Intrinsic dynamics of randomly clustered networks generate place fields and preplay of novel environments.

During both sleep and awake immobility, hippocampal place cells reactivate time-compressed versions of sequences representing recently experienced trajectories in a phenomenon known as replay. Intriguingly, spontaneous sequences can also correspond to forthcoming trajectories in novel environments experienced later, in a phenomenon known as preplay. Here, we present a model showing that sequences of spikes correlated with the place fields underlying spatial trajectories in both previously experienced and future novel environments can arise spontaneously in neural circuits with random, clustered connectivity rather than pre-configured spatial maps. Moreover, the realistic place fields themselves arise in the circuit from minimal, landmark-based inputs. We find that preplay quality depends on the network's balance of cluster isolation and overlap, with optimal preplay occurring in small-world regimes of high clustering yet short path lengths. We validate the results of our model by applying the same place field and preplay analyses to previously published rat hippocampal place cell data. Our results show that clustered recurrent connectivity can generate spontaneous preplay and immediate replay of novel environments. These findings support a framework whereby novel sensory experiences become associated with preexisting "pluripotent" internal neural activity patterns.

Development of Microcystoid Macular Degeneration in the Retina of Nonhuman Primates: Time-Course and Associated Pathologies.

PURPOSE: Microcystoid macular degeneration (MMD) is a condition where cystoid vacuoles develop within the inner nuclear layer of the retina in humans in a variety of disorders. Here we report the occurrence of MMD in non-human primates (NHPs) with various retinal ganglion cell (RGC) pathologies and evaluate the hypothesis that MMD does not precede RGC loss but follows it. METHODS: Morphological studies were performed of the retinas of NHPs, specifically both rhesus (Macaca mulatta) and cynomolgus macaques (Macaca fascicularis), in which MMD was identified after induction of experimental glaucoma (EG), hemiretinal endodiathermy axotomy (HEA), and spontaneous idiopathic bilateral optic atrophy. In vivo imaging analyses included fundus photography, fluorescein angiography (FA), optical coherence tomography (OCT), adaptive optics scanning laser ophthalmoscopy (AOSLO), light microscopy, and electron microscopy. RESULTS: MMD, like that seen on OCT scans of humans, was found in both rhesus and cynomolgus macaques with EG. Of 13 cynomolgus macaques with chronic EG imaged once with OCT six of 13 animals were noted to have MMD. MMD was also evident in a cynomolgus macaque with bilateral optic atrophy. Following HEA, MMD did not develop until at least 2 weeks following the RNFL loss. CONCLUSION: These data suggest that MMD may be caused by a retrograde trans-synaptic process related to RGC loss. MMD is not associated with inflammation, nor would it be an independent indicator of drug toxicity per se in pre-clinical regulatory studies. Because of its inconsistent appearance and late development, MMD has limited use as a clinical biomarker.

Ozone sensitivity to high energy demand day electricity and onroad emissions during LISTOS.

Using a high-resolution, 1.33 km by 1.33 km coupled Weather Research and Forecasting-Community Multi-scale Air Quality Model (WRF-CMAQ), we quantify the impact of emissions of nitrogen oxides (NOx) from high energy demand day (HEDD) electricity generating units (EGU) and onroad vehicles on ambient ozone air quality in the Long Island Sound Tropospheric Ozone Study (LISTOS) region covering New York City (NYC); Long Island, NY; coastal Connecticut; and neighboring areas. We test sensitivity scenarios to quantify HEDD EGU NOx contributions to ozone: (1) zero out HEDD EGU emissions, (2) dispatch HEDD EGUs starting with the lowest NOx emitting units first, (3) reduce onroad emissions by 90%, (4) combine zero out HEDD EGU emissions and reducing onroad emissions by 90%, and (5) dispatch HEDD EGUs starting with the lowest emitting units coupled with a reduction in onroad emissions by 90%. Results determine that HEDD EGUs lead to highly localized impacts on ambient concentrations of ozone while onroad emission reductions lead to large-scale regional concentration impacts. Further, reducing onroad emissions by 90% leads to spatially smaller VOC-limited regions and spatially larger transitional and NOX-limited regions around NYC. Despite the limited scale at which the EGU emission reductions occur, modifying HEDD EGU NOX emissions still provides substantial benefits in reducing ozone concentrations in the region, particularly at elevated ozone concentrations above 70 ppb.Implications: High-resolution coupled meteorology-chemistry modeling was used to quantify the impacts of high energy demand day (HEDD) electricity generating units (EGUs) and onroad transportation emissions changes on ozone air quality in the LISTOS region. Despite being highly localized and variable, HEDD EGUs NOX emissions sensitivity tests led to quantifiable changes in ozone. Further, reducing onroad emissions by 90% produced large decreases in ozone concentrations and led to a more NOX-sensitive ozone photochemical regime. With a transition to greater NOX-sensitivity, urban NOX-titration weakens and ozone is more likely to decline with the removal of additional NOX from sources like HEDD EGUs.

Targeting microbial pathogenic mechanisms as a novel therapeutic strategy in IBD.

BACKGROUND: Current therapy for patients suffering from inflammatory bowel diseases (IBD) is focused on inflammatory mechanisms exclusively and not the dysbiotic microbiota, despite growing evidence implicating a role for intestinal microbes in disease. MAIN BODY: Ongoing research into the intestinal microbiota of IBD patients, using new technologies and/or deeper application of existing ones, has identified a number of microorganisms whose properties and behaviors warrant consideration as causative factors in disease. Such studies have implicated both bacteria and fungi in the pathogenesis of disease. Some of these organisms manifest mechanisms that should be amenable to therapeutic intervention via either conventional or novel drug discovery platforms. Of particular note is a deeper characterization of microbial derived proteases and their destructive potential. CONCLUSION: Given the steady progress on the mechanistic role of the microbiota in inflammatory diseases, it is reasonable to anticipate a future in which therapeutics targeting microbial derived pathogenic factors play an important role in improving the lives of IBD patients.

Single nucleus transcriptomics supports a role for CCNA2-induced human adult cardiomyocyte cytokinesis.

Cyclin A2 (CCNA2) is a master regulatory gene of the cell cycle that is normally silenced in postnatal mammalian cardiomyocytes. We have previously demonstrated that it can induce significant cardiac repair in both small and large animals when delivered to the heart via a viral vector. To date, whether CCNA2 gene delivery can induce cytokinesis in isolated cardiomyocytes from adult human hearts has not been investigated. Therefore, we designed a human gene therapy vector featuring a replication-deficient, E1/E3-deleted human adenovirus five encoding human CCNA2 driven by the cardiac Troponin T promoter to enable the expression of CCNA2 in freshly isolated human cardiomyocytes. Utilizing time-lapse microscopy live imaging of cultured adult human cardiomyocytes isolated from a 21-year-old male, 41-year-old female, and 55-year-old male, we now report that human adult cardiomyocytes can be induced to undergo complete cytokinesis in response to CCNA2 gene delivery with preservation of sarcomere integrity in the resulting daughter cells. To elucidate the mechanistic underpinnings of CCNA2-dependent gene regulation in governing cardiomyocyte cytokinesis, we conducted single nucleus transcriptomics (snRNA-seq, 10X Genomics) analysis in hearts isolated from adult transgenic mice that constitutively express CCNA2 in cardiomyocytes (CCNA2-Tg) and non-transgenic mice (nTg). Remarkably, we identified a subpopulation of cardiomyocytes enriched with cytokinesis, proliferative, and reprogramming genes in hearts obtained from CCNA2-Tg mice as compared to hearts obtained from nTg mice. We also performed bulk RNA sequencing of human adult and fetal hearts, and we identified key reprogramming genes that are involved in CCNA2-induced cytokinesis. These results provide a compelling path forward for the clinical development of cardiac regenerative therapy based on strategic manipulation of the cardiomyocyte cell cycle.

Post-Pandemic Growth in 9-1-1 Paramedic Calls and Emergency Department Transports Surpasses Pre-Pandemic Rates in the COVID-19 Era: Implications for Paramedic Resource Planning.

OBJECTIVES: The COVID-19 pandemic led to a decline in emergency department (ED) visits and a subsequent return to baseline pre-pandemic levels. It is unclear if this trend extended to paramedic services and if patient cohorts accessing paramedics changed. We examined trends and associations between paramedic utilization (9-1-1 calls and ED transports) and the COVID-19 timeframe. METHODS: We conducted a retrospective cross-sectional study using paramedic call data from the Hamilton Paramedic Services from January 2016 to December 2023. We included all 9-1-1 calls where paramedics responded to an incident, excluding paramedic interfacility transfers. We calculated lines of best fit for the pre-pandemic period (January 2016 to January 2020) and compared their predictions to the actual volumes in the post-pandemic period (May 2021 to December 2023). We used an interrupted time series regression model to determine the association between pandemic timeframes (pre-, during-, post-COVID-19) and paramedic utilization (9-1-1 calls and ED transports), while testing for annual seasonality. RESULTS: During the study timeframe, 577,278 calls for paramedics were received and 413,491 (71.6%) were transported to the ED. Post-pandemic, 9-1-1 calls exceeded predicted pre-pandemic levels by 1,298 per month, while ED transports exceeded by 543 per month. The pandemic significantly reduced monthly 9-1-1 calls (-588.2, 95% CI -928.8 to -247.5) and ED transports (-677.3, 95% CI -927.0 to -427.5). Post-pandemic, there was a significant and sustained resurgence in monthly 9-1-1 calls (1,208.0, 95% CI 822.1 to 1,593.9) and ED transports (868.8, 95% CI 585.8 to 1,151.7). Both models exhibited seasonal variations. CONCLUSIONS: Post-pandemic, 9-1-1-initiated paramedic calls experienced a substantial increase, surpassing pre-pandemic growth rates. ED transports returned to pre-pandemic levels but with a steeper and continuous pattern of growth. The resurgence in paramedic 9-1-1 calls and ED transports post-COVID-19 emphasizes an urgent necessity to expedite development of new care models that address how paramedics respond to 9-1-1 calls and transport to overcrowded EDs.

Incorporating Molecular Data Into Treatment Decision Making in Gastroesophageal and Pancreaticobiliary Cancers: Timing and Strategies.

Gastroesophageal (GE) and pancreatobiliary (PB) cancers represent a significant clinical challenge. In this context, it is critical to understand the key molecular targets within these malignancies including how they are assayed for as well as the clinical actionability of these targets. Integrating biomarkers into the standard of care presents a critical avenue for refining treatment paradigms. This review aims to explore these complexities, offering insights into the optimal sequencing of chemotherapy and targeted therapies and their utility in the management of GE and PB cancers. The timely integration of promising investigational therapies into clinical practice has broader implications around strategies for future clinical trial designs, which would pave the way for advancements in the management of GE and PB cancers. This review provides guidance in navigating the evolving landscape of GE and PB cancer care, which ultimately will drive forward progress in the field and lead to improved patient outcomes.

Immunogenicity of third dose COVID-19 vaccine strategies in patients who are immunocompromised with suboptimal immunity following two doses (OCTAVE-DUO): an open-label, multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: The humoral and T-cell responses to booster COVID-19 vaccine types in multidisease immunocompromised individuals who do not generate adequate antibody responses to two COVID-19 vaccine doses, is not fully understood. The OCTAVE DUO trial aimed to determine the value of third vaccinations in a wide range of patients with primary and secondary immunodeficiencies. METHODS: OCTAVE-DUO was a prospective, open-label, multicentre, randomised, controlled, phase 3 trial investigating humoral and T-cell responses in patients who are immunocompromised following a third vaccine dose with BNT162b2 or mRNA-1273, and of NVX-CoV2373 for those with lymphoid malignancies. We recruited patients who were immunocompromised from 11 UK hospitals, aged at least 18 years, with previous sub-optimal responses to two doses of SARS-CoV-2 vaccine. Participants were randomly assigned 1:1 (1:1:1 for those with lymphoid malignancies), stratified by disease, previous vaccination type, and anti-spike antibody response following two doses. Individuals with lived experience of immune susceptibility were involved in the study design and implementation. The primary outcome was vaccine-specific immunity defined by anti-SARS-CoV-2 spike antibodies (Roche Diagnostics UK and Ireland, Burgess Hill, UK) and T-cell responses (Oxford Immunotec, Abingdon, UK) before and 21 days after the third vaccine dose analysed by a modified intention-to-treat analysis. The trial is registered with the ISRCTN registry, ISRCTN 15354495, and the EU Clinical Trials Register, EudraCT 2021-003632-87, and is complete. FINDINGS: Between Aug 4, 2021 and Mar 31, 2022, 804 participants across nine disease cohorts were randomly assigned to receive BNT162b2 (n=377), mRNA-1273 (n=374), or NVX-CoV2373 (n=53). 356 (45%) of 789 participants were women, 433 (55%) were men, and 659 (85%) of 775 were White. Anti-SARS-CoV-2 spike antibodies measured 21 days after the third vaccine dose were significantly higher than baseline pre-third dose titres in the modified intention-to-treat analysis (median 1384 arbitrary units [AU]/mL [IQR 4·3-7990·0] compared with median 11·5 AU/mL [0·4-63·1]; p<0·001). Of participants who were baseline low responders, 380 (90%) of 423 increased their antibody concentrations to more than 400 AU/mL. Conversely, 166 (54%) of 308 baseline non-responders had no response after the third dose. Detectable T-cell responses following the third vaccine dose were seen in 494 (80%) of 616 participants. There were 24 serious adverse events (BNT612b2 eight [33%] of 24, mRNA-1273 12 [50%], NVX-CoV2373 four [17%]), two (8%) of which were categorised as vaccine-related. There were seven deaths (1%) during the trial, none of which were vaccine-related. INTERPRETATION: A third vaccine dose improved the serological and T-cell response in the majority of patients who are immunocompromised. Individuals with chronic renal disease, lymphoid malignancy, on B-cell targeted therapies, or with no serological response after two vaccine doses are at higher risk of poor response to a third vaccine dose. FUNDING: Medical Research Council, Blood Cancer UK.

The Influence of Manipulating and Accentuating Task-Irrelevant Information on Learning Efficiency: Insights for Cognitive Load Theory.

The paper endorses Cognitive Load Theory and offers insights into the characterization of the mechanisms underlying extraneous cognitive load and their impact on basic learning. Students were asked to learn associations between eight base-code words and eight digits, based on an example, and to rapidly apply their new knowledge in a test section. Two groups of 60 university students participated in two experiments. The study was implemented as two distinct experiments, one using color names (e.g., blue, yellow) and the other using color-related word concepts (e.g., sky, banana) for stimulation. Each experiment had two conditions that manipulated the location and salience of task-irrelevant color information (extraneous cognitive load) and its congruity with the digits' corresponding base-code words. Findings indicated extraneous cognitive load has the potential to both sustain and undermine learning processes by varying the overall cognitive load, with gains and costs in learning efficiency resulting from essentially different processing scenarios.

Assessing Student-Reported Perceptions of Prerequisite Usefulness in Preparation for Didactic Physician Assistant Education.

INTRODUCTION: To gain admittance to a physician assistant (PA) school, applicants must complete program-specific prerequisite courses and experiences. The lack of standardization contributes to complexity, expense, and limits diversity. This research assessed current didactic PA students' perceptions of prerequisite courses, course delivery methods, and direct patient care (DPC) experiences to determine which were perceived as the most useful in preparation for didactic PA education. METHODS: An online cross-sectional survey was sent to eligible PA students across the United States. The survey collected opinions on the usefulness of commonly required prerequisite courses, course delivery methods, and DPC experiences. Collected data underwent statistical analysis and qualitative analysis for open-response questions. RESULTS: A total of 527 students completed the survey. Greater than 50% reported prerequisite courses in science and psychology as well as speech, ethics, cardiopulmonary resuscitation (CPR), medical ethics, medical terminology, and nutrition "prepared them well" or "extremely well." The most frequently recommended educational delivery method was "in person." The DPC experiences reported to best prepare students were Medical Assistant, Certified Nursing Assistant, and Scribe. The reported recommended number of DPC hours was 1000 to 1499. Chi-square tests for courses that prepared students "well" and "extremely well" revealed that in-person delivery had a statistically significant association with anatomy, physiology, ethics, CPR, medical ethics, and Spanish. DISCUSSION: These significant findings should be considered by PA programs when evaluating their requirements for admission. Furthermore, PA education associations should consider universal requirements to reduce applicant barriers, complexity, and expense, which may lead to improved diversity.

Renal denervation for uncontrolled hypertension: a systematic review and meta-analysis examining multiple subgroups.

This systematic review and meta-analysis was conducted to assess the randomized controlled trial (RCT) evidence available for renal denervation (RDN) in uncontrolled arterial hypertension. Twenty-five RCTs met the eligibility criteria for the systematic review, and 16 RCTs were included in the meta-analysis. The results of the random effects meta-analysis estimated a mean difference of -8.5 mmHg [95% confidence interval (CI) -13.5 to -3.6] for office SBP, -3.6 mmHg (95% CI -5.2 to -2.0) for 24 h SBP and -3.9 mmHg (95% CI -5.6 to -2.2) for ambulatory daytime SBP in favour of RDN compared with control (medication and/or sham-only) at primary follow-up. Similarly favourable results were observed across a range of prespecified subgroup analyses, including treatment-resistant hypertension. This meta-analysis suggests that the use of RDN in uncontrolled hypertension leads to consistent reductions in blood pressure. Reductions appear to be statistically consistent in the presence or absence of medications and in populations resistant to the use of three medications.

Congenitally Corrected Transposition of the Great Arteries in Utero: Morphological Spectrum, Outcomes and Pitfalls in Fetal Diagnosis.

Congenitally corrected transposition of the great arteries (ccTGA) is a rare malformation with diverse morphology. We assessed features of fetuses with ccTGA and evaluated neonatal and pediatric outcomes. This was a retrospective review of fetuses with ccTGA at Birmingham Women's and Children's Hospital born from 2005 to 2019. Of thirty-six fetuses identified, six had unavailable prenatal data, one was postnatally diagnosed with isomerism and 29 fetuses were evaluated. ccTGA without associated cardiac lesions was found in 28% (8/29), ccTGA with significant VSD in 31% (9/29), ccTGA with pulmonary obstruction in 24% (7/29) and ccTGA with complex anomalies in 17% (5/29). Tricuspid regurgitation (TR) was observed in 17% (5/29) and heart block (HB) in 10% (3/29) prenatally. Six, that is 21% underwent genetic testing of which one was abnormal. Five extra-cardiac anomalies were reported prenatally and postnatally. Pregnancy was discontinued in five, of which two had moderate TR. There were thirty-one liveborn. Coarctation of the aorta was found in five postnatally but not suspected prenatally. In one, pulmonary stenosis was underestimated; otherwise, prenatal morphology was confirmed. Cardiac interventions were performed in 77% (24/31) liveborn with 39% (12/31) undergoing neonatal intervention. Overall, 6/31 liveborn died including all three with prenatal heart block and one with TR. Estimated survival for all liveborn at 1, 5 and 10 years was 87% (95% CI 76-100%), 83% (95% CI 72-98%) and 80% (95% CI 66-96%) respectively. Accurate prenatal diagnosis of ccTGA is critical for counseling. Early outcomes are favorable with 77% of liveborn undergoing surgery. Fetuses with prenatal diagnosis of complex associated abnormalities, HB and TR appear to do less well.

Metal-Ligand Exchange Coupling Alters the Open-Shell Ligand Electronic Structure in a Bis(semiquinone) Complex.

The electronic structure of the bis(dioxolene) bridging ligand -SQ2Th2- is responsive to metal-ligand magnetic exchange coupling. Comparison of the crystal structure of (NiSQ)2Th2 to that of (ZnSQ)2Th2 indicates an open-shell biradical ground state for the dinuclear Ni(II) complex compared to the closed-shell quinoidal character found in the dinuclear Zn(II) complex. Consistent with a comparison of bond lengths obtained by X-ray diffraction, the analysis of the variable-temperature magnetic susceptibility data for crystalline (NiSQ)2Th2 yields reduced SQ-SQ radical-radical magnetic exchange coupling (JSQ-SQ = -203 cm-1) compared to that of (ZnSQ)2Th2 (JSQ-SQ = -321 cm-1). The reduced SQ-SQ exchange coupling in (NiSQ)2Th2 derives from an attenuation of the SQ spin densities, which in turn is derived from the Ni-SQ antiferromagnetic exchange interactions. This reduction in SQ--SQ exchange that we observe for (NiSQ)2Th2 correlates with an effective lengthening of the bridge unit by ∼2.1 Šrelative to that of (ZnSQ)2Th2. This magnitude of the effective increase in the bridge distance is consistent with the (NiSQ)2Th2 JSQ-SQ value lying between those of (ZnSQ)2Th2 and (ZnSQ)2Th3. The ability to modulate spin populations on an organic radical via pairwise Ni-SQ magnetic exchange interactions is a general way to affect electronic coupling in the Th-Th bridge. Our results suggest that metal-radical exchange coupling represents a powerful mechanism for tuning organic molecular electronic structure, with important implications for molecular electronics and molecular electron transport.

Slaughterhouse by-products composting: can microorganisms inoculum addition mitigate final compost odor emission?

Small slaughterhouses generate biowaste, which for economic reasons, is generally destined for composting. Inoculating appropriate microorganisms can improve biodegradation efficiency and mitigate odor generation during the composting process and can give rise to composts with neutral or pleasant odors. Therefore, the aim of this study was to compare the odor intensity reduction of compost generated with and without a formulated inoculum (Saccharomyces cerevisiae, Bacillus subtilis, and Rhodopseudomonas palustris). A set of experimental data was collected and analyzed according to the German "Verein Deutscher Ingenieure" odor protocol. The results showed that adding microorganisms was effective in reducing unpleasant odors in all three composts generated from swine, cattle, and poultry slaughterhouse by-products during both summer and winter seasons. Additionally, soil odor was predominant in composts that were inoculated in the two tested seasons (i.e., summer and winter). On the other hand, composts without inoculation had odors similar to peat for swine compost, ammonia for cattle compost, and manure for poultry compost, regardless of the season tested. Overall, composting process with appropriate inoculum can help in the correct disposal of slaughterhouse wastes by transforming organic matter into composts, which can have economic and environmental value as a soil conditioner and/or fertilizer.

Systematic Review and Metaanalysis of Pharmacological Interventions in Adult-Onset Still Disease and the Role of Biologic Disease-Modifying Antirheumatic Drugs.

OBJECTIVE: To conduct a systematic review of the effectiveness and safety of pharmacological treatments for adult-onset Still disease (AOSD). METHODS: Six databases, 2 trial registries, and conference abstracts were searched from January 2012 to February 2023 for studies of pharmacological interventions in people with AOSD. Outcomes were rates of remission and response, discontinuation of concurrent treatments, complications of AOSD, and treatment-related adverse events. Risk of bias was assessed with the Cochrane risk of bias tool and the Joanna Briggs Institute tool for case series. RESULTS: Forty-four studies evaluated treatments, including nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids (CS), conventional synthetic disease-modifying antirheumatic drugs (DMARDs), and biologic DMARDs (bDMARDs). For bDMARDs, tocilizumab (TCZ), anakinra (ANK), and canakinumab (CNK) had the most available data. Although 3 randomized controlled trials did not show statistically significant benefits of bDMARDs, metaanalyses showed high rates of complete remission and CS discontinuation. Complete remission was 80% (95% CI 59-92%, I 2 36%), 73% (95% CI 58-84%, I 2 66%), and 77% (95% CI 29-97%, I 2 82%) and CS discontinuation was 57% (95% CI 29-81%, I 2 66%), 47% (95% CI 18-78%, I 2 79%), and 34% (95% CI 6-81%, I 2 59%), respectively, for TCZ, ANK, and CNK. Studies with a higher proportion of patients previously treated with bDMARDs showed a trend toward lower rates of CS discontinuation (P = 0.05). The analyses had high clinical heterogeneity, largely because treatments were prescribed as different lines of therapy. CONCLUSION: Evidence supports TCZ, ANK, and CNK therapy for AOSD. However, the magnitude of effect and comparative effectiveness of treatments is uncertain.

Validating the Emergency Department Avoidability Classification (EDAC): A cluster randomized single-blinded agreement study.

INTRODUCTION: The Emergency Department Avoidability Classification (EDAC) retrospectively classifies emergency department (ED) visits that could have been safely managed in subacute primary care settings, but has not been validated against a criterion standard. A validated EDAC could enable accurate and reliable quantification of avoidable ED visits. We compared agreement between the EDAC and ED physician judgements to specify avoidable ED visits. MATERIALS AND METHODS: We conducted a cluster randomized, single-blinded agreement study in an academic hospital in Hamilton, Canada. ED visits between January 1, 2019, and December 31, 2019 were clustered based on EDAC classes and randomly sampled evenly. A total of 160 ED visit charts were randomly assigned to ten participating ED physicians at the academic hospital for evaluation. Physicians judged if the ED visit could have been managed appropriately in subacute primary care (an avoidable visit); each ED visit was evaluated by two physicians independently. We measured interrater agreement between physicians with a Cohen's kappa and 95% confidence intervals (CI). We evaluated the correlation between the EDAC and physician judgements using a Spearman rank correlation and ordinal logistic regression with odds ratios (ORs) and 95% CIs. We examined the EDAC's precision to identify avoidable ED visits using accuracy, sensitivity and specificity. RESULTS: ED physicians agreed on 139 visits (86.9%) with a kappa of 0.69 (95% CI 0.59-0.79), indicating substantial agreement. Physicians judged 96.2% of ED visits classified as avoidable by the EDAC as suitable for management in subacute primary care. We found a high correlation between the EDAC and physician judgements (0.64), as well as a very strong association to classify avoidable ED visits (OR 80.0, 95% CI 17.1-374.9). The EDACs avoidable and potentially avoidable classes demonstrated strong accuracy to identify ED visits suitable for management in subacute care (82.8%, 95% CI 78.2-86.8). DISCUSSION: The EDAC demonstrated strong evidence of criterion validity to classify avoidable ED visits. This classification has important potential for accurately monitoring trends in avoidable ED utilization, measuring proportions of ED volume attributed to avoidable visits and informing interventions intended at reducing ED use by patients who do not require emergency or life-saving healthcare.

Stressed and Depressed: Prevalence of Anxiety and/or Depression in Physician Assistant Students.

INTRODUCTION: This research highlights the prevalence of anxiety and/or depression among physician assistant (PA) students compared with the general population. It is believed that the results of this study will encourage graduate programs to place a stronger emphasis on the mental health of students and create a more positive learning environment. METHODS: An original survey was created using questions from Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, and several original questions. The survey was distributed using a SurveyMonkey link to directors of all accredited US PA programs. Program directors were asked to distribute the survey to their students. The survey remained open for 6 weeks, after which a cross-sectional statistical analysis was performed to compare the results with national anxiety and depression data in the United States. RESULTS: There is a statistically significant increase in the rate of occurrence of anxiety and/or depression among PA students compared with the general population. According to survey results, 84.4% of respondents experienced feelings of anxiety and 80.9% experienced feelings of depression while enrolled in PA school. Physician assistant students found the greatest need for anxiety and depression treatment during the didactic portion of their program. DISCUSSION: When compared with the national population, the level of anxiety in PA students was found to be 65.3% higher and the levels of depression in PA students to be 72.5% higher. These results should encourage PA programs and health care providers to take action regarding the mental health of future providers.

Multistability in neural systems with random cross-connections.

Neural circuits with multiple discrete attractor states could support a variety of cognitive tasks according to both empirical data and model simulations. We assess the conditions for such multistability in neural systems using a firing rate model framework, in which clusters of similarly responsive neurons are represented as single units, which interact with each other through independent random connections. We explore the range of conditions in which multistability arises via recurrent input from other units while individual units, typically with some degree of self-excitation, lack sufficient self-excitation to become bistable on their own. We find many cases of multistability-defined as the system possessing more than one stable fixed point-in which stable states arise via a network effect, allowing subsets of units to maintain each others' activity because their net input to each other when active is sufficiently positive. In terms of the strength of within-unit self-excitation and standard deviation of random cross-connections, the region of multistability depends on the response function of units. Indeed, multistability can arise with zero self-excitation, purely through zero-mean random cross-connections, if the response function rises supralinearly at low inputs from a value near zero at zero input. We simulate and analyze finite systems, showing that the probability of multistability can peak at intermediate system size, and connect with other literature analyzing similar systems in the infinite-size limit. We find regions of multistability with a bimodal distribution for the number of active units in a stable state. Finally, we find evidence for a log-normal distribution of sizes of attractor basins, which produces Zipf's Law when enumerating the proportion of trials within which random initial conditions lead to a particular stable state of the system.

Intrinsic dynamics of randomly clustered networks generate place fields and preplay of novel environments.

During both sleep and awake immobility, hippocampal place cells reactivate time-compressed versions of sequences representing recently experienced trajectories in a phenomenon known as replay. Intriguingly, spontaneous sequences can also correspond to forthcoming trajectories in novel environments experienced later, in a phenomenon known as preplay. Here, we present a model showing that sequences of spikes correlated with the place fields underlying spatial trajectories in both previously experienced and future novel environments can arise spontaneously in neural circuits with random, clustered connectivity rather than pre-configured spatial maps. Moreover, the realistic place fields themselves arise in the circuit from minimal, landmark-based inputs. We find that preplay quality depends on the network's balance of cluster isolation and overlap, with optimal preplay occurring in small-world regimes of high clustering yet short path lengths. We validate the results of our model by applying the same place field and preplay analyses to previously published rat hippocampal place cell data. Our results show that clustered recurrent connectivity can generate spontaneous preplay and immediate replay of novel environments. These findings support a framework whereby novel sensory experiences become associated with preexisting "pluripotent" internal neural activity patterns.