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Optical and x-ray streak cameras are used to study transient phenomena, particularly in the high-energy density physics regime. The Orion laser facility employs many different types of streak cameras, which are used to collect data on laser-plasma interactions as well as to verify the temporal profile and timing between the multiple Orion beamlines. Streak cameras are complex devices with very precise timing associated with them, which can often malfunction, resulting in the loss of shot data. Since Orion is a kJ-class Nd:glass laser system, it is not optimal to try and fault-find using Orion shots since this is both time consuming and prohibitively expensive. To enable the facile set-up, fault-finding, timing-in, and in-house calibration of Orion optical and x-ray diagnostics, a single laboratory system has been commissioned to provide an adjustable stimulus to streak cameras and other Orion short pulse diagnostics (such as pulse dilation photomultiplier tubes). The system comprises a Ti:Sapphire laser system capable of generating 400 nm or 266 nm laser pulses of duration less than 0.1 ps; an optical system to deliver single pulses, pulse pairs, or a train of pulses; and timing electronics to synchronize the streak cameras with the laser and to record output data. The system can operate at Hertz repetition rates rather than the sub-mHz rate of the Orion laser. We present the commissioned system and results from initial testing of both optical and x-ray streak cameras used on Orion laser-plasma experiments.
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BACKGROUND: The Anti-Amyloid in Asymptomatic Alzheimer's Disease (A4) Study failed to show a treatment benefit with solanezumab, but the longitudinal consequences of elevated amyloid were observed in study participants with objective decline on the Preclinical Alzheimer Cognitive Composite (PACC) and subjective decline on the combined Cognitive Function Index (participant + study partner CFI), during the trial period. OBJECTIVES: We sought to expand on previous findings by comparing longitudinal patterns of participant and study partner CFI separately and their associations with the PACC stratified by baseline amyloid tertile over the course of the A4 Study. DESIGN: Cognitively unimpaired older adult participants and their study partners were independently administered the CFI at screen prior to amyloid PET disclosure and then at 3 subsequent visits (week 48, week 168, week 240) of the study. PACC collected at visits concurrent with CFI administration were also examined longitudinally. SETTING: The A4 Study was conducted at 67 sites in Australia, Canada, Japan, and the United States. PARTICIPANTS: 1,147 participants with elevated amyloid based on florbetapir PET were enrolled in the A4 Study and included in these analyses. 583 were on placebo and 564 were treated with solanezumab. MEASUREMENTS: The PACC was used to assess objective cognitive performance and the CFI was used to assess change in everyday cognitive functioning by the participant and their study partner independently. Amyloid level was characterized by Centiloid tertiles (<46.1 CL, 46.1 to 77.2 CL, >77.2 CL). Participants were aware of their elevated amyloid status, but not their CL tertile, or specific level of amyloid. Longitudinal correlations between participant and study partner CFI and PACC were examined at all visits where assessments were available. The impact of baseline amyloid tertile on CFI and PACC associations was also examined. RESULTS: Both participant and study partner CFI increased over the duration of the study indicating worsening cognitive functioning. Results did not differ by treatment group. The association between higher CFI and worse PACC for both for participant and study partner became progressively stronger over the course of the study. PACC had a significantly higher correlation with study partner CFI than with participant CFI by week 168. The stronger correlations between study partner CFI and PACC were driven by those in the highest amyloid tertile. CONCLUSION: Both participant and study partner report captured subtle changes in everyday cognitive functioning for participants with biomarker confirmed and disclosed preclinical AD. Moreover, study partner report was most highly aligned with cognitive decline, particularly among those with the highest amyloid load.
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Enfermedad de Alzheimer , Anticuerpos Monoclonales Humanizados , Tomografía de Emisión de Positrones , Humanos , Masculino , Femenino , Anciano , Enfermedad de Alzheimer/psicología , Enfermedad de Alzheimer/tratamiento farmacológico , Estudios Longitudinales , Anticuerpos Monoclonales Humanizados/uso terapéutico , Cognición/fisiología , Disfunción Cognitiva , Pruebas Neuropsicológicas , Compuestos de Anilina , Glicoles de Etileno , Péptidos beta-Amiloides/metabolismo , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Declining ability to independently perform instrumental activities of daily living (IADL) is a hallmark of early-stage Alzheimer's disease (AD). Financial capacity, an aspect of IADL, includes financial skills such as balancing a checkbook and making change and is potentially sensitive to early decline in cognitive abilities, raising the question of how financial capacity is affected by buildup of cerebral tau and amyloid-hallmarks of AD pathology. OBJECTIVES: This study aimed to examine the relationship between cerebral tau, amyloid, and their interaction with change in financial capacity over time. DESIGN: Participants were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to have at least one yearly follow-up Financial Capacity Instrument-Short Form (FCI-SF) exam and a flortaucipir (tau) PET scan within 6 months of baseline (and in a subset, a florbetapir (amyloid) PET scan within a year of baseline). SETTING: Multi-center international cohort study. PARTICIPANTS: Sample size was 507-322 cognitively normal (CN) and 185 with amnestic mild cognitive impairment (MCI). Sixty-two percent (N=316) had amyloid data. MEASUREMENTS: Linear mixed-effects models predicted FCI-SF total score from baseline tau, age, gender, premorbid intelligence, executive function, memory, and the interaction of each with time. Regions of interest included inferior temporal, entorhinal cortex, precuneus, posterior cingulate, supramarginal, and dorsolateral prefrontal (DLPF). Additional models examined amyloid and its interaction with tau. Results were adjusted for multiple comparisons. RESULTS: Among the whole sample and in CN participants alone, higher baseline tau in all regions, most prominently in the inferior temporal, entorhinal cortex, and supramarginal regions, was significantly associated with worse performance on the FCI-SF over time. Among MCI participants alone, this relationship was significant in the entorhinal cortex (unstandardized b = 0.27, t = 3.71, adjusted p = 0.001), inferior temporal (b = 0.27, t = 3.96, p < 0.001), precuneus (b = 0.27, t = 3.04, p = 0.01), and supramarginal (b = 0.27, t = 2.74, p = 0.02) regions. Amyloid alone was significantly associated with worse FCI-SF performance in only the whole sample (b = 0.15, t = 2.37, p = 0.04), and a three-way interaction between tau, amyloid, and time was only present for entorhinal cortex tau in CN individuals (b = -1.61, t = -2.61, p = 0.03). CONCLUSIONS: Early tau accumulation is linked to worsening financial capacity over time in CN older adults and MCI. Declining financial capacity may signal pathological buildup and serve as an early warning sign for AD, and future research should continue to investigate the longitudinal relationship between tau, financial capacity, and other IADL.
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Actividades Cotidianas , Disfunción Cognitiva , Tomografía de Emisión de Positrones , Proteínas tau , Humanos , Disfunción Cognitiva/metabolismo , Femenino , Anciano , Masculino , Proteínas tau/metabolismo , Estudios Longitudinales , Cognición/fisiología , Anciano de 80 o más Años , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Compuestos de Anilina , Carbolinas , Péptidos beta-Amiloides/metabolismo , Glicoles de Etileno , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagenRESUMEN
Zygomaticomaxillary complex (ZMC) fractures typically result from traumatic injuries, such as motor vehicle-related incidents, assaults, falls, and sports-related injuries. These fractures characteristically occur along suture lines where the zygomatic bone borders the frontal bone, maxilla, temporal bone, and sphenoid bone, resulting in a "tetrapod" fracture pattern that can be surgically fixated utilizing one, two, and three-point plate and screw fixation. However, fractures with complete loss of bone stock are less common, and standardized methods of fixation are not suitable for such complex fractures. Here, we present an interesting case of implantation of a custom-made alloplastic implant in a patient with complex ZMC fractures with loss of bone stock. A 52-year-old male sustained a traumatic gunshot wound to the face, resulting in significant destruction of bones involving the left orbital floor, left lateral orbital wall, and left zygomatic arch. Routine plating was not feasible, so a custom spanning plating system by DePuy Synthes (Synthes USA Products, LLC, West Chester, PA) was designed using the patient's CT scans. The patient recovered well with no complications. This case illustrates the successful application of patient-specific custom plates for complex ZMC fractures when standard plating methods are not suitable.
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BACKGROUND: Despite advances in therapeutics for adverse-risk acute myeloid leukaemia (AML), overall survival remains poor, especially in refractory disease. Comprehensive tumour profiling and pre-clinical drug testing can identify effective personalised therapies. CASE: We describe a case of ETV6-MECOM fusion-positive refractory AML, where molecular analysis and in vitro high throughput drug screening identified a tolerable, novel targeted therapy and provided rationale for avoiding what could have been a toxic treatment regimen. Ruxolitinib combined with hydroxyurea led to disease control and enhanced quality-of-life in a patient unsuitable for intensified chemotherapy or allogeneic stem cell transplantation. CONCLUSION: This case report demonstrates the feasibility and role of combination pre-clinical high throughput screening to aid decision making in high-risk leukaemia. It also demonstrates the role a JAK1/2 inhibitor can have in the palliative setting in select patients with AML.
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Toma de Decisiones Clínicas , Ensayos Analíticos de Alto Rendimiento , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Toma de Decisiones Clínicas/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Pirazoles/uso terapéutico , Nitrilos/uso terapéutico , Pirimidinas/uso terapéutico , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Hidroxiurea/uso terapéutico , Hidroxiurea/administración & dosificación , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genéticaRESUMEN
In this article we present a quantitative analysis of the second positive system of molecular nitrogen and the first negative system of the molecular nitrogen cation excited in the presence of ionizing radiation. Optical emission spectra of atmospheric air and nitrogen surrounding 210Po sources were measured from 250 to 400 nm. Multi-Boltzmann and non-Boltzmann vibrational distribution spectral models were used to determine the vibrational temperature and vibrational distribution function of the emitting N2(C3Πu) and N2+(B2Σ+u) states. A zero-dimensional kinetic model, based on the electron energy distribution function (EEDF) and steady-state excitation and de-excitation of N2(X1Σ+g), N2+(B2Σ+u), N2+(X2Σ+g), N4+, O2+, and N2(C3Πu, v), was developed for the prediction of the relative spectral intensity of both the N2+(B2Σ+u â X2Σ+g) emission band and the vibrational bands of N2(C3Πu â B3Πg) for comparison with the experimental data.
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BACKGROUND: The opioid epidemic in the United States continues to lead to a substantial number of preventable deaths and disability. The development of opioid dependence has been strongly linked to previous opioid exposure. Trauma patients are at particular risk since opioids are frequently required to control pain after injury. The purpose to this study was to examine the prevalence of opioid use before and after injury and to identify risk factors for persistent long-term opioid use after trauma. METHODS: Records for all patients admitted to a Level 1 trauma center over a 1-year period were analyzed. Demographics, injury characteristics, and hospital course were recorded. A multistate Prescription Drug Monitoring Program database was queried to obtain records of all controlled substances prescribed from 6 months before the date of injury to 12 months after hospital discharge. Patients still receiving narcotics at 1 year were defined as persistent long-term users and were compared against those who were not. RESULTS: A total of 2,992 patients were analyzed. Of all patients, 20.4% had filled a narcotic prescription within the 6 months before injury, 53.5% received opioids at hospital discharge, and 12.5% had persistent long-term use after trauma with the majority demonstrating preinjury use. Univariate risk factors for long-term use included female sex, longer length of stay, higher Injury Severity Score, anxiety, depression, orthopedic surgeries, spine injuries, multiple surgical locations, discharge to acute inpatient rehab, and preinjury opioid use. On multivariate analysis, the only significant predictors of persistent long-term prescription opioid use were preinjury use and a much smaller effect associated with use at discharge. CONCLUSION: During a sustained opioid epidemic, concerns and caution are warranted in the use of prescription narcotics for trauma patients. However, persistent long-term opioid use among opioid-naive patients is rare and difficult to predict after trauma. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level III.
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Analgésicos Opioides , Trastornos Relacionados con Opioides , Humanos , Femenino , Estados Unidos/epidemiología , Analgésicos Opioides/efectos adversos , Incidencia , Trastornos Relacionados con Opioides/epidemiología , Trastornos Relacionados con Opioides/etiología , Factores de Riesgo , Narcóticos , Dolor Postoperatorio/tratamiento farmacológico , Estudios Retrospectivos , Pautas de la Práctica en MedicinaRESUMEN
Complex sternal and chest wall reconstruction can be a challenging clinical situation, with the main objectives being restoration of chest wall rigidity, protection of intrathoracic organs, preservation of respiratory function, and reduction of pain and clicking. The treatment of choice is varied, with several different materials available to aid in adequate reconstruction. We present the case of a 60-year-old male with a post-sternectomy defect and debilitating symptoms who underwent reconstruction with a customized, three-dimensional (3D)-printed polyetheretherketone (PEEK) implant and pectoralis muscle flaps. There were no complications in the perioperative period, and the patient reported significant improvement in pain and subjective improvement in chest stability and respiration. The use of PEEK as a reconstructive material for cardiothoracic defects is a viable and safe method that has several important benefits over other utilized materials in the literature. The early success of this case in relieving patient symptoms opens the door for further exploration of PEEK as an alternative for cardiothoracic reconstruction.
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Alzheimer's disease (AD) is associated with amyloidosis and dysfunction of the cholinergic system, which is crucial for learning and memory. However, the nature of acetylcholine signaling within regions of cholinergic-dependent plasticity and how it changes with experience is poorly understood, much less the impact of amyloidosis on this signaling. Therefore, we optically measure the release profile of acetylcholine to unexpected, predicted, and predictive events in visual cortex (VC)-a site of known cholinergic-dependent plasticity-in a preclinical mouse model of AD that develops amyloidosis. We find that acetylcholine exhibits reinforcement signaling qualities, reporting behaviorally relevant outcomes and displaying release profiles to predictive and predicted events that change as a consequence of experience. We identify three stages of amyloidosis occurring before the degeneration of cholinergic synapses within VC and observe that cholinergic responses in amyloid-bearing mice become impaired over these stages, diverging progressively from age- and sex-matched littermate controls. In particular, amyloidosis degrades the signaling of unexpected rewards and punishments, and attenuates the experience-dependent (1) increase of cholinergic responses to outcome predictive visual cues, and (2) decrease of cholinergic responses to predicted outcomes. Hyperactive spontaneous acetylcholine release occurring transiently at the onset of impaired cholinergic signaling is also observed, further implicating disrupted cholinergic activity as an early functional biomarker in AD. Our findings suggest that acetylcholine acts as a reinforcement signal that is impaired by amyloidosis before pathologic degeneration of the cholinergic system, providing a deeper understanding of the effects of amyloidosis on acetylcholine signaling and informing future interventions for AD.SIGNIFICANCE STATEMENT The cholinergic system is especially vulnerable to the neurotoxic effects of amyloidosis, a hallmark of Alzheimer's disease (AD). Though amyloid-induced cholinergic synaptic loss is thought in part to account for learning and memory impairments in AD, little is known regarding how amyloid impacts signaling of the cholinergic system before its anatomic degeneration. Optical measurement of acetylcholine (ACh) release in a mouse model of AD that develops amyloidosis reveals that ACh signals reinforcement and outcome prediction that is disrupted by amyloidosis before cholinergic degeneration. These observations have important scientific and clinical implications: they implicate ACh signaling as an early functional biomarker, provide a deeper understanding of the action of acetylcholine, and inform on when and how intervention may best ameliorate cognitive decline in AD.
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Enfermedad de Alzheimer , Amiloidosis , Ratones , Animales , Enfermedad de Alzheimer/metabolismo , Acetilcolina/metabolismo , Amiloidosis/patología , Amiloide , Colinérgicos/farmacología , Biomarcadores , Péptidos beta-Amiloides/metabolismoRESUMEN
Abnormal α-synuclein (α-syn) aggregation characterizes α-synucleinopathies, including Parkinson's disease (PD) and multiple system atrophy (MSA). However, no suitable positron emission tomography (PET) radiotracer for imaging α-syn in PD and MSA exists currently. Our structure-activity relationship studies identified 4-methoxy-N-(4-(3-(pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)benzamide (4i) as a PET radiotracer candidate for imaging α-syn. In vitro assays revealed high binding of 4i to recombinant α-syn fibrils (inhibition constant (Ki) = 6.1 nM) and low affinity for amyloid beta (Aß) fibrils in Alzheimer's disease (AD) homogenates. However, [3H]4i also exhibited high specific binding to AD, progressive supranuclear palsy, and corticobasal degeneration tissues as well as PD and MSA tissues, suggesting notable affinity to tau. Nevertheless, the specific binding to pathologic α-syn aggregates in MSA post-mortem brain tissues was significantly higher than in PD tissues. This finding demonstrated the potential use of [11C]4i as a PET tracer for imaging α-syn in MSA patients. Nonhuman primate PET studies confirmed good brain uptake and rapid washout for [11C]4i.
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Enfermedad de Alzheimer , Atrofia de Múltiples Sistemas , Enfermedad de Parkinson , Animales , alfa-Sinucleína , Atrofia de Múltiples Sistemas/diagnóstico por imagen , Péptidos beta-Amiloides , Tomografía de Emisión de Positrones , Encéfalo/diagnóstico por imagenRESUMEN
Introduction Preoperative marking is an essential safety practice to prevent "never" events, including wrong site surgery. Moreover, the Joint Commission regulations of the Universal Protocol require that patients be marked to indicate the operative site. Marking typically occurs with a pen or marker, which may be disposable or reusable. Previous studies have demonstrated that methicillin-resistant Staphylococcus aureus (MRSA) can survive in the dark, moist, capped environment of the marking pen and thus could plausibly be a nidus for transmission from patient to patient. The Joint Commission has established no increased risk of postoperative infection with these markings. With this study, we aimed to determine the colonization of surgical marking pens in the plastic surgery population. Methods Two marking pens from five different attending plastic surgeons at a single institution were cultured in standard fashion for aerobic and anaerobic growth. All pens were used repeatedly in office settings for performing patient markings. Those same ten marking pens were then used to mark incision sites on mock patients. Standard povidone-iodine prepping was then performed in a paint-only fashion over the skin markings, and cultures were again taken. A control group consisted of cultures from five sterile pens from the operating room. Each sterile pen was opened, uncapped, and then swabbed. All twenty-five cultures were analyzed in the hospital laboratory in a blinded fashion. Results The five control pens revealed no bacterial growth. Of the 10 direct pen cultures, two samples grew coagulase-negative staphylococci and one culture contained Pseudomonas aeruginosa. The 10-patient marked and prepped specimens showed eight negative cultures and two with coagulase-negative staphylococci. Although Pseudomonas was detected on standard pen culture, no pseudomonal growth was present in any of the samples after patient marking and prepping with povidone-iodine. Conclusions Our findings reaffirm that marking pens may be vehicles for bacterial transmission and expand upon previous studies by describing the presence of bacterial colonization on marking pens even after surgical site preparation with povidone-iodine.
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On exploratory class missions, such as a mission to Mars, astronauts will be exposed to doses of particles of high energy and charge and protons up to 30 - 40 cGy. These exposures will most likely occur at random intervals across the estimated 3-yr duration of the mission. As such, the possibility of an interaction between particles must be taken into account: a prior subthreshold exposure to one particle may prevent or minimize the effect of a subsequent exposure (adaptation), or there may be an additive effect such that the prior exposure may sensitize the individual to a subsequent exposure of the same or different radiations. Two identical replications were run in which rats were exposed to a below threshold dose of 4He particles and 2, 24 or 72 h later given either a second below threshold or an above threshold dose of 4He particles and tested for performance on an operant task. The results indicate that preexposure to a subthreshold dose of 4He particles can either sensitize or attenuate the effects of the subsequent dose, depending upon the interval between exposures and the doses. These results suggest that exposure to multiple doses of heavy particles may have implications for astronaut health on exploratory class missions.
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Radiación Cósmica , Helio , Masculino , Ratas , Animales , Radiación Cósmica/efectos adversosRESUMEN
Förster resonance energy transfer (FRET) is a valuable method for monitoring protein conformation and biomolecular interactions. Intrinsically fluorescent amino acids that can be genetically encoded, such as acridonylalanine (Acd), are particularly useful for FRET studies. However, quantitative interpretation of FRET data to derive distance information requires careful use of controls and consideration of photophysical effects. Here we present two case studies illustrating how Acd can be used in FRET experiments to study small molecule induced conformational changes and multicomponent biomolecular complexes.
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Aminoácidos , Transferencia Resonante de Energía de Fluorescencia , Aminoácidos/genética , Aminoácidos/química , Transferencia Resonante de Energía de Fluorescencia/métodos , Colorantes Fluorescentes/química , Conformación ProteicaRESUMEN
PURPOSE: Previous studies from our lab utilized an ultra-high throughput screening method to identify compound 1 as a small molecule that binds to alpha-synuclein (α-synuclein) fibrils. The goal of the current study was to conduct a similarity search of 1 to identify structural analogs having improved in vitro binding properties for this target that could be labeled with radionuclides for both in vitro and in vivo studies for measuring α-synuclein aggregates. METHODS: Using 1 as a lead compound in a similarity search, isoxazole derivative 15 was identified to bind to α-synuclein fibrils with high affinity in competition binding assays. A photocrosslinkable version was used to confirm binding site preference. Derivative 21, the iodo-analog of 15, was synthesized, and subsequently radiolabeled isotopologs [125I]21 and [11C]21 were successfully synthesized for use in in vitro and in vivo studies, respectively. [125I]21 was used in radioligand binding studies in post-mortem Parkinson's disease (PD) and Alzheimer's disease (AD) brain homogenates. In vivo imaging of an α-synuclein mouse model and non-human primates was performed with [11C]21. RESULTS: In silico molecular docking and molecular dynamic simulation studies for a panel of compounds identified through a similarity search, were shown to correlate with Ki values obtained from in vitro binding studies. Improved affinity of isoxazole derivative 15 for α-synuclein binding site 9 was indicated by photocrosslinking studies with CLX10. Design and successful (radio)synthesis of iodo-analog 21 of isoxazole derivative 15 enabled further in vitro and in vivo evaluation. Kd values obtained in vitro with [125I]21 for α-synuclein and Aß42 fibrils were 0.48 ± 0.08 nM and 2.47 ± 1.30 nM, respectively. [125I]21 showed higher binding in human postmortem PD brain tissue compared with AD tissue, and low binding in control brain tissue. Lastly, in vivo preclinical PET imaging showed elevated retention of [11C]21 in PFF-injected mouse brain. However, in PBS-injected control mouse brain, slow washout of the tracer indicates high non-specific binding. [11C]21 showed high initial brain uptake in a healthy non-human primate, followed by fast washout that may be caused by rapid metabolic rate (21% intact [11C]21 in blood at 5 min p.i.). CONCLUSION: Through a relatively simple ligand-based similarity search, we identified a new radioligand that binds with high affinity (<10 nM) to α-synuclein fibrils and PD tissue. Although the radioligand has suboptimal selectivity for α-synuclein towards Aß and high non-specific binding, we show here that a simple in silico approach is a promising strategy to identify novel ligands for target proteins in the CNS with the potential to be radiolabeled for PET neuroimaging studies.
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Enfermedad de Alzheimer , Enfermedad de Parkinson , Ratones , Animales , Humanos , alfa-Sinucleína/metabolismo , Simulación del Acoplamiento Molecular , Radioisótopos de Yodo , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Neuroimagen , Ligandos , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Tomografía de Emisión de Positrones/métodosRESUMEN
Particle-in-cell simulations of a picosecond-resolution bilamellar streak tube are described, and the results are compared to measurements of key specifications. A novel laser diode setup with a small focal spot has been used to investigate the sensitive width of the photocathode, a previously unpublished parameter. Simulations have shown that the tubes, while performing at high spatiotemporal resolution, have electron efficiencies of just 1.6% due to the action of the temporal focusing electrode, contributing to an effective dynamic range of around 10. The virtual photocathode created by this electrode was predicted to be 144 µm, in excellent agreement with the measured width of 136 µm. A simple method to improve the tube's dynamic range by narrowing the slit width is investigated and shown to have a modest simulated improvement.
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BACKGROUND: Performance of cognitively complex "instrumental activities of daily living" (IADL) has previously been related to amyloid deposition in preclinical Alzheimer's disease. OBJECTIVES: We aimed to investigate the relationship between IADL performance and cerebral tau accumulation in cognitively normal older adults. DESIGN: Cross-sectional. SETTING: Data was collected in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies. PARTICIPANTS: Participants (n = 447, age 71.9±4.9 years, 57.5% female) who underwent tau positron emission tomography were selected from the A4 and LEARN studies. MEASUREMENTS: IADL performance was measured using the self- and study partner-reported versions of the Alzheimer's Disease Cooperative Study Activities of Daily Living - Prevention Instrument (ADCS ADL-PI). We also investigated discordance between participants and their study partners. Cross-sectional associations between entorhinal and inferior temporal tau (independent variables) and ADCS ADL-PI total scores, item-level scores and discordance (dependent variables) were investigated in linear and logistic regressions. Analyses were adjusted for age, sex and education and a tau by amyloid interaction was also included. RESULTS: Participants and their study partners reported high levels of IADL performance. Entorhinal and inferior temporal tau were related to study partner but not to self-reported total ADCS ADL-PI scores. The association was not retained after adjustment for global cerebral amyloid burden. At the item level, greater entorhinal tau was associated with study partner-reported difficulties remembering important dates (odds ratio (OR) = 1.24, 95% confidence interval (95%CI) = [1.06, 1.45], p = 0.008) and difficulties remembering the details of TV programs and movies (OR = 1.32, 95%CI = [1.08, 1.61], p = 0.007). Greater inferior temporal tau was associated with self-reported difficulties managing to find personal belongings (OR = 1.23, 95%CI = [1.04, 1.46], p = 0.018) and study partner-reported difficulties remembering the details of TV programs and movies (OR = 1.39, 95%CI = [1.11, 1.75], p = 0.005). Discordance between participant and study partner-report was more likely with greater entorhinal (OR = 1.18, 95%CI = [1.05, 1.33], p = 0.005) and inferior temporal tau burden (OR = 1.29, 95%CI = [1.10, 1.51], p = 0.002). DISCUSSION: We found a cross-sectional relationship between study partner-reported everyday functioning and tau in cognitively normal older adults. Participants were more likely to self-report difficulties differently from their study partners when tau burden was higher. This may hint at an altered early-disease awareness of functional changes and underscores the importance of self-report of IADL functioning in addition to collateral report by a study partner.
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Enfermedad de Alzheimer , Humanos , Femenino , Anciano , Masculino , Proteínas tau , Actividades Cotidianas , Tomografía de Emisión de Positrones , AmiloideRESUMEN
The intrinsic photochemistry of the isoxazole, a common heterocycle in medicinal chemistry, can be applied to offer an alternative to existing strategies using more perturbing, extrinsic photo-crosslinkers. The utility of isoxazole photo-crosslinking is demonstrated in a wide range of biologically relevant experiments, including common proteomics workflows.
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Química Farmacéutica , Isoxazoles , FotoquímicaRESUMEN
BACKGROUND: With the increasing focus on prevention of Alzheimer's disease, there is need for characterization of preclinical populations. Local participant registries offer an opportunity to facilitate research engagement via remote data collection, inform recruitment, and characterize preclinical samples, including individuals with subjective cognitive decline. OBJECTIVES: We sought to characterize subjective cognitive decline in a registry sample, as related to psychiatric history and related variables, including personality and loneliness, quality of life, and factors related to dementia risk (e.g., family history of dementia). DESIGN, SETTING, PARTICIPANTS: Participants were 366 individuals (mean age=67.2 (range 50-88), 65% female, 94% white, 97% non-Hispanic or Latino, 82% with at least a bachelor's degree) with no reported history of mild cognitive impairment or dementia. All participants had expressed interest in research, primarily via community outreach events and prior research involvement. Data was collected via electronic surveys, distributed using REDCap. Electronic questionnaires included questions on demographic variables, subjective cognitive decline, quality of life, loneliness, and personality. RESULTS: There was a high prevalence of risk factors for dementia in the registry sample (68% with family history of dementia, 31% with subjective cognitive decline). Subjective cognitive decline was more common in women and associated with history of depression, but not with family history of dementia. Subjective cognitive decline was also associated with lower conscientiousness and lower emotional stability, as well as higher loneliness and lower quality of life. Among participants who endorsed a psychiatric history, most reported onset more than 10 years prior, rather than within the last 10 years. CONCLUSIONS: Subjective cognitive decline in a registry sample may be more strongly associated with longstanding psychiatric and personality variables, rather than family history of dementia, adding to the literature on characterization of subjective cognitive decline across different settings. These findings highlight the acceptability of remote data collection and the potential of registries to inform recruitment by characterizing registrants, which may help to stratify dementia risk and match participants to eligible trials.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Anciano , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/psicología , Femenino , Humanos , Soledad , Masculino , Personalidad , Calidad de Vida , Sistema de RegistrosRESUMEN
Siliconoma-induced hypercalcemia is a rare complication of siliconoma, occurring secondary to a foreign body granulomatous process induced by the introduction of silicone into soft tissue. This is a case report of a woman presenting with sequelae of illicit silicone injections performed in an unknown woman's basement in Florida 20 years before presentation. A 39-year-old woman presented with a 2-month history of 20-pound weight loss, malaise, and intractable vomiting with a remote history of unregulated cosmetic injections to the bilateral gluteal and thigh regions. Her laboratory studies were consistent with severe hypercalcemia secondary to a foreign body granulomatous process. Initially, she was medically managed, with mild improvements in her symptomatic hypercalcemia and later underwent palliative debridement with siliconoma removal. Postoperatively, her course was complicated by delayed wound healing and graft failure, but the surgical defect was later closed successfully with split-thickness skin grafting after months of wound care. Although the procedure was not intended to treat her hypercalcemia, there were significant improvements in serum and ionized calcium in the months following her procedure. Severe hypercalcemia in the context of previous unregulated cosmetic injections or possible silicone implant rupture should prompt consideration of siliconoma-induced hypercalcemia as the underlying etiology. In addition to the established utility of IV fluids, bisphosphonates, and glucocorticoids, there may also be a role for surgical intervention in the management of this unique patient population's hypercalcemia.
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Pyoderma gangrenosum (PG) is a rare skin disorder primarily treated with immunosuppression medication. We report a case of a large, chronic PG wound treated with adjunct negative pressure wound therapy with instillation and dwell time (NPWTi-d) using nonadherent dressing (Mepitel) and reticular open-cell foam with through holes (ROCF-CC) with positive outcomes. The patient was a 62-year-old female with rheumatoid arthritis, Hashimoto's thyroiditis, lymphedema, and morbid obesity who presented with a 19.5 cm x 13.2 cm x 2.1 cm wound of three years duration on the right posterolateral lower extremity that successfully responded to a multimodality approach of immunosuppression and wound vac therapy. We conclude in our case that NPWTi-d with Mepitel and ROCF-CC enhanced the wound healing process, and we discuss NPWTi-d's potential role and benefit as an adjunctive therapy option for chronic and poorly controlled PG on patients taking concurrent immunosuppression.