The National Institute for Health and Care Excellence (NICE) in England introduced early value assessments (EVAs) as an evidence-based method of accelerating access to promising health technologies that could address unmet needs and contribute to the National Health Service’s Long Term Plan. However, there are currently no published works considering differences and commonalities in methods used between Assessment Reports for EVAs.

This rapid scoping review included all completed EVAs published on the NICE website up to 23 July 2024. One reviewer screened potentially relevant records for eligibility, checked by a second reviewer. Pairs of independent reviewers extracted information on the methods used in included EVAs using a prepiloted form; these were checked for accuracy. Data were described in graphical or tabular format with an accompanying narrative summary.

In total, seventeen EVA Reports of sixteen EVAs were included in this scoping review. Five Reports did not specify how many reviewers undertook screening, whereas five did not report data extraction methods. Five EVAs planned to conduct meta-analyses, nine planned narrative syntheses, and seven planned narrative summaries. Eleven conceptual decision models were presented, with available evidence used to construct cost-utility analyses (N = 5); cost-effectiveness analyses (CEAs; N = 4); a mix of CEAs and cost-consequence analyses (CCA; N = 2); one CCA; and one cost-comparison.

Future EVA Reports should enhance the transparency of the methods used. Furthermore, EVAs could provide opportunities for the adoption of innovative methodological approaches and more flexible communication between EVA authors and key stakeholders, including patients and clinicians, companies, and NICE.

Although clozapine is the most effective antipsychotic for people with treatment-resistant schizophrenia (TRS), only 40% of people with TRS respond, and there is limited evidence for augmentation agents. Cannabidiol (CBD) reduces positive symptoms in individuals with schizophrenia, but no trials have specifically examined its efficacy in those with clozapine-resistant schizophrenia.

To examine the clinical efficacy of CBD augmentation in people with clozapine-resistant schizophrenia.

This is a 12-week randomised, placebo-controlled, double-blind, parallel-group trial (registration number: ACTRN12622001112752). We will recruit 88 individuals with clozapine-resistant schizophrenia, randomised (1:1) to 1000 mg daily CBD versus placebo. Eligible individuals will be aged between 18 and 64 years, fulfil DSM-IV criteria for schizophrenia or schizoaffective disorder, have a total PANSS (Positive and Negative Syndrome Scale) score ≥60, have received oral clozapine for at least 18 weeks and have a clozapine level of >350 ng/mL. Interim analyses will be conducted at 25, 50 and 75% recruitment; these will also provide an opportunity to reallocate participants dependent on conditional power. The primary endpoint will be the difference in PANSS positive scores at the end of week 12. Secondary endpoints include depression, anxiety, sleep, quality of life, alcohol consumption, change in weight and metabolic syndrome components, and neurocognitive measures, as well as safety and tolerability.

Novel treatments for clozapine-resistant schizophrenia are urgently needed. If found to be effective, CBD may have a role as a novel and safe adjunct to clozapine.

To determine whether poorer performance on the Boston Naming Test (BNT) in individuals with transactive response DNA-binding protein 43 pathology (TDP-43+) is due to greater loss of word knowledge compared to retrieval-based deficits.

Retrospective clinical-pathologic study of 282 participants with Alzheimer’s disease neuropathologic changes (ADNC) and known TDP-43 status. We evaluated item-level performance on the 60-item BNT for first and last available assessment. We fit cross-sectional negative binomial count models that assessed total number of incorrect items, number correct of responses with phonemic cue (reflecting retrieval difficulties), and number of “I don’t know” (IDK) responses (suggestive of loss of word knowledge) at both assessments. Models included TDP-43 status and adjusted for sex, age, education, years from test to death, and ADNC severity. Models that evaluated the last assessment adjusted for number of prior BNT exposures.

43% were TDP-43+. The TDP-43+ group had worse performance on BNT total score at first (p = .01) and last assessments (p = .01). At first assessment, TDP-43+ individuals had an estimated 29% (CI: 7%–56%) higher mean number of incorrect items after adjusting for covariates, and a 51% (CI: 15%–98%) higher number of IDK responses compared to TDP-43−. At last assessment, compared to TDP-43−, the TDP-43+ group on average missed 31% (CI: 6%–62%; p = .01) more items and had 33% more IDK responses (CI: 1% fewer to 78% more; p = .06).

An important component of poorer performance on the BNT in participants who are TDP-43+ is having loss of word knowledge versus retrieval difficulties.

White matter microstructure (WMM) potentially mediates the relation between APOE4 and memory performance. This study’s purpose was to understand whether p-tau effects this mediation model and whether education level differentially impacts the relations between these genetic and biological biomarkers’ influence on memory.

Participants included 161 older adults (M=74 years, 40.4% female, 92% White, 74 e4 non-carriers, 87 e4 carriers) with subjective and objective cognitive impairment from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). A composite memory score created by ADNI was used as the outcome variable. Mean fractional anisotropy (FA) and radial diffusivity (RD) values of white matter tracts within regions of interest (i.e., fornix (FX), hippocampal cingulum (CGH)) were individually used as the measures of WMM. A moderated mediation was run to examine whether p-tau was a moderator of the mediation between APOE4, white matter microstructure, and memory. An exploratory dual moderated mediation analysis examined education as a moderator of the moderated mediation. Indirect effects were tested using bootstrapping procedures.

In the FA moderated mediation model, APOE4 was significantly related to FA of the fornix and memory performance. FA of the CGH and FX were also related to memory performance. With FA of the fornix as the mediator, the conditional indirect effect was not significant (95% CI[-.0009, .0070]). There was a trend suggesting at low (95% CI[-.2421, -.0140]) and average (95% CI[-.1658, -.0083]) levels of p-tau, FA of the fornix was a significant mediator but was non-significant at high levels of p-tau (95% CI [-.1322, .0341]). The RD moderated mediation model was non-significant. The FA and RD exploratory dual moderated mediation models were non-significant. However, the APOE4 x p-tau interaction with FA of the fornix as the mediator suggested a trend. At low levels of p-tau, increased education was related to a significant moderated mediation.

Results suggest that FA of the fornix is a significant mediator between the relation of APOE4 and memory, and this may be dependent upon p-tau levels. When p-tau burden load was high, the path by which APOE4 impacts memory performance was not through white matter microstructure degradation. Additionally, the potential buffering effects of education may be most robust at lower levels of p-tau burden.

People with schizophrenia die almost 20 years earlier than the general population, most commonly from avertable cardiometabolic disease. Existing pharmacological weight-loss agents including metformin have limited efficacy. Recently available glucagon-like peptide (GLP-1) receptor agonists such as semaglutide have shown promise for weight loss but have yet to be trialled in this population.

To examine the efficacy of semaglutide to ameliorate antipsychotic-induced obesity in people with schizophrenia who have been treated with clozapine for more than 18 weeks.

This is a 36-week, double-blinded, randomised placebo-controlled trial. We will recruit 80 clozapine-treated patients with schizophrenia or schizoaffective disorder, aged 18–64 years, with a baseline body mass index ≥26 kg/m2, who will be randomised to subcutaneous semaglutide of 2.0 mg once a week or placebo for 36 weeks. The primary endpoint will be percentage change in body weight from baseline.

This trial will assess the efficacy and side-effects of the GLP-1 receptor agonist semaglutide on body weight and provide evidence on the possible clinical utility of semaglutide in patients with inadequate response to metformin. The study is registered with the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) with clinical trial registration number ACTRN12621001539820.

This research could benefit individuals with schizophrenia who experience significant health issues, leading to premature mortality, owing to antipsychotic-induced weight gain. Study findings will be disseminated through peer-reviewed publications and conference presentations.

Cognitive behavioural therapy (CBT) is an effective treatment for depression but a significant minority of clients do not complete therapy, do not respond to it, or subsequently relapse. Non-responders, and those at risk of relapse, are more likely to have adverse childhood experiences, early-onset depression, co-morbidities, interpersonal problems and heightened risk. This is a heterogeneous group of clients who are currently difficult to treat.

The aim was to develop a CBT model of depression that will be effective for difficult-to-treat clients who have not responded to standard CBT.

The method was to unify theory, evidence and clinical strategies within the field of CBT to develop an integrated CBT model. Single case methods were used to develop the treatment components.

A self-regulation model of depression has been developed. It proposes that depression is maintained by repeated interactions of self-identity disruption, impaired motivation, disengagement, rumination, intrusive memories and passive life goals. Depression is more difficult to treat when these processes become interlocked. Treatment based on the model builds self-regulation skills and restructures self-identity, rather than target negative beliefs. A bespoke therapy plan is formed out of ten treatment components, based on an individual case formulation.

A self-regulation model of depression is proposed that integrates theory, evidence and practice within the field of CBT. It has been developed with difficult-to-treat cases as its primary purpose. A case example is described in a concurrent article (Barton et al., 2022) and further empirical tests are on-going.

Provision of critical care and resuscitation was not practical during early missions into space. Given likely advancements in commercial spaceflight and increased human presence in low Earth orbit (LEO) in the coming decades, development of these capabilities should be considered as the likelihood of emergent medical evacuation increases.

PubMed, Web of Science, Google Scholar, National Aeronautics and Space Administration (NASA) Technical Server, and Defense Technical Information Center were searched from inception to December 2018. Articles specifically addressing critical care and resuscitation during emergency medical evacuation from LEO were selected. Evidence was graded using Oxford Centre for Evidence-Based Medicine guidelines.

The search resulted in 109 articles included in the review with a total of 2,177 subjects. There were two Level I systematic reviews, 33 Level II prospective studies with 647 subjects, seven Level III retrospective studies with 1,455 subjects, and two Level IV case series with four subjects. There were two Level V case reports and 63 pertinent review articles.

The development of a medical evacuation capability is an important consideration for future missions. This review revealed potential hurdles in the design of a dedicated LEO evacuation spacecraft. The ability to provide critical care and resuscitation during transport is likely to be limited by mass, volume, cost, and re-entry forces. Stabilization and treatment of the patient should be performed prior to departure, if possible, and emphasis should be on a rapid and safe return to Earth for definitive care.

Schizophrenia affects 1% of the population. Clozapine is the only medication licensed for treatment-resistant schizophrenia and is intensively monitored to prevent harm from neutropenia. Clozapine is also associated with increased risk of pneumonia although the mechanism is poorly understood.

To investigate the potential association between clozapine and antibody deficiency.

Patients taking clozapine and patients who were clozapine-naive and receiving alternative antipsychotics were recruited and completed a lifestyle, medication and infection-burden questionnaire. Serum total immunoglobulins (immunoglobulin (Ig)G, IgA, IgM) and specific IgG antibodies to haemophilus influenzae type B, tetanus and IgG, IgA and IgM to pneumococcus were measured.

Immunoglobulins were all significantly reduced in the clozapine-treated group (n = 123) compared with the clozapine-naive group (n = 111). Odds ratios (ORs) for a reduction in clozapine:control immunoglobulin values below the fifth percentile were IgG, OR = 6.00 (95% CI 1.31–27.44); IgA, OR = 16.75 (95% CI 2.18–128.60); and IgM, OR = 3.26 (95% CI 1.75–6.08). These findings remained significant despite exclusion of other potential causes of hypogammaglobulinaemia. In addition, duration on clozapine was associated with decline in IgG. A higher proportion of the clozapine-treated group reported taking more than five courses of antibiotics in the preceding year (5.3% (n = 5) versus 1% (n = 1).

Clozapine use was associated with significantly reduced immunoglobulin levels and an increased proportion of patients using more than five antibiotic courses in a year. Antibody testing is not included in existing clozapine monitoring programmes but may represent a mechanistic explanation and modifiable risk factor for the increased rates of pneumonia and sepsis-related mortality previously reported in this vulnerable cohort.

S.J. has received support from CSL Behring, Shire, LFB, Biotest, Binding Site, Sanofi, GSK, UCB Pharma, Grifols, BPL SOBI, Weatherden, Zarodex and Octapharma for projects, advisory boards, meetings, studies, speaker and clinical trials.