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.

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.

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.

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.

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.

Disminución de la debilidad muscular adquirida en una unidad de cuidados intensivos con la implementación de un protocolo multicomponente: ensayo clínico cuasiexperimental

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.

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.

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.

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.

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.

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.

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.

Cost-effectiveness of extracorporeal membrane oxygenation in patients with acute respiratory distress syndrome in Colombia / Costo-efectividad de la oxigenación con membrana extracorpórea en pacientes con síndrome de dificultad respiratoria aguda en Colombia

Introduction: Extracorporeal membrane oxygenation therapy is expensive. There is evidence in the literature that it can be a cost-effective intervention in developed countries; however, in countries with low gross domestic product per capita, such as Colombia, there are still some doubts. Objective: To determine the incremental cost-effectiveness ratio of extracorporeal membrane oxygenation in patients with acute respiratory distress syndrome in Colombia. Materials and methods: Cost-effectiveness analysis in healthcare in relation to adult patients diagnosed with acute respiratory distress syndrome with mechanical ventilation with low volumes compared to extracorporeal membrane oxygenation. The direct medical costs and the incremental cost-effectiveness ratio were determined at 6 months. Results: The expected cost per patient on protective mechanical ventilation was COP$17,609,909. The cost of extracorporeal membrane oxygenation therapy support in surviving patients was COP$ 98,784,116. The average cost-effectiveness ratio of extracorporeal membrane oxygenation was COP$ 141,662,435 for each life saved (USD$ 41,276). Conclusions: Support with extracorporeal membrane oxygenation therapy had an average cost of COP$ 141,662,435 for each life saved equivalent to USD$ 41,276. The incremental cost-effectiveness ratio COP$ was 608,783,750 (USD$ 177,384); almost ten times higher than the decision rule of three gross domestic product per capita (COP$ 59,710,479).

Introducción. La terapia con oxigenación con membrana extracorpórea es costosa y, aunque existe existen indicios en la literatura de que puede ser una intervención costoefectiva en los países desarrollados, hay dudas sobre su costo-efectividad en un país con un producto interno bruto per cápita bajo, como Colombia. Objetivo. Determinar el incremento de la relación costo-efectividad de la terapia con oxigenación con membrana extracorpórea en pacientes con síndrome de dificultad respiratoria aguda en Colombia. Materiales y métodos. Se eligieron pacientes adultos con diagnóstico de síndrome de dificultad respiratoria aguda para el análisis de costo-efectividad desde la perspectiva del sistema de salud. Se compararon aquellos pacientes con asistencia respiratoria mecánica con volúmenes bajos con aquellos tratados con oxigenación con membrana extracorpórea. Se determinaron los costos médicos directos de la atención y el incremento de la relación costo-efectividad a los 6 meses. Resultados. El costo esperado por paciente en asistencia respiratoria mecánica protectora fue de COP$ 17'609.909. El costo del soporte mediante terapia de oxigenación con membrana extracorpórea fue de COP$ 98'784.116. La relación de costo-efectividad promedio fue de COP$ 141'662.435 por cada vida salvada (USD$ 41.276). Conclusiones. El soporte con terapia de oxigenación con membrana extracorpórea tuvo un costo promedio de COP$ 141'662.435 por cada vida salvada, equivalente a USD$ 41.276 dólares y el incremento de la relación costo-efectividad fue de COP$ 608'783.750 (USD$ 177.384), casi diez veces superior a la regla de decisión de 3 PBI per cápita (COP$ 59'710.479).

Costo-efectividad de la oxigenación con membrana extracorpórea en pacientes con síndrome de dificultad respiratoria aguda en Colombia / Cost-effectiveness of extracorporeal membrane oxygenation in patients with acute respiratory distress syndrome in Colombia

Introducción. La terapia con oxigenación con membrana extracorpórea es costosa y, aunque existe existen indicios en la literatura de que puede ser una intervención costo-efectiva en los países desarrollados, hay dudas sobre su costo-efectividad en un país con un producto interno bruto per cápita bajo, como Colombia. Objetivo. Determinar el incremento de la relación costo-efectividad de la terapia con oxigenación con membrana extracorpórea en pacientes con síndrome de dificultad respiratoria aguda en Colombia. Materiales y métodos. Se eligieron pacientes adultos con diagnóstico de síndrome de dificultad respiratoria aguda para el análisis de costo-efectividad desde la perspectiva del sistema de salud. Se compararon aquellos pacientes con asistencia respiratoria mecánica con volúmenes bajos con aquellos tratados con oxigenación con membrana extracorpórea. Se determinaron los costos médicos directos de la atención y el incremento de la relación costo-efectividad a los 6 meses. Resultados. El costo esperado por paciente en asistencia respiratoria mecánica protectora fue de COP$ 17'609.909. El costo del soporte mediante terapia de oxigenación con membrana extracorpórea fue de COP$ 98'784.116. La relación de costo-efectividad promedio fue de COP$ 141'662.435 por cada vida salvada (USD$ 41.276). Conclusiones. El soporte con terapia de oxigenación con membrana extracorpórea tuvo un costo promedio de COP$ 141'662.435 por cada vida salvada, equivalente a USD$ 41.276 dólares y el incremento de la relación costo-efectividad fue de COP$ 608'783.750 (USD$ 177.384), casi diez veces superior a la regla de decisión de 3 PBI per cápita (COP$ 59'710.479).

Introduction: Extracorporeal membrane oxygenation therapy is expensive. There is evidence in the literature that it can be a cost-effective intervention in developed countries; however, in countries with low gross domestic product per capita, such as Colombia, there are still some doubts. Objective: To determine the incremental cost-effectiveness ratio of extracorporeal membrane oxygenation in patients with acute respiratory distress syndrome in Colombia. Materials and methods: Cost-effectiveness analysis in healthcare in relation to adult patients diagnosed with acute respiratory distress syndrome with mechanical ventilation with low volumes compared to extracorporeal membrane oxygenation. The direct medical costs and the incremental cost-effectiveness ratio were determined at 6 months. Results: The expected cost per patient on protective mechanical ventilation was COP$ 17,609,909. The cost of extracorporeal membrane oxygenation therapy support in surviving patients was COP$ 98,784,116. The average cost-effectiveness ratio of extracorporeal membrane oxygenation was COP$ 141,662,435 for each life saved (USD$ 41,276). Conclusions: Support with extracorporeal membrane oxygenation therapy had an average cost of COP$ 141,662,435 for each life saved equivalent to USD$ 41,276. The incremental cost-effectiveness ratio COP$ was 608,783,750 (USD$ 177,384); almost ten times higher than the decision rule of three gross domestic product per capita (COP$ 59,710,479).

Benchmark of Data Processing Methods and Machine Learning Models for Gut Microbiome-Based Diagnosis of Inflammatory Bowel Disease.

Patients with inflammatory bowel disease (IBD) wait months and undergo numerous invasive procedures between the initial appearance of symptoms and receiving a diagnosis. In order to reduce time until diagnosis and improve patient wellbeing, machine learning algorithms capable of diagnosing IBD from the gut microbiome's composition are currently being explored. To date, these models have had limited clinical application due to decreased performance when applied to a new cohort of patient samples. Various methods have been developed to analyze microbiome data which may improve the generalizability of machine learning IBD diagnostic tests. With an abundance of methods, there is a need to benchmark the performance and generalizability of various machine learning pipelines (from data processing to training a machine learning model) for microbiome-based IBD diagnostic tools. We collected fifteen 16S rRNA microbiome datasets (7,707 samples) from North America to benchmark combinations of gut microbiome features, data normalization and transformation methods, batch effect correction methods, and machine learning models. Pipeline generalizability to new cohorts of patients was evaluated with two binary classification metrics following leave-one-dataset-out cross (LODO) validation, where all samples from one study were left out of the training set and tested upon. We demonstrate that taxonomic features processed with a compositional transformation method and batch effect correction with the naive zero-centering method attain the best classification performance. In addition, machine learning models that identify non-linear decision boundaries between labels are more generalizable than those that are linearly constrained. Lastly, we illustrate the importance of generating a curated training dataset to ensure similar performance across patient demographics. These findings will help improve the generalizability of machine learning models as we move towards non-invasive diagnostic and disease management tools for patients with IBD.

Management of Relapsed Hairy Cell Leukemia: A Systematic Review of Novel Agents and Targeted Therapies.

BACKGROUND: Hairy cell leukemia (HCL) responds well to purine analogs with an overall median relapse free survival of 11-16 years. Most patients can be retreated with the same or a different purine analog however a subset of patients will become resistant or develop cumulative toxicities. Novel agents such as Vemurafenib (BRAF kinase inhibitor), Bendamustine/Rituximab (BR), Moxetumomab pasudotox (anti CD-22 recombinant immunotoxin) and Ibrutinib have emerging roles in patients with relapsed HCL. METHODS: Five databases (PubMed, Embase, Cochrane Library, Web of Science and ClinicalTrials.gov) were searched using the following search terms: "hairy cell leukemia" or "leukemia, hairy cell" AND "relapse" or "recurrence". We included only prospective clinical trials with outcome data. RESULTS: Vemurafenib monotherapy was evaluated in two separate arms of a phase 2 trial. In the US arm (n=24), the ORR was 100% (CR 42%; PR 58%). In the Italian arm (n=26), the ORR was 96% (CR 35%; PR 62%). In a phase 2 study (n=25), the combination of vemurafenib and rituximab showed CR of 100%. The combination of BR achieved an ORR of 100% whereas CR was 50% and 67% at a bendamustine dose of 70mg/m2 (n=6) and 90 mg/m2 (n=6) respectively. In a phase 3 trial, moxetumomab pasudotox (n=80) had an ORR of 75% (CR 41%). Single agent Ibrutinib (n=37) had an ORR of 54%. Therapies were generally well tolerated. CONCLUSION: Novel agents have good efficacy in HCL in patients with multiple relapses.

Granuloma no caseificante como primera manifestación de artritis reumatoide. A propósito de un caso / Noncaseating granuloma as first manifestation of rheumatoid arthritis: a case report

RESUMEN Los nódulos reumatoides se han descrito en cerca del 30% de los pacientes con artritis reumatoide, se localizan generalmente a nivel subcutáneo, pero son poco frecuentes en órganos viscerales; generalmente aparecen en estados tardíos de la enfermedad. Su apariencia puede ser confundida con otras condiciones clínicas en las localizaciones atípicas. Presentamos el caso de una paciente que comenzó con nódulos reumatoides en el hígado como primera manifestación de artritis reumatoide.

ABSTRACT The rheumatoid nodules have been described in 30% of patients with rheumatoid arthritis. There are localized generally at subcutaneous planes, are rare in visceral organs, and appear tipically in advance stages of the disease. Its appearance in atyipical localizations can be confused with other conditions. We are going to discuss a patient who debuted with rheumatoid nodules in the liver as first manifestation of rheumatoid arthritis.

Computational Methods for Continuous Eye-Tracking Perimetry Based on Spatio-Temporal Integration and a Deep Recurrent Neural Network.

The measurement of retinal sensitivity at different visual field locations-perimetry-is a fundamental procedure in ophthalmology. The most common technique for this scope, the Standard Automated Perimetry, suffers from several issues that make it less suitable to test specific clinical populations: it can be tedious, it requires motor manual feedback, and requires from the patient high levels of compliance. Previous studies attempted to create user-friendlier alternatives to Standard Automated Perimetry by employing eye movements reaction times as a substitute for manual responses while keeping the fixed-grid stimuli presentation typical of Standard Automated Perimetry. This approach, however, does not take advantage of the high spatial and temporal resolution enabled by the use of eye-tracking. In this study, we introduce a novel eye-tracking method to perform high-resolution perimetry. This method is based on the continuous gaze-tracking of a stimulus moving along a pseudo-random walk interleaved with saccadic jumps. We then propose two computational methods to obtain visual field maps from the continuous gaze-tracking data: the first is based on the spatio-temporal integration of ocular positional deviations using the threshold free cluster enhancement (TFCE) algorithm; the second is based on using simulated visual field defects to train a deep recurrent neural network (RNN). These two methods have complementary qualities: the TFCE is neurophysiologically plausible and its output significantly correlates with Standard Automated Perimetry performed with the Humphrey Field Analyzer, while the RNN accuracy significantly outperformed the TFCE in reconstructing the simulated scotomas but did not translate as well to the clinical data from glaucoma patients. While both of these methods require further optimization, they show the potential for a more patient-friendly alternative to Standard Automated Perimetry.

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.