Cost-effectiveness analysis of health tapestry, a complex primary care program for older adults: a post-hoc analysis.

BACKGROUND: We initially reported on the cost-effectiveness of a 6-month randomized controlled implementation trial which evaluated Health TAPESTRY, a primary care program for older adults, at the McMaster Family Health Team (FHT) site and 5 other FHT sites in Ontario, Canada. While there were no statistically significant between-group differences in outcomes at month 6 post randomization, positive outcomes were observed at the McMaster FHT site, which recruited 40% (204/512) of the participants. The objective of this post-hoc study was to determine the cost-effectiveness of Health TAPESTRY based on data from the McMaster FHT site. METHODS: Costs included the cost to implement Health TAPESTRY at McMaster as well as healthcare resource consumed, which were costed using publicly available sources. Health-related-quality-of-life was evaluated with the EQ-5L-5L at baseline and at month 6 post randomization. Quality-adjusted-life-years (QALYs) were calculated under an-area-under the curve approach. Unadjusted and adjusted regression analyses (two independent regression analyses on costs and QALYs, seemingly unrelated regression [SUR], net benefit regression) as well as difference-in-difference and propensity score matching (PSM) methods, were used to deal with the non-randomized nature of the trial. Sampling uncertainty inherent to the trial data was estimated using non-parametric bootstrapping. The return on investment (ROI) associated with Health TAPESTRY was calculated. All costs were reported in 2021 Canadian dollars. RESULTS: With an intervention cost of $293/patient, Health TAPESTRY was the preferred strategy in the unadjusted and adjusted analyses. The results of our bootstrap analyses indicated that Health TAPESTRY was cost-effective compared to usual care at commonly accepted WTP thresholds. For example, if decision makers were willing to pay $50,000 per QALY gained, the probability of Health TAPESTRY to be cost effective compared to usual care varied from 0.72 (unadjusted analysis) to 0.96 (SUR) when using a WTP of $50,000/QALY gained. The DID and ROI analyses indicated that Health Tapestry generated a positive ROI. CONCLUSION: Health TAPESTRY was the preferred strategy when implemented at the McMaster FHT. We caution care in interpreting the results because of the post-hoc nature of the analyses and limited sample size based on one site.

Intraoral ultrasonography image registration for evaluation of partial edentulous ridge: A methodology and validation study.

OBJECTIVES: Ultrasound (US) reveals details for diagnosing soft- and hard-tissue dimensions around teeth, implants, and the edentulous ridge, not seen in 2D radiographs. Co-registering free-hand US scans with other 3D modalities presents reliability challenges. This study first aims to develop and validate a registration method to longitudinally reproduce US images of the jawbone on a simulator. In addition, it also evaluates the degree of the anatomical match in humans between US images acquired by the proposed registration method and the commonly used freehand acquisitions in comparison to cone beam computed tomography (CBCT) and intra-oral optical scan (IOS), used as references. METHODS: A previously introduced ultrasound phantom was employed as a CBCT-US hybrid, suitable for training and technique development of US guides in edentulous ridges. After establishing feasibility in the phantom, the methodology was validated in a cohort of 24 human subjects (26 cases). Soft tissues were delineated on US and IOS, and hard tissues on US and CBCT. US accuracy and repeatability from both guided and freehand scans (non-guided) was assessed as the average distance between US and the references. RESULTS: Guided US images resembled the references more closely than freehand (non-guided) scans. Notably, delineation of soft and hard tissues was significantly more accurate when employing guides. In the phantom, guided scans exhibited an absolute mean deviation of 81.8 µm for gingiva and 90.4 µm for bone, whereas non-guided scans showed deviations of 150.4 µm and 177.2 µm, respectively. Similarly, in vivo, guided US outperformed non-guided US, with gingiva deviations of 125 µm and 196 µm, and bone deviations of 354 µm and 554 µm, respectively. CONCLUSIONS: By using a registration method, guided US scans improved repeatability and accuracy of mapping hard and soft tissue of the edentulous ridge when compared to non-guided scans. CLINICAL RELEVANCE: This guided US imaging method could lay the foundation for longitudinal evaluation of tissue behavior and dimensional changes with improved accuracy.

Mesostriatal Dopaminergic Circuit Dysfunction in Schizophrenia: A Multimodal Neuromelanin-sensitive MRI and [18F]-DOPA PET Study.

BACKGROUND: Striatal hyperdopaminergia is implicated in the pathoetiology of schizophrenia, but how this relates to dopaminergic midbrain activity is unclear. Neuromelanin-sensitive MRI (NM-MRI) provides a marker of long-term dopamine function. We examined if midbrain NM-MRI contrast-to-noise ratio (NM-CNR) was higher in people with schizophrenia relative to controls and if this correlated with dopamine synthesis capacity. METHODS: N=154 participants (n=74 individuals with schizophrenia and n=80 healthy controls) underwent NM-MRI of the substantia nigra and ventral tegmental area (SN-VTA). A subset of the schizophrenia group (n=38) also received [18F]-DOPA PET to measure dopamine synthesis capacity (Kicer) in the SN-VTA and striatum. RESULTS: SN-VTA NM-CNR was significantly higher in patients with schizophrenia relative to controls (effect size=0.38, p=0.019). This effect was greatest for voxels in the medial and ventral SN-VTA. In patients, SN-VTA Kicer positively correlated with SN-VTA NM-CNR (r=0.44, p=0.005) and striatal Kicer (r=0.71, p<0.001). Voxelwise analysis demonstrated that SN-VTA NM-CNR was positively associated with striatal Kicer (r=0.53, p=0.005) and that this relationship appeared strongest between the ventral SN-VTA and associative striatum in schizophrenia. CONCLUSIONS: Our results suggest that neuromelanin levels are higher in patients with schizophrenia relative to controls, particularly in midbrain regions that project to parts of the striatum which receive innervation from the limbic and association cortices. The direct relationship between measures of neuromelanin and dopamine synthesis suggests that these aspects of schizophrenia pathophysiology are linked. Our findings highlight specific mesostriatal circuits as the loci of dopamine dysfunction in schizophrenia and, thus, potential therapeutic targets.

Comparative physiological effects of antipsychotic drugs in children and young people: a network meta-analysis.

BACKGROUND: The degree of physiological responses to individual antipsychotic drugs is unclear in children and adolescents. With network meta-analysis, we aimed to investigate the effects of various antipsychotic medications on physiological variables in children and adolescents with neuropsychiatric and neurodevelopmental conditions. METHODS: For this network meta-analysis, we searched Medline, EMBASE, PsycINFO, Web of Science, and Scopus from database inception until Dec 22, 2023, and included randomised controlled trials comparing antipsychotics with placebo in children or adolescents younger than 18 years with any neuropsychiatric and neurodevelopmental condition. Primary outcomes were mean change from baseline to end of acute treatment in bodyweight, BMI, fasting glucose, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, prolactin, heart rate, systolic blood pressure (SBP), and QT interval corrected for heart rate (QTc) for patients receiving either active treatment or placebo. For multigroup trials reporting several doses, we calculated a summary value for each physiological variable for all doses. After transitivity assessment, we fitted frequentist random-effects network meta-analyses for all comparisons in the network. A Kilim plot was used to summarise the results for all treatments and outcomes, providing information regarding the strength of the statistical evidence of treatment effects, using p values. Network heterogeneity was assessed with τ, risk of bias of individual trials was assessed with the Cochrane Collaboration's Tool for Assessing Risk of Bias, and the credibility of findings from each network meta-analysis was assessed with the Confidence in Network Meta-Analysis (CINEMA) app. This study is registered on PROSPERO (CRD42021274393). FINDINGS: Of 6676 studies screened, 47 randomised controlled trials were included, which included 6500 children (mean age 13·29 years, SD 2·14) who received treatment for a median of 7 weeks (IQR 6-8) with either placebo (n=2134) or one of aripiprazole, asenapine, blonanserin, clozapine, haloperidol, lurasidone, molindone, olanzapine, paliperidone, pimozide, quetiapine, risperidone, or ziprasidone (n=4366). Mean differences for bodyweight change gain compared with placebo ranged from -2·00 kg (95% CI -3·61 to -0·39) with molindone to 5·60 kg (0·27 to 10·94) with haloperidol; BMI -0·70 kg/m2 (-1·21 to -0·19) with molindone to 2·03 kg/m2 (0·51 to 3·55) with quetiapine; total cholesterol -0·04 mmol/L (-0·39 to 0·31) with blonanserin to 0·35 mmol/L (0·17 to 0·53) with quetiapine; LDL cholesterol -0·12 mmol/L (-0·31 to 0·07) with risperidone or paliperidone to 0·17 mmol/L (-0·06 to 0·40) with olanzapine; HDL cholesterol 0·05 mmol/L (-0·19 to 0·30) with quetiapine to 0·48 mmol/L (0·18 to 0·78) with risperidone or paliperidone; triglycerides -0·03 mmol/L (-0·12 to 0·06) with lurasidone to 0·29 mmol/L (0·14 to 0·44) with olanzapine; fasting glucose from -0·09 mmol/L (-1·45 to 1·28) with blonanserin to 0·74 mmol/L (0·04 to 1·43) with quetiapine; prolactin from -2·83 ng/mL (-8·42 to 2·75) with aripiprazole to 26·40 ng/mL (21·13 to 31·67) with risperidone or paliperidone; heart rate from -0·20 bpm (-8·11 to 7·71) with ziprasidone to 12·42 bpm (3·83 to 21·01) with quetiapine; SBP from -3·40 mm Hg (-6·25 to -0·55) with ziprasidone to 10·04 mm Hg (5·56 to 14·51) with quetiapine; QTc from -0·61 ms (-1·47 to 0·26) with pimozide to 0·30 ms (-0·05 to 0·65) with ziprasidone. INTERPRETATION: Children and adolescents show varied but clinically significant physiological responses to individual antipsychotic drugs. Treatment guidelines for children and adolescents with a range of neuropsychiatric and neurodevelopmental conditions should be updated to reflect each antipsychotic drug's distinct profile for associated metabolic changes, alterations in prolactin, and haemodynamic alterations. FUNDING: UK Academy of Medical Sciences, Brain and Behaviour Research Foundation, UK National Institute of Health Research, Maudsley Charity, the Wellcome Trust, Medical Research Council, National Institute of Health and Care Research Biomedical Centre at King's College London and South London and Maudsley NHS Foundation Trust, the Italian Ministry of University and Research, the Italian National Recovery and Resilience Plan, and Swiss National Science Foundation.

Placebo effects in randomized trials of pharmacological and neurostimulation interventions for mental disorders: An umbrella review.

There is a growing literature exploring the placebo response within specific mental disorders, but no overarching quantitative synthesis of this research has analyzed evidence across mental disorders. We carried out an umbrella review of meta-analyses of randomized controlled trials (RCTs) of biological treatments (pharmacotherapy or neurostimulation) for mental disorders. We explored whether placebo effect size differs across distinct disorders, and the correlates of increased placebo effects. Based on a pre-registered protocol, we searched Medline, PsycInfo, EMBASE, and Web of Knowledge up to 23.10.2022 for systematic reviews and/or meta-analyses reporting placebo effect sizes in psychopharmacological or neurostimulation RCTs. Twenty meta-analyses, summarising 1,691 RCTs involving 261,730 patients, were included. Placebo effect size varied, and was large in alcohol use disorder (g = 0.90, 95% CI [0.70, 1.09]), depression (g = 1.10, 95% CI [1.06, 1.15]), restless legs syndrome (g = 1.41, 95% CI [1.25, 1.56]), and generalized anxiety disorder (d = 1.85, 95% CI [1.61, 2.09]). Placebo effect size was small-to-medium in obsessive-compulsive disorder (d = 0.32, 95% CI [0.22, 0.41]), primary insomnia (g = 0.35, 95% CI [0.28, 0.42]), and schizophrenia spectrum disorders (standardized mean change = 0.33, 95% CI [0.22, 0.44]). Correlates of larger placebo response in multiple mental disorders included later publication year (opposite finding for ADHD), younger age, more trial sites, larger sample size, increased baseline severity, and larger active treatment effect size. Most (18 of 20) meta-analyses were judged 'low' quality as per AMSTAR-2. Placebo effect sizes varied substantially across mental disorders. Future research should explore the sources of this variation. We identified important gaps in the literature, with no eligible systematic reviews/meta-analyses of placebo response in stress-related disorders, eating disorders, behavioural addictions, or bipolar mania.

Sonography in the diagnosis of peri-implant bone defects: An in vitro study on native human mandibles.

AIM: The aim of this study on native human cadavers was to compare clinical, sonographic, and radiological measurements of fenestrations, dehiscences, and 3-wall bone defects on implants. MATERIALS AND METHODS: The examination was carried out on five human mandibles. After the insertion of 27 implants, dehiscences (n = 14), fenestrations (n = 7) and 3-wall bone defects (n = 6) were prepared in a standardized manner. The direct measurement of the bone defects was carried out with a periodontal probe and the radiological examination was carried out using digital volume tomography (DVT). The ultrasound examination (US) was performed using a clinical 24-MHz US imaging probe. Means and standard deviations of the direct, US, and DVT measurements were calculated. Measurements were statistically compared using the Pearson correlation coefficient and Bland-Altman analysis. RESULTS: Bone defects were on average 3.22 ± 1.58 mm per direct measurement, 2.90 ± 1.47 mm using US, and 2.99 ± 1.52 mm per DVT assessment. Pairwise correlations of these measurements were R = .94 (p < .0001) between direct and US, R = .95 (p < .0001) between DVT and US, and R = .96 (p < .0001) between direct and DVT. The mean differences of the measurements (and 95% CI) between direct and US was 0.41 (-0.47 to 1.29), US and DVT 0.33 (-0.30 to 0.97), and direct and DVT 0.28 (-0.50 to 1.07). CONCLUSION: All peri-implant bone defects could be identified and sonographically measured. US measurements showed a strong correlation with direct and DVT measurements. The sonographic measurement accuracy was highest for dehiscences, followed by fenestrations and 3-wall bone defects.

The Potential of Plant-Produced Virus-like Particle Vaccines for African Horse Sickness and Other Equine Orbiviruses.

African horse sickness is a devastating viral disease of equids. It is transmitted by biting midges of the genus Culicoides with mortalities reaching over 90% in naïve horses. It is endemic to sub-Saharan Africa and is seasonally endemic in many parts of southern Africa. However, outbreaks in Europe and Asia have occurred that caused significant economic issues. There are attenuated vaccines available for control of the virus but concerns regarding the safety and efficacy means that alternatives are sought. One promising alternative is the use of virus-like particles in vaccine preparations, which have the potential to be safer and more efficacious as vaccines against African horse sickness. These particles are best made in a complex, eukaryotic system, but due to technical challenges, this may cause significant economic strain on the developing countries most affected by the disease. Therefore, this review also summarises the success so far, and potential, of recombinant protein expression in plants to reduce the economic strain of production.

Targeting the autophagy-NAD axis protects against cell death in Niemann-Pick type C1 disease models.

Impairment of autophagy leads to an accumulation of misfolded proteins and damaged organelles and has been implicated in plethora of human diseases. Loss of autophagy in actively respiring cells has also been shown to trigger metabolic collapse mediated by the depletion of nicotinamide adenine dinucleotide (NAD) pools, resulting in cell death. Here we found that the deficit in the autophagy-NAD axis underpins the loss of viability in cell models of a neurodegenerative lysosomal storage disorder, Niemann-Pick type C1 (NPC1) disease. Defective autophagic flux in NPC1 cells resulted in mitochondrial dysfunction due to impairment of mitophagy, leading to the depletion of both the reduced and oxidised forms of NAD as identified via metabolic profiling. Consequently, exhaustion of the NAD pools triggered mitochondrial depolarisation and apoptotic cell death. Our chemical screening identified two FDA-approved drugs, celecoxib and memantine, as autophagy activators which effectively restored autophagic flux, NAD levels, and cell viability of NPC1 cells. Of biomedical relevance, either pharmacological rescue of the autophagy deficiency or NAD precursor supplementation restored NAD levels and improved the viability of NPC1 patient fibroblasts and induced pluripotent stem cell (iPSC)-derived cortical neurons. Together, our findings identify the autophagy-NAD axis as a mechanism of cell death and a target for therapeutic interventions in NPC1 disease, with a potential relevance to other neurodegenerative disorders.

New drug treatments for schizophrenia: a review of approaches to target circuit dysfunction.

Schizophrenia is a leading cause of global disease burden. Current drug treatments are associated with significant side-effects and have limited efficacy for many patients; highlighting the need to develop new approaches that target other aspects of the neurobiology of schizophrenia. Preclinical, in vivo imaging, post-mortem, genetic and pharmacological studies have highlighted the key role of cortical GABA-glutamatergic microcircuits and their projections to subcortical dopaminergic circuits in the pathoetiology of negative, cognitive and psychotic symptoms. Antipsychotics primarily act downstream of the dopaminergic component of this circuit. However, multiple drugs are currently in development that could target other elements of this circuit to treat schizophrenia. These include drugs for GABA or glutamatergic targets, including glycine transporters, d-amino acid oxidase, sodium channels or potassium channels. Other drugs in development are likely to primarily act on pathways that regulate the dopaminergic system such as muscarinic or trace amine receptors or serotonin 2A receptors, whilst phosphodiesterase 10 A inhibitors are being developed to modulate the downstream consequences of dopaminergic dysfunction. Our review considers where new drugs may act on this circuit and their latest clinical trial evidence in terms of indication, efficacy and side-effects. Limitations of the circuit model, including whether there are neurobiologically distinct subgroups of patients, and future directions are also considered. Several drugs based on the mechanisms reviewed have promising clinical data, with the muscarinic agonist KarXT most advanced. If they are approved for clinical use, they have the potential to revolutionise understanding of the pathophysiology and treatment of schizophrenia.

Model compounds for evaluating the reactivity of amphetamine-type stimulants.

The use of controlled precursors for reaction optimisation is not always practical. One approach to limiting the use of controlled substances is to instead use 'model compounds'. Herein, two model compounds resembling norephedrine and ephedrine were selected based on their (i) structural similarity (i.e., presence of key functional groups) and (ii) availability from multiple suppliers without restriction. Model compounds 2-amino-1-phenylethanol and 2-(methylamino)-1-phenylethanol (halostachine), were compared to norephedrine and pseudoephedrine by firstly subjecting them to transformations known in the synthesis of amphetamines, and secondly, comparing the compounds using colourimetric spot tests, FTIR and NMR.

Color Flow Ultrasound Spatial Sampling Beam Density for Partial Volume-Corrected Three-Dimensional Volume Flow (3DVF): Theory, Simulation, and Experiment.

OBJECTIVE: The purpose of this study was to quantify the accuracy of partial volume-corrected three-dimensional volume flow (3DVF) measurements as a function of spatial sampling beam density using carefully-designed parametric analyses in order to inform the target applications of 3DVF. METHODS: Experimental investigations employed a mechanically-swept curvilinear ultrasound array to acquire 3D color flow (6.3 MHz) images in flow phantoms consisting of four lumen diameters (6.35, 4.88, 3.18 and 1.65 mm) with volume flow rates of 440, 260, 110 and 30 mL/min, respectively. Partial volume-corrected three-dimensional volume flow (3DVF) measurements, based on the Gaussian surface integration principle, were computed at five regions of interest positioned between depths of 2 and 6 cm in 1 cm increments. At each depth, the color flow beam point spread function (PSF) was also determined, using in-phase/quadrature data, such that 3DVF bias could then be related to spatial sampling beam density. Corresponding simulations were performed for a laminar parabolic flow profile that was sampled using the experimentally-measured PSFs. Volume flow was computed for all combinations of lumen diameters and the PSFs at each depth. RESULTS: Accurate 3DVF measurements, i.e., bias less than ±20%, were achieved for spatial sampling beam densities where at least 6 elevational color flow beams could be positioned across the lumen. In these cases, greater than 8 lateral color flow beams were present. PSF measurements showed an average lateral-to-elevational beam width asymmetry of 1:2. Volume flow measurement bias increased as the color flow beam spatial sampling density within the lumen decreased. CONCLUSION: Applications of 3DVF, particularly those in the clinical domain, should focus on areas where a spatial sampling density of 6 × 6 (lateral x elevational) beams can be realized in order to minimize measurement bias. Matrix-based ultrasound arrays that possess symmetric PSFs may be advantageous to achieve adequate beam densities in smaller vessels.

Ultrasound-based jawbone surface quality evaluation after alveolar ridge preservation.

BACKGROUND: Bone readiness for implant placement is typically evaluated by bone quality/density on 2-dimensional radiographs and cone beam computed tomography at an arbitrary time between 3 and 6 months after tooth extraction and alveolar ridge preservation (ARP). The aim of this study is to investigate if high-frequency ultrasound (US) can classify bone readiness in humans, using micro-CT as a reference standard to obtain bone mineral density (BMD) and bone volume fraction (BVTV) of healed sockets receiving ARP in humans. METHODS: A total of 27 bone cores were harvested during the implant surgery from 24 patients who received prior extraction with ARP. US images were taken immediately before the implant surgery at a site co-registered with the tissue biopsy collection location, made possible with a specially designed guide, and then classified into 3 tiers using B-mode image criteria (1) favorable, (2) questionable, and (3) unfavorable. Bone mineral density (hydroxyapatite) and BVTV were obtained from micro-CT as the gold standard. RESULTS: Hydroxyapatite and BVTV were evaluated within the projected US slice plane and thresholded to favorable (>2200 mg/cm3; >0.45 mm3/mm3), questionable (1500-2200 mg/cm3; 0.4-0.45 mm3/mm3), and unfavorable (<1500 mg/cm3; <0.4 mm3/mm3). The present US B-mode classification inversely scales with BMD. Regression analysis showed a significant relation between US classification and BMD as well as BVTV. T-test analysis demonstrated a significant correlation between US reader scores and the gold standard. When comparing Tier 1 with the combination of Tier 2 and 3, US achieved a significant group differentiation relative to mean BMD (p = 0.004, true positive 66.7%, false positive 0%, true negative 100%, false negative 33.3%, specificity 100%, sensitivity 66.7%, receiver operating characteristics area under the curve 0.86). Similar results were found between US-derived tiers and BVTV. CONCLUSION: Preliminary data suggest US could classify jawbone surface quality that correlates with BMD/BVTV and serve as the basis for future development of US-based socket healing evaluation after ARP.

Quantitative Ultrasound for Periodontal Soft Tissue Characterization.

Periodontal diseases affect 45.9\% of adults aged 30 or older in the United States. Current diagnostic methods for clinical assessment of these diseases are visual examination and bleeding on probing that are subjective, qualitative, and/or invasive. Thus, there is a critical need for research on noninvasive modalities for periodontal tissue characterization. Quantitative Ultrasound (QUS) has shown promising results in noninvasive characterization of various soft tissues; however, it has not been used in periodontics. This study is among initial investigations into the application of QUS for periodontal tissue characterization in the literature. Here, QUS analysis of oral soft tissues (alveolar mucosa and gingiva) is performed in an in vivo animal study including 10 swine. US scanning was performed at the first molar of all four oral quadrants, resulting in a total of 40 scans. We investigated first order speckle statistics of oral tissues by using the two-parameter Burr (power-law b and scale factor l) and Nakagami models (shape factor m and scale factor $\alpha$). Parametric imaging of these parameters was created using a sliding kernel method sweeping regions of interest with a kernel size of 10 wavelengths from a phantom study. Results showed that the difference between gingiva and alveolar mucosa were statistically significant using Burr and Nakagami parameters ($p-value<0.0001$). The Burr b and Nakagami m were higher in gingiva while the Burr l and Nakagami {$\alpha$} were higher in alveolar mucosa. Findings from QUS analyses agreed with observation from histology that showed denser stains for gingiva. Linear classifications of these tissues using 2D parameter spaces of the Burr and Nakagami models resulted in a segmentation accuracy of 93.51\% and 90.91\%, respectively. We propose that QUS holds promising potentials as an augmented tool for disease diagnosis in periodontology.

Transcatheter heart valve explant with infective endocarditis-associated prosthesis failure and outcomes: the EXPLANT-TAVR international registry.

BACKGROUND AND AIMS: Surgical explantation of transcatheter heart valves (THVs) is rapidly increasing, but there are limited data on patients with THV-associated infective endocarditis (IE). This study aims to assess the outcomes of patients undergoing THV explant for IE. METHODS: All patients who underwent THV explant between 2011 and 2022 from 44 sites in the EXPLANT-TAVR registry were identified. Patients with IE as the reason for THV explant were compared to those with other mechanisms of bioprosthetic valve dysfunction (BVD). RESULTS: A total of 372 patients from the EXPLANT-TAVR registry were included. Among them, 184 (49.5%) patients underwent THV explant due to IE and 188 (50.5%) patients due to BVD. At the index transcatheter aortic valve replacement, patients undergoing THV explant for IE were older (74.3 ± 8.6 vs. 71 ± 10.6 years) and had a lower Society of Thoracic Surgeons risk score [2.6% (1.8-5.0) vs. 3.3% (2.1-5.6), P = .029] compared to patients with BVD. Compared to BVD, IE patients had longer intensive care unit and hospital stays (P < .05) and higher stroke rates at 30 days (8.6% vs. 2.9%, P = .032) and 1 year (16.2% vs. 5.2%, P = .010). Adjusted in-hospital, 30-day, and 1-year mortality was 12.1%, 16.1%, and 33.8%, respectively, for the entire cohort, with no significant differences between groups. Although mortality was numerically higher in IE patients 3 years postsurgery (29.6% for BVD vs. 43.9% for IE), Kaplan-Meier analysis showed no significant differences between groups (P = .16). CONCLUSIONS: In the EXPLANT-TAVR registry, patients undergoing THV explant for IE had higher 30-day and 1-year stroke rates and longer intensive care unit and hospital stays. Moreover, patients undergoing THV explant for IE had a higher 3-year mortality rate, which did not reach statistical significance given the relatively small sample size of this unique cohort and the reduced number of events.

Overcoming the barriers to identifying and managing treatment-resistant schizophrenia and to improving access to clozapine: A narrative review and recommendation for clinical practice.

Clozapine is the only approved antipsychotic for treatment-resistant schizophrenia (TRS). Although a large body of evidence supports its efficacy and favorable risk-benefit ratio in individuals who have failed two or more antipsychotics, clozapine remains underused. However, variations in clozapine utilization across geographic and clinical settings suggest that it could be possible to improve its use. In this narrative review and expert opinion, we summarized information available in the literature on the mechanisms of action, effectiveness, and potential adverse events of clozapine. We identified barriers leading to discouragement in clozapine prescription internationally, and we proposed practical solutions to overcome each barrier. One of the main obstacles identified to the use of clozapine is the lack of appropriate training for physicians: we highlighted the need to develop specific professional programs to train clinicians, both practicing and in residency, on the relevance and efficacy of clozapine in TRS treatment, initiation, maintenance, and management of potential adverse events. This approach would facilitate physicians to identify eligible patients and offer clozapine as a treatment option in the early stage of the disease. We also noted that increasing awareness of the benefits of clozapine among healthcare professionals, people with TRS, and their caregivers can help promote the use of clozapine. Educational material, such as leaflets or videos, could be developed and distributed to achieve this goal. The information provided in this article may be useful to improve disease burden and support healthcare professionals, patients, and caregivers navigating the complex pathways to TRS management.

Mitochondrial complex I density is associated with IQ and cognition in cognitively healthy adults: an in vivo [18F]BCPP-EF PET study.

BACKGROUND: Mitochondrial function plays a key role in regulating neurotransmission and may contribute to general intelligence. Mitochondrial complex I (MC-I) is the largest enzyme of the respiratory chain. Recently, it has become possible to measure MC-I distribution in vivo, using a novel positron emission tomography tracer [18F]BCPP-EF, thus, we set out to investigate the association between MC-I distribution and measures of cognitive function in the living healthy brain. RESULTS: Analyses were performed in a voxel-wise manner and identified significant associations between [18F]BCPP-EF DVRCS-1 in the precentral gyrus and parietal lobes and WAIS-IV predicted IQ, WAIS-IV arithmetic and WAIS-IV symbol-digit substitution scores (voxel-wise Pearson's correlation coefficients transformed to Z-scores, thresholded at Z = 2.3 family-wise cluster correction at p < 0.05, n = 16). Arithmetic scores were associated with middle frontal and post-central gyri tracer uptake, symbol-digit substitution scores were associated with precentral gyrus tracer uptake. RAVLT recognition scores were associated with [18F]BCPP-EF DVRCS-1 in the middle frontal gyrus, post-central gyrus, occipital and parietal regions (n = 20). CONCLUSIONS: Taken together, our findings support the theory that mitochondrial function may contribute to general intelligence and indicate that interindividual differences in MC-I should be a key consideration for research into mitochondrial dysfunction in conditions with cognitive impairment.