Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is associated with abnormalities in white matter structural integrity and connectivity: An ex-vivo diffusion MRI and pathology investigation.

Limbic predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is common in older adults and is associated with neurodegeneration, cognitive decline and dementia. In this MRI and pathology investigation we tested the hypothesis that LATE-NC is associated with abnormalities in white matter structural integrity and connectivity of a network of brain regions typically harboring TDP-43 inclusions in LATE, referred to here as the "LATE-NC network". Ex-vivo diffusion MRI and detailed neuropathological data were collected on 184 community-based older adults. Linear regression revealed an independent association of higher LATE-NC stage with lower diffusion anisotropy in a set of white matter connections forming a pattern of connectivity that is consistent with the stereotypical spread of this pathology in the brain. Graph theory analysis revealed an association of higher LATE-NC stage with weaker integration and segregation in the LATE-NC network. Abnormalities were significant in stage 3, suggesting that they are detectable in later stages of the disease. Finally, LATE-NC network abnormalities were associated with faster cognitive decline, specifically in episodic and semantic memory.

Association of Age-Related Neuropathologic Findings at Autopsy With a Claims-Based Epilepsy Diagnosis in Older Adults.

BACKGROUND AND OBJECTIVES: Epilepsy is 1 of the 3 most common neurologic diseases of older adults, but few studies have examined its underlying pathologies in older age. We examined the associations of age-related brain pathologies with epilepsy in older persons. METHODS: Clinical and pathologic data came from 2 ongoing clinical pathologic cohort studies of community-dwelling older adults. Epilepsy was ascertained using Medicare fee-for-service Parts A and B claims data that were linked to data from the cohort studies. The postmortem pathologic assessment collected indices of 9 pathologies including Alzheimer disease, hippocampal sclerosis, macroinfarcts, and cerebral amyloid angiopathy. The fixed brain hemisphere was imaged using 3T MRI scanners before the pathologic assessments in a subgroup of participants. RESULTS: The participants (n = 1,369) were on average 89.3 (6.6) years at death, and 67.0% were women. Epilepsy was identified in 58 (4.2%) participants. Cerebral amyloid angiopathy (odds ratio [OR] = 2.21, 95% CI 1.24-3.95, p = 0.007) and cortical macroinfarcts (OR = 2.74, 95% CI 1.42-5.28, p = 0.003) were associated with a higher odds of epilepsy. Of note, hippocampal sclerosis and Alzheimer disease pathology were not associated with epilepsy (both p's > 0.25), although hippocampal sclerosis was not common and thus hard to examine with the modest number of epilepsy cases here. In 673 participants with MRI data, the association of cerebral amyloid angiopathy and cortical macroinfarcts with epilepsy did not change after controlling for cortical gray matter atrophy, which was independently associated with a higher odds of epilepsy (OR = 1.06, 95% CI 1.02-1.10, p = 0.003). By contrast, hippocampal volume was not associated with epilepsy. DISCUSSION: Cerebrovascular pathologies and cortical atrophy were associated with epilepsy in older persons.

Atherosclerosis and Hippocampal Volumes in Older Adults: The Role of Age and Blood Pressure.

BACKGROUND: Lower hippocampal volume is associated with late-life cognitive decline and is an important, but nonspecific marker for clinical Alzheimer's dementia. Cerebrovascular disease may also be associated with hippocampal volume. Here we study the role of intracranial large vessel disease (atherosclerosis) in association with hippocampal volume and the potential role of age, average late-life blood pressure across all visits, and other factors (sex, apolipoprotein ε4 [APOE ε4], and diabetes). METHODS AND RESULTS: Data came from 765 community-based older people (91 years old on average at death; 72% women), from 2 ongoing clinical-pathologic cohort studies. Participants completed baseline assessment, annual standardized blood pressure measurements, vascular risk assessment for diabetes, and blood draws to determine APOE genotype, and at death, brains were removed and underwent ex vivo magnetic resonance imaging and neuropathologic evaluation for atherosclerosis pathology and other cerebrovascular and neurodegenerative pathologies. Linear regression models examined the association of atherosclerosis and hippocampal to hemisphere volume ratio and whether age at death, blood pressure, and other factors modified associations. In linear regression models adjusted for demographics and neurodegenerative and other cerebrovascular pathologies, atherosclerosis severity was associated with a lower hippocampal to hemisphere volume ratio. In separate models, we found the effect of atherosclerosis on the ratio of hippocampal to hemisphere volume was attenuated among advanced age at death or having higher systolic blood pressure (interaction terms P≤0.03). We did not find confounding or interactions with sex, diabetes, or APOE ε4. CONCLUSIONS: Atherosclerosis severity is associated with lower hippocampal volume, independent of neurodegenerative and other cerebrovascular pathologies. Higher systolic blood pressures and advanced age attenuate associations.

A new role for IFRD1 in regulation of ER stress in bladder epithelial homeostasis.

A healthy bladder requires the homeostatic maintenance of and rapid regeneration of urothelium upon stress/injury/infection. Several factors have been identified to play important roles in urothelial development, injury and disease response, however, little is known about urothelial regulation at homeostasis. Here, we identify a new role for IFRD1, a stress-induced gene that has recently been demonstrated to play a critical role in adult tissue proliferation and regeneration, in maintenance of urothelial function/ homeostasis in a mouse model. We show that the mouse bladder expresses IFRD1 at homeostasis and its loss alters the global transcriptome of the bladder with significant accumulation of cellular organelles including multivesicular bodies with undigested cargo, lysosomes and mitochondria. We demonstrate that IFRD1 interacts with several mRNA-translation-regulating factors in human urothelial cells and that the urothelium of Ifrd1-/- mice reveal decreased global translation and enhanced endoplasmic reticulum (ER) stress response. Ifrd1-/- bladders have activation of the unfolded protein response (UPR) pathway, specifically the PERK arm, with a concomitant increase in oxidative stress and spontaneous exfoliation of urothelial cells. Further, we show that such increase in cell shedding is associated with a compensatory proliferation of the basal cells but impaired regeneration of superficial cells. Finally, we show that upon loss of IFRD1, mice display aberrant voiding behavior. Thus, we propose that IFRD1 is at the center of many crucial cellular pathways that work together to maintain urothelial homeostasis, highlighting its importance as a target for diagnosis and/or therapy in bladder conditions.

Impact of dementia special care units for short-stay nursing home patients.

BACKGROUND: Improving quality of care provided to short-stay patients with dementia in nursing homes is a policy priority. However, it is unknown whether dementia-focused care strategies are associated with improved clinical outcomes or lower utilization and costs for short-stay dementia patients. METHODS: We performed a national survey of nursing home administrators in 2020-2021, asking about the presence of three dementia-focused care services used for their short-stay patients: (1) a dementia care unit, (2) cognitive deficiency training for staff, and (3) dementia-specific occupational therapy. Using Medicare claims, we identified short-stay episodes for beneficiaries residing in surveyed skilled nursing facilities (SNFs) with and without dementia. We compared clinical, cost, and utilization outcomes for dementia patients in SNFs, which did and did not offer dementia-focused care services. As a counterfactual control, we compared these differences to those for non-dementia patients in the same facilities. Our primary quantity of interest was an interaction term between a patients' dementia status and the presence of a dementia-focused care tool. RESULTS: The study population included 102,860 Medicare episodes of care from 377 SNF survey respondents in 2018-2019. In adjusted comparisons of the interaction between dementia status and the presence of each dementia-focused care tool, dementia care units were associated with a 1.5-day increase in healthy days at home in the 90 days following discharge (p = 0.01) and a 3.1% decrease in the likelihood of a subsequent SNF admission (p = 0.001). Cognitive deficiency training was also associated with a 2.0% increase in antipsychotics (p = 0.03), whereas dementia-specific occupational therapy was associated with a 1.2% increase in falls (p = 0.01) per patient episode. CONCLUSIONS: Self-reported use of dementia care units for short-stay patients was associated with modestly better performance in some, but not all, outcome measures. This provides hypothesis-generating evidence that dementia care units could be a promising mechanism to improve care delivery in nursing homes.

D-Mannose reduces cellular senescence and NLRP3/GasderminD/IL-1ß-driven pyroptotic uroepithelial cell shedding in the murine bladder.

Aging is a risk factor for disease via increased susceptibility to infection, decreased ability to maintain homeostasis, inefficiency in combating stress, and decreased regenerative capacity. Multiple diseases, including urinary tract infection (UTI), are more prevalent with age; however, the mechanisms underlying the impact of aging on the urinary tract mucosa and the correlation between aging and disease remain poorly understood. Here, we show that, relative to young (8-12 weeks) mice, the urothelium of aged (18-24 months) female mice accumulates large lysosomes with reduced acid phosphatase activity and decreased overall autophagic flux in the aged urothelium, indicative of compromised cellular homeostasis. Aged bladders also exhibit basal accumulation of reactive oxygen species (ROS) and a dampened redox response, implying heightened oxidative stress. Furthermore, we identify a canonical senescence-associated secretory phenotype (SASP) in the aged urothelium, along with continuous NLRP3-inflammasome- and Gasdermin-D-dependent pyroptotic cell death. Consequently, aged mice chronically exfoliate urothelial cells, further exacerbating age-related urothelial dysfunction. Upon infection with uropathogenic E. coli, aged mice harbor increased bacterial reservoirs and are more prone to spontaneous recurrent UTI. Finally, we discover that treatment with D-mannose, a natural bioactive monosaccharide, rescues autophagy flux, reverses the SASP, and mitigates ROS and NLRP3/Gasdermin/interleukin (IL)-1ß-driven pyroptotic epithelial cell shedding in aged mice. Collectively, our results demonstrate that normal aging affects bladder physiology, with aging alone increasing baseline cellular stress and susceptibility to infection, and suggest that mannose supplementation could serve as a senotherapeutic to counter age-associated urothelial dysfunction.

ACR Appropriateness Criteria® Breast Implant Evaluation: 2023 Update.

This document discusses the appropriate initial imaging in both asymptomatic and symptomatic patients with breast implants. For asymptomatic patients with saline implants, no imaging is recommended. If concern for rupture exists, ultrasound is usually appropriate though saline rupture is often clinically evident. The FDA recently recommended patients have an initial ultrasound or MRI examination 5 to 6 years after initial silicone implant surgery and then every 2 to 3 years thereafter. In a patient with unexplained axillary adenopathy with current or prior silicone breast implants, ultrasound and/or mammography are usually appropriate, depending on age. In a patient with concern for silicone implant rupture, ultrasound or MRI without contrast is usually appropriate. In the setting of a patient with breast implants and possible implant-associated anaplastic large cell lymphoma, ultrasound is usually appropriate as the initial imaging. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Multichannel laser diode to polymer waveguide array coupling with a double-aspheric lens.

An optical system for multichannel coupling of laser arrays to polymer waveguide array probes with a single biconvex lens is developed. The developed cylindrical module with 13 mm and 20 mm in diameter and length, respectively, enables coupling of eight individual optical channels using an aspheric lens. Specific coupling with crosstalk below -13d B for each channel and quasi-uniform coupling over all channels is achieved for a waveguide array with 100 µm lateral facet pitch at the incoupling site. The polymer waveguide technology allows for tapering of the lateral waveguide pitch to 25 µm toward the tip of the flexible waveguide array. SU-8 and PMMA are used as the waveguide core and cladding, respectively. The optical coupling module is designed as a prototype for preclinical evaluation of optical neural stimulators.

Multi-Site Cross-Site Inter-Rater and Test-Retest Reliability and Construct Validity of the MarkVCID White Matter Hyperintensity Growth and Regression Protocol.

BACKGROUND: White matter hyperintensities (WMH) that occur in the setting of vascular cognitive impairment and dementia (VCID) may be dynamic increasing or decreasing volumes or stable over time. Quantifying such changes may prove useful as a biomarker for clinical trials designed to address vascular cognitive-impairment and dementia and Alzheimer's Disease. OBJECTIVE: Conducting multi-site cross-site inter-rater and test-retest reliability of the MarkVCID white matter hyperintensity growth and regression protocol. METHODS: The NINDS-supported MarkVCID Consortium evaluated a neuroimaging biomarker developed to track WMH change. Test-retest and cross-site inter-rater reliability of the protocol were assessed. Cognitive test scores were analyzed in relation to WMH changes to explore its construct validity. RESULTS: ICC values for test-retest reliability of WMH growth and regression were 0.969 and 0.937 respectively, while for cross-site inter-rater ICC values for WMH growth and regression were 0.995 and 0.990 respectively. Word list long-delay free-recall was negatively associated with WMH growth (p < 0.028) but was not associated with WMH regression. CONCLUSIONS: The present data demonstrate robust ICC validity of a WMH growth/regression protocol over a one-year period as measured by cross-site inter-rater and test-retest reliability. These data suggest that this approach may serve an important role in clinical trials of disease-modifying agents for VCID that may preferentially affect WMH growth, stability, or regression.

Unlocking the Potential of CuAgZr Metallic Glasses: A Comprehensive Exploration with Combinatorial Synthesis, High-Throughput Characterization, and Machine Learning.

In this work, the CuAgZr metallic glasses (MGs) are investigated, a promising material for biomedical applications due to their high strength, corrosion resistance, and antibacterial activity. Using an integrated approach of combinatorial synthesis, high-throughput characterization, and machine learning (ML), the mechanical properties of CuAgZr MGs are efficiently explored. The investigation find that post-deposition oxidation in inter-columnar regions with looser packing causes high oxygen content in Cu-rich regions, significantly affecting the alloys' mechanical behavior. The study also reveals that nanoscale structural features greatly impact plastic yielding and flow in the alloys. ML algorithms are tested, and the multi-layer perceptron algorithm produced satisfactory predictions for the alloys' hardness of untested alloys, providing valuable clues for future research. The work demonstrates the potential of using combinatorial synthesis, high-throughput characterization, and ML  techniques to facilitate the development of new MGs with improved strength and economic feasibility.

Changes in Cardiovascular Spending, Care Utilization, and Clinical Outcomes Associated With Participation in Bundled Payments for Care Improvement - Advanced.

BACKGROUND: Bundled Payments for Care Improvement - Advanced (BPCI-A) is a Medicare initiative that aims to incentivize reductions in spending for episodes of care that start with a hospitalization and end 90 days after discharge. Cardiovascular disease, an important driver of Medicare spending, is one of the areas of focus BPCI-A. It is unknown whether BPCI-A is associated with spending reductions or quality improvements for the 3 cardiovascular medical events or 5 cardiovascular procedures in the model. METHODS: In this retrospective cohort study, we conducted difference-in-differences analyses using Medicare claims for patients discharged between January 1, 2017, and September 30, 2019, to assess differences between BPCI-A hospitals and matched nonparticipating control hospitals. Our primary outcomes were the differential changes in spending, before versus after implementation of BPCI-A, for cardiac medical and procedural conditions at BPCI-A hospitals compared with controls. Secondary outcomes included changes in patient complexity, care utilization, healthy days at home, readmissions, and mortality. RESULTS: Baseline spending for cardiac medical episodes at BPCI-A hospitals was $25 606. The differential change in spending for cardiac medical episodes at BPCI-A versus control hospitals was $16 (95% CI, -$228 to $261; P=0.90). Baseline spending for cardiac procedural episodes at BPCI-A hospitals was $37 961. The differential change in spending for cardiac procedural episodes was $171 (95% CI, -$429 to $772; P=0.58). There were minimal differential changes in physicians' care patterns such as the complexity of treated patients or in their care utilization. At BPCI-A versus control hospitals, there were no significant differential changes in rates of 90-day readmissions (differential change, 0.27% [95% CI, -0.25% to 0.80%] for medical episodes; differential change, 0.31% [95% CI, -0.98% to 1.60%] for procedural episodes) or mortality (differential change, -0.14% [95% CI, -0.50% to 0.23%] for medical episodes; differential change, -0.36% [95% CI, -1.25% to 0.54%] for procedural episodes). CONCLUSIONS: Participation in BPCI-A was not associated with spending reductions, changes in care utilization, or quality improvements for the cardiovascular medical events or procedures offered in the model.

Intra-Arterial Thrombolysis is Associated with Delayed Reperfusion of Remaining Vessel Occlusions following Incomplete Thrombectomy.

BACKGROUND AND PURPOSE: Intra-arterial thrombolytics may be used to treat distal vessel occlusions, which cause incomplete reperfusion following mechanical thrombectomy. Because immediate reperfusion after intra-arterial thrombolytics occurs rarely, the aim of this study was to assess the delayed effect of intra-arterial thrombolytics using follow-up perfusion imaging. MATERIALS AND METHODS: We included patients from a prospective stroke registry (February 2015 to September 2022) who had undergone mechanical thrombectomy and had incomplete reperfusion (expanded TICI 2a-2c) and available 24 hour perfusion imaging. Perfusion imaging was rated as delayed reperfusion if time-sensitive perfusion maps did not show wedge-shaped delays suggestive of persisting occlusions corresponding to the post-mechanical thrombectomy angiographic deficit. Patients treated with intra-arterial thrombolytics were compared with controls using multivariable logistic regression and inverse probability of treatment weighting matching for baseline differences and factors associated with delayed reperfusion. RESULTS: The median age of the final study population (n = 459) was 74 years (interquartile range, 63-81 years), and delayed reperfusion occurred in 61% of cases. Patients treated with additional intra-arterial thrombolytics (n = 40) were younger and had worse expanded TICI scores. After matching was performed, intra-arterial thrombolytics was associated with higher rates of delayed reperfusion (adjusted OR = 2.7; 95% CI, 1.1-6.4) and lower rates of new infarction in the residually hypoperfused territory after mechanical thrombectomy (adjusted OR = 0.3; 95% CI, 0.1-0.7). No difference was found in the rates of functional independence (90-day mRS, 0-2; adjusted OR = 1.4; 95% CI, 0.4-4.1). CONCLUSIONS: Rescue intra-arterial thrombolytics is associated with delayed reperfusion of remaining vessel occlusions following incomplete mechanical thrombectomy. The value of intra-arterial thrombolytics as a potential therapy for incomplete reperfusions after mechanical thrombectomy should be assessed in the setting of randomized controlled trials.

Diagnosis and Management of Severe Water-Related Skin and Soft Tissue Sepsis: A Summative Review of the Literature.

BACKGROUND: Skin and soft tissue infections (SSTIs) are common presentations in the emergency department. However, this is less common after contact with contaminated saltwater or freshwater. This review presents the diagnosis and management of water-related soft tissue sepsis in this vulnerable and difficult-to-treat subgroup of necrotizing soft tissue sepsis. METHODS: A summative literature overview is presented regarding bacterial and fungal SSTI after contact with contaminated water, with practical diagnostic and management aspects. RESULTS: The literature indicates that these wounds and infections remain difficult to treat. An approach using appropriate diagnostic tools with both medical and surgical management strategies is provided. CONCLUSIONS: SSTIs due to water contamination of wounds involve unusual organisms with unusual resistance patterns, and require a nuanced and directed diagnostic approach with an adaptation of the usual antibiotic or antifungal selection to achieve a successful cure, along with aggressive debridement and wound care.

Neuropathologic correlates of cerebral microbleeds in community-based older adults.

Cerebral microbleeds (CMBs) appearing as hypointense foci on T2*-weighted magnetic resonance images are small hemorrhages that have been linked to cognitive decline and increased mortality. However, the neuropathologic correlates of CMBs in community-based older adults are poorly understood. The present study investigated the association of age-related neuropathologies with CMBs in community-based older adults. Cerebral hemispheres from 289 participants of the Rush Memory and Aging Project, Religious Orders Study, Minority Aging Research Study, and Rush Alzheimer's Disease Clinical Core underwent ex vivo MRI and detailed neuropathologic examination. Following Bonferroni correction, CMBs in the cerebrum overall and in the frontal lobe were associated with cerebral amyloid angiopathy, CMBs in the frontal lobe were also associated with arteriolosclerosis, and CMBs in the basal ganglia showed a borderline significant association with microinfarcts. These findings suggest that CMBs can aid in the prediction of small vessel disease in community-based older adults. Finally, CMBs were not associated with dementia, suggesting that CMBs in community-based older adults may not be linked to substantial cognitive impairment.

Applications of machine learning in animal and veterinary public health surveillance.

Machine learning (ML) is an approach to artificial intelligence characterised by the use of algorithms that improve their own performance at a given task (e.g. classification or prediction) based on data and without being explicitly and fully instructed on how to achieve this. Surveillance systems for animal and zoonotic diseases depend upon effective completion of a broad range of tasks, some of them amenable to ML algorithms. As in other fields, the use of ML in animal and veterinary public health surveillance has greatly expanded in recent years. Machine learning algorithms are being used to accomplish tasks that have become attainable only with the advent of large data sets, new methods for their analysis and increased computing capacity. Examples include the identification of an underlying structure in large volumes of data from an ongoing stream of abattoir condemnation records, the use of deep learning to identify lesions in digital images obtained during slaughtering, and the mining of free text in electronic health records from veterinary practices for the purpose of sentinel surveillance. However, ML is also being applied to tasks that previously relied on traditional statistical data analysis. Statistical models have been used extensively to infer relationships between predictors and disease to inform risk-based surveillance, and increasingly, ML algorithms are being used for prediction and forecasting of animal diseases in support of more targeted and efficient surveillance. While ML and inferential statistics can accomplish similar tasks, they have different strengths, making one or the other more or less appropriate in a given context.

L'apprentissage automatique (AA) est une approche de l'intelligence artificielle caractérisée par l'utilisation d'algorithmes qui améliorent leurs propres performances sur une tâche donnée (par exemple, la classification ou la prédiction) sur la base de données et sans avoir reçu d'instructions spécifiques ou complètes concernant la marche à suivre. Les systèmes de surveillance des maladies animales et des zoonoses sont tributaires de la mise en oeuvre efficace d'un large éventail de tâches, parmi lesquelles certaines sont susceptibles de fonctionner avec des algorithmes d'AA. Comme dans d'autres domaines, l'utilisation de l'AA s'est beaucoup développée ces dernières années dans le secteur de la surveillance de la santé animale et de la santé publique vétérinaire. Les algorithmes d'AA sont utilisés pour accomplir des tâches qui ne sont devenues possibles que grâce à l'arrivée de grandes séries de données, de nouvelles méthodes d'analyse et de capacités informatiques accrues. Parmi les exemples, on peut citer la capacité à déceler une structure sous-jacente dans de grands volumes de données provenant d'un flux continu de registres de saisies d'abattoirs, l'utilisation de l'apprentissage profond pour identifier les lésions révélées par les images numériques obtenues pendant l'abattage et l'extraction de texte libre à partir des registres sanitaires électroniques des cabinets vétérinaires à des fins de surveillance sentinelle. L'AA est cependant également appliqué dans des tâches qui s'appuyaient précédemment sur une analyse classique de données statistiques. Les modèles statistiques ont été largement utilisés pour déduire des relations entre prédicteurs et maladie afin d'étayer la surveillance fondée sur le risque ; les algorithmes d'AA sont de plus en plus utilisés pour prédire et pronostiquer des maladies animales en vue d'une surveillance plus ciblée et efficace. S'il est vrai que l'AA et la statistique inférentielle peuvent accomplir des tâches similaires, chaque approche présente ses propres atouts et pourra se révéler plus ou moins pertinente selon le contexte spécifique.

El aprendizaje automático es una vertiente de la inteligencia artificial que se caracteriza por el uso de algoritmos capaces de mejorarse a sí mismos en la ejecución de una determinada tarea (p.ej., procesos de clasificación o predicción) con empleo de datos y sin necesidad de recibir instrucciones explícitas y completas sobre la manera de lograrlo. Los sistemas de vigilancia de enfermedades animales y zoonóticas dependen de la ejecución eficaz de numerosas y muy diversas tareas, algunas de las cuales se prestan al uso de algoritmos de aprendizaje automático. Al igual que en otros campos, la aplicación del aprendizaje automático en sanidad animal y salud pública veterinaria se ha extendido sobremanera en los últimos años. Ahora se utilizan algoritmos de aprendizaje automático para realizar tareas que solo han empezado a ser factibles con el advenimiento de ingentes conjuntos de datos, nuevos métodos para analizarlos y una mayor capacidad de tratamiento informático. Entre otros ejemplos, cabe citar la determinación de la estructura subyacente de grandes volúmenes de datos procedentes de un flujo continuo de registros de los descartes de matadero; la utilización del aprendizaje profundo para detectar lesiones en imágenes digitales obtenidas durante las operaciones de sacrificio, o el análisis del texto libre de registros sanitarios electrónicos de procedimientos veterinarios con fines de vigilancia centinela. Con todo, el aprendizaje automático se está aplicando también a tareas que anteriormente reposaban en el análisis estadístico clásico de los datos. Los modelos estadísticos han sido extensamente utilizados para inferir relaciones entre una enfermedad y uno u otro predictor y alimentar a partir de ahí la vigilancia basada en el riesgo. Por otro lado, cada vez más se vienen empleando algoritmos de aprendizaje automático para predecir y anticipar enfermedades animales y conferir así más eficacia y especificidad a las actividades de vigilancia. Aunque el aprendizaje automático y la estadística inferencial realizan tareas parecidas, sus puntos fuertes son distintos, con lo cual, en función del contexto de que se trate, será preferible recurrir a uno u otro método.

Reservoir computing using networks of memristors: effects of topology and heterogeneity.

Reservoir computing (RC) has attracted significant interest as a framework for the implementation of novel neuromorphic computing architectures. Previously attention has been focussed on software-based reservoirs, where it has been demonstrated that reservoir topology plays a role in task performance, and functional advantage has been attributed to small-world and scale-free connectivity. However in hardware systems, such as electronic memristor networks, the mechanisms responsible for the reservoir dynamics are very different and the role of reservoir topology is largely unknown. Here we compare the performance of a range of memristive reservoirs in several RC tasks that are chosen to highlight different system requirements. We focus on percolating networks of nanoparticles (PNNs) which are novel self-assembled nanoscale systems that exhibit scale-free and small-world properties. We find that the performance of regular arrays of uniform memristive elements is limited by their symmetry but that this symmetry can be broken either by a heterogeneous distribution of memristor properties or a scale-free topology. The best perfomance across all tasks is observed for a scale-free network with uniform memistor properties. These results provide insight into the role of topology in neuromorphic reservoirs as well as an overview of the computational performance of scale-free networks of memristors in a range of benchmark tasks.

Mechanisms underlying the efficacy of a rodent model of vertical sleeve gastrectomy - A focus on energy expenditure.

OBJECTIVE: Bariatric surgery remains the only effective and durable treatment option for morbid obesity. Vertical Sleeve Gastrectomy (VSG) is currently the most widely performed of these surgeries primarily because of its proven efficacy in generating rapid onset weight loss, improved glucose regulation and reduced mortality compared with other invasive procedures. VSG is associated with reduced appetite, however, the relative importance of energy expenditure to VSG-induced weight loss and changes in glucose regulation, particularly that in brown adipose tissue (BAT), remains unclear. The aim of this study was to investigate the role of BAT thermogenesis in the efficacy of VSG in a rodent model. METHODS: Diet-induced obese male Sprague-Dawley rats were either sham-operated, underwent VSG surgery or were pair-fed to the food consumed by the VSG group. Rats were also implanted with biotelemetry devices between the interscapular lobes of BAT to assess local changes in BAT temperature as a surrogate measure of thermogenic activity. Metabolic parameters including food intake, body weight and changes in body composition were assessed. To further elucidate the contribution of energy expenditure via BAT thermogenesis to VSG-induced weight loss, a separate cohort of chow-fed rats underwent complete excision of the interscapular BAT (iBAT lipectomy) or chemical denervation using 6-hydroxydopamine (6-OHDA). To localize glucose uptake in specific tissues, an oral glucose tolerance test was combined with an intraperitoneal injection of 14C-2-deoxy-d-glucose (14C-2DG). Transneuronal viral tracing was used to identify 1) sensory neurons directed to the stomach or small intestine (H129-RFP) or 2) chains of polysynaptically linked neurons directed to BAT (PRV-GFP) in the same animals. RESULTS: Following VSG, there was a rapid reduction in body weight that was associated with reduced food intake, elevated BAT temperature and improved glucose regulation. Rats that underwent VSG had elevated glucose uptake into BAT compared to sham operated animals as well as elevated gene markers related to increased BAT activity (Ucp1, Dio2, Cpt1b, Cox8b, Ppargc) and markers of increased browning of white fat (Ucp1, Dio2, Cited1, Tbx1, Tnfrs9). Both iBAT lipectomy and 6-OHDA treatment significantly attenuated the impact of VSG on changes in body weight and adiposity in chow-fed animals. In addition, surgical excision of iBAT following VSG significantly reversed VSG-mediated improvements in glucose tolerance, an effect that was independent of circulating insulin levels. Viral tracing studies highlighted a patent neural link between the gut and BAT that included groups of premotor BAT-directed neurons in the dorsal raphe and raphe pallidus. CONCLUSIONS: Collectively, these data support a role for BAT in mediating the metabolic sequelae following VSG surgery, particularly the improvement in glucose regulation, and highlight the need to better understand the contribution from this tissue in human patients.

Effects of rIL2/anti-IL2 antibody complex on chikungunya virus-induced chronic arthritis in a mouse model.

Chikungunya virus (CHIKV) is characterized by disabling joint pain that can cause persistent arthritis in approximately one-fourth of patients. Currently, no standard treatments are available for chronic CHIKV arthritis. Our preliminary data suggest that decreases in interleukin-2 (IL2) levels and regulatory T cell (Treg) function may play a role in CHIKV arthritis pathogenesis. Low-dose IL2-based therapies for autoimmune diseases have been shown to up-regulate Tregs, and complexing IL2 with anti-IL2 antibodies can prolong the half-life of IL2. A mouse model for post-CHIKV arthritis was used to test the effects of recombinant IL2 (rIL2), an anti-IL2 monoclonal antibody (mAb), and the complex on tarsal joint inflammation, peripheral IL2 levels, Tregs, CD4 + effector T cells (Teff), and histological disease scoring. The complex treatment resulted in the highest levels of IL2 and Tregs, but also increased Teffs, and therefore did not significantly reduce inflammation or disease scores. However, the antibody group, which had moderately increased levels of IL2 and activated Tregs, resulted in a decreased average disease score. These results suggest the rIL2/anti-IL2 complex stimulates both Tregs and Teffs in post-CHIKV arthritis, while the anti-IL2 mAb increases IL2 availability enough to shift the immune environment towards a tolerogenic one.

Association of Radiotherapy Duration With Clinical Outcomes in Patients With Esophageal Cancer Treated in NRG Oncology Trials: A Secondary Analysis of NRG Oncology Randomized Clinical Trials.

Importance: For many types of epithelial malignant neoplasms that are treated with definitive radiotherapy (RT), treatment prolongation and interruptions have an adverse effect on outcomes. Objective: To analyze the association between RT duration and outcomes in patients with esophageal cancer who were treated with definitive chemoradiotherapy (CRT). Design, Setting, and Participants: This study was an unplanned, post hoc secondary analysis of 3 prospective, multi-institutional phase 3 randomized clinical trials (Radiation Therapy Oncology Group [RTOG] 8501, RTOG 9405, and RTOG 0436) of the National Cancer Institute-sponsored NRG Oncology (formerly the National Surgical Adjuvant Breast and Bowel Project, RTOG, and Gynecologic Oncology Group). Enrolled patients with nonmetastatic esophageal cancer underwent definitive CRT in the trials between 1986 and 2013, with follow-up occurring through 2014. Data analyses were conducted between March 2022 to February 2023. Exposures: Treatment groups in the trials used standard-dose RT (50 Gy) and concurrent chemotherapy. Main Outcomes and Measures: The outcomes were local-regional failure (LRF), distant failure, disease-free survival (DFS), and overall survival (OS). Multivariable models were used to examine the associations between these outcomes and both RT duration and interruptions. Radiotherapy duration was analyzed as a dichotomized variable using an X-Tile software to choose a cut point and its median value as a cut point, as well as a continuous variable. Results: The analysis included 509 patients (median [IQR] age, 64 [57-70] years; 418 males [82%]; and 376 White individuals [74%]). The median (IQR) follow-up was 4.01 (2.93-4.92) years for surviving patients. The median cut point of RT duration was 39 days or less in 271 patients (53%) vs more than 39 days in 238 patients (47%), and the X-Tile software cut point was 45 days or less in 446 patients (88%) vs more than 45 days in 63 patients (12%). Radiotherapy interruptions occurred in 207 patients (41%). Female (vs male) sex and other (vs White) race and ethnicity were associated with longer RT duration and RT interruptions. In the multivariable models, RT duration longer than 45 days was associated with inferior DFS (hazard ratio [HR], 1.34; 95% CI, 1.01-1.77; P = .04). The HR for OS was 1.33, but the results were not statistically significant (95% CI, 0.99-1.77; P = .05). Radiotherapy duration longer than 39 days (vs ≤39 days) was associated with a higher risk of LRF (HR, 1.32; 95% CI, 1.06-1.65; P = .01). As a continuous variable, RT duration (per 1 week increase) was associated with DFS failure (HR, 1.14; 95% CI, 1.01-1.28; P = .03). The HR for LRF 1.13, but the result was not statistically significant (95% CI, 0.99-1.28; P = .07). Conclusions and Relevance: Results of this study indicated that in patients with esophageal cancer receiving definitive CRT, prolonged RT duration was associated with inferior outcomes; female patients and those with other (vs White) race and ethnicity were more likely to have longer RT duration and experience RT interruptions. Radiotherapy interruptions should be minimized to optimize outcomes.

Medicare Skilled Nursing Facility Use and Spending Before and After Introduction of the Public Health Emergency Waiver During the COVID-19 Pandemic.

Importance: In response to the COVID-19 pandemic, Medicare introduced a public health emergency (PHE) waiver in March 2020, removing a 3-day hospitalization requirement before fee-for-service beneficiaries could receive skilled nursing facility (SNF) care benefits. Objective: To assess whether there were changes in SNF episode volume and Medicare spending on SNF care before and during the PHE among long-term care (LTC) residents and other Medicare beneficiaries. Design, Setting, and Participants: This retrospective cohort study used Medicare fee-for-service claims and the Minimum Data Set for Medicare beneficiaries who were reimbursed for SNF care episodes from January 2018 to September 2021 in US SNFs. Exposures: The prepandemic period (January 2018-February 2020) vs the PHE period (March 2020-September 2021). Main Outcomes and Measures: The main outcomes were SNF episode volume, characteristics, and costs. Episodes were defined as standard (with a preceding 3-day hospitalization) or waiver (with other or no acute care use). Results: Skilled nursing facility care was provided to 4 299 863 Medicare fee-for-service beneficiaries. Medicare beneficiaries had on average 130 400 monthly SNF episodes in the prepandemic period (mean [SD] age of beneficiaries, 78.9 [11.0] years; 59% female) and 108 575 monthly episodes in the PHE period (mean [SD] age of beneficiaries, 79.0 [11.1] years; 59% female). All waiver episodes increased from 6% to 32%, and waiver episodes without preceding acute care increased from 3% to 18% (from 4% to 49% among LTC residents). Skilled nursing facility episodes provided for LTC residents increased by 77% (from 15 538 to 27 537 monthly episodes), primarily due to waiver episodes provided for residents with COVID-19 in 2020 and early 2021 (62% of waiver episodes without preceding acute care). Skilled nursing facilities in the top quartile of waiver episodes were more often for-profit (80% vs 68%) and had lower quality ratings (mean [SD] overall star rating, 2.7 [1.4] vs 3.2 [1.4]; mean [SD] staffing star rating, 2.5 [1.1] vs 3.0 [1.2]) compared with SNFs in the other quartiles. Monthly Medicare spending on SNF care was $2.1 billion before the pandemic and $2.0 billion during the PHE. For LTC residents, monthly SNF spending increased from $301 million to $585 million while spending on hospitalizations remained relatively stable. Conclusions and Relevance: This cohort study found that the PHE waiver for SNF care was associated with a marked increase in the prevalence of SNF episodes without a preceding hospitalization, especially in the first year of the COVID-19 pandemic. The waiver was used primarily among certain types of facilities and for LTC residents with COVID-19. Although the effect of the waiver cannot be differentiated from that of the pandemic, overall SNF care costs did not increase substantially; for LTC residents, the waiver was applied primarily for COVID-19 care, suggesting the waiver's successful implementation.