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.

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.

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.

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.

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.

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.

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.

Variation from closed-shell to open shell electronic structures in oligothiophene bis(dioxolene) complexes.

A series of oligothiophene bis(dioxolene) complexes, SQ-Thn-SQ (SQ = S = ½TpCum,MeZnII(3-tert-butyl-orthosemiquinonate); TpCum,Me = tris(5-cumenyl-3-methylpyrazolyl)borate anion) have been synthesized, structurally characterized, and studied as a function of the number of thiophene bridging units, n (n = 0-3) using a combination of variable-temperature (VT) electronic absorption and EPR spectroscopies, and VT magnetic susceptibility measurements. The thiophene bridge bond lengths determined by X-ray crystallography display dramatic differences across the SQ-Thn-SQ series. Bridge bond deviation values (Σ|Δi|) display a progressive change in the nature of the bridge fragment bonding as the number of thiophene groups increases, with quinoidal bridge character for n = 1 (SQ-Th-SQ) and biradical character with "aromatic" bridge bond lengths for n = 3 (SQ-Th3-SQ). Remarkably, for n = 2 (SQ-Th2-SQ) the nature of the bridge fragment is intermediate between quinoid and biradical aromatic, which we describe as having open-shell character as opposed to biradicaloid since the open-shell biradical configuration does not have the correct symmetry to mix with the quinoidal ground-state configuration. This bridge bonding character is reflected in the energies of the lowest lying open-shell states for these three molecules. The SQ-Th-SQ molecule is diamagnetic at all temperatures studied, and we provide evidence for SQ-SQ antiferromagnetic exchange coupling and population of triplet states in SQ-Th2-SQ and SQ-Th3-SQ, with JSQ-SQ(ave) = -279 cm-1 (VT EPR/electronic absorption/magnetic susceptibility) and JSQ-SQ = -117 cm-1 (VT EPR/electronic absorption/magnetic susceptibility), respectively. The results have been interpreted in the context of state configurational mixing within a simplified 4-electron, 3-orbital model that explicitly contains contributions of a bridge fragment. Variable-temperature spectroscopic- and magnetic susceptibility data are consistent with two low-lying open-shell states for SQ-Th3-SQ, but three low-lying states (one closed-shell and two open-shell) for SQ-Th2-SQ. This model provides a simple symmetry-based framework to understand the continuum of electronic and geometric structures of this class of molecules as a function of the number of thiophene units in the bridge.

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.

Physician Assistant Program Accreditation Analysis and Survey of Program Directors.

PURPOSE: To inform physician assistant program directors through citation analysis after implementation of the Accreditation Review Commission on Education for the Physician Assistant (ARC-PA) Accreditation Standards, 5th edition. METHODS: This research used descriptive statistics, Pearson correlation, and the coefficient of determination to analyze the citations reported by ARC-PA during January 2021 to February 2023. Concurrent first-time taker Physician Assistant National Certifying Exam (PANCE) results were used to determine whether a correlation exists between pass rates and citations. In addition, a survey was sent to each institution's current program director to investigate leadership concerns and differences between programs placed on a provisional, continued, or probation status by ARC-PA. RESULTS: Of the 98 program submissions for accreditation, 13 submissions resulted in a probation status outcome. For these 13 programs placed on probation, 46.2% and 30.8% were cited for being noncompliant with leadership Standards A2.09 and A1.02, respectively. Pearson correlation analysis indicates a significant negative correlation between ARC-PA citations and first-time taker PANCE pass rates (P = .023, 95% confidence interval [CI] = [-0.49 to -0.04]). This is particularly true for programs with continued accreditation (P = .007, 95% CI = [-0.67 to -0.13]) and programs that performed below the 85% benchmark (P = .013, 95% CI = [-0.94 to -0.22]) for first-time taker PANCE pass rates. Although a negative correlation is observed between the number of levied citations and PANCE pass rates, the coefficient of determination does not indicate that the number of citations can predict PANCE pass rates (R2 = 0.0368). Regarding survey data, 42.86% of programs placed on probation cited institutional support as their biggest program weakness or threat. Conversely, 22.22% of programs with provisional status and 12.5% of programs with continued status reported institutional support as their biggest weakness or threat. CONCLUSION: This research identifies leadership as a deficit of concern associated with programs placed on probation. In addition, a significant negative correlation exists between the number of citations and first-time taker PANCE pass rates-especially for programs with first-time taker PANCE pass rates below 85% or for programs with continued accreditation status.

Was Virtual Care as Safe as In-Person Care? Analyzing Patient Outcomes at Seven and Thirty Days in Ontario during the COVID-19 Pandemic.

In 2020, almost overnight, the paradigm for healthcare interactions changed in Ontario. To limit person-to-person transmission of COVID-19, the norm of in-person interactions shifted to virtual care. While this shift was part of broader public health measures and an acknowledgment of patient and societal concerns, it also represented a change in care modalities that had the potential to affect the quality of care provided, as well as short- and long-term patient outcomes. While public policy decisions were being made to moderate the use of virtual care at the end of the declared pandemic, a thorough analysis of short-term patient outcomes was needed to quantify the impact of virtual care on the population of Ontario.

Type 2 cytokines sensitize human sensory neurons to itch-associated stimuli.

Introduction: Chronic itch is a central symptom of atopic dermatitis. Cutaneous afferent neurons express receptors interleukins (IL)-4, IL-13, and IL-33, which are type 2 cytokines that are elevated in atopic dermatitis. These neuronal cytokine receptors were found to be required in several murine models of itch. Prior exposure of neurons to either IL-4 or IL-33 increased their response to subsequent chemical pruritogens in mice but has not been previously examined in humans. The objective of the present study was to determine if type 2 cytokine stimulation sensitizes sensory neurons to future itch stimuli in a fully human ex vivo system. Methods: We measured calcium flux from human dorsal root ganglia cultures from cadaveric donors in response to pruritogens following transient exposure to type 2 cytokines. We also measured their effect on neuronal calcium flux and changes in gene expression by RNA sequencing. Results: Type 2 cytokines (IL-4, IL-13, and IL-33) were capable of sensitizing human dorsal root ganglia neurons to both histaminergic and nonhistaminergic itch stimuli. Sensitization was observed after only 2 h of pruritogen incubation. We observed rapid neuronal calcium flux in a small subset of neurons directly in response to IL-4 and to IL-13, which was dependent on the presence of extracellular calcium. IL-4 and IL-13 induced a common signature of upregulated genes after 24 h of exposure that was unique from IL-33 and non-type 2 inflammatory stimuli. Discussion: This study provides evidence of peripheral neuron sensitization by type 2 cytokines as well as broad transcriptomic effects in human sensory ganglia. These studies identify both unique and overlapping roles of these cytokines in sensory neurons.

The molecular basis of drug selectivity for α5 subunit-containing GABAA receptors.

α5 subunit-containing γ-aminobutyric acid type A (GABAA) receptors represent a promising drug target for neurological and neuropsychiatric disorders. Altered expression and function contributes to neurodevelopmental disorders such as Dup15q and Angelman syndromes, developmental epilepsy and autism. Effective drug action without side effects is dependent on both α5-subtype selectivity and the strength of the positive or negative allosteric modulation (PAM or NAM). Here we solve structures of drugs bound to the α5 subunit. These define the molecular basis of binding and α5 selectivity of the ß-carboline, methyl 6,7-dimethoxy-4-ethyl-ß-carboline-3-carboxylate (DMCM), type II benzodiazepine NAMs, and a series of isoxazole NAMs and PAMs. For the isoxazole series, each molecule appears as an 'upper' and 'lower' moiety in the pocket. Structural data and radioligand binding data reveal a positional displacement of the upper moiety containing the isoxazole between the NAMs and PAMs. Using a hybrid molecule we directly measure the functional contribution of the upper moiety to NAM versus PAM activity. Overall, these structures provide a framework by which to understand distinct modulator binding modes and their basis of α5-subtype selectivity, appreciate structure-activity relationships, and empower future structure-based drug design campaigns.

Burden of adult-onset Still's disease: A systematic review of health-related quality of life, utilities, costs and resource use.

Adult-onset Still's disease (AOSD) poses a not well estimated burden on patients and healthcare systems. To assess this burden, a systematic review (SR) was undertaken to identify health-related quality of life (HRQoL), utilities, costs and healthcare resource use data. Searches of twelve databases, four conferences, and three key technology assessment and regulatory agency websites were conducted in August 2022. Reference lists of retrieved SRs published since 2017 were also checked. Overall, 16 studies were eligible for inclusion. Eight studies reported HRQoL outcomes, one of which also reported utilities data. Two studies reported direct costs outcomes, and seven reported healthcare resource use data. No indirect costs were identified. A range of outcomes were reported, thus limiting the comparability of results across studies. SF-36 data were impaired in AOSD on most scales, especially those concerning physical activity. Mean SF-36 data were lower across all subscales in patients with active AOSD compared with inactive AOSD. Biologic therapy showed improvements in the SF-36 physical health summary. Utility scores (one study) were significantly lower for AOSD than for healthy controls. Limited direct economic costs data were identified but were substantial where reported. Hospital length of stay ranged from 6.1 to 23.5 days. The SR showed there is a paucity of research reporting the HRQoL and cost burden of AOSD.

Quantifying the escalating impact of paramedic transported emergency department visits for opioid-related conditions in Ontario, Canada: A population-based cohort study.

INTRODUCTION: While overdoses comprise the majority of opioid research, the comprehensive impact of the opioid crisis on emergency departments (EDs) and paramedic services has not been reported. We examined temporal changes in population-adjusted incidence rates of ED visits and paramedic transports due to opioid-related conditions. MATERIALS AND METHODS: We conducted a population-based cohort study of all ED visits in the National Ambulatory Care Reporting System from January 1, 2009 to December 31, 2019 in Ontario, Canada. We included all patients with a primary diagnosis naming opioids as the underlying cause for the visit, without any other drugs or substances. We clustered geographic regions using Local Health Integration Network boundaries. Descriptive statistics, incidence rate ratios (IRR) and 95% confidence intervals (CIs) were calculated to analyze population-adjusted temporal changes. RESULTS: Overall, 86,403 ED visits were included in our study. Incidence of opioid-related ED visits increased by 165% in the study timeframe, with paramedic transported patients increasing by 429%. Per 100,000 residents, annual ED visits increased from 40.4 to 97.2, and paramedic transported patients from 12.1 to 67.9. The proportion of opioid-related ED visits transported by paramedics increased from 35.0% to 69.9%. The medical acuity of opioid-related ED visits increased throughout the years (IRR 6.8. 95% CI 5.9-7.7), though the proportion of discharges remained constant (~75%). The largest increases in ED visits and paramedic transports were concentrated to urbanized regions. DISCUSSION: Opioid-related ED visits and paramedic transports increased substantially between 2009 and 2019. The proportion of ED visits transported by paramedics doubled. Our findings could provide valuable support to health stakeholders in implementing timely strategies aimed at safely reducing opioid-related ED visits. The increased use of paramedics followed by high rates of ED discharge calls for exploration of alternative care models within paramedic systems, such as direct transport to specialized substance abuse centres.