Molecular profiling of pre- and post- 5-azacytidine myelodysplastic syndrome samples identifies predictors of response.

Treatment with the hypomethylating agent 5-azacytidine (AZA) increases survival in high-risk (HR) myelodysplastic syndrome (MDS) patients, but predicting patient response and overall survival remains challenging. To address these issues, we analyzed mutational and transcriptional profiles in CD34+ hematopoietic stem/progenitor cells (HSPCs) before and following AZA therapy in MDS patients. AZA treatment led to a greater reduction in the mutational burden in both blast and hematological responders than non-responders. Blast and hematological responders showed transcriptional evidence of pre-treatment enrichment for pathways such as oxidative phosphorylation, MYC targets, and mTORC1 signaling. While blast non-response was associated with TNFa signaling and leukemia stem cell signature, hematological non-response was associated with cell-cycle related pathways. AZA induced similar transcriptional responses in MDS patients regardless of response type. Comparison of blast responders and non-responders to normal controls, allowed us to generate a transcriptional classifier that could predict AZA response and survival. This classifier outperformed a previously developed gene signature in a second MDS patient cohort, but signatures of hematological responses were unable to predict survival. Overall, these studies characterize the molecular consequences of AZA treatment in MDS HSPCs and identify a potential tool for predicting AZA therapy responses and overall survival prior to initiation of therapy.

An integrative analysis of SARS-CoV 2 during the first and second waves of COVID-19 in Salta, Argentina.

Wastewater surveillance has been extensively applied to provide information about SARS-CoV-2 circulation in the community. However, its applicability is limited in regions lacking adequate sewerage infrastructure, without wastewater treatment plants (WWTP) or with insufficient coverage. During the COVID-19 pandemic, from July 2020 to September 2021, comprehensive epidemiological data encompassing positive, recovered, and deceased cases were collected alongside precipitation records. Additionally, wastewater samples from 13 main sewersheds and river water from two points (up- and downstream the main WWTP), in the city of Salta, were gathered. A total of 452 water samples were analyzed for quantitative detection of SARS-CoV-2 using reverse transcription real-time PCR. Across the 62-week study period, two distinct waves of COVID-19 were identified. The dynamics of deceased cases showed peaks 10 and 28 days after the peaks of positive cases in the first and second waves, respectively. Downstream river water exhibited higher fecal contamination than the upstream samples, evincing the impact of the WWTP discharges. Viral concentration in river waters mirrored those from wastewater, reflecting the progression of cases. Despite the lower reported number of cases during the first wave in comparison to the second (5420 vs. 8516 cases at the respective peaks), higher viral concentrations were detected in water samples (1.97 × 107 vs. 2.36 × 106 gc/L, respectively), suggesting underreporting during the first wave, and highlighting the positive effect of vaccination during the second. To the best of our knowledge, this is the first study that simultaneously and systematically analyzed surface water and wastewater over a prolonged period, the effect of precipitations were considered for the variations in the concentrations, and the findings compared with epidemiological information. Environmental surveillance was demonstrated to be a great tool to obtain valuable information about the circulation patterns of SARS-CoV-2, especially under resource constraints to massively test the population, thus, underreporting cases. Furthermore, the methodology employed herein can be easily expanded to the community-level surveillance of other pathogens excreted in urine and feces, encompassing viruses, bacteria, and protozoa.

Gender differences in outcomes of ambulatory and hospitalized patient with obesity hypoventilation syndrome.

BACKGROUND: Obesity hypoventilation syndrome (OHS) is associated with high morbidity and mortality. There is a paucity of data on whether there are gender differences in outcomes. Research Question Is female gender associated with worse outcomes in ambulatory and hospitalized patients with OHS? STUDY DESIGN AND METHODS: We performed post hoc analyses on two separate OHS cohorts: 1) stable ambulatory patients from the two Pickwick randomized controlled trials and 2) hospitalized patients with acute-on-chronic hypercapnic respiratory failure from a retrospective international cohort. We first conducted bivariate analyses of baseline characteristics and therapeutics between genders. Variables of interest from these analyses were then grouped into linear mixed effects models, Cox proportional hazards models or logistic regression models to assess the association of gender on various clinical outcomes. RESULTS: The ambulatory prospective cohort included 300 patients (64% female) and the hospitalized retrospective cohort included 1,162 patients (58% female). For both cohorts, women were significantly older and more obese than men. Compared to men, baseline PaCO2 was similar in ambulatory patients, but higher in hospitalized women. In the ambulatory cohort, in unadjusted analysis, women had increased risk of emergency room visits. However, gender was not associated with the composite outcome of emergency room visit, hospitalization, or all-cause mortality in the fully adjusted model. In the hospitalized cohort, positive airway pressure (PAP) prescription was less prevalent in women upon discharge. In unadjusted analysis, hospitalized women had a higher mortality at 3, 6, and 12 months after hospital discharge compared to men. However, after adjusting for age, gender was not associated with mortality. INTERPRETATION: Although the diagnosis of OHS is established at a more advanced age in women, gender is not independently associated with worse clinical outcomes after adjusting for age. Future studies are needed to examine gender-related health disparities in diagnosis and treatment of OHS.

Cardiac events occurring after allogeneic hematopoietic cell transplantation with post-transplant cyclophosphamide. Study conducted on behalf of the GETH-TC.

This multicenter study investigates the incidence and predictors of cardiac events (CE) following allo-HCT with PTCY in 453 AML patients. CE occurred in 57 (12.3%) patients within a median of 52 days (IQR: 13-289), with day 100 and 5-year cumulative incidences of 7.7% and 13.5%. Early (first 100 days) and late CE occurred at rates of 7.7% and 4.8%. The most prevalent CE were heart failure (n = 18, 31.6%), pericardial complications (n = 16, 28.1%), and arrhythmia (n = 14, 24.6%). The proportions of patients older than 55 years (64.9% vs. 46.1%, P = 0.010), with hypertension (36.8% vs. 18.4%, P = 0.001) and dyslipidemia (28.1% vs. 11.1%, P = 0.001) were higher in patients with CE. Patients undergoing haplo-HCT trend to have more CE (68.4% vs. 56.8%, P = 0.083). The multivariate regression analysis revealed that only hypertension (HR 1.88, P = 0.036) and dyslipidemia (HR 2.20, P = 0.018) were predictors for CE, with no differences according to donor type (haplo-HCT vs. others: HR 1.33, P = 0.323). Among the 57 patients with CE, the mortality rate was 12.2%. Notably, the diagnosis of CE negatively impacted NRM (HR 2.57, P = 0.011) and OS (HR 1.80, P = 0.009), underscoring necessity of aggressively treating cardiovascular risk factors, and implementing post-transplant cardiac monitoring protocols to prevent these complications.

Emerging lactic acid bacteria bacteriocins as anti-cancer and anti-tumor agents for human health.

Modern cancer diagnostics and treatment options have greatly improved survival rates; the illness remains a major cause of mortality worldwide. Current treatments for cancer, such as chemotherapy, are not cancer-specific and may cause harm to healthy cells; therefore, it is imperative that new drugs for cancer be developed that are both safe and effective. It has been found that lactic acid bacteria (LAB) have the potential to produce bacteriocins, which could potentially offer a promising alternative for cancer treatment. They have been shown in several studies to be effective against cancer cells while having no effect on healthy cells. More research is needed to fully understand the potential of LAB bacteriocins as anti-cancer medicines, to find the appropriate dose and delivery route, and to conduct clinical trials to evaluate the effectiveness and safety of the products in human patients, as is suggested by this work. Furthermore, LAB bacteriocins may evolve into a significant new class of anti-cancer drugs and food products. Patients with cancer may have a safe and effective alternative treatment option in the form of anti-cancer foods and drugs. Therefore, the aim of this study is to provide an in-depth analysis of the recent breakthroughs and potential future technical advancements of significant bacteriocins that are produced by LAB, how these bacteriocins function, and how these bacteriocins may be utilized as an anti-cancer agent. In addition, the current analysis emphasizes the significant constraints and boundaries that bacteriocins face when they are used as an anti-cancer factor.

Toward a responsible future: recommendations for AI-enabled clinical decision support.

BACKGROUND: Integrating artificial intelligence (AI) in healthcare settings has the potential to benefit clinical decision-making. Addressing challenges such as ensuring trustworthiness, mitigating bias, and maintaining safety is paramount. The lack of established methodologies for pre- and post-deployment evaluation of AI tools regarding crucial attributes such as transparency, performance monitoring, and adverse event reporting makes this situation challenging. OBJECTIVES: This paper aims to make practical suggestions for creating methods, rules, and guidelines to ensure that the development, testing, supervision, and use of AI in clinical decision support (CDS) systems are done well and safely for patients. MATERIALS AND METHODS: In May 2023, the Division of Clinical Informatics at Beth Israel Deaconess Medical Center and the American Medical Informatics Association co-sponsored a working group on AI in healthcare. In August 2023, there were 4 webinars on AI topics and a 2-day workshop in September 2023 for consensus-building. The event included over 200 industry stakeholders, including clinicians, software developers, academics, ethicists, attorneys, government policy experts, scientists, and patients. The goal was to identify challenges associated with the trusted use of AI-enabled CDS in medical practice. Key issues were identified, and solutions were proposed through qualitative analysis and a 4-month iterative consensus process. RESULTS: Our work culminated in several key recommendations: (1) building safe and trustworthy systems; (2) developing validation, verification, and certification processes for AI-CDS systems; (3) providing a means of safety monitoring and reporting at the national level; and (4) ensuring that appropriate documentation and end-user training are provided. DISCUSSION: AI-enabled Clinical Decision Support (AI-CDS) systems promise to revolutionize healthcare decision-making, necessitating a comprehensive framework for their development, implementation, and regulation that emphasizes trustworthiness, transparency, and safety. This framework encompasses various aspects including model training, explainability, validation, certification, monitoring, and continuous evaluation, while also addressing challenges such as data privacy, fairness, and the need for regulatory oversight to ensure responsible integration of AI into clinical workflow. CONCLUSIONS: Achieving responsible AI-CDS systems requires a collective effort from many healthcare stakeholders. This involves implementing robust safety, monitoring, and transparency measures while fostering innovation. Future steps include testing and piloting proposed trust mechanisms, such as safety reporting protocols, and establishing best practice guidelines.

Low dose lenalidomide versus placebo in non-transfusion dependent patients with low risk, del(5q) myelodysplastic syndromes (SintraREV): a randomised, double-blind, phase 3 trial.

BACKGROUND: Lenalidomide is the standard of care for patients who are transfusion dependent with chromosome 5q deletion (del[5q]) myelodysplastic syndromes. In the SintraREV trial, we aimed to investigate whether an early intervention of low lenalidomide doses for 2 years could delay transfusion dependency in patients with anaemia who were not transfusion dependent. METHODS: This randomised, double-blind, phase 3 trial, was conducted at 22 sites (University Hospitals) in Spain, France, and Germany. Eligible patients were aged 18 years or older diagnosed with low-risk or intermediate-1-risk del(5q) myelodysplastic syndromes with non-transfusion-dependent anaemia (according to the IPSS), were erythropoietin-stimulating agents naive, and had an ECOG performance status of 2 or less. Patients were randomly assigned (2:1) by means of a telephone system to receive lenalidomide 5 mg daily in 28-day cycles versus placebo for 2 years. The primary endpoint was time to transfusion dependency based on blinded independent central review. Analysis were by intent-to-treat (ITT) and evaluable population. Safety analyses included all participants who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov (NCT01243476) and EudraCT (2009-013619-36) and is complete. FINDINGS: Between Feb 15, 2010, and Feb 21, 2018, 61 patients were randomly assigned to receive lenalidomide (n=40; two did not receive treatment) or placebo (n=21). The median age was 72·2 (IQR 65·4-81·9) years, 50 (82%) patients were female, and 11 (18%) were male. The median follow-up time was 60·6 (IQR 32·1-73·9) months. Regarding primary endpoint, median time to transfusion dependency was not reached (95% CI not applicable) in the lenalidomide group versus 11·6 months (95% CI 0·00-30·11) in the placebo group (p=0·0027). Lenalidomide significantly reduced the risk of transfusion dependency by 69·8% (hazard ratio 0·302, 95% CI 0·132-0·692; p=0·0046). The most frequent treatment-related adverse event was neutropenia, occurring in 24 (63%) of 38 patients in the lenalidomide group (grade 3 and 4 in 17 [45%] patients and one [3%], respectively) and in four (19%) of 21 patients in the placebo group (grade 3 in one [5%] patient). Thrombocytopenia was detected in seven (18%) of 38 patients receiving lenalidomide (grade 3 in two [5%] patients). Regarding the non-haematological toxicity, skin disorders (rash nine [23%] of 38 patients) were the most frequently described toxicities among patients receiving lenalidomide, being grade 3 in one (3%) of 38 patients. 19 serious adverse events were reported in 13 patients, 18 in the lenalidomide group and one in the placebo group, five of which were potentially related to the study drug. No treatment-related deaths were identified. INTERPRETATION: An early approach with low doses of lenalidomide across two years delays the time to transfusion dependency and improves the rate and quality of the responses, with a manageable safety profile in patients who are non-transfusion dependent with del(5q) low-risk myelodysplastic syndromes. FUNDING: Bristol Myers Squibb.

Change in Body Mass Index in Youth in the First 5 Years After Type 1 Diabetes Mellitus Diagnosis.

OBJECTIVE: Examine body mass index (BMI) trajectories in American youth with type 1 diabetes (T1D) over the first 5 years following diagnosis. METHODS: Retrospective record review of BMI trajectories in youth with T1D diagnosed in 2015 to 2016. RESULTS: Near the time of diabetes diagnosis, 35.5% of youth had BMIs in the overweight/obesity range. These rates increased over time (P < .001), with 52.8% having overweight/obesity 5 years after diagnosis. Average age when BMI rose from healthy to overweight/obese or overweight to obese (rise group) was at 12.7 years, occurring 2.5 years after diagnosis. There were no differences between hemoglobin A1c, use of continuous glucose monitors, or use of insulin pumps between the rise group and those with healthy BMI throughout the study period. CONCLUSIONS: Alarmingly high rates of overweight/obesity in youth were observed within 5 years following T1D diagnosis. Awareness and further research are necessary to address this independent risk factor for morbidities.

Testing for t(3;8) in MYC/BCL6-rearranged large B-cell lymphoma identifies a high-risk subgroup with inferior survival.

ABSTRACT: A reciprocal t(3;8) BCL6::MYC fusion is common in large B-cell lymphoma (LBCL) with MYC and BCL6 disruption. These pseudo-double-hit cases are not adverse, whereas t(3;8)-MYC/BCL6 lymphoma has an inferior prognosis relative to other MYC-rearranged LBCL.

Emotion regulation unveiled through the categorical lens of attachment.

BACKGROUND: Emotion regulation, the process by which individuals manage and modify their emotional experiences, expressions, and responses to adaptively navigate and cope with various situations, plays a crucial role in daily life. Our study investigates the variations in emotion regulation strategies among individuals with different attachment styles (AS). Specifically, we examine how individuals with secure, anxious, avoidant, and fearful attachment styles effectively utilize cognitive reappraisal and expressive suppression to regulate their emotions. METHODS: A total of n = 98 adults were instructed to attend, reappraise, or suppress their emotions while viewing negative and neutral images from the International Affective Picture System (IAPS) in an experimental emotion regulation task. After completing the task, participants rated the valence and arousal elicited by the images. Attachment styles were measured using the ECR-12 questionnaire and then categorized into four AS. RESULTS: Our study revealed that individuals with secure AS (n = 39) effectively reduced displeasure through cognitive reappraisal but experienced levels of displeasure with expressive suppression. Anxious AS (n = 16) individuals successfully reduced displeasure using cognitive reappraisal but struggled to regulate arousal and effectively use expressive suppression. Avoidant AS (n = 24) individuals could reduce displeasure with both strategies but experienced high arousal during suppression attempts. Fearful AS (n = 19) individuals effectively regulated both displeasure and arousal using either strategy. However, Secure AS individuals showed superior reappraisal efficacy, significantly reducing arousal levels compared to the Fearful AS group. Both Secure and Avoidant AS groups experienced higher valence during reappraisal relative to a baseline, indicating a decrease in displeasure. CONCLUSIONS: Individuals with different AS exhibit variations in the effectiveness of their use of emotion regulation strategies. Our findings reinforce the significance of AS in shaping emotion regulation processes and emphasize the need for tailored approaches to support individuals with different attachment orientations.

Brain oscillations during emotion regulation and the two-dimensional model of adult attachment.

Emotion Regulation (ER) refers to the processes by which individuals influence their own emotions. It is a crucial aspect of human behavior, affecting everything from interpersonal relationships to mental health. The relationship between ER and Attachment Theory (AT) is pivotal. AT suggests that early bonds with primary caregivers influence future relationship expectations and behaviors. These initial experiences shape internal models of self and others, affecting how individuals regulate their emotions. Understanding the interplay between ER and AT is essential for comprehending the human affective system. In this study, we explored the neural underpinnings of ER, focusing on two distinct strategies: cognitive reappraisal and expressive suppression. Using electroencephalography (EEG), we examined changes in neural oscillations from 52 adults during an ER task. Specifically, we observed increased frontal theta activity (3-6 Hz) during reappraisal compared to suppression strategies. This frontal theta activity suggests enhanced cognitive control engagement. Conversely, during suppression, we noted a decrease in beta frequency (15-30 Hz) activity from central electrodes, indicative of differing neural processes. Further integrating psychological theories, we explored the relationship between these neural markers and dimensions of human attachment. Employing the Experiences in Close Relationships-12 scale (ECR-12), we identified a negative correlation between attachment anxiety and frontal theta activity. Lower levels of attachment anxiety were associated with increased theta activity, reflecting potentially more effective emotion regulation. Additionally, we found that higher theta activity corresponded with fewer difficulties in emotional control measured by the Difficulties in Emotion Regulation Scale (DERS). Regarding central beta activity, our findings revealed an interesting correlation with Emotional Inattention, a concept tied to Attachment Avoidance. This suggests that central beta activity may serve as a neural marker for specific attachment-related ER processing. These results highlight the distinct neural pathways involved in different ER strategies and their relationship with the AT and neural responses during emotional processing.

Patient-Reported Outcome Measures in Atopic Dermatitis and Chronic Urticaria Are Underused in Clinical Practice.

BACKGROUND: Patient-reported outcome measures (PROMs) are validated and standardized tools that complement physician evaluations and guide treatment decisions. They are crucial for monitoring atopic dermatitis (AD) and chronic urticaria (CU) in clinical practice, but there are unmet needs and knowledge gaps regarding their use in clinical practice. OBJECCTIVE: We investigated the global real-world use of AD and CU PROMs in allergology and dermatology clinics as well as their associated local and regional networks. METHODS: Across 72 specialized allergy and dermatology centers and their local and regional networks, 2,534 physicians in 73 countries completed a 53-item questionnaire on the use of PROMs for AD and CU. RESULTS: Of 2,534 physicians, 1,308 were aware of PROMs. Of these, 14% and 15% used PROMs for AD and CU, respectively. Half of physicians who use PROMs do so only rarely or sometimes. Use of AD and CU PROM is associated with being female, younger, and a dermatologist. The Patient-Oriented Scoring Atopic Dermatitis Index and Urticaria Activity Score were the most common PROMs for AD and CU, respectively. Monitoring disease control and activity are the main drivers of the use of PROMs. Time constraints were the primary obstacle to using PROMs, followed by the impression that patients dislike PROMs. Users of AD and CU PROM would like training in selecting the proper PROM. CONCLUSIONS: Although PROMs offer several benefits, their use in routine practice is suboptimal, and physicians perceive barriers to their use. It is essential to attain higher levels of PROM implementation in accordance with national and international standards.

Importance of Certain Varieties of Cucurbits in Enhancing Health: A Review.

The Cucurbitaceae family is an extensive group of fruits and vegetables that exhibit common characteristics; for example, they are farmed on a global scale and exhibit a wide range of applications, including fresh consumption and use in various food and beverage products. As is frequent, many species or genera share a common name, and this can lead to some confusion when looking for information about a specific variety. In this review, we describe the findings about the biological activity, like antibacterial, antiviral, antidiabetic, and anticancer properties, of two genera of this family, Cucumis and Momordica, which have been characterized and evaluated in several research studies and regarding which information is readily accessible. Those activities rely on the various physicochemical qualities and nutritional content of each variety, including factors like ß-carotene and polyphenols, among others. The goal of this review is to provide a rapid search for each activity examined in the literature, enabling future research on their potential uses in functional foods and nutraceutical supplements.

An attachment-based pilot program to promote adolescent adjustment to parental divorce.

The study aimed to assess the impact of an attachment-based intervention on adolescent adaptation to parental divorce. The Adolescent Adjustment Pilot Program to Parental Divorce (AAPPD) employed an experimental group format, targeting improvements in various adaptation indicators (life satisfaction, positive affect, and negative affect). The sample comprised 30 Chilean adolescents aged 12 to 16 (M = 13.6, SD = 1.35), with 60% females and 40% males. After the intervention, the adolescents showed a decrease in negative affect at 6 and 12 months. However, no differences were identified in other dimensions of subjective well-being considered as indicators of divorce adaptation. The findings prompt discussion on theoretical and clinical implications.

Borolatonin limits cognitive deficit and neuron loss while increasing proBDNF in ovariectomised rats.

BACKGROUND: Borolatonin is a potential therapeutic agent for some neuronal diseases such as Alzheimer's disease (AD). Its administration exerts ameliorative effects such as those induced by the equimolar administration of melatonin in behavioral tests on male rats and in neuronal immunohistochemistry assays. OBJECTIVE: In this study, motivated by sex differences in neurobiology and the incidence of AD, the ability of borolatonin to induce changes in female rats was assessed. METHODS: Effects of borolatonin were measured by the evaluation of both behavioral and immunohistopathologic approaches; additionally, its ability to limit amyloid toxicity was determined in vitro. RESULTS: Surprisingly, behavioral changes were similar to those reported in male rats, but not those evaluated by immunoassays regarding neuronal survival; while pro-brain-derived neurotrophic factor (BDNF) immunoreactivity and the limitation of toxicity by amyloid in vitro were observed for the first time. CONCLUSION: Borolatonin administration induced changes in female rats. Differences induced by the administration of borolatonin or melatonin could be related to the differences in the production of steroid hormones in sex dependence. Further studies are required to clarify the possible mechanism and origin of differences in disturbed memory caused by the gonadectomy procedure between male and female rats.