Case Report: Refractory macrophage activation syndrome requiring high-dose anakinra, emapalumab, and etoposide therapy in early-onset systemic juvenile idiopathic arthritis associated with adenoviremia

Macrophage activation syndrome (MAS) is a life-threatening condition characterized by the excessive stimulation of macrophages and T lymphocytes, provoked by infections, malignancy, and autoimmune or autoinflammatory conditions such as systemic juvenile idiopathic arthritis (sJIA). Clinical signs of sJIA may include high-spiking, quotidian fevers, lymphadenopathy, hepatosplenomegaly, and a salmon-colored migratory, evanescent rash. By contrast, MAS is characterized by unremitting fevers and diffuse, fixed, maculopapular rashes. In addition to hepatosplenomegaly and lymphadenopathy, patients with MAS may also have clinical signs of coagulopathy, as well as cardiac, lung, renal, and central nervous system dysfunction. The empiric treatment for MAS is initially high-dose IV corticosteroids, but usually requires addition of immunomodulators such as tacrolimus or a biologic such as Anakinra to control. The addition of immunotherapies for MAS has improved patient outcomes. We present a 2-year-old male patient with a history of early-onset sJIA, who presented with MAS refractory to corticosteroids and anakinra triggered by adenoviremia that required addition of emapalumab to control. We believe this is the first reported case of a combination of immunosuppressive therapy of emapalumab, etoposide, anakinra, tacrolimus, and corticosteroids used in the successful treatment of infection-induced MAS in early-onset sJIA. Given the lack of treatment guidelines and approved therapies for MAS, alternative strategies should be considered for patients with an intractable course

Application of the Beers Criteria to Alternate Level of Care Patients in Hospital Inpatient Units

ABSTRACTBackground: The Beers criteria were developed to help in identifying potentially inappropriate medications (PIMs) for elderly patients. These medications are often associated with adverse events and limited effectiveness in older adults. Patients awaiting an alternate level of care (ALC patients) are those who no longer require acute care hospital services and are waiting for placement elsewhere. They are often elderly, have complex medication regimens, and are at high risk of adverse events. At the time of this study no studies had applied the Beers criteria to ALC patients in Canadian hospitals.Objectives: To determine the proportion of ALC patients receiving PIMs and the proportion experiencing selected PIM-related adverse events. Methods: A retrospective chart review of ALC patients 65 years of age or older was performed to identify PIMs and the occurrence of selected adverse events (specifically central nervous system [CNS] events, falls, bradycardia, hypoglycemia, seizures, insomnia, gastrointestinal bleeding, and urinary tract infections). A logistic regression model with a random intercept for each patient was constructed to estimate odds ratios and probabilities of adverse events.Results: Fifty-two ALC patients were included in the study. Of these, 48 (92%) were taking a PIM. Of the 922 adverse events evaluated, 407 (44.1%) were associated with a regularly scheduled PIM. Among patients who were taking regularly scheduled PIMs, there was a significantly increased probability of an adverse CNS event and of a fall (p < 0.001 for both). The most common PIM medication classes were first-generation antihistamines (24 [46%] of the 52 patients), antipsychotics (21 patients [40%]), short-acting benzodiazepines (15 patients [29%]), and nonbenzodiazepine hypnotics (14 patients [27%]).Conclusions: A high proportion of ALC patients were taking PIMs and experienced an adverse event that may have been related to these drugs. These findings suggest that the ALC population might benefit from regular medication review and monitoring to prevent or detect adverse events.RÉSUMÉContexte : Les critères de Beers ont été élaborés afin d’aider à détecter l’utilisation de médicaments potentiellement inappropriés (MPI) auprès des patients âgés. L’on associe souvent les MPI à des événements indésirables, et leur efficacité chez les personnes âgées est limitée. Les patients en attente d’un autre niveau de soins (patients ANS) sont ceux qui ne nécessitent plus de soins de courte durée de l’hôpital et qui attendent d’être déplacés vers un autre établissement. Il s’agit souvent de personnes âgées ayant une panoplie complexe de traitements médicamenteux et présentant un risque élevé de subir des événements indésirables. Au moment de la présente recherche, aucune étude n’avait appliqué les critères de Beers aux patients ANS des hôpitaux canadiens.Objectifs : Déterminer quelles sont les proportions de patients ANS qui reçoivent des MPI et qui subissent certains événements indésirables choisis liés à ces médicaments.Méthodes : Une analyse rétrospective des dossiers médicaux de patients ANS âgés de 65 ans et plus a été réalisée dans le but de relever les MPI ainsi que les cas de certains événements indésirables choisis (particulièrement les événements liés au système nerveux central, les chutes, la bradycardie, l’hypoglycémie, les convulsions, l’insomnie, les hémorragies gastro-intestinales et les infections urinaires). On a mis au point un modèle de régression logistique avec ordonnée à l’origine aléatoire pour chaque patient afin d’estimer les risques relatifs approchés ainsi que les probabilités d’événements indésirables.Résultats : Au total, 52 patients ANS ont été admis à l’étude. De ceuxci, 48 (92 %) prenaient un MPI. Des 922 événements indésirables analysés, 407 (44,1 %) ont été associés à un MPI administré régulièrement. Parmi les patients prenant des MPI à une fréquence régulière, la probabilité de subir une chute ou un événement indésirable lié au système nerveux central était grandement accrue (p < 0,001 pour chacun). Les MPI les plus fréquents étaient : les antihistaminiques de première génération (24 [46 %] des 52 patients), les antipsychotiques (21 patients [40 %]), les benzodiazépines à action brève (15 patients [29 %]) et les hypnotiques non-benzodiazépines (14 patients [27 %]).Conclusions : Un grand nombre de patients ANS prenaient des MPI et avaient subi un événement indésirable qui ouvait avoir été en lien avec ces médicaments. Ces résultats laissent croire que les patients ANS pourraient tirer avantage d’évaluations fréquentes de la pharmacothérapie et de surveillance afin de prévenir les événements indésirables ou de les détecter

Application of the Beers Criteria to Alternate Level of Care Patients in Hospital Inpatient Units

BACKGROUND: The Beers criteria were developed to help in identifying potentially inappropriate medications (PIMs) for elderly patients. These medications are often associated with adverse events and limited effectiveness in older adults. Patients awaiting an alternate level of care (ALC patients) are those who no longer require acute care hospital services and are waiting for placement elsewhere. They are often elderly, have complex medication regimens, and are at high risk of adverse events. At the time of this study no studies had applied the Beers criteria to ALC patients in Canadian hospitals. OBJECTIVES: To determine the proportion of ALC patients receiving PIMs and the proportion experiencing selected PIM-related adverse events. METHODS: A retrospective chart review of ALC patients 65 years of age or older was performed to identify PIMs and the occurrence of selected adverse events (specifically central nervous system [CNS] events, falls, bradycardia, hypoglycemia, seizures, insomnia, gastrointestinal bleeding, and urinary tract infections). A logistic regression model with a random intercept for each patient was constructed to estimate odds ratios and probabilities of adverse events. RESULTS: Fifty-two ALC patients were included in the study. Of these, 48 (92%) were taking a PIM. Of the 922 adverse events evaluated, 407 (44.1%) were associated with a regularly scheduled PIM. Among patients who were taking regularly scheduled PIMs, there was a significantly increased probability of an adverse CNS event and of a fall (p < 0.001 for both). The most common PIM medication classes were first-generation antihistamines (24 [46%] of the 52 patients), antipsychotics (21 patients [40%]), short-acting benzodiazepines (15 patients [29%]), and nonbenzodiazepine hypnotics (14 patients [27%]). CONCLUSIONS: A high proportion of ALC patients were taking PIMs and experienced an adverse event that may have been related to these drugs. These findings suggest that the ALC population might benefit from regular medication review and monitoring to prevent or detect adverse events

Fuz Mutant Mice Reveal Shared Mechanisms between Ciliopathies and FGF-Related Syndromes

SummaryCiliopathies are a broad class of human disorders with craniofacial dysmorphology as a common feature. Among these is high arched palate, a condition that affects speech and quality of life. Using the ciliopathic Fuz mutant mouse, we find that high arched palate does not, as commonly suggested, arise from midface hypoplasia. Rather, increased neural crest expands the maxillary primordia. In Fuz mutants, this phenotype stems from dysregulated Gli processing, which in turn results in excessive craniofacial Fgf8 gene expression. Accordingly, genetic reduction of Fgf8 ameliorates the maxillary phenotypes. Similar phenotypes result from mutation of oral-facial-digital syndrome 1 (Ofd1), suggesting that aberrant transcription of Fgf8 is a common feature of ciliopathies. High arched palate is also a prevalent feature of fibroblast growth factor (FGF) hyperactivation syndromes. Thus, our findings elucidate the etiology for a common craniofacial anomaly and identify links between two classes of human disease: FGF-hyperactivation syndromes and ciliopathies

Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder.

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patient donors, we measured circadian rhythms in skin fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-Rs were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD

Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder.

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patient&nbsp;donors, we measured circadian rhythms in skin&nbsp;fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-Rs were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD

Applications and Future Opportunities

Cost-benefit analysis (CBA) is the root of Health Economics and is based on the welfare theory. CBA is the broadest economic evaluation (EE) method that assesses all benefits and costs in monetary units; the production of welfare is expressed in terms of net benefit (the difference between benefits and costs). The main goal in the welfarist approach is to maximize welfare according to individuals preferences. The application of CBA principles faces multiple obstacles, mainly because valuing health in terms of monetary units is challenging and raises ethical and methodological constraints. In the health sector, CBA has received relevant criticism, leading to the emergence and adoption of other methods of EE, such as cost-effectiveness analysis (CEA) and cost-utility analysis (CUA). However, attempts to apply welfarist principles to CEA were far of being accepted, and consensus among health economists in this regard still does not exist. The extra-welfarist approach encompassing CEA and CUA has progressed toward maximizing health outcomes and focusing on equity and fairness issues. The most common technique used in CBA to elicit preferences is the contingent valuation (willingness to pay). Despite the challenging task of valuing mental health outcomes, some studies demonstrate the feasibility of this technique in people with mental disorders, though some level of inconsistency and inaccuracy in respondents answers was reported. Despite methodological limitations among all EE methods applied to health, there is a growing interest in CBA and, more specifically, in discrete choice experiment, especially for health services and public health policies, and in exploring patients treatment preferences. The Mental Health field adds challenges to CBA regarding the complexity of defining and measuring outcomes representing mental health maximization. Document type: Boo

Effect of self-monitoring of blood pressure on blood pressure control in pregnant individuals with chronic or gestational hypertension: the BUMP 2 randomized clinical trial

Importance: inadequate management of elevated blood pressure is a significant contributing factor to maternal deaths. The role of blood pressure self-monitoring in pregnancy in improving clinical outcomes for the pregnant individual and infant is unclear. Objective: To evaluate the effect of blood pressure self-monitoring, compared with usual care alone, on blood pressure control and other related maternal and infant outcomes, in individuals with pregnancy hypertension. Design, setting, and participants: unblinded, randomized clinical trial that recruited between November 2018 and September 2019 in 15 hospital maternity units in England. Individuals with chronic hypertension (enrolled up to 37 weeks' gestation) or with gestational hypertension (enrolled between 20 and 37 weeks' gestation). Final follow-up was in May 2020. Interventions: Participants were randomized to either blood pressure self-monitoring using a validated monitor and a secure telemonitoring system in addition to usual care (n = 430) or to usual care alone (n = 420). Usual care comprised blood pressure measured by health care professionals at regular antenatal clinics. Main outcomes and measures: the primary maternal outcome was the difference in mean systolic blood pressure recorded by health care professionals between randomization and birth. Results: Among 454 participants with chronic hypertension (mean age, 36 years; mean gestation at entry, 20 weeks) and 396 with gestational hypertension (mean age, 34 years; mean gestation at entry, 33 weeks) who were randomized, primary outcome data were available from 444 (97.8%) and 377 (95.2%), respectively. In the chronic hypertension cohort, there was no statistically significant difference in mean systolic blood pressure for the self-monitoring groups vs the usual care group (133.8 mm Hg vs 133.6 mm Hg, respectively; adjusted mean difference, 0.03 mm Hg [95% CI, -1.73 to 1.79]). In the gestational hypertension cohort, there was also no significant difference in mean systolic blood pressure (137.6 mm Hg compared with 137.2 mm Hg; adjusted mean difference, -0.03 mm Hg [95% CI, -2.29 to 2.24]). There were 8 serious adverse events in the self-monitoring group (4 in each cohort) and 3 in the usual care group (2 in the chronic hypertension cohort and 1 in the gestational hypertension cohort). Conclusions andrelevance: among pregnant individuals with chronic or gestational hypertension, blood pressure self-monitoring with telemonitoring, compared with usual care, did not lead to significantly improved clinic-based blood pressure control. Trial Registration: ClinicalTrials.gov Identifier: NCT03334149.</p