Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression.

BACKGROUND: In treatment-resistant depression, commonly defined as a lack of response to two or more consecutive treatments during the current depressive episode, the percentage of patients with remission is low and the percentage with relapse is high. The efficacy and safety of esketamine nasal spray as compared with extended-release quetiapine augmentation therapy, both in combination with ongoing treatment with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), in patients with treatment-resistant depression are unknown. METHODS: In an open-label, single-blind (with raters unaware of group assignments), multicenter, phase 3b, randomized, active-controlled trial, we assigned patients, in a 1:1 ratio, to receive flexible doses (according to the summary of product characteristics) of esketamine nasal spray (esketamine group) or extended-release quetiapine (quetiapine group), both in combination with an SSRI or SNRI. The primary end point was remission, defined as a score of 10 or less on the Montgomery-Åsberg Depression Rating Scale (MADRS), at week 8 (scores range from 0 to 60, with higher scores indicating more severe depression). The key secondary end point was no relapse through week 32 after remission at week 8. All patients were included in the analysis; patients who discontinued the trial treatment were considered as having had an unfavorable outcome (i.e., they were grouped with patients who did not have remission or who had a relapse). Analyses of the primary and key secondary end points were adjusted for age and number of treatment failures. RESULTS: Overall, 336 patients were assigned to the esketamine group and 340 to the quetiapine group. More patients in the esketamine group than in the quetiapine group had remission at week 8 (91 of 336 patients [27.1%] vs. 60 of 340 patients [17.6%]; P = 0.003) and had no relapse through week 32 after remission at week 8 (73 of 336 patients [21.7%] vs. 48 of 340 patients [14.1%]). Over 32 weeks of follow-up, the percentage of patients with remission, the percentage of patients with a treatment response, and the change in the MADRS score from baseline favored esketamine nasal spray. The adverse events were consistent with the established safety profiles of the trial treatments. CONCLUSIONS: In patients with treatment-resistant depression, esketamine nasal spray plus an SSRI or SNRI was superior to extended-release quetiapine plus an SSRI or SNRI with respect to remission at week 8. (Funded by Janssen EMEA; ESCAPE-TRD ClinicalTrials.gov number, NCT04338321.).

Children and Restraints Study in Emergency Ambulance Transport: An Observational Study and Analysis of Current Pediatric Ambulance Transport Practices.

OBJECTIVES: The aims of this study were to identify the pediatric transport methods used by Emergency Medical Services (EMS) personnel in our area and to highlight the need for federal standards to unify prehospital transport of children. METHODS: Children and Restraints Study in Emergency Ambulance Transport is a retrospective observational study of EMS arrivals to an academic pediatric emergency department for 1 year. Review of existing security footage from the ambulance entrance focused on the appropriateness of the selected restraints and the correctness of their application. A total of 3034 encounters were adequate for review and were matched to an emergency department encounter. Weight and age were identified from the chart. Patient weight was used in conjunction with video review to assess for the appropriateness of restraint selection. RESULTS: A total of 53.5% (1622) of patients were transported using a weight appropriate device or restraint system. In 77.1% of all cases (2339), the devices or restraint systems were applied incorrectly. The best results were observed for commercial pediatric restraint devices (54.5% secured appropriately) and for convertible car seats (55.5%). Ambulance cot was used alone in 69.35% of all transports despite it being the appropriate choice in just 18.2% of transports. CONCLUSIONS: Our findings confirmed that most pediatric patients transported by EMS are not appropriately secured and are at increased injury in a crash and potentially during normal vehicle operation. Opportunity exists for regulators, industry, and leaders in EMS and pediatrics to develop fiscally and operationally prudent techniques and devices to improve the safety of children in ambulances.

The arrhythmogenic N53I variant subtly changes the structure and dynamics in the calmodulin N-terminal domain, altering its interaction with the cardiac ryanodine receptor.

Mutations in the genes encoding the highly conserved Ca2+-sensing protein calmodulin (CaM) cause severe cardiac arrhythmias, including catecholaminergic polymorphic ventricular tachycardia or long QT syndrome and sudden cardiac death. Most of the identified arrhythmogenic mutations reside in the C-terminal domain of CaM and mostly affect Ca2+-coordinating residues. One exception is the catecholaminergic polymorphic ventricular tachycardia-causing N53I substitution, which resides in the N-terminal domain (N-domain). It does not affect Ca2+ coordination and has only a minor impact on binding affinity toward Ca2+ and on other biophysical properties. Nevertheless, the N53I substitution dramatically affects CaM's ability to reduce the open probability of the cardiac ryanodine receptor (RyR2) while having no effect on the regulation of the plasmalemmal voltage-gated Ca2+ channel, Cav1.2. To gain more insight into the molecular disease mechanism of this mutant, we used NMR to investigate the structures and dynamics of both apo- and Ca2+-bound CaM-N53I in solution. We also solved the crystal structures of WT and N53I CaM in complex with the primary calmodulin-binding domain (CaMBD2) from RyR2 at 1.84-2.13 Å resolutions. We found that all structures of the arrhythmogenic CaM-N53I variant are highly similar to those of WT CaM. However, we noted that the N53I substitution exposes an additional hydrophobic surface and that the intramolecular dynamics of the protein are significantly altered such that they destabilize the CaM N-domain. We conclude that the N53I-induced changes alter the interaction of the CaM N-domain with RyR2 and thereby likely cause the arrhythmogenic phenotype of this mutation.

Arrhythmia mutations in calmodulin cause conformational changes that affect interactions with the cardiac voltage-gated calcium channel.

Calmodulin (CaM) represents one of the most conserved proteins among eukaryotes and is known to bind and modulate more than a 100 targets. Recently, several disease-associated mutations have been identified in the CALM genes that are causative of severe cardiac arrhythmia syndromes. Although several mutations have been shown to affect the function of various cardiac ion channels, direct structural insights into any CaM disease mutation have been lacking. Here we report a crystallographic and NMR investigation of several disease mutant CaMs, linked to long-QT syndrome, in complex with the IQ domain of the cardiac voltage-gated calcium channel (CaV1.2). Surprisingly, two mutants (D95V, N97I) cause a major distortion of the C-terminal lobe, resulting in a pathological conformation not reported before. These structural changes result in altered interactions with the CaV1.2 IQ domain. Another mutation (N97S) reduces the affinity for Ca2+ by introducing strain in EF hand 3. A fourth mutant (F141L) shows structural changes in the Ca2+-free state that increase the affinity for the IQ domain. These results thus show that different mechanisms underlie the ability of CaM disease mutations to affect Ca2+-dependent inactivation of the voltage-gated calcium channel.

Arrhythmia mutations in calmodulin can disrupt cooperativity of Ca2+ binding and cause misfolding.

KEY POINTS: Mutations in the calmodulin protein (CaM) are associated with arrhythmia syndromes. This study focuses on understanding the structural characteristics of CaM disease mutants and their interactions with the voltage-gated calcium channel CaV 1.2. Arrhythmia mutations in CaM can lead to loss of Ca2+ binding, uncoupling of Ca2+ binding cooperativity, misfolding of the EF-hands and altered affinity for the calcium channel. These results help us to understand how different CaM mutants have distinct effects on structure and interactions with protein targets to cause disease. ABSTRACT: Calmodulinopathies are life-threatening arrhythmia syndromes that arise from mutations in calmodulin (CaM), a calcium sensing protein whose sequence is completely conserved across all vertebrates. These mutations have been shown to interfere with the function of cardiac ion channels, including the voltage-gated Ca2+ channel CaV 1.2 and the ryanodine receptor (RyR2), in a mutation-specific manner. The ability of different CaM disease mutations to discriminate between these channels has been enigmatic. We present crystal structures of several C-terminal lobe mutants and an N-terminal lobe mutant in complex with the CaV 1.2 IQ domain, in conjunction with binding assays and complementary structural biology techniques. One mutation (D130G) causes a pathological conformation, with complete separation of EF-hands within the C-lobe and loss of Ca2+ binding in EF-hand 4. Another variant (Q136P) has severely reduced affinity for the IQ domain, and shows changes in the CD spectra under Ca2+ -saturating conditions when unbound to the IQ domain. Ca2+ binding to a pair of EF-hands normally proceeds with very high cooperativity, but we found that N98S CaM can adopt different conformations with either one or two Ca2+ ions bound to the C-lobe, possibly disrupting the cooperativity. An N-lobe variant (N54I), which causes severe stress-induced arrhythmia, does not show any major changes in complex with the IQ domain, providing a structural basis for why this mutant does not affect function of CaV 1.2. These findings show that different CaM mutants have distinct effects on both the CaM structure and interactions with protein targets, and act via distinct pathological mechanisms to cause disease.

The Arrhythmogenic Calmodulin p.Phe142Leu Mutation Impairs C-domain Ca2+ Binding but Not Calmodulin-dependent Inhibition of the Cardiac Ryanodine Receptor.

A number of point mutations in the intracellular Ca2+-sensing protein calmodulin (CaM) are arrhythmogenic, yet their underlying mechanisms are not clear. These mutations generally decrease Ca2+ binding to CaM and impair inhibition of CaM-regulated Ca2+ channels like the cardiac Ca2+ release channel (ryanodine receptor, RyR2), and it appears that attenuated CaM Ca2+ binding correlates with impaired CaM-dependent RyR2 inhibition. Here, we investigated the RyR2 inhibitory action of the CaM p.Phe142Leu mutation (F142L; numbered including the start-Met), which markedly reduces CaM Ca2+ binding. Surprisingly, CaM-F142L had little to no aberrant effect on RyR2-mediated store overload-induced Ca2+ release in HEK293 cells compared with CaM-WT. Furthermore, CaM-F142L enhanced CaM-dependent RyR2 inhibition at the single channel level compared with CaM-WT. This is in stark contrast to the actions of arrhythmogenic CaM mutations N54I, D96V, N98S, and D130G, which all diminish CaM-dependent RyR2 inhibition. Thermodynamic analysis showed that apoCaM-F142L converts an endothermal interaction between CaM and the CaM-binding domain (CaMBD) of RyR2 into an exothermal one. Moreover, NMR spectra revealed that the CaM-F142L-CaMBD interaction is structurally different from that of CaM-WT at low Ca2+ These data indicate a distinct interaction between CaM-F142L and the RyR2 CaMBD, which may explain the stronger CaM-dependent RyR2 inhibition by CaM-F142L, despite its reduced Ca2+ binding. Collectively, these results add to our understanding of CaM-dependent regulation of RyR2 as well as the mechanistic effects of arrhythmogenic CaM mutations. The unique properties of the CaM-F142L mutation may provide novel clues on how to suppress excessive RyR2 Ca2+ release by manipulating the CaM-RyR2 interaction.

Treatment-Resistant Depression in Real-World Clinical Practice: A Systematic Literature Review of Data from 2012 to 2022.

OBJECTIVE: Real-world evidence in treatment-resistant depression (TRD; commonly defined as non-response to ≥ 2 consecutive treatments at adequate dosage and duration) is lacking. A systematic literature review was conducted to understand disease burden and treatment outcomes for patients with TRD, studied in a real-world setting over the last decade. DATA SOURCES: A literature search was conducted in May 2022 in MEDLINE, Embase, The Cochrane Libraries and PsycINFO, comprising studies published from 2012 to 2022. Bibliographies of all relevant identified systematic reviews and relevant conference proceedings from 2020 to 2022 were manually hand-searched. STUDY SELECTION: Real-world studies, including cohort, cross-sectional, case-control, chart review and registry studies, published in English and reporting outcomes in adults with TRD, were included. DATA EXTRACTION: Extracted data included study and baseline disease characteristics, treatment type, treatment response, clinical outcomes and health-related quality of life. RESULTS: Twenty studies were included. Criteria for TRD varied, but patients typically experienced long-lasting depression (range 1.4 to 16.5 years). Across studies, mean disease severity scores demonstrated moderate to severe depression, reflecting a high burden of disease at baseline. Remission rates were typically low but generally increased with longer follow-up durations. However, the heterogeneity of interventions, follow-up durations (range 2 weeks to 9.4 years) and assessment tools precluded their quantitative synthesis. Studies were frequently limited by low sample size (range 14 to 411 patients) and health-related quality of life was infrequently assessed. CONCLUSIONS: There is a lack of clinical consensus regarding the definition, assessment and monitoring of TRD in real-world practice. Nevertheless, TRD carries a high burden of illness and there is an unmet need for faster and more effective treatments. To better understand the personal burden of affected patients, future studies would benefit from standardisation of severity assessment and measures of treatment effectiveness, as well as greater consideration of health-related quality of life.

Many people continue to experience depression even after trying two or more medications. This is called treatment-resistant depression (TRD). Most of the information we have on TRD comes from clinical trials, which take place under tightly-controlled conditions. It is important to understand the effects of TRD and TRD treatments on people in their day-to-day lives. Researchers studying people's day-to-day lives call this researching in a "real-world setting". We searched for studies carried out in real-world settings in the last 10 years. We found 20 relevant studies. As these studies were in real-world settings, there were many differences between them, including differences in how TRD was diagnosed, the treatments used, how long people were monitored and how results were measured. This made it difficult to compare how successful different treatments were. Most studies included a small number of people and monitored them for a relatively short time. We found people with TRD had usually lived with it for many years and their symptoms were moderate or severe. Only two studies asked people how TRD affected their lives. These two studies found health-related quality of life and work productivity was low. Most studies found lots of people still had symptoms of depression after treatment. However, symptoms typically improved more when studies monitored people for a longer time. To improve our knowledge of TRD, future studies should monitor more people for longer and use the same ways of measuring results. They should also ask how TRD affects people's daily lives.

Why Parents Say No to Having Their Children Vaccinated against Measles: A Systematic Review of the Social Determinants of Parental Perceptions on MMR Vaccine Hesitancy.

Ongoing outbreaks of measles threaten its elimination status in the United States. Its resurgence points to lower parental vaccine confidence and local pockets of unvaccinated and undervaccinated individuals. The geographic clustering of hesitancy to MMR indicates the presence of social drivers that shape parental perceptions and decisions on immunization. Through a qualitative systematic review of published literature (n = 115 articles; 7 databases), we determined major themes regarding parental reasons for MMR vaccine hesitancy, social context of MMR vaccine hesitancy, and trustworthy vaccine information sources. Fear of autism was the most cited reason for MMR hesitancy. The social drivers of vaccine hesitancy included primary care/healthcare, education, economy, and government/policy factors. Social factors, such as income and education, exerted a bidirectional influence, which facilitated or hindered vaccine compliance depending on how the social determinant was experienced. Fear of autism was the most cited reason for MMR hesitancy. Vaccine hesitancy to MMR and other childhood vaccines clustered in middle- to high-income areas among mothers with a college-level education or higher who preferred internet/social media narratives over physician-based vaccine information. They had low parental trust, low perceived disease susceptibility, and were skeptical of vaccine safety and benefits. Combating MMR vaccine misinformation and hesitancy requires intersectoral and multifaceted approaches at various socioecological levels to address the social drivers of vaccine behavior.

Disparities in Acute Pain Treatment by Cognitive Status in Older Adults With Hip Fracture.

BACKGROUND: We examined the disparities in emergency department (ED) pain treatment based on cognitive status in older adults with an acute hip fracture. METHODS: Observational study in an academic ED in the Bronx, New York. One hundred forty-four adults aged 65 years and older with acute hip fracture were administered the Telephone Interview for Cognitive Status (TICS) while in the ED. The primary outcome was receipt of any parenteral analgesic. The risk factor of interest was cognitive impairment (TICS ≤ 25). Secondary outcomes included receipt of any opioid, receipt of any analgesic, total dose of analgesics in intravenous morphine equivalent units (MEQ), and time to receiving first analgesic. RESULTS: Of the 87 (60%) study patients who were cognitively impaired, 60% received a parenteral analgesic compared to 79% of the 57 cognitively unimpaired patients (RR 0.76 [95% CI 0.61, 0.94]). The effect of cognitive impairment on receiving any opioids (RR: 0.81, 95% CI 0.67, 0.98) and any analgesic (RR: 0.85; 95% CI: 0.71, 1.01) was similar. The median analgesic dose in cognitively impaired patients was significantly lower than in cognitively unimpaired patients (4 MEQ vs 8 MEQ, p = .003). CONCLUSION: Among older adults presenting to the ED with acute hip fracture, cognitive impairment was independently associated with lower likelihood of receiving analgesia and lower amount of opioid analgesia.