The Cost-Effectiveness of Tocilizumab (Actemra) Therapy in Giant Cell Arteritis.

BACKGROUND: Tocilizumab (Actemra) is a humanized anti-interleukin-6 receptor antibody that has been used as a steroid-sparing agent in giant cell arteritis (GCA). Although the clinical effects are well described in GCA, the cost-effectiveness of the use of tocilizumab in GCA is ill defined. The purpose of this study was to determine the cost-effectiveness of tocilizumab in GCA compared with prednisone alone. METHODS: A retrospective study of 32 patients with biopsy-proven GCA comparing prednisone alone (16 patients) and prednisone with tocilizumab (16 patients) was performed. The cost for tocilizumab therapy for 26 weeks with mild and severe side effects (Groups 1 and 2, respectively) and for 52 weeks with mild and severe side effects (Group 3 and 4, respectively) was compared with estimated costs of mild and severe steroid-induced side effects (Groups 5 and 6, respectively). Statistical analysis between groups was conducted using independent sample t tests. RESULTS: Three out of the 4 group combinations of tocilizumab with prednisone demonstrated a statistically significant (P < 0.05) difference in cost compared with prednisone alone for GCA. Group 2 (26-week tocilizumab therapy with severe steroid-induced side effects), with no statically significant difference in price when compared with steroid therapy alone and far fewer side effects, demonstrated the potential use of tocilizumab in GCA therapy. As expected, longer treatment duration with tocilizumab was associated with greater cost. With respect to side effect severity, the number of side effects of steroid therapy was inversely associated with difference in cost between tocilizumab therapy and steroid side effect treatment. CONCLUSION: This study demonstrates that combination therapy of tocilizumab and prednisone is significantly more expensive than steroids alone with or without accounting for the cost of steroid-induced side effects in treated GCA. The difference in cost between the 2 therapy types is directly related to tocilizumab therapy duration and inversely related to the number or severity of steroid side effects. Patients with GCA who require a shorter duration of steroid therapy and are at risk for a high number of side effects from steroid use may be potential candidates for tocilizumab therapy, from an economic perspective.

Annulation of Oxime-Ether Tethered Donor-Acceptor Cyclopropanes.

Novel oxime-ether tethered cyclopropanes, when exposed to Yb(OTf)3 and heat, annulate to generate hydropyrrolo-oxazines products that can be taken to their respective pyrrolidines via hydrogenative N-O bond cleavage. The hydropyrrolo-oxazines are generated in a diastereoselective manner isolating the cis or trans product based on the temperature of the reaction. 20 examples of selective cis and trans hydropyrrolo-oxazines were generated in high yields by temperature control.

Is There a Functional Relation Between Set Shifting and Hyperactivity in Children with Attention-Deficit/Hyperactivity Disorder (ADHD)?

OBJECTIVE: Replicated evidence indicates that children with attention-deficit/hyperactivity disorder (ADHD) show disproportionate increases in hyperactivity/physical movement when their underdeveloped executive functions are taxed. However, our understanding of hyperactivity's relation with set shifting is limited, which is surprising given set shifting's importance as the third core executive function alongside working memory and inhibition. The aim of this study was to experimentally examine the effect of imposing set shifting and inhibition demands on objectively measured activity level in children with and without ADHD. METHOD: The current study used a validated experimental manipulation to differentially evoke set shifting, inhibition, and general cognitive demands in a carefully phenotyped sample of children aged 8-13 years with ADHD (n = 43) and without ADHD (n = 34). Activity level was sampled during each task using multiple, high-precision actigraphs; total hyperactivity scores (THS) were calculated. RESULTS: Results of the 2 × 5 Bayesian ANOVA for hyperactivity revealed strong support for a main effect of task (BF10 = 1.79 × 1018, p < .001, ω2 = .20), such that children upregulated their physical movement in response to general cognitive demands and set shifting demands specifically, but not in response to increased inhibition demands. Importantly, however, this manipulation did not disproportionally increase hyperactivity in ADHD as demonstrated by significant evidence against the task × group interaction (BF01 = 18.21, p = .48, ω2 = .002). CONCLUSIONS: Inhibition demands do not cause children to upregulate their physical activity. Set shifting produces reliable increases in children's physical movement/hyperactivity over and above the effects of general cognitive demands but cannot specifically explain hyperactivity in children with ADHD.

Treatment-resistant depression: problematic illness or a problem in our approach?

Treatment-resistant depression is widely defined as non-response to two 'adequate' courses of treatment. However, the definitions of treatment and depression are inconsistent reflecting gaps in our understanding. We argue that a failure to respond is often the result of administering inappropriate treatment, which occurs principally because of paradigm failure.Declaration of interestNone.

Effect of stress gene-by-environment interactions on hippocampal volumes and cortisol secretion in adolescent girls.

OBJECTIVE: Adolescence is a time of increased susceptibility to environmental stress and mood disorders, and girls are particularly at risk. Genes interacting with the environment (G × E) are implicated in hypothalamic-pituitary-adrenal axis dysregulation, hippocampal volume changes and risk or resilience to mood disorders. In this study, we assessed the effects of stress system G × E interactions on hippocampal volumes and cortisol secretion in adolescent girls. METHODS: We recruited 229 girls aged 12-18 years, and scans were obtained from 202 girls. Of these, 76 had been exposed to higher emotional trauma (abuse or neglect). Hippocampal volumes were measured using Freesurfer and high-resolution structural magnetic resonance imaging scans. Saliva samples were collected for measurement of cortisol levels and genotyping of stress system genes: FKBP5, NR3C1 (both N = 194) and NR3C2 ( N = 193). RESULTS: Among girls with the 'G' allelic variant of the NR3C1 gene, those who had been exposed to higher emotional trauma had significantly smaller left hippocampal volumes ( N = 44; mean = 4069.58 mm3, standard deviation = 376.99) than girls who had been exposed to minimal emotional trauma with the same allelic variant ( N = 69; mean = 4222.34 mm3, standard deviation = 366.74). CONCLUSION: In healthy adolescents, interactions between emotional trauma and the 'protective' NR3C1 'GG' variant seem to induce reductions in left hippocampal volumes. These G × E interactions suggest that vulnerability to mood disorders is perhaps driven by reduced 'protection' that may be specific to emotional trauma. This novel but preliminary evidence has implications for targeted prevention of mood disorders and prospective multimodal neuroimaging and longitudinal studies are now needed to investigate this possibility.

The effects of childhood trauma on adolescent hippocampal subfields.

OBJECTIVE: Mood disorders are more common among girls and typically emerge during adolescence. The precise reasons for this are unknown, but among the many mechanisms implicated are stress-induced hippocampal structural changes during this developmental stage. The hippocampus is a complex structure comprised of subfields that develop differentially and respond variably to stress and childhood adversity, both of which are risk factors for mood disorders. To better understand vulnerability to mood disorders, we investigated a cohort of adolescent girls and determined volumetric changes in their hippocampal subfields to elucidate the potential effects of childhood trauma. METHODS: Of the 229 participants, 201 girls (aged 12-17 years) fulfilled our analysis inclusion criteria. Of these, 76 had been exposed to higher emotional trauma (emotional abuse or neglect). The girls underwent high-resolution structural magnetic resonance imaging scans, and hippocampal subfield volumes were measured using FreeSurfer. We compared hippocampal subfield volumes in those exposed to higher emotional trauma and those exposed to minimal emotional trauma, at three time-points of adolescent development: early (12-13 years), mid (14-15 years) and late (16-17 years). RESULTS: Mid-adolescent girls exposed to higher emotional trauma had significantly smaller left CA3 volumes than minimal emotional trauma girls ( p = 0.028). Within the minimal emotional trauma group, mid-adolescents had significantly larger left CA3 volumes than early ( p = 0.034) and late ( p = 0.036) adolescents. Within the higher emotional trauma group, early adolescents had significantly larger left CA3 volumes than late adolescents ( p = 0.036). CONCLUSION: In our exploratory study, we observed higher emotional trauma-induced volume changes in the left CA3 hippocampal subfield, which varied depending on age, and may ultimately produce deficits in behavioural, cognitive and emotional processes. We propose that these changes (1) may provide a mechanism through which vulnerability to mood disorders may be increased in adolescent girls, and (2) may signal the best times to implement targeted prevention interventions.

Long-acting injectable antipsychotics as maintenance treatments for bipolar disorder-A critical review of the evidence.

OBJECTIVES: The maintenance phase of bipolar disorder is arguably the most important. The aim of management during this time is to maintain wellness and prevent future episodes of illness. Medication is often the mainstay of treatment during this phase, but adherence to treatment is a significant problem. In recent years, long-acting injectable (LAI) solutions have been proposed, but these too have limitations. This paper discusses the options that are currently available and critically appraises the effectiveness of this strategy. METHOD: The authors reviewed the small number of open-label and randomised studies on LAI medications in bipolar disorder and evaluated the efficacy and safety of these medications. RESULTS: The studies reviewed show benefit of LAIs for the management of bipolar disorder but have several key limitations to the generalisability of findings to routine practice. CONCLUSIONS: LAIs have an emerging role in the management of bipolar disorder and, although it is not without limitations, this strategy addresses some issues of long-term treatment and medication. Patients with bipolar disorder that are non-adherent or have an unstable illness with a predilection towards mania are possibly better suited to the use of LAIs, though more research is required to fully assess the effectiveness of this approach.

Treating depression with adjunctive antipsychotics.

OBJECTIVES: To evaluate the efficacy and safety of using adjunctive antipsychotics in patients with major depressive disorder. METHOD: Studies published since the last Cochrane review conducted in 2010 were identified via a literature search of recognised databases, using the keywords "adjunct*", "augment*", "antipsychotic" and "depression", and systematically evaluated. A targeted review of relevant guidelines was undertaken. RESULTS: Adjunctive antipsychotics produce a small but significant improvement in depressive symptoms in most studies. Most of the studies focussed on patients with an inadequate response to antidepressants rather than patients with treatment resistant depression. Treatment guidelines were variable but generally supported the use of adjunctive antipsychotics while cautioning about the risk of side effects. Most were non-specific about the length of time adjunctive antipsychotics should be prescribed. CONCLUSIONS: The studies do not support the routine use of adjunctive antipsychotics in patients with an inadequate response to antidepressants. They may be beneficial when used short-term in patients with treatment resistant depression who have specific symptoms (severe ruminations, melancholia, major sleep disturbance) that appear to respond well to adjunctive antipsychotics. There is no support for long-term use. Research should focus on specifying which symptom profiles are responsive and how adjunctive antipsychotics compare to other strategies in treatment resistant depression.

Modelling mood disorders: An ACE solution?

OBJECTIVES: The treatment of mood disorders remains sub-optimal. A major reason for this is our lack of understanding of the underlying pathophysiology of depression and bipolar disorder. A core problem is the lack of specificity of our current diagnoses. This paper discusses the history of this problem and posits a solution in the form of a more sophisticated model. METHOD: The authors review the notable historical works that laid the foundations of mood disorder nosology; discuss the more recent influences that shaped modern diagnoses; and examine the evidence that mood disorders are characterised by multidimensional and longitudinal symptom profiles. RESULTS: The ACE model considers mood disorders as a combination of symptoms across three domains: Activity, Cognition, and Emotion; that vary over time. This multidimensional and longitudinal perspective is consistent with the prevalence of complex clinical presentations, such as mixed states, and highlights the importance of recurrence in mood disorders. CONCLUSIONS: The ACE model encourages researchers to characterise patients from a number of equally important perspectives and, by doing so, add specificity to the treatment of mood disorders.

Nucleophilic Opening of Donor-Acceptor Cyclopropanes with Indoles via Hydrogen Bond Activation with 1,1,1,3,3,3-Hexafluoroisopropanol.

The treatment of donor-acceptor cyclopropanes with the a strong hydrogen bond donor, HFIP, activated the cyclopropanes (via presumed hydrogen bonding) toward homo-Michael additions with indoles as the nucleophiles. This reaction proceeded without the need for high pressure or catalysis.

Differential effects of aging on motor and cognitive functioning in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) patients are impaired in motor and cognitive performance, but the extent to which these deficits are magnified by aging is unknown. In one prior study, differences in cognitive processing speed between MS patients and healthy individuals were of similar magnitude across the lifespan. Here, we have improved on this work by expanding assessment to multiple cognitive domains and motor functioning. OBJECTIVE: To determine whether the degree of cognitive and motor dysfunction in MS is magnified with increasing age. METHODS: In all, 698 MS patients (aged 29-71 years) and 226 healthy controls (HCs; aged 18-72 years) completed neuroperformance tests covering ambulation, upper extremity function, information processing speed, and memory. RESULTS: Linear regression models predicting cognitive and motor function revealed main effects of MS/HC diagnosis, age, and education across all measures. There was also an interaction between age and diagnosis on measures of motor function, but not on cognitive outcomes. CONCLUSION: The progression of motor decline is amplified by aging in MS. However, the degree of cognitive impairment does not vary across the lifespan. Thus, evidence of accelerated cognitive impairment in older adults with MS may signal the presence of other age-related cognitive pathologies.

Benchmarks of meaningful impairment on the MSFC and BICAMS.

BACKGROUND: Cognitive and motor abilities in multiple sclerosis (MS) are typically quantified using reliable, consensus standard tests validated in the MS population. While these performance measures are associated with vocational disability in parametric analyses, translation of raw scores into anchors reflecting clinically relevant, functional impairment requires further research. OBJECTIVE: To examine performance-based motor and cognitive outcomes among definitive anchors that designate varying degrees of functional impairment, thereby establishing benchmarks for score interpretation. METHODS: We evaluated MS patients and healthy controls, all undergoing a brief test battery. Outcomes were derived from the MS Functional Composite (MSFC) and the Brief International Cognitive Assessment for MS (BICAMS). Functional impairment anchors were (1) disability benefits, (2) employed with negative work events, and (3) employed without problems. RESULTS: All measures yielded statistically significant differences across all levels of work status, after accounting for the effects of age and education. Benchmark values distinguished the functional impairment groups. When evaluated in combination, the Timed 25-Foot Walk and the Symbol Digit Modalities Test were the most robust predictors of functional decline. CONCLUSION: We have established benchmark scores for popular motor and cognitive tests that are associated with specific degrees of impairment in work status.

Child life specialist services, practice, and utilization across health care: a scoping review.

OBJECTIVE: The objective of this review was to map the available evidence regarding the scope of child life specialist services, practice, and utilization. INTRODUCTION: Child life specialists are members of multidisciplinary health care system teams who prioritize the developmental needs of pediatric patients to support and improve patient and family health care experiences. Evidence of the effectiveness of child life specialist services and the utilization of those services is often incorporated in multidisciplinary research reports and thus overlooked. INCLUSION CRITERIA: All quantitative, qualitative, and mixed methods research study reports and systematic reviews investigating child life specialist services, practice, and utilization in health care systems were included. METHODS: This review was guided by the JBI methodology for scoping reviews and a published a priori protocol. CINAHL (EBSCOhost), MEDLINE (PubMed), Scopus, and PsycINFO (APA) were searched for evidence published from January 1980 to August 2022. RESULTS: Research publications about child life specialist services, practice, and utilization have increased dramatically over the past decade with more than 50% of studies published in the last 5 years. Although the first authors of the majority of the research publications were physicians, these multidisciplinary author teams depicted child life specialist services in a variety of roles, including co-investigators, interventionists, and research subjects. The 105 full-text publications reviewed were from 10 countries and occurred across a wide scope of health care settings and medical subspecialties, but primarily in hospitals and health centers, and to a lesser extent, in ambulatory clinics and communities. A wide variety of child life specialist services were described across these settings. CONCLUSION: The concept of child life services began in 1922 and emerged as the child life specialist services specialty in the United States in the 1970s and 1980s. Mapping the research can help delineate the barriers and facilitators to these services in health care systems. This scoping review provides evidence of the global diffusion of child life specialist services across health care system settings with recent increases in research publications involving child life specialist services.