DEFINE: A Prospective, Randomized, Phase 4 Trial to Assess a Protease Inhibitor-based Regimen Switch Strategy to Manage Integrase Inhibitor-related Weight Gain.

BACKGROUND: Integrase strand transfer inhibitor (InSTI)-based antiretroviral therapies have been associated with greater weight gain in people living with HIV versus on protease inhibitor (PI)-based regimens. The DEFINE study investigated whether switching from an InSTI- to a PI-based regimen could mitigate/reverse weight gain. METHODS: DEFINE (NCT04442737) was a randomized, 48-week, open-label, prospective, phase 4 study in virologically suppressed adults with HIV-1 and ≥10% weight gain on InSTI+tenofovir alafenamide (TAF)/emtricitabine (FTC) (<36 months pre-screening). Participants either switched immediately to darunavir/cobicistat/emtricitabine/TAF (D/C/F/TAF) or continued InSTI+TAF/FTC during Weeks 0-24 then switched to D/C/F/TAF for Weeks 24-48. The primary endpoint was least squares (LS) mean (95% confidence interval [CI]) percent weight change from baseline to Week 24. RESULTS: Overall, 103 adults were randomized (D/C/F/TAF, n=53; InSTI+TAF/FTC, n=50); 30% female; 61% Black/African American. No significant difference in weight change was observed at Week 24 (LS mean change: D/C/F/TAF, 0.63% [95%CI: -0.44, 1.70] vs InSTI+TAF/FTC, -0.24% [-1.35, 0.87]; p=0.24); however, a trend towards weight loss was observed with extended time post-ARV switch to D/C/F/TAF (baseline to Week 48, -0.36% [-1.77, 1.06]), particularly in subgroups at higher weight gain risk (eg, females, Black/African Americans). Metabolic endpoints paralleled weight change over time. D/C/F/TAF was well tolerated, with comparable virologic efficacy between arms. CONCLUSIONS: While no significant change in body weight was observed at 24 weeks after switching from InSTI+TAF/FTC to D/C/F/TAF among adults with weight gain, a trend towards weight loss emerged with longer time post-ARV switch, supporting further investigation of antiretroviral selection/switch for weight management.

Saphenous Vein Graft Pseudoaneurysm Treated With Covered Stenting.

Saphenous vein graft (SVG) pseudoaneurysms are an infrequent, but life-threatening complication of coronary artery bypass grafting (CABG) surgery if left untreated. Here, we discuss the case of a 77-year-old patient, with a prior history of CABG and transcatheter aortic valve implantation (TAVI), who was incidentally found on computed tomography angiography (CTA) to have a pseudoaneurysm of his SVG with an initial chief complaint of dizziness. Despite increasing reports of SVG pseudoaneurysm, there is no consensus on definitive treatment. Due to the high mortality risk of this patient with surgical intervention, a minimally invasive percutaneous coronary intervention was performed. The patient was effectively treated with two overlapping Viabahn-covered stents, which completely excluded the pseudoaneurysm. Follow-up imaging at two months showed two well-positioned overlapping self-expanding stents with total occlusion of the pseudoaneurysm.

Sarcopenia and the management of spinal disease in the elderly.

Sarcopenia, generally defined by the loss of skeletal mass and function, may disproportionately affect elderly individuals and heavily influence spinal disease. Muscle atrophy is associated with myriad clinical problems, including thoracic kyphosis, increased sagittal vertical axis (SVA), spinal implant failures, and postoperative complications. As such, the aim of this narrative review is to synthesize pertinent literature detailing the intersection between sarcopenia and the impact of sarcopenia on the management of spine disease. Specifically, we focus on the domains of etiology, diagnosis and assessment, impact on the cervical and lumbar spine, spinal augmentation procedures, neoplastic disease, whiplash injury, and recovery/prevention. A narrative review was conducted by searching the PubMed and Google Scholar databases from inception to July 12, 2024, for any cohort studies, systematic reviews, or randomized controlled trials. Case studies and conference abstracts were excluded. Diagnosis of sarcopenia relies on the assessment of muscle strength and quantity/quality. Strength may be assessed using clinical tools such as gait speed, timed up and go (TUG) test, or hand grip strength, whereas muscle quantity/quality may be assessed via computed tomography (CT scan), magnetic resonance imaging (MRI), and dual-energy X-ray absorptiometry (DXA scan). Sarcopenia has a generally negative impact on the clinical course of those undergoing cervical and lumbar surgery, and may be predictive of mortality in those with neoplastic spinal disease. In addition, severe acceleration-deceleration (whiplash) injuries may result in cervical extensor muscle atrophy. Intervention and recovery measures include nutrition or exercise therapy, although the evidence for nutritional intervention is lacking. Sarcopenia is a widely prevalent pathology in the advanced-age population, in which the diagnostic criteria, impact on spinal pathology, and recovery/prevention measures remain understudied. However, further understanding of this therapeutically challenging pathology is paramount, as surgical outcome may be heavily influenced by sarcopenia status.

Encoding of female mating dynamics by a hypothalamic line attractor.

Females exhibit complex, dynamic behaviors during mating with variable sexual receptivity depending on hormonal status1-4. However, how their brains encode the dynamics of mating and receptivity remains largely unknown. The ventromedial hypothalamus, ventro-lateral subdivision contains estrogen receptor type 1-positive neurons that control mating receptivity in female mice5,6. Unsupervised dynamical systems analysis of calcium imaging data from these neurons during mating uncovered a dimension with slow ramping activity, generating a line attractor in neural state space. Neural perturbations in behaving females demonstrated relaxation of population activity back into the attractor. During mating population activity integrated male cues to ramp up along this attractor, peaking just before ejaculation. Activity in the attractor dimension was positively correlated with the degree of receptivity. Longitudinal imaging revealed that attractor dynamics appear and disappear across the estrus cycle and are hormone-dependent. These observations suggest that a hypothalamic line attractor encodes a persistent, escalating state of female sexual arousal or drive during mating. They also demonstrate that attractors can be reversibly modulated by hormonal status, on a timescale of days.

Causal evidence of a line attractor encoding an affective state.

Line attractors are emergent population dynamics hypothesized to encode continuous variables such as head direction and internal states1-4. In mammals, direct evidence of neural implementation of a line attractor has been hindered by the challenge of targeting perturbations to specific neurons within contributing ensembles2,3. Linear dynamical systems modeling has revealed that neurons in the hypothalamus exhibit approximate line attractor dynamics in male mice during aggressive encounters5. We have previously hypothesized that these dynamics may encode the variable intensity of an aggressive internal motive state. Here, we report that these neurons also showed line attractor dynamics in head-fixed mice observing aggression6. We identified and perturbed line attractor-contributing neurons using 2-photon calcium imaging and holographic optogenetic perturbations. On-manifold perturbations yielded integration and persistent activity that drove the system along the line attractor, while transient off-manifold perturbations were followed by rapid relaxation back into the attractor. Furthermore, single-cell stimulation and imaging revealed selective functional connectivity among attractor-contributing neurons. Intriguingly, individual differences among mice in line attractor stability were correlated with the degree of functional connectivity among attractor neurons. Mechanistic RNN modelling indicated that dense subnetwork connectivity and slow neurotransmission7 best recapitulate our empirical findings. Our work bridges circuit and manifold levels3, providing causal evidence of continuous attractor dynamics encoding an affective internal state in the mammalian hypothalamus.

A minimum data set-Core outcome set, core data elements, and core measurement set-For degenerative cervical myelopathy research (AO Spine RECODE DCM): A consensus study.

BACKGROUND: Degenerative cervical myelopathy (DCM) is a progressive chronic spinal cord injury estimated to affect 1 in 50 adults. Without standardised guidance, clinical research studies have selected outcomes at their discretion, often underrepresenting the disease and limiting comparability between studies. Utilising a standard minimum data set formed via multi-stakeholder consensus can address these issues. This combines processes to define a core outcome set (COS)-a list of key outcomes-and core data elements (CDEs), a list of key sampling characteristics required to interpret the outcomes. Further "how" these outcomes should be measured and/or reported is then defined in a core measurement set (CMS). This can include a recommendation of a standardised time point at which outcome data should be reported. This study defines a COS, CDE, and CMS for DCM research. METHODS AND FINDINGS: A minimum data set was developed using a series of modified Delphi processes. Phase 1 involved the setup of an international DCM stakeholder group. Phase 2 involved the development of a longlist of outcomes, data elements, and formation into domains. Phase 3 prioritised the outcomes and CDEs using a two-stage Delphi process. Phase 4 determined the final DCM minimal data set using a consensus meeting. Using the COS, Phase 5 finalised definitions of the measurement construct for each outcome. In Phase 6, a systematic review of the literature was performed, to scope and define the psychometric properties of measurement tools. Phase 7 used a modified Delphi process to inform the short-listing of candidate measurement tools. The final measurement set was then formed through a consensus meeting (Phase 8). To support implementation, the data set was then integrated into template clinical research forms (CRFs) for use in future clinical trials (Phase 9). In total, 28 outcomes and 6 domains (Pain, Neurological Function, Life Impact, Radiology, Economic Impact, and Adverse Events) were entered into the final COS. Thirty two outcomes and 4 domains (Individual, Disease, Investigation, and Intervention) were entered into the final CDE. Finally, 4 outcome instruments (mJOA, NDI, SF-36v2, and SAVES2) were identified for the CMS, with a recommendation for trials evaluating outcomes after surgery, to include baseline measurement and at 6 months from surgery. CONCLUSIONS: The AO Spine RECODE-DCM has produced a minimum data set for use in DCM clinical trials today. These are available at https://myelopathy.org/minimum-dataset/. While it is anticipated the CDE and COS have strong and durable relevance, it is acknowledged that new measurement tools, alongside an increasing transition to study patients not undergoing surgery, may necessitate updates and adaptation, particularly with respect to the CMS.

What is normal age-related thigh muscle composition among 45- to 84-year-old adults from the UK Biobank study.

A loss of skeletal muscle mass and an increase in intramuscular fat are known to occur as we enter middle and older age, but the expected changes or normative values have remained unknown. The primary reason for this is that imaging studies are difficult and expensive to conduct, and consequently, the sample sizes have remained small. The development of the UK Biobank which provides access to a large magnetic resonance imaging (MRI) data set of more than 50,000 participants provides an opportunity to finally address this question of normative values for each age group. The study's primary aim was to determine the age-related changes in thigh muscle composition (e.g., thigh fat-free muscle volume and intramuscular fat) between the ages of 45 and 84 years. The second aim was to analyse associations between thigh fat-free muscle volume and intramuscular fat with lifestyle behaviours (smoking, alcohol consumption, and physical activity), leg pain, and bone mineral density. Fifty thousand three hundred thirty-two participants were included in the study. Total fat-free thigh muscle declined between the ages of 45 and 84 years, while intramuscular fat of the thigh continued to increase. The changes were stable between these age groups. The mean volume of fat-free muscle ranged from 11.16 (SD: 1.40) to 13.26 L (SD: 1.85) in adult males and 7.60 (SD: 0.97) to 8.80 L (SD 1.29) in females between the ages of 45 and 84 years. For intramuscular fat, the change among women was from 6.94% (SD: 1.59) in the 45 to 54 years age bracket to 8.83% (SD: 1.92) in the 75 to 84 age bracket, while for men, it was 5.83% (SD: 1.30) in the 45 to 54 age bracket to 7.85% (SD 1.89) in the 75 to 84 age bracket. The total fat-free muscle volume and intramuscular fat percentage provided can be used for the purpose of reference standards or normative values for adults in the age groups provided. Fat-free muscle and intramuscular fat were found to be associated with a range of health, activity, and leg pain outcomes, and these should be investigated in a follow-up longitudinal imaging study.

Ten-year statewide cross-sectional review of pediatric sinogenic intracranial abscess and empyema in Queensland, Australia: microbial profile before and after COVID-19.

OBJECTIVE: Sinogenic intracranial infections in children, such as subdural empyema or intracranial abscess, are a rare disease process with significant associated morbidity. Recent literature has suggested that there may have been an increase in frequency of these infections following the COVID-19 pandemic, but the literature has been conflicting, perhaps related to the heterogenous management of COVID-19 lockdowns in various states and differences in data capture between methods. The collection of statewide Australian data overcomes these limitations by capturing a comprehensive sample though the public healthcare system of patients who were subject to a homogeneous statewide approach to public health policy during the COVID-19 pandemic (population 5.6 million, including 1.3 million children). The objective of this study was to present population-level data to address the question of whether the incidence of intracranial infections changed in pediatric patients before and after the COVID-19 pandemic. METHODS: The authors present a retrospective 10-year statewide description of sinogenic intracranial infections in Queensland, Australia. A comparison was made between the incidence and microbiological profile before and after the onset of COVID-19 lockdowns on March 22, 2020. RESULTS: Forty-four pediatric intracranial infections undergoing neurosurgical intervention were identified within the review period. After exclusion of postsurgical and cardioembolic causes, 33 sinogenic intracranial infections were included (16 before and 17 after 2020, with a mean annualized incidence of 0.25 vs 0.37 cases per 100,000 children, respectively; p > 0.05). The most frequent organisms identified were Streptococcus milleri (n = 19), polymicrobial (n = 4), and S. aureus (n = 3). No significant differences in antimicrobial profile, susceptibility, parenchymal involvement, or clinical outcome were identified between the pre- and post-COVID-19 groups. CONCLUSIONS: No statistically significant differences in the epidemiology of pediatric intracranial infection have occurred in the state of Queensland, Australia, before and after March 22, 2020, and the COVID-19 pandemic.

Population coding of predator imminence in the hypothalamus.

Hypothalamic VMHdm SF1 neurons are activated by predator cues and are necessary and sufficient for instinctive defensive responses. However, such data do not distinguish which features of a predator encounter are encoded by VMHdm SF1 neural activity. To address this issue, we imaged VMHdm SF1 neurons at single-cell resolution in freely behaving mice exposed to a natural predator in varying contexts. Our results reveal that VMHdm SF1 neurons do not represent different defensive behaviors, but rather encode predator identity and multiple predator-evoked internal states, including threat-evoked fear/anxiety; neophobia or arousal; predator imminence; and safety. Notably, threat and safety are encoded bi-directionally by anti-correlated subpopulations. Finally, individual differences in predator defensiveness are correlated with differences in VMHdm SF1 response dynamics. Thus, different threat-related internal state variables are encoded by distinct neuronal subpopulations within a genetically defined, anatomically restricted hypothalamic cell class. Highlights: Distinct subsets of VMHdm SF1 neurons encode multiple predator-evoked internal states. Anti-correlated subsets encode safety vs. threat in a bi-directional mannerA population code for predator imminence is identified using a novel assay VMHdm SF1 dynamics correlate with individual variation in predator defensiveness.

A line attractor encoding a persistent internal state requires neuropeptide signaling.

Internal states drive survival behaviors, but their neural implementation is poorly understood. Recently, we identified a line attractor in the ventromedial hypothalamus (VMH) that represents a state of aggressiveness. Line attractors can be implemented by recurrent connectivity or neuromodulatory signaling, but evidence for the latter is scant. Here, we demonstrate that neuropeptidergic signaling is necessary for line attractor dynamics in this system by using cell-type-specific CRISPR-Cas9-based gene editing combined with single-cell calcium imaging. Co-disruption of receptors for oxytocin and vasopressin in adult VMH Esr1+ neurons that control aggression diminished attack, reduced persistent neural activity, and eliminated line attractor dynamics while only slightly reducing overall neural activity and sex- or behavior-specific tuning. These data identify a requisite role for neuropeptidergic signaling in implementing a behaviorally relevant line attractor in mammals. Our approach should facilitate mechanistic studies in neuroscience that bridge different levels of biological function and abstraction.

Jellyfish for the study of nervous system evolution and function.

Jellyfish comprise a diverse clade of free-swimming predators that arose prior to the Cambrian explosion. They play major roles in ocean ecosystems via a suite of complex foraging, reproductive, and defensive behaviors. These behaviors arise from decentralized, regenerative nervous systems composed of body parts that generate the appropriate part-specific behaviors autonomously following excision. Here, we discuss the organization of jellyfish nervous systems and opportunities afforded by the recent development of a genetically tractable jellyfish model for systems and evolutionary neuroscience.

Out-of-hospital paramedic interactions with people living with dementia: a scoping review.

BACKGROUND: Dementia encompasses neurodegenerative disorders that account for a global estimated healthcare expenditure of 1.3 trillion US dollars. In Australia, one in 12 people aged ≥65 has a diagnosis of dementia and it is the second leading cause of death. Paramedics play a crucial role in person-centred dementia care, particularly in the community. While consensus has been established on paramedicine's integration into interdisciplinary care teams, there remains a lack of clarity regarding the paramedic role in dementia care. OBJECTIVE: This study aimed to examine and report paramedic interactions with people living with dementia in the out-of-hospital setting. DESIGN AND SETTING: This was a scoping review study of paramedics and people living with dementia within the out-of-hospital setting. METHODS: This study was guided by the Joanna Briggs Institute (JBI) scoping review framework. Databases were searched without date limits, up to 4 April 2023. These encompassed OVID Medline, CINAHL, Scopus, APA PsycInfo and OVID Embase. Articles were included if they were primary, peer-reviewed studies in English and reporting on paramedic-specific interactions with people living with dementia in the out-of-hospital setting. Data extraction was performed based on study setting, design, population and key findings. RESULTS: Twenty-nine articles were included in the thematic analysis. Four themes emerged: need for training, patterns of attendances, patterns of documentation and the integrative potential of paramedicine. Paramedics reported feeling ill-equipped and unprepared in caring for patients living with dementia due to challenges in assessment and management of caregiver tensions. They were often called as a last resort due to poor service integration and a lack of alternative care pathways. Despite high conveyance rates, there was low incidence of paramedic interventions initiated. Underdocumentation of dementia and pain was found. CONCLUSION: Emergency ambulance conveyance of people living with dementia is a surface reaction compounded by a lack of direction for paramedics in the provision of out-of-hospital care. There is a pressing need for establishment of research and educational priorities to improve paramedic training in dementia-specific skillsets.

Clinical effectiveness and analytical quality of a national point-of-care testing network for sexually transmitted infections integrated into rural and remote primary care clinics in Australia, 2016-2022: an observational program evaluation.

Background: To address inequitable diagnostic access and improve time-to-treatment for First Nations peoples, molecular point-of-care (POC) testing for chlamydia, gonorrhoea and trichomonas was integrated into 49 primary care clinics across Australia. We conducted an observational evaluation to determine clinical effectiveness and analytical quality of POC testing delivered through this national program. Methods: We evaluated (i) implementation by measuring trends in mean monthly POC testing; ii) clinical effectiveness by comparing proportions of positive patients treated by historical control/intervention period and by test type, and calculated infectious days averted; (iii) analytical quality by calculating result concordance by test type, and proportion of unsuccessful POC tests. Findings: Between 2016 and 2022, 46,153 POC tests were performed; an increasing mean monthly testing trend was observed in the first four years (p < 0.0001). A greater proportion of chlamydia/gonorrhoea positives were treated in intervention compared with historical control periods (≤2 days: 37% vs 22% [RR 1.68; 95% CI 1.12, 2.53]; ≤7 days: 48% vs 30% [RR 1.6; 95% CI 1.10, 2.33]; ≤120 days: 79% vs 54% [RR 1.46; 95% CI 1.10, 1.95]); similarly for trichomonas positives and by test type. POC testing for chlamydia, gonorrhoea and trichomonas averted 4930, 5620 and 7075 infectious days, respectively. Results concordance was high [99.0% (chlamydia), 99.3% (gonorrhoea) and 98.9% (trichomonas)]; unsuccessful POC test proportion was 1.8% for chlamydia/gonorrhoea and 2.1% for trichomonas. Interpretation: Molecular POC testing was successfully integrated into primary care settings as part of a routinely implemented program achieving significant clinical benefits with high analytical quality. In addition to the individual health benefits of earlier treatment, fewer infective days could contribute to reduced transmissions in First Nations communities. Funding: This work was supported by an Australian National Health and Medical Research Council Partnership Grant (APP1092503), the Australian Government Department of Health, Western Australia and Queensland Departments of Health.

Same-visit hepatitis C testing and treatment to accelerate cure among people who inject drugs (the QuickStart Study): a cluster randomised cross-over trial protocol.

INTRODUCTION: Despite universal access to government-funded direct-acting antivirals (DAAs) in 2016, the rate of hepatitis C treatment uptake in Australia has declined substantially. Most hepatitis C is related to injecting drug use; reducing the hepatitis C burden among people who inject drugs (PWID) is, therefore, paramount to reach hepatitis C elimination targets. Increasing DAA uptake by PWID is important for interrupting transmission and reducing incidence, as well as reducing morbidity and mortality and improving quality of life of PWID and meeting Australia's hepatitis C elimination targets. METHODS AND ANALYSIS: A cluster randomised cross-over trial will be conducted with three intervention arms and a control arm. Arm A will receive rapid hepatitis C virus (HCV) antibody testing; arm B will receive rapid HCV antibody and rapid RNA testing; arm C will receive rapid HCV antibody testing and same-day treatment initiation for HCV antibody-positive participants; the control arm will receive standard of care. The primary outcomes will be (a) the proportion of participants with HCV commencing treatment and (b) the proportion of participants with HCV achieving cure. Analyses will be conducted on an intention-to-treat basis with mixed-effects logistic regression models. ETHICS AND DISSEMINATION: The study has been approved by the Alfred Ethics Committee (number HREC/64731/Alfred-2020-217547). Each participant will provide written informed consent. Reportable adverse events will be reported to the reviewing ethics committee. The findings will be presented at scientific conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05016609. TRIAL PROGRESSION: The study commenced recruitment on 9 March 2022 and is expected to complete recruitment in December 2024.

Sex Disparities in Resuscitation Quality Following Out of Hospital Cardiac Arrest.

BACKGROUND: Women are known to be disadvantaged compared with men in the early links of the Chain of Survival, receiving fewer bystander interventions. We aimed to describe sex-based disparities in emergency medical service resuscitation quality and processes of care for out-of-hospital cardiac arrest. METHODS AND RESULTS: We conducted a retrospective analysis of patients who were nontraumatic with out-of-hospital cardiac arrest aged ≥16 years where resuscitation was attempted between March 2019 and June 2023. We investigated 18 routinely captured performance metrics and performed adjusted logistic and quantile regression analyses to assess sex-based differences in these metrics. During the study period, 10 161 patients with out-of-hospital cardiac arrest met the eligibility criteria, of whom 3216 (32%) were women. There were no clinically relevant sex-based differences observed in regard to external cardiac compressions; however, women were 34% less likely to achieve a systolic blood pressure >100 mm Hg on arrival at the hospital (adjusted odds ratio [AOR], 0.66 [95% CI, 0.47-0.92]). Furthermore, women had a longer time to 12-lead ECG acquisition after return of spontaneous circulation (median adjusted difference, 1.00 minute [95% CI, 0.38-1.62]) and 33% reduced odds of being transported to a 24-hour percutaneous coronary intervention-capable facility (AOR, 0.67 [95% CI, 0.49-0.91]). Resuscitation was also terminated sooner for women compared with men (median adjusted difference, -4.82 minutes [95% CI, -6.77 to -2.87]). CONCLUSIONS: Although external cardiac compression quality did not vary by sex, significant sex-based disparities were seen in emergency medical services processes of care following out-of-hospital cardiac arrest. Further investigation is required to elucidate the underlying causes of these differences and examine their influence on patient outcomes.

Outcomes of adult patients discharged at scene by emergency medical services.

BACKGROUND: The outcomes of patients who call an ambulance but are discharged at scene reflect the safety and quality of emergency medical service (EMS) care. While previous studies have examined the outcomes of patients discharged at scene, none have specifically focused on paramedic-initiated discharge. This study aims to describe the outcomes of adult patients discharged at scene by paramedics and identify factors associated with 72-hour outcomes. METHODS: This was a retrospective data linkage study on consecutive adult EMS patients discharged at scene by paramedics in Victoria, Australia, between 1 January 2015 and 30 June 2019. Multivariable logistic regression was used to investigate factors associated with EMS recontact, ED presentation, hospital admission and serious adverse events (death, cardiac arrest, category 1 triage or intensive care unit admission) within 72 hours of the initial emergency call. RESULTS: There were 375 758 cases of adults discharged at scene following EMS attendance, of which 222 571 (59.2%) were paramedic-initiated decisions. Of these, 6.8% recontacted EMS, 5.0% presented to ED, 2.4% were admitted to hospital and 0.3% had a serious adverse event in the following 72 hours. The odds of EMS recontact were increased in cases related to mental health (adjusted OR (AOR) 1.41 (95% CI 1.33 to 1.49)), among low-income government concession holders (AOR 1.61 (95% CI 1.55 to 1.67)) and in areas of low socioeconomic advantage (AOR 1.19 (95% CI 1.13 to 1.25)). The odds of hospital admission were increased in cases related to infection (AOR 3.14 (95% CI 2.80 to 3.52)) and pain (AOR 1.93 (95% CI 1.75 to 2.14)). The strongest driver of serious adverse events was an abnormal vital sign (AOR 4.81 (95% CI 3.87 to 5.98)). CONCLUSION: The occurrence of hospital admission and adverse events is rare in those discharged at scene, suggesting generally safe decision-making. However, increased attention to elderly, multimorbid patients or patients with infection and pain is recommended, as is further research examining the use of tools to aid paramedic recognition of potential for deterioration.

Enhancing prosthesis stability at the cricoid cartilage in equine laryngoplasty using 3-D-printed laryngeal clamps: An ex vivo model study.

OBJECTIVE: To assess a three-dimensional (3-D)-printed laryngeal clamp (LC) designed to enhance the anchoring of laryngeal prostheses at the cricoid cartilage. STUDY DESIGN: Ex vivo biomechanical study. SAMPLE POPULATION: A total of 22 equine larynges. METHODS: Two experimental groups included larynges with standard prosthetic laryngoplasty (PL; n = 10) and larynges with prosthetic laryngoplasty modified with laryngeal clamps (PLLC; n = 10). All constructs underwent 3000 cycles of tension loading and a single tension to failure. Recorded biomechanical parameters included maximum load, actuator displacement, and construct failure. Finite element analysis (FEA) was performed on one PL and one PLLC construct. RESULTS: The maximum load at single tension to failure was 183.7 ± 46.8 N for the PL construct and 292.7 ± 82.3 N for the PLLC construct (p = .003). Actuator displacement at 30 N was 1.7 ± 0.5 mm and 2.7 ± 0.7 mm for the PL and PLLC constructs, respectively (p = .011). The cause of PL constructs failure was mostly tearing through the cartilage whereas the PLLC constructs failed through fracture of the cricoid cartilage (p = .000). FEA revealed an 11-fold reduction in the maximum equivalent plastic strain, a four-fold reduction in maximum compressive stress, and a two-fold increase in the volume of engaged cartilage in PLLC constructs. CONCLUSION: The PLLC constructs demonstrated superior performance in biomechanical testing and FEA compared to standard PL constructs. CLINICAL SIGNIFICANCE: The use of 3-D-printed laryngeal clamps may enhance the outcomes of laryngoplasty in horses. In vivo studies are necessary to determine the feasibility of performing laryngoplasty using the laryngeal clamp in horses.

Intrinsic Dynamics and Neural Implementation of a Hypothalamic Line Attractor Encoding an Internal Behavioral State.

Line attractors are emergent population dynamics hypothesized to encode continuous variables such as head direction and internal states. In mammals, direct evidence of neural implementation of a line attractor has been hindered by the challenge of targeting perturbations to specific neurons within contributing ensembles. Estrogen receptor type 1 (Esr1)-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl) show line attractor dynamics in male mice during fighting. We hypothesized that these dynamics may encode continuous variation in the intensity of an internal aggressive state. Here, we report that these neurons also show line attractor dynamics in head-fixed mice observing aggression. We exploit this finding to identify and perturb line attractor-contributing neurons using 2-photon calcium imaging and holographic optogenetic perturbations. On-manifold perturbations demonstrate that integration and persistent activity are intrinsic properties of these neurons which drive the system along the line attractor, while transient off-manifold perturbations reveal rapid relaxation back into the attractor. Furthermore, stimulation and imaging reveal selective functional connectivity among attractor-contributing neurons. Intriguingly, individual differences among mice in line attractor stability were correlated with the degree of functional connectivity among contributing neurons. Mechanistic modelling indicates that dense subnetwork connectivity and slow neurotransmission are required to explain our empirical findings. Our work bridges circuit and manifold paradigms, shedding light on the intrinsic and operational dynamics of a behaviorally relevant mammalian line attractor.

Using a smartwatch and smartphone to assess early Parkinson's disease in the WATCH-PD study over 12 months.

Digital measures may provide objective, sensitive, real-world measures of disease progression in Parkinson's disease (PD). However, multicenter longitudinal assessments of such measures are few. We recently demonstrated that baseline assessments of gait, tremor, finger tapping, and speech from a commercially available smartwatch, smartphone, and research-grade wearable sensors differed significantly between 82 individuals with early, untreated PD and 50 age-matched controls. Here, we evaluated the longitudinal change in these assessments over 12 months in a multicenter observational study using a generalized additive model, which permitted flexible modeling of at-home data. All measurements were included until participants started medications for PD. Over one year, individuals with early PD experienced significant declines in several measures of gait, an increase in the proportion of day with tremor, modest changes in speech, and few changes in psychomotor function. As measured by the smartwatch, the average (SD) arm swing in-clinic decreased from 25.9 (15.3) degrees at baseline to 19.9 degrees (13.7) at month 12 (P = 0.004). The proportion of awake time an individual with early PD had tremor increased from 19.3% (18.0%) to 25.6% (21.4%; P < 0.001). Activity, as measured by the number of steps taken per day, decreased from 3052 (1306) steps per day to 2331 (2010; P = 0.16), but this analysis was restricted to 10 participants due to the exclusion of those that had started PD medications and lost the data. The change of these digital measures over 12 months was generally larger than the corresponding change in individual items on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale but not greater than the change in the overall scale. Successful implementation of digital measures in future clinical trials will require improvements in study conduct, especially data capture. Nonetheless, gait and tremor measures derived from a commercially available smartwatch and smartphone hold promise for assessing the efficacy of therapeutics in early PD.