α7 nicotinic acetylcholine receptors are necessary for basal forebrain activation to increase expression of the nerve growth factor receptor TrkA.

Activation of the basal forebrain leads to increases in the expression of the nerve growth factor receptor, Tropomyosin receptor kinase A (TrkA) and decreases in expression of the beta amyloid cleavage enzyme 1 (BACE1) in the cerebral cortex of both sexes of 5xFAD mice. The studies described in this report were designed to determine if these changes were dependent on acetylcholine receptors. Mice were stimulated unilaterally in the basal forebrain for two weeks. Animals were administered a cholinergic antagonist, or saline, 30 minutes prior to stimulation. Animals administered saline exhibited significant increases in TrkA expression and decreases in BACE1 in the stimulated hemisphere relative to the unstimulated. While both nonselective nicotinic and muscarinic acetylcholine receptor blockade attenuated the BACE1 decline, only the nicotinic receptor antagonism blocked the TrkA increase. Next, we applied selective nicotinic antagonists, and the α7 antagonist blocked the TrkA increases, but the α4ß2 antagonist did not. BACE1 declines were not blocked by either intervention. Mice with a loxP conditional knockout of the gene for the α7 nicotinic receptor were also employed in these studies. Animals were either stimulated bilaterally for two weeks, or left unstimulated. With or without stimulation, the expression of TrkA receptors was lower in the cortical region with the α7 nicotinic receptor knockdown. We thus conclude that α7 nicotinic receptor activation is necessary for normal expression of TrkA and increases caused by basal forebrain activation, while BACE1 declines caused by stimulation have dependency on a broader array of receptor subtypes.

Declaration on infection prevention and management in global surgery.

Surgeons in their daily practice are at the forefront in preventing and managing infections. However, among surgeons, appropriate measures of infection prevention and management are often disregarded. The lack of awareness of infection and prevention measures has marginalized surgeons from this battle. Together, the Global Alliance for Infections in Surgery (GAIS), the World Society of Emergency Surgery (WSES), the Surgical Infection Society (SIS), the Surgical Infection Society-Europe (SIS-E), the World Surgical Infection Society (WSIS), the American Association for the Surgery of Trauma (AAST), and the Panamerican Trauma Society (PTS) have jointly completed an international declaration, highlighting the threat posed by antimicrobial resistance globally and the need for preventing and managing infections appropriately across the surgical pathway. The authors representing these surgical societies call all surgeons around the world to participate in this global cause by pledging support for this declaration for maintaining the effectiveness of current and future antibiotics.

Assessing risks for bovine and zoonotic tuberculosis through spatial analysis and a questionnaire survey in Fiji - A pilot study.

Mycobacterium bovis causes tuberculosis in cattle and when transmitted to humans typically causes extra-pulmonary tuberculosis (EPTB). Bovine tuberculosis (bTB) has a global distribution and is controlled in most countries to protect animal and public health. Recent studies revealed that bTB is established on dairy farms in Fiji where EPTB cases have been reported in people. The aims of this pilot investigation were to look for putative zoonotic TB (EPTB) cases in people and to evaluate practices that might contribute to the persistence and transmission of M. bovis between cattle and to humans. Existing data sets were shared between the Fiji Ministry of Agriculture and Ministry of Health and a questionnaire-based survey was implemented using One Health principles. Statistically significant co-location and close proximity of EPTB cases and bovine TB affected farms were identified. The bTB infection status of farms was significantly associated with unfenced water sources where cattle grazed. Of 247 households, 65 % shared drinking water sources with cattle and 36 % consumed raw milk without boiling, while 62 % of participants reported backyard slaughter of cattle. Several participants reported current symptoms potentially suggestive of TB (chronic cough) but the impact of smoking and history of previous TB treatment could not be evaluated. Farmers had limited understanding of the practices required to prevent bTB at farm level. Further study is recommended and should include an assessment of lifetime EPTB diagnoses, classification of farms based on more recent bTB test data and molecular typing of mycobacterial isolates from humans, cattle and the environment. A targeted awareness and education approach is required to reduce the future risk of zoonotic TB and to help ensure uptake of recommendations and practices aimed at controlling and preventing bTB.

Evaluation of a co-designed Parkinson's awareness audio podcast for undergraduate nursing students in Northern Ireland.

BACKGROUND: Parkinson's Disease (PD) is a common neurological condition that often causes stiffness, tremor and slow movement. People living with PD are likely to encounter nursing students throughout their journey from pre-diagnosis to death. Despite this, there is a paucity of evidence about current practice in PD education amongst nursing students. The present study provides an evaluation of a co-designed Parkinson's Awareness audio podcast amongst nursing students in Northern Ireland. METHODS: Following co-design of an audio podcast about PD, a mixed methods evaluation was carried out. 332 student nurses completed pre-/post-test questionnaires about their knowledge and perceptions of PD before and after listening to the audio podcast. Further to this, 35 student nurses participated in focus-group interviews six months following listening to explore how the podcast influenced practice. RESULTS: Student nurses posted a mean score of 52% before listening to the audio podcast. This mean increased to 80% post-test. These findings were statistically significant (p < 0.001), demonstrating significant increases in PD awareness after listening. Findings from the focus groups suggested that the audio podcast improved empathy and practice towards people with PD. The findings also suggested that students perceived audio podcasts to be a good way to learn about PD. CONCLUSION: Provision of a co-designed audio podcast about PD has the potential to improve student nurse knowledge and practice related to PD as evidenced in this study.

Are trauma surgeons prepared? A survey of trauma surgeons' disaster preparedness before and during the COVID-19 pandemic.

Objective: US trauma centers (TCs) must remain prepared for mass casualty incidents (MCIs). However, trauma surgeons may lack formal MCI training. The recent COVID-19 pandemic drove multiple patient surges, overloaded Emergency Medical Services (EMS) agencies, and stressed TCs. This survey assessed trauma surgeons' MCI training, experience, and system and personal preparedness before the pandemic compared with the pandemic's third year. Methods: Survey invitations were emailed to all 1544 members of the American Association for the Surgery of Trauma in 2019, and then resent in 2022 to 1575 members with additional questions regarding the pandemic. Questions assessed practice type, TC characteristics, training, experience, beliefs about personal and hospital preparedness, likelihood of MCI scenarios, interventions desired from membership organizations, and pandemic experiences. Results: The response rate was 16.7% in 2019 and 12% in 2022. In 2022, surgeons felt better prepared than their hospitals for pandemic care, mass shootings, and active shooters, but remained feeling less well prepared for cyberattack and hazardous material events, compared with 2019. Only 35% of the respondents had unintentional MCI response experience in 2019 or 2022, and even fewer had experience with intentional MCI. 78% had completed a Stop the Bleed (STB) course and 63% own an STB kit. 57% had engaged in family preparedness activities; less than 40% had a family action plan if they could not come home during an MCI. 100% of the respondents witnessed pandemic-related adverse events, including colleague and coworker illness, patient surges, and resource limitations, and 17% faced colleague or coworker death. Conclusions: Trauma surgeons thought that they became better at pandemic care and rated themselves as better prepared than their hospitals for MCI care, which is an opportunity for them to take greater leadership roles. Opportunities remain to improve surgeons' family and personal MCI preparedness. Surgeons' most desired professional organization interventions include advocacy, national standards for TC preparedness, and online training. Level of evidence: VII, survey of expert opinion.

Chronic basal forebrain activation improves spatial memory, boosts neurotrophin receptor expression, and lowers BACE1 and Aß42 levels in the cerebral cortex in mice.

The etiology of Alzheimer's dementia has been hypothesized in terms of basal forebrain cholinergic decline, and in terms of reflecting beta-amyloid neuropathology. To study these different biological elements, we activated the basal forebrain in 5xFAD Alzheimer's model mice and littermates. Mice received 5 months of 1 h per day intermittent stimulation of the basal forebrain, which includes cholinergic projections to the cortical mantle. Then, mice were behaviorally tested followed by tissue analysis. The 5xFAD mice performed worse in water-maze testing than littermates. Stimulated groups learned the water maze better than unstimulated groups. Stimulated groups had 2-3-fold increases in frontal cortex immunoblot measures of the neurotrophin receptors for nerve growth factor and brain-derived neurotrophic factor, and a more than 50% decrease in the expression of amyloid cleavage enzyme BACE1. Stimulation also led to lower Aß42 in 5xFAD mice. These data support a causal relationship between basal forebrain activation and both neurotrophin activation and reduced Aß42 generation and accumulation. The observation that basal forebrain activation suppresses Aß42 accumulation, combined with the known high-affinity antagonism of nicotinic receptors by Aß42, documents bidirectional antagonism between acetylcholine and Aß42.

Effect of fire on characteristics of dissolved organic matter in forested catchments in the Mediterranean biome: A review.

Fires in forested catchments pose a water contamination risk from fire-derived dissolved organic matter (DOM). Fire events are expected to increase under a projection of warmer and drier climatic conditions; therefore, understanding the consequences of fire-derived DOM is critical for water supply and management of drinking water and catchments. This paper addresses how fire regime - the intensity, severity and frequency of fires - influences DOM quantity and composition in surface waters in forested catchments, and how long it takes for water quality to recover to pre-fire levels. A review of post-fire studies in Mediterranean regions reporting on DOM related parameters has been conducted. The literature shows that post-fire DOM composition and reactivity is different from DOM generated under processes of biological degradation, and hence our reliance on DOM 'bulk properties' and surrogate DOM bulk parameters may not provide sufficient information to deal with the potential complexity of the organic compounds produced by a catchment fire. Appropriate measures are important to adequately operate conventional water treatment facilities, for example. Critical parameters for the effects of burning include the alteration of DOM composition, aromaticity, and the relative amounts of labile/recalcitrant organic components. The literature shows mixed information for the influence of both burn severity and fire intensity, on these parameters, which indicates DOM response to fire is highly variable. For fire frequency, the evidence is more unequivocal, indicating that frequent fires change the composition of DOM to components that are less bioavailable, and elevate the degree of aromaticity, which may be detrimental to water quality. In addition, and in general terms, the more recent the fire, the more aromatic and humified DOM components are found, and vice versa. The recovery of surface water quality to pre-fire conditions was variable, with no safe temporal thresholds suggested in the literature. In some cases, fire-induced changes in DOM composition were observable up to 16 years post-fire. The lack of clearly observed trends in post-fire DOM with fire regimes could be attributed to numerous factors such as limited long-term and event-based observations, experimental design challenges, and site-specific biological, physical and hydrological factors. The application of terminologies used to describe fire regimes such as burn severity and fire intensity also creates challenges in comparing the outcomes and results from numerous studies.

Improved synthesis of deoxyalpinoid B and quantification of antileishmanial activity of deoxyalpinoid B and sulforaphane.

The total synthesis and antileishmanial activity of deoxyalpinoid B is reported via a cationic gold-catalyzed Meyer-Schuster rearrangement. The activity of deoxyalpinoid B and a known inducer of oxidative stress, sulforaphane, against Leishmania donovani and Leishmania infantatum are both reported for the first time. Both compounds exhibit potent antileishmanial activity against both species. We hypothesize that the activation of intracellular oxidative stress is a key molecular response for the inhibition of Leishmania.

Development and Characterization of a Micromagnetic Alternative to Cochlear Implant Electrode Arrays.

To stimulate the auditory nerve, cochlear implants directly inject electrical current into surrounding tissue via an implanted electrode array. While many cochlear implant users achieve strong speech perception scores, there remains significant variability. Since cochlear implant electrode arrays are surrounded by a conductive fluid, perilymph, a spread of excitation occurs. The functionality of the cochlea is spatially dependent, and a wider area of excitation negatively affects the hearing of the user. Importantly, magnetic fields are unaffected by the material properties of biological components. To utilize the electromagnetic properties of the human ear, a microcoil array was developed. The microcoils are 4-turn solenoids with a 250- [Formula: see text] turn radius and a 31.75- [Formula: see text] wire radius, coated with Parylene-C. The efficient design was implemented to accelerate testing. The obtained results describe stimulation capabilities. Functionality was validated using a frequency response analyzer to measure how the generated electromagnetic power radiates in space. 99.8% power loss was observed over a 100- [Formula: see text] separation between a pair of identical microcoils. Obtained through finite-element modeling, the microcoils can be driven by a 60 mA, 5 kHz, sinusoidal input for 10 minutes before predicted inflammation. Rattay's activating function was calculated to evaluate the magnetic stimulation effect of external fields on target neurons. Combined with the frequency response analysis, magnitude and spatial effects of the generated potential is established. As a result, each microcoil requires a 400- [Formula: see text]-wide area for each independent stimulation channel, which is 84% narrower than a commercial cochlear array channel, thereby suggesting greater spatial selectivity.

A skeptical reflection: Contextualizing police shooting decisions with skin-tone.

This commentary expands the discussion of Cesario's Missing Forces Flaw by identifying and discussing variables that influence police shooting decisions but are often absent from bias-based research. Additionally, the closing identifies novel recommendations for future contextually related research.

Cyclin-dependent kinase inhibitor fadraciclib (CYC065) depletes anti-apoptotic protein and synergizes with venetoclax in primary chronic lymphocytic leukemia cells.

Fadraciclib (CYC065) is a second-generation aminopurine CDK2/9 inhibitor with increased potency and selectivity toward CDK2 and CDK9 compared to seliciclib (R-roscovitine). In chronic lymphocytic leukemia (CLL), a disease that depends on the over-expression of anti-apoptotic proteins for its survival, inhibition of CDK9 by fadraciclib reduced phosphorylation of the C-terminal domain of RNA polymerase II and blocked transcription in vitro; these actions depleted the intrinsically short-lived anti-apoptotic protein Mcl-1 and induced apoptosis. While the simulated bone marrow and lymph node microenvironments induced Mcl-1 expression and protected CLL cells from apoptosis, these conditions did not prolong the turnover rate of Mcl-1, and fadraciclib efficiently abrogated the protective effect. Further, fadraciclib was synergistic with the Bcl-2 antagonist venetoclax, inducing more profound CLL cell death, especially in samples with 17p deletion. While fadraciclib, venetoclax, and the combination each had distinct kinetics of cell death induction, their activities were reversible, as no additional cell death was induced upon removal of the drugs. The best combination effects were achieved when both drugs were maintained together. Altogether, this study provides a rationale for the clinical development of fadraciclib in CLL, either alone or in combination with a Bcl-2 antagonist.

Characterisation of lung function trajectories and associated early-life predictors in an Australian birth cohort study.

Background: There is growing evidence that lung function in early-life predicts later lung function. Adverse events over the lifespan might influence an individual's lung function trajectory, resulting in poor respiratory health. The aim of this study is to identify early-life risk factors and their impact on lung function trajectories to prevent long-term lung impairments. Methods: Our study included participants from the Raine Study, a prospective pregnancy cohort, with at least two spirometry measurements. Lung function trajectories from the 6- to 22-year follow-ups were characterised using finite mixture modelling. Multinomial logistic regression analyses were used to evaluate the association between early-life predictors and lung function trajectories. Main results: A total of 1512 participants (768 males, 744 females), representing 53% of the whole cohort, were included in this analysis. Four lung function trajectories of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC (z-scores) were identified. FEV1 and FVC trajectories were categorised as: "very low", "low", "average" and "above average", respectively. Based on their shape, lung function trajectories of FEV1/FVC were categorised as "very low", "low-average", "average-low" and "average". Asthma and maternal smoking were identified as risk factors for low lung function trajectories in this cohort, as well as early-life exposure to PM2.5Absorbance. Conclusions: Early-life risk factors may influence lung function trajectories over time. Nonetheless, identifying children with a high risk of having low lung function trajectories should be prioritised to prevent deficits in later life.

Protocol for behavioral and neural recording during stimulation of the macaque monkey nucleus basalis.

We present an experimental protocol to record neuronal activity during intermittent stimulation of nucleus basalis (NB), as macaque monkeys perform cognitive tasks. This protocol includes implantation of electrodes and generator devices to deliver electrical stimulation to NB using multiple approaches in monkeys. Direct stimulation of NB avoids peripheral cholinergic side effects, optimizes timing, and activates non-cholinergic projection neurons. We describe electrode preparation, surgery, and implantation for direct evaluation of how stimulation affects monkeys' behavior and neuronal activity. For complete details on the use and execution of this profile, please refer to Qi et al. (2021).

Prefrontal cortical plasticity during learning of cognitive tasks.

Training in working memory tasks is associated with lasting changes in prefrontal cortical activity. To assess the neural activity changes induced by training, we recorded single units, multi-unit activity (MUA) and local field potentials (LFP) with chronic electrode arrays implanted in the prefrontal cortex of two monkeys, throughout the period they were trained to perform cognitive tasks. Mastering different task phases was associated with distinct changes in neural activity, which included recruitment of larger numbers of neurons, increases or decreases of their firing rate, changes in the correlation structure between neurons, and redistribution of power across LFP frequency bands. In every training phase, changes induced by the actively learned task were also observed in a control task, which remained the same across the training period. Our results reveal how learning to perform cognitive tasks induces plasticity of prefrontal cortical activity, and how activity changes may generalize between tasks.

Rhythmicity of Prefrontal Local Field Potentials after Nucleus Basalis Stimulation.

The action of acetylcholine in the cortex is critical for cognitive functions and cholinergic drugs can improve functions such as attention and working memory. An alternative means of enhancing cholinergic neuromodulation in primates is the intermittent electrical stimulation of the cortical source of acetylcholine, the nucleus basalis (NB) of Meynert. NB stimulation generally increases firing rate of neurons in the prefrontal cortex, however its effects on single neurons are diverse and complex. We sought to understand how NB stimulation affects global measures of neural activity by recording and analyzing local field potentials (LFPs) in monkeys as they performed working memory tasks. NB stimulation primarily decreased power in the alpha frequency range during the delay interval of working memory tasks. The effect was consistent across variants of the task. No consistent modulation in the delay interval of the task was observed in the gamma frequency range, which has previously been implicated in the maintenance of working memory. Our results reveal global effects of cholinergic neuromodulation via deep brain stimulation, an emerging intervention for the improvement of cognitive function.

Developing a National Trauma Research Action Plan: Results from the prehospital and mass casualty research Delphi survey.

BACKGROUND: The National Academies of Sciences, Engineering, and Medicine 2016 trauma system report recommended a National Trauma Research Action Plan to strengthen and guide future trauma research. To address this recommendation, 11 expert panels completed a Delphi survey process to create a comprehensive research agenda, spanning the continuum of trauma care. We describe the gap analysis and high-priority research questions generated from the National Trauma Research Action Plan panel on prehospital and mass casualty trauma care. METHODS: We recruited interdisciplinary national experts to identify gaps in the prehospital and mass casualty trauma evidence base and generate prioritized research questions using a consensus-driven Delphi survey approach. We included military and civilian representatives. Panelists were encouraged to use the Patient/Population, Intervention, Compare/Control, and Outcome format to generate research questions. We conducted four Delphi rounds in which participants generated key research questions and then prioritized the questions on a 9-point Likert scale to low-, medium-, and high-priority items. We defined consensus as ≥60% agreement on the priority category and coded research questions using a taxonomy of 118 research concepts in 9 categories. RESULTS: Thirty-one interdisciplinary subject matter experts generated 490 research questions, of which 433 (88%) reached consensus on priority. The rankings of the 433 questions were as follows: 81 (19%) high priority, 339 (78%) medium priority, and 13 (3%) low priority. Among the 81 high-priority questions, there were 46 taxonomy concepts, including health systems of care (36 questions), interventional clinical trials and comparative effectiveness (32 questions), mortality as an outcome (30 questions), prehospital time/transport mode/level of responder (24 questions), system benchmarks (17 questions), and fluid/blood product resuscitation (17 questions). CONCLUSION: This Delphi gap analysis of prehospital and mass casualty care identified 81 high-priority research questions to guide investigators and funding agencies for future trauma research.

Nucleus basalis stimulation enhances working memory by stabilizing stimulus representations in primate prefrontal cortical activity.

Acetylcholine plays a critical role in the neocortex. Cholinergic agonists and acetylcholinesterase inhibitors can enhance cognitive functioning, as does intermittent electrical stimulation of the cortical source of acetylcholine, the nucleus basalis (NB) of Meynert. Here we show in two male monkeys how NB stimulation affects working memory and alters its neural code. NB stimulation increases dorsolateral prefrontal activity during the delay period of spatial working memory tasks and broadens selectivity for stimuli but does not strengthen phasic responses to each neuron's optimal visual stimulus. Paradoxically, despite this decrease in neuronal selectivity, performance improves in many task conditions, likely indicating increased delay period stability. Performance under NB stimulation does decline if distractors similar to the target are presented, consistent with reduced prefrontal selectivity. Our results indicate that stimulation of the cholinergic forebrain increases prefrontal neural activity, and this neuromodulatory tone can improve cognitive performance, subject to a stability-accuracy tradeoff.