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.

Mapping multiscale breeding bird species distributions across the United States and evaluating their conservation applications.

Species distribution models are vital to management decisions that require understanding habitat use patterns, particularly for species of conservation concern. However, the production of distribution maps for individual species is often hampered by data scarcity, and existing species maps are rarely spatially validated due to limited occurrence data. Furthermore, community-level maps based on stacked species distribution models lack important community assemblage information (e.g., competitive exclusion) relevant to conservation. Thus, multispecies, guild, or community models are often used in conservation practice instead. To address these limitations, we aimed to generate fine-scale, spatially continuous, nationwide maps for species represented in the North American Breeding Bird Survey (BBS) between 1992 and 2019. We developed ensemble models for each species at three spatial resolutions-0.5, 2.5, and 5 km-across the conterminous United States. We also compared species richness patterns from stacked single-species models with those of 19 functional guilds developed using the same data to assess the similarity between predictions. We successfully modeled 192 bird species at 5-km resolution, 160 species at 2.5-km resolution, and 80 species at 0.5-km resolution. However, the species we could model represent only 28%-56% of species found in the conterminous US BBSs across resolutions owing to data limitations. We found that stacked maps and guild maps generally had high correlations across resolutions (median = 84%), but spatial agreement varied regionally by resolution and was most pronounced between the East and West at the 5-km resolution. The spatial differences between our stacked maps and guild maps illustrate the importance of spatial validation in conservation planning. Overall, our species maps are useful for single-species conservation and can support fine-scale decision-making across the United States and support community-level conservation when used in tandem with guild maps. However, there remain data scarcity issues for many species of conservation concern when using the BBS for single-species models.

Enhanced laser-induced damage performance of all-glass metasurfaces for energetic pulsed laser applications.

To fabricate optical components with surface layers compatible with high-power laser applications that may operate as antireflective coatings, polarization rotators, or harness physical anisotropy for other uses, metasurfaces are becoming an appealing candidate. In this study, large-beam (1.05 cm diameter) 351-nm laser-induced damage testing was performed on an all-glass metasurface structure composed of cone-like features with a subwavelength spacing of adjacent features. These structures were fabricated on untreated fused silica glass and damage tested, as were structures that were fabricated on fused silica glass that experienced a preliminary etching process to remove the surface Beilby layer that is characteristic of polished fused silica. The laser-induced damage onset for structures on untreated fused silica glass was 19.3J⋅c m -2, while the sample that saw an initial pretreatment etch exhibited an improved damage onset of 20.4J⋅c m -2, only 6% short of the reference pretreated glass damage onset of 21.7J⋅c m -2. For perspective, the National Ignition Facility operational average fluence at this wavelength and pulse length is about 10J/c m 2. At a fluence of 25.5J⋅c m -2, the reference (pretreated) fused silica initiated 5.2 damage sites per m m 2, while the antireflective metasurface sample with a preliminary etching process treatment initiated 9.8 damage sites per m m 2. These findings demonstrate that substrate-engraved metasurfaces are compatible with high energy and power laser applications, further broadening their application space.

Mapping breeding bird species richness at management-relevant resolutions across the United States.

Human activities alter ecosystems everywhere, causing rapid biodiversity loss and biotic homogenization. These losses necessitate coordinated conservation actions guided by biodiversity and species distribution spatial data that cover large areas yet have fine-enough resolution to be management-relevant (i.e., ≤5 km). However, most biodiversity products are too coarse for management or are only available for small areas. Furthermore, many maps generated for biodiversity assessment and conservation do not explicitly quantify the inherent tradeoff between resolution and accuracy when predicting biodiversity patterns. Our goals were to generate predictive models of overall breeding bird species richness and species richness of different guilds based on nine functional or life-history-based traits across the conterminous United States at three resolutions (0.5, 2.5, and 5 km) and quantify the tradeoff between resolution and accuracy and, hence, relevance for management of the resulting biodiversity maps. We summarized 18 years of North American Breeding Bird Survey data (1992-2019) and modeled species richness using random forests, including 66 predictor variables (describing climate, vegetation, geomorphology, and anthropogenic conditions), 20 of which we newly derived. Among the three spatial resolutions, the percentage variance explained ranged from 27% to 60% (median = 54%; mean = 57%) for overall species richness and 12% to 87% (median = 61%; mean = 58%) for our different guilds. Overall species richness and guild-specific species richness were best explained at 5-km resolution using ~24 predictor variables based on percentage variance explained, symmetric mean absolute percentage error, and root mean square error values. However, our 2.5-km-resolution maps were almost as accurate and provided more spatially detailed information, which is why we recommend them for most management applications. Our results represent the first consistent, occurrence-based, and nationwide maps of breeding bird richness with a thorough accuracy assessment that are also spatially detailed enough to inform local management decisions. More broadly, our findings highlight the importance of explicitly considering tradeoffs between resolution and accuracy to create management-relevant biodiversity products for large areas.

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.

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.

Fused silica optics damage from downstream intensification on laser-induced damage precursors.

Management and control of damage initiation and growth on high-value National Ignition Facility (NIF) optics are critical to its operation. Cone-shaped features are currently being used on the input surfaces to arrest growth of exit surface damage by creating "shadows." Light refracted from the walls of the cones interferes with the incident beam at the exit surface to create an intensified annulus. Significant exit surface damage was observed at the locations of these annuli. Analysis showed that this damage is consistent with a recently reported new mechanism that degrades damage resistance by dispersing damage precursors over the surface upon exposure to UV laser radiation. This has significant implications for the design and operation of high-energy and power laser systems such as the NIF.

Preventing opioid use among justice-involved youth as they transition to adulthood: leveraging safe adults (LeSA).

BACKGROUND: Juvenile justice (JJ) youth are at high risk of opioid and other substance use (SU), dysfunctional family/social relationships, and complex trauma. The purpose of the Leveraging Safe Adults (LeSA) Project is to examine the effectiveness of Trust-Based Relational Intervention® (TBRI®; leveraging family systems by providing emotional and instrumental guidance, support, and role modeling) in preventing opioid and other SU among youth after release from secure residential facilities. METHODS: An effectiveness-implementation Hybrid Type 1 design is used to test the effectiveness of TBRI for preventing non-medical use of opioids among JJ-youth (delayed-start at the site level; a randomized controlled trial at participant level) and to gain insight into facility-level barriers to TBRI implementation as part of JJ re-entry protocols. Recruitment includes two samples (effectiveness: 360 youth/caregiver dyads; implementation: 203 JJ staff) from nine sites in two states over 3 years. Participant eligibility includes 15 to 18-year-olds disposed to community supervision and receiving care in a secure JJ facility, without active suicide risk, and with one caregiver willing to participate. Effectiveness data come from (1) youth and caregiver self-report on background, SU, psychosocial functioning, and youth-caregiver relationships (Months 0, 3, 6, 12, and 18), youth monthly post-release check-ins, and caregiver report on youth psychological/behavioral symptoms, and (2) JJ facility records (e.g., recidivism, treatment utilization). Fidelity assessment includes post-session checklists and measures of TBRI strategy use. Collected four times over four years, implementation data include (1) JJ staff self-report on facility and staff characteristics, use of trauma-informed care and TBRI strategies, and (2) focus groups (line staff, leadership separately) on use of trauma-informed strategies, uptake of new interventions, and penetration, sustainment, and expansion of TBRI practices. DISCUSSION: The LeSA study is testing TBRI as a means to empower caregivers to help prevent opioid use and other SU among JJ-youth. TBRI's multiple components offer an opportunity for caregivers to supplement and extend gains during residential care. If effective and implemented successfully, the LeSA protocol will help expand the application of TBRI with a wider audience and provide guidance for implementing multi-component interventions in complex systems spanning multiple contexts. TRIAL REGISTRATION: ClinicalTrials.gov NCT04678960 ; registered November 11, 2020; https://clinicaltrials.gov/ct2/show/NCT04678960 .

TISSUE CHANGES OBSERVED IN EASTERN BOX TURTLES (TERRAPENE CAROLINA CAROLINA) FOLLOWING A PRESCRIBED FIRE.

Necropsies were performed on five eastern box turtles (Terrapene carolina carolina), found in an area recently subjected to an early-season prescribed fire, to determine whether mortality was burn related. External injuries primarily consisted of burns to exposed extremities and carapacial scutes which ranged from two burned scales to >80% of the shell. Internally, there was no evidence of smoke inhalation, but multiorgan and multifocal inflammation may have contributed to mortality.

The Impact of Population-Based Disease Management Services on Health Care Utilisation and Costs: Results of the CAPICHe Trial.

BACKGROUND: Disease management programmes may improve quality of care, improve health outcomes and potentially reduce total healthcare costs. To date, only one very large population-based study has been undertaken and indicated reductions in hospital admissions > 10%. OBJECTIVE: We sought to confirm the effectiveness of population-based disease management programmes. The objective of this study was to evaluate the relative impact on healthcare utilisation and cost of participants the Costs to Australian Private Insurance - Coaching Health (CAPICHe) trial. DESIGN: Parallel-group randomised controlled trial, intention-to-treat analysis SETTING: Australian population PARTICIPANTS: Forty-four thousand four hundred eighteen individuals (18-90 years of age) with private health insurance and diagnosis of heart failure, chronic obstructive pulmonary disease (COPD), coronary artery disease (CAD), diabetes, or low back pain, with predicted high cost claims for the following 12 months. INTERVENTION: Health coaching for disease management from Bupa Health Dialog, vs Usual Care. MAIN OUTCOME MEASURES: Total cost of claims per member to the private health insurer 1 year post-randomisation for hospital admissions, including same-day, medical and prostheses hospital claims, excluding any maternity costs. Analysis was based on the intent-to-treat population. RESULTS: Estimated total cost 1 year post-randomisation was not significantly different (means: intervention group A$4934; 95% CI A$4823-A$5045 vs control group A$4868; 95% CI A$4680-A$5058; p = 0.524). However, the intervention group had significantly lower same-day admission costs (A$468; 95% CI A$454-A$482 vs A$508; 95% CI A$484-A$533; p = 0.002) and fewer same-day admissions per 1000 person-years (intervention group, 530; 95% CI 508-552 vs control group, 614; 95% CI 571-657; p = 0.002). Subgroup analyses indicated that the intervention group had significantly fewer admissions for patients with COPD and fewer same-day admissions for patients with diabetes. CONCLUSIONS: Chronic disease health coaching was not effective to reduce the total cost after 12 months of follow-up for higher risk individuals with a chronic condition. Statistically significant changes were found with fewer same-day admissions; however, these did not translate into cost savings from a private health insurance perspective.

MENTAL STATE LANGUAGE DEVELOPMENT: THE LONGITUDINAL ROLES OF ATTACHMENT AND MATERNAL LANGUAGE.

Maternal mental state language is thought to influence children's mental state language and sociocognitive understanding (e.g., theory of mind), but the mechanism is unclear. The current study examined the longitudinal development of mental state language in mother-child interactions. The methodology included assessments of the child and/or mother-child dyad at six time points between 12 to 52 months of the child's age. Measures determined child's attachment style and language abilities, and mental state language used by mother and child during a block-building task. Results showed that (a) mental state talk, including belief and desire language, increased over time; (b) there were differences between the type of mental state words used by the mother in insecure versus secure dyads; (c) there were differences in patterns of mental state words used in both mothers and children in insecure versus secure dyads; and (d) attachment appeared to exert a consistent influence over time.

Laser-induced Hertzian fractures in silica initiated by metal micro-particles on the exit surface.

Laser-induced Hertzian fractures on the exit surface of silica glass are found to result from metal surface-bound micro particles. Two types of metal micro-spheres are studied (stainless-steel and Al) using ultraviolet laser light. The fracture initiation probability curve as a function of fluence is obtained, resulting in an initiation threshold fluence of 11.1 ± 4.7 J/cm2 and 16.5 ± 4.5 J/cm2 for the SS and Al particles, accordingly. The modified damage density curve is calculated based on the fracture probability. The calculated momentum coupling coefficient linking incident laser fluence to the resulting plasma pressure is found to be similar for both particles: 32.6 ± 15.4 KN/J and 28.1 ± 10.4 KN/J for the SS and Al cases accordingly.

Picosecond laser damage performance assessment of multilayer dielectric gratings in vacuum.

Precise assessment of the high fluence performance of pulse compressor gratings is necessary to determine the safe operational limits of short-pulse high energy lasers. We have measured the picosecond laser damage behavior of multilayer dielectric (MLD) diffraction gratings used in the compression of chirped pulses on the Advanced Radiographic Capability (ARC) kilojoule petawatt laser system at the Lawrence Livermore National Laboratory (LLNL). We present optical damage density measurements of MLD gratings using the raster scan method in order to estimate operational performance. We also report results of R-on-1 tests performed with varying pulse duration (1-30 ps) in air, and clean vacuum. Measurements were also performed in vacuum with controlled exposure to organic contamination to simulate the grating use environment. Results show sparse defects with lower damage resistance which were not detected by small-area damage test methods.

Clinical Exercise Stress Testing in Adults (2014).

This position paper provide guidelines on the minimum requirements of both personnel and equipment for the safe performance of clinical exercise electrocardiography, and for the adequate interpretation and assessment of results. This document was originally developed by Professor Ben Freedman and members of the Rehabilitation, Exercise and Prevention Working Group in 1996. It has been recently reviewed by a Working Group chaired by Associate Professor David Colquhoun. The resulting, revised Statement was considered by the Continuing Education and Recertification Committee and ratified at the CSANZ Board meeting held on 1st August 2014.

Should fee-for-service be for all guideline-advocated acute coronary syndrome (ACS) care? Observations from the Snapshot ACS study.

OBJECTIVE: The aim of the present study was to explore the association of health insurance status on the provision of guideline-advocated acute coronary syndrome (ACS) care in Australia. METHODS: Consecutive hospitalisations of suspected ACS from 14 to 27 May 2012 enrolled in the Snapshot study of Australian and New Zealand patients were evaluated. Descriptive and logistic regression analysis was performed to evaluate the association of patient risk and insurance status with the receipt of care. RESULTS: In all, 3391 patients with suspected ACS from 247 hospitals (23 private) were enrolled in the present study. One-third of patients declared private insurance coverage; of these, 27.9% (304/1088) presented to private facilities. Compared with public patients, privately insured patients were more likely to undergo in-patient echocardiography and receive early angiography; furthermore, in those with a discharge diagnosis of ACS, there was a higher rate of revascularisation (P < 0.001). Each of these attracts potential fee-for-service. In contrast, proportionately fewer privately insured ACS patients were discharged on selected guideline therapies and were referred to a secondary prevention program (P = 0.056), neither of which directly attracts a fee. Typically, as GRACE (the Global Registry of Acute Coronary Events) risk score rose, so did the level of ACS care; however, propensity-adjusted analyses showed lower in-hospital adverse events among the insured group (odds ratio 0.68; 95% confidence interval 0.52-0.88; P = 0.004). CONCLUSION: Fee-for-service reimbursement may explain differences in the provision of selected guideline-advocated components of ACS care between privately insured and public patients.

Growth model for laser-induced damage on the exit surface of fused silica under UV, ns laser irradiation.

We present a comprehensive statistical model which includes both the probability of growth and growth rate to describe the evolution of exit surface damage sites on fused silica optics over multiple laser shots spanning a wide range of fluences. We focus primarily on the parameterization of growth rate distributions versus site size and laser fluence using Weibull statistics and show how this model is consistent with established fracture mechanics concepts describing brittle materials. Key growth behaviors and prediction errors associated with the present model are also discussed.

Developments in autotransplantation of teeth.

Transplantation of teeth has been done for hundreds of years. In the late 18th and early 19th century transplants of teeth between individuals were relatively common at specialist dental practices in London. Surprisingly tooth allotransplants have been found to last 6 years on average. In Scandinavia during the 1950 and 1960's autotransplantation of teeth began to be carried out under increasingly controlled conditions. These have proved to be very successful in long term studies with autotransplants surviving up to 45 years post-surgery. Recent developments in cone beam CT and rapid 3D prototyping have enabled the fabrication of accurate surgical templates which can be used to prepare the recipient site immediately prior to transplantation. This has resulted in a drastically reduced extra-oral time for the transplant teeth which can be expected to improve success rates further. Autotransplants provide significant advantages compared to single tooth implants and should be considered the treatment of choice in the growing child.

Necrotizing ulcerative gingivitis and the orthodontic patient: a case series.

Necrotizing ulcerative gingivitis (NUG) can be a painful periodontal disease that can lead to loss of the interdental papillae. It is usually accompanied by systemic signs of fever, malaise and cervical and submandibular lymphadenopathy. It is caused by the profileration of anaerobic bacteria and has been linked to smoking and immunosuppression. This case series reports the occurrence of NUG in orthodontic patients and demonstrates that there is a varying scale of severity of the condition. Orthodontists should be aware of the clinical signs of NUG to ensure early detection and treatment of their patients in order to prevent irreversible loss of the interdental papillae and reduce the likelihood of recurrence. A treatment regime is suggested.

First Report of Imported Fire Ants, Solenopsis invicta, S. richteri, and S. invicta X richteri (Hymenoptera: Formicidae) from Kentucky.

Since their introduction into the United States in the early 1900's, imported fire ants, namely Solenopsis invicta Buren (Red Imported Fire Ant), S. richteri Forel (Black Imported Fire Ant), and their hybrid form Solenopsis invicta X richteri have spread throughout portions of the USA, especially in the southeastern region. Imported fire ants are a serious invasive and economically significant species in the USA and elsewhere, and their spread into new parts of the country is of great concern. Although early models predicted that the fire ants would not be able to survive very far north into the USA, these ants have nonetheless successfully continued their spread into higher latitudes. Based on Cooperative Agricultural Pest Survey (CAPS) samples, the Mississippi Entomological Museum Invasive Insect Screening Center, at Mississippi State University, has verified the presence of imported fire ants collected in Kentucky at multiple locations from 2014 to 2022.

Complete chromosome-level genome assembly data from the tawny crazy ant, Nylanderia fulva (Mayr) (Hymenoptera: Formicidae).

The tawny crazy ant, Nylanderia fulva (Mayr) (Hymenoptera: Formicidae) has a native range that extends from northern Argentina to southern Brazil. In the U.S.A. this species has often been misidentified as Nylanderia (Paratrechina) pubens or N. cf. pubens and has likely been present in Florida and Texas for several decades [1]. In the early 2000's explosive population growth in Texas and neighboring states drew renewed taxonomic focus. Genetic analyses [2,3] aided in identifying the pest species as N. fulva. This species poses an invasive threat to native flora and fauna and human structures. In its invasive range it has been reported to displace another invasive species, the red imported fire ant. The specimens used for genome sequencing were obtained from the coastal region of Mississippi. DNA was extracted from pupae. The genome data set was deposited to the National Center for Biotechnology Information as submission ID: SUB10775679, Project ID: PRJNA796544, Accession IDs: SAMN24895442 and JAKFQQ000000000. The organism taxid is 613905, locus tag prefixes are L1K79. The assembly, USDA_Nfulva_1.0, was generated in collaboration with Dovetail Genomics (now Cantata Bio) to yield a chromosome-level assembly of 375 Mb with a 15.67 Mb N50 and 78X coverage and revealing 16 putative chromosomes. This high-quality chromosome-level genome assembly was released prior to publication as a public service to the research community.