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Biofilms aid bacterial adhesion to surfaces via direct and indirect mechanisms, and formation of biofilms is considered as an important strategy for adaptation and survival in sub-optimal environmental conditions. However, the molecular underpinnings of biofilm formation in subsurface sediment/groundwater ecosystems where microorganisms often experience fluctuations in nutrient input, pH, nitrate or metal concentrations is underexplored. We examined biofilm formation under different nutrient, pH, metal, and nitrate regimes of 16 Rhodanobacter strains isolated from subsurface groundwater wells spanning diverse pH (3.5 to 5) and nitrate levels (13.7 to 146 mM). Eight Rhodanobacter strains demonstrated significant biofilm growth under low pH, suggesting adaptation to survive and grow at low pH. Biofilms intensified under aluminum stress, particularly in strains possessing fewer genetic traits associated with biofilm formation warranting further investigation. Through RB-TnSeq, proteomics, use of specific mutants and transmission electron microscopy analysis, we discovered flagellar loss under aluminum stress, indicating a potential relationship between motility, metal tolerance, and biofilm growth. Comparative genomic analyses revealed absence of flagella and chemotaxis genes, and presence of putative Type VI secretion system in the high biofilm-forming strain FW021-MT20. This study identifies genetic determinants associated with biofilm growth in a predominant environmental genus, Rhodanobacter, under metal stress and identifies traits aiding survival and adaptation to contaminated subsurface environments.
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OBJECTIVE: ICU delirium commonly complicates critical illness associated with factors such as cardiopulmonary bypass (CPB) time and the requirement of mechanical ventilation (MV). Recent reports associate hyperoxia with poorer outcomes in critically ill children. This study sought to determine whether hyperoxia on CPB in pediatric patients was associated with a higher prevalence of postoperative delirium. DESIGN: Secondary analysis of data obtained from a prospective cohort study. SETTING: Twenty-two-bed pediatric cardiac ICU in a tertiary children's hospital. PATIENTS: All patients (18 yr old or older) admitted post-CPB, with documented delirium assessment scores using the Preschool/Pediatric Confusion Assessment Method for the ICU and who were enrolled in the Precision Medicine in Pediatric Cardiology Cohort from February 2021 to November 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 148 patients, who underwent cardiac surgery, 35 had delirium within the first 72 hours (24%). There was no association between hyperoxia on CPB and postoperative delirium for all definitions of hyperoxia, including hyperoxic area under the curve above 5 predetermined Pao2 levels: 150 mm Hg (odds ratio [95% CI]: 1.176 [0.605-2.286], p = 0.633); 175 mm Hg (OR 1.177 [95% CI, 0.668-2.075], p = 0.572); 200 mm Hg (OR 1.235 [95% CI, 0.752-2.026], p = 0.405); 250 mm Hg (OR 1.204 [95% CI, 0.859-1.688], p = 0.281), 300 mm Hg (OR 1.178 [95% CI, 0.918-1.511], p = 0.199). In an additional exploratory analysis, comparing patients with delirium within 72 hours versus those without, only the z score for weight differed (mean [sd]: 0.09 [1.41] vs. -0.48 [1.82], p < 0.05). When comparing patients who developed delirium at any point during their ICU stay (n = 45, 30%), MV days, severity of illness (Pediatric Index of Mortality 3 Score) score, CPB time, and z score for weight were associated with delirium (p < 0.05). CONCLUSIONS: Postoperative delirium (72 hr from CPB) occurred in 24% of pediatric patients. Hyperoxia, defined in multiple ways, was not associated with delirium. On exploratory analysis, nutritional status (z score for weight) may be a significant factor in delirium risk. Further delineation of risk factors for postoperative delirium versus ICU delirium warrants additional study.
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Puente Cardiopulmonar , Delirio , Hiperoxia , Unidades de Cuidado Intensivo Pediátrico , Complicaciones Posoperatorias , Humanos , Hiperoxia/complicaciones , Masculino , Femenino , Puente Cardiopulmonar/efectos adversos , Estudios Prospectivos , Niño , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/epidemiología , Delirio/etiología , Delirio/epidemiología , Preescolar , Adolescente , Lactante , Estudios de Cohortes , Factores de Riesgo , Respiración Artificial/efectos adversosRESUMEN
Sediments in cryoconite holes and meltwater streams in the McMurdo Dry Valleys, Antarctica, provide both substrates and conditions that support life in an arid polar desert. Here, we report the genomic sequences of eight environmental, bacterial isolates from Canada Glacier cryoconite holes and stream. These isolates span three major phyla.
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Mobile genetic elements (MGEs) like plasmids, viruses, and transposable elements can provide fitness benefits to their hosts for survival in the presence of environmental stressors. Heavy metal resistance genes (HMRGs) are frequently observed on MGEs, suggesting that MGEs may be an important driver of adaptive evolution in environments contaminated with heavy metals. Here, we report the meta-mobilome of the heavy metal-contaminated regions of the Oak Ridge Reservation subsurface. This meta-mobilome was compared with one derived from samples collected from unimpacted regions of the Oak Ridge Reservation subsurface. We assembled 1615 unique circularized DNA elements that we propose to be MGEs. The circular elements from the highly contaminated subsurface were enriched in HMRG clusters relative to those from the nearby unimpacted regions. Additionally, we found that these HMRGs were associated with Gamma and Betaproteobacteria hosts in the contaminated subsurface and potentially facilitate the persistence and dominance of these taxa in this region. Finally, the HMRGs were associated with conjugative elements, suggesting their potential for future lateral transfer. We demonstrate how our understanding of MGE ecology, evolution, and function can be enhanced through the genomic context provided by completed MGE assemblies.
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Ice-covered and remote landscapes in the McMurdo Dry Valleys, Antarctica, are likely seeded by aeolian transport of biological material from ice-free local or distant environments. Here, we report the genome sequences of seven bacteria isolated from aerosols collected on top of two dry valley glaciers.
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Titin is the largest protein produced by living cells and its function as a molecular spring in striated muscle is well characterized (1, 2). Here we demonstrate that titin isoforms in the same size range as found in muscle are prominent neuronal proteins in both the central and peripheral nervous systems, including motor neurons in the spinal cord and brain. Within these neurons, titin localizes to the dense fibrillar component of the nucleolus, the site of ribosomal RNA biogenesis and modification, and a critical site of dysfunction in neurodegenerative disease (3-5). Additionally, we show that the levels of both titin mRNA and protein are altered in the spinal cord of SOD1G93A mice, a commonly used model of amyotrophic lateral sclerosis, indicating that titin mediated nucleolar events may in fact contribute to the pathobiology of disease.
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On 22 March 2023, the FDA approved rezafungin (Rezzayo) for the treatment of candidemia and invasive candidiasis in adults with limited or no alternative treatment options. Rezafungin is an echinocandin that supports weekly dosing, enabling outpatient parenteral treatment that potentially avoids the need for a central venous catheter. Approval of rezafungin was based on a single adequate and well-controlled phase 3 study designed with a day 30 all-cause mortality primary end point and 20% noninferiority margin, which demonstrated that rezafungin is noninferior to the comparator echinocandin. Nonclinical studies of rezafungin in nonhuman primates identified a neurotoxicity safety signal; however, rezafungin's safety profile in the completed clinical studies was similar to other Food and Drug Administration-approved echinocandins. Here we describe the rationale for this approval and important considerations during the review process for a flexible development program intended to expedite the availability of antimicrobial therapies to treat serious infections in patients with limited treatment options. Clinical Trials Registration . NCT02734862 and NCT03667690.
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Antifúngicos , Candidemia , Candidiasis Invasiva , Aprobación de Drogas , Equinocandinas , Humanos , Equinocandinas/uso terapéutico , Candidiasis Invasiva/tratamiento farmacológico , Antifúngicos/uso terapéutico , Candidemia/tratamiento farmacológico , Adulto , Estados Unidos , United States Food and Drug Administration , Animales , Ensayos Clínicos Fase III como AsuntoRESUMEN
BACKGROUND: Although age is the biggest known risk factor for dementia, there remains uncertainty about other factors over the life course that contribute to a person's risk for cognitive decline later in life. Furthermore, the pathological processes leading to dementia are not fully understood. The main goals of Insight 46-a multi-phase longitudinal observational study-are to collect detailed cognitive, neurological, physical, cardiovascular, and sensory data; to combine those data with genetic and life-course information collected from the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort); and thereby contribute to a better understanding of healthy ageing and dementia. METHODS/DESIGN: Phase 1 of Insight 46 (2015-2018) involved the recruitment of 502 members of the NSHD (median age = 70.7 years; 49% female) and has been described in detail by Lane and Parker et al. 2017. The present paper describes phase 2 (2018-2021) and phase 3 (2021-ongoing). Of the 502 phase 1 study members who were invited to a phase 2 research visit, 413 were willing to return for a clinic visit in London and 29 participated in a remote research assessment due to COVID-19 restrictions. Phase 3 aims to recruit 250 study members who previously participated in both phases 1 and 2 of Insight 46 (providing a third data time point) and 500 additional members of the NSHD who have not previously participated in Insight 46. DISCUSSION: The NSHD is the oldest and longest continuously running British birth cohort. Members of the NSHD are now at a critical point in their lives for us to investigate successful ageing and key age-related brain morbidities. Data collected from Insight 46 have the potential to greatly contribute to and impact the field of healthy ageing and dementia by combining unique life course data with longitudinal multiparametric clinical, imaging, and biomarker measurements. Further protocol enhancements are planned, including in-home sleep measurements and the engagement of participants through remote online cognitive testing. Data collected are and will continue to be made available to the scientific community.
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Demencia , Anciano , Femenino , Humanos , Masculino , Envejecimiento , Atención Ambulatoria , Encéfalo , Estudios Observacionales como AsuntoRESUMEN
BACKGROUND: Consistent patterns of reduced cortical thickness have been identified in early Alzheimer's disease (AD). However, the pathological factors that influence rates of cortical thinning within these AD signature regions remain unclear. METHODS: Participants were from the Insight 46 substudy of the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort), a prospective longitudinal cohort study. Linear regression was used to examine associations of baseline cerebral ß-amyloid (Aß) deposition, measured using florbetapir positron emission tomography, and baseline white matter hyperintensity volume (WMHV) on MRI, a marker of cerebral small vessel disease, with subsequent longitudinal changes in AD signature cortical thickness quantified from baseline and repeat MRI (mean [SD] interval 2.4 [0.2] years). RESULTS: In a population-based sample of 337 cognitively normal older white adults (mean [SD] age at baseline 70.5 [0.6] years; 48.1% female), higher global WMHV at baseline related to faster subsequent rates of cortical thinning in both AD signature regions (~0.15%/year faster per 10 mL additional WMHV), whereas baseline Aß status did not. Among Aß positive participants (n=56), there was some evidence that greater global Aß standardised uptake value ratio at baseline related to faster cortical thinning in the AD signature Mayo region, but this did not reach statistical significance (p=0.08). CONCLUSIONS: Cortical thinning within AD signature regions may develop via cerebrovascular pathways. Perhaps reflecting the age of the cohort and relatively low prevalence of Aß-positivity, robust Aß-related differences were not detected. Longitudinal follow-up incorporating additional biomarkers will allow assessment of how these relationships evolve closer to expected dementia onset.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Adelgazamiento de la Corteza Cerebral , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Sustancia Blanca , Humanos , Femenino , Masculino , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Estudios Longitudinales , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Adelgazamiento de la Corteza Cerebral/diagnóstico por imagen , Adelgazamiento de la Corteza Cerebral/patología , Estudios Prospectivos , Glicoles de Etileno , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Corteza Cerebral/metabolismo , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Enfermedades de los Pequeños Vasos Cerebrales/patología , Compuestos de AnilinaRESUMEN
Dissolved organic matter (DOM) in Antarctic inland waters is unique in that its precursor molecules are microbially derived and lack the chemical signature of higher plants. Here, we report the genomic sequences of seven environmental, bacterial isolates from Pony Lake, Antarctica, to explore the genetic potential linked to DOM processing.
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OBJECTIVES: Sedation and analgesia for infants and children requiring mechanical ventilation in the PICU is uniquely challenging due to the wide spectrum of ages, developmental stages, and pathophysiological processes encountered. Studies evaluating the safety and efficacy of sedative and analgesic management in pediatric patients have used heterogeneous methodologies. The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research (SCEPTER) IV hosted a series of multidisciplinary meetings to establish consensus statements for future clinical study design and implementation as a guide for investigators studying PICU sedation and analgesia. DESIGN: Twenty-five key elements framed as consensus statements were developed in five domains: study design, enrollment, protocol, outcomes and measurement instruments, and future directions. SETTING: A virtual meeting was held on March 2-3, 2022, followed by an in-person meeting in Washington, DC, on June 15-16, 2022. Subsequent iterative online meetings were held to achieve consensus. SUBJECTS: Fifty-one multidisciplinary, international participants from academia, industry, the U.S. Food and Drug Administration, and family members of PICU patients attended the virtual and in-person meetings. Participants were invited based on their background and experience. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Common themes throughout the SCEPTER IV consensus statements included using coordinated multidisciplinary and interprofessional teams to ensure culturally appropriate study design and diverse patient enrollment, obtaining input from PICU survivors and their families, engaging community members, and using developmentally appropriate and validated instruments for assessments of sedation, pain, iatrogenic withdrawal, and ICU delirium. CONCLUSIONS: These SCEPTER IV consensus statements are comprehensive and may assist investigators in the design, enrollment, implementation, and dissemination of studies involving sedation and analgesia of PICU patients requiring mechanical ventilation. Implementation may strengthen the rigor and reproducibility of research studies on PICU sedation and analgesia and facilitate the synthesis of evidence across studies to improve the safety and quality of care for PICU patients.
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Analgesia , Enfermedad Crítica , Lactante , Niño , Humanos , Enfermedad Crítica/terapia , Reproducibilidad de los Resultados , Analgesia/métodos , Dolor , Respiración Artificial , Hipnóticos y Sedantes/uso terapéuticoRESUMEN
We investigate associations between normal-appearing white matter microstructural integrity in cognitively normal â¼70-year-olds and concurrently measured brain health and cognition, demographics, genetics and life course cardiovascular health. Participants born in the same week in March 1946 (British 1946 birth cohort) underwent PET-MRI around age 70. Mean standardized normal-appearing white matter integrity metrics (fractional anisotropy, mean diffusivity, neurite density index and orientation dispersion index) were derived from diffusion MRI. Linear regression was used to test associations between normal-appearing white matter metrics and (i) concurrent measures, including whole brain volume, white matter hyperintensity volume, PET amyloid and cognition; (ii) the influence of demographic and genetic predictors, including sex, childhood cognition, education, socio-economic position and genetic risk for Alzheimer's disease (APOE-É4); (iii) systolic and diastolic blood pressure and cardiovascular health (Framingham Heart Study Cardiovascular Risk Score) across adulthood. Sex interactions were tested. Statistical significance included false discovery rate correction (5%). Three hundred and sixty-two participants met inclusion criteria (mean age 70, 49% female). Higher white matter hyperintensity volume was associated with lower fractional anisotropy [b = -0.09 (95% confidence interval: -0.11, -0.06), P < 0.01], neurite density index [b = -0.17 (-0.22, -0.12), P < 0.01] and higher mean diffusivity [b = 0.14 (-0.10, -0.17), P < 0.01]; amyloid (in men) was associated with lower fractional anisotropy [b = -0.04 (-0.08, -0.01), P = 0.03)] and higher mean diffusivity [b = 0.06 (0.01, 0.11), P = 0.02]. Framingham Heart Study Cardiovascular Risk Score in later-life (age 69) was associated with normal-appearing white matter {lower fractional anisotropy [b = -0.06 (-0.09, -0.02) P < 0.01], neurite density index [b = -0.10 (-0.17, -0.03), P < 0.01] and higher mean diffusivity [b = 0.09 (0.04, 0.14), P < 0.01]}. Significant sex interactions (P < 0.05) emerged for midlife cardiovascular health (age 53) and normal-appearing white matter at 70: marginal effect plots demonstrated, in women only, normal-appearing white matter was associated with higher midlife Framingham Heart Study Cardiovascular Risk Score (lower fractional anisotropy and neurite density index), midlife systolic (lower fractional anisotropy, neurite density index and higher mean diffusivity) and diastolic (lower fractional anisotropy and neurite density index) blood pressure and greater blood pressure change between 43 and 53 years (lower fractional anisotropy and neurite density index), independently of white matter hyperintensity volume. In summary, poorer normal-appearing white matter microstructural integrity in â¼70-year-olds was associated with measures of cerebral small vessel disease, amyloid (in males) and later-life cardiovascular health, demonstrating how normal-appearing white matter can provide additional information to overt white matter disease. Our findings further show that greater 'midlife' cardiovascular risk and higher blood pressure were associated with poorer normal-appearing white matter microstructural integrity in females only, suggesting that women's brains may be more susceptible to the effects of midlife blood pressure and cardiovascular health.
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OBJECTIVES: Assess clinical outcomes following PICU Liberation ABCDEF Bundle utilization. DESIGN: Prospective, multicenter, cohort study. SETTING: Eight academic PICUs. PATIENTS: Children greater than 2 months with expected PICU stay greater than 2 days and need for mechanical ventilation (MV). INTERVENTIONS: ABCDEF Bundle implementation. MEASUREMENT AND MAIN RESULTS: Over an 11-month period (3-mo baseline, 8-mo implementation), Bundle utilization was measured for 622 patients totaling 5,017 PICU days. Risk of mortality was quantified for 532 patients (4,275 PICU days) for correlation between Bundle utilization and MV duration, PICU length of stay (LOS), delirium incidence, and mortality. Utilization was analyzed as subject-specific (entire PICU stay) and day-specific (single PICU day). Median overall subject-specific utilization increased from 50% during the 3-month baseline to 63.9% during the last four implementation months ( p < 0.001). Subject-specific utilization for elements A and C did not change; utilization improved for B (0-12.5%; p = 0.007), D (22.2-61.1%; p < 0.001), E (17.7-50%; p = 0.003), and F (50-79.2%; p = 0.001). We observed no association between Bundle utilization and MV duration, PICU LOS, or delirium incidence. In contrast, on adjusted analysis, every 10% increase in subject-specific utilization correlated with mortality odds ratio (OR) reduction of 34%, p < 0.001; every 10% increase in day-specific utilization correlated with a mortality OR reduction of 1.4% ( p = 0.006). CONCLUSIONS: ABCDEF Bundle is applicable to children. Although enhanced Bundle utilization correlated with decreased mortality, increased utilization did not correlate with duration of MV, PICU LOS, or delirium incidence. Additional research in the domains of comparative effectiveness, implementation science, and human factors engineering is required to understand this clinical inconsistency and optimize PICU Liberation concept integration into clinical practice.
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Enfermedad Crítica , Delirio , Humanos , Niño , Estudios de Cohortes , Estudios Prospectivos , Enfermedad Crítica/terapia , Enfermedad Crítica/epidemiología , Unidades de Cuidados Intensivos , Delirio/epidemiología , Unidades de Cuidado Intensivo PediátricoRESUMEN
The addition of small amounts of algal biomass to stimulate methane production in coal seams is a promising low carbon renewable coalbed methane enhancement technique. However, little is known about how the addition of algal biomass amendment affects methane production from coals of different thermal maturity. Here, we show that biogenic methane can be produced from five coals ranging in rank from lignite to low-volatile bituminous using a coal-derived microbial consortium in batch microcosms with and without algal amendment. The addition of 0.1 g/l algal biomass resulted in maximum methane production rates up to 37 days earlier and decreased the time required to reach maximum methane production by 17-19 days when compared to unamended, analogous microcosms. Cumulative methane production and methane production rate were generally highest in low rank, subbituminous coals, but no clear association between increasing vitrinite reflectance and decreasing methane production could be determined. Microbial community analysis revealed that archaeal populations were correlated with methane production rate (p = 0.01), vitrinite reflectance (p = 0.03), percent volatile matter (p = 0.03), and fixed carbon (p = 0.02), all of which are related to coal rank and composition. Sequences indicative of the acetoclastic methanogenic genus Methanosaeta dominated low rank coal microcosms. Amended treatments that had increased methane production relative to unamended analogs had high relative abundances of the hydrogenotrophic methanogenic genus Methanobacterium and the bacterial family Pseudomonadaceae. These results suggest that algal amendment may shift coal-derived microbial communities towards coal-degrading bacteria and CO2-reducing methanogens. These results have broad implications for understanding subsurface carbon cycling in coal beds and the adoption of low carbon renewable microbially enhanced coalbed methane techniques across a diverse range of coal geology.
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The design and conduct of pediatric sedation studies in critically ill patients have historically been challenging due to the complexity of the pediatric intensive care unit (PICU) environment and the difficulty of establishing equipoise. Clinical trials, for instance, represent 1 important means of advancing our knowledge in this field, but there is a paucity of such studies in the literature. Accounting for ground-level factors in planning for each trial phase (eg, enrollment, intervention, assessment, and follow-up) and the presence of broader system limitations is of key importance. In addition, there is a need for early planning, coordination, and obtaining buy-in from individual study sites and staff to ensure success, particularly for multicenter studies. This review synthesizes the current state of pediatric sedation research and the myriad of challenges in designing and conducting successful trials in this particular area. The review poses consideration for future research directions, including novel study designs, and discusses electroencephalography monitoring and neurodevelopmental outcomes of PICU survivors.
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Anestesia , Niño , Humanos , Unidades de Cuidado Intensivo Pediátrico , Enfermedad CríticaRESUMEN
Few studies can address how adulthood cognitive trajectories relate to brain health in 70-year-olds. Participants (n = 468, 49% female) from the 1946 British birth cohort underwent 18F-Florbetapir PET/MRI. Cognitive function was measured in childhood (age 8 years) and across adulthood (ages 43, 53, 60-64 and 69 years) and was examined in relation to brain health markers of ß-amyloid (Aß) status, whole brain and hippocampal volume, and white matter hyperintensity volume (WMHV). Taking into account key contributors of adult cognitive decline including childhood cognition, those with greater Aß and WMHV at age 70 years had greater decline in word-list learning memory in the preceding 26 years, particularly after age 60. In contrast, those with smaller whole brain and hippocampal volume at age 70 years had greater decline in processing search speed, subtly manifest from age 50 years. Subtle changes in memory and processing speed spanning 26 years of adulthood were associated with markers of brain health at 70 years of age, consistent with detectable prodromal cognitive effects in early older age.
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Cohorte de Nacimiento , Disfunción Cognitiva , Humanos , Femenino , Adulto , Anciano , Masculino , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Cognición , Disfunción Cognitiva/psicología , Péptidos beta-Amiloides/metabolismoRESUMEN
BACKGROUND: A neuroimaging-based biomarker termed the brain age is thought to reflect variability in the brain's ageing process and predict longevity. Using Insight 46, a unique narrow-age birth cohort, we aimed to examine potential drivers and correlates of brain age. METHODS: Participants, born in a single week in 1946 in mainland Britain, have had 24 prospective waves of data collection to date, including MRI and amyloid PET imaging at approximately 70 years old. Using MRI data from a previously defined selection of this cohort, we derived brain-predicted age from an established machine-learning model (trained on 2001 healthy adults aged 18-90 years); subtracting this from chronological age (at time of assessment) gave the brain-predicted age difference (brain-PAD). We tested associations with data from early life, midlife, and late life, as well as rates of MRI-derived brain atrophy. FINDINGS: Between May 28, 2015, and Jan 10, 2018, 502 individuals were assessed as part of Insight 46. We included 456 participants (225 female), with a mean chronological age of 70·7 years (SD 0·7; range 69·2 to 71·9). The mean brain-predicted age was 67·9 years (8·2, 46·3 to 94·3). Female sex was associated with a 5·4-year (95% CI 4·1 to 6·8) younger brain-PAD than male sex. An increase in brain-PAD was associated with increased cardiovascular risk at age 36 years (ß=2·3 [95% CI 1·5 to 3·0]) and 69 years (ß=2·6 [1·9 to 3·3]); increased cerebrovascular disease burden (1·9 [1·3 to 2·6]); lower cognitive performance (-1·3 [-2·4 to -0·2]); and increased serum neurofilament light concentration (1·2 [0·6 to 1·9]). Higher brain-PAD was associated with future hippocampal atrophy over the subsequent 2 years (0·003 mL/year [0·000 to 0·006] per 5-year increment in brain-PAD). Early-life factors did not relate to brain-PAD. Combining 12 metrics in a hierarchical partitioning model explained 33% of the variance in brain-PAD. INTERPRETATION: Brain-PAD was associated with cardiovascular risk, and imaging and biochemical markers of neurodegeneration. These findings support brain-PAD as an integrative summary metric of brain health, reflecting multiple contributions to pathological brain ageing, and which might have prognostic utility. FUNDING: Alzheimer's Research UK, Medical Research Council Dementia Platforms UK, Selfridges Group Foundation, Wolfson Foundation, Wellcome Trust, Brain Research UK, Alzheimer's Association.
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Enfermedad de Alzheimer , Acontecimientos que Cambian la Vida , Adulto , Anciano , Enfermedad de Alzheimer/patología , Atrofia/patología , Encéfalo/diagnóstico por imagen , Femenino , Humanos , Masculino , Estudios ProspectivosRESUMEN
Introduction: Delirium is a disturbance of attention and awareness that represents a change from baseline mental status. Accurate diagnosis of delirium is of paramount importance to improving the management of pediatric delirium in the intensive care unit. Despite ongoing education, inconsistencies in delirium assessments occur. Here, we aimed to determine the extent of the problem and increase compliance with delirium assessments. Methods: We collected preintervention data to assess baseline compliance of delirium assessments in the Pediatric Intensive Care Unit (PICU) and Pediatric Cardiac Intensive Care Unit (PCICU) at Monroe Carell Jr Children's Hospital at Vanderbilt in November 2020. We executed 2 Plan-Do-Study-Act cycles with different interventions and collected data after each and approximately 1 year after the interventions. The first intervention consisted of virtual lectures on delirium assessments for the nursing staff. The second intervention included an educational handout and a new electronic medical record documentation tool. Results: Five hundred five individual nurse-patient encounters were assessed and collected throughout the project. The mean compliance of delirium documentation before the interventions was 52.5%. Target compliance after interventions was 70%. Mean compliance was 70% after cycle 1, 78% after cycle 2, and 86% in March 2022. Conclusions: Using pre- and postintervention data from chart reviews and nurse interviews regarding delirium screenings, we found that interventions targeting nurse education and EMR flowsheet improved compliance with delirium assessment and documentation in the PICU and PCICU. Future work should focus on assessing the clinical implications of this project in diagnosing and treating delirium.