A randomized proof-of-mechanism trial of TNF antagonism for motivational anhedonia and related corticostriatal circuitry in depressed patients with high inflammation.

Chronic, low-grade inflammation has been associated with motivational deficits in patients with major depression (MD). In turn, impaired motivation has been linked to poor quality of life across psychiatric disorders. We thus determined effects of the anti-inflammatory drug infliximab-a potent tumor necrosis factor (TNF) antagonist-on behavioral and neural measures of motivation in 42 medically stable, unmedicated MD patients with a C-reactive protein > 3mg/L. All patients underwent a double-blind, placebo-controlled, single-dose, randomized clinical trial with infliximab (5mg/kg) versus placebo. Behavioral performance on an effort-based decision-making task, self-report questionnaires, and neural responses during event-related functional magnetic resonance imaging were assessed at baseline and 2 weeks following infusion. We found that relative to placebo, patients receiving infliximab were more willing to expend effort for rewards. Moreover, increase in effortful choices was associated with reduced TNF signaling as indexed by decreased soluble TNF receptor type 2 (sTNFR2). Changes in effort-based decision-making and sTNFR2 were also associated with changes in task-related activity in a network of brain areas, including dmPFC, ventral striatum, and putamen, as well as the functional connectivity between these regions. Changes in sTNFR2 also mediated the relationships between drug condition and behavioral and neuroimaging measures. Finally, changes in self-reported anhedonia symptoms and effort-discounting behavior were associated with greater responses of an independently validated whole-brain predictive model (aka "neural signature") sensitive to monetary rewards. Taken together, these data support the use of anti-inflammatory treatment to improve effort-based decision-making and associated brain circuitry in depressed patients with high inflammation.

A mesocorticolimbic signature of pleasure in the human brain.

Pleasure is a fundamental driver of human behaviour, yet its neural basis remains largely unknown. Rodent studies highlight opioidergic neural circuits connecting the nucleus accumbens, ventral pallidum, insula and orbitofrontal cortex as critical for the initiation and regulation of pleasure, and human neuroimaging studies exhibit some translational parity. However, whether activation in these regions conveys a generalizable representation of pleasure regulated by opioidergic mechanisms remains unclear. Here we use pattern recognition techniques to develop a human functional magnetic resonance imaging signature of mesocorticolimbic activity unique to states of pleasure. In independent validation tests, this signature is sensitive to pleasant tastes and affect evoked by humour. The signature is spatially co-extensive with mu-opioid receptor gene expression, and its response is attenuated by the opioid antagonist naloxone. These findings provide evidence for a basis of pleasure in humans that is distributed across brain systems.

Effects of acute stress and depression on functional connectivity between prefrontal cortex and the amygdala.

Stress is known to be a significant risk factor for the development of Major Depressive Disorder (MDD), yet the neural mechanisms that underlie this risk are poorly understood. Prior work has heavily implicated the corticolimbic system in the pathophysiology of MDD. In particular, the prefrontal cortex (PFC) and amygdala play a central role in regulating the response to stress, with dorsal PFC and ventral PFC exhibiting reciprocal excitatory and inhibitory influences on amygdala subregions. However, it remains unclear how best to disentangle the impact of stress from the impact of current MDD symptoms on this system. Here, we examined stress-induced changes in resting state functional connectivity (rsFC) within an a priori corticolimbic network in MDD patients and healthy controls (total n = 80) before and after an acute stressor or a "no stress" control condition. Using graph theoretic analysis, we found that connectivity between basolateral amygdala and dorsal prefrontal nodes of the corticolimbic network had a negative association with individual differences in chronic perceived stress at baseline. Following the acute stressor, healthy individuals showed a reduction of the amygdala node strength, while MDD patients exhibited little change. Finally, dorsal PFC-particularly dorsomedial PFC- connectivity to the basolateral amygdala was associated with the strength of the basolateral amygdala responses to loss feedback during a reinforcement learning task. These findings highlight attenuated connectivity between basolateral amygdala and prefrontal cortex in patients with MDD. In healthy individuals, acute stress exposure was found to push the corticolimbic network to a "stress-phenotype" that may be chronically present in patients with current depression and high levels of perceived stress. In sum, these results help to identify circuit mechanisms underlying the effects of acute stress and their role in mood disorders.

Incidence of cardiovascular disease and mortality in childhood solid organ transplant recipients: a population-based study.

BACKGROUND: With improved survival among children after transplantation, our understanding of the risk for developing other comorbidities is improving, yet little is known about the long-term risk of cardiovascular events and mortality after solid organ transplantation. METHODS: In a cohort study using health administrative data, we compared cardiovascular events in children (n = 615) with liver, lung, kidney, small bowel, or multi-organ transplant at the Hospital for Sick Children, Toronto, Canada, with asthmatic children (n = 481,697) between 1996 and 2014. Outcomes included non-fatal cardiovascular events, cardiovascular death, all-cause mortality, and a composite of non-fatal and fatal cardiovascular events. Time-stratified Cox proportional hazards models were used. RESULTS: Among 615 children, 317 (52%) were recipients of kidneys, 253 (41%) of livers, and the remaining 45 (7%) had lung, small bowel, or multi-organ transplants. Median follow-up was 12.1 [7.2, 16.7] years. Non-fatal incident cardiovascular events were 34 times higher among solid organ transplant recipients than non-transplanted children (incidence rate ratio (IRR) 34.4, 95% CI: 25.5, 46.4). Among transplant recipients, the cumulative incidence of non-fatal and fatal cardiovascular events was 2.3% and 13.0%, 5 and 15 years after transplantation, respectively. CONCLUSIONS: Increased rate of cardiovascular events in children after transplantation highlights the need for surveillance during transition into adulthood and beyond. A higher resolution version of the Graphical abstract is available as Supplementary information.

Reduced adaptation of glutamatergic stress response is associated with pessimistic expectations in depression.

Stress is a significant risk factor for the development of major depressive disorder (MDD), yet the underlying mechanisms remain unclear. Preclinically, adaptive and maladaptive stress-induced changes in glutamatergic function have been observed in the medial prefrontal cortex (mPFC). Here, we examine stress-induced changes in human mPFC glutamate using magnetic resonance spectroscopy (MRS) in two healthy control samples and a third sample of unmedicated participants with MDD who completed the Maastricht acute stress task, and one sample of healthy control participants who completed a no-stress control manipulation. In healthy controls, we find that the magnitude of mPFC glutamate response to the acute stressor decreases as individual levels of perceived stress increase. This adaptative glutamate response is absent in individuals with MDD and is associated with pessimistic expectations during a 1-month follow-up period. Together, this work shows evidence for glutamatergic adaptation to stress that is significantly disrupted in MDD.

Outcomes of an Inpatient Dialysis Start in Patients With Kidney Graft Failure: A Population-Based Multicentre Cohort Study.

BACKGROUND: The frequency and outcomes of starting maintenance dialysis in the hospital as an inpatient in kidney transplant recipients with graft failure are poorly understood. OBJECTIVE: To determine the frequency of inpatient dialysis starts in patients with kidney graft failure and examine whether dialysis start status (hospital inpatient vs outpatient setting) is associated with all-cause mortality and kidney re-transplantation. DESIGN: Population-based cohort study. SETTING: We used linked administrative healthcare databases from Ontario, Canada. PATIENTS: We included 1164 patients with kidney graft failure from 1994 to 2016. MEASUREMENTS: All-cause mortality and kidney re-transplantation. METHODS: The cumulative incidence function was used to calculate the cumulative incidence of all-cause mortality and kidney re-transplantation, accounting for competing risks. Subdistribution hazard ratios from the Fine and Gray model were used to examine the relationship between inpatient dialysis starts (vs outpatient dialysis start [reference]) and the dependent variables (ie, mortality or re-transplant). RESULTS: We included 1164 patients with kidney graft failure. More than half (55.8%) of patients with kidney graft failure, initiated dialysis as an inpatient. Compared with outpatient dialysis starters, inpatient dialysis starters had a significantly higher cumulative incidence of mortality and a significantly lower incidence of kidney re-transplantation (P < .001). The 10-year cumulative incidence of mortality was 51.9% (95% confidence interval [CI]: 47.4, 56.9%) (inpatient) and 35.3% (95% CI: 31.1, 40.1%) (outpatient). After adjusting for clinical characteristics, we found inpatient dialysis starters had a significantly increased hazard of mortality in the first year after graft failure (hazard ratio: 2.18 [95% CI: 1.43, 3.33]) but at 1+ years there was no significant difference between groups. LIMITATIONS: Possibility of residual confounding and unable to determine inpatient dialysis starts that were unavoidable. CONCLUSIONS: In this study we identified that most patients with kidney graft failure had inpatient dialysis starts, which was associated with an increased risk of mortality. Further research is needed to better understand the reasons for an inpatient dialysis start in this patient population.

CONTEXTE: On en sait peu sur la fréquence à laquelle est amorcé un traitement de dialyse d'entretien pendant l'hospitalisation des patients qui subissent une défaillance du greffon rénal. On en sait également peu sur les issues liées à cette procédure. OBJECTIFS: Déterminer la fréquence à laquelle un traitement de dialyse est amorcé pendant l'hospitalisation des patients qui subissent une défaillance du greffon, et vérifier si le statut du patient avant le traitement (hospitalisé vs ambulatoire) est associé à la mortalité toutes causes confondues et à la retransplantation. TYPE D'ÉTUDE: Étude de cohorte basée sur la population. CADRE: Nous avons utilisé les bases de données couplées du système de santé de l'Ontario (Canada). SUJETS: Ont été inclus 1 164 patients ayant subi une défaillance du greffon rénal entre 1994 et 2016. MESURES: La mortalité toutes causes confondues et la retransplantation d'un rein. MÉTHODOLOGIE: La fonction d'incidence cumulative a été utilisée pour calculer l'incidence cumulative de la mortalité toutes causes confondues et de la retransplantation, en tenant compte des risques concurrents. Les rapports de risque de sous-distribution du modèle Fine et Gray ont été employés pour examiner le lien entre l'amorce de la dialyse pendant l'hospitalisation (par rapport à l'amorce en ambulatoire [référence]) et les variables dépendantes (mortalité et retransplantation). RÉSULTATS: L'étude porte sur 1 164 patients ayant subi une défaillance du greffon. Plus de la moitié des patients inclus (55,8 %) avaient amorcé la dialyse pendant l'hospitalisation. Comparativement aux patients ayant amorcé la dialyse en ambulatoire, les patients hospitalisés ont montré une incidence cumulative significativement plus élevée de mortalité et une incidence significativement plus faible de retransplantation d'un rein (p<0,001). L'incidence cumulative de mortalité après 10 ans se situait à 51,9 % (IC 95 %: 47,4-56,9 %) pour les patients hospitalisés et à 35,3 % (IC 95 %: 31,1-40,1 %) pour les patients ambulatoires. Après l'ajustement en fonction des caractéristiques cliniques, nous avons constaté que les patients qui avaient amorcé la dialyse à l'hôpital avaient un risque significativement plus élevé de décéder dans l'année suivant la défaillance du greffon (rapport de risque: 2,18 [IC 95 %: 1,43-3,33]), mais aucune différence significative n'était observable entre les deux groupes au-delà d'un an. LIMITES: Possibilité de facteurs de confusion résiduels et incapacité de déterminer les amorces de dialyse inévitables chez des patients hospitalisés. CONCLUSION: Nous avons constaté que la plupart des patients ayant subi une défaillance du greffon avaient amorcé la dialyse pendant l'hospitalisation, et que cette procédure était associée à un risque accru de mortalité. Des recherches supplémentaires sont nécessaires pour mieux comprendre les raisons qui mènent à une amorce de dialyse pendant l'hospitalisation chez ces patients.

Caregiver worry and injury hazards in the daily lives of Ugandan children.

BACKGROUND: Over 95% of unintentional injury-related childhood deaths globally occur in low- and middle-income countries, such as Uganda. Risks for injury in settings like rural Uganda are vastly understudied despite differing patterns of child injury risk. The present study investigated the prevalence and type of hazards in children's environments in rural Uganda, as well as the relationship between hazard exposure and parent attitudes and perceptions regarding unintentional injury. METHODS: Our sample included 152 primary caregivers in Eastern Rural Uganda who had children in either 1st or 6th grade. All parents/guardians completed caregiver surveys following verbal instructions. Surveys assessed demographic information, child hazard exposure, and parent beliefs regarding child injury. RESULTS: Almost all parents (98.5%) reported daily exposure for their children to at least one of the hazards assessed. Caregiver's perceived likelihood of child injury was positively related to hazard exposure (r = .21, p less than .05). This relationship remained significant when controlling for family demographics, child grade level, and child injury history (F (7, 126) = 2.25, p less than .05). CONCLUSIONS: Our results suggest that Ugandan parents are aware of the risks of children's exposure to hazards, but may lack the tools to address it. Development of injury prevention interventions focusing on behavioral change techniques may help reduce childhood injury and injury-related deaths in Uganda.

Cultivating Innovative Pragmatic Cluster-Randomized Registry Trials Embedded in Hemodialysis Care: Workshop Proceedings From 2018.

Hemodialysis is a life-sustaining treatment for persons with kidney failure. However, those on hemodialysis still face a poor quality of life and a short life expectancy. High-quality research evidence from large randomized controlled trials is needed to identify interventions that improve the experiences, outcomes, and health care of persons receiving hemodialysis. With the support of the Canadian Institutes of Health Research and its Strategy for Patient-Oriented Research, the Innovative Clinical Trials in Hemodialysis Centers initiative brought together Canadian and international kidney researchers, patients, health care providers, and health administrators to participate in a workshop held in Toronto, Canada, on June 2 and 3, 2018. The workshop served to increase knowledge and awareness about the conduct of innovative, pragmatic, cluster-randomized registry trials embedded into routine hemodialysis care and provided an opportunity to discuss and build support for new trial ideas. The workshop content included structured presentations, facilitated group discussions, and expert panel feedback. Partnerships and promising trial ideas borne out of the workshop will continue to be developed to support the implementation of future large-scale trials.

L'hémodialyse constitue un traitement essentiel au maintien de la vie pour les personnes atteintes d'insuffisance rénale. Les patients hémodialysés voient cependant leur qualité et leur espérance de vie réduites. Des données de recherches probantes, provenant de vastes essais cliniques contrôlés à répartition aléatoire, sont nécessaires pour améliorer l'expérience, les résultats et les soins des patients hémodialysés. Grâce au soutien des Instituts de recherche en santé du Canada (IRSC) et de leur Stratégie de recherche axée sur le patient (SRAP), l'initiative sur les essais cliniques novateurs (ECN) en centres d'hémodialyse a réuni divers intervenants en santé rénale (chercheurs, patients, fournisseurs de soins et administrateurs), du Canada et de partout dans le monde, lors d'un colloque qui s'est tenu à Toronto les 2 et 3 juin 2018. Ce colloque a permis d'accroître la sensibilisation et les connaissances sur la conduite d'essais cliniques novateurs, répartis en grappes, pragmatiques et intégrés aux soins d'hémodialyse de routine. Cette rencontre a également fourni une occasion de discuter de nouvelles idées d'essais cliniques et de susciter les appuis nécessaires à leur réalisation. Le colloque s'est déroulé sous forme de présentations structurées, de discussions animées en groupe et de rétroaction de la part d'un comité d'experts. Les idées de recherche prometteuses et les partenariats issus de ce colloque continueront d'être développés pour soutenir la réalisation d'essais cliniques futurs de grande envergure.