Long-acting muscarinic antagonist and long-acting ß2-agonist combination for the treatment of maintenance therapy-naïve patients with chronic obstructive pulmonary disease: a narrative review.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Faster lung function impairment occurs earlier in the disease, particularly in mild-to-moderate COPD, highlighting the need for early and effective targeted interventions. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2024 report recommends initial pharmacologic treatment with a long-acting muscarinic antagonist (LAMA) and long-acting ß2-agonist (LABA) combination in group B (0 or 1 moderate exacerbation not leading to hospitalization, modified Medical Research Council score of ⩾2, and COPD Assessment Test™ score of ⩾10) and E (⩾2 moderate exacerbations or ⩾1 exacerbation leading to hospitalization and blood eosinophil count <300 cells/µL) patients. In randomized controlled trials (RCTs), LAMA/LABA combination therapy improved lung function, St. George's Respiratory Questionnaire (SGRQ) total score, and Transitional Dyspnea Index (TDI) focal score and reduced the use of rescue medications, exacerbation risk, and risk of first clinically important deterioration (CID), compared with LAMA or LABA monotherapy. However, there is limited evidence regarding the efficacy and safety of LAMA/LABA combination therapy versus LAMA or LABA monotherapy in maintenance therapy-naïve patients. This review discusses the rationale for the early initiation of LAMA/LABA combination therapy in maintenance therapy-naïve patients with COPD. In post hoc analyses of pooled data from RCTs, compared with LAMA or LABA monotherapy, LAMA/LABA combination therapy improved lung function and quality of life and reduced COPD symptoms, risk of first moderate/severe exacerbation, risk of first CID, and use of rescue medication, with no new safety signals. In a real-world study, patients initiating LAMA/LABA had significantly reduced risk of COPD-related inpatient admissions and rate of on-treatment COPD-related inpatient admissions over 12 months than those initiating LAMA. Consequently, LAMA/LABA combination therapy could be considered the treatment of choice in maintenance therapy-naïve patients with COPD, as recommended by the GOLD 2024 report.

Long-acting bronchodilator combination therapy for the treatment of maintenance therapy­naïve patients with chronic obstructive pulmonary diseaseChronic obstructive pulmonary disease (COPD) is a common lung disease that makes it hard to breathe and is a leading cause of death and disability worldwide. This disease tends to worsen lung function from an early stage, especially in people who only have mild or moderate symptoms. To help stop the loss of lung function and maintain the quality of life for patients with COPD, two main types of long-lasting inhaler medications are used: one type focuses on relaxing the muscles around the airways, and the other type helps open the airways making it easier to breathe. Some medications combine these two types of action and are approved for long-term management of COPD. However, there is not much information on the effectiveness and safety of these combination medications in patients who have never taken long-lasting COPD medication before. Current health guidelines suggest starting these combination medications in patients who are likely to see their symptoms get worse quickly, and who do not have a high level of a specific type of white blood cell. In this review, we discuss the evidence for starting these combination treatments early in patients who have never used long-lasting COPD medications before. There is no strong evidence yet that shows starting treatment early benefits patients with newly diagnosed COPD. However, about 30% of patients in clinical trials designed to study the effectiveness of these combination medications, had never received any long-lasting treatment before. After-the-fact analyses of these patients showed that these combination medications could reduce symptoms such as breathlessness, improve lung function, enhance quality of life, lessen the need for emergency medications, and decrease the risk of severe symptom flare-ups. Overall, the evidence supports using these combination inhaler medications as the first choice of treatment for patients with moderate COPD symptoms who have not previously been treated with long-lasting inhalers.

Olanzapine-Induced Weight Gain and Glycolipid Metabolism Aberrations in First-Episode and Antipsychotic-Naïve Schizophrenia Patients: A Longitudinal Study.

OBJECTIVE: Limited research has delved into the comprehensive impact of monotherapy on weight and glycolipid metabolism in schizophrenia (SCZ) patients. Our study aims to longitudinally investigate the multidimensional effects of olanzapine (OLA) monotherapy on weight and glycolipid metabolism in first-episode and antipsychotic-naïve (FEAN) SCZ patients. METHODS: A total of 74 FEAN-SCZ patients were recruited, as well as 58 sex- and age-matched healthy controls. Eligible patients underwent a 4-week OLA treatment regimen, with weight assessments conducted at baseline and week 4. Moreover, lipid profiles and fasting plasma glucose (FPG) were measured at baseline and week 4. Insulin, leptin (LEP), and adiponectin (APN) levels were determined using enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: At baseline, FEAN-SCZ patients showed elevated levels of insulin, low-density lipoprotein (LDL), impaired insulin sensitivity, and reduced levels of APN compared to the healthy controls. Following 4-week OLA treatment, patients showed an increase in body mass index (BMI) of 0.96 kg/m2. Additionally, FPG, quantitative insulin sensitivity check index (QUICKI), HOMA-insulin sensitivity index (HOMA-ISI), and fasting plasma glucose to insulin ratio (G/I) displayed significant decreases, while insulin, HOMA-IR, and LEP levels showed significant increases. Stepwise regression analysis revealed that baseline FPG independently predicted the change in BMI after 4 weeks of OLA treatment. CONCLUSION: FEAN-SCZ patients exhibited pre-existing alterations in glucose homeostasis. After 4 weeks of OLA treatment, SCZ patients experienced significant weight gain, deteriorating insulin resistance, and increased LEP levels. In addition, baseline FPG emerged as a predictor of BMI changes after 4 weeks of OLA treatment.

Multidimensional profiling of human T cells reveals high CD38 expression, marking recent thymic emigrants and age-related naive T cell remodeling.

Thymic involution is a key factor in human immune aging, leading to reduced thymic output and a decline in recent thymic emigrant (RTE) naive T cells in circulation. Currently, the precise definition of human RTEs and their corresponding cell surface markers lacks clarity. Analysis of single-cell RNA-seq/ATAC-seq data distinguished RTEs by the expression of SOX4, IKZF2, and TOX and CD38 protein, whereby surface CD38hi expression universally identified CD8+ and CD4+ RTEs. We further determined the dynamics of RTEs and mature cells in a cohort of 158 individuals, including age-associated transcriptional reprogramming and shifts in cytokine production. Spectral cytometry profiling revealed two axes of aging common to naive CD8+ and CD4+ T cells: (1) a decrease in CD38++ cells (RTEs) and (2) an increase in CXCR3hi cells. Identification of RTEs enables direct assessment of thymic health. Furthermore, resolving the dynamics of naive T cell remodeling yields insight into vaccination and infection responsiveness throughout aging.

Characterization of unique B-cell populations in the circulation of people living with HIV prior to non-Hodgkin lymphoma diagnosis.

People living with HIV (PLWH) are at higher risk of developing lymphoma. In this study, we performed cytometry by time-of-flight (CyTOF) on peripheral blood mononuclear cells of cART-naïve HIV+ individuals and cART-naïve HIV+ individuals prior to AIDS-associated non-Hodgkin lymphoma (pre-NHL) diagnosis. Participants were enrolled in the Los Angeles site of the MACS/WIHS Combined Cohort Study (MWCCS). Uniform Manifold Approximation and Projection (UMAP) and unsupervised clustering analysis were performed to identify differences in the expression of B-cell activation markers and/or oncogenic markers associated with lymphomagenesis. CD10+CD27- B cells, CD20+CD27- B cells, and B-cell populations with aberrant features (CD20+CD27+CXCR4+CD71+ B cells and CD20+CXCR4+cMYC+ B cells) were significantly elevated in HIV+ cART-naïve compared to HIV-negative samples. CD20+CD27+CD24+CXCR4+CXCR5+ B cells, CD20+CD27+CD10+CD24+CXCR4+cMYC+ B cells, and a cluster of CD20+CXCR4hiCD27-CD24+CXCR5+CD40+CD4+AICDA+ B cells were significantly elevated in HIV+ pre-NHL (cART-naïve) compared to HIV+ cART-naïve samples. A potentially clonal cluster of CD20+CXCR4+CXCR5+cMYC+AICDA+ B cells and a cluster of germinal center B-cell-like cells (CD19-CD20+CXCR4+Bcl-6+PD-L1+cMYC+) were also found in the circulation of HIV+ pre-NHL (cART-naïve) samples. Moreover, significantly elevated clusters of CD19+CD24hiCD38hi cMYC+ AICDA+ B regulatory cells were identified in HIV+ pre-NHL (cART-naïve) compared to HIV+ cART-naïve samples. The present study identifies unique B-cell subsets in PLWH with potential pre-malignant features that may contribute to the development of pre-tumor B cells in PLWH and that may play a role in lymphomagenesis.

Real-World Comparison of Effectiveness, Treatment Persistence, and Safety of First-Line Advanced Therapies at 1 Year for Ulcerative Proctitis.

In this retrospective cohort study, vedolizumab was associated with higher odds of steroid-free clinical remission at 1 year compared to anti-TNF agents for bio-naïve patients with ulcerative proctitis.

Decoding Breast Cancer: Using Radiomics to Non-Invasively Unveil Molecular Subtypes Directly from Mammographic Images.

Breast cancer is the most commonly diagnosed cancer worldwide. The therapy used and its success depend highly on the histology of the tumor. This study aimed to explore the potential of predicting the molecular subtype of breast cancer using radiomic features extracted from screening digital mammography (DM) images. A retrospective study was performed using the OPTIMAM Mammography Image Database (OMI-DB). Four binary classification tasks were performed: luminal A vs. non-luminal A, luminal B vs. non-luminal B, TNBC vs. non-TNBC, and HER2 vs. non-HER2. Feature selection was carried out by Pearson correlation and LASSO. The support vector machine (SVM) and naive Bayes (NB) ML classifiers were used, and their performance was evaluated with the accuracy and the area under the receiver operating characteristic curve (AUC). A total of 186 patients were included in the study: 58 luminal A, 35 luminal B, 52 TNBC, and 41 HER2. The SVM classifier resulted in AUCs during testing of 0.855 for luminal A, 0.812 for luminal B, 0.789 for TNBC, and 0.755 for HER2, respectively. The NB classifier showed AUCs during testing of 0.714 for luminal A, 0.746 for luminal B, 0.593 for TNBC, and 0.714 for HER2. The SVM classifier outperformed NB with statistical significance for luminal A (p = 0.0268) and TNBC (p = 0.0073). Our study showed the potential of radiomics for non-invasive breast cancer subtype classification.

Patterns of Use of e-Cigarettes and Their Respiratory Effects: Protocol for an Umbrella Review.

BACKGROUND: Electronic nicotine delivery systems (ENDS)-e-cigarettes or vapes-have been shown to substantially reduce or eliminate many toxins compared with cigarette smoke, but simultaneously ENDS use also produces their own unique toxins. Yet the patterns of use among people who use ENDS are not homogeneous. Some people who use ENDS also smoke cigarettes (dual use). Other people who formerly smoked cigarettes are completely substituting ENDS (exclusive use). A small number of people who have never smoked cigarettes are using ENDS (naïve use of nicotine). Each of these patterns of use results in different exposures to toxins. Unfortunately, epidemiological studies routinely group together any ENDS use regardless of other tobacco use. OBJECTIVE: This umbrella review primarily aims to present all the evidence available on the respiratory effects of ENDS use by adults based on their pattern of use: dual use, exclusive use, and naïve use. With each of these patterns of use, are there benefits, no changes, or harmful effects on respiratory functioning? Our objective is to provide clinicians with a detailed analysis of how different patterns of ENDS use impact respiratory functioning and to point to the best sources of evidence. METHODS: This umbrella review follows the Methods for Overviews of Reviews framework and the PRIOR (Preferred Reporting Items for Overviews of Reviews) statement. Systematic reviews published since 2019 will be searched across 4 databases and 3 gray literature sources. Additional searches will include citation chasing, references lists, and referrals from respiratory specialists. The quality of included reviews will be evaluated using the AMSTAR2 (A Measurement Tool to Assess Systematic Reviews) checklist. We will document biases in 3 areas: protocol deviations, biases from the Oxford Catalogue of Bias, and internal data discrepancies. Two reviewers will independently conduct the search and quality assessments. Our analysis will focus on reviews rated as moderate or high confidence by AMSTAR2. We will use the Vote Counting Direction of Effect method to manage expected data heterogeneity, assessing whether ENDS use is beneficial or detrimental, or has no effect on respiratory functions based on the pattern of use. RESULTS: The review is expected to be completed by December 2024. The database search was concluded in April 2024, and data extraction and bias assessment were completed in June 2024. The analysis phase is planned to be completed by October 2024. CONCLUSIONS: A thorough and comprehensive assessment of the evidence will better inform the contentious debate over the respiratory effects of ENDS providing much needed clarity by linking their effects to specific usage patterns. This analysis is particularly crucial in understanding the risks associated with continued cigarette smoking. TRIAL REGISTRATION: PROSPERO CRD42024540034; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=540034. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/60325.

Ex Vivo Analysis of the Association of GFP-Expressing L. aethiopica and L. mexicana with Human Peripheral Blood-Derived (PBD) Leukocytes over 24 Hours.

Leishmania parasites are transmitted to mammalian hosts through the bite of sandflies. These parasites can infect phagocytic cells (macrophages, dendritic cells, and neutrophils) and non-phagocytic cells (B cells and fibroblasts). In mice models, the disease development or resolution is linked to T cell responses involving inflammatory cytokines and the activation of macrophages with the M1/M2 phenotype. However, this mechanism does not apply to human infection where a more complex immunological response occurs. The understanding of interactions between immune cells during Leishmania infection in humans is still limited, as current infection models focus on individual cell types or late infection using controlled human infection models (CHIMs). This study investigated the early parasite infection in freshly isolated peripheral blood-derived (PBD) leukocytes over 24 h. Flow cytometer analysis is used in immunophenotyping to identify different subpopulations. The study found that among the L. aethiopicaGFP-associated leukocytes, most cells were neutrophils (55.87% ± 0.09 at 4 h) and monocytes (23.50% ± 0.05% at 24 h). B cells were 12.43% ± 0.10% at 24 h. Additionally, 10-20% of GFP+ leukocytes did not belong to the aforementioned cell types, and further investigation revealed their identity as CD4+ T cells. Data not only confirm previous findings of Leishmania infection with PBD leukocytes and association with B cells but also suggest that CD4+ T cells might influence the early-stage of infection.

Multi-Fingerprints Indoor Localization for Variable Spatial Environments: A Naive Bayesian Approach.

Fingerprint-based indoor localization has been a hot research topic. However, the current fingerprint-based indoor localization approaches still rely on a single fingerprint database, where the average level of data at reference points is used as the fingerprint representation. In variable environmental conditions, the variations in signals caused by changes in the environmental states introduce significant deviations between the average level and the actual fingerprint characteristics. This deviation leads to a mismatch between the constructed fingerprint database and the real-world conditions, thereby affecting the effectiveness of fingerprint matching. Meanwhile, the sharp noise interference caused by uncertainties such as personnel movement has a significant interference on the creation of the fingerprint database and fingerprint matching in online stage. Examination of the sampling data after denoising with Robust Principal Component Analysis (RPCA) revealed distinct multi-fingerprint characteristics with clear boundaries at certain access points. Based on these observations, the concept of constructing a fingerprint database using multiple fingerprints is introduced and its feasibility is explored. Additionally, a multi-fingerprint solution based on naive Bayes classification is proposed to accurately represent fingerprint characteristics under different environmental conditions. This method is based on the online stage fingerprints. The corresponding state space is selected using the naive Bayes classifier, enabling the selection of an appropriate fingerprint database for matching. Through simulations and empirical evaluations, the proposed multi-fingerprints construction scheme consistently outperforms the traditional single-fingerprint database in terms of positioning accuracy across all tested localization algorithms.

Treatment Management Challenges in Naïve and Experienced HIV-1-Infected Individuals Carrying the M184V Mutation.

M184V is a single-base mutation in the YMDD domain of reverse transcriptase (RT). The M184V resistance-associated mutation (RAM) is related to virological unresponsiveness to lamivudine (3TC) and emtricitabine (FTC) and induces high-level resistance to these two antiretroviral agents. M184V is rapidly selected in the setting of non-suppressive antiretroviral therapy (ART) and accumulates in the HIV reservoir. There were continuous efforts to evaluate the impact of the M184V mutation on the treatment outcomes in people living with HIV (PLWH). Since 3TC remains an extensively used part of recommended antiretroviral combinations, M184V is commonly detected in patients with virological failure (VF). ART guidelines do not recommend the use of drugs impacted by RAMs as they have been confirmed to comprise a risk factor for VF. However, there is evidence that 3TC/FTC can remain active even in the presence of M184V. Given the potential benefits of 3TC in ART combinations, the investigation of M184V remains of high interest to clinicians and researchers, especially in certain regions with limited resources, and especially for its unusual effects. This is a review of the literature on the challenges in treating both naïve and experienced individuals carrying the M184V mutation, including virological failure, virological suppression, and resistance to ART.

Comparative real-world outcomes between ustekinumab, infliximab, and adalimumab in bio-naïve and bio-experienced Crohn's disease patients: a retrospective multicenter study.

BACKGROUND: Numerous studies have compared the efficacy of ustekinumab (UST) and anti-TNF agents [infliximab (IFX) or adalimumab(ADA)] in moderate to severe Crohn's disease (CD) patients. This study aims to compare the efficacy of UST, IFX, and ADA while differentiating between bio-naïve and bio-experienced patients, which is an underexplored aspect, particularly in Asia. METHODS: We conducted a retrospective multi-center study from 2012 to 2023, categorizing patients into bio-naïve and bio-experienced groups. We evaluated clinical remission rates after induction therapy and clinical outcomes, including CD-related hospitalization, intestinal resection, and drug discontinuation during maintenance therapy. RESULTS: Among the 214 bio-naïve CD patients, 60 received UST, 108 received IFX, and 46 received ADA. After 1:1 propensity score matching between UST and anti-TNF agents groups, 59 patients were analyzed in each group (45 in the IFX group and 14 in the ADA group). We found no significant differences in clinical remission rates (P = 0.071), CD-related hospitalization (P = 0.800), intestinal resection (P = 0.390), or drug discontinuation (P = 0.052) between the UST, IFX, and ADA groups in bio-naïve CD patients. In bio-experienced CD patients, with 35 in the UST group and 13 in the anti-TNF agents group, the UST group showed a lower risk of drug discontinuation (P = 0.004) than the anti-TNF agents group. CONCLUSIONS: This study suggests that UST, IFX, and ADA are equally effective in bio-naïve CD patients, while in bio-experienced patients, mostly with previous exposure to anti-TNF agents, UST may offer superior drug durability.

A post-hoc pooled analysis to evaluate efficacy and safety of insulin glargine 300 U/mL in insulin-naïve people with type 2 diabetes with/without prior use of glucagon-like peptide-1 receptor agonist therapy.

AIMS: To evaluate treatment advancement with insulin glargine 300 U/mL (Gla-300), with or without prior glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy in type 2 diabetes (T2D). METHODS: Efficacy and safety outcomes of insulin-naïve patients intensifying with Gla-300, with/without prior GLP-1 RA therapy, were evaluated in three analyses (N = 3562): a pooled analysis of seven interventional studies, a subanalysis comparing participants who stopped GLP-1 RA therapy and initiated Gla-300 with those who received add-on Gla-300, and an expanded analysis including two observational studies. RESULTS: Glycaemic outcomes, including HbA1c improvement and fasting plasma glucose, were similar between groups with/without prior GLP-1 RA use. HbA1c least squares mean change from baseline was - 1.7 % and - 1.6 % with and without prior GLP-1 RA, respectively. Glycaemic outcomes were similar between participants who stopped GLP-1 RA therapy when initiating Gla-300 and those who received add-on Gla-300, although more participants receiving add-on Gla-300 achieved HbA1c targets. The expanded analysis yielded similar results. Incidence of hypoglycaemia was low with no clinically relevant weight changes in all analyses. CONCLUSIONS: Treatment advancement with Gla-300 in patients with T2D, with/without prior GLP-1 RA therapy, improved glycaemic outcomes with no relevant impact on weight, while maintaining a low hypoglycaemia risk.

The relationship between sphingomyelin and ceramide levels and soft neurological signs in ADHD.

Attention deficit hyperactivity disorder (ADHD), characterized by attention deficit, hyperactivity, and impulsivity, has recently been associated with lipid metabolism. In particular, the roles of sphingomyelin, ceramide, andgalactosylceramidase in the pathophysiology of ADHD are being investigated. This study aims to explore the relationship between sphingolipid metabolism markers and soft neurological signs (SNS) in children diagnosed with ADHD who are not undergoing medication treatment. A cross-sectional analysis was conducted on 41 children and adolescents aged 7-12 years diagnosed with ADHD and 39 neurotypically developing controls. Plasma levels of ceramide, sphingomyelin, and galactosylceramidase were measuredusing Enzyme-Linked Immunosorbent Assay (ELISA). SNS were assessed using the Physical and Neurological Examination for Soft Signs (PANESS). Statistical analyses included Student's t-tests, Mann-Whitney U tests, and Multivariate Analysis ofCovariance (MANCOVA), along with logistic regression analysis. Plasma levels of ceramide and sphingomyelin in children with ADHD showed significant differences compared to the neurotypically developing control group; however, there were no significant differences in galactosylceramidase levels between the two groups. Positive correlations were found between plasma levels of ceramide and sphingomyelin and the PANESS subscales F1 (Total Gait and Station) and F3 (Total Dysrhythmia). Additionally, logistic regression analysis indicated that high ceramide levels were positively associated with ADHD. This study underscores a significant association between alterations in sphingolipid metabolism (specifically increased levels of ceramide and sphingomyelin) and the presence of SNS in children with ADHD. These findings elucidate the potential role of sphingolipid metabolism in the pathophysiology of ADHD and provide suggestions for future therapeutic research targeting sphingolipid metabolism in the treatment of ADHD.

Impaired calcium influx underlies skewed T helper cell differentiation in children with IgE-mediated food allergies.

BACKGROUND: Reasons for Th2 skewing in IgE-mediated food allergies remains unclear. Clinical observations suggest impaired T cell activation may drive Th2 responses evidenced by increased atopic manifestations in liver transplant patients on tacrolimus (a calcineurin inhibitor). We aimed to assess differentiation potential, T cell activation and calcium influx of naïve CD4+ T cells in children with IgE-mediated food allergies. METHODS: Peripheral blood mononuclear cells from infants in the Starting Time for Egg Protein (STEP) Trial were analyzed by flow cytometry to assess Th1/Th2/Treg development. Naïve CD4+ T cells from children with and without food allergies were stimulated for 7 days to assess Th1/Th2/Treg transcriptional factors and cytokines. Store operated calcium entry (SOCE) was measured in children with and without food allergies. The effect of tacrolimus on CD4+ T cell differentiation was assessed by treating stimulated naïve CD4+ T cells from healthy volunteers with tacrolimus for 7 days. RESULTS: Egg allergic infants had impaired development of IFNγ+ Th1 cells and FoxP3+ transitional CD4+ T cells compared with non-allergic infants. This parallels reduced T-bet, IFNγ and FoxP3 expression in naïve CD4+ T cells from food allergic children after in vitro culture. SOCE of naïve CD4+ T cells was impaired in food allergic children. Naïve CD4+ T cells treated with tacrolimus had reduced IFNγ, T-bet, and FoxP3, but preserved IL-4 expression. CONCLUSIONS: In children with IgE-mediated food allergies, dysregulation of T helper cell development is associated with impaired SOCE, which underlies an intrinsic impairment in Th1 and Treg differentiation. Along with tacrolimus-induced Th2 skewing, this highlights an important role of SOCE/calcineurin pathway in T helper cell differentiation.

Combined bictegravir, emtricitabine and tenofovir alafenamide for treating people with HIV: a plain language summary of the BICSTaR study up to 1 year.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of an article about an ongoing study called the BICSTaR study.The BICSTaR study includes people with HIV (human immunodeficiency virus) who are taking a medicine called bictegravir/emtricitabine/tenofovir alafenamide (shortened to B/F/TAF). B/F/TAF is a single tablet that contains 3 different drugs for the treatment of HIV. The drugs work together to reduce the levels of HIV so that the virus can no longer be detected by a blood test.People taking part in the study are adults with HIV living in Europe, Canada, Israel, Japan, South Korea, Singapore and Taiwan. People take 1 tablet of B/F/TAF once a day. They are either taking B/F/TAF as their first treatment for HIV, or they have switched to B/F/TAF from another HIV treatment.Researchers looked at how well B/F/TAF worked and how safe it was in people who took B/F/TAF for a year. WHAT ARE THE KEY TAKEAWAYS?: Researchers found that B/F/TAF worked well in almost all people in the study by reducing levels of HIV in the blood. The virus could not be found in the blood of more than 9 out of 10 (94%) people who were taking B/F/TAF as their first HIV medicine and more than 9 out of 10 people (97%) who had taken another HIV medicine before starting B/F/TAF. This is known as having an 'undetectable viral load' and is a major goal for HIV treatment success. Researchers did not find any evidence of HIV developing resistance to B/F/TAF, which might stop B/F/TAF from working properly.Around 1 out of 10 people (13%) had side effects (any unwanted sign or symptom that people have when taking a medicine that researchers think might be caused by the medicine) that might have been caused by B/F/TAF. Most of these side effects were not classified as serious. Less than 1 out of 100 (0.1%) people had serious side effects that might have been caused by B/F/TAF. Only 6 out of 100 people stopped taking B/F/TAF due to side effects caused by B/F/TAF. As a result, more than 9 out of 10 people (95%) took B/F/TAF for at least 1 year. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: B/F/TAF worked well in people with HIV in this study. Most people (around 9 out of 10) did not have any side effects.

Two 5-year studies of bictegravir/emtricitabine/tenofovir alafenamide in people with HIV: a plain-language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a plain-language summary of an article that reported on two studies of the medication bictegravir/emtricitabine/tenofovir alafenamide (shortened to B/F/TAF). B/F/TAF is a single pill containing three different drugs used to treat human immunodeficiency virus (known as HIV). The drugs work together to lower the levels of HIV (called viral load) in the body and make the virus undetectable in the blood. Researchers measured whether B/F/TAF was safe and effective when taken over 5 years in over 400 people in 10 countries who had never taken HIV medication before. WHAT WERE THE RESULTS?: After 5 years, almost all (99%) of the people who took B/F/TAF had an undetectable viral load. This does not mean that they were cured, but that the levels of HIV were so low that the tests used by researchers could not detect the virus in the blood. CD4 is a type of immune system cell. HIV causes CD4 cell numbers to decrease. On average, the number of CD4 cells increased by more than 300 cells per microliter (cells/µL) of blood over 5 years. This means that the immune system was improving. HIV is able to change its genes to escape the effects of the drugs. This is known as HIV resistance to treatment. Nine people had a viral load high enough to suggest that the drugs might not be working, but no resistance to B/F/TAF was seen. Some people (less than one in three) experienced medical problems thought to be linked to B/F/TAF treatment, known as side effects. The most common side effects were headache, diarrhea, nausea, tiredness (fatigue), dizziness, and difficulty falling or staying asleep (insomnia). On average, people's body weight increased by 3 kg in the first year of taking B/F/TAF. This might be because their general health improved after starting HIV treatment. Weight gained after that time was similar to the level of weight gain expected in the general population. Very few people (less than 1 in 100) stopped taking B/F/TAF because of side effects thought to have been caused by B/F/TAF. WHAT DO THE RESULTS MEAN?: B/F/TAF was effective at treating HIV in people who had never taken HIV medication before. Most (70%) people were still taking B/F/TAF after 5 years.Clinical Trial Registration: NCT02607930 (Study 1489); NCT02607956 (Study 1490) (ClinicalTrials.gov).

The associations between duration of untreated psychosis, growth factors, and neurocognition in patients with drug-naïve schizophrenia.

BACKGROUND: Cognitive impairment is a core feature of schizophrenia with unclear mechanisms, particularly neurocognition. The objective of this study was to investigate the association between duration of untreated psychosis (DUP) and neurocognition, as well as potential biological mechanisms. METHODS: A total of 219 patients were recruited in this study. DUP was measured in years, reflecting the untreated period. Neurocognition was assessed by the MATRICS Consensus Cognitive Battery (MCCB). The plasma concentrations of three growth factors, vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and epidermal Growth Factor (EGF) were detected by enzyme-linked immunosorbent assay in 128 patients. Multiple linear regression analysis was used to analyze the association between DUP, growth factors, and neurocognition. RESULTS: Our findings showed that DUP was significantly negatively correlated with speed of processing and reasoning and problem-solving in all patients (N = 219, P < 0.05). Five years was defined as cut-off point for long and short DUP group in the present study. Only in the short DUP patients, DUP was strongly associated with visual learning and neurocognition (P < 0.05). In patients with growth factor (N = 128), DUP was independently associated with speed of processing, verbal learning, and neurocognition (P < 0.05). Further, plasma concentrations of VEGF, BDNF, and EGF were all significantly correlated with neurocognition (P < 0.05). Additionally, we found a potential trend of correlation between DUP and BDNF (P = 0.061). CONCLUSION: Our study provides insights into a negative correlation between DUP and neurocognition, and BDNF may serve as a potential biological mechanism.

Efficacy and safety of insulin degludec biosimilar B01411 versus originator insulin degludec in Chinese patients with type 2 diabetes inadequately controlled on oral antidiabetic drugs: a multicenter, randomized, open-label, phase 3 study.

OBJECTIVE: To compare the efficacy and safety of insulin degludec biosimilar B01411 (HS-IDeg) with originator insulin degludec-Tresiba (NN-IDeg) in Chinese patients with type 2 diabetes mellitus (T2DM) who were inadequately controlled on oral antidiabetic drugs (OADs) for at least 3 months. METHODS: This multicenter, randomized, open-label, parallel-group, active-controlled, phase 3 study enrolled 362 participants with T2DM. Participants were stratified according to whether the insulin secretagogue (sulfonylurea or glinide) had been used before the screening and then randomized 1:1 to receive once-daily subcutaneous injections of HS-IDeg (n = 180) or NN-IDeg (n = 182) for 18 weeks. The primary endpoint was the change from baseline in glycated hemoglobin (HbA1c) to week 18. RESULTS: At week 18, the least squares (LS) mean change in HbA1c from baseline was -1.34% (95% CI -1.47 to -1.21) and -1.25% (95% CI -1.38 to -1.12) with HS-IDeg and NN-IDeg, respectively. The LS mean difference (HS-IDeg minus NN-IDeg) in HbA1c at week 18 was -0.09% (95% CI -0.28 to 0.10), demonstrating non-inferiority of HS-IDeg to NN-IDeg. Participants achieving HbA1c <7.0% at week 18 were 34.5% and 29.5% with HS-IDeg and NN-IDeg, respectively. Mean decreases in fasting plasma glucose and standard deviation of blood glucose were similar between both groups. Safety and tolerability, including hypoglycemia, adverse events, and weight change were similar between both groups. No severe hypoglycemia and no death occurred in the study. CONCLUSIONS: HS-IDeg and NN-IDeg demonstrated similar efficacy and safety over 18 weeks of treatment in Chinese patients with T2DM who had inadequate responses to OADs for at least 3 months.

Cognitive profiles across the psychosis continuum.

Cognitive impairments are core features in individuals across the psychosis continuum and predict functional outcomes. Nevertheless, substantial variability in cognitive functioning within diagnostic groups, along with considerable overlap with healthy controls, hampers the translation of research findings into personalized treatment planning. Aligned with precision medicine, we employed a data driven machine learning method, self-organizing maps, to conduct transdiagnostic clustering based on cognitive functions in a sample comprising 228 healthy controls, 200 individuals at ultra-high risk for psychosis, and 98 antipsychotic-naïve patients with first-episode psychosis. The self-organizing maps revealed six clinically distinct cognitive profiles that significantly predicted baseline functional level and changes in functional level after one year. Cognitive flexibility in particular, as well as specific executive functions emerged as cardinal in differentiating the profiles. The application of self-organizing maps appears to be a promising approach to inform clinical decision-making based on individualized cognitive profiles, including patient allocation to different interventions. Moreover, this method has the potential to enable cross-diagnostic stratification in research trials, utilizing data-driven subgrouping informed by categories from underlying dimensions of cognition rather than from clinical diagnoses. Finally, the method enables cross-diagnostic profiling across other data modalities, such as brain networks or metabolic subtypes.

Activation of circulating TFH17 cells associated with activated naive and double negative 2 B cell expansion, and disease activity in systemic lupus erythematosus patients.

BACKGROUND: Systemic lupus erythematosus (SLE) is the quintessential autoimmune disease, as it is characterized by hyperactivity of CD4+ T cells and subsequently drives lupus pathology. Follicular helper T (TFH) cells play an important role in B cell maturation and antibody production. However, which specific subset of cTFH cells drives B cell function and contributes to the development of anti-dsDNA antibodies and SLE pathogenesis remains unclear. METHODS: Peripheral blood mononuclear cells from SLE patients with inactive (n = 11) and active (n = 21) were used to determine and detect frequencies and phenotypes of circulating TFH cells (cTFH), memory cTFH, and B cell subsets. The correlations among cTFH cell subsets and phenotypes, B cell subsets, anti-dsDNA autoantibodies, and clinical parameters were analyzed. RESULTS: In subjects with active SLE, cTFH1 and cTFH17 cells were significantly expanded and activated. These expanded cTFH cells expressed memory phenotypes; cTFH1 cells were predominantly central memory (CM) type, while cTFH17 cells were largely effector memory (EM) type. Phenotyping B cell subsets in these patients showed increased frequencies of aNAV and DN2 B cells. Clinically, ICOS+ cTFH1, ICOS+ cTFH17 cells, and SLEDAI-2k scores were found to be correlated. Analysis of cTFH-B cell relationship revealed positive correlations among ICOS+ cTFH1 cells, aNAV B cells, and anti-dsDNA antibodies. Activation of ICOS+ cTFH17 cells was significantly related to the expansion of aNAV and DN2 B cells. The presence of CM cells in cTFH1 and cTFH17 subsets was correlated with aNAV and DN2 B cell frequencies. CONCLUSION: SLE cTFH cells were found to be polarized toward cTFH1 and cTFH17 cells; activation of these cTFH subsets was significantly associated with disease activity score, aNAV, DN2 B cell expansion, and anti-dsDNA antibody level. Thus, the interactions among cTFH1, cTFH17, and B cells likely contribute to the development of autoantibodies and the pathogenesis in SLE.