Association between antidepressant use and delirium in older adults: an analysis of the World Health Organization's global pharmacovigilance database.

BACKGROUND: Psychoactive drugs frequently cause delirium adverse events in older adults. However, few data on the relationship between antidepressants and delirium are available. Here, we investigated the association between antidepressant prescription and pharmacovigilance reports of delirium in older adults. METHODS: Using the World Health Organization's VigiBase® global pharmacovigilance database from 1967 to 2022, we performed a disproportionality analysis in order to probe the putative associations between each antidepressant class (non-selective monoamine reuptake inhibitors (NSMRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), alpha-2-adrenergic receptor antagonists, and other antidepressants) and reports of delirium in people aged 65 or over. We calculated the reporting odds ratios (r-OR) and their 95% confidence interval ([95%CI]) with logistic regression models before and after adjustment for confounding factors. Secondary analyses were performed for each drug and within each class by age group (65-74, and 75 and over). We also studied the reports of concomitant delirium and hyponatremia. RESULTS: Our main analysis included 87,524 cases of delirium. After adjustment for confounders, a significant association was found between delirium and all antidepressant classes other than SNRIs. Intraclass disparities were found for the association between the most frequently prescribed antidepressants and reports of delirium. An elevated risk of reports of concomitant delirium and hyponatremia was found for SSRIs (4.46 [4.01-4.96]), SNRIs (1.25 [1.07-1.46]), MAOIs (1.72 [1.41-2.09]), and the "other antidepressants" class (1.47 [1.30-1.65]). CONCLUSIONS: There was a significant association between reports of delirium and antidepressant classes (other than SNRIs). However, this association varied from one drug to another within a given antidepressant class. Moreover, this association could not always be explained by antidepressant-induced hyponatremia.

Case Study: Innovation Procurement for a Cardiac Program.

This case describes a competitive dialogue strategy to procure a cardiac program solution to strengthen performance, outcomes and value in an Ontario hospital. All major contracts for the cardiac program were expiring, offering a unique opportunity for procurement of innovation. Procurement was completed in two phases, with an additional request for proposals issued for the unique specialty products not included in the initial procurement. The implementation of contracts was monitored to ensure that outcomes and deliverables were achieved. The procurement for the entire cardiac program was complex; however, it resulted in substantial cost savings and value-added services for the cardiac program.

Case Study: Innovation Procurement for a "Smart" Privacy Solution.

This case describes an initiative to procure a "smart" privacy solution with machine learning capabilities that could eliminate false-positive alerts of privacy risks for an Ontario hospital. A competitive dialogue procurement strategy proceeded over a two-year period and involved two stages of competitive dialogue and a pilot phase to test the procured privacy solution. Discussions and sharing feedback on solutions with vendors, followed by dialogue on solution pricing and service offerings, resulted in a vendor contract that allowed other hospitals to benefit from the established agreement. This approach supported scalability of the procured privacy solution.

Innovation Procurement in Health Systems: Exploring Practice and Lessons Learned.

As rising healthcare costs continue to challenge the sustainability of global health systems, there has been a strategic shift toward a focus on value, which considers the outcomes and value of healthcare delivery relative to the costs of care delivery. A unique feature of this focus on value has influenced a shift in procurement whereby health organizations are advancing the procurement of innovative solutions to achieve defined outcomes that overcome challenges such as the quality, safety and cost of care delivery. In this paper, we report on the implementation of three innovation procurement models in four Ontario healthcare organizations. These case studies provide evidence of the value and impact of innovation procurement approaches emerging from the four healthcare organizations. Three models of innovation procurement are described in the four cases, along with qualitative analysis of experiences and outcomes for both the organizations and the participating vendors. Evidence of the value and impact of procuring innovative solutions to address health organization challenges offers insights and new approaches to leveraging public procurement methodologies to achieve value and impact for health systems.

Case Study: Innovation Procurement for a Digital Services Platform.

This case describes a design contest strategy to procure a solution to coordination of care transitions across healthcare programs to strengthen patient outcomes. The fit of the vendors' approach with the organization and the potential for building a strong relationship with the vendor teams were evaluated. A consortium of small Canadian companies was selected to proceed to a proof-of-concept phase and full implementation of the digital solution across the region. This design contest approach resulted in a successful vendor partnership for the organization to co-design, develop, implement and scale an innovative solution to support care transitions across the region.

Case Study: Innovation Procurement for a Patient and Caregiver Support Solution in the Home.

This case describes an innovation partnership procurement strategy by a community care health organization to procure a digital solution able to support both caregivers and older adults receiving homecare services. Vendor submissions proposed both existing technologies and new solutions that were challenging to evaluate. An existing technology was procured and first pilot tested in a laboratory setting prior to a field trial with seniors and their caregivers in the home. Recruitment of seniors to participate was unsuccessful. The importance of early engagement of seniors and greater clarity in partnership expectations were key learning outcomes of this case.

Value of biomarkers for predicting immunoglobulin A vasculitis nephritis outcome in an adult prospective cohort.

Background: Henoch-Schönlein purpura, more recently renamed immunoglobulin A vasculitis (IgAV), is a systemic vasculitis characterized by IgA deposits. The current markers used to assess IgAV inaccurately evaluate the risk of nephritis occurrence and its long-term outcomes. The current study assessed biomarkers of nephritis outcomes. Methods: This French multicentre prospective study enrolled 85 adult patients at the time of disease onset. Patients were assessed for clinical and biological parameters and re-examined after 1 year. Immunoglobulins, cytokines, IgA glycosylation, IgA complexes and neutrophil gelatinase-associated lipocalin (NGAL) concentrations were assessed in blood and urine. Results: We identified 60 patients with IgAV-related nephritis (IgAV-N) and 25 patients without nephritis (IgAV-woN). At the time of inclusion (Day 1), the serum levels of galactose-deficient IgA1 (Gd-IgA1) and urinary concentrations of IgA, IgG, IgM, NGAL, interleukin (IL)-1ß, IL-6, IL-8, IL-10, IgA-IgG and IgA-sCD89 complexes were higher in the IgAV-N patients than in the IgAV-woN patients (P < 0.005 for all comparisons). After follow-up (1 year), 22 patients showed a poor outcome. Among the tested markers, urine IgA at disease onset adequately reclassified the risk of poor outcome over conventional clinical factors, including estimated glomerular filtration rate, proteinuria and age (continuous net reclassification improvement = 0.72, P = 0.001; integrated discrimination improvement = 0.13, P = 0.009) in IgAV patients. Conclusions: Taken together, these results showed that serum Gd-IgA1 and urinary IgA, IgG, IgM, NGAL, IL-1ß, IL-6, IL-8, IL-10, IgA-IgG and IgA-sCD89 complexes were associated with nephritis in IgAV patients. Urinary IgA level may improve patient risk stratification for poor outcome.

Lesbian disclosure and health care seeking in the United States: A replication study.

The current study explored factors associated with lesbian disclosure to health care providers (HCPs) and engagement in preventative health behaviors by replicating and extending a Canadian path analysis study with a sample of U.S. lesbians. Both patient (education, feminism, global outness, and internalized homophobia) and HCP-related (lesbian-friendly HCPs and patient comfort) factors were either directly or indirectly associated with disclosure and engagement in preventative health behaviors, including avoidance of health-compromising behaviors (e.g., smoking) and health care seeking. Importantly, findings suggest that HCPs-particularly those who are inclusive of lesbian patients-may play a role in assuaging their patients' experiences of minority stress. Overall, the findings were similar to those originally reported in the Canadian study, with the exception of internalized homophobia playing a more visible role in the current study.

Dual Oxidase 2 (Duox2) Regulates Pannexin 1-mediated ATP Release in Primary Human Airway Epithelial Cells via Changes in Intracellular pH and Not H2O2 Production.

Human airway epithelial cells express pannexin 1 (Panx1) channels to release ATP, which regulates mucociliary clearance. Airway inflammation causes mucociliary dysfunction. Exposure of primary human airway epithelial cell cultures to IFN-γ for 48 h did not alter Panx1 protein expression but significantly decreased ATP release in response to hypotonic stress. The IFN-γ-induced functional down-regulation of Panx1 was due to the up-regulation of dual oxidase 2 (Duox2). Duox2 suppression by siRNA led to an increase in ATP release in control cells and restoration of ATP release in cells treated with IFN-γ. Both effects were reduced by the pannexin inhibitor probenecid. Duox2 up-regulation stoichiometrically increases H2O2 and proton production. H2O2 inhibited Panx1 function temporarily by formation of disulfide bonds at the thiol group of its terminal cysteine. Long-term exposure to H2O2, however, had no inhibitory effect. To assess the role of cellular acidification upon IFN-γ treatment, fully differentiated airway epithelial cells were exposed to ammonium chloride to alkalinize the cytosol. This led to a 2-fold increase in ATP release in cells treated with IFN-γ that was also inhibited by probenecid. Duox2 knockdown also partially corrected IFN-γ-mediated acidification. The direct correlation between intracellular pH and Panx1 open probability was shown in oocytes. Therefore, airway epithelial cells release less ATP in response to hypotonic stress in an inflammatory environment (IFN-γ exposure). Decreased Panx1 function is a response to cell acidification mediated by IFN-γ-induced up-regulation of Duox2, representing a novel mechanism for mucociliary dysfunction in inflammatory airway diseases.

A novel neural substrate for the transformation of olfactory inputs into motor output.

It is widely recognized that animals respond to odors by generating or modulating specific motor behaviors. These reactions are important for daily activities, reproduction, and survival. In the sea lamprey, mating occurs after ovulated females are attracted to spawning sites by male sex pheromones. The ubiquity and reliability of olfactory-motor behavioral responses in vertebrates suggest tight coupling between the olfactory system and brain areas controlling movements. However, the circuitry and the underlying cellular neural mechanisms remain largely unknown. Using lamprey brain preparations, and electrophysiology, calcium imaging, and tract tracing experiments, we describe the neural substrate responsible for transforming an olfactory input into a locomotor output. We found that olfactory stimulation with naturally occurring odors and pheromones induced large excitatory responses in reticulospinal cells, the command neurons for locomotion. We have also identified the anatomy and physiology of this circuit. The olfactory input was relayed in the medial part of the olfactory bulb, in the posterior tuberculum, in the mesencephalic locomotor region, to finally reach reticulospinal cells in the hindbrain. Activation of this olfactory-motor pathway generated rhythmic ventral root discharges and swimming movements. Our study bridges the gap between behavior and cellular neural mechanisms in vertebrates, identifying a specific subsystem within the CNS, dedicated to producing motor responses to olfactory inputs.

Under what conditions do lesbians disclose their sexual orientation to primary healthcare providers? A review of the literature.

Under what conditions do lesbians disclose their sexual orientation to primary healthcare providers? A review of the literature was undertaken to answer this question and to provide insight into the ways healthcare professionals can play an active role assisting their lesbian patients in "coming out." Thirty empirical studies met the inclusion criteria and were reviewed. Collectively, these separate studies have found that a myriad of internal (patient attributes) and external (healthcare context, patient-provider relationship) factors influence disclosure. The discussion highlights the critical role of healthcare professionals in supporting disclosure.

Hypotension, lipodystrophy, and insulin resistance in generalized PPARgamma-deficient mice rescued from embryonic lethality.

We rescued the embryonic lethality of global PPARgamma knockout by breeding Mox2-Cre (MORE) mice with floxed PPARgamma mice to inactivate PPARgamma in the embryo but not in trophoblasts and created a generalized PPARgamma knockout mouse model, MORE-PPARgamma knockout (MORE-PGKO) mice. PPARgamma inactivation caused severe lipodystrophy and insulin resistance; surprisingly, it also caused hypotension. Paradoxically, PPARgamma agonists had the same effect. We showed that another mouse model of lipodystrophy was hypertensive, ruling out the lipodystrophy as a cause. Further, high salt loading did not correct the hypotension in MORE-PGKO mice. In vitro studies showed that the vasculature from MORE-PGKO mice was more sensitive to endothelial-dependent relaxation caused by muscarinic stimulation, but was not associated with changes in eNOS expression or phosphorylation. In addition, vascular smooth muscle had impaired contraction in response to alpha-adrenergic agents. The renin-angiotensin-aldosterone system was mildly activated, consistent with increased vascular capacitance or decreased volume. These effects are likely mechanisms contributing to the hypotension. Our results demonstrated that PPARgamma is required to maintain normal adiposity and insulin sensitivity in adult mice. Surprisingly, genetic loss of PPARgamma function, like activation by agonists, lowered blood pressure, likely through a mechanism involving increased vascular relaxation.

Stress-induced senescence exaggerates postinjury neointimal formation in the old vasculature.

This study aims to demonstrate the role of stress-induced senescence in aged-related neointimal formation. We demonstrated that aging increases senescence-associated beta-galactosidase activity (SA-beta-Gal) after vascular injury and the subsequent neointimal formation (neointima-to-media ratio: 0.8 +/- 0.2 vs. 0.54 +/- 0.15) in rats. We found that senescent cells (SA-beta-Gal(+) p21(+)) were scattered throughout the media and adventitia of the vascular wall at day 7 after injury and reached their maximum number at day 14. However, senescent cells only persisted in the injured arteries of aged animals until day 30. No senescent cells were observed in the noninjured, contralateral artery. Interestingly, vascular senescent cells accumulated genomic 8-oxo-7,8-dihydrodeoxyguanine, indicating that these cells were under intense oxidative stress. To demonstrate whether senescence worsens intimal hyperplasia after injury, we seeded matrigel-embedded senescent and nonsenescent vascular smooth muscle cells around injured vessels. The neointima was thicker in arteries treated with senescent cells with respect to those that received normal cells (neointima-to-media ratio: 0.41 +/- 0.105 vs. 0.26 +/- 0.04). In conclusion, these results demonstrate that vascular senescence is not only a consequence of postinjury oxidative stress but is also a worsening factor for neointimal development in the aging vasculature.

External barriers to help-seeking encountered by Canadian gay and lesbian victims of intimate partner abuse: an application of the barriers model.

While understanding of intimate partner abuse (IPA) in gay and lesbian relationships has increased within the past decade, there remain several gaps in the help-seeking research. In particular, research examining the external barriers to help-seeking encountered by gay and lesbian victims of IPA has been largely atheoretical. To address this gap, an application of The Barriers Model was undertaken. This mixed-methods study surveyed 280 gay, lesbian, and/or queer participants living in Canada. Findings revealed that victims encountered external barriers in the environment (i.e., Layer 1 of the model), such as lack of availability of gay and lesbian specific services. Results also suggested that barriers due to family/socialization/role expectations (i.e., Layer 2 of the model), such as concealment of sexual orientation, had an impact on help-seeking.

A Framework for Enhancing Access to Equitable Home Care for 2SLGBTQ+ Communities.

Canadian, US, and UK public health and clinical research has identified barriers to health service access for Two-Spirit, lesbian, gay, bisexual, transgender, queer, non-binary, and intersex (2SLGBTQ+) communities. While offering important insight into the health service experiences of 2SLGBTQ+ communities, this body of research only recently, and still only minimally, reports on home care access experiences. Drawing on key findings from the 2SLGBTQ+ Home Care Access Project, a mixed-methods, Ontario-wide study, this paper animates an Access and Equity Framework, using participant stories and perspectives to underscore the relevance and effectiveness of the Framework as a tool to support systematic organizational assessment, evaluation, and implementation of access and equity strategies. Home care organizations can use this tool to assess their programs and services along a continuum of intentionally inviting, unintentionally inviting, unintentionally disinviting, and intentionally disinviting care for 2SLGBTQ+ people. To support this process, the framework includes six indicators of access to care: community engagement, leadership, environment, policies and processes, education and training, and programs and services.

Long-term modulation of cardiac activity induced by inhibitory control over emotional memories.

Efforts to exclude past experiences from conscious awareness can lead to forgetting. Memory suppression is central to affective disorders, but we still do not really know whether emotions, including their physiological causes, are also impacted by this process in normal functioning individuals. In two studies, we measured the after-effects of suppressing negative memories on cardiac response in healthy participants. Results of Study 1 revealed that efficient control of memories was associated with long-term inhibition of the cardiac deceleration that is normally induced by disgusting stimuli. Attempts to suppress sad memories, by contrast, aggravated the cardiac response, an effect that was closely related to the inability to forget this specific material. In Study 2, electroencephalography revealed a reduction in power in the theta (3-8 Hz), alpha (8-12 Hz) and low-beta (13-20 Hz) bands during the suppression of unwanted memories, compared with their voluntary recall. Interestingly, however, the reduction of power in the theta frequency band during memory control was related to a subsequent inhibition of the cardiac response. These results provide a neurophysiological basis for the influence of memory control mechanisms on the cardiac system, opening up new avenues and questions for treating intrusive memories using motivated forgetting.

Initiation of locomotion in lampreys.

The spinal circuitry underlying the generation of basic locomotor synergies has been described in substantial detail in lampreys and the cellular mechanisms have been identified. The initiation of locomotion, on the other hand, relies on supraspinal networks and the cellular mechanisms involved are only beginning to be understood. This review examines some of the findings relative to the neural mechanisms involved in the initiation of locomotion of lampreys. Locomotion can be elicited by sensory stimulation or by internal cues associated with fundamental needs of the animal such as food seeking, exploration, and mating. We have described mechanisms by which escape swimming is elicited in lampreys in response to mechanical skin stimulation. A rather simple neural connectivity is involved, including sensory and relay neurons, as well as the brainstem rhombencephalic reticulospinal cells, which act as command neurons. We have shown that reticulospinal cells have intrinsic membrane properties that allow them to transform a short duration sensory input into a long-lasting excitatory command that activates the spinal locomotor networks. These mechanisms constitute an important feature for the activation of escape swimming. Other sensory inputs can also elicit locomotion in lampreys. For instance, we have recently shown that olfactory signals evoke sustained depolarizations in reticulospinal neurons and chemical activation of the olfactory bulbs with local injections of glutamate induces fictive locomotion. The mechanisms by which internal cues initiate locomotion are less understood. Our research has focused on one particular locomotor center in the brainstem, the mesencephalic locomotor region (MLR). The MLR is believed to channel inputs from many brain regions to generate goal-directed locomotion. It activates reticulospinal cells to elicit locomotor output in a graded fashion contrary to escape locomotor bouts, which are all-or-none. MLR inputs to reticulospinal cells use both glutamatergic and cholinergic transmission; nicotinic receptors on reticulospinal cells are involved. MLR excitatory inputs to reticulospinal cells in the middle (MRRN) are larger than those in the posterior rhombencephalic reticular nucleus (PRRN). Moreover at low stimulation strength, reticulospinal cells in the MRRN are activated first, whereas those in the PRRN require stronger stimulation strengths. The output from the MLR on one side activates reticulospinal neurons on both sides in a highly symmetrical fashion. This could account for the symmetrical bilateral locomotor output evoked during unilateral stimulation of the MLR in all animal species tested to date. Interestingly, muscarinic receptor activation reduces sensory inputs to reticulospinal neurons and, under natural conditions, the activation of MLR cholinergic neurons will likely reduce sensory inflow. Moreover, exposing the brainstem to muscarinic agonists generates sustained recurring depolarizations in reticulospinal neurons through pre-reticular effects. Cells in the caudal half of the rhombencephalon appear to be involved and we propose that the activation of these muscarinoceptive cells could provide additional excitation to reticulospinal cells when the MLR is activated under natural conditions. One important question relates to sources of inputs to the MLR. We found that substance P excites the MLR, whereas GABA inputs tonically maintain the MLR inhibited and removal of this inhibition initiates locomotion. Other locomotor centers exist such as a region in the ventral thalamus projecting directly to reticulospinal cells. This region, referred to as the diencephalic locomotor region, receives inputs from several areas in the forebrain and is likely important for goal-directed locomotion. In summary, this review focuses on the most recent findings relative to initiation of lamprey locomotion in response to sensory and internal cues in lampreys.

Oral Lorazepam is not Superior to Placebo for Lowering Stress in Children Before Digestive Endoscopy: A Double-Blind, Randomized, Controlled Trial.

BACKGROUND: Digestive endoscopies must be performed within a safe and comfortable environment. We have previously shown that the quality of intravenous sedation is influenced by preoperative stress. AIM: Our primary objective was to compare the effects of oral lorazepam and placebo on the salivary cortisol response of children undergoing a digestive endoscopy. Secondary objectives were the assessment of procedural pain and comfort as well as the occurrence of adverse events. METHODS: Participants were randomized and received either lorazepam, placebo, or no premedication. Saliva was collected upon arrival at the hospital and 1 h following randomization. The sedation protocol included midazolam and fentanyl ± ketamine. Procedural pain was evaluated with the Nurse Assessed Patient Comfort Score (NAPCOMS). Patients completed a postoperative questionnaire. The primary outcome was defined as the proportion of children having a cortisol decrease ≥ 15 nmol/L. RESULTS: 101 participants (54 females) were included. The rate of children having a cortisol decrease ≥ 15 nmol/L was 27.3%, 35.3%, and 19.4% for lorazepam, placebo, and no premedication, respectively (p = 0.356). The median (IQR) NAPCOMS pain score was 3.0 (0-6) for lorazepam, 4.4 (0-6) for placebo, and 3.4 (3-4) for no premedication (p = 0.428). With lorazepam, 75.9% of children reported experiencing a comfortable procedure, compared with 41.9% taking placebo and 34.5% with no premedication (p = 0.013). Transient tachycardia was the most frequent intraoperative adverse event, particularly with lorazepam (62.5%, p = 0.029). CONCLUSIONS: Oral lorazepam had no effect on patients' preoperative stress, as measured by salivary cortisol, but was associated with a higher rate of comfortable procedures. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, Identifier NCT03180632.

Biomarkers of IgA vasculitis nephritis in children.

Henoch-Schönlein purpura is a systemic vasculitis characterized by IgA deposits, which target the skin, joints, and kidneys, among other organs. In children, prognosis is often good but little is known about biomarkers of pediatric nephritis. We hypothesized that biological markers, including cytokines, immunoglobulins, IgA-immune complexes, IgA glycosylation and neutrophil gelatinase-associated lipocalin (NGAL), may discriminate IgA vasculitis (IgAV) pediatric patients with renal involvement from those without renal involvement. Fifty children at the time of IgAV rash between 2010 and 2015 were prospectively enrolled and compared to 21 controls. All patients were assessed for clinical and biological parameters at the time of diagnosis, including the levels of cytokines, immunoglobulins, immune complexes, IgA glycosylation and NGAL in serum and urine. Among IgAV patients, 33 patients exhibited nephritis (IgAV-N) and 17 children were without nephritis (IgAV-woN). The serum level of galactose-deficient (Gd)-IgA1 (p<0.01) and the urinary concentrations of IgA, IgG, IgM, IL-6, IL-8, IL-10, IgA-IgG complexes and IgA-sCD89 complexes (p<0.001 for all) were higher in the IgAV-N patients than in the IgAV-woN patients. Among those markers, urinary IgA and IgM had the highest AUC (0.86 and 0.87 respectively, p<0.0001). This prospective cohort study furthers our understanding of the pathophysiology of IgAV. We identified biomarkers that are able to distinguish patients initially with or without nephritis. To conclude, serum Gd-IgA1 and urinary IgA, IgG, IgM, IL-6, IL-8, IL-10, and IgA-IgG and IgA-sCD89 complexes could identify IgAV pediatric patients with renal involvement at the time of diagnosis.

Variations in women's help seeking in response to intimate partner violence: findings from a Canadian population-based study.

This study examined the role of sociodemographic factors and violence characteristics in influencing women's use of informal and formal supports in response to intimate partner violence (IPV) in a national survey of Canadian households. A subset of female respondents in the 1999 Canadian General Social Survey who experienced at least one incident of physical or sexual IPV by a male current or former intimate partner was used for this analysis. Findings suggest that although there are significant sociodemographic variations in women's help seeking, the largest independent predictor of women's use of supports is fear that one's life is in danger.