Neuropsychiatric symptom burden in early-onset and late-onset Alzheimer's disease as a function of age.

INTRODUCTION: We examined the burden of neuropsychiatric symptoms (NPSs) in early-onset (EO) and late-onset (LO) Alzheimer's disease (AD) and adjusted for age effects via the inclusion of cognitively unimpaired (CU) individuals. METHODS: Cross-sectional data from 2940 EOAD, 8665 LOAD, and 8775 age-stratified CU individuals (early-CU, n = 2433; late-CU, n = 6342) from the National Alzheimer's Coordinating Center database were included. Fisher's exact tests compared EOAD and LOAD on the presence and severity of NPSs. Multiple logistic regression models included an age*diagnosis interaction to examine age effects. RESULTS: Presence (ps < 0.0001) and severity (ps < 0.05) of NPS were greater in EOAD than in LOAD. However, after adjusting for base rates in NPS in CU individuals (age effects), only elation and eating behaviors were more frequent in EOAD (ps < 0.05) and nighttime behaviors more frequent and severe in LOAD (ps < 0.05). DISCUSSION: Few NPSs were specific to the EOAD versus LOAD. Previous findings of greater NPS burden in EOAD may partially reflect age effects. HIGHLIGHTS: Adjusting for age effect, elation and eating problems are more frequent in EOAD. Adjusting for age effect, sleep disturbances are more frequent and severe in LOAD. Age effects underlie higher neuropsychiatric symptom presentation in EOAD than in LOAD.

Outcomes of patients with limited-stage plasmablastic lymphoma: A multi-institutional retrospective study.

Plasmablastic lymphoma (PBL) is a rare entity, commonly associated with immunosuppressed states such as human immunodeficiency virus (HIV) infection or solid organ transplant. The clinical course is characterized by high relapse rates and a poor prognosis, leading some clinicians to recommend aggressive frontline therapy. However, a specific review of limited stage (LS) PBL patients is not available to evaluate outcomes and justify treatment recommendations. We performed a retrospective review of LS PBL cases to provide insight into this rare disease. Our cohort consisted of 80 stage I or II PBL patients from 13 US academic centers. With a median follow up of 34 months (1-196), the 3-year progression-free survival (PFS) and overall survival (OS) of the entire cohort were 72% (95% CI 62, 83) and 79% (95% CI 70, 89), respectively. The 3-year PFS and OS of patients treated with frontline chemotherapy alone was 65% (95% CI 50, 84) and 71% (95% CI 56, 89), respectively, compared to 85% (95% CI 72, 100) and 96% (95% CI 89, 100), respectively, in patients treated with combined frontline chemotherapy with radiation consolidation. Our data demonstrate favorable outcomes in LS PBL with no improvements in outcome from aggressive frontline treatment including Hyper-CVAD or auto-SCT consolidation. Multivariate regression analysis (MRA) demonstrated improved PFS for patients receiving EPOCH based frontline therapy versus CHOP (HR: 0.23; p = 0.029). Frontline chemotherapy followed by radiation consolidation versus chemotherapy alone appeared to be associated with improved relapse and survival outcomes but did not show statistical significance in MRA.

Do Socioeconomic Status and Race Impact the Safety and Efficacy of Breast Reconstruction?

INTRODUCTION: Immediate breast reconstruction after mastectomy has increased in recent years when compared with delayed reconstruction. Despite this encouraging trend, racial and socioeconomic disparities in the receipt of postmastectomy breast reconstruction have been well documented. We sought to assess the effect of race, socioeconomic status, and patient comorbidities on muscle sparing transverse rectus abdominis myocutaneous outcomes at our safety net hospital institution in the southeast. METHODS: The database of a tertiary referral center was queried for patients who received free transverse rectus abdominis myocutaneous flaps for immediate reconstruction after mastectomy meeting inclusion criteria from 2006 to 2020. Patient demographics and outcomes were compared based on socioeconomic status. The primary outcome (reconstructive success) was defined as breast reconstruction without flap loss. Statistical analysis included analysis of variance and χ2 tests were appropriate using Rstudio. RESULTS: Three-hundred fourteen patients were included in the study, with 76% White, 16% Black, and 8% other. Overall complication rate at our institution was 17% and reconstructive success was 94%. Non-White race, older age at time of breast cancer diagnosis, higher body mass index, and presence of comorbid conditions including current smoking and hypertension were all associated with low socioeconomic status. Despite this, surgical complication rates were not predicted by non-White race, older age, or presence of diabetes mellitus. When analyzing major and minor complications based on radiation received or reconstructive success, there was no significant difference regardless of radiation treatment with the group overall achieving a 94% success rate (P = 0.229). CONCLUSIONS: This study aimed to characterize the impact of socioeconomic status and race/ethnic status of patients on breast reconstruction outcomes at an institution in the South. We found that despite the greater morbidity in low income and ethnic/minority patients that when treated by a comprehensive safety net institution, they had excellent reconstructive outcomes due to low complications and minimal reoperations.

Baseline neuropsychiatric symptoms and psychotropic medication use midway through data collection of the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) cohort.

INTRODUCTION: We examined neuropsychiatric symptoms (NPS) and psychotropic medication use in a large sample of individuals with early-onset Alzheimer's disease (EOAD; onset 40-64 years) at the midway point of data collection for the Longitudinal Early-onset Alzheimer's Disease Study (LEADS). METHODS: Baseline NPS (Neuropsychiatric Inventory - Questionnaire; Geriatric Depression Scale) and psychotropic medication use from 282 participants enrolled in LEADS were compared across diagnostic groups - amyloid-positive EOAD (n = 212) and amyloid negative early-onset non-Alzheimer's disease (EOnonAD; n = 70). RESULTS: Affective behaviors were the most common NPS in EOAD at similar frequencies to EOnonAD. Tension and impulse control behaviors were more common in EOnonAD. A minority of participants were using psychotropic medications, and use was higher in EOnonAD. DISCUSSION: Overall NPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants. Future research will investigate moderators and etiological drivers of NPS, and NPS differences in EOAD versus late-onset AD.

Validation of the IMPEDE VTE score for prediction of venous thromboembolism in multiple myeloma: a retrospective cohort study.

The IMPEDE VTE score has recently emerged as a novel risk prediction tool for venous thromboembolism (VTE) in multiple myeloma (MM). We retrospectively reviewed 839 patients with newly diagnosed MM between 2010 and 2015 at Cleveland Clinic and included 575 patients in final analysis to validate this score. The c-statistic of the IMPEDE VTE score to predict VTE within 6 months of treatment start was 0·68 (95% CI: 0·61-0·75). The 6-month cumulative incidence of VTE was 5·0% (95% CI: 2·1-7·9) in the low risk group, compared to 12·6% (95% CI: 8·9-16·4%) and 24·1% (95% CI: 12·2-36·1) in the intermediate and high risk groups (P < 0·001 for both). In addition, a higher proportion of patients in the VTE cohort had ECOG performance status of ≥2 as compared to the no VTE cohort (33% vs. 16%, P = 0·001). Other MM characteristics such as stage, immunoglobulin subtype, and cytogenetics were not predictors of VTE. In summary, we have validated the IMPEDE VTE score in our patient cohort and our findings suggest that it can be utilized as a VTE risk stratification tool in prospective studies looking into investigating VTE prophylaxis strategies in MM patients.

"Se extraña todo:" Family separation and reunification experiences among unaccompanied adolescent migrants from Central America.

There has been a record surge of unaccompanied immigrant minors (UAMs) entering the United States, with 86% of those apprehended at the US-Mexico border originating from the Central American countries of El Salvador, Guatemala, and Honduras. A majority of immigrant children are separated from either one or both parents at various points during the migration process. Although average separations last 4 or more years, and may be deeply distressing, there is little research on family separations among Central American UAMs. Further, little is known about the developmental impact of separations from extended family networks, or about reunification. To address these empirical gaps, this study used community-participatory qualitative methods to deeply explore the lived experiences and emotional repercussions of family separation and reunification. The sample included 42 adolescents who had all recently migrated to the Western United States from Central America. Thematic analyses revealed that separation experiences are distressing, multifaceted, and have important developmental implications for Central American UAMs. Results illustrate the socioemotional toll that family separation and reunification can have on this vulnerable population, and highlight the need for culturally responsive, developmentally informed, and contextually appropriate care focused on family reunification in order to foster healthy psychosocial adjustment among UAMs.

Venous thromboembolism risk with contemporary lenalidomide-based regimens despite thromboprophylaxis in multiple myeloma: A systematic review and meta-analysis.

BACKGROUND: Thromboprophylaxis is routinely used with lenalidomide-based regimens in multiple myeloma because of a substantial risk of venous thromboembolism (VTE). However, little is known about the incidence of VTE with contemporary lenalidomide-based regimens. The objective of the current study was to estimate the incidence of VTE despite thromboprophylaxis with currently used lenalidomide-based regimens in patients with myeloma. METHODS: The Ovid MEDLINE, Embase, and Cochrane databases were queried from study inception to January 2019 for keywords to cover the following concepts: "lenalidomide," "venous thromboembolism," and "multiple myeloma." Phase 1, 2, and 3 clinical trials evaluating lenalidomide-based regimens with thromboprophylaxis were included. The pooled incidence rate of VTE was estimated using a random-effects model. RESULTS: The search generated 1372 citations, with 51 clinical trials and 9069 patients included for analysis. The most common thromboprophylaxis agents were aspirin, low-molecular-weight heparin or warfarin, administered either per risk-stratification or at investigators' discretion. The pooled incidence of VTE in trials of patients who had newly diagnosed and relapsed/refractory myeloma was 6.2% (95% CI, 5.4%-7.1%) over median treatment durations ranging from 2 to 34 cycles, which translated into 1.2 VTE events per 100 patient-cycles (95% CI, 0.9-1.7 VTE events per 100 patient-cycles). Among contemporary regimens, the risk of VTE was low with combined lenalidomide and low-dose dexamethasone (0.2 [95% CI, 0.1-0.6] events/100 patient-cycles) and lenalidomide maintenance (0.0 [95% CI, 0.0-0.7] events per 100 patient-cycles). VTE risk was higher with combined lenalidomide and low-dose dexamethasone plus proteasome inhibitors (1.3 [95% CI, 0.7-2.3] events per 100 patient-cycles). CONCLUSIONS: Despite adequate thromboprophylaxis, lenalidomide-based regimens have a substantial risk of VTE in controlled clinical trial settings. Further studies are needed on new thromboprophylaxis strategies with regimens that have a high VTE risk.

Socioeconomic associations of poorly controlled epilepsy in the Republic of Guinea: cross-sectional study.

OBJECTIVE: To explore the socioeconomic factors associated with epilepsy in the Republic of Guinea. METHODS: People living with epilepsy (PLWE) were prospectively recruited at Ignace Deen Hospital, Conakry, in 2018. An instrument exploring household assets as a measure of wealth was designed and administered. Multivariate logistic regression models with fixed effects were fitted to assess the associations of sociodemographic and microeconomic factors with self-reported frequency of seizures in the prior month and regular intake of antiseizure medications (ASMs). Participants were stratified by age group: children (<13 years), adolescents (13-21) and adults (>21). RESULTS: A total of 285 participants (mean age 19.5 years; 129 females; 106 children, 72 adolescents, 107 adults, median household size 8) had an average of 4.2 seizures in the prior month. 64% were regularly taking ASMs. Direct costs of epilepsy were similar across income strata, averaging 60 USD/month in the lowest and 75 USD/month in the highest wealth quintiles (P = 0.42). The poorest PLWE were more likely to spend their money on traditional treatments (average 35USD/month) than on medical consultations (average 11 USD/month) (P = 0.01), whereas the wealthiest participants were not. Higher seizure frequency was associated with a lower household education level in adolescents and children (P = 0.028; P = 0.026) and with being male (P = 0.009) in children. Adolescents in higher-educated households were more likely to take ASMs (P = 0.004). Boys were more likely to regularly take ASMs than girls (P = 0.047). CONCLUSIONS: Targeted programming for children and adolescents in the households with the lowest education and for girls would help improve epilepsy care in Guinea.

OBJECTIF: Explorer les facteurs socioéconomiques associés à l'épilepsie en République de Guinée. MÉTHODES: Des personnes vivant avec l'épilepsie (PVE) ont été recrutées prospectivement à l'hôpital Ignace Deen, à Conakry, en 2018. Un outil explorant les actifs des ménages en tant que mesure de la richesse a été conçu et administré. Des modèles de régression logistique multivariée avec des effets fixes ont été ajustés pour évaluer les associations de facteurs sociodémographiques et microéconomiques avec la fréquence autodéclarée des crises au cours du mois précédent et la prise régulière de médicaments antiépileptiques (MAE). Les participants ont été stratifiés par groupe d'âge: enfants (<13 ans), adolescents (13-21) et adultes (> 21). RÉSULTATS: 285 participants (âge moyen 19,5 ans; 129 femmes; 106 enfants, 72 adolescents, 107 adultes, taille médiane du ménage 8) ont eu en moyenne 4,2 crises au cours du mois précédent. 64% prenaient régulièrement des MAE. Les coûts directs de l'épilepsie étaient similaires dans toutes les strates de revenus, atteignant en moyenne 60 USD/mois dans les quintiles de richesse les plus bas et 75 USD/mois dans les quintiles de richesse les plus élevés (p = 0,42). Les PVE les plus pauvres étaient plus susceptibles de dépenser leur argent pour des traitements traditionnels (35 USD/mois en moyenne) que pour des consultations médicales (11 USD/mois en moyenne) (p = 0,01), contrairement aux participants les plus riches. Une fréquence de crises plus élevée était associée à un niveau d'éducation du ménage plus faible chez les adolescents et les enfants (p = 0,028; p = 0,026) et au fait d'être de sexe masculin (p = 0,009) chez les enfants. Les adolescents des ménages avec un niveau d'éducation plus élevé étaient plus susceptibles de prendre des MAE (p = 0,004). Les garçons étaient plus susceptibles de prendre régulièrement des MAE que les filles (p = 0,047). CONCLUSIONS: Des programmes ciblés pour les enfants et les adolescents dans les ménages les moins scolarisés et pour les filles aideraient à améliorer les soins de l'épilepsie en Guinée.

Global visual salience of competing stimuli.

Current computational models of visual salience accurately predict the distribution of fixations on isolated visual stimuli. It is not known, however, whether the global salience of a stimulus, that is, its effectiveness in the competition for attention with other stimuli, is a function of the local salience or an independent measure. Further, do task and familiarity with the competing images influence eye movements? Here, we investigated the direction of the first saccade to characterize and analyze the global visual salience of competing stimuli. Participants freely observed pairs of images while eye movements were recorded. The pairs balanced the combinations of new and already seen images, as well as task and task-free trials. Then, we trained a logistic regression model that accurately predicted the location-left or right image-of the first fixation for each stimulus pair, accounting too for the influence of task, familiarity, and lateral bias. The coefficients of the model provided a reliable measure of global salience, which we contrasted with two distinct local salience models, GBVS and Deep Gaze. The lack of correlation of the behavioral data with the former and the small correlation with the latter indicate that global salience cannot be explained by the feature-driven local salience of images. Further, the influence of task and familiarity was rather small, and we reproduced the previously reported left-sided bias. Summarized, we showed that natural stimuli have an intrinsic global salience related to the human initial gaze direction, independent of the local salience and little influenced by task and familiarity.

Ancient and novel small RNA pathways compensate for the loss of piRNAs in multiple independent nematode lineages.

Small RNA pathways act at the front line of defence against transposable elements across the Eukaryota. In animals, Piwi interacting small RNAs (piRNAs) are a crucial arm of this defence. However, the evolutionary relationships among piRNAs and other small RNA pathways targeting transposable elements are poorly resolved. To address this question we sequenced small RNAs from multiple, diverse nematode species, producing the first phylum-wide analysis of how small RNA pathways evolve. Surprisingly, despite their prominence in Caenorhabditis elegans and closely related nematodes, piRNAs are absent in all other nematode lineages. We found that there are at least two evolutionarily distinct mechanisms that compensate for the absence of piRNAs, both involving RNA-dependent RNA polymerases (RdRPs). Whilst one pathway is unique to nematodes, the second involves Dicer-dependent RNA-directed DNA methylation, hitherto unknown in animals, and bears striking similarity to transposon-control mechanisms in fungi and plants. Our results highlight the rapid, context-dependent evolution of small RNA pathways and suggest piRNAs in animals may have replaced an ancient eukaryotic RNA-dependent RNA polymerase pathway to control transposable elements.

Computational modeling of cellular signaling processes embedded into dynamic spatial contexts.

Cellular signaling processes depend on spatiotemporal distributions of molecular components. Multicolor, high-resolution microscopy permits detailed assessment of such distributions, providing input for fine-grained computational models that explore mechanisms governing dynamic assembly of multimolecular complexes and their role in shaping cellular behavior. However, it is challenging to incorporate into such models both complex molecular reaction cascades and the spatial localization of signaling components in dynamic cellular morphologies. Here we introduce an approach to address these challenges by automatically generating computational representations of complex reaction networks based on simple bimolecular interaction rules embedded into detailed, adaptive models of cellular morphology. Using examples of receptor-mediated cellular adhesion and signal-induced localized mitogen-activated protein kinase (MAPK) activation in yeast, we illustrate the capacity of this simulation technique to provide insights into cell biological processes. The modeling algorithms, implemented in a new version of the Simmune toolset, are accessible through intuitive graphical interfaces and programming libraries.

Effect of Varus-Producing Distal Femoral Osteotomy and High Tibial Osteotomy on Compartment Pressures and Contact Area at Varying Degrees of Knee Flexion.

Background: In patients with valgus alignment and degenerative changes in the lateral compartment, both distal femoral osteotomy (DFO) and high tibial osteotomy (HTO) can be used to unload the lateral compartment. Prior studies have shown that in valgus knees, the tibial wear is posterior and DFO exerts the greatest effect in extension; however, its effect is decreased as flexion angle rises. Hypothesis: Medial closing-wedge (MCW) HTO would significantly decrease contact area, mean contact pressure (MCP), and peak contact pressure (PCP) in the lateral knee compartment through knee flexion to a greater extent compared with lateral opening-wedge (LOW) DFO. Study Design: Controlled laboratory study. Methods: MCWHTO and LOWDFO were performed, correcting a mean of 8° of valgus alignment, in 10 cadaveric knees using plate fixation. Tibiofemoral contact pressure of the medial and lateral compartments was measured in 0°, 30°, 60°, and 90° of knee flexion before and after osteotomy using thin electronic sensors and load applied through an Instron device. PCP, MCP, and contact area were measured for each condition. Results: The lateral MCP was significantly decreased in the HTO state compared with the native state in 30° (P = .015), 60° (P = .0199), and 90° (P < .0001) of flexion. The lateral MCP was also significantly decreased in the HTO state when compared with the DFO state in 60° (P = .0093) and 90° of flexion (P < .0001). After DFO, the lateral MCP returned to that of the native state in 60° (P > .999) and 90° (P > .999) of flexion. The lateral PCP decreased for all test states in all degrees of flexion; the HTO state was significantly decreased when compared with the native state in 60° (P < .0001) and 90° (P < .0001). Conclusion: With varus corrections of 8°, MCWHTO was more effective at unloading the lateral compartment than LOWDFO. This effect was significant as the knee flexion angle increased. This study should be considered as one aspect of the surgical decision-making process. Clinical Relevance: In patients with mild to moderate valgus deformity without hypoplastic lateral femoral condyle and without significant joint line obliquity, MCWHTO may improve offloading of the lateral compartment in flexion.

Structural and vibrational properties of Sb2S3: Practical methodologies for accelerated research and application of this low dimensional material.

Recently, the interest for the family of low dimensional materials has increased significantly due to the anisotropic nature of their fundamental properties. Among them, antimony sulfide (Sb2S3) is considered a suitable material for various solid-state devices. Although the main advantages and physicochemical properties of Sb2S3 are known, some doubtful information remains in literature and methodologies to easily assess its critical properties are missing. In this study, an advanced characterization of several types of Sb2S3 samples, involving the Rietveld refinement of structural properties, and Raman spectroscopy analysis, completed with lattice dynamics investigations reveal important insights into the structural and vibrational characteristics of the material. Based on the gathered data, fast, non-destructive, and non-invasive methodologies for assessment of the crystallographic orientation and point defect concentration of Sb2S3 are proposed. With a high resolution in-sample and in-situ assessment, these methodologies will serve for accelerating the research and application of Sb2S3 in the research field.

Murine Progeria Model Exhibits Delayed Fracture Healing with Dysregulated Local Immune Response.

Background: Bone fracture is one of the most globally prevalent injuries, with an estimated 189 million bone fractures occurring annually. Delayed union or nonunion occurs in up to 15% of fractures and involves the interruption or complete failure of bone continuity following fracture. Preclinical testing is essential to support the translation of novel strategies to promote improved fracture repair treatment, but there is a paucity of small animal models that recapitulate clinical attributes associated with delayed fracture healing. This study explores whether the Zmpste24 -/- (Z24 -/- ) knockout mouse model of Hutchinson-Gilford progeria syndrome presents with delayed fracture healing. Leveraging the previously characterized Z24 -/- phenotype of genomic instability, epigenetic changes, and fragility, we hypothesize that these underlying alterations will lead to significantly delayed fracture healing relative to age-matched wild type (WT) controls. Methods: WT and Z24 -/- mice received intramedullary fixed tibia fractures at ∼12 weeks of age. Mice were sacrificed throughout the time course of repair for the collection of organs that would provide information regarding the local (fracture callus, bone marrow, inguinal lymph nodes) versus peripheral (peripheral blood, contralateral tibia, abdominal organs) tissue microenvironments. Analyses of these specimens include histomorphometry, µCT, mechanical strength testing, protein quantification, gene expression analysis, flow cytometry for cellular senescence, and immunophenotyping. Results: Z24 -/- mice demonstrated a significantly delayed rate of healing compared to WT mice with consistently smaller fracture calli containing higher proportion of cartilage and less bone after injury. Cellular senescence and pro-inflammatory cytokines were elevated in the Z24 -/- mice before and after fracture. These mice further presented with a dysregulated immune system, exhibiting generally decreased lymphopoiesis and increased myelopoiesis locally in the bone marrow, with more naïve and less memory T cell but greater myeloid activation systemically in the peripheral blood. Surprisingly, the ipsilateral lymph nodes had increased T cell activation and other pro-inflammatory NK and myeloid cells, suggesting that elevated myeloid abundance and activation contributes to an injury-specific hyperactivation of T cells. Conclusion: Taken together, these data establish the Z24 -/- progeria mouse as a model of delayed fracture healing that exhibits decreased bone in the fracture callus, with weaker overall bone quality, immune dysregulation, and increased cellular senescence. Based on this mechanism for delayed healing, we propose this Z24 -/- progeria mouse model could be useful in testing novel therapeutics that could address delayed healing. The Translational Potential of this Article: This study employs a novel animal model for delayed fracture healing that researchers can use to screen fracture healing therapeutics to address the globally prevalent issue of aberrant fracture healing.

Microsporidian diversity in soil, sand, and compost of the Pacific Northwest.

Microsporidia are intracellular parasites considered to be ubiquitous in the environment. Yet the true extent of their diversity in soils, sand, and compost remains unclear. We examined microsporidian diversity found in the common urban environments of soil, sand, and compost. We retrieved 22 novel microsporidian sequences and only four from described species. Their distribution was generally restricted to a single site and sample type. Surprisingly, one novel microsporidian showed a wide distribution, and high prevalence, as it was detected in five different compost samples and in soil samples collected over 200 km apart. These results suggest that the majority of Microsporidia appear to have a narrow distribution. Our phylogenetic analysis indicated that the Microsporidia detected in this study include representatives from four of the five major microsporidian groups. Furthermore, the addition of our new sequences calls into question the cohesiveness of microsporidian clade II. These results highlight the importance of increasing our knowledge of microsporidian diversity to better understand the phylogenetic relationships and evolutionary history of this important group of emerging parasites.

A latent class approach for sepsis diagnosis supports use of procalcitonin in the emergency room for diagnosis of severe sepsis.

BACKGROUND: Given the acknowledged problems in sepsis diagnosis, we use a novel way with the application of the latent class analysis (LCA) to determine the operative characteristics of C-reactive protein (CRP), D-dimer (DD) and Procalcitonin (PCT) as diagnostic tests for sepsis in patients admitted to hospital care with a presumptive infection. METHODS: Cross-sectional study to determine the diagnostic accuracy of three biological markers against the gold standard of clinical definition of sepsis provided by an expert committee, and also against the likelihood of sepsis according to LCA. Patients were recruited in the emergency room within 24 hours of hospitalization and were follow-up daily until discharge. RESULTS: Among 765 patients, the expert committee classified 505 patients (66%) with sepsis, 112 (15%) with infection but without sepsis and 148 (19%) without infection. The best cut-offs points for CRP, DD, and PCT were 7.8 mg/dl, 1616 ng/ml and 0.3 ng/ml, respectively; but, neither sensitivity nor specificity reach 70% for any biomarker. The LCA analysis with the same three tests identified a "cluster" of 187 patients with several characteristics suggesting a more severe condition as well as better microbiological confirmation. Assuming this subset of patients as the new prevalence of sepsis, the ROC curve analysis identified new cut-off points for the tests and suggesting a better discriminatory ability for PCT with a value of 2 ng/ml. CONCLUSIONS: Under a "classical" definition of sepsis three typical biomarkers (CRP, PCT and DD) are not capable enough to differentiate septic from non-septic patients in the ER. However, a higher level of PCT discriminates a selected group of patients with severe sepsis.

Diversifying Design of Nucleic Acid Aptamers Using Unsupervised Machine Learning.

Inverse design of short single-stranded RNA and DNA sequences (aptamers) is the task of finding sequences that satisfy a set of desired criteria. Relevant criteria may be, for example, the presence of specific folding motifs, binding to molecular ligands, sensing properties, and so on. Most practical approaches to aptamer design identify a small set of promising candidate sequences using high-throughput experiments (e.g., SELEX) and then optimize performance by introducing only minor modifications to the empirically found candidates. Sequences that possess the desired properties but differ drastically in chemical composition will add diversity to the search space and facilitate the discovery of useful nucleic acid aptamers. Systematic diversification protocols are needed. Here we propose to use an unsupervised machine learning model known as the Potts model to discover new, useful sequences with controllable sequence diversity. We start by training a Potts model using the maximum entropy principle on a small set of empirically identified sequences unified by a common feature. To generate new candidate sequences with a controllable degree of diversity, we take advantage of the model's spectral feature: an "energy" bandgap separating sequences that are similar to the training set from those that are distinct. By controlling the Potts energy range that is sampled, we generate sequences that are distinct from the training set yet still likely to have the encoded features. To demonstrate performance, we apply our approach to design diverse pools of sequences with specified secondary structure motifs in 30-mer RNA and DNA aptamers.

Decrease in the intensive care unit-acquired weakness with a multicomponent protocol implementation: A quasi-experimental clinical trial / Disminución de la debilidad muscular adquirida en una unidad de cuidados intensivos con la implementación de un protocolo multicomponente: ensayo clínico cuasiexperimental

Introduction: Intensive care unit-acquired weakness is a frequent complication that affects the prognosis of critical illness during hospital stay and after hospital discharge. Objectives: To determine if a multicomponent protocol of early active mobility involving adequate pain control, non-sedation, non-pharmacologic delirium prevention, cognitive stimulation, and family support, reduces intensive care unit-acquired weakness at the moment of discharge. Materials and methods: We carried out a non-randomized clinical trial in two mixed intensive care units in a high-complexity hospital, including patients over 14 years old with invasive mechanical ventilation for more than 48 hours. We compared the intervention ­the multicomponent protocol­ during intensive care hospitalization versus the standard care. Results: We analyzed 82 patients in the intervention group and 106 in the control group. Muscle weakness acquired in the intensive care unit at the moment of discharge was less frequent in the intervention group (41.3% versus 78.9%, p<0.00001). The mobility score at intensive unit care discharge was better in the intervention group (median = 3.5 versus 2, p < 0.0138). There were no statistically significant differences in the invasive mechanical ventilation-free days at day 28 (18 versus 15 days, p<0.49), and neither in the mortality (18.2 versus 27.3%, p<0.167). Conclusion: A multi-component protocol of early active mobility significantly reduces intensive care unit-acquired muscle weakness at the moment of discharge.

Introducción: La debilidad adquirida en las unidades de cuidados intensivos es una complicación frecuente de los pacientes con enfermedades críticas, que puede tener un impacto negativo en su pronóstico a corto y a largo plazo. OBJETIVOS: Evaluar si la utilización de un protocolo multicomponente, que incluye movilidad activa temprana, manejo efectivo del dolor, reducción de la sedación, medidas no farmacológicas para prevenir el delirium, estimulación cognitiva y apoyo familiar, puede disminuir la incidencia de debilidad adquirida en las unidades de cuidados intensivos al momento del egreso del paciente. Materiales y métodos: Se trata de un ensayo clínico, no aleatorizado, en dos unidades de cuidados intensivos mixtas de un hospital de tercer nivel. Los participantes fueron pacientes mayores de 14 años con ventilación mecánica invasiva por más de 48 horas. Se aplicó como intervención un protocolo multicomponente y como control se utilizó el cuidado usual o estándar. RESULTADOS: Ingresaron 188 pacientes al estudio, 82 al grupo de intervención y 106 al grupo control. La tasa de debilidad adquirida en las unidades de cuidados intensivos al egreso de la unidad fue significativamente menor en el grupo de intervención (41,3 % versus 78,9 %, p<0,00001). La mediana del puntaje de movilidad al momento del alta de la unidad de cuidados intensivos fue mayor en el grupo de intervención (3,5 versus 2, p<0,0138). No se encontraron diferencias estadísticamente significativas en las medianas de días libres de respiración mecánica asistida, ni de unidad de cuidados intensivos al día 28, tampoco en la tasa de mortalidad general al egreso del hospital (18 versus 15 días, p<0,49; 18,2 % versus 27,3 %, p<0,167). CONCLUSIONES: Un protocolo multicomponente que incluía movilidad activa temprana tuvo un impacto significativo en la reducción de la debilidad adquirida en las unidades de cuidados intensivos al egreso en comparación con el cuidado estándar.

A multicenter analysis of the outcomes with venetoclax in patients with relapsed mantle cell lymphoma.

To report the activity of venetoclax in patients with relapsed mantle cell lymphoma (MCL), we identified 81 patients treated with venetoclax monotherapy (n = 50, 62%) or in combination with a Bruton tyrosine kinase inhibitor (BTKi) (n = 16, 20%), an anti-CD20 monoclonal antibody (n = 11, 14%), or other active agents at 12 US academic medical centers. Patients had high-risk disease features including Ki67 >30% (61%), blastoid/pleomorphic histology (29%), complex karyotype (34%), and TP53 alterations (49%), and received a median of 3 prior treatments including BTKis in 91%. Venetoclax alone or in combination resulted in an overall response rate (ORR) of 40% and median progression-free (PFS) and overall survival (OS) of 3.7 and 12.5 months, respectively. The receipt of ≤3 prior treatments was associated with higher odds of response to venetoclax in a univariable analysis. In a multivariable analysis, having a high-risk Mantle Cell Lymphoma International Prognostic Index score before receiving venetoclax and disease relapse or progression within 24 months of diagnosis were associated with inferior OS whereas the use of venetoclax in combination was associated with superior OS. Although most patients (61%) had low risk for tumor lysis syndrome (TLS), 12.3% of patients developed TLS despite the implementation of several mitigation strategies. In conclusion, venetoclax resulted in good ORR but short PFS in patients with MCL who are at high risk, and may have a better role in earlier lines of treatment and/or in conation with other active agents. TLS remains an important risk in patients with MCL who initiate treatment with venetoclax.

Accelerating diversity in Alzheimer's disease research by partnering with a community advisory board.

Introduction: Community advisory boards (CABs) and researcher partnerships present a promising opportunity to accelerate enrollment of underrepresented groups (URGs). We outline the framework for how the CAB and researchers at the Indiana Alzheimer's Disease Research Center (IADRC) partnered to accelerate URG participation in AD neuroimaging research. Methods: CAB and the IADRC researchers partnered to increase the CAB's impact on URG study enrollment through community and research interactions. Community interactions included the CAB collaboratively building a network of URG focused community organizations and collaborating with those URG-focused organizations to host IADRC outreach and recruitment events. Research interactions included direct impact (CAB members referring themselves or close contacts as participants) and strategic impact, mainly by the CAB working with researchers to develop and refine URG focused outreach and recruitment strategies for IADRC and affiliated studies to increase URG representation. We created a database infrastructure to measure how these interactions impacted URG study enrollment. Results: Out of the 354 URG research referrals made to the IADRC between October 2019 and December 2022, 267 referrals were directly referred by the CAB (N = 36) or from community events in which CAB members organized and/or volunteered at (N = 231). Out of these 267 referrals, 34 were enrolled in IADRC and 2 were enrolled in Indiana University Longitudinal Early Onset AD Study (IU LEADS). Of note, both studies require the prospective participants to be willing to do MRI and PET scans. As of December 2022, 30 out of the 34 enrolled participants have received a consensus diagnosis; the majority were cognitively normal (64.7%), with the remainder having mild cognitive impairment (17.6%) or early-stage AD (2.9%). Discussion: The IADRC CAB-researcher partnership had a measurable impact on the enrollment of African American/Black adults in AD neuroimaging studies. Future studies will need to test whether this conceptual model works for other sites and for other URGs.