A pilot study to investigate the safety and feasibility of antiretroviral therapy for Alzheimer's disease (ART-AD).

Retrotransposons are viral-like DNA sequences that constitute approximately 41% of the human genome. Studies in Drosophila, mice, cultured cells, and human brain indicate that retrotransposons are activated in settings of tauopathy, including Alzheimer's disease, and causally drive neurodegeneration. The anti-retroviral medication 3TC (lamivudine), a nucleoside analog reverse transcriptase inhibitor, limits retrotransposon activation and suppresses neurodegeneration in tau transgenic Drosophila, two mouse models of tauopathy, and in brain assembloids derived from patients with sporadic Alzheimer's disease. We performed a 24-week phase 2a open-label clinical trial of 300 mg daily oral 3TC (NCT04552795) in 12 participants aged 52-83 years with a diagnosis of mild cognitive impairment due to suspected Alzheimer's disease. Primary outcomes included feasibility, blood brain barrier penetration, effects of 3TC on reverse transcriptase activity in the periphery, and safety. Secondary outcomes included changes in cognition and fluid-based biomarkers of neurodegeneration and neuroinflammation. All participants completed the six-month trial; one event of gastrointestinal bleeding due to a peptic ulcer was reported. 3TC was detected in blood and cerebrospinal fluid (CSF) of all participants, suggestive of adherence to study drug and effective brain penetration. Cognitive measures remained stable throughout the study. Glial fibrillary acidic protein (GFAP) (P=0.03) and Flt1 (P=0.05) were significantly reduced in CSF over the treatment period; Aß42/40 (P=0.009) and IL-15 (P=0.006) were significantly elevated in plasma. While this is an open label study of small sample size, the significant decrease of some neurodegeneration- and neuroinflammation-related biomarkers in CSF, significantly elevated levels of plasma Aß42/40, and a trending decrease of CSF NfL after six months of 3TC exposure suggest a beneficial effect on subjects with mild cognitive impairment due to suspected Alzheimer's disease. Feasibility, safety, tolerability, and central nervous system (CNS) penetration assessments further support clinical evaluation of 3TC in a larger placebo-controlled, multi-dose clinical trial.

Facilitators of and barriers to gastric cancer and precursor diagnosis among South Texas residents: Social determinants of health.

BACKGROUND: Latinos/Hispanics are at higher risk for developing gastric cancer (GC) compared with non-Hispanic whites, and social determinants of health (SDoH) are thought to contribute. AIMS/MATERIALS AND METHODS: This study addressed SDoH and their interactions contributing to disparities in the testing and treatment of Helicobacter pylori (HP) infection and diagnosis of GC and its known precursors, among Latinos/Hispanics relative to non-Latinos at two affiliated but independent health systems in San Antonio, Texas, using a mixed methods approach. RESULTS: Secondary data abstraction and analysis showed that GCs represented 2.6% (n = 600) of our population. Men and older individuals were at higher GC risk. Individuals with military insurance were 2.7 times as likely to be diagnosed as private insurance. Latinos/Hispanics had significantly (24%) higher GC risk than Whites. Poverty and lack of insurance contributed to GC risk among the minorities classified as other (Asians, Native Americans, Multiracial; all p < 0.01). All SDoH were associated with H. pylori infection (p < 0.001). Qualitative analysis of patient and provider interviews showed providers reporting insurance as a major care barrier; patients reported appointment delays, and lack of clinic staff. Providers universally agreed treatment of H. pylori was necessary, but disagreed on its prevalence. Patients did not report discussing H. pylori or its cancer risk with providers. DISCUSSION/CONCLUSION: These data indicate the importance of considering SDoH in diagnosis and treatment of GC and its precursors, and educating providers and patients on H. pylori risks for GC.

p63 controls metabolic activation of hepatic stellate cells and fibrosis via an HER2-ACC1 pathway.

The p63 protein has pleiotropic functions and, in the liver, participates in the progression of nonalcoholic fatty liver disease (NAFLD). However, its functions in hepatic stellate cells (HSCs) have not yet been explored. TAp63 is induced in HSCs from animal models and patients with liver fibrosis and its levels positively correlate with NAFLD activity score and fibrosis stage. In mice, genetic depletion of TAp63 in HSCs reduces the diet-induced liver fibrosis. In vitro silencing of p63 blunts TGF-ß1-induced HSCs activation by reducing mitochondrial respiration and glycolysis, as well as decreasing acetyl CoA carboxylase 1 (ACC1). Ectopic expression of TAp63 induces the activation of HSCs and increases the expression and activity of ACC1 by promoting the transcriptional activity of HER2. Genetic inhibition of both HER2 and ACC1 blunt TAp63-induced activation of HSCs. Thus, TAp63 induces HSC activation by stimulating the HER2-ACC1 axis and participates in the development of liver fibrosis.

Further Studies on the Highly Active Des-C-Ring and Aromatic-D-Ring Analogues of 1α,25-Dihydroxyvitamin D3 (Calcitriol): Refinement of the Side Chain.

Current efforts in the vitamin D field are directed toward the development of highly antiproliferative yet noncalcemic analogues of the natural hormone 1α,25-dihydroxyvitamin D3 (1,25D3). We have recently reported the design, synthesis, biological evaluation, and crystal structures of a series of novel analogues that both lack the steroidal C-ring and have an m-phenylene ring replacing the steroidal cyclopentane D-ring. We have now investigated the potentiating effects of incorporating selected modifications (hexafluorination and/or an internal triple bond) within the steroidal side chain in our series. An alternative synthetic strategy (Wittig-Horner approach instead of our previously used Pd-catalyzed tandem cyclization/cross-coupling) for the construction of the vitamin D triene system was found convenient for the target compounds 2, 3a, 3b, and 3c of this report. These modifications enhance vitamin D nuclear receptor (VDR) interactions and consequently VDR-associated biological properties compared to parental PG-136 compound while maintaining normal calcium levels.

Psychometric properties of the self-efficacy scale for chronic disease management (SEMCD-S) in older Colombian adults.

BACKGROUND: Self-efficacy alludes to personal competence in an individual's effectiveness when facing stressful situations. This construct has been related to different domains of the health field, finding that high levels of self-efficacy benefit human functioning and enhance well-being. METHODS: The present study aimed to determine the psychometric properties of the self-efficacy scale for managing chronic diseases (SEMCD-S) by assessing factorial, convergent and divergent validity, reliability, and measurement invariance. Likewise, the comparison of self-efficacy according to socio-demographic characteristics was proposed by contrasting latent factors. An instrumental, transactional, descriptive, and non-experimental design study was carried out with the participation of 325 Colombian senior citizens. RESULTS: The findings suggest that the scale has appropriate psychometric properties. The one-factor structure exhibited a satisfactory fit, the mean-variance extracted reported acceptable figures and the correlation analysis with other constructs supported this instrument's convergent and discriminant validity. Likewise, it was invariant to the different socio-demographic aspects examined, while the internal consistency figures were high. Differences in the means of the latent factors were only detected in the academic grade. In this case, older adults with a primary school level attained higher self-efficacy values than those who had completed high school or university studies. CONCLUSIONS: It is concluded that the self-efficacy scale for chronic disease management is a valid and reliable instrument that can be used in the Colombian context to measure and compare this construct.

Endogenous adenine mediates kidney injury in diabetic models and predicts diabetic kidney disease in patients.

Diabetic kidney disease (DKD) can lead to end-stage kidney disease (ESKD) and mortality; however, few mechanistic biomarkers are available for high-risk patients, especially those without macroalbuminuria. Urine from participants with diabetes from the Chronic Renal Insufficiency Cohort (CRIC) study, the Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes (SMART2D), and the American Indian Study determined whether urine adenine/creatinine ratio (UAdCR) could be a mechanistic biomarker for ESKD. ESKD and mortality were associated with the highest UAdCR tertile in the CRIC study and SMART2D. ESKD was associated with the highest UAdCR tertile in patients without macroalbuminuria in the CRIC study, SMART2D, and the American Indian study. Empagliflozin lowered UAdCR in nonmacroalbuminuric participants. Spatial metabolomics localized adenine to kidney pathology, and single-cell transcriptomics identified ribonucleoprotein biogenesis as a top pathway in proximal tubules of patients without macroalbuminuria, implicating mTOR. Adenine stimulated matrix in tubular cells via mTOR and stimulated mTOR in mouse kidneys. A specific inhibitor of adenine production was found to reduce kidney hypertrophy and kidney injury in diabetic mice. We propose that endogenous adenine may be a causative factor in DKD.

Role of endogenous adenine in kidney failure and mortality with diabetes.

Diabetic kidney disease (DKD) can lead to end-stage kidney disease (ESKD) and mortality, however, few mechanistic biomarkers are available for high risk patients, especially those without macroalbuminuria. Urine from participants with diabetes from Chronic Renal Insufficiency Cohort (CRIC), Singapore Study of Macro-Angiopathy and Reactivity in Type 2 Diabetes (SMART2D), and the Pima Indian Study determined if urine adenine/creatinine ratio (UAdCR) could be a mechanistic biomarker for ESKD. ESKD and mortality were associated with the highest UAdCR tertile in CRIC (HR 1.57, 1.18, 2.10) and SMART2D (HR 1.77, 1.00, 3.12). ESKD was associated with the highest UAdCR tertile in patients without macroalbuminuria in CRIC (HR 2.36, 1.26, 4.39), SMART2D (HR 2.39, 1.08, 5.29), and Pima Indian study (HR 4.57, CI 1.37-13.34). Empagliflozin lowered UAdCR in non-macroalbuminuric participants. Spatial metabolomics localized adenine to kidney pathology and transcriptomics identified ribonucleoprotein biogenesis as a top pathway in proximal tubules of patients without macroalbuminuria, implicating mammalian target of rapamycin (mTOR). Adenine stimulated matrix in tubular cells via mTOR and stimulated mTOR in mouse kidneys. A specific inhibitor of adenine production was found to reduce kidney hypertrophy and kidney injury in diabetic mice. We propose that endogenous adenine may be a causative factor in DKD.

Reorganization of Brain Networks as a Substrate of Resilience: An Analysis of Cytochrome c Oxidase Activity in Rats.

The unpredictable chronic mild stress (UCMS) model has been used to induce depressive-like symptoms in animal models, showing adequate predictive validity. Our work aims to evaluate the effects of environmental enrichment (EE) on resilience in this experimental model of depression. We also aim to assess changes in brain connectivity using cytochrome c oxidase histochemistry in cerebral regions related to cognitive-affective processes associated with depressive disorder: dorsal hippocampus, prefrontal cortex, amygdala, accumbens, and habenula nuclei. Five groups of rats were used: UCMS, EE, EE + UCMS (enrichment + stress), BG (basal level of brain activity), and CONT (behavioral tests only). We assessed the hedonic responses elicited by sucrose solution using a consumption test; the anxiety level was evaluated using the elevated zero maze test, and the unconditioned fear responses were assessed by the cat odor test. The behavioral results showed that the UCMS protocol induces elevated anhedonia and anxiety. But these responses are attenuated previous exposure to EE. Regarding brain activity, the UCMS group showed greater activity in the habenula compared to the EE + UCMS group. EE induced a functional reorganization of brain activity. The EE + UCMS and UCMS groups showed different patterns of connections between brain regions. Our results showed that EE favors greater resilience and could reduce vulnerability to disorders such as depression and anxiety, modifying metabolic brain activity.

Hepatic p63 regulates glucose metabolism by repressing SIRT1.

OBJECTIVE: p63 is a transcription factor within the p53 protein family that has key roles in development, differentiation and prevention of senescence, but its metabolic actions remain largely unknown. Herein, we investigated the physiological role of p63 in glucose metabolism. DESIGN: We used cell lines and mouse models to genetically manipulate p63 in hepatocytes. We also measured p63 in the liver of patients with obesity with or without type 2 diabetes (T2D). RESULTS: We show that hepatic p63 expression is reduced on fasting. Mice lacking the specific isoform TAp63 in the liver (p63LKO) display higher postprandial and pyruvate-induced glucose excursions. These mice have elevated SIRT1 levels, while SIRT1 knockdown in p63LKO mice normalises glycaemia. Overexpression of TAp63 in wild-type mice reduces postprandial, pyruvate-induced blood glucose and SIRT1 levels. Studies carried out in hepatocyte cell lines show that TAp63 regulates SIRT1 promoter by repressing its transcriptional activation. TAp63 also mediates the inhibitory effect of insulin on hepatic glucose production, as silencing TAp63 impairs insulin sensitivity. Finally, protein levels of TAp63 are reduced in obese persons with T2D and are negatively correlated with fasting glucose and homeostasis model assessment index. CONCLUSIONS: These results demonstrate that p63 physiologically regulates glucose homeostasis.

Implementation of a methodology to assess patient reported outcomes in lung cancer patients: The PeOpLe (Patient-reported Outcomes in Lung cancer ) study protocol.

OBJECTIVE: The purpose of this article is to describe the PeOpLe study protocol, developed to assess patient-reported health outcomes in  advanced or metastatic non-small-cell lung cancer in routine clinical practice using the methodology provided by the International Consortium for Health Outcomes Measurement tool. METHOD: The study envisaged will be multicenter, longitudinal, ambispective and observational. Two groups will be compared: a control group (followed up according to standard clinical practice) and an experimental group (followed up using the International Consortium for Health  Outcomes Measurement methodology adapted to the Spanish setting for 6  months). The variables collected will be related to demography (age, sex,  degree of family support), clinical factors (smoking, comorbidities, lung  capacity), the neoplasm (histology, staging, mutations), pharmacotherapy  (treatment schedule, modifications, and complications), health status  (functional status, quality of life, satisfaction and overall survival) and resource consumption (emergency visits, hospital admissions and time spent by health providers). The PeOpLe study protocol has been approved by the Ethics Committee for Research into Medicinal Products of the Gregorio Marañón General University Hospital and will be conducted in compliance with prevailing ethical principles and standards. CONCLUSIONS: The PeOpLe study will explore how patient-reported outcomes collection can be developed and integrated with the clinical processes used in  the management of patients with locally advanced or metastatic nonsmall cell  lung cancer what patient-reported outcomes can be measured with systems  that can conveniently be used both by patients and by healthcare providers.  Systematic evaluation of patient-reported outcomes will help determine their  impact in terms of effectiveness (survival), safety (complications of systemic  therapy), and quality of life and patient satisfaction. The multidisciplinary and  multicenter nature of the study will facilitate a comprehensive view of the  subject analyzed and allow external reproducibility.

OBJETIVO: El objetivo es describir el protocolo del estudio PeOpLe, cuyo fin es  evaluar los resultados en salud centrados en el paciente con cáncer de pulmón  no microcítico avanzado o metastásico en la práctica clínica habitual mediante  una metodología adaptada de la herramienta del International Consortium for  Health Outcomes Measurement.Método: Estudio observacional, ambispectivo, longitudinal y multicéntrico. Se  compararán dos grupos: grupo control (seguimiento según práctica clínica  habitual) frente a un grupo intervención (seguimiento mediante la metodología  del International Consortium for Health Outcomes Measurement adaptada al entorno español) durante un período de 6 meses.  Las variables recogidas incluirán aspectos demográficos (edad, sexo, apoyo familiar), clínicos (hábito tabáquico, comorbilidades, capacidad   pulmonar), del tumor (histología, estadiaje, mutaciones), farmacoterapéutico (esquema de tratamiento, modificaciones y  complicaciones), grado de salud (estado funcional, calidad de vida, satisfacción y supervivencia global) y consumo de recursos (visitas a urgencias, ingresos  hospitalarios y tiempo dedicado por los profesionales sanitarios). El protocolo  del estudio PeOpLe ha sido aprobado por el Comité de Ética de la Investigación con medicamentos y se realizará respetando los principios y las normas éticas  básicas. CONCLUSIONES: El estudio PeOpLe explorará cómo se pueden desarrollar e  integrar los procesos de medición de resultados en salud centrados en los  pacientes, especialmente los patient-reported outcomes, en pacientes con  cáncer de pulmón no microcítico localmente avanzado o metastásico en la  práctica clínica. La evaluación sistemática de estos patient-reported outcomes  permitirá conocer su impacto en términos de efectividad (supervivencia),  seguridad (complicaciones de la terapia sistémica) y calidad de vida y  satisfacción. El carácter multidisciplinar y multicéntrico facilitará una visión  integral y su reproducibilidad externa.

Design, Synthesis, Biological Activity, and Structural Analysis of Novel Des-C-Ring and Aromatic-D-Ring Analogues of 1α,25-Dihydroxyvitamin D3.

The toxic calcemic effects of the natural hormone 1α,25-dihydroxyvitamin D3 (1,25D3, 1,25-dihydroxycholecalciferol) in the treatment of hyperproliferative diseases demand the development of highly active and noncalcemic vitamin D analogues. We report the development of two highly active and noncalcemic analogues of 1,25D3 that lack the C-ring and possess an m-phenylene ring that replaces the natural D-ring. The new analogues (3a, 3b) are characterized by an additional six-carbon hydroxylated side chain attached either to the aromatic nucleus or to the triene system. Both compounds were synthesized by the Pd-catalyzed tandem cyclization/cross coupling approach starting from alkyne 6 and diphenol 8. Key steps include a stereoselective Cu-assisted addition of a Grignard reagent to an aromatic alkyne and a Takai olefination of an aromatic aldehyde. The new compounds are noncalcemic and show transcriptional and antiproliferative activities similar to 1,25D3. Structural analysis revealed that they induce a large conformational rearrangement of the vitamin D receptor around helix 6.

Examining the Delivery of a Tailored Chinese Mind-Body Exercise to Low-Income Community-Dwelling Older Latino Individuals for Healthy Aging: Feasibility and Acceptability Study.

BACKGROUND: Older Latino individuals are disproportionally affected by various chronic conditions including impairments in physical and cognitive functions, which are essential for healthy aging and independent living. OBJECTIVE: This study aimed to evaluate the feasibility and acceptability of FITxOlder, a 12-week mind-body exercise program, in community-dwelling low-income, predominantly older Latino individuals, and assess its preliminary effects on health parameters relevant to healthy aging and independent living. METHODS: This 12-week, single-arm, stage 1B feasibility study had a pre- and poststudy design. A total of 13 older adults (mean age 76.4, SD 7.9 years; 11/13, 85% Latino) of a congregate meal program in a senior center were enrolled. FITxOlder was a tailored Chinese mind-body exercise program using Five Animal Frolics led by a bilingual community health worker (CHW) participating twice a week at the senior center and facilitated by mobile health technology for practice at home, with incrementally increasing goals moving from once a week to at least 3 times a week. The feasibility and acceptability of the study were examined using both quantitative and qualitative data. Healthy aging-related outcomes (eg, physical and cognitive function) were assessed using paired 2-tailed t tests. Qualitative interview data were analyzed using thematic analysis. RESULTS: The attendance rate for the 24 exercise sessions was high (22.7/24, 95%), ranging from 93% (1.8/2) to 97% (1.9/2) over the 12 weeks. Participants were compliant with the incremental weekly exercise goals, with 69.2% (9/13) and 75.0% (9/12) meeting the home and program goals in the last 4 weeks, respectively. Approximately 83% (10/12) to 92% (11/12) of the participants provided favorable feedback on survey questions regarding the study and program implementation, such as program content and support, delivery by the CHW, enjoyment and appeal of the Five Animal Frolics, study burden and incentives, and safety concerns. The qualitative interview data revealed that FITxOlder was well accepted; participants reported enjoyment and health benefits and the desire to continue to practice and share it with others. The 5-time sit-to-stand test (mean change at posttest assessment=-1.62; P<.001; Cohen d=0.97) and 12-Item Short Form Health Survey physical component scores (mean change at post intervention=5.71; P=.01; Cohen d=0.88) exhibited changes with large effect sizes from baseline to 12 weeks; the other parameters showed small or medium effect sizes. CONCLUSIONS: The research findings indicated that the CHW-led and mobile health-facilitated Chinese qigong exercise program is feasible and acceptable among low-income Latino older adults. The trending health benefits of the 12-week FITxOlder program suggest it is promising to promote physical activity engagement in underserved older populations to improve health outcomes for healthy aging and independent living. Future research with larger samples and longer interventions is warranted to assess the health benefits and suitability of FITxOlder.

In Vivo Effects of Conditioned Medium from Human Uterine Cervical Stem Cells in an Ovarian Cancer Xenograft Mouse Model.

BACKGROUND/AIM: Ovarian cancer is the most lethal of all gynecological cancers, despite advances in surgical techniques and medical treatments. During the last years, therapies based on mesenchymal stem cells and particularly their secretome (conditioned medium, CM) have emerged as promising treatments for various types of tumors. MATERIALS AND METHODS: In the present study, we evaluated the in vivo antitumor effect of human uterine cervical stem cell conditioned medium (hUCESC-CM) after intraperitoneal administration in an ovarian cancer mouse model. RESULTS: We found that intraperitoneal injection of hUCESC-CM in immunodeficient mice, injected fifty days previously with the human ovarian adenocarcinoma SKOV-3 cell line, significantly reduced abdominal tumor growth, and significantly increased overall survival, compared to control mice. CONCLUSION: hUCESC-CM could be an alternative approach to intraperitoneal treatment of ovarian cancer, either administered alone and/or with conventional chemotherapy.

Implantación de una metodología para evaluarpatient-reported outcomes en pacientes con cáncer de pulmón: Protocolo del estudio PeOpLe(Patient-reported Outcomes in Lung cancer) / Implementation of a methodology to assess patient reported outcomes in lung cancer patients: The PeOpLe (Patient-reported Outcomes in Lung cancer) study protocol

Objetivo: El objetivo es describir el protocolo del estudio PeOpLe, cuyofin es evaluar los resultados en salud centrados en el paciente con cáncerde pulmón no microcítico avanzado o metastásico en la práctica clínicahabitual mediante una metodología adaptada de la herramienta del International Consortium for Health Outcomes Measurement.Método: Estudio observacional, ambispectivo, longitudinal y multicéntrico. Se compararán dos grupos: grupo control (seguimiento según práctica clínica habitual) frente a un grupo intervención (seguimiento mediantela metodología del International Consortium for Health Outcomes Measurement adaptada al entorno español) durante un período de 6 meses. Lasvariables recogidas incluirán aspectos demográficos (edad, sexo, apoyofamiliar), clínicos (hábito tabáquico, comorbilidades, capacidad pulmonar), del tumor (histología, estadiaje, mutaciones), farmacoterapéutico(esquema de tratamiento, modificaciones y complicaciones), grado desalud (estado funcional, calidad de vida, satisfacción y supervivencia global) y consumo de recursos (visitas a urgencias, ingresos hospitalariosy tiempo dedicado por los profesionales sanitarios). El protocolo del estudio PeOpLe ha sido aprobado por el Comité de Ética de la Investigacióncon medicamentos y se realizará respetando los principios y las normaséticas básicas. (AU)

Objective: The purpose of this article is to describe the PeOpLe studyprotocol, developed to assess patient-reported health outcomes in advanced or metastatic non-small-cell lung cancer in routine clinical practiceusing the methodology provided by the International Consortium forHealth Outcomes Measurement tool.Method: The study envisaged will be multicenter, longitudinal, ambispective and observational. Two groups will be compared: a control group(followed up according to standard clinical practice) and an experimentalgroup (followed up using the International Consortium for Health OutcomesMeasurement methodology adapted to the Spanish setting for 6 months).The variables collected will be related to demography (age, sex, degreeof family support), clinical factors (smoking, comorbidities, lung capacity),the neoplasm (histology, staging, mutations), pharmacotherapy (treatmentschedule, modifications, and complications), health status (functionalstatus, quality of life, satisfaction and overall survival) and resource consumption (emergency visits, hospital admissions and time spent by healthproviders). The PeOpLe study protocol has been approved by the EthicsCommittee for Research into Medicinal Products of the Gregorio MarañónGeneral University Hospital and will be conducted in compliance withprevailing ethical principles and standards. (AU)

High Fundamental Frequency (HFF) Monolithic Quartz Crystal Microbalance with Dissipation Array for the Simultaneous Detection of Pesticides and Antibiotics in Complex Food.

As in the case of the food industry in general, there is a global concern about safety and quality in complex food matrices, such as honey, which is driving the demand for fast, sensitive and affordable analytical techniques across the honey-packaging industry. Although excellent techniques such as liquid chromatography-tandem mass spectrometry (LC-MS/MS) are available, these are located in centralized laboratories and are still lacking in speed, simplicity and cost-effectiveness. Here, a new approach is presented where a competitive immunoassay is combined with a novel High Fundamental Frequency Quartz Crystal Microbalance with Dissipation (HFF-QCMD) array biosensor for the simultaneous detection of antibiotics and pesticides in honey. Concretely, thiabendazole and sulfathiazole residues were monitored in spiked honey samples. Results revealed that HFF-QCMD arrays provide a complementary and reliable tool to LC-MS/MS for the analysis of contaminants in these kinds of complex matrices, while avoiding elaborate sample pre-treatment. The good sensitivity achieved (I50 values in the 70-720 µg/kg range) and the short analysis time (60 min for 24 individual assays), together with the ability for multiple analyte detection (24 sensor array) and its cost-effectiveness, pave the way for the implementation of a fast on-line, in situ routine control of potentially hazardous chemical residues in honey.

Defining a Standard Set of Patient-Reported Outcomes for Patients With Advanced Ovarian Cancer.

Purpose: Advanced ovarian cancer (AOC) and its treatment cause several symptoms and impact on patients' health-related quality of life (HRQoL). We aim to reach a consensus on the most relevant patient-reported outcome (PROs), the corresponding measures (PROMs), and measurement frequency during AOC patients' follow-up from patients' and healthcare professionals' (HCP) perspective. Methods: The project comprised five steps: 1) a literature review, 2) a focus group with patients, 3) a nominal group with HCP, 4) two round-Delphi consultations with patients and HCP, and 5) a final meeting with HCP. Delphi questionnaire was elaborated based on literature review, focus group (n=5 patients), and nominal group (n=16 HCP). The relevance of each PRO and the appropriateness (A) and feasibility (F) of the proposed PROM were assessed (Likert scale 1=strongly agree; 9=strongly disagree). The consensus was reached when at least 75% of the panelists rated it as 'relevant', 'appropriate', or 'feasible' (score 7-9). Results: A total of 56 HCP [51.8% Hospital Pharmacy; 41.1% Oncology; 3.6% Nursing; and 3.6% Psycho-oncology; mean time in specialty 12.5 (8.0) years] and 10 AOC patients [mean time diagnosis 5.4 (3.0) years] participated in the 1st round. All PROs achieved consensus regarding their relevance, except dry skin (58.0%). Agreement was reached for PRO-CTCAE to be used to assess fatigue (A:84.9%; F:75.8%), neuropathy (A:92.4%; F:77.3%), diarrhea (A:87.9%; F:88.7%), constipation (A:86.4%; F:75.8%), nausea (A:89.4%; F:75.8%), insomnia (A:81.8%; F:88.7%), abdominal bloating (A:82.2%; F:82.2%) and sexuality (A:78.8%; F:88.6%); EQ-5D to determine patients' HRQoL (A:87.9%; F:80.3%), pain (A:87.9%; F:75.8%) and mood (A:77.7%; F:85.5%); to assess treatment adherence the Morisky-Green (A:90.9%; F:84.9%) and the dispensing register (A:80.3%; F:80.3%) were chosen. It was agreed to note in the medical record whether the patient's treatment preferences had been considered during decision-making (A:78.8%; F:78.8%) and to use a 5-point Likert scale to assess treatment satisfaction (A:86.4%; F:86.4%). Panelists agreed (A:92.4%; F: 77.3%) to collect these PROs (1) at the time of diagnosis/relapse; (2) one month after starting treatment/change therapeutic strategy; (3) every three months during the 1st-year of treatment; and later (4) every six months until treatment completion/change. Conclusions: The consensus reached represents the first step towards including the patient's perspective in AOC follow-up. The standardized collection of PROs in clinical practice may contribute to optimizing the follow-up of these patients and thus improving the quality of care.

Lenalidomide plus R-GDP (R2-GDP) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Final Results of the R2-GDP-GOTEL Trial and Immune Biomarker Subanalysis.

PURPOSE: New therapeutic options are needed in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Lenalidomide-based schedules can reverse rituximab refractoriness in lymphoma. PATIENTS AND METHODS: In the phase II R2-GDP trial, 78 patients unsuitable for autologous stem cell transplant received treatment with the following schedule: lenalidomide 10 mg Days (D)1-14, rituximab 375 mg/m2 D1, cisplatin 60 mg/m2 D1, gemcitabine 750 mg/m2 D1 and D8, and dexamethasone 20 mg D1-3, up to 6 cycles (induction phase), followed by lenalidomide 10 mg (or last lenalidomide dose received) D1-21 every 28 days (maintenance phase). Primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and monitorization of key circulating immune biomarkers (EU Clinical Trials Register number: EudraCT 2014-001620-29). RESULTS: After a median follow-up of 37 months, ORR was 60.2% [37.1% complete responses (CR) and 23.1% partial responses (PR)]. Median OS was 12 months (47 vs. 6 months in CR vs. no CR); median PFS was 9 months (34 vs. 5 months in CR vs. no CR). In the primary refractory population, ORR was 45.5% (21.2% CR and 24.3% PR). Most common grade 3-4 adverse events were thrombocytopenia (60.2%), neutropenia (60.2%), anemia (26.9%), infections (15.3%), and febrile neutropenia (14.1%). Complete responses were associated with a sharp decrease in circulating myeloid-derived suppressor cells and regulatory T cells. CONCLUSIONS: R2-GDP schedule is feasible and highly active in R/R DLBCL, including the primary refractory population. Immune biomarkers showed differences in responders versus progressors.

Factors Associated With Morbidity and Retreatment After Surgical Management of Nonacute Subdural Hematomas in Elderly Patients.

Background Preoperative identification of clinical, radiographic, and surgery-specific factors associated with nonacute subdural hematomas (SDHs) may enable clinicians to optimize the efficacy of the initial surgical intervention, improve outcomes, and decrease rates of surgical recurrence. Methods The authors identified patients aged ≥65 years who underwent surgical treatment of chronic, subacute, or mixed-density SDH at a level-1 trauma hospital over a ten-year period (2010-2019). Pre-and postoperative clinical, radiographic, and surgery-specific data were collected. Predictors of surgical recurrence as well as morbidity, mortality, and discharge disposition were analyzed. Results There were 268 nonacute SDHs treated surgically; 46 were chronic, 19 were subacute, and 203 were mixed density. Of these, 179 were treated with burr hole(s), 62 with miniature craniotomy, and 27 via a large craniotomy and removal of subdural membranes. Statin use was protective (OR 0.22; 95% CI 0.08, 0.60) against recurrence requiring reoperation. Preoperative use of antithrombotic agents was not significantly associated with increased recurrence requiring reoperation. Smaller preoperative hematoma thickness was associated with significantly lower mortality risk, whereas mixed-density hematomas, patient age, change in thickness after surgery, density, and presence of cisternal effacement were significantly associated with discharge disposition. Hematoma type was also associated with hospital and intensive care length of stay. Conclusions Our experience suggests that, in elderly patients, premorbid statin usage is associated with lower recurrence rates and preoperative antithrombotic use does not affect recurrence when appropriately reversed before surgery. Patient age, preoperative thickness, and hematoma type contribute to postoperative outcomes such as discharge disposition and length of stay.

Persistence of SARS-CoV-2 Infection in Severely Immunocompromised Patients With Complete Remission B-Cell Lymphoma and Anti-CD20 Monoclonal Antibody Therapy: A Case Report of Two Cases.

Immunosuppressant conditions such as hematological malignancies increase the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. It has been described in the literature that patients on anti-CD20 maintenance therapies for lymphoid malignancies are susceptible to having recurrent flares together with viral replication or reinfections, although these cases are scarce. These patients are not well represented in randomized controlled trials, and as a consequence, the evidence for the use of certain treatments in this scenario is lacking. We present two cases of patients with B-cell lymphoma on remission and treated with rituximab on maintenance. They developed at least 1 flare of coronavirus disease 2019 (COVID-19) after acute infection and always after receiving rituximab. RT-PCR was positive in the nasopharyngeal swab and also in plasma. Patients were treated during flares with remdesivir, hyperimmune plasma, and corticosteroids. These two cases showed the unresolved problem of COVID-19 in immunosuppressant patients and showed that despite the vast amount of information available on SARS-CoV-2, information in this subgroup of patients is lacking.