Case-control Comparison Research Articles

Coronary microvascular dysfunction as assessed by cardiac MRI and its association with aerobic exercise capacity in dilated cardiomyopathy

Abstract Background Dilated cardiomyopathy (DCM) has a poor prognosis. Aerobic exercise capacity (peak VO2) is an independent predictor of mortality but the central mechanisms contributing to exercise intolerance in DCM are unknown. Purpose To characterise myocardial perfusion reserve (MPR) and determine if cardiovascular magnetic resonance (CMR) measures of structure, function and microvascular function are associated with aerobic exercise capacity in DCM. Methods Single centre, prospective, case-control comparison of adults with DCM and matched controls. Adenosine-stress perfusion CMR to assess cardiac structure, function and quantitative perfusion, and cardiopulmonary exercise testing (CPET) to determine peak VO2, was performed. Controls were propensity matched based on age, sex, body mass index and diabetes status, and between group comparison was adjusted for other key clinical characteristics (CMR: ethnicity and systolic blood pressure; CPET: ethnicity, systolic blood pressure, smoking history and lung disease). Comparison of perfusion in segments with and without late gadolinium enhancement was performed using mixed effects linear regression taking into account individual patient segmental perfusion. Pre-specified multivariable linear regression, including key clinical and cardiac variables, was undertaken in patients with DCM to identify independent associations with percentage predicted peak VO2, which incorporates age, sex, height and weight. Results Sixty-six patients with DCM (median age 61 years, 71% male) were matched to 66 controls (median age 59 years, 71% male). The DCM group had greater left ventricular (LV) end-diastolic and end-systolic volumes, lower systolic and diastolic function, and had more focal and diffuse fibrosis compared to controls (Table 1). There was lower rest (0.58±0.14 versus 0.65±0.17 mL/min/g; P=0.033) and stress (1.53±0.49 versus 2.01±0.60 mL/g/min; P<0.001) myocardial blood flow, and lower MPR (2.69±0.84 versus 3.15±0.84 mL/g/min; P=0.002) in the DCM group. In DCM patients, mixed effects linear regression demonstrated lower rest (adjusted mean 0.54(95% CI 0.50-0.57) versus 0.58(0.55-0.62) mL/g/min; P<0.001) and stress MBF (1.38(1.25-1.51) versus 1.55(1.43-1.67) mL/g/min; P<0.001) in segments with LGE compared to segments without LGE, but there was no difference in MPR (2.71(2.47-2.96) versus 2.76(2.55-2.97) mL/g/min; P=0.496). DCM patients had markedly lower peak VO2 (19.8±5.5 versus 25.2±7.3 mL/kg/min; P<0.001). Multivariable linear regression demonstrated that LV ejection fraction, extracellular volume fraction and MPR, but not LV mass, were independently associated with percentage predicted peak VO2 in DCM (R squared=0.531, P<0.001; Table 2). Conclusions DCM patients have lower rest and stress myocardial blood flow and lower MPR compared to controls. In DCM, MPR, LV ejection fraction and fibrosis are independently associated with aerobic exercise capacity.

Association Between Coronary Microvascular Dysfunction and Exercise Capacity in Dilated Cardiomyopathy.

Aerobic exercise capacity is an independent predictor of mortality in dilated cardiomyopathy (DCM), but the central mechanisms contributing to exercise intolerance in DCM are unknown. Characterize coronary microvascular function in DCM and determine if cardiovascular magnetic resonance (CMR) measures are associated with aerobic exercise capacity. Prospective case-control comparison of adults with DCM and matched controls. Adenosine-stress perfusion CMR to assess cardiac structure, function and automated inline myocardial blood flow quantification, and cardiopulmonary exercise testing (CPET) to determine peak VO2, were performed. Pre-specified multivariable linear regression, including key clinical and cardiac variables, was undertaken to identify independent associations with peak VO2. Sixty-six patients with DCM (mean age 61 years, 71% male) were propensity-matched to 66 controls (mean age 59 years, 71% male) based on age, sex, body mass index and diabetes. DCM patients had markedly lower peak VO2 (19.8±5.5 versus 25.2±7.3mL/kg/min; P<0.001). The DCM group had greater left ventricular (LV) volumes, lower systolic function, and had more fibrosis compared to controls. In the DCM group, there was similar rest but lower stress myocardial blood flow (1.53±0.49 versus 2.01±0.60mL/g/min; P<0.001) and lower MPR (2.69±0.84 versus 3.15±0.84; P=0.002). Multivariable linear regression demonstrated that LV ejection fraction, extracellular volume fraction and MPR, were independently associated with percentage predicted peak VO2 in DCM (R2=0.531, P<0.001). In comparison to controls, DCM patients have lower stress myocardial blood flow and MPR. In DCM, MPR, LV ejection fraction and fibrosis are independently associated with aerobic exercise capacity.

Clinical symptoms and psychosocial functioning in patients with schizophrenia spectrum disorders testing seropositive for anti-NMDAR antibodies: a case–control comparison with patients testing negative

Antibodies against the N-methyl-D-aspartate receptor (NMDAR) have been described in the serum of people with schizophrenia spectrum disorders (schizophrenia). However, the prevalence and clinical relevance of these antibodies in schizophrenia is unclear. This knowledge gap includes the possibility of such antibodies being associated with a distinct clinical profile, which in turn might warrant a distinct treatment approach. We aimed to assess the seroprevalence of anti-NMDAR antibodies in schizophrenia, and compare symptoms and psychosocial functioning between patients with schizophrenia who were seropositive and seronegative for these antibodies. In this case-control comparison, by combining new and existing studies, we included patients diagnosed with schizophrenia from four independent cohorts for whom anti-NMDAR serostatus had been assessed (or could be assessed by us) with live cell-based assays. Included cohorts were from the EULAST study (a trial conducted across 15 European countries and Israel), the OPTiMiSE study (an interventional study in Europe), and the PPiP1 and PPiP2 studies (conducted in the UK). Patients from these cohorts were analysed if they had complete Positive and Negative Syndrome Scale (PANSS) data. No participant had been diagnosed with autoimmune encephalitis or received treatment for this condition. After calculating the prevalence of serum anti-NMDAR antibodies, we examined possible differences in PANSS scores (negative, positive, and general symptom subscales, and total score) between anti-NMDAR-seropositive and anti-NMDAR-seronegative patients. Psychosocial functioning as measured by Personal Social Performance (PSP) score was also compared. All analyses were exploratory and no adjustment was done for multiple testing. People with lived experience were not involved in the conduct of this study. We collected individual patient data from 1114 patients with schizophrenia across the four cohorts. The study population had a mean age of 28·6 years (SD 7·6) and comprised 382 (34·3%) women and 732 (65·7%) men, including patients of White (929 [83·4%]), Asian (54 [4·8%]), Black (68 [6·1%]), and other (62 [5·6%]) ethnicities. Overall, 41 (3·7%) participants (range 3·1-4·0% across cohorts) tested positive for serum anti-NMDAR antibodies. Lower symptom severity on the negative symptoms PANSS subscale was observed for anti-NMDAR-seropositive patients (mean score 15·8 [SD 6·4]) than for anti-NMDAR-seronegative patients (18·2 [6·8]; Cohen's d=0·36; p=0·026), as well as on the general symptoms PANSS subscale (32·9 [8·9] vs 36·1 [10·1]; d=0·33; p=0·029) and total PANSS score (65·5 [18·5] vs 72·6 [19·3]; d=0·37; p=0·013). Mean PSP score was better in anti-NMDAR-positive patients (62·0 [17·0]) than in anti-NMDAR-negative patients (53·5 [16·3]; d=0·52; p=0·014). Serum NMDAR antibodies are present in 3-4% of patients with schizophrenia and are associated with relatively low severity of negative symptoms and relatively good psychosocial functioning. Thus, although the findings await replication in cohorts from other geographical regions, serum anti-NMDAR antibodies might be associated with a different form of psychotic illness. These findings could inform future prognostic and interventional studies examining whether anti-NMDAR antibodies are associated with a specific course of illness or with treatment response. None.

Immunometabolic Signature and Tauopathy Markers in Blood Cells of Progressive Supranuclear Palsy.

Peripheral immune cells critically contribute to the clinical-pathological progression of neurodegenerative diseases and also represent a reliable frame for translational applications. However, data on progressive supranuclear palsy (PSP) are almost scarce in this regard. Our goal is to provide a broad biological characterization of peripheral immune cells in a selected PSP cohort. Seventy-one PSP patients scored on the PSP Rating Scale (PSPRS), and 59 controls were enrolled. The blood cell count was collected, together with the neutrophil-to-lymphocyte ratio (NLR) calculation. In a subgroup of patients and controls, the peripheral blood mononuclear cells (PBMCs) were analyzed by the mitochondrial bioenergetic performance and the western blot assay of the nuclear factor erythroid 2-related factor (NRF2)/heme oxygenase 1 (HO-1) pathway and the total tau (t-tau) and phosphorylated tau (p-tau) proteins. Case-control comparison and correlation analyses were performed. PSP patients had a NLR higher than controls, with increased circulating neutrophils. The leukocyte metabolism was also globally increased and the NRF2/HO-1 pathway activated in patients. P-tau, but not t-tau, significantly accumulated in PSP PBMCs and inversely correlated with the PSPRS. PSP displays a systemic inflammatory shift of the peripheral immunity, which may justify a metabolic reprogramming of the blood leukocytes. Consistently, the NRF2/HO-1 pathway, a master regulator of inflammatory and metabolic response, was activated. PBMCs also engulf tau proteins, especially p-tau, in a way inverse to the disease severity, allowing for a peripheral tracking of tauopathy in patients. Immunometabolic targets may, therefore, gain relevance to PSP in biomarker or therapeutic purposes. © 2024 International Parkinson and Movement Disorder Society.

Neural response to monetary incentives in acquired adolescent depression after mild traumatic brain injury: Stage 2 Registered Report.

Depression is a common consequence of traumatic brain injury. Separately, spontaneous depression-arising without brain injury-has been linked to abnormal responses in motivational neural circuitry to the anticipation or receipt of rewards. It is unknown if post-injury and spontaneously occurring depression share similar phenotypic profiles. This issue is compounded by the fact that nearly all examinations of these psychiatric sequelae are post hoc: there are rarely any prospective assessments of mood and neural functioning before and after a brain injury. In this Stage 2 Registered Report, we used the Adolescent Brain Cognitive Development Consortium dataset to examine if a disruption in functional neural responses to rewards is present in patients with depression after a mild traumatic brain injury. Notably, this study provides an unparalleled opportunity to examine the trajectory of neuropsychiatric symptoms longitudinally within-subjects. This allowed us to isolate mild traumatic brain injury-specific variance independent from pre-existing functioning. Here, we focus on a case-control comparison between 43 youth who experienced a mild traumatic brain injury between MRI visits, and 43 well-matched controls. Contrary to pre-registered predictions (https://osf.io/h5uba/), there was no statistically credible increase in depression in mild traumatic brain injury cases relative to controls. Mild traumatic brain injury was associated with subtle changes in motivational neural circuit recruitment during the anticipation of incentives on the Monetary Incentive Delay paradigm. Specifically, changes in neural recruitment appeared to reflect a failure to deactivate 'task-negative' brain regions (ventromedial prefrontal cortex), alongside blunted recruitment of 'task-positive' regions (anterior cingulate, anterior insula and caudate), during the anticipation of reward and loss in adolescents following mild brain injuries. Critically, these changes in brain activity were not correlated with depressive symptoms at either visit or depression change scores before and after the brain injury. Increased time since injury was associated with a recovery of cognitive functioning-driven primarily by processing speed differences-but depression did not scale with time since injury. These cognitive changes were also uncorrelated with neural changes after mild traumatic brain injury. This report provides evidence that acquired depression may not be observed as commonly after a mild traumatic brain injury in late childhood and early adolescence, relative to findings in adult cases. Several reasons for these differing findings are considered, including sampling enrichment in retrospective cohort studies, under-reporting of depressive symptoms in parent-report data, and neuroprotective factors in childhood and adolescence.

Hippocampal, thalamic, and amygdala subfield morphology in major depressive disorder: an ultra-high resolution MRI study at 7-Tesla.

Morphological changes in the hippocampal, thalamic, and amygdala subfields have been suggested to form part of the pathophysiology of major depressive disorder (MDD). However, the use of conventional MRI scanners and acquisition techniques has prevented in-depth examinations at the subfield level, precluding a fine-grained understanding of these subfields and their involvement in MDD pathophysiology. We uniquely employed ultra-high field MRI at 7.0 Tesla to map hippocampal, thalamic, and amygdala subfields in MDD. Fifty-six MDD patients and 14 healthy controls (HCs) were enrolled in the final analysis. FreeSurfer protocols were used to segment hippocampal, thalamic, and amygdala subfields. Bayesian analysis was then implemented to assess differences between groups and relations with clinical features. While no effect was found for MDD diagnosis (i.e., case-control comparison), clinical characteristics of MDD patients were associated with subfield volumes of the hippocampus, thalamus, and amygdala. Specifically, the severity of depressive symptoms, insomnia, and childhood trauma in MDD patients related to lower thalamic subfield volumes. In addition, MDD patients with typical MDD versus those with atypical MDD showed lower hippocampal, thalamic, and amygdala subfield volumes. MDD patients with recurrent MDD versus those with first-episode MDD also showed lower thalamic subfield volumes. These findings allow uniquely fine-grained insights into hippocampal, thalamic, and amygdala subfield morphology in MDD, linking some of them to the clinical manifestation of MDD.

Precision of trunk movement in people with chronic low back pain

BackgroundMotor control exercise is commonly applied in people with chronic low back pain (CLBP), but possibly not all people with CLBP have motor control impairments. We suggest movement precision as measure to identify motor control impairments. Movement precision has been operationalized as trunk movement variability (TMV) and as trunk tracking error(s) (TTE). Objectives: To compare the known-group validity and the responsiveness of TMV and TTE. DesignWe used a case-control comparison (Healthy controls (n = 30) vs CLBP (n = 60)) to assess the known-group validity. A cohort study, (measurements in week 3 and week 12 of treatment), was used to assess responsiveness. MethodsTMV (temporal (CyclSD) and spatial (MeanSD)) was analyzed during standing, repetitive flexion and rotation tasks (35x). TTE was measured during movement target tracking tasks, again in flexion and rotation. Participants with CLBP followed a multidisciplinary intervention and both measures were assessed in week 3 and week 12 of treatment. 2-way MANOVA and 2-way ANOVA were used to assess the effect of Group (CLBP vs healthy controls) and direction (flexion vs rotation) on TMV and TTE. For responsiveness, 2-way MANOVA and 2-way ANOVA were used to assess the effect of treatment and direction on both measures. FindingsAt baseline, TMV was not different between groups, while TTE was higher in the people with CLBP (p = 0.005, np2 = 0.09). Treatment strongly decreased temporal TMV (p = 0.025, np2 = 0.33) and TTE (p < 0.001, np2 = 0.844). ConclusionsThese results demonstrate that TTE is more sensitive to CLBP and more responsive to treatment than TMV.

Altered white matter connectivity of ventral language networks in autism spectrum disorder: An automated fiber quantification analysis with multi-site datasets

Comprehension and pragmatic deficits are prevalent in autism spectrum disorder (ASD) and are potentially linked to altered connectivity in the ventral language networks. However, previous magnetic resonance imaging studies have not sufficiently explored the microstructural abnormalities in the ventral fiber tracts underlying comprehension dysfunction in ASD. Additionally, the precise locations of white matter (WM) changes in the long tracts of patients with ASD remain poorly understood. In the current study, we applied the automated fiber-tract quantification (AFQ) method to investigate the fine-grained WM properties of the ventral language pathway and their relationships with comprehension and symptom manifestation in ASD. The analysis included diffusion/T1 weighted imaging data of 83 individuals with ASD and 83 age-matched typically developing (TD) controls. Case-control comparisons were performed on the diffusion metrics of the ventral tracts at both the global and point-wise levels. We also explored correlations between diffusion metrics, comprehension performance, and ASD traits, and conducted subgroup analyses based on age range to examine developmental moderating effects. Individuals with ASD exhibited remarkable hypoconnectivity in the ventral tracts, particularly in the temporal portions of the left inferior longitudinal fasciculus (ILF) and the inferior fronto-occipital fasciculus (IFOF). These WM abnormalities were associated with poor comprehension and more severe ASD symptoms. Furthermore, WM alterations in the ventral tract and their correlation with comprehension dysfunction were more prominent in younger children with ASD than in adolescents. These findings indicate that WM disruptions in the temporal portions of the left ILF/IFOF are most notable in ASD, potentially constituting the core neurological underpinnings of comprehension and communication deficits in autism. Moreover, impaired WM connectivity and comprehension ability in patients with ASD appear to improve with age.

Cerebellum and social abilities: A structural and functional connectivity study in a transdiagnostic sample.

The cerebellum has been involved in social abilities and autism. Given that the cerebellum is connected to the cortex via the cerebello-thalamo-cortical loop, the connectivity between the cerebellum and cortical regions involved in social interactions, that is, the right temporo-parietal junction (rTPJ) has been studied in individuals with autism, who suffer from prototypical deficits in social abilities. However, existing studies with small samples of categorical, case-control comparisons have yielded inconsistent results due to the inherent heterogeneity of autism, suggesting that investigating how clinical dimensions are related to cerebellar-rTPJ functional connectivity might be more relevant. Therefore, our objective was to study the functional connectivity between the cerebellum and rTPJ, focusing on its association with social abilities from a dimensional perspective in a transdiagnostic sample. We analyzed structural magnetic resonance imaging (MRI) and functional MRI (fMRI) scans obtained during naturalistic films watching from a large transdiagnostic dataset, the Healthy Brain Network (HBN), and examined the association between cerebellum-rTPJ functional connectivity and social abilities measured with the social responsiveness scale (SRS). We conducted univariate seed-to-voxel analysis, multivariate canonical correlation analysis (CCA), and predictive support vector regression (SVR). We included 1404 subjects in the structural analysis (age: 10.516 ± 3.034, range: 5.822-21.820, 506 females) and 414 subjects in the functional analysis (age: 11.260 ± 3.318 years, range: 6.020-21.820, 161 females). Our CCA model revealed a significant association between cerebellum-rTPJ functional connectivity, full-scale IQ (FSIQ) and SRS scores. However, this effect was primarily driven by FSIQ as suggested by SVR and univariate seed-to-voxel analysis. We also demonstrated the specificity of the rTPJ and the influence of structural anatomy in this association. Our results suggest that there is a complex relationship between cerebellum-rTPJ connectivity, social performance and IQ. This relationship is specific to the cerebellum-rTPJ connectivity, and is largely related to structural anatomy in these two regions. PRACTITIONER POINTS: We analyzed cerebellum-right temporoparietal junction (rTPJ) connectivity in a pediatric transdiagnostic sample. We found a complex relationship between cerebellum and rTPJ connectivity, social performance and IQ. Cerebellum and rTPJ functional connectivity is related to structural anatomy in these two regions.

Extracting interpretable signatures of whole-brain dynamics through systematic comparison.

The brain's complex distributed dynamics are typically quantified using a limited set of manually selected statistical properties, leaving the possibility that alternative dynamical properties may outperform those reported for a given application. Here, we address this limitation by systematically comparing diverse, interpretable features of both intra-regional activity and inter-regional functional coupling from resting-state functional magnetic resonance imaging (rs-fMRI) data, demonstrating our method using case-control comparisons of four neuropsychiatric disorders. Our findings generally support the use of linear time-series analysis techniques for rs-fMRI case-control analyses, while also identifying new ways to quantify informative dynamical fMRI structures. While simple statistical representations of fMRI dynamics performed surprisingly well (e.g., properties within a single brain region), combining intra-regional properties with inter-regional coupling generally improved performance, underscoring the distributed, multifaceted changes to fMRI dynamics in neuropsychiatric disorders. The comprehensive, data-driven method introduced here enables systematic identification and interpretation of quantitative dynamical signatures of multivariate time-series data, with applicability beyond neuroimaging to diverse scientific problems involving complex time-varying systems.

Matched case-control comparison of surgical success after XEN45 Gel Stent and PRESERFLO MicroShunt implantation in a Caucasian population.

The aim of this study was to compare the outcome of implantation of a XEN45 Gel Stent with the outcome of implantation of a Preserflo MicroShunt in a matched-pair analysis in eyes being naïve to filtering surgery. In this comparative, retrospective study, 50 eyes that had undergone XEN45 Gel Stent implantation were compared with 50 eyes after Preserflo implantation. Follow-up was at least 6 months, and surgical success was measured by criteria A (IOP < 21 mmHg, IOP reduction >20%, no repeat surgery); criteria B (IOP < 18 mmHg, IOP reduction >20%, no repeat surgery); and criteria C (IOP ≤15 mmHg, IOP reduction ≥40%, no repeat surgery). After a follow-up period of 12 months, mean IOP had decreased from preoperative 25.2 ± 4.8 mmHg in the XEN group to 14.5 ± 4.0 (n = 35) and from 25.3 ± 6.8 mmHg to 11.9 ± 2.9 (n = 41) in the Preserflo group, respectively. The IOP at the last follow-up of the two groups differed significantly (p < 0.01). The probability of surgical success did not differ concerning Criteria A and B, but surgical success was significantly higher in the Preserflo group for Criteria C (60%, p < 0.01). Both the Preserflo and XEN45 Gel Stent provide an effective and safe treatment option for advanced glaucoma and have a high potential to reduce intraocular pressure. Absolute IOP levels of <16 mmHg after 12 months were significantly more frequent in the Preserflo group.

The relationship between clinical symptoms of oral lichen planus and quality of life related to oral health

IntroductionOral Lichen Planus (OLP) is a chronic and relatively common mucocutaneous disease that often affects the oral mucosa. Although, OLP is generally not life-threatening, its consequences can significantly impact the quality of life in physical, psychological, and social aspects. Therefore, the aim of this research is to investigate the relationship between clinical symptoms of OLP and oral health-related quality of life in patients using the OHIP-14 (Oral Health Impact Profile-14) questionnaire.Materials and methodsThis descriptive-analytical study has a cross-sectional design, with case–control comparison. In this study, 56 individuals were examined as cases, and 68 individuals were included as controls. After recording demographic characteristics and clinical features by reviewing patients' records, the OHIP-14 questionnaire including clinical severity of lesions assessed using the Thongprasom scoring system, and pain assessed by the Visual Analog Scale (VAS) were completed. The ADD (Additive) and SC (Simple Count) methods were used for scoring, and data analysis was performed using the T-test, Mann–Whitney U test, Chi-Square, Spearman's Correlation Coefficient, and SPSS 24.ResultsNearly all patients (50 individuals, 89.3%) reported having pain, although the average pain intensity was mostly mild. This disease has affected the quality of life in 82% of the patients (46 individuals). The patient group, in comparison to the control group, significantly expressed a lower quality of life in terms of functional limitations and physical disability. There was a statistically significant positive correlation between clinical symptoms of OLP, gender, location (palate), and clinical presentation type (erosive, reticular, and bullous) of OLP lesions with OHIP-14 scores, although the number or bilaterality of lesions and patient age did not have any significant correlation with pain or OHIP scores.ConclusionIt appears that certain aspects of oral health-related quality of life decrease in patients with OLP, and that of the OLP patient group is significantly lower in terms of functional limitations and physical disability compared to the control group. Additionally, there was a significant correlation between clinical symptoms of OLP and pain as well as OHIP scores.

Effect of increasing doses of colchicine on the treatment of 333 COVID-19 inpatients.

Previous research done in Bulgaria demonstrated a fivefold reduction in mortality from COVID-19 with increased doses of colchicine from two hospitals in the country. We report here a further 333 cases of COVID-19 inpatients, treated with different doses of colchicine and its effect on mortality. A case-control comparison from two additional hospitals was conducted between increased doses of colchicine and added bromhexine to standard of care (SOC) versus current SOC. Risk and odds ratio, as well as subgroup analysis, was conducted with newly reported data, alongside aggregate data from all hospital centers to determine the extent of mortality reduction in COVID-19 inpatients. There was a clear reduction in the mortality of inpatients with increasing doses of colchicine-between twofold and sevenfold. Colchicine loading doses of 4 mg are more effective than those with 2 mg. Despite these doses being higher than the so-called "standard doses," colchicine inpatients experienced lower mortality than SOC patients (5.7% vs. 19.53%). This mortality benefit was evident in different age subgroups, with a 4-mg loading dose of colchicine proving slightly superior to a 2-mg loading dose. Colchicine led to an overall relative risk reduction of 70.7%, with SOC patients having 3.91 higher odds of death. The safety of the doses was not different than the reported in the summary of product characteristics. Inpatients in Bulgaria with added colchicine and bromhexine to SOC achieved better clinical and mortality outcomes than those on SOC alone. These results question the World Health Organization-recommended strategy to inhibit viral replication. We posit that our treatment strategy to inhibit the Severe acute respiratory syndrome coronavirus 2 entry into the cell with inhaled bromhexine and the hyperactivated NLRP3 inflammasome with higher doses of colchicine, prevents the development of cytokine storm. The timing of the initiation of treatment seems critical.

Impact of specialized training for emergency department nurses screening or undetected HIV infection: the "Urgències VIHgila" project experience.

To evaluate the impact of specialized training for nurses on selective screening for undetected HIV infection in the emergency department. The intervention group was comprised of 6 emergency departments that had been participating in a screening program (the "Urgències VIHgila" project) for at least 3 months. Nurses on all shifts attended training sessions that emphasized understanding the circumstances that should lead to suspicion of unidentified HIV infection and the need to order serology. Two studies were carried out: 1) a quasi-experimental pre-post study to compare the number of orders for HIV serology in each time period and measures of sensitivity, and 2) a case-control study to compare the changes made in the 6 hospitals where specialized training was provided (cases) vs 6 control hospitals in the HIV screening program where no training was given. A total of 280 HIV serologies were ordered for the 81015 patients (0.3%) attended during the period before training; 331 serologies were ordered for the 79620 patients in the period after training (0.4%). The relative increase in serologies was 20.3% (95% CI, 2.9% to 34.5%; P = .022). The relative increase in measures of sensitivity ranged between 19% and 39%, consistent with the main comparison. Serologies in the control group decreased between periods, from 0.9% to 0.8%, indicating a relative decrease of 15.7% (95% CI, -25.1% to -6.2%; P = .001). The absolute number of patients tested in the training group was 0.2% higher in the training hospitals (95% CI, 0.11% to 0.31%; P .001) than in the control hospitals. Training nurses to screen for undetected HIV infection in the emergency department increased the number of patients tested, according to the pre-post and case-control comparisons.

Signature of Altered Retinal Microstructures and Electrophysiology in Schizophrenia Spectrum Disorders Is Associated With Disease Severity and Polygenic Risk

BackgroundOptical coherence tomography and electroretinography studies have revealed structural and functional retinal alterations in individuals with schizophrenia spectrum disorders (SSDs). However, it remains unclear which specific retinal layers are affected; how the retina, brain, and clinical symptomatology are connected; and how alterations of the visual system are related to genetic disease risk. MethodsOptical coherence tomography, electroretinography, and brain magnetic resonance imaging were applied to comprehensively investigate the visual system in a cohort of 103 patients with SSDs and 130 healthy control individuals. The sparse partial least squares algorithm was used to identify multivariate associations between clinical disease phenotype and biological alterations of the visual system. The association of the revealed patterns with individual polygenic disease risk for schizophrenia was explored in a post hoc analysis. In addition, covariate-adjusted case-control comparisons were performed for each individual optical coherence tomography and electroretinography parameter. ResultsThe sparse partial least squares analysis yielded a phenotype-eye-brain signature of SSDs in which greater disease severity, longer duration of illness, and impaired cognition were associated with electrophysiological alterations and microstructural thinning of most retinal layers. Higher individual loading onto this disease-relevant signature of the visual system was significantly associated with elevated polygenic risk for schizophrenia. In case-control comparisons, patients with SSDs had lower macular thickness, thinner retinal nerve fiber and inner plexiform layers, less negative a-wave amplitude, and lower b-wave amplitude. ConclusionsThis study demonstrates multimodal microstructural and electrophysiological retinal alterations in individuals with SSDs that are associated with disease severity and individual polygenic burden.

Abstract 6119: Association of genetic African ancestry and triple-negative breast cancer risk: Findings from the African-ancestry breast cancer genetics consortium

Abstract Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that lacks target treatments. It has been reported that African-American women have a higher incidence of TNBC and are diagnosed at an earlier age than women of European ancestry. This disparity may be attributed to both genetic and non-genetic risk factors that are associated with the African ancestry. In this study, we investigated whether genotype-derived African ancestry might be related to an elevated risk of TNBC, with adjustments for several known genetic and non-genetic risk factors. Included in the study are self-reported Black breast cancer patients diagnosed with TNBC (n =2,292) or estrogen receptor (ER)-positive cancer (n =7,863) and 9,324 controls included in the African-ancestry Breast Cancer Genetics (AABCG) Consortium. We estimated the global ancestry by Admixture and the local ancestry by FLARE, using reference of the European- and African-ancestry samples from the 1000 Genome Project. Odds ratios (OR) and 95% confidence interval (CI) per ten percent increase of the global African ancestry proportion were estimated using logistic regressions comparing TNBC with controls (case-control analyses) or with ER-positive cases (case-case analyses), adjusted for age. Similar analyses were conducted for the local African ancestry proportion at each of the 12 genomic regions that were identified in AABCG in relation to TNBC risk. Results for each participating study were meta-analyzed using fixed or random effect models. We further adjusted for non-genetic risk factors including body mass index (BMI), number of live births, breastfeeding, and menopausal status. A polygenic risk score (PRS) was constructed using 13 independent risk variants at the 12 TNBC risk loci. The PRS was additionally adjusted to investigate whether these risk variants mediated the association of African ancestry with TNBC risk. No significant association was observed between TNBC risk and global African ancestry proportion (OR: 1.03, 95% CI: 0.98-1.08) in case-control comparisons. Compared with ER-positive cases, however, TNBC cases had a higher global African ancestry, resulted in an OR of 1.09 (95% CI: 1.04, 1.13, P =5.35×10-5). A similar association was observed with additional adjustment for non-genetic risk factors, with an OR of 1.08 (95% CI: 1.03, 1.12, P =0.003). Similar patterns were also found for local ancestry proportion at six of the 12 TNBC risk loci (P &amp;lt;0.05). Further adjustment for the PRS attenuated the association between global ancestry and a TNBC diagnosis in case-case comparisons (OR: 1.05, 95% CI: 1.01, 1.10, P =0.013). Our study suggests that women with a higher African ancestry are more likely to be diagnosed with a TNBC than ER-positive breast cancer and genetic factors identified to date partially explain this association. Citation Format: Guochong Jia, Lili Liu, Julie R. Palmer, Christopher A. Haiman, Wei Zheng. Association of genetic African ancestry and triple-negative breast cancer risk: Findings from the African-ancestry breast cancer genetics consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6119.

Cortical thickness and sub-cortical volumes in post-H1N1 narcolepsy type 1: A brain-wide MRI case-control study

ObjectiveThere was more than a 10-fold increase in the incidence of narcolepsy type 1 (NT1) after the H1N1 mass vaccination in 2009/2010 in several countries. NT1 is associated with loss and increase of cell groups in the hypothalamus which may be associated with secondary affected sub-cortical and cortical gray matter. We performed a case-control comparison of MRI-based global and sub-cortical volume and cortical thickness in post-H1N1 NT1 patients compared with controls. MethodsWe included 54 post-H1N1 NT1 patients (51 with confirmed hypocretin-deficiency; 48 H1N1-vaccinated with Pandemrix®; 39 females, mean age 21.8 ± 11.0 years) and 114 healthy controls (77 females, mean age 23.2 ± 9.0 years). 3T MRI brain scans were obtained, and the T1-weighted MRI data were processed using FreeSurfer. Group differences among three global, 10 sub-cortical volume measures and 34 cortical thickness measures for bilateral brain regions were tested using general linear models with permutation testing. ResultsPatients had significantly thinner brain cortex bilaterally in the temporal poles (Cohen's d = 0.68, p = 0.00080), entorhinal cortex (d = 0.60, p = 0.0018) and superior temporal gyrus (d = 0.60, p = 0.0020) compared to healthy controls. The analysis revealed no significant group differences for sub-cortical volumes. ConclusionsPost-H1N1(largely Pandemrix®-vaccinated) NT1 patients have significantly thinner cortex in temporal brain regions compared to controls. We speculate that this effect can be partly attributed to the hypothalamic neuronal change in NT1, including loss of function of the widely projecting hypocretin-producing neurons and secondary effects of the abnormal sleep-wake pattern in NT1 or could be specific for post-H1N1 (largely Pandemrix®-vaccinated) NT1 patients.

Functional magnetic resonance imaging in schizophrenia: current evidence, methodological advances, limitations and future directions.

Functional neuroimaging emerged with great promise and has provided fundamental insights into the neurobiology of schizophrenia. However, it has faced challenges and criticisms, most notably a lack of clinical translation. This paper provides a comprehensive review and critical summary of the literature on functional neuroimaging, in particular functional magnetic resonance imaging (fMRI), in schizophrenia. We begin by reviewing research on fMRI biomarkers in schizophrenia and the clinical high risk phase through a historical lens, moving from case-control regional brain activation to global connectivity and advanced analytical approaches, and more recent machine learning algorithms to identify predictive neuroimaging features. Findings from fMRI studies of negative symptoms as well as of neurocognitive and social cognitive deficits are then reviewed. Functional neural markers of these symptoms and deficits may represent promising treatment targets in schizophrenia. Next, we summarize fMRI research related to antipsychotic medication, psychotherapy and psychosocial interventions, and neurostimulation, including treatment response and resistance, therapeutic mechanisms, and treatment targeting. We also review the utility of fMRI and data-driven approaches to dissect the heterogeneity of schizophrenia, moving beyond case-control comparisons, as well as methodological considerations and advances, including consortia and precision fMRI. Lastly, limitations and future directions of research in the field are discussed. Our comprehensive review suggests that, in order for fMRI to be clinically useful in the care of patients with schizophrenia, research should address potentially actionable clinical decisions that are routine in schizophrenia treatment, such as which antipsychotic should be prescribed or whether a given patient is likely to have persistent functional impairment. The potential clinical utility of fMRI is influenced by and must be weighed against cost and accessibility factors. Future evaluations of the utility of fMRI in prognostic and treatment response studies may consider including a health economics analysis.

Maternal risk factors for fetal alcohol spectrum disorders: Distal variables.

A variety of maternal risk factors for fetal alcohol spectrum disorders (FASD) have been described in the literature. Here, we conducted a multivariate analysis of a large array of potential distal influences on FASD risk. Interviews were conducted with 2515 mothers of first-grade students whose children were evaluated to assess risk for FASD. Topics included: physical/medical status, childbearing history, demographics, mental health, domestic violence, and trauma. Regression modeling utilized usual level of alcohol consumption by trimester and six selected distal variables (maternal head circumference, body mass index, age at pregnancy, gravidity, marital status, and formal years of education) to differentiate children with FASD from control children. Despite individual variation in distal maternal risk factors among and within the mothers of children with each of the common diagnoses of FASD, patterns emerged that differentiated risk among mothers of children with FASD from mothers whose children were developing typically. Case-control comparisons indicate that mothers of children with FASD were significantly smaller physically, had higher gravidity and parity, and experienced more miscarriages and stillbirths, were less likely to be married, reported later pregnancy recognition, more depression, and lower formal educational achievement. They were also less engaged with a formal religion, were less happy, suffered more childhood trauma and interpersonal violence, were more likely to drink alone or with her partner, and drank to deal with anxiety, tension, and to be part of a group. Regression analysis showed that the predictor variables explain 57.5% of the variance in fetal alcohol syndrome (FAS) diagnoses, 30.1% of partial FAS (PFAS) diagnoses, and 46.4% of alcohol-related neurodevelopmental disorder (ARND) diagnoses in children with FASD compared to controls. While the proximal variables explained most of the diagnostic variance, six distal variables explained 16.7% (1 /6 ) of the variance in FAS diagnoses, 13.9% (1 /7 ) of PFAS, and 12.1% (1 /8 ) of ARND. Differences in distal FASD risks were identified. Complex models to quantify risk for FASD hold promise for guiding prevention/intervention.

Circulating sphingolipids and relationship to cardiac remodelling before and following a low-energy diet in asymptomatic Type 2 Diabetes

BackgroundHeart failure with preserved ejection fraction (HFpEF) is a heterogenous multi-system syndrome with limited efficacious treatment options. The prevalence of Type 2 diabetes (T2D) continues to rise and predisposes patients to HFpEF, and HFpEF remains one of the biggest challenges in cardiovascular medicine today. Novel therapeutic targets are required to meet this important clinical need. Deep phenotyping studies including -OMIC analyses can provide important pathogenic information to aid the identification of such targets. The aims of this study were to determine; 1) the impact of a low-energy diet on plasma sphingolipid/ceramide profiles in people with T2D compared to healthy controls and, 2) if the change in sphingolipid/ceramide profile is associated with reverse cardiovascular remodelling.MethodsPost-hoc analysis of a randomised controlled trial (NCT02590822) including adults with T2D with no cardiovascular disease who completed a 12-week low-energy (∼810 kcal/day) meal-replacement plan (MRP) and matched healthy controls (HC). Echocardiography, cardiac MRI and a fasting blood for lipidomics were undertaken pre/post-intervention. Candidate biomarkers were identified from case–control comparison (fold change > 1.5 and statistical significance p < 0.05) and their response to the MRP reported. Association between change in biomarkers and change indices of cardiac remodelling were explored.ResultsTwenty-four people with T2D (15 males, age 51.1 ± 5.7 years), and 25 HC (15 male, 48.3 ± 6.6 years) were included. Subjects with T2D had increased left ventricular (LV) mass:volume ratio (0.84 ± 0.13 vs. 0.70 ± 0.08, p < 0.001), increased systolic function but impaired diastolic function compared to HC. Twelve long-chain polyunsaturated sphingolipids, including four ceramides, were downregulated in subjects with T2D at baseline. Three sphingomyelin species and all ceramides were inversely associated with LV mass:volume. There was a significant increase in all species and shift towards HC following the MRP, however, none of these changes were associated with reverse cardiac remodelling.ConclusionThe lack of association between change in sphingolipids/ceramides and reverse cardiac remodelling following the MRP casts doubt on a causative role of sphingolipids/ceramides in the progression of heart failure in T2D.Trial registrationNCT02590822.