RESUMEN
PURPOSE: The EXTEND trial tested the hypothesis that adding comprehensive metastasis-directed therapy (MDT) to chemotherapy would improve progression-free survival (PFS) over chemotherapy alone among patients with oligometastatic pancreatic ductal adenocarcinoma (PDAC). METHODS: EXTEND (ClinicalTrials.gov identifier: NCT03599765) is a multicenter, phase II basket trial randomly assigning patients with ≤five metastases 1:1 to MDT plus systemic therapy versus systemic therapy. Disease progression was defined by radiologic criteria (RECIST v1.1), clinical progression, or death. The primary end point was PFS in the per-protocol population, evaluated after all patients achieved at least 6 months of follow-up. Exploratory end points included systemic immune response measures. RESULTS: Between March 19, 2019, and February 13, 2023, 41 patients were randomly assigned and 40 were eligible for the primary analysis of PFS (19 patients in the MDT arm; 21 patients in the control arm). At a median follow-up time of 17 months, the median PFS time was 10.3 months (95% CI, 4.6 to 14.0) in the MDT arm versus 2.5 months (95% CI, 1.7 to 5.1) in the control arm. PFS was significantly improved by the addition of MDT to systemic therapy (P = .030 for stratified log-rank test) with a hazard ratio of 0.43 (95% CI, 0.20 to 0.94). No grade ≥3 or greater adverse events related to MDT were observed. Systemic immune activation events were associated with MDT and correlated with improved PFS. CONCLUSION: This study supports the addition of MDT to systemic therapy for patients with oligometastatic PDAC. Induction of systemic immunity is a possible mechanism of benefit. These results warrant confirmatory trials to refine treatment strategy and provide external validation.
RESUMEN
The progression of Parkinson's disease (PD) is associated with microstructural alterations in neural pathways, contributing to both motor and cognitive decline. However, conflicting findings have emerged due to the use of heterogeneous methods in small studies. Here we performed a large diffusion MRI study in PD, integrating data from 17 cohorts worldwide, to identify stage-specific profiles of white matter differences. Diffusion-weighted MRI data from 1654 participants diagnosed with PD (age: 20-89 years; 33% female) and 885 controls (age: 19-84 years; 47% female) were analyzed using the ENIGMA-DTI protocol to evaluate white matter microstructure. Skeletonized maps of fractional anisotropy (FA) and mean diffusivity (MD) were compared across Hoehn and Yahr (HY) disease groups and controls to reveal the profile of white matter alterations at different stages. We found an enhanced, more widespread pattern of microstructural alterations with each stage of PD, with eventually lower FA and higher MD in almost all regions of interest: Cohen's d effect sizes reached d = -1.01 for FA differences in the fornix at PD HY Stage 4/5. The early PD signature in HY stage 1 included higher FA and lower MD across the entire white matter skeleton, in a direction opposite to that typical of other neurodegenerative diseases. FA and MD were associated with motor and non-motor clinical dysfunction. While overridden by degenerative changes in the later stages of PD, early PD is associated with paradoxically higher FA and lower MD in PD, consistent with early compensatory changes associated with the disorder.
RESUMEN
Ultra-high contrast (UHC) MRI describes forms of MRI in which little or no contrast is seen on conventional MRI images but very high contrast is seen with UHC techniques. One of these techniques uses the divided subtracted inversion recovery (dSIR) sequence, which, in modelling studies, can produce ten times the contrast of conventional inversion recovery (IR) sequences. When used in cases of mild traumatic brain injury (mTBI), the dSIR sequence frequently shows extensive abnormalities in white matter that appears normal when imaged with conventional T2-fluid-attenuated IR (T2-FLAIR) sequences. The changes are bilateral and symmetrical in white matter of the cerebral and cerebellar hemispheres. They partially spare the anterior and posterior central corpus callosum and peripheral white matter of the cerebral hemispheres and are described as the whiteout sign. In addition to mTBI, the whiteout sign has also been seen in methamphetamine use disorder and Grinker's myelinopathy (delayed post-hypoxic leukoencephalopathy) in the absence of abnormalities on T2-FLAIR images, and is a central component of post-insult leukoencephalopathy syndromes. This paper describes the concept of ultra-high contrast MRI, the whiteout sign, the theory underlying the use of dSIR sequences and post-insult leukoencephalopathy syndromes.
Asunto(s)
Leucoencefalopatías , Imagen por Resonancia Magnética , Humanos , Imagen por Resonancia Magnética/métodos , Leucoencefalopatías/diagnóstico por imagen , Lesiones Encefálicas/diagnóstico por imagen , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patologíaRESUMEN
The current study estimated effects of intervention dose (attendance) of a cognitive behavioral prevention (CBP) program on depression-free days (DFD) in adolescent offspring of parents with a history of depression. As part of secondary analyses of a multi-site randomized controlled trial, we analyzed the complete intention-to-treat sample of 316 at-risk adolescents ages 13-17. Youth were randomly assigned to the CBP program plus usual care (n=159) or to usual care alone (n=157). The CBP program involved 8 weekly acute sessions and 6 monthly continuation sessions. Results showed that higher CBP program dose predicted more DFDs, with a key threshold of approximately 75% of a full dose in analyses employing instrumental variable methodology to control multiple channels of bias. Specifically, attending at more than 75% of acute phase sessions led to 45.3 more DFDs over the 9-month period post randomization, which accounted for over 12% of the total follow-up days. Instrument sets were informed by study variables and external data including weather and travel burden. In contrast, conventional analysis methods failed to find a significant dose-outcome relation. Application of the instrumental variable approach, which better controls the influence of confounding, demonstrated that higher CBP program dose resulted in more DFDs.
RESUMEN
In this study, we compared the fat-saturated (FS) and non-FS turbo spin echo (TSE) magnetic resonance imaging knee sequences reconstructed conventionally (conventional-TSE) against a deep learning-based reconstruction of accelerated TSE (DL-TSE) scans. A total of 232 conventional-TSE and DL-TSE image pairs were acquired for comparison. For each consenting patient, one of the clinically acquired conventional-TSE proton density-weighted sequences in the sagittal or coronal planes (FS and non-FS), or in the axial plane (non-FS), was repeated using a research DL-TSE sequence. The DL-TSE reconstruction resulted in an image resolution that increased by at least 45% and scan times that were up to 52% faster compared to the conventional TSE. All images were acquired on a MAGNETOM Vida 3T scanner (Siemens Healthineers AG, Erlangen, Germany). The reporting radiologists, blinded to the acquisition time, were requested to qualitatively compare the DL-TSE against the conventional-TSE reconstructions. Despite having a faster acquisition time, the DL-TSE was rated to depict smaller structures better for 139/232 (60%) cases, equivalent for 72/232 (31%) cases and worse for 21/232 (9%) cases compared to the conventional-TSE. Overall, the radiologists preferred the DL-TSE reconstruction in 124/232 (53%) cases and stated no preference, implying equivalence, for 65/232 (28%) cases. DL-TSE reconstructions enabled faster acquisition times while enhancing spatial resolution and preserving the image contrast. From these results, the DL-TSE provided added or comparable clinical value and utility in less time. DL-TSE offers the opportunity to further reduce the overall examination time and improve patient comfort with no loss in diagnostic accuracy.
RESUMEN
INTRODUCTION: Recent work suggests that amyloid beta (Aß) positron emission tomography (PET) tracer uptake shortly after injection ("early phase") reflects brain metabolism and perfusion. We assessed this modality in a predominantly amyloid-negative neurodegenerative condition, Parkinson's disease (PD), and hypothesized that early-phase 18F-florbetaben (eFBB) uptake would reproduce characteristic hypometabolism and hypoperfusion patterns associated with cognitive decline in PD. METHODS: One hundred fifteen PD patients across the spectrum of cognitive impairment underwent dual-phase Aß PET, structural and arterial spin labeling (ASL) magnetic resonance imaging (MRI), and neuropsychological assessments. Multiple linear regression models compared eFBB uptake to cognitive performance and ASL MRI perfusion. RESULTS: Reduced eFBB uptake was associated with cognitive performance in brain regions previously linked to hypometabolism-associated cognitive decline in PD, independent of amyloid status. Furthermore, eFBB uptake correlated with cerebral perfusion across widespread regions. DISCUSSION: EFBB uptake is a potential surrogate measure for cerebral perfusion/metabolism. A dual-phase PET imaging approach may serve as a clinical tool for assessing cognitive impairment. Highlights: Images taken at amyloid beta (Aß) positron emission tomography tracer injection may reflect brain perfusion and metabolism.Parkinson's disease (PD) is a predominantly amyloid-negative condition.Early-phase florbetaben (eFBB) in PD was associated with cognitive performance.eFBB uptake reflects hypometabolism-related cognitive decline in PD.eFBB correlated with arterial spin labeling magnetic resonance imaging measured cerebral perfusion.eFBB distinguished dementia from normal cognition and mild cognitive impairment.Findings were independent of late-phase Aß burden.Thus, eFBB may serve as a surrogate measure for brain metabolism/perfusion.
RESUMEN
BACKGROUND AND OBJECTIVES: A robust understanding of the natural history of apathy in Parkinson disease (PD) is foundational for developing effective clinical management tools. However, large longitudinal studies are lacking while the literature is inconsistent about even cross-sectional associations. We aimed to determine the longitudinal predictors of apathy development in a large cohort of people with PD and its cross-sectional associations and trajectories over time, using sophisticated Bayesian modeling techniques. METHODS: People with PD followed up in the longitudinal New Zealand Parkinson's progression project were included. Apathy was defined using the neuropsychiatric inventory subscale ≥4, and analyses were also repeated using a less stringent cutoff of ≥1. Both MoCA and comprehensive neuropsychological testing were used as appropriate to the model. Depression was assessed using the hospital anxiety and depression scale. Cross-sectional Bayesian regressions were conducted, and a multistate predictive model was used to identify factors that predict the initial onset of apathy in nonapathetic PD, while also accounting for the competing risk of death. The relationship between apathy presence and mortality was also investigated. RESULTS: Three hundred forty-six people with PD followed up for up to 14 years across a total of 1,392 sessions were included. Apathy occurrence did not vary significantly across the disease course (disease duration odds ratio [OR] = 0.55, [95% CI 0.28-1.12], affecting approximately 11% or 22% of people at any time depending on the NPI cutoff used. Its presence was associated with a significantly higher risk of death after controlling for all other factors (hazard ratio [HR] = 2.92 [1.50-5.66]). Lower cognition, higher depression levels, and greater motor severity predicted apathy development in those without motivational deficits (HR [cognition] = 0.66 [0.48-0.90], HR [depression] = 1.45 [1.04-2.02], HR [motor severity] = 1.37 [1.01-1.86]). Cognition and depression were also associated with apathy cross-sectionally, along with male sex and possibly lower dopaminergic therapy level, but apathy still occurred across the full spectrum of each variable (OR [cognition] = 0.58 [0.44-0.76], OR [depression] = 1.43 [1.04-1.97], OR [female sex] = 0.45 [0.22-0.92], and OR [levodopa equivalent dose] = 0.78 [0.59-1.04]. DISCUSSION: Apathy occurs across the PD time course and is associated with higher mortality. Depressive symptoms and cognitive impairment in particular predict its future development in those with normal motivation.
Asunto(s)
Apatía , Enfermedad de Parkinson , Humanos , Apatía/fisiología , Enfermedad de Parkinson/psicología , Enfermedad de Parkinson/complicaciones , Masculino , Femenino , Estudios Transversales , Anciano , Persona de Mediana Edad , Estudios Longitudinales , Teorema de Bayes , Depresión/epidemiología , Depresión/etiología , Depresión/psicología , Pruebas Neuropsicológicas , Progresión de la Enfermedad , Nueva Zelanda/epidemiología , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Estimation of prevalence and diagnostic test accuracy in tuberculosis (TB) prevalence surveys suffer from reference standard and verification biases. The former is attributed to the imperfect reference test used to bacteriologically confirm TB disease. The latter occurs when only the participants screening positive for any TB-compatible symptom or chest X-ray abnormality are selected for bacteriological testing (verification). Bayesian latent class analysis (LCA) alleviates the reference standard bias but suffers verification bias in TB prevalence surveys. This work aims to identify best-practice approaches to simultaneously alleviate the reference standard and verification biases in the estimates of pulmonary TB prevalence and diagnostic test performance in TB prevalence surveys. METHODS: We performed a secondary analysis of 9869 participants aged ≥15 years from a community-based multimorbidity screening study in a rural district of KwaZulu-Natal, South Africa (Vukuzazi study). Participants were eligible for bacteriological testing using Xpert Ultra and culture if they reported any cardinal TB symptom or had an abnormal chest X-ray finding. We conducted Bayesian LCA in five ways to handle the unverified individuals: (i) complete-case analysis, (ii) analysis assuming the unverified individuals would be negative if bacteriologically tested, (iii) analysis of multiply-imputed datasets with imputation of the missing bacteriological test results for the unverified individuals using multivariate imputation via chained equations (MICE), and simultaneous imputation of the missing bacteriological test results in the analysis model assuming the missing bacteriological test results were (iv) missing at random (MAR), and (v) missing not at random (MNAR). We compared the results of (i)-(iii) to the analysis based on a composite reference standard (CRS) of Xpert Ultra and culture. Through simulation with an overall true prevalence of 2.0%, we evaluated the ability of the models to alleviate both biases simultaneously. RESULTS: Based on simulation, Bayesian LCA with simultaneous imputation of the missing bacteriological test results under the assumption that the missing data are MAR and MNAR alleviate the reference standard and verification biases. CRS-based analysis and Bayesian LCA assuming the unverified are negative for TB alleviate the biases only when the true overall prevalence is <3.0%. Complete-case analysis produced biased estimates. In the Vukuzazi study, Bayesian LCA with simultaneous imputation of the missing bacteriological test results under the MAR and MNAR assumptions produced overall PTB prevalence of 0.9% (95% Credible Interval (CrI): 0.6-1.9) and 0.7% (95% CrI: 0.5-1.1) respectively alongside realistic estimates of overall diagnostic test sensitivity and specificity with substantially overlapping 95% CrI. The CRS-based analysis and Bayesian LCA assuming the unverified were negative for TB produced 0.7% (95% CrI: 0.5-0.9) and 0.7% (95% CrI: 0.5-1.2) overall PTB prevalence respectively with realistic estimates of overall diagnostic test sensitivity and specificity. Unlike CRS-based analysis, Bayesian LCA of multiply-imputed data using MICE mitigates both biases. CONCLUSION: The findings demonstrate the efficacy of these advanced techniques in alleviating the reference standard and verification biases, enhancing the robustness of community-based screening programs. Imputing missing values as negative for bacteriological tests is plausible under realistic assumptions.
Asunto(s)
Teorema de Bayes , Análisis de Clases Latentes , Tamizaje Masivo , Estándares de Referencia , Humanos , Adulto , Femenino , Sudáfrica/epidemiología , Masculino , Tamizaje Masivo/normas , Tamizaje Masivo/métodos , Prevalencia , Persona de Mediana Edad , Sesgo , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/epidemiología , Adolescente , Adulto Joven , AncianoRESUMEN
Optimal oxygen management during pediatric cardiopulmonary bypass (CPB) is unknown. We previously demonstrated an increase in cortical mitochondrial reactive oxygen species and decreased mitochondrial function after CPB using hyperoxic oxygen management. This study investigates whether controlled oxygenation (normoxia) during CPB reduces cortical mitochondrial dysfunction and oxidative injury. Ten neonatal swine underwent three hours of continuous CPB at 34 °C (flow > 100 mL/kg/min) via cervical cannulation targeting a partial pressure of arterial oxygen (PaO2) goal < 150 mmHg (normoxia, n = 5) or >300 mmHg (hyperoxia, n = 5). The animals underwent continuous hemodynamic monitoring and serial arterial blood sampling. Cortical microdialysate was serially sampled to quantify the glycerol concentration (represents neuronal injury) and lactate-to-pyruvate ratio (represents bioenergetic dysfunction). The cortical tissue was analyzed via high-resolution respirometry to quantify mitochondrial oxygen consumption and reactive oxygen species generation, and cortical oxidized protein carbonyl concentrations were quantified to assess for oxidative damage. Serum PaO2 was higher in hyperoxia animals throughout CPB (p < 0.001). There were no differences in cortical glycerol concentration between groups (p > 0.2). The cortical lactate-to-pyruvate ratio was modestly elevated in hyperoxia animals (p < 0.03) but the values were not clinically significant (<30). There were no differences in cortical mitochondrial respiration (p = 0.48), protein carbonyls (p = 0.74), or reactive oxygen species generation (p = 0.93) between groups. Controlled oxygenation during CPB does not significantly affect cortical mitochondrial function or oxidative injury in the acute setting. Further evaluation of the short and long-term effects of oxygen level titration during pediatric CPB on cortical tissue and other at-risk brain regions are needed, especially in the presence of cyanosis.
Asunto(s)
Animales Recién Nacidos , Puente Cardiopulmonar , Mitocondrias , Oxígeno , Especies Reactivas de Oxígeno , Animales , Porcinos , Puente Cardiopulmonar/efectos adversos , Puente Cardiopulmonar/métodos , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Oxígeno/metabolismo , Consumo de Oxígeno , Ácido Láctico/metabolismo , Ácido Láctico/sangre , Estrés Oxidativo , Corteza Cerebral/metabolismo , Ácido Pirúvico/metabolismo , Hiperoxia/metabolismoRESUMEN
Brain-wide association studies (BWASs) have attempted to relate cognitive abilities with brain phenotypes, but have been challenged by issues such as predictability, test-retest reliability, and cross-cohort generalisability. To tackle these challenges, we proposed "stacking" that combines brain magnetic resonance imaging of different modalities, from task-fMRI contrasts and functional connectivity during tasks and rest to structural measures, into one prediction model. We benchmarked the benefits of stacking, using the Human Connectome Projects: Young Adults and Aging and the Dunedin Multidisciplinary Health and Development Study. For predictability, stacked models led to out-of-sample r â¼.5-.6 when predicting cognitive abilities at the time of scanning and 36 years earlier. For test-retest reliability, stacked models reached an excellent level of reliability (ICC>.75), even when we stacked only task-fMRI contrasts together. For generalisability, a stacked model with non-task MRI built from one dataset significantly predicted cognitive abilities in other datasets. Altogether, stacking is a viable approach to undertake the three challenges of BWAS for cognitive abilities.
RESUMEN
The high prevalence of dental caries and periodontal disease place a significant burden on society, both socially and economically. Recent advances in genomic technologies have linked both diseases to shifts in the oral microbiota - a community of >700 bacterial species that live within the mouth. The development of oral microbiome transplantation draws on the success of fecal microbiome transplantation for the treatment of gut pathologies associated with disease. Many current in vitro oral biofilm models have been developed but do not fully capture the complexity of the oral microbiome which is required for successful OMT. To address this, we developed an in vitro biofilm system that maintained an oral microbiome with 252 species on average over 14 days. Six human plaque samples were grown in 3D printed flow cells on hydroxyapatite discs using artificial saliva medium (ASM). Biofilm composition and growth were monitored by high throughput sequencing and confocal microscopy/SEM, respectively. While a significant drop in bacterial diversity occurred, up to 291 species were maintained in some flow cells over 14 days with 70% viability grown with ASM. This novel in vitro biofilm model represents a marked improvement on existing oral biofilm systems and provides new opportunities to develop oral microbiome transplant therapies.
Asunto(s)
Bacterias , Biopelículas , Microbiota , Boca , Biopelículas/crecimiento & desarrollo , Humanos , Boca/microbiología , Bacterias/genética , Bacterias/clasificación , Bacterias/aislamiento & purificación , Encía/microbiología , Placa Dental/microbiología , Saliva/microbiología , Microscopía Confocal , Secuenciación de Nucleótidos de Alto Rendimiento , Trasplante de Microbiota Fecal/métodos , Caries Dental/microbiología , Caries Dental/terapiaRESUMEN
Stuttering affects approximately 1 in 100 adults and can result in significant communication problems and social anxiety. It most often occurs as a developmental disorder but can also be caused by focal brain damage. These latter cases may lend unique insight into the brain regions causing stuttering. Here, we investigated the neuroanatomical substrate of stuttering using three independent datasets: (i) case reports from the published literature of acquired neurogenic stuttering following stroke (n = 20, 14 males/six females, 16-77 years); (ii) a clinical single study cohort with acquired neurogenic stuttering following stroke (n = 20, 13 males/seven females, 45-87 years); and (iii) adults with persistent developmental stuttering (n = 20, 14 males/six females, 18-43 years). We used the first two datasets and lesion network mapping to test whether lesions causing acquired stuttering map to a common brain network. We then used the third dataset to test whether this lesion-based network was relevant to developmental stuttering. In our literature dataset, we found that lesions causing stuttering occurred in multiple heterogeneous brain regions, but these lesion locations were all functionally connected to a common network centred around the left putamen, including the claustrum, amygdalostriatal transition area and other adjacent areas. This finding was shown to be specific for stuttering (PFWE < 0.05) and reproducible in our independent clinical cohort of patients with stroke-induced stuttering (PFWE < 0.05), resulting in a common acquired stuttering network across both stroke datasets. Within the common acquired stuttering network, we found a significant association between grey matter volume and stuttering impact for adults with persistent developmental stuttering in the left posteroventral putamen, extending into the adjacent claustrum and amygdalostriatal transition area (PFWE < 0.05). We conclude that lesions causing acquired neurogenic stuttering map to a common brain network, centred to the left putamen, claustrum and amygdalostriatal transition area. The association of this lesion-based network with symptom severity in developmental stuttering suggests a shared neuroanatomy across aetiologies.
Asunto(s)
Encéfalo , Accidente Cerebrovascular , Tartamudeo , Humanos , Tartamudeo/patología , Tartamudeo/etiología , Masculino , Femenino , Persona de Mediana Edad , Adulto , Adolescente , Anciano , Anciano de 80 o más Años , Adulto Joven , Encéfalo/patología , Encéfalo/diagnóstico por imagen , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/patología , Imagen por Resonancia Magnética , Mapeo Encefálico/métodosRESUMEN
PURPOSE: It is well established that, together with a multitude of other adverse effects on health, severe obstructive sleep apnoea causes reduced cerebral perfusion and, in turn, reduced cerebral function. Less clear is the impact of moderate obstructive sleep apnoea (OSA). Our aim was to determine if cerebral blood flow is impaired in people diagnosed with moderate OSA. METHODS: Twenty-four patients diagnosed with moderate OSA (15 ≤ apnoea-hypopnea index (AHI) < 30) were recruited (aged 32-72, median 59 years, 10 female). Seven controls (aged 42-73 years, median 62 years, 4 female) with an AHI < 5 were also recruited. The OSA status of all participants was confirmed at baseline by unattended polysomnography and they had an MRI arterial-spin-labelling scan of cerebral perfusion. RESULTS: Neither global perfusion nor voxel-wise perfusion differed significantly between the moderate-OSA and control groups. We also compared the average perfusion across three regional clusters, which had been found in a previous study to have significant perfusion differences with moderate-severe OSA versus control, and found no significant difference in perfusion between the two groups. The perfusions were also very close, with means of 50.2 and 51.8 mL/100 g/min for the moderate-OSAs and controls, respectively, with a negligible effect size (Cohen's d = 0.10). CONCLUSION: We conclude that cerebral perfusion is not impaired in people with moderate OSA and that cerebral flow regulatory mechanisms can cope with the adverse effects which occur in moderate OSA. This is an important factor in clinical decisions for prescription of continuous positive airway pressure therapy (CPAP).
Asunto(s)
Circulación Cerebrovascular , Polisomnografía , Apnea Obstructiva del Sueño , Vigilia , Humanos , Apnea Obstructiva del Sueño/fisiopatología , Apnea Obstructiva del Sueño/terapia , Femenino , Persona de Mediana Edad , Masculino , Adulto , Anciano , Circulación Cerebrovascular/fisiología , Vigilia/fisiología , Imagen por Resonancia Magnética , Valores de Referencia , Encéfalo/fisiopatología , Encéfalo/irrigación sanguínea , Encéfalo/diagnóstico por imagenRESUMEN
Background: Rising rates of adolescent depression in the wake of COVID-19 and a youth mental health crisis highlight the urgent need for accessible mental healthcare and prevention within primary care. Digital mental health interventions (DMHIs) may increase access for underserved populations. However, these interventions are not well studied in adolescents, nor healthcare settings. The purpose of this study was to identify barriers and facilitators to screening and recruitment activities for PATH 2 Purpose (P2P): Primary Care and Community-Based Prevention of Mental Disorders in Adolescents, a multi-site adolescent depression prevention trial comparing two digital prevention programs within four diverse health systems in two U.S. states. Method: This qualitative study is a component of a larger Hybrid Type I trial. We conducted semi-structured key informant interviews with clinical and non-clinical implementers involved with screening and recruitment for the P2P trial. Informed by the Consolidated Framework for Implementation Research (CFIR), interviews were conducted at the midpoint of the trial to identify barriers, facilitators, and needed adaptations, and to gather information on determinants that may affect future implementation. Findings: Respondents perceived the P2P trial as valuable, well aligned with the mission of their health systems. However, several barriers were identified, many of which stemmed from influences outside of the healthcare settings. Universal and site-specific outer setting influences (COVID-19 pandemic, youth mental health crisis, local community conditions) interacted with Inner Setting and Innovation domains to create numerous challenges to the implementation of screening and recruitment. Conclusion: Our findings emphasize the need for ongoing, comprehensive assessment of dynamic inner and outer setting contexts prior to and during implementation of clinical trials, as well as flexibility for adaptation to unique clinical contexts. The CFIR is useful for assessing determinants during times of rapid inner and outer setting change, such as those brought on by the COVID-19 pandemic, youth mental health crisis, and the corresponding exacerbation of resource strain within healthcare settings. Clinical trial registration: PATH 2 Purpose: Primary Care and Community-Based Prevention of Mental Disorders in Adolescents https://www.clinicaltrials.gov/study/NCT04290754.
Adolescent mental health problems such as depression, anxiety, and suicidal behavior are prevalent, and have been increasing in the wake of the COVID-19 pandemic. In 2021, the Surgeon General declared a "youth mental health crisis," and the American Academy of Pediatrics issued a joint statement declaring a national youth mental health emergency. Accessible, affordable, evidence-based interventions are needed to prevent the development of depressive symptoms into major depressive disorder. The integration of digital mental health interventions (DMHIs) into primary care may reduce access barriers. Primary care clinical settings are well suited to identify individuals at-risk for developing depression, and facilitate preventive treatment planning. While preventive DMHIs for adolescents exist, more evidence is needed on their effectiveness, and how to best integrate them into healthcare. Our study team interviewed primary care-based staff, administrators, and clinical providers involved with implementing screening and recruitment activities for the P2P trial, a randomized controlled trial comparing the effectiveness of two digital depression prevention programs. Respondents shared experiences with trial recruitment in their settings, including perceived challenges. Our findings suggest that multiple factors influenced recruitment, including influences situated outside of the clinical settings, such as the COVID-19 pandemic and worsening adolescent mental health. These influences interacted with factors affecting recruitment inside of health clinics, such as demands on staff and provider time, and perceived importance of prevention programming versus other initiatives. Identifying these influencing factors during the trial helps to inform considerations for planning future integration of similar programs into primary care settings.
RESUMEN
Objectives: We previously demonstrated cerebral mitochondrial dysfunction in neonatal swine immediately following a period of full-flow cardiopulmonary bypass (CPB). The extent to which this dysfunction persists in the postoperative period and its correlation with other markers of cerebral bioenergetic failure and injury is unknown. We utilized a neonatal swine model to investigate the early evolution of mitochondrial function and cerebral bioenergetic failure after CPB. Methods: Twenty piglets (mean weight 4.4 ± 0.5 kg) underwent 3â h of CPB at 34 °C via cervical cannulation and were followed for 8, 12, 18, or 24â h (n = 5 per group). Markers of brain tissue damage (glycerol) and bioenergetic dysfunction (lactate to pyruvate ratio) were continuously measured in cerebral microdialysate samples. Control animals (n = 3, mean weight 4.1 ± 1.2 kg) did not undergo cannulation or CPB. Brain tissue was extracted immediately after euthanasia to obtain ex-vivo cortical mitochondrial respiration and frequency of cortical microglial nodules (indicative of cerebral microinfarctions) via neuropathology. Results: Both the lactate to pyruvate ratio (P < .0001) and glycerol levels (P = .01) increased in cerebral microdialysate within 8â h after CPB. At 24â h post-CPB, cortical mitochondrial respiration was significantly decreased compared with controls (P = .046). The presence of microglial nodules increased throughout the study period (24â h) (P = .01, R2 = 0.9). Conclusion: CPB results in impaired cerebral bioenergetics that persist for at least 24â h. During this period of bioenergetic impairment, there may be increased susceptibility to secondary injury related to alterations in metabolic delivery or demand, such as hypoglycemia, seizures, and decreased cerebral blood flow.
Asunto(s)
Animales Recién Nacidos , Puente Cardiopulmonar , Metabolismo Energético , Mitocondrias , Animales , Puente Cardiopulmonar/efectos adversos , Porcinos , Metabolismo Energético/fisiología , Mitocondrias/metabolismo , Modelos Animales de Enfermedad , Encéfalo/metabolismo , Ácido Láctico/metabolismo , Ácido Láctico/sangre , Ácido Láctico/análisis , Ácido Pirúvico/metabolismo , Glicerol/metabolismoRESUMEN
Effective and sustainable strategies are needed to address the burden of preventable deaths among children under-five in resource-constrained settings. The Tools for Integrated Management of Childhood Illness (TIMCI) project aims to support healthcare providers to identify and manage severe illness, whilst promoting resource stewardship, by introducing pulse oximetry and clinical decision support algorithms (CDSAs) to primary care facilities in India, Kenya, Senegal and Tanzania. Health impact is assessed through: a pragmatic parallel group, superiority cluster randomised controlled trial (RCT), with primary care facilities randomly allocated (1:1) in India to pulse oximetry or control, and (1:1:1) in Tanzania to pulse oximetry plus CDSA, pulse oximetry, or control; and through a quasi-experimental pre-post study in Kenya and Senegal. Devices are implemented with guidance and training, mentorship, and community engagement. Sociodemographic and clinical data are collected from caregivers and records of enrolled sick children aged 0-59 months at study facilities, with phone follow-up on Day 7 (and Day 28 in the RCT). The primary outcomes assessed for the RCT are severe complications (mortality and secondary hospitalisations) by Day 7 and primary hospitalisations (within 24 hours and with referral); and, for the pre-post study, referrals and antibiotic. Secondary outcomes on other aspects of health status, hypoxaemia, referral, follow-up and antimicrobial prescription are also evaluated. In all countries, embedded mixed-method studies further evaluate the effects of the intervention on care and care processes, implementation, cost and cost-effectiveness. Pilot and baseline studies started mid-2021, RCT and post-intervention mid-2022, with anticipated completion mid-2023 and first results late-2023. Study approval has been granted by all relevant institutional review boards, national and WHO ethical review committees. Findings will be shared with communities, healthcare providers, Ministries of Health and other local, national and international stakeholders to facilitate evidence-based decision-making on scale-up.Study registration: NCT04910750 and NCT05065320.
Pulse oximetry and clinical decision support algorithms show potential for supporting healthcare providers to identify and manage severe illness among children under-five attending primary care in resource-constrained settings, whilst promoting resource stewardship but scale-up has been hampered by evidence gaps.This study design article describes the largest scale evaluation of these interventions to date, the results of which will inform country- and global-level policy and planning .
Asunto(s)
Algoritmos , Sistemas de Apoyo a Decisiones Clínicas , Oximetría , Humanos , Lactante , Preescolar , Recién Nacido , Kenia , Atención Primaria de Salud/organización & administración , Senegal , India , TanzaníaRESUMEN
The Ross procedure is an excellent option for aortic valve replacement resulting in outstanding hemodynamic performance and the ability to avoid systemic anticoagulation. The long-term durability of the autograft is generally good but concerns for later aortic root dilation with ensuing neoaortic insufficiency have prompted efforts to stabilize the autograft, root, sinuses and Sino-tubular junction in order to delay or entirely avoid late reinterventions on the neoaortic root. We have employed an inclusion technique, supporting the Auto-graft in a Terumo Gelweave™ Valsalva graft. We performed a retrospective study of all 129 patients undergoing the Ross procedure from 1992 to 2019 at Children's Wisconsin. Fifty-one underwent the supported Ross (SR) and 78 underwent unsupported Ross (UR). Structured clinical data was collected and echocardiograms were reviewed. Median follow-up was 4.9 years (up to 22.6 years) for UR patients and 3.6 years (up to 11.4 years) for SR patients. In order to provide a fair comparison, we sub -analyzed patients aged 10 to 18 years who underwent the Ross procedure, 16 who underwent the UR and 18 patients who underwent the SR. Change in aortic annulus diameter (P = 0.002), aortic sinus diameter (P = 0.001) change in left ventricular function (P = 0.039) and change in aortic insufficiency (P = 0.008) were all worse in UR. The SR is simple, reproducible, and predictable. It seems to prevent change in annulus diameter, sinus diameter and to reduce late neoaortic insufficiency. Longer follow-up with a larger group of patients is required to draw definitive conclusions.
Asunto(s)
Insuficiencia de la Válvula Aórtica , Estenosis de la Válvula Aórtica , Válvula Pulmonar , Niño , Humanos , Autoinjertos , Estudios Retrospectivos , Dilatación , Trasplante Autólogo , Válvula Aórtica/cirugía , Insuficiencia de la Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/cirugía , Dilatación Patológica , Válvula Pulmonar/cirugía , Estudios de SeguimientoRESUMEN
Depression is more common in youth with type 1 diabetes (T1D) compared to youth without diabetes. This study aims to assess the efficacy of Competent Adulthood Transition with Cognitive Humanistic and Interpersonal Teaching (CATCH-IT), an internet-based cognitive behavioral therapy (CBT) intervention, in adolescents with T1D and depressive symptoms. Adolescents (13 to 17 years old) with T1D and mild (score 5-9) or moderate (score 10-14) depressive symptoms on Patient Health Questionnaire-Adolescent (PHQ-A) screening assessment were recruited to participate and received online access to the CATCH-IT modules for 6 months (requested to complete in 12 weeks). Statistical analyses included paired t-test for changes in Center for Epidemiologic Studies Depression Scale (CES-D), PHQ-A, Problem Areas in Diabetes-Teen version (PAID-T), and hemoglobin A1c (HbA1c). Nineteen patients were consented, 15 met inclusion criteria and received the intervention. In the seven participants that completed the modules, there was a trend towards improvements in PHQ-A, CES-D and HbA1c. Participants provided robust qualitative feedback on the modules and areas for improvement in subsequent iterations, such as inclusion of diabetes-related content. Given the prevalence of depression in diabetes, feasible, low resource interventions are needed. Internet programs such as CATCH-IT can serve as an effective first line intervention in this high-risk population. A modified version of CATCH-IT tailored for adolescents with T1D may be beneficial in this patient population.
RESUMEN
Background: Delayed Post-Hypoxic Leukoencephalopathy (DPHL), or Grinker's myelinopathy, is a syndrome in which extensive changes are seen in the white matter of the cerebral hemispheres with MRI weeks or months after a hypoxic episode. T2-weighted spin echo (T2-wSE) and/or T2-Fluid Attenuated Inversion Recovery (T2-FLAIR) images classically show diffuse hyperintensities in white matter which are thought to be near pathognomonic of the condition. The clinical features include Parkinsonism and akinetic mutism. DPHL is generally regarded as a rare condition. Methods and Results: Two cases of DPHL imaged with MRI nine months and two years after probable hypoxic episodes are described. No abnormalities were seen on the T2-FLAIR images with MRI, but very extensive changes were seen in the white matter of the cerebral and cerebellar hemisphere on divided Subtraction Inversion Recovery (dSIR) images. dSIR sequences may produce ten times the contrast of conventional inversion recovery (IR) sequences from small changes in T1. The clinical findings in both cases were of cognitive impairment without Parkinsonism or akinetic mutism. Conclusion: The classic features of DPHL may only represent the severe end of a spectrum of diseases in white matter following global hypoxic injury to the brain. The condition may be much more common than is generally thought but may not be recognized using conventional clinical and MRI criteria for diagnosis. Reappraisal of the syndrome of DPHL to include clinically less severe cases and to encompass recent advances in MRI is advocated.