Systematic review and indirect treatment comparisons of ritlecitinib against baricitinib in alopecia areata.

Ritlecitinib and baricitinib are recently approved systemic treatments for severe alopecia areata (AA). Both demonstrated superiority over placebo in hair regrowth measured by the Severity of Alopecia Tool (SALT), but they have not been directly compared in randomized controlled trials (RCTs). We conducted a systematic review of RCTs evaluating treatments in AA and estimated the efficacy and safety of ritlecitinib and baricitinib at Week 24 using Bayesian network meta-analysis. To adjust and explore effect modifiers, population-adjusted indirect comparison was performed via multilevel network meta-regression (ML-NMR) using ritlecitinib individual patient data (IPD). Co-primary endpoints were SALT ≤20 and SALT ≤10 at Week 24. Unanchored population adjusted ITCs were also computed to evaluate SALT ≤10 and SALT ≤20 endpoints at Week 48/52. Four RCTs (ALLEGRO 2a [NCT02974868], ALLEGRO 2b/3 [NCT03732807], BRAVE-AA1 [NCT03570749] and BRAVE-AA2 [NCT03899259]) were included. No evidence of a difference between ritlecitinib 50 mg and baricitinib 4 mg on SALT ≤10 (odds ratio, OR: 0.96, 95% credible interval, CrI: 0.18-7.21) and SALT ≤20 (OR: 2.16, 95% CrI: 0.48-16.46) at Week 24 was found. ML-NMR using ALLEGRO IPD adjusted for sex, SALT score at baseline, duration of current episode and disease duration found evidence of effect modification, although relative efficacy between ritlecitinib 50 mg and baricitinib 4 mg remained unchanged. Unanchored population-adjusted ITC at Week 48/52 was consistent with previous results. We found similar efficacy between ritlecitinib 50 mg and baricitinib 4 mg. These ITCs was informed by only four RCTs, uncertainty was considerable, and there was evidence of effect modification, highlighting the need for further quality research in AA.

Ontario dairy producers' and veterinarians' perspectives: Barriers to biosecurity implementation.

Implementing biosecurity protocols is necessary to reduce the spread of disease on dairy farms. In Ontario biosecurity implementation is variable among farms, and the barriers to implementing biosecurity are unknown. Thirty-five semistructured interviews were conducted between July 2022 and January 2023 with dairy producers (n = 17) and veterinarians (n = 18). Participants also completed a demographic survey. Thematic analysis was performed with constructivist and grounded theory paradigms. Thematic coding was done inductively using NVivo software. Dairy producers' understanding of the definition of biosecurity varied, with all understanding that it was to prevent the spread of disease. Furthermore, the most common perception was that biosecurity prevented the spread of disease onto the farm. Both veterinarians and producers stated that closed herds were one of the most important biosecurity protocols. Barriers to biosecurity implementation included a lack of resources, internal and external business influencers, individual perceptions of biosecurity, and a lack of industry initiative. Understanding the barriers producers face provides veterinarians with the chance to tailor their communication to ensure barriers are reduced or for other industry members to reduce the barriers.

Graduate Student Literature Review: Perceptions of biosecurity in a Canadian dairy context.

The objective of this review was to outline current implementation of biosecurity, the impact of biosecurity on the industry, and producers' and veterinarians' perceptions of biosecurity, with a focus on the Canadian dairy industry. Biosecurity has an important role in farm safety by reducing the spread of pathogens and contaminants, improving animal health and production, and maintaining human safety. Implementation of biosecurity practices varies among farms and countries. Because Canada's supply management system is different than other countries, different barriers and perceptions of biosecurity may exist. Producers may have negative perspectives on biosecurity, such as it being expensive or time consuming. Producers are motivated or deterred from biosecurity implementation for many reasons, including perceived value, disease risk, and financial incentives or deterrents. In addition, because veterinarians are a trusted source of information, their approaches to discussions on biosecurity implementation are important to understand. Veterinarians and producers appear to have differing opinions on the importance of biosecurity and approaches to discussing biosecurity. Improving biosecurity implementation requires a multifactorial approach, such as individualized education and awareness for producers, further research into efficacy of and barriers to biosecurity, and development of strategies for effective communication between veterinarians and producers.

Perianal Fistulas Are Associated with Persistently Higher Direct Health Care Costs in Crohn's Disease: A Population-Based Study.

BACKGROUND: The economic impact of perianal fistulas in Crohn's disease (CD) has not been formally assessed in population-based studies in the biologic era. AIM: To compare direct health care costs in persons with and without perianal fistulas. METHODS: We performed a longitudinal population-based study using administrative data from Ontario, Canada. Adults (> 17 years) with CD were identified between 2007 and 2013 using validated algorithms. Perianal fistula positive "cases" were matched to up to 4 "controls" with CD without perianal fistulas based on age, sex, geographic region, year of CD diagnosis and duration of follow-up. Direct health care costs, excluding drug costs from private payers, were estimated annually beginning 5 years before (lookback) and up to 9 years after perianal fistula diagnosis (study completion) for cases and a standardized date for matched controls. RESULTS: A total of 581 cases were matched to 1902 controls. The annual per capita direct cost for cases was similar at lookback compared to controls ($2458 ± 6770 vs $2502 ± 10,752; p = 0.952), maximally greater in the first year after perianal fistulas diagnosis ($16,032 ± 21,101 vs $6646 ± 13,021; p < 0.001) and remained greater at study completion ($11,358 ± 17,151 vs $5178 ± 9792; p < 0.001). At perianal fistula diagnosis, the cost difference was driven primarily by home care cost (tenfold greater), publicly-covered prescription drugs (threefold greater) and hospitalizations (twofold greater), whereas at study completion, prescription drugs were the dominant driver (threefold greater). CONCLUSION: In our population-based cohort, perianal fistulas were associated with significantly higher direct healthcare costs at the time of perianal fistulas diagnosis and sustained long-term.

Real-world persistence of erenumab for preventive treatment of chronic and episodic migraine: Retrospective real-world study.

OBJECTIVE: To describe the real-world treatment persistence (defined as the continuation of medication for the prescribed treatment duration), demographics and clinical characteristics, and treatment patterns for patients prescribed erenumab for migraine prevention in Canada. BACKGROUND: The effectiveness of prophylactic migraine treatments is often undermined by poor treatment persistence. In clinical trials, erenumab has demonstrated efficacy and tolerability as a preventive treatment, but less is known about the longer term treatment persistence with erenumab. METHODS: This is a real-world retrospective cohort study where a descriptive analysis of secondary patient data was conducted. Enrollment and prescription data were extracted from a patient support program for a cohort of patients prescribed erenumab in Canada between September 2018 and December 2019 and analyzed for persistence, baseline demographics, clinical characteristics, and treatment patterns. Descriptive analyses and unadjusted Kaplan-Meier (KM) curves were used to summarize the persistence and dose escalation/de-escalation at different timepoints. RESULTS: Data were analyzed for 14,282 patients. Median patient age was 47 years, 11,852 (83.0%) of patients were female, and 9443 (66.1%) had chronic migraine at treatment initiation. Based on KM methods, 71.0% of patients overall were persistent to erenumab 360 days after treatment initiation. Within 360 days of treatment initiation, it is estimated that 59.3% (KM-derived) of patients who initiated erenumab at 70 mg escalated to 140 mg, and 4.4% (KM-derived) of patients who initiated at 140 mg de-escalated to 70 mg. CONCLUSIONS: The majority of patients prescribed erenumab remained persistent for at least a year after treatment initiation, and most patients initiated or escalated to a 140 mg dose. These results suggest that erenumab is well tolerated, and its uptake as a new class of prophylactic treatment for migraine in real-world clinical practice is not likely to be undermined by poor persistence when coverage for erenumab is easily available.

A real-world, observational study of erenumab for migraine prevention in Canadian patients.

OBJECTIVES: To assess real-world effectiveness, safety, and usage of erenumab in Canadian patients with episodic and chronic migraine with prior ineffective prophylactic treatments. BACKGROUND: In randomized controlled trials, erenumab demonstrated efficacy for migraine prevention in patients with ≤4 prior ineffective prophylactic migraine therapies. The "Migraine prevention with AimoviG: Informative Canadian real-world study" (MAGIC) assessed real-world effectiveness of erenumab in Canadian patients with migraine. METHODS: MAGIC was a prospective open-label, observational study conducted in Canadian patients with chronic migraine (CM) and episodic migraine (EM) with two to six categories of prior ineffective prophylactic therapies. Participants were administered 70 mg or 140 mg erenumab monthly based on physician's assessment. Migraine attacks were self-assessed using an electronic diary and patient-reported outcome questionnaires. The primary outcome was the proportion of subjects achieving ≥50% reduction in monthly migraine days (MMD) after the 3-month treatment period. RESULTS: Among the 95 participants who mostly experienced two (54.7%) or three (32.6%) prior categories of ineffective prophylactic therapies and who initiated erenumab, treatment was generally safe and well tolerated; 89/95 (93.7%) participants initiated treatment with 140 mg erenumab. At week 12, 32/95 (33.7%) participants including 17/64 (26.6%) CM and 15/32 (48.4%) EM achieved ≥50% reduction in MMD while 30/86 (34.9%) participants including 19/55 (34.5%) CM and 11/31 (35.5%) EM achieved ≥50% reduction in MMD at week 24. Through patient-reported outcome questionnaires, 62/95 (65.3%) and 45/86 (52.3%) participants reported improvement of their condition at weeks 12 and 24, respectively. Physicians observed improvement in the condition of 78/95 (82.1%) and 67/86 (77.9%) participants at weeks 12 and 24, respectively. CONCLUSION: One-third of patients with EM and CM achieved ≥50% MMD reduction after 3 months of erenumab treatment. This study provides real-world evidence of erenumab effectiveness, safety, and usage for migraine prevention in adult Canadian patients with multiple prior ineffective prophylactic treatments.

The promise of transformed long-term care homes: Evidence from the pandemic.

A combination of factors during the SARS-CoV-2 pandemic led to a disproportionately high mortality rate among residents of long-term care homes in Canada and around the globe. Retrospectively, some of these factors could have been avoided or minimized. Many infection control approaches recommended by public health experts and regulators, while well intended to keep people safe from disease exposure, threatened other vital aspects of health and well-being. Furthermore, focusing narrowly on infection control practices does not address long-standing operational and infrastructural factors that contributed significantly to the pandemic toll. In this article, we review traditional (ie. institutional) long-term care practices that were associated with increased risk during the pandemic and highlight one transformational model (the Green House Project) that worked well to protect the lives and livelihood of people within congregate care settings. Drawing on this evidence, we identify specific strategies for necessary and overdue improvements in long-term care homes.

Transcutaneous electrical nerve stimulation improves fatigue performance of the treated and contralateral knee extensors.

PURPOSE: Transcutaneous electrical nerve stimulation (TENS) can reduce acute and chronic pain. Unilateral fatigue can produce discomfort in the affected limb and force and activation deficits in contralateral non-exercised muscles. TENS-induced local pain analgesia effects on non-local fatigue performance are unknown. Hence, the aim of the study was to determine if TENS-induced pain suppression would augment force output during a fatiguing protocol in the treated and contralateral muscles. METHODS: Three experiments were integrated for this article. Following pre-tests, each experiment involved 20 min of TENS, sham, or a control condition on the dominant quadriceps. Then either the TENS-treated quadriceps (TENS_Treated) or the contralateral quadriceps (TENS_Contra) was tested. In a third experiment, the TENS and sham conditions involved two\; 100-s isometric maximal voluntary contractions (MVC) (30-s recovery) followed by testing of the contralateral quadriceps (TENS_Contra-Fatigue). Testing involved single knee extensors (KE) MVCs (pre- and post-test) and a post-test 30% MVC to task failure. RESULTS: The TENS-treated study induced greater (p = 0.03; 11.0%) time to KE (treated leg) failure versus control. The TENS_Contra-Fatigue induced significant (p = 0.04; 11.7%) and near-significant (p = 0.1; 7.1%) greater time to contralateral KE failure versus sham and control, respectively. There was a 14.5% (p = 0.02) higher fatigue index with the TENS (36.2 ± 10.1%) versus sham (31.6 ± 10.6%) conditions in the second fatigue intervention set (treated leg). There was no significant post-fatigue KE fatigue interaction with the TENS_Contra. CONCLUSIONS: Unilateral TENS application to the dominant KE prolonged time to failure in the treated and contralateral KE suggesting a global pain modulatory response.

Trial of early, goal-directed resuscitation for septic shock.

BACKGROUND: Early, goal-directed therapy (EGDT) is recommended in international guidelines for the resuscitation of patients presenting with early septic shock. However, adoption has been limited, and uncertainty about its effectiveness remains. METHODS: We conducted a pragmatic randomized trial with an integrated cost-effectiveness analysis in 56 hospitals in England. Patients were randomly assigned to receive either EGDT (a 6-hour resuscitation protocol) or usual care. The primary clinical outcome was all-cause mortality at 90 days. RESULTS: We enrolled 1260 patients, with 630 assigned to EGDT and 630 to usual care. By 90 days, 184 of 623 patients (29.5%) in the EGDT group and 181 of 620 patients (29.2%) in the usual-care group had died (relative risk in the EGDT group, 1.01; 95% confidence interval [CI], 0.85 to 1.20; P=0.90), for an absolute risk reduction in the EGDT group of -0.3 percentage points (95% CI, -5.4 to 4.7). Increased treatment intensity in the EGDT group was indicated by increased use of intravenous fluids, vasoactive drugs, and red-cell transfusions and reflected by significantly worse organ-failure scores, more days receiving advanced cardiovascular support, and longer stays in the intensive care unit. There were no significant differences in any other secondary outcomes, including health-related quality of life, or in rates of serious adverse events. On average, EGDT increased costs, and the probability that it was cost-effective was below 20%. CONCLUSIONS: In patients with septic shock who were identified early and received intravenous antibiotics and adequate fluid resuscitation, hemodynamic management according to a strict EGDT protocol did not lead to an improvement in outcome. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment Programme; ProMISe Current Controlled Trials number, ISRCTN36307479.).

Measurement of pH, exudate composition and temperature in wound healing: a systematic review.

OBJECTIVE: To assess the potential of measurements of pH, exudate composition and temperature in wounds to predict healing outcomes and to identify the methods that are employed to measure them. METHOD: A systematic review based on the outcomes of a search strategy of quantitative primary research published in the English language was conducted. Inclusion criteria limited studies to those involving in vivo and human participants with an existing or intentionally provoked wound, defined as 'a break in the epithelial integrity of the skin', and excluded in vitro and animal studies. Data synthesis and analysis was performed using structured narrative summaries of each included study arranged by concept, pH, exudate composition and temperature. The Evidence Based Literature (EBL) Critical Appraisal Checklist was implemented to appraise the quality of the included studies. RESULTS: A total of 23 studies, three for pH (mean quality score 54.48%), 12 for exudate composition (mean quality score 46.54%) and eight for temperature (mean quality score 36.66%), were assessed as eligible for inclusion in this review. Findings suggest that reduced pH levels in wounds, from alkaline towards acidic, are associated with improvements in wound condition. Metalloproteinase-9 (MMP-9), matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase (TIMP), neutrophil elastase (NE) and albumin, in descending order, were the most frequently measured analytes in wounds. MMP-9 emerged as the analyte which offers the most potential as a biomarker of wound healing, with elevated levels observed in acute or non-healing wounds and decreasing levels in wounds progressing in healing. Combined measures of different exudate components, such as MMP/TIMP ratios, also appeared to offer substantial potential to indicate wound healing. Finally, temperature measurements are highest in non-healing, worsening or acute wounds and decrease as wounds progress towards healing. Methods used to measure pH, exudate composition and temperature varied greatly and, despite noting some similarities, the studies often yielded significantly contrasting results. Furthermore, a limitation to the generalisability of the findings was the overall quality scores of the research studies, which appeared suboptimal. CONCLUSION: Despite some promising findings, there was insufficient evidence to confidently recommend the use of any of these measures as predictors of wound healing. pH measurement appeared as the most practical method for use in clinical practice to indicate wound healing outcomes. Further research is required to increase the strength of evidence and develop a greater understanding of wound healing dynamics.

National survey and point prevalence study of sedation practice in UK critical care.

BACKGROUND: The present study was designed to (1) establish current sedation practice in UK critical care to inform evidence synthesis and potential future primary research and (2) to compare practice reported via a survey with actual practice assessed in a point prevalence study (PPS). METHODS: UK adult general critical care units were invited to participate in a survey of current sedation practice, and a representative sample of units was invited to participate in a PPS of sedation practice at the patient level. Survey responses were compared with PPS data where both were available. RESULTS: Survey responses were received from 214 (91 %) of 235 eligible critical care units. Of these respondents, 57 % reported having a written sedation protocol, 94 % having a policy of daily sedation holds and 94 % using a sedation scale to assess depth of sedation. In the PPS, across units reporting a policy of daily sedation holds, a median of 50 % (IQR 33-75 %) of sedated patients were considered for a sedation hold. A median of 88 % (IQR 63-100 %) of patients were assessed using the same sedation scale as reported in the survey. Both the survey and the PPS indicated propofol as the preferred sedative and alfentanil, fentanyl and morphine as the preferred analgesics. In most of the PPS units, all patients had received the unit's reported first-choice sedative (median across units 100 %, IQR 64-100 %), and a median of 80 % (IQR 67-100 %) of patients had received the unit's reported first-choice analgesic. Most units (83 %) reported in the survey that sedatives are usually administered in combination with analgesics. Across units that participated in the PPS, 69 % of patients had received a combination of agents - most frequently propofol combined with either alfentanil or fentanyl. CONCLUSIONS: Clinical practice reported in the national survey did not accurately reflect actual clinical practice at the patient level observed in the PPS. Employing a mixed methods approach provided a more complete picture of sedation practice in terms of breadth and depth of information.

The Assessment of Risk in Cardiothoracic Intensive Care (ARCtIC): prediction of hospital mortality after admission to cardiothoracic critical care.

The models used to predict outcome after adult general critical care may not be applicable to cardiothoracic critical care. Therefore, we analysed data from the Case Mix Programme to identify variables associated with hospital mortality after admission to cardiothoracic critical care units and to develop a risk-prediction model. We derived predictive models for hospital mortality from variables measured in 17,002 patients within 24 h of admission to five cardiothoracic critical care units. The final model included 10 variables: creatinine; white blood count; mean arterial blood pressure; functional dependency; platelet count; arterial pH; age; Glasgow Coma Score; arterial lactate; and route of admission. We included additional interaction terms between creatinine, lactate, platelet count and cardiac surgery as the admitting diagnosis. We validated this model against 10,238 other admissions, for which the c index (95% CI) was 0.904 (0.89-0.92) and the Brier score was 0.055, while the slope and intercept of the calibration plot were 0.961 and -0.183, respectively. The discrimination and calibration of our model suggest that it might be used to predict hospital mortality after admission to cardiothoracic critical care units.

Why try to predict ICU outcomes?

PURPOSE OF REVIEW: To describe why the prediction of ICU outcomes is essential to underpin critical care quality improvement programmes. RECENT FINDINGS: Recent literature demonstrates that risk-adjusted mortality is a widely used and well-accepted quality indicator for benchmarking ICU performance. Ongoing research continues to address the best ways to present the results of benchmarking through either direct comparison among institutions (e.g., by funnel plots) or indirect comparison against the risk predictions from a risk model (e.g., by process control charts). There is also ongoing research and debate regarding event-based outcomes (e.g., hospital mortality) versus time-based outcomes (e.g., 30-day mortality). Beyond benchmarking, ICU outcome prediction models have a role in risk adjustment and risk stratification in randomized controlled trials, and adjusting for confounding in nonrandomized, observational research. Recent examples include comparing risk-adjusted outcomes according to 'capacity strain' on the ICU and extending propensity matching methods to evaluate outcomes of patients managed with a pulmonary artery catheter, among others. Risk models may have a role in communicating risk, but their utility for individual patient decision-making is limited. SUMMARY: Risk-adjusted mortality has strong support from the critical care community as a quality indicator for benchmarking ICU performance but is dependent on up-to-date, accurate risk models. ICU outcome prediction can also contribute to both randomized and nonrandomized research and potentially contribute to individual patient management, although generic risk models should not be used to guide individual treatment decisions.

Motor unit properties from three synergistic muscles during ramp isometric elbow extensions.

Many tasks require synergistic activation of muscles that possess different architectural, mechanical, and neural control properties. However, investigations of the motor unit (MU) mechanisms which modulate force are mostly restricted to individual muscles and low forces. To explore the pattern of MU recruitment and discharge behavior among three elbow extensors (lateral and long heads of the triceps brachii, and anconeus) during ramp isometric contractions, recruitment thresholds of 77 MUs in five young men were determined and corresponding MU discharge rates were tracked in 1-s epochs over forces ranging from 0 to 75 % of maximal voluntary isometric force (MVC). Across all forces, MUs in the lateral head discharged at higher rates than those in the anconeus (p < 0.001, Δ = 0.23). When all MUs were considered, recruitment thresholds in the long head of the triceps brachii were higher than the lateral head (p < 0.05, Δ = 0.70) with a trend (p = 0.08, Δ = 0.48) for higher recruitment thresholds in the long head compared with the anconeus. Together, these data indicate a potential mechanical disadvantage of the long head of the triceps brachii at 0° shoulder flexion. However, among low-threshold MUs (<10 % MVC), recruitment thresholds were lower in the anconeus than in both heads of the triceps brachii consistent with the expected twitch contractile and fiber type differences among these muscles. These findings illustrate the importance of considering synergistic relations among muscles used for a coordinated task, and the sensitivity of synergies to muscle architectural, mechanical, and possibly specific synaptic input factors.

Debye process and dielectric state of an alcohol in a nonpolar solvent.

To investigate the origin of the first order molecular kinetics of the most prominent, Debye-type polarization, a detailed dielectric relaxation study of 66.5, 40, and 20 mole% solutions of 5-methyl-2-hexanol in 2-methylpentane (2:1, 0.67:1, and 0.25:1 molar ratios) was performed. The Debye-type polarization remains prominent in the solutions, despite the extensive loss of intermolecular hydrogen bonds. At high temperatures, its contribution to permittivity extrapolates close to the statistically scaled values for the 2:1 solution. For others, the measured values of its contribution crossover the scaled values in a temperature plane. The faster relaxation process of about 4% magnitude has an asymmetric distribution of times in the solutions and, relative to those of the pure alcohol, their values decrease on heating more at high temperatures and less at low. This is attributed to an increase in the alcohol cluster size by consumption of monomers as well as the growth of smaller clusters as the solution is cooled. It is argued that structural fluctuation in solutions, as in the pure alcohol, is determined by the rates of both the Debye-type and the faster polarizations in the ultraviscous state.

Training response to 8 weeks of blood flow restricted training is not improved by preferentially altering tissue hypoxia or lactate accumulation when training to repetition failure.

Despite compelling muscular structure and function changes resulting from blood flow restricted (BFR) resistance training, mechanisms of action remain poorly characterized. Alterations in tissue O2 saturation (TSI%) and metabolites are potential drivers of observed changes, but their relationships with degree of occlusion pressure are unclear. We examined local TSI% and blood lactate (BL) concentration during BFR training to failure using different occlusion pressures on strength, hypertrophy, and muscular endurance over an 8-week training period. Twenty participants (11 males/9 females) trained 3/wk for 8 wk using high pressure (100% resting limb occlusion pressure, LOP; 20% one-repetition maximum (1RM)), moderate pressure (50% LOP, 20%1RM), or traditional resistance training (TRT; 70%1RM). Strength, size, and muscular endurance were measured pre/post training. TSI% and BL were quantified during a training session. Despite overall increases, no group preferentially increased strength, hypertrophy, or muscular endurance (p > 0.05). Neither TSI% nor BL concentration differed between groups (p > 0.05). Moderate pressure resulted in greater accumulated deoxygenation stress (TSI% × time) (-6352 ± 3081, -3939 ± 1835, -2532 ± 1349 au for moderate pressure, high pressure, and TRT, p = 0.018). We demonstrate that BFR training to task-failure elicits similar strength, hypertrophy, and muscular endurance changes to TRT. Further, varied occlusion pressure does not impact these outcomes or elicit changes in TSI% or BL concentrations. Novelty: Training to task failure with low-load blood flow restriction elicits similar improvements to traditional resistance training, regardless of occlusion pressure. During blood flow restriction, altering occlusion pressure does not proportionally impact tissue O2 saturation nor blood lactate concentrations.

Adenosine A(1) receptor mediated suppression of adrenal activity in near-term fetal sheep.

Activation of the hypothalamic-pituitary-adrenal (HPA) axis is a critical response to perinatal hypoxia. Recent data show that adenosine appears to inhibit baseline levels of fetal cortisol and to restrict the increase in ACTH and cortisol during moderate hypoxia. Because adenosine increases substantially during profound asphyxia, it is possible, but untested, that counterintuitively it might restrict the HPA response to more severe insults. It is unclear which receptors mediate the effects of adenosine on the HPA axis; however, adenosine A(1) receptor activation is important for adaptation to hypoxia. We therefore investigated whether adenosine A(1) receptor blockade modulates ACTH and cortisol levels in fetal sheep at 118 to 126 days gestation, randomly allocated to receive an intravenous infusion of either vehicle (vehicle-occlusion, n = 7) or 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, an A(1) receptor antagonist, DPCPX-occlusion, n = 7) infused 60 min before and during 10 min of umbilical cord occlusion, or infusion of DPCPX for 70 min without occlusion (DPCPX-sham, n = 6). Experiments were terminated after 72 h. Fetal ACTH levels increased significantly (P < 0.01) during occlusion, but not sham occlusion, and returned to baseline values by 60 min after occlusion. In the vehicle-occlusion group, fetal cortisol and cortisone plasma levels increased significantly (P < 0.05) 60 min after the occlusion and returned to baseline values by 24 h. In contrast, there was a marked increase in both fetal cortisol and cortisone during DPCPX infusion before occlusion to a level greater even than the maximum rise seen after occlusion alone. This increase was sustained after occlusion, with increased cortisol levels compared with occlusion alone up to 72 h. In conclusion, fetal cortisol concentrations are suppressed by adenosine A(1) receptor activity, largely though a direct adrenal mechanism. This suppression can be partially overcome by supraphysiological stimuli such as asphyxia.

Burden of Treatment Resistant Depression (TRD) in patients with major depressive disorder in Ontario using Institute for Clinical Evaluative Sciences (ICES) databases: Economic burden and healthcare resource utilization.

INTRODUCTION: The burden of treatment-resistant depression (TRD) in Canada requires empirical characterization to better inform clinicians and policy decision-making in mental health. Towards this aim, this study utilized the Institute for Clinical Evaluative Sciences (ICES) databases to quantify the economic burden and resource utilization of Patients with TRD in Ontario. METHODS: TRD, Non-TRD Major Depressive Disorder (Non-TRD MDD) and Non-MDD cohorts were selected from the ICES databases between April 2006-March 2015 and followed-up for at least two years. TRD was defined as a minimum of two treatment failures within one-year of the index MDD diagnosis. Non-TRD and Non-MDD patients were matched with patients with TRD to analyze costs, resource utilization, and demographic information. RESULTS: Out of 277 patients with TRD identified, the average age was 52 years (SD 16) and 53% were female. Compared to Non-TRD, the patients with TRD had more all-cause visits to outpatient (38.2 vs. 24.2) and emergency units (2.7 vs. 2.0) and more depression-related visits to GPs (3.06 vs. 1.63) and psychiatrists (5.88 vs. 1.95) (all p < 0.05). The average two-year cost for TRD patients was $20,998 (CAD). LIMITATIONS: This study included patients with only public plan coverage; therefore, overall TRD population and cash and private claims were not captured. CONCLUSIONS: Patients with TRD exhibit a significantly higher demand on healthcare resources and higher overall payments compared to Non-TRD patients. The findings suggest that there are current challenges in adequately managing this difficult-to-treat patient group and there remains a high unmet need for new therapies.