Obstructive Sleep Apnea and Oxygenation in Very Old Adults: A Propensity-Score Match Study.

OBJECTIVES: The prevalence of obstructive sleep apnea (OSA) escalates with advancing age. Although the apnea-hypopnea index (AHI) is the standard measure for assessing OSA severity, it does not account for additional oximetric parameters that may influence disease progression in older adults. This study aimed to evaluate disparities in respiratory polygraphy/polysomnography parameters among patients with OSA, stratified by age and sex. DESIGN: Retrospective propensity score-matched study. SETTING AND PARTICIPANTS: Sleep unit of a university hospital; 11,747 participants, 210 aged 80 years or older. METHODS: Propensity score matching was used to establish 4 age cohorts, with the 210 oldest adults serving as the reference group. Primary outcome variables included the total sleep time with oxygen saturation (SaO2) below 90% (T90), average SaO2, minimum SaO2, and AHI. The association between T90 and AHI, as well as the severity of OSA, was assessed across the 4 age categories. RESULTS: Despite comparable AHI scores, the oldest OSA patients exhibited the highest T90 and the lowest SaO2 levels compared to younger counterparts. The proportion of patients with severe OSA and T90 in the highest quartile increased with age: 12.5% in young adults, 14.8% in adults, 21.7% in the old, and 34% in the very old participants (P < .001). old and very old patients had a greater likelihood of being in the most severe OSA category compared to the younger ones, with odds ratios (OR) 2.57 (95% CI 1.42-4.65) and 5.52 (95% CI 3.06-9.97), respectively. These patterns were more pronounced in women of advanced age, indicating a sex-specific variation in disease severity with increasing age. CONCLUSIONS AND IMPLICATIONS: Old OSA patients, particularly women, demonstrate elevated T90 and reduced SaO2 levels, irrespective of AHI, indicating a hypoxemia increased risk. The diagnostic criteria, management, and outcomes for OSA may require adaptations to address the unique needs of very old populations.

ESASO classification relevance in the diagnosis and evolution in diabetic macular edema patients after dexamethasone implant treatment.

PURPOSE: To assess the clinical relevance of The European School for Advanced Studies in Ophthalmology (ESASO) classification in patients with diabetic macular edema (DME) after their first dexamethasone implant (DEXI) treatment. METHODS: Retrospective real-world study conducted on consecutive DME patients who underwent DEXI treatment and were controlled at month-2. Subjects were initially classified according to the ESASO classification stages. The outcomes were anatomical biomarkers with spectral-domain optical coherence tomography (SD-OCT) and best-corrected visual acuity (BCVA). RESULTS: A total of 128 patients were classified according to ESASO classification stages as early (7; 5.5%), advanced (100; 78.1%), and severe (21; 16.4%). At baseline, there were significant differences between stages in BCVA, central macular thickness (CMT), and tomography anatomical biomarkers (p < 0.05). Initial BCVA (logMAR) was 0.33 ± 0.10, 0.58 ± 0.34, and 0.71 ± 0.35 in the early, advanced, and severe stages, respectively (p < 0.05). At month-2, BCVA was 0.17 ± 0.15, 0.46 ± 0.29, and 0.69 ± 0.27 in those classified as early, advanced, and severe stages, respectively. At month-2, DME was resolved or improved in 6 (85.7%), 60 (60%), and 12 (60%) patients classified as early, advanced, and severe stages, respectively. CONCLUSIONS: There was a good correlation between BCVA and ESASO classification stages. Patients in the severe stage did not achieve visual acuity improvement over the study period.

New approaches in the nutritional treatment of advanced chronic kidney disease.

INTRODUCTION: Patients with advanced chronic kidney disease (ACKD) have a high prevalence of malnutrition. The dietary restrictions that we usually apply in terms of macro and micronutrients force our patients to follow dietary guidelines that deviate from healthy patterns. OBJETIVES: To determine if a personalized nutritional intervention program, minimizing the usual restrictions would be justified in case it improved the evolution of kidney disease compared to standard treatment. SECUNDARY OBJETIVES: To determine changes in nutrient intakes and in anthropometric and biochemical parameters, as well as quantify episodes of hyperkalemia. MATERIAL AND METHODS: A single-center, randomized and controlled educational intervention clinical trial was conduct in patients from the ERCA outpatients clinic at the Complejo Hospitalario Universitario de Albacete. 75 patients were included, assigning 35 to a Control group and 40 to the Intervention group with 1-year follow-up. The nutritional status was determined using anthropometric data, body composition by Bioimpedance, blood and urine biochemical parameters and a 24-h recall questionnaire. The nutritional intervention was carried out in three different ways: individual, collective and telephone recall. RESULTS: At the beginning of the study, the BMI showed a situation of weight excess with a mean of 28.83 kg/m2 (5.4) in men and 26.96 kg/m2 (4.09) in women. 70% of our patients had overweight. The abdominal circumference was 105.3 cm (10.2) and 92.3 cm (13.7) for men and women respectively without significant changes throughout the study. The percentage of fat mass (FM) was high in both groups for men and women throughout the study. We did not find biochemical parameters of malnutrition and only significant differences were observed in glomerular filtration rate (GFR), which increased in the intervention group. No patient presented any episodes of hyperkalemia during the study. The energy intake in both groups showed an inadequate distribution of macronutrients with a poor intake of carbohydrates (CH) that was supplemented with an excess of fat. In the case of micronutrients, we did observe an increase in potassium and fiber intakes with a decrease in sodium and phosphorus in the intervention group. CONCLUSIONS: Malnutrition is not exclusively an intake defficit and encompasses both the problems derived from a deficit and an excess of nutrients intake. Un to 70% of our patients showed weight excess and a fat mass higher than desirable. The implementation of an individualized nutritional education program, including a vegetables and fiber rich diet, less atherogenic, not only did not cause electrolyte alterations but also slowed the progression of kidney disease.

Limits of stability and falls during a multicomponent exercise program in faller older adults: A retrospective cohort study.

BACKGROUND/OBJETIVES: Multicomponent exercise programs have been demonstrated to prevent falls in older adults. However, the underlying responsible mechanisms are not clear. We aimed to analyze the association between changes in the limits of stability (LOS) as a relevant balance component, and falls occurrence during a multicomponent physical exercise program. METHODS: Retrospective study, including ninety-one participants who had experienced a fall in the previous year, and were attended in a falls unit. All of them were included in a twice-a-week multicomponent exercise program during 16 weeks. Pre- and post-program measurements were collected for leg press, gait speed, the short physical performance battery (SPPB), and LOS (point of excursion [POE] and maximal excursion [MEX]) with posturography. Falls occurrence was assessed between the beginning and the completion of the exercise program (16 week). RESULTS: The mean age was 77.2 years, and 72 were female. Thirty-two participants fell at least once during the exercise period. The global baseline POE was 47.6 %, and the MEX was 64.7 %, and there were no differences between fallers and nonfallers. Nonfallers presented greater improvements in POE (6.3 % versus 1.3 %; p < .05) and MEX (9.2 % versus 3.0 %; p < .01) than fallers. The POE and MEX were independently associated with a reduced probability of having had a fall, OR: 0.95 (95 % CI: 0.91 to 0.99) and 0.94 (95 % CI: 0.90 to 0.99), respectively. Changes in SPPB results or leg press strength were not associated with decreased falls. Adjusted probability of fall occurrence decreased by 5 % and 6 % per 1 % improvement in absolute values in POE and MEX, respectively. CONCLUSIONS: Improvements in LOS after a multicomponent physical exercise program in older adults with previous falls may be associated with a decreased occurrence of falls.

Common Laboratory Parameters Are Useful for Screening for Alcohol Use Disorder: Designing a Predictive Model Using Machine Learning.

The diagnosis of alcohol use disorder (AUD) remains a difficult challenge, and some patients may not be adequately diagnosed. This study aims to identify an optimum combination of laboratory markers to detect alcohol consumption, using data science. An analytical observational study was conducted with 337 subjects (253 men and 83 women, with a mean age of 44 years (10.61 Standard Deviation (SD)). The first group included 204 participants being treated in the Addictive Behaviors Unit (ABU) from Albacete (Spain). They met the diagnostic criteria for AUD specified in the Diagnostic and Statistical Manual of mental disorders fifth edition (DSM-5). The second group included 133 blood donors (people with no risk of AUD), recruited by cross-section. All participants were also divided in two groups according to the WHO classification for risk of alcohol consumption in Spain, that is, males drinking more than 28 standard drink units (SDUs) or women drinking more than 17 SDUs. Medical history and laboratory markers were selected from our hospital's database. A correlation between alterations in laboratory markers and the amount of alcohol consumed was established. We then created three predicted models (with logistic regression, classification tree, and Bayesian network) to detect risk of alcohol consumption by using laboratory markers as predictive features. For the execution of the selection of variables and the creation and validation of predictive models, two tools were used: the scikit-learn library for Python, and the Weka application. The logistic regression model provided a maximum AUD prediction accuracy of 85.07%. Secondly, the classification tree provided a lower accuracy of 79.4%, but easier interpretation. Finally, the Naive Bayes network had an accuracy of 87.46%. The combination of several common biochemical markers and the use of data science can enhance detection of AUD, helping to prevent future medical complications derived from AUD.

Immunogenicity after 6 months of BNT162b2 vaccination in frail or disabled nursing home residents: The COVID-A Study.

BACKGROUND: There is incomplete information regarding evolution of antibody titers against SARS-CoV-2 after a two-dose strategy vaccination with BNT162b2 in older adults in long-term care facilities (LTCFs) with frailty, disability, or cognitive impairment. We aimed to determine IgG antibody titer loss in older adults in LTCFs. METHODS: This is a multicenter longitudinal cohort study including 127 residents (90 females and 37 males) with a mean age of 82.7 years (range 65-99) with different frailty and disability profiles in two LTCFs in Albacete, Spain. Residents received two doses of BNT162b2 as per label, and antibody levels were determined 1 and 6 months after the second dose. Age, sex, previous history of coronavirus disease 2019 (COVID-19), comorbidity (Charlson Index), performance in activities of daily living (Barthel Index), frailty (FRAIL instrument), and cognitive status were assessed. RESULTS: The mean antibody titers 1 and 6 months after the second vaccine dose were 32,145 AU/ml (SD 41,206) and 6182 AU/ml (SD 13,316), respectively. Across all participants, the median antibody titer loss measured 77.6% (interquartile range [IQR] 23.8%). Notably, the decline of titers in individuals with pre-vaccination COVID-19 infection was significantly lower than in those without a history of SARS-CoV-2 infection (72.2% vs. 85.3%; p < 0.001). The median titer decrease per follow-up day was 0.47% (IQR 0.14%) and only pre-vaccination COVID-19 was associated with lower rate of antibody decline at 6 months (hazard ratio 0.17; 95% confidence interval 0.07-0.41; p < 0.001). Frailty, disability, older age, cognitive impairment, or comorbidity were not associated with the extent of antibody loss. CONCLUSIONS: Older adults in LTCFs experience a rapid loss of antibodies over the first 6 months after the second dose of BNT162b2 vaccine. Only pre-vaccination COVID-19 is associated with a slower rate of antibody decrease. Our data support immunization with a third dose in this vulnerable, high-risk population.

New approaches in the nutritional treatment of advanced chronic kidney disease. / Nuevo enfoque en el tratamiento nutricional de la enfermedad renal crónica avanzada.

INTRODUCTION: Patients with advanced chronic kidney disease (ACKD) have a high prevalence of malnutrition. The dietary restrictions that we usually apply in terms of macro and micronutrients force our patients to follow dietary guidelines that deviate from healthy patterns. OBJECTIVES: To determine if a personalized nutritional intervention program, minimizing the usual restrictions would be justified in case it improved the evolution of kidney disease compared to standard treatment. SECONDARY OBJECTIVES: To determine changes in nutrient intakes and in anthropometric and biochemical parameters, as well as quantify episodes of hyperkalemia. MATERIAL AND METHODS: A single-center, randomized and controlled educational intervention clinical trial was conduct in patients from the ERCA outpatients clinic at the Complejo Hospitalario Universitario de Albacete. 75 patients were included, assigning 35 to a Control group and 40 to the Intervention group with 1-year follow-up. The nutritional status was determined using anthropometric data, body composition by Bioimpedance, blood and urine biochemical parameters and a 24-h recall questionnaire. The nutritional intervention was carried out in three different ways: individual, collective and telephone recall. RESULTS: At the beginning of the study, the BMI showed a situation of weight excess with a mean of 28.83 kg/m2 (5.4) in men and 26.96 kg/m2 (4.09) in women. 70% of our patients had overweight. The abdominal circumference was 105.3 cm (10.2) and 92.3 cm (13.7) for men and women respectively without significant changes throughout the study. The percentage of fat mass (FM) was high in both groups for men and women throughout the study. We did not find biochemical parameters of malnutrition and only significant differences were observed in glomerular filtration rate (GFR), which increased in the intervention group. No patient presented any episodes of hyperkalemia during the study. The energy intake in both groups showed an inadequate distribution of macronutrients with a poor intake of carbohydrates (CH) that was supplemented with an excess of fat. In the case of micronutrients, we did observe an increase in potassium and fiber intakes with a decrease in sodium and phosphorus in the intervention group. CONCLUSIONS: Malnutrition is not exclusively an intake deficit and encompasses both the problems derived from a deficit and an excess of nutrients intake. Un to 70% of our patients showed weight excess and a fat mass higher than desirable. The implementation of an individualized nutritional education program, including a vegetables and fiber rich diet, less atherogenic, not only did not cause electrolyte alterations but also slowed the progression of kidney disease.

Baricitinib reduces 30-day mortality in older adults with moderate-to-severe COVID-19 pneumonia.

BACKGROUND: Older adults are at the highest risk of severe disease and death due to COVID-19. Randomized data have shown that baricitinib improves outcomes in these patients, but focused stratified analyses of geriatric cohorts are lacking. Our objective was to analyze the efficacy of baricitinib in older adults with COVID-19 moderate-to-severe pneumonia. METHODS: This is a propensity score [PS]-matched retrospective cohort study. Patients from the COVID-AGE and Alba-Score cohorts, hospitalized for moderate-to-severe COVID-19 pneumonia, were categorized in two age brackets of age <70 years old (86 with baricitinib and 86 PS-matched controls) or ≥70 years old (78 on baricitinib and 78 PS-matched controls). Thirty-day mortality rates were analyzed with Kaplan-Meier and Cox proportional hazard models. RESULTS: Mean age was 79.1 for those ≥70 years and 58.9 for those <70. Exactly 29.6% were female. Treatment with baricitinib resulted in a significant reduction in death from any cause by 48% in patients aged 70 or older, an 18.5% reduction in 30-day absolute mortality risk (n/N: 16/78 [20.5%] baricitinib, 30/78 [38.5%] in PS-matched controls, p < 0.001) and a lower 30-day adjusted fatality rate (HR 0.21; 95% CI 0.09-0.47; p < 0.001). Beneficial effects on mortality were also observed in the age group <70 (8.1% reduction in 30-day absolute mortality risk; HR 0.14; 95% CI 0.03-0.64; p = 0.011). CONCLUSIONS: Baricitinib is associated with an absolute mortality risk reduction of 18.5% in adults older than 70 years hospitalized with COVID-19 pneumonia.

Immunogenicity of the BNT162b2 vaccine in frail or disabled nursing home residents: COVID-A study.

BACKGROUND/OBJECTIVES: The safety and immunogenicity of the BNT162b2 coronavirus disease 2019 (COVID-19) vaccine in older adults with different frailty and disability profiles have not been well determined. Our objective was to analyze immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in older adults across frailty and disability profiles. DESIGN: Multicenter longitudinal cohort study. SETTING AND PARTICIPANTS: A total of 134 residents aged ≥65 years with different frailty and disability profiles in five long-term care facilities (LTCFs) in Albacete, Spain. INTERVENTION AND MEASUREMENTS: Residents were administered two vaccine doses as per the label, and antibody levels were determined 21.9 days (SD 9.3) after both the first and second dose. Functional variables were assessed using activities of daily living (Barthel Index), and frailty status was determined with the FRAIL instrument. Cognitive status and comorbidity were also evaluated. RESULTS: Mean age was 82.9 years (range 65-99), and 71.6% were female. The mean antibody titers in residents with and without previous COVID-19 infection were 49,878 AU/ml and 15,274 AU/ml, respectively (mean difference 34,604; 95% confidence interval [CI]: 27,699-41,509). No severe adverse reactions were observed, after either vaccine dose. Those with prevaccination COVID-19 had an increased antibody level after the vaccine (B = 31,337; 95% CI: 22,725-39,950; p < 0.001). Frailty, disability, older age, sex, cognitive impairment, or comorbidities were not associated with different antibody titers. CONCLUSIONS: The BNT162b2 mRNA COVID-19 vaccine in older adults is safe and produces immunogenicity, independently of the frailty and disability profiles. Older adults in LTCFs should receive a COVID-19 vaccine.

The Functional Continuum Scale in Relation to Hospitalization Density in Older Adults: The FRADEA Study.

BACKGROUND: There is a need to know the relationship between function and hospitalization risk in older adults. We aimed at investigating whether the Functional Continuum Scale (FCS), based on basic (BADL) and instrumental (IADL) activities of daily living and frailty, is associated with hospitalization density in older adults across 12 years of follow-up. METHODS: Cohort study, with a follow-up of 12 years. A total of 915 participants aged 70 years and older from the Frailty and Dependence in Albacete (FRADEA) study, a population-based study in Spain, were included. At baseline, the FCS, sociodemographic characteristics, comorbidity, number of medications, and place of residence were assessed. Associations with first hospitalization, number of hospitalizations, and 12-year density of hospitalizations were assessed using Kaplan-Meier curves, Poisson regression analyses, and density models. RESULTS: The median time until the first hospitalization was shorter toward the less functionally independent end of the FCS, from 3917 days (95% confidence interval [CI] 3701-3995) to 1056 days (95% CI 785-1645) (p < .001). The incidence rate ratio (IRR) for all hospitalizations increased from the robust category until the frail one (IRR 1.89), and thereafter it decreased until the worse functional category. Those who were BADL dependent presented an increased hospitalization density in the first 4 follow-up years (58%), those who were frail in the third-to-sixth follow-up years (55%), while in those prefrail or robust the hospitalization density was homogeneous during the complete follow-up. CONCLUSIONS: The FCS is useful for stratifying the risk of hospitalization and for predicting the density of hospitalizations in older adults.

Analysis of solitary pulmonary nodule after surgical resection in patients with 18F-FDG positron emission tomography integrated computed tomography in the preoperative work-up. / Análisis del nódulo pulmonar solitario tras su resección quirúrgica en pacientes con 18F-FDG PET-TC integrado en el estudio preoperatorio.

INTRODUCTION: To analyse clinicopathological characteristics of patients operated for pulmonary solitary nodule (PSN) and 18F-FDG integrated PET-CT scan after surgical resection. METHODOLOGY: Retrospective study on a prospective database of patients operated from January 2007 to October 2017 for PSN without preoperative diagnosis. Dependent variable was anatomopathological result (benign vs malignant) of PSN. Variables of the study were: age, sex, PET-CT uptake, SUVmax, smoking history, COPD, previous history of malignant disease, tumoral location, and tumour size on CT-scan. RESULTS: A total of 305 patients were included in this study, 225 (73.8%) men, 80 (26.2%) women, mean age = 63.9 (range 29-86 years), mean size PSN = 1.68 (s.d. .65 cm), benign = 46 (15.1%), malignant = 258 (84.6%), type of resection: pulmonary wedge = 151 (49.5%), lobectomy = 141 (46.2%), segmentectomy = 12 (3.9%), exploratory intervention = 1 (0.3%). Postoperative mortality was 1.9%. COPD = 50.8% cases, previous cancer disease = 172 cases (56.4%), smoking history = 250 cases (82.0%), positive PET = 280 cases (91.8%), PSN in upper pulmonary fields = 204 cases (66.9%), median SUVmax = 3.4 (range 0-20.7). Backward stepwise binary logistic regression model showed that age, SUVmax, previous malignant disease and female sex were independent risk factors with statistical significance (p < .05). Sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were 94.6%, 23.4%, 87.1%, 44.0%, and 83.6% respectively. There were 14 false negative cases (4.6%) and 36 false positive cases (11.8%). CONCLUSIONS: Age, SUVmax, previous malignant disease, and female sex were independent risk factors in our study. Each case should be individually evaluated in a multidisciplinary committee, and the patient's preferences or concerns should be kept in mind in decision-making. Surgical resection of PSN is not exempt from morbidity and mortality, even in sublobar or pulmonary wedge resection.

JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality.

Using AI, we identified baricitinib as having antiviral and anticytokine efficacy. We now show a 71% (95% CI 0.15 to 0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age, 81 years). An additional 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-α2 increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by greater than fivefold. RNA-seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and superresolution microscopy, we found that baricitinib exerts activity rapidly through the inhibition of host proteins (numb-associated kinases), uniquely among antivirals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication, and the cytokine storm and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivize further randomized controlled trials.

Autobiographical emotional induction in older people through popular songs: Effect of reminiscence bump and enculturation.

AIMS: This study is based on two experiments, the first, with an exploratory character. The aim of which is to assess the capacity of native vs international pop songs (NAT vs INT) from two consecutive life stages, Reminiscence bump (RB) and the immediately subsequent period (No reminiscence bump, NORB) to elicit positive emotions and autobiographical memories. METHOD: A total of 15 middle-aged adults and 15 older adults participated in Experiment 1 (E1). Emotionality, song familiarity and associated autobiographical memories were assessed. Each participant was exposed to 20 randomly selected age-specific songs. Pre-and post-test measures of mood state were also included. Experiment 2 (E2) focused on late adulthood, using a sample of 35 persons. The experimental design was similar to that used in E1. However, this second experiment also included an analysis of the types of autobiographical memories generated by the experimental task and a study of their relationship with the characteristics of the songs, their familiarity and the emotions they produced, and the number of trials. The aim was to delve into the effects that influence the effectiveness of the induction procedure, particularly as regards emotional positivity and memory specificity. RESULTS: Regarding age effect, E1 results varied: under some conditions, emotionality showed no difference between groups, others showed positive older adult bias. In E2, the analysis of the relationships between memory types and the selected variables suggests the latter are not useful predictors of differences between memory types. The study design yielded a relatively high level of memory specificity and emotional positivity. CONCLUSION: The findings question positivity bias in the elderly. RB music produces different effects depending on age. Enculturation can be an important mediating factor in emotionality and memory. Finally, experimental design improves specific memory and positivity.

Expression of MHC class I, HLA-A and HLA-B identifies immune-activated breast tumors with favorable outcome.

Antigen recognition by MHC class I molecules is a key step for the initiation of the immune response. We hypothesized that expression of these molecules could be a marker of immune-activated breast cancers. Data from KM Plotter were extracted to develop an exploratory cohort. Information from Cancer Genome Atlas (TCGA) and METABRIC was used to create two validation cohorts. Raw data were re-processed and analyzed using plyr R and Bioconductor. We predicted epitope-HLA binding to MHC I molecules by using NetMHC 4.0. Cox proportional hazards regression was computed to correlate gene expression and survival outcome. There was a weak but positive correlation between mutational burden and the expression of most MHC class I molecules. In the exploratory cohort, expression of HLA-A and HLA-B was associated with favorable relapse-free survival (RFS) and overall survival (OS) in the basal-like subgroup. This was confirmed in the METABRIC and TCGA dataset. Expression of HLA-A and HLA-B was associated with biomarkers of T cell activation (GZMA, GZMB, and PRF1) and improved the predictive capacity of known immunologic signatures. Several neopeptides expressed in breast cancer were also identified including FUK, SNAPC3, GC, ANO8, DOT1L, HIST1H3F, MYBPH, STX2, FRMD6, CPSF1, or SMTN, among others. Expression of HLA A and B is associated with T cell activation and identifies immune activated, basal-like breast cancers with favorable prognosis. Antigen recognition markers should be incorporated into the assessment of the tumor immune state of basal-like breast patients.

Role of cooperative groups and funding source in clinical trials supporting guidelines for systemic therapy of breast cancer.

INTRODUCTION: Clinical research is conducted by academia, cooperative groups (CGs) or pharmaceutical industry. Here, we evaluate the role of CGs and funding sources in the development of guidelines for breast cancer therapies. RESULTS: We identified 94 studies. CGs were involved in 28 (30%) studies while industry either partially or fully sponsored 64 (68%) studies. The number of industry funded studies increased over time (from 0% in 1976 to 100% in 2014; p for trend = 0.048). Only 10 (11%) government or academic studies were identified. Studies conducted by GCs included a greater number of subjects (median 448 vs. 284; p = 0.015), were more common in the neo/adjuvant setting (p < 0.0001), and were more often randomized (p = 0.018) phase III (p < 0.0001) trials. Phase III trial remained significant predictor for CG-sponsored trials (OR 7.1 p = 0.004) in a multivariable analysis. Industry funding was associated with higher likelihood of positive outcomes favoring the sponsored experimental arm (p = 0.013) but this relationship was not seen for CG-sponsored trials (p = 0.53). MATERIALS AND METHODS: ASCO, ESMO, and NCCN guidelines were searched to identify systemic anti-cancer therapies for early-stage and metastatic breast cancer. Trial characteristics and outcomes were collected. We identified sponsors and/or the funding source(s) and determined whether CGs, industry, or government or academic institutions were involved. Chi-square tests were used for comparison between studies. CONCLUSIONS: Industry funding is present in the majority of studies providing the basis for which recommendations about treatment of breast cancer are made. Industry funding, but not CG-based funding, was associated with higher likelihood of positive outcomes in clinical studies supporting guidelines for systemic therapy.

Functional transcriptomic annotation and protein-protein interaction network analysis identify NEK2, BIRC5, and TOP2A as potential targets in obese patients with luminal A breast cancer.

PURPOSE: Although obesity is a risk factor for breast cancer, little effort has been made in the identification of druggable molecular alterations in obese-breast cancer patients. Tumors are controlled by their surrounding microenvironment, in which the adipose tissue is a main component. In this work, we intended to describe molecular alterations at a transcriptomic and protein-protein interaction (PPI) level between obese and non-obese patients. METHODS AND RESULTS: Gene expression data of 269 primary breast tumors were compared between normal-weight (BMI < 25, n = 130) and obese (IMC > 30, n = 139) patients. No significant differences were found for the global breast cancer population. However, within the luminal A subtype, upregulation of 81 genes was observed in the obese group (FC ≥ 1.4). Next, we explored the association of these genes with patient outcome, observing that 39 were linked with detrimental outcome. Their PPI map formed highly compact cluster and functional annotation analyses showed that cell cycle, cell proliferation, cell differentiation, and cellular response to extracellular stimuli were the more altered functions. Combined analyses of genes within the described functions are correlated with poor outcome. PPI network analyses for each function were to search for druggable opportunities. We identified 16 potentially druggable candidates. Among them, NEK2, BIRC5, and TOP2A were also found to be amplified in breast cancer, suggesting that they could act as strategic players in the obese-deregulated transcriptome. CONCLUSION: In summary, our in silico analysis describes molecular alterations of luminal A tumors and proposes a druggable PPI network in obese patients with potential for translation to the clinical practice.

Synthetic Lethality Interaction Between Aurora Kinases and CHEK1 Inhibitors in Ovarian Cancer.

Ovarian cancer is characterized by frequent mutations at TP53. These tumors also harbor germline mutations at homologous recombination repair genes, so they rely on DNA-damage checkpoint proteins, like the checkpoint kinase 1 (CHEK1) to induce G2 arrest. In our study, by using an in silico approach, we identified a synthetic lethality interaction between CHEK1 and mitotic aurora kinase A (AURKA) inhibitors. Gene expression analyses were used for the identification of relevant biological functions. OVCAR3, OVCAR8, IGROV1, and SKOV3 were used for proliferation studies. Alisertib was tested as AURKA inhibitor and LY2603618 as CHEK1 inhibitor. Analyses of cell cycle and intracellular mediators were performed by flow cytometry and Western blot analysis. Impact on stem cell properties was evaluated by flow cytometry analysis of surface markers and sphere formation assays. Gene expression analyses followed by functional annotation identified a series of deregulated genes that belonged to cell cycle, including AURKA/B, TTK kinase, and CHEK1. AURKA and CHEK1 were amplified in 8.7% and 3.9% of ovarian cancers, respectively. AURKA and CHEK1 inhibitors showed a synergistic interaction in different cellular models. Combination of alisertib and LY2603618 triggered apoptosis, reduced the stem cell population, and increased the effect of taxanes and platinum compounds. Finally, expression of AURKA and CHEK1 was linked with detrimental outcome in patients. Our data describe a synthetic lethality interaction between CHEK1 and AURKA inhibitors with potential translation to the clinical setting. Mol Cancer Ther; 16(11); 2552-62. ©2017 AACR.

Circulating DNA and Survival in Solid Tumors.

BACKGROUND: The ability to undertake molecular analysis to inform on prognosis and predictors of response to therapy is limited by accessibility of tissue. Measurement of total circulating free DNA (cfDNA) or circulating tumor DNA (ctDNA) in peripheral blood may allow easier access to tumor material and help to predict clinical outcomes. METHODS: A systematic review of electronic databases identified publications exploring the association between cfDNA or ctDNA and overall survival (OS) in solid tumors. HRs for OS were extracted from multivariable analyses and included in a meta-analysis. Pooled HRs were computed and weighted using generic inverse variance and random-effect modeling. For studies not reporting multivariable analyses, univariable ORs were estimated from Kaplan-Meier curves for OS at 1 and 3 years. RESULTS: Thirty-nine studies comprising 4,052 patients were included in the analysis. Detection of ctDNA was associated with a significantly worse OS in multivariable analyses [HR, 2.70; 95% confidence interval (CI), 2.02-3.61; P < 0.001). Similar results were observed in the univariable analyses at 3 and 1 year (OR, 4.83; 95% CI, 3.20-7.28; P < 0.001).There was also a statistically significant association between high total cfDNA and worse OS for studies reporting multivariable and univariate data at 3 years (HR, 1.91; 95% CI, 1.59-2.29; P < 0.001 and OR, 2.82; 95% CI, 1.93-4.13; P < 0.001, respectively). CONCLUSIONS: High levels of total cfDNA and presence of ctDNA are associated with worse survival in solid tumors. IMPACT: Circulating DNA is associated with worse outcome in solid tumors.

Efecto a largo plazo de los estanoles vegetales en el perfil lipídico de pacientes con hipercolesterolemia. Ensayo clínico aleatorizado / Long-term effects of plant stanols on the lipid profile of patients with hypercholesterolemia. A randomized clinical trial

Introducción y objetivos. El consumo de estanoles vegetales puede contribuir a un mejor control a largo plazo del colesterol. El objetivo es evaluar la eficacia del aporte de estanoles vegetales, a dosis de 2 g/día, en la reducción de las cifras de colesterol unido a lipoproteínas de baja densidad de los pacientes con hipercolesterolemia. Métodos. Se realizó un ensayo clínico aleatorizado, a doble ciego y controlado con placebo, en el que se incluyó a 182 sujetos adultos diagnosticados de hipercolesterolemia. Se administró yogur líquido con 2 g de estanoles vegetales a 91 sujetos del grupo intervención y yogur no suplementado a 91 del grupo control. La variable principal fue la variación del perfil lipídico a los 12 meses. Resultados. En comparación con el placebo, a los 12 meses se observó una disminución significativamente superior del colesterol unido a lipoproteínas de baja densidad en el grupo que tomó estanoles: 13,7 (intervalo de confianza del 95%, 3,2-24,1) mg/dl (p = 0,011). En este grupo fue significativamente superior la proporción de sujetos que redujeron en más del 10% sus cifras de colesterol unido a lipoproteínas de baja densidad (riesgo relativo = 1,7; intervalo confianza del 95%, 1,1-2,7). En el grupo tratado, el colesterol unido a lipoproteínas de baja densidad descendió, en promedio, un 11,0 ± 23,9%. Conclusiones. Los resultados confirman que la administración de estanoles vegetales en dosis de 2 g/día durante 1 año produce una reducción significativa (ligeramente superior al 10%) de las concentraciones de colesterol unido a lipoproteínas de baja densidad en sujetos con hipercolesterolemia (AU)

Introduction and objectives. Plant stanol consumption may improve long-term cholesterol control. The aim of the present study was to evaluate the effectiveness of 2 g/day of plant stanols in reducing low-density lipoprotein cholesterol levels in patients with hypercholesterolemia. Methods. This randomized, double-blind, and placebo-controlled study included 182 adults diagnosed with hypercholesterolemia. A yogurt drink containing 2 g of plant stanols was administered to 91 participants in the intervention group; 91 participants in the control group received unsupplemented yogurt. The primary end point was the change in the lipid profile at 12 months. Results. Low-density lipoprotein cholesterol levels at 12 months were significantly more reduced in the stanol intervention group than in the control group: 13.7 (95% confidence interval, 3.2-24.1) mg/dL (P = .011). A reduction of more than 10% in low-density lipoprotein cholesterol was achieved by a significantly higher proportion of participants in the intervention group (relative risk = 1.7; 95% confidence interval, 1.1-2.7). In this group, the mean (standard deviation) level of low-density lipoprotein cholesterol decreased by 11.0% (23.9%). Conclusions. Our results confirm that administration of plant stanols at a dosage of 2 g/day for 12 months significantly reduces (by slightly more than 10%) the concentrations of low-density lipoprotein cholesterol in individuals with hypercholesterolemia (AU)

Group cognitive-behavioral therapy for insomnia: a meta-analysis / Terapia cognitivo-conductual grupal para el tratamiento del insomnio: metaanálisis

Background: insomnia is a highly prevalent disorder in the general population and in clinical practice. Although pharmacological treatment is the most widespread choice, psychological treatment appears to havelonger lasting effects. The main objective of this meta-analysis was to assess the cognitive-behavioural group therapy treatment for insomnia. Method: a systematic search for cognitive-behavioural therapy clinical trialsin Pubmed, PsycINFO, PsycARTICLES, Scielo, WOK, Cochrane, Scopusand Embase. 153 articles were reviewed, of which 9 met inclusion criteria for the metaanalysis. Adding up the data from all 9 trials, a total of 699people completed the post-test phase. Results: after finishing cognitive-behavioural therapy, significant improvements regarding insomnia were found according to the Pittsburgh SleepQuality Index and Insomnia Severity Index, sleep latency, wake after sleeponset and sleep efficiency. There were no significant improvements in total sleep time. Conclusions: the results from experimental studies on cognitive behavioural therapy as an insomnia treatment clearly suggest a positive impact on symptoms, as assessed using both validated scales and sleep diaries

Antecedentes: el insomnio es un trastorno de elevada prevalencia tanto entre la población general como en la práctica clínica. Aunque el tratamiento farmacológico para el insomnio es el más extendido, es el tratamiento psicológico el que mantiene sus efectos a lo largo del tiempo. El objetivo principal de este metaanálisis es evaluar la eficacia de la terapia cognitivo-conductual grupal para el tratamiento del insomnio. Método: búsqueda sistemática de ensayos clínicos de terapia cognitivo-conductual para el insomnio en Medline, PsycINFO, PsycARTICLES, Scielo, WOK, Cochrane, Scopus y Embase. Se revisaron 153 artículos, de los que 9 cumplieron con los criterios de inclusión para formar parte del metaanálisis. En estos 9 estudios 692 personas completaron el post-test. Resultados: aparecen mejoras significativas con el tratamiento cognitivo-conductual para el insomnio en las escalas Pittsburgh Sleep Quality Index e Insomnia Severity Index, en latencia del sueño, en tiempo despierto después de iniciar el sueño y en eficiencia del sueño. No aparecen mejoras significativas en el tiempo total de sueño. Conclusiones: los resultados de los estudios experimentales sobre terapia cognitivo-conductual para el tratamiento del insomnio sugieren que esta tiene un claro impacto positivo sobre los síntomas, evaluados tanto mediante escalas validadas como mediante diarios del sueño