were no statistically significant effects on cognitive function but the study was not powered to detect small to moderate effect sizes of clinical relevance. CONCLUSION: HTL0018318 showed well-characterized pharmacokinetics and following single doses were generally well tolerated in the dose range studied. These provide encouraging data in support of the development for HTL0018318 for Alzheimer's disease and other dementias.

Analysing interactions among the sustainable development goals: findings and emerging issues from local and global studies.

The topic of SDG interactions is a relatively new research area with many knowledge gaps. Some of these gaps are addressed in this summary of a Special Feature of Sustainability Science, including new findings and emerging issues on (1) the characteristics of SDG interactions; (2) methods/methodology to analyse these interactions; and (3) the elaboration of drivers that influence SDG synergies. The importance of scale is clear in two emerging issues. First, there is evidence of a disconnect between national planning for SDGs and their implementation at the local scale which is leading to SDG trade-offs between these scales. Second, the concept of a "critical transition zone" is introduced where SDG trade-offs pose a particular challenge to SDG implementation. These are areas (e.g., peri-urban and forest margin areas in the Global South) undergoing rapid biophysical and/or socio-economic changes and inhabited by populations especially vulnerable to these changes. While trade-offs occur among the SDGs, there are also many examples of synergies which provide opportunities for advancing multiple goals. To distinguish between synergies and the actions that exploit them, the term "synergy driver" is introduced to refer to policies and measures that positively advance two or more goals. Several examples of synergy drivers are presented, including sustainable global supply chains, people-centred early warning systems, and joint conservation-public health programmes. To make synergy drivers relevant to the broader policy community, the research community (working with stakeholders) should first consolidate knowledge about these drivers and then evaluate their effectiveness/applicability to different policy settings.

Molecular and isotopic evidence for milk, meat, and plants in prehistoric eastern African herder food systems.

The development of pastoralism transformed human diets and societies in grasslands worldwide. The long-term success of cattle herding in Africa has been sustained by dynamic food systems, consumption of a broad range of primary and secondary livestock products, and the evolution of lactase persistence (LP), which allows digestion of lactose into adulthood and enables the milk-based, high-protein, low-calorie diets characteristic of contemporary pastoralists. Despite the presence of multiple alleles associated with LP in ancient and present-day eastern African populations, the contexts for selection for LP and the long-term development of pastoralist foodways in this region remain unclear. Pastoral Neolithic (c 5000 to 1200 BP) faunas indicate that herders relied on cattle, sheep, and goats and some hunting, but direct information on milk consumption, plant use, and broader culinary patterns is rare. Combined chemical and isotopic analysis of ceramic sherds (n = 125) from Pastoral Neolithic archaeological contexts in Kenya and Tanzania, using compound-specific δ13C and Δ13C values of the major fatty acids, provides chemical evidence for milk, meat, and plant processing by ancient herding societies in eastern Africa. These data provide the earliest direct evidence for milk product consumption and reveal a history of reliance on animal products and other nutrients, likely extracted through soups or stews, and plant foods. They document a 5,000-y temporal framework for eastern Africa pastoralist cuisines and cultural contexts for selection for alleles distinctive of LP in eastern Africa.

Comparison of Orexin 1 and Orexin 2 Ligand Binding Modes Using X-ray Crystallography and Computational Analysis.

The orexin system, which consists of the two G protein-coupled receptors OX1 and OX2, activated by the neuropeptides OX-A and OX-B, is firmly established as a key regulator of behavioral arousal, sleep, and wakefulness and has been an area of intense research effort over the past two decades. X-ray structures of the receptors in complex with 10 new antagonist ligands from diverse chemotypes are presented, which complement the existing structural information for the system and highlight the critical importance of lipophilic hotspots and water molecules for these peptidergic GPCR targets. Learnings from the structural information regarding the utility of pharmacophore models and how selectivity between OX1 and OX2 can be achieved are discussed.

An ethnographic study comparing approaches to inter-professional knowledge sharing and learning in discharge planning and care transitions.

PURPOSE: The purpose of this paper is to investigate how three communication interventions commonly used during discharge planning and care transitions enable inter-professional knowledge sharing and learning as a foundation for more integrated working. These interventions include information communication systems, dedicated discharge planning roles and group-based planning activities. DESIGN/METHODOLOGY/APPROACH: A two-year ethnographic study was carried out across two regional health and care systems in the English National Health Service, focussing on the discharge of stroke and hip fracture patients. Data collection involved in-depth observations and 213 semi-structured interviews. FINDINGS: Information systems (e.g. e-records) represent a relatively stable conduit for routine and standardised forms of syntactic information exchange that can "bridge" time-space knowledge boundaries. Specialist discharge roles (e.g. discharge coordinators) support personalised and dynamic forms of "semantic" knowledge sharing that can "broker" epistemic and cultural boundaries. Group-based activities (e.g. team meetings) provide a basis for more direct "pragmatic" knowledge translation that can support inter-professional "bonding" at the cultural and organisational level, but where inclusion factors complicate exchange. RESEARCH LIMITATIONS/IMPLICATIONS: The study offers analysis of how professional boundaries complicate discharge planning and care transition, and the potential for different communication interventions to support knowledge sharing and learning. ORIGINALITY/VALUE: The paper builds upon existing research on inter-professional collaboration and patient safety by focussing on the problems of communication and coordination in the context of discharge planning and care transitions. It suggests that care systems should look to develop multiple complementary approaches to inter-professional communication that offer opportunities for dynamic knowledge sharing and learning.

Identification of a novel allosteric GLP-1R antagonist HTL26119 using structure- based drug design.

A series of novel allosteric antagonists of the GLP-1 receptor (GLP-1R), exemplified by HTL26119, are described. SBDD approaches were employed to identify HTL26119, exploiting structural understanding of the allosteric binding site of the closely related Glucagon receptor (GCGR) (Jazayeri et al., 2016) and the homology relationships between GCGR and GLP-1R. The region around residue C3476.36b of the GLP-1R receptor represents a key difference from GCGR and was targeted for selectivity for GLP-1R.

Structure-Based Optimization Strategies for G Protein-Coupled Receptor (GPCR) Allosteric Modulators: A Case Study from Analyses of New Metabotropic Glutamate Receptor 5 (mGlu5) X-ray Structures.

Two interesting new X-ray structures of negative allosteric modulator (NAM) ligands for the mGlu5 receptor, M-MPEP (3) and fenobam (4), are reported. The new structures show how the binding of the ligands induces different receptor water channel conformations to previously published structures. The structure of fenobam, where a urea replaces the acetylenic linker in M-MPEP and mavoglurant, reveals a binding mode where the ligand is rotated by 180° compared to a previously proposed docking model. The need for multiple ligand structures for accurate GPCR structure-based drug design is demonstrated by the different growing vectors identified for the head groups of M-MPEP and mavoglurant and by the unexpected water-mediated receptor interactions of a new chemotype represented by fenobam. The implications of the new structures for ligand design are discussed, with extensive analysis of the energetics of the water networks of both pseudoapo and bound structures providing a new design strategy for allosteric modulators.