Engineering artificial cross-species promoters with different transcriptional strengths.

As a fundamental tool in synthetic biology, promoters are pivotal in regulating gene expression, enabling precise genetic control and spurring innovation across diverse biotechnological applications. However, most advances in engineered genetic systems rely on host-specific regulation of the genetic portion. With the burgeoning diversity of synthetic biology chassis cells, there emerges a pressing necessity to broaden the universal promoter toolkit spectrum, ensuring adaptability across various microbial chassis cells for enhanced applicability and customization in the evolving landscape of synthetic biology. In this study, we analyzed and validated the primary structures of natural endogenous promoters from Escherichia coli, Bacillus subtilis, Corynebacterium glutamicum, Saccharomyces cerevisiae, and Pichia pastoris, and through strategic integration and rational modification of promoter motifs, we developed a series of cross-species promoters (Psh) with transcriptional activity in five strains (prokaryotic and eukaryotic). This series of cross species promoters can significantly expand the synthetic biology promoter toolkit while providing a foundation and inspiration for standardized development of universal components The combinatorial use of key elements from prokaryotic and eukaryotic promoters presented in this study represents a novel strategy that may offer new insights and methods for future advancements in promoter engineering.

Structural analysis of noncanonical translation initiation complexes.

Translation initiation is a highly regulated, multi-step process which is critical for efficient and accurate protein synthesis. In bacteria, initiation begins when mRNA, initiation factors, and a dedicated initiator fMet-tRNAfMet bind the small (30S) ribosomal subunit. Specific binding of fMet-tRNAfMet in the peptidyl (P) site is mediated by the inspection of the fMet moiety by initiation factor IF2 and of three conserved G-C base pairs in the tRNA anticodon stem by the 30S head domain. Tandem A-minor interactions form between 16S ribosomal RNA nucleotides A1339 and G1338 and tRNA base pairs G30-C40 and G29-C41, respectively. Swapping the G30-C40 pair of tRNAfMet with C-G reduces discrimination against the noncanonical start codon CUG in vitro, suggesting crosstalk between gripping of the anticodon stem and recognition of the start codon. Here, we solved electron cryomicroscopy structures of E. coli 70S initiation complexes containing an fMet-tRNAfMet G30-C40 variant paired to noncanonical CUG start codon, in the presence or absence of IF2 and the non-hydrolyzable GTP analog GDPCP, alongside structures of 70S initiation complexes containing this tRNAfMet variant paired to the canonical bacterial start codons AUG, GUG, and UUG. We find that the M1 mutation weakens A-minor interactions between tRNAfMet and 16S nucleotides A1339 and G1338, with IF2 strengthening the interaction of G1338 with the tRNA minor groove. These structures suggest how even slight changes to the recognition of the fMet-tRNAfMet anticodon stem by the ribosome can impact start codon selection.

Serum calciprotein particle-to-phosphate ratio as a predictor of cardiovascular events in incident hemodialysis patients.

INTRODUCTION: Recent studies have identified increased blood calciprotein particle (CPP) levels as risk factors for vascular calcification and cardiovascular events in patients undergoing maintenance hemodialysis. Although positively correlated with serum phosphate levels, serum CPP levels vary considerably among patients with similar serum phosphate levels. We investigated the capacity of the ratio of serum CPP levels to serum phosphate levels (CPP/Pi ratio) to predict cardiovascular events in incident hemodialysis patients compared to the serum calcification propensity test (T50). METHODS AND RESULTS: The association between the CPP/Pi ratio and major adverse cardiac and cerebrovascular events (MACCE) was investigated in 174 incident hemodialysis patients. Multivariate analysis revealed that the CPP/Pi ratio was independently associated with MACCE [hazard ratio 1.60, 95% confidence interval (1.15-2.23), p = 0.006] but serum T50 levels were not. CONCLUSIONS: The CPP/Pi ratio is a useful, novel biomarker for predicting the risk of cardiovascular events in patients undergoing incident hemodialysis.

Factors Associated With Sacubitril/Valsartan Continuation and the Methods of Combining Heart Failure Medications in Patients With Heart Failure.

BACKGROUND: Sacubitril/valsartan (SV) is recommended for patients with heart failure (HF). In addition, a combination of 4 HF medications, including SV, is recommended in patients with HF with reduced ejection fraction (HFrEF). However, evidence on the characteristics of patients who could continue SV and its initiation methods is limited. OBJECTIVE: To investigate the factors associated with SV continuation and methods of combining HF medications. METHODS: This retrospective cohort study included HF patients who initiated with SV at our institution. The endpoint was SV continuation for 6 months after its initiation. Multivariate analysis was used to extract factors associated with SV continuation. The relationship between the methods of combining HF medications (renin-angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists, or sodium-glucose cotransporter 2 inhibitors), including the number of HF medications, their combination patterns, and the timing of their initiation, and SV continuation was examined in patients with HFrEF. RESULTS: Of 186 eligible patients, 68.8% had HFrEF, and 79.0% continued SV for 6 months. Significant factors associated with SV continuation were albumin ≥ 3.5 g/dL (odds ratio, 4.81; 95% confidence interval, 2.19-10.59), body mass index (BMI) ≥ 18.5 kg/m2 (4.17; 1.10-15.85), and systolic blood pressure (SBP) ≥ 110 mmHg (2.66; 1.12-6.28). In patients with HFrEF, the proportion of HF medications not initiated simultaneously with SV was significantly higher in the continuation group than in the discontinuation group (67.3% vs 33.3%, P = 0.002). The number of HF medications and their combination patterns were not significantly associated with SV continuation. CONCLUSION AND RELEVANCE: Albumin, BMI, and SBP are useful indicators for selecting patients who are likely to continue SV. In addition, initiating only SV without simultaneously initiating other HF medications in patients with HFrEF may lead to SV continuation.

Provider Perspectives on Rapid Treatment Initiation Among People Newly Diagnosed With HIV: A New Message of "Urgency"?

BACKGROUND: Early initiation of antiretroviral therapy improves human immunodeficiency virus (HIV) outcomes. However, achieving earlier treatment initiation is challenging for many reasons including provider awareness and clinic barriers; this study sought to understand perceptions of an early initiation program. METHODS: We interviewed 10 providers from 3 HIV clinics in North Carolina (October-November 2020). We asked providers about overall perceptions of early initiation and the pilot program. We developed narrative summaries to understand individual contexts and conducted thematic analysis using NVivo. RESULTS: Providers believed earlier initiation would signal an "extra sense of urgency" about the importance of antiretroviral therapy-a message not currently reflected in standard of care. Safety was a consistent concern. Cited implementation barriers included transportation assistance, medication sustainability, and guidance to address increased staff time and appointment availability. CONCLUSION: Our qualitative findings highlight the need for training on the safety of early initiation and addressing staffing needs to accommodate quicker appointments.

Doctor and clinic staff perspectives on a program to immediately start HIV treatment among patients newly diagnosed with HIVTreating human immunodeficiency virus (HIV) is easier than ever. Starting newly diagnosed persons on HIV medication as soon as possible is a now recommended goal. However, starting patients right away can be challenging. This study interviewed doctors and clinic staff to better understand their perspectives prior to implementing a program that would provide newly diagnosed patients with HIV treatment immediately. Results showed that some doctors are worried patients will not return after receiving their medications. Providers want support for linking patients to the clinic and ensuring they will be able to receive their next dose of medication when they come in. Other providers saw the benefits of reducing HIV stigma if the program can more quickly start patients on treatment. Some providers explained that when you go to the doctor and are sick you receive medications immediately, yet for newly diagnosed patients living with HIV, patients can be told to come back a month later to start treatment. Some providers believe shifting this messaging may also help patients take their medications better. Most providers saw the need for clinics to have more same-day appointment availability to meet the needs of the new program. Overall, providers were excited about the opportunity to improve the HIV care by offering HIV medications to newly diagnosed patients immediately.

Association between single-person household wage workers in South Korea and insomnia symptoms: the 6th Korean Working Conditions Survey (KWCS).

BACKGROUND: The rise in single-person households is a global phenomenon with well-documented implications for both physical and mental well-being. However, there remains a scarcity of studies focusing specifically on the health impacts of single-person households on workers. This study aims to address this gap by comparing insomnia symptoms between single- and multi-person household workers, shedding light on the health implications of household composition. METHODS: This study utilized data from the Sixth Korean Working Conditions Survey. Insomnia symptoms were categorized into normal sleep and insomnia symptom groups utilizing the 3-item Minimal Insomnia Symptom Scale. Multiple logistic regression analysis was employed to examine the association between single-person household wage workers and insomnia symptoms. RESULTS: In comparison to wage workers from multi-person households, those from single-person households exhibited heightened risks of reporting insomnia symptoms. In the fully adjusted model, the odds ratios for symptoms of insomnia among single-person household wage workers was 1.173 (95% confidence interval: 1.020-1.349). CONCLUSIONS: This study underscores that single-person household wage workers in Korea face an elevated risk of insomnia symptoms compared to their counterparts in multi-person households.

Multifaceted role of the DNA replication protein MCM10 in maintaining genome stability and its implication in human diseases.

MCM10 plays a vital role in genome duplication and is crucial for DNA replication initiation, elongation, and termination. It coordinates several proteins to assemble at the fork, form a functional replisome, trigger origin unwinding, and stabilize the replication bubble. MCM10 overexpression is associated with increased aggressiveness in breast, cervical, and several other cancers. Disruption of MCM10 leads to altered replication timing associated with initiation site gains and losses accompanied by genome instability. Knockdown of MCM10 affects the proliferation and migration of cancer cells, manifested by DNA damage and replication fork arrest, and has recently been shown to be associated with clinical conditions like CNKD and RCM. Loss of MCM10 function is associated with impaired telomerase activity, leading to the accumulation of abnormal replication forks and compromised telomere length. MCM10 interacts with histones, aids in nucleosome assembly, binds BRCA2 to maintain genome integrity during DNA damage, prevents lesion skipping, and inhibits PRIMPOL-mediated repriming. It also interacts with the fork reversal enzyme SMARCAL1 and inhibits fork regression. Additionally, MCM10 undergoes several post-translational modifications and contributes to transcriptional silencing by interacting with the SIR proteins. This review explores the mechanism associated with MCM10's multifaceted role in DNA replication initiation, chromatin organization, transcriptional silencing, replication stress, fork stability, telomere length maintenance, and DNA damage response. Finally, we discuss the role of MCM10 in the early detection of cancer, its prognostic significance, and its potential use in therapeutics for cancer treatment.

A systematic review of interventions to enhance initiation of and adherence to treatment for alcohol use disorders.

BACKGROUND: Alcohol use disorders (AUDs) contribute significantly to the global disease burden in terms of morbidity and mortality. While effective treatment options exist, engagement with care remains a challenge, impacting treatment outcomes and resource allocation, particularly in resource-constrained settings. In this review, we aim to systematically examine and synthesize the evidence on interventions targeting initiation of and adherence to treatment for AUDs. METHODS: A search was conducted on six electronic databases (MEDLINE, PsycINFO, Embase, Global Health, CINAHL and CENTRAL) using search terms under the following concepts: alcohol use disorders, initiation/adherence, treatments, and controlled trial study design. Due to the heterogeneity in intervention content and outcomes among the included studies, a narrative synthesis was conducted. Risk of bias was assessed using the Joanna Briggs Institute (JBI) critical appraisal tools. RESULTS: The search yielded 32 distinct studies testing eleven categories of interventions. 23 out of 32 studies reported effectiveness of interventions in improving at least one initiation or adherence outcome, with 11 studies reporting an improvement in at least one outcome related to drinking, and four studies reporting improvements in at least one measure of well-being or disability. Community Reinforcement Approach and Family Training (CRAFT) emerged as a prominent approach for treatment initiation, contingency management for adherence, and motivational interviewing (MI) for both treatment initiation and adherence. CONCLUSION: Integrating initiation and adherence interventions into AUD treatment services holds immense potential for optimizing client outcomes and fostering overall well-being. However, generalizability of these strategies remains uncertain owing to the lack of studies conducted in low- and middle-income countries. Addressing this gap is crucial for enhancing global access to effective treatments for AUDs.

Exploring the mortality and cardiovascular outcomes with SGLT-2 inhibitors in patients with T2DM at dialysis commencement: a health global federated network analysis.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT-2is) have demonstrated associations with lowering cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM). However, the impact of SGLT-2is on individuals at dialysis commencement remains unclear. The aim of this real-world study is to study the association between SGLT-2is and outcomes in patients with T2DM at dialysis commencement. METHODS: This is a retrospective cohort study of electronic health records (EHRs) of patients with T2DM from TriNetX Research Network database between January 1, 2012, and January 1, 2024. New-users using intention to treatment design was employed and propensity score matching was utilized to select the cohort. Clinical outcomes included major adverse cardiac events (MACE) and all-cause mortality. Safety outcomes using ICD-10 codes, ketoacidosis, urinary tract infection (UTI) or genital infection, dehydration, bone fracture, below-knee amputation, hypoglycemia, and achieving dialysis-free status at 90 days and 90-day readmission. RESULTS: Of 49,762 patients with T2DM who initiated dialysis for evaluation, a mere 1.57% of patients utilized SGLT-2is within 3 months after dialysis. 771 SGLT-2i users (age 63.3 ± 12.3 years, male 65.1%) were matched with 771 non-users (age 63.1 ± 12.9 years, male 65.8%). After a median follow-up of 2.0 (IQR 0.3-3.9) years, SGLT-2i users were associated with a lower risk of MACE (adjusted Hazard Ratio [aHR] = 0.52, p value < 0.001), all-cause mortality (aHR = 0.49, p < 0.001). SGLT-2i users were more likely to become dialysis-free 90 days after the index date (aHR = 0.49, p < 0.001). No significant differences were observed in the incidence of ketoacidosis, UTI or genital infection, hypoglycemia, dehydration, bone fractures, below-knee amputations, or 90-day readmissions. CONCLUSIONS: Our findings indicated a lower incidence of all-cause mortality and MACE after long-term follow-up, along with a higher likelihood of achieving dialysis-free status at 90 days in SGLT-2i users. Importantly, they underscored the potential cardiovascular protection and safety of SGLT-2is use in T2DM patients at the onset of dialysis.

Longitudinal associations of e-cigarette use with cigarette, marijuana, and other drug use initiation among US adolescents and young adults: Findings from the population assessment of tobacco and health study (Waves 1-6).

INTRODUCTION: Research examining prospective links of e-cigarette use with cigarette, marijuana, and other substance use has been limited largely to 1-2-year follow-up periods and focused on younger adolescents. This study examined longitudinal associations of e-cigarette use with cigarette, marijuana, and other substance use initiation among U.S. adolescents and young adults (AYAs) across an eight-year period. METHODS: Adolescent (ages 12-17) and young adult (ages 18-25) data from waves 1-6 of the nationally representative Population Assessment of Tobacco and Health study (2013-2021) were used. Discrete time survival models with time-varying weights were employed to examine the risk of cigarette, marijuana, and other drug use initiation over an eight-year follow-up period among AYAs with no lifetime use of e-cigarettes/other tobacco, lifetime but no past 30-day use of e-cigarettes/other tobacco, past 30-day e-cigarettes only, other tobacco use only, or past 30-day e-cigarette/other tobacco use. We compare our time-varying weighting approach to a traditional time-invariant/complete case weighting approach. RESULTS: Across six follow-up waves, all three past 30-day nicotine/tobacco use groups, including e-cigarettes only, had greater risk for cigarette, marijuana, and other drug use initiation relative to those not using nicotine/tobacco. The three past 30-day nicotine/tobacco use groups did not differ from each other in risk for marijuana use initiation. Associations were smaller in magnitude for young adults compared to adolescents, but significant for both age groups. CONCLUSIONS: Substance use initiation risks persist beyond 1-2 years for U.S. AYAs using e-cigarettes. Prevention strategies to reduce AYA e-cigarette use are needed to reduce cancer-related risk.

Digital Cognitive-Behavioral Therapy for Insomnia in Cancer Survivors: Protocol for a Pragmatic Clinical Trial.

INTRODUCTION: Insomnia is one of the most prevalent, persistent, and distressing conditions associated with cancer, affecting almost half of all cancer survivors. Although cognitive-behavioral therapy for insomnia is well established as the gold-standard treatment for insomnia, its accessibility is very limited in routine care. We aim to examine the real-world effectiveness and acceptability of a digital cognitive-behavioral therapy for insomnia for cancer survivors with insomnia symptoms through a randomized controlled trial in Portugal. METHODS AND ANALYSIS: Our cancer trial will test the effects and acceptability of an accessible internet-delivered self-administered cognitive-behavioral therapy for insomnia digital intervention with clinician support, OncoSleep. This online program includes six interactive, personalized weekly sessions featuring evidence-based techniques targeting psychophysiological hyperarousal and maladaptive conditioning, tailored for cancer survivors. Research study procedures include screening for eligibility in the general population and randomization into one of two arms: the digital CBT-I program or a waitlist control group. Insomnia severity (primary outcome), fatigue, sleep diary outcomes, psychological distress, and quality of life (secondary outcomes) will be assessed at baseline and post-intervention.

Initiation of Oral Endocrine Therapy and Survival Benefit Among Women with Early-Stage Breast Cancer.

Introduction: Endocrine therapy (ET) is the cornerstone of systemic treatment for patients with estrogen receptor positive breast cancer, but its uptake and adherence need further improvement. This observational study assessed ET initiation and 1-year adherence and its survival benefit among female Medicare beneficiaries with early-stage breast cancer. Materials and Methods: This retrospective cohort study analyzed the linked 2011-2019 Surveillance, Epidemiology, and End Results-Medicare data. Female beneficiaries newly diagnosed with hormone receptor positive, stage I-III breast cancer were included. Beneficiaries who initiated tamoxifen, anastrozole, letrozole, or exemestane within 3 months after cancer diagnosis were defined as initiators (n = 24,289), and those who never initiated these treatments were noninitiators (n = 8,899). Adherence was measured using proportion of days covered (PDC) in the continuous 12 months follow-up period. Multivariable logistic regression models were used to assess factors associated with ET initiation and adherence (PDC ≥ 80%), controlling for covariates. Weighted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause and breast cancer related mortality between initiators and noninitiators and by adherence status. Results: Among eligible female beneficiaries (n = 55,893), 43% initiated ET within 3 months of cancer diagnosis. Among initiators, 77% had PDC ≥ 80% during the first year. Patient's demographics (e.g., older age, race/ethnicity) and baseline health services utilization (e.g., mammography) were associated with ET initiation and adherence. ET initiation and adherence was associated with reduced risk of all-cause (adjusted HR = 0.62, 0.59-0.66; HR = 0.55, 0.53-0.59; respectively) and breast cancer related (adjusted HR = 0.57, 0.50-0.64; HR = 0.41, 0.36-0.47; respectively) mortality compared with noninitiators. Conclusion: Women with early-stage breast cancer who initiate ET and are adherent to treatment may achieve survival benefits compared with noninitiators.

Initiation of Chronic Non-invasive Ventilation.

Initiation of home non-invasive ventilation (NIV) requires careful consideration of the patient's condition, motivation, expectations, wishes, and social circumstances. The decision to start NIV depends on a combination of factors including patient symptoms and objective evidence of nocturnal hypoventilation. A solid understanding of the underlying pathophysiology is key to a systematic and well-balanced clinical approach to titrating NIV. The location where NIV is initiated is not the most relevant issue, provided that it is a comfortable, safe environment in which adequate monitoring can be assured. The majority of patients prefer their own home for treatment initiation.

Experiences of and treatment preferences for insomnia in autistic adults: An Interpretative Phenomenological Analysis.

Insomnia and insomnia symptoms are frequent experiences of autistic people resulting in pronounced daytime effects and poor quality of life. This study employed an Interpretive Phenomenological Analysis approach to explore lived experiences of autistic adults with insomnia, perspectives on current available interventions and future treatment preferences. Twelve participants (aged 21-48 years old) were interviewed following screening for insomnia, using the Sleep Condition Indicator (scores ranged from 1 to 12; cut off >16). Each interview was analysed individually developing Personal Experiential Themes for each case, which were then mapped across cases based on identified patterns and connections. Results yielded rich personal accounts and identified two Group Experiential Themes: "The Night is Friendlier" and "It Doesn't Really Work for Me". Participants described experiences with sleeplessness throughout their adult lives and often since childhood. They discussed how the night time offers them a more relaxed and safe space to freely behave as they wish. Advice and interventions were viewed by participants via the prism of underlying social issues, such as autism acceptance and trust, and how these structures can affect participants' experiences with insomnia, help seeking and effectiveness of current interventions. Our results highlight the need for inclusion of autistic people in insomnia research through co-production and co-creation as well as clinical practice and delivery. This is the first study to integrate perspectives and experiences of autistic people towards insomnia and sleep-related advice by health care professionals. Findings are discussed in relation to theoretical and practical implications, as well as directions for future research.

Stepping into emotions: investigating the effect of angry and fearful faces on forward stepping and quiet stance.

Introduction: Facial expressions conveying an emotion may affect social interactions, such as approach- or avoidance-related behaviors. A specific facial feature is the gaze direction. An emotional facial expression such as anger will elicit distinct behavioral tendencies, depending on whether the angry gaze is directed toward the onlooker, or in a different direction. We tested whether facial expressions of anger and fear, combined with direct or averted gaze, elicit approach- or avoidance tendencies, using a go/no-go variant of the whole-body stepping task. Method: Healthy adults stood on a force plate, recording the center of pressure (COP). Participants were presented with angry or fearful faces; either with direct or averted gaze. Participants had to identify the emotion, and "depending on instructions- either make a single step forward, or remain in a quiet stance. From the COP of the forward steps, we derived parameters such as reaction time and step size. From the quiet standing trials we derived parameters of postural sway, indicative of postural "freeze." We used analysis of variance to analyze the outcomes. Results and discussion: First, we found that steps were initiated faster with angry faces than with fearful faces, in line with existing literature. Second, we did not observe a significant effect of gaze direction. Forward steps with direct and averted gaze had similar COP characteristics. Finally, we had expected to find freeze (postural immobility) with fearful faces, but this was also not observed. We discuss various explanations for the finding, and implications for research into the motoric grounding of social interactions.

Effectiveness and safety of East Asian herbal medicine for menopausal insomnia: a systematic review and meta-analysis.

Background: Menopausal insomnia significantly impacts the quality of life in women. East Asian herbal medicines (EAHMs) have been traditionally used in Asian countries, but their efficacy and safety require systematic evaluation. This systematic review and meta-analysis aimed to evaluate the effectiveness and safety of EAHM for treating menopausal insomnia. Methods: A comprehensive literature search was conducted across 10 electronic databases from inception until 19 July 2023. Randomized controlled trials (RCTs) investigating EAHM for menopausal insomnia were included. Two reviewers independently screened studies, extracted data, and assessed the risk of bias using the Cochrane risk of bias tool. The primary outcome was sleep quality, insomnia severity, and sleep architecture. Secondary outcomes included total effective rate (TER), menopausal symptoms, and adverse effects. Meta-analysis was conducted using a random-effects model, and the results were calculated as mean differences (MDs) or risk ratios (RRs) and their 95% confidence intervals (CIs). Also, the certainty of evidence was assessed using the GRADE approach. Results: A total of 70 RCTs involving 6,035 participants met the inclusion criteria. The most frequently used EAHMs were modified Suan Zao Ren Tang, and the most frequently used herbal component was Zizyphus jujuba Miller var. spinosa Hu ex H. F. Chou [Rhamnaceae; Zizyphi Semen]. Compared with sedative-hypnotics, EAHM significantly improved sleep quality, as measured by the Pittsburgh Sleep Quality Index (PSQI) (MD -2.18, 95% CI -2.56 to -1.80), and reduced menopausal symptoms, as assessed by the Kupperman Index (MD -4.92, 95% CI -6.03 to -3.80). Similar results were seen when EAHM was added to sedative-hypnotics. When EAHM was additionally used in sedative-hypnotics, similar benefits were shown for PSQI (MD -2.46, 95% CI -3.09 to -1.82) and the Kupperman Index (MD -4.64, 95% CI -5.07 to -4.21). EAHM was generally safer than sedative-hypnotics, with significantly fewer adverse reactions (RR 0.15, 95% CI 0.07-0.34). However, the certainty of evidence was moderate to low. Conclusion: EAHMs, alone or with sedative-hypnotics, may be effective and safe for improving sleep quality and managing menopausal symptoms. Future studies should include diverse populations, rigorous methodologies, and explore mechanisms of action to confirm these findings. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?], identifier [CRD42023446708].

The cascade of care for commercially-insured persons with opioid use disorder and comorbid HIV and HCV infections.

BACKGROUND: Opioid use disorder (OUD) significantly impacts individual and public health and exacerbated further by concurrent infectious diseases. A syndemic approach is needed to address the intertwined OUD, HIV, and HCV epidemics, including the expanded use of medications for opioid use disorder (MOUD). METHODS: To identify MOUD scale-up opportunities, we conducted a retrospective cohort study, representing commercially insured persons, and created the OUD care continuum, including HIV and HCV influences in adults (18-64 years) newly diagnosed with OUD in 2019 using Merative MarketSan data. RESULTS: Among 124,467,633 individuals, the prevalence of OUD was 0.4 % (95 % CI: 0.36 %-0.46 %; N = 497,871), with 327,277 (65.7 %, 95 % CI: 65.60 %-65.87 %) newly diagnosed in 2019. Among these newly diagnosed individuals (54 % men, mean age 44±0.01), 53,568 (27.0 %, 95 % CI: 26.4 %-27.5 %) were prescribed MOUD, with retention rates at 1, 3, and 6 months being 89.0 % (95 % CI: 88.2 %-89.8 %), 66.0 % (95 % CI: 64.8 %-67.2 %), and 50.3 % (95 % CI: 48.3 %-51.6 %), respectively. Buprenorphine was the most prescribed MOUD (79.6 %, 95 % CI: 78.6 %-80.7 %), followed by XR-NTX (14.9 %, 95 % CI:14.0 %-15.8 %) and methadone (5.5 %, 95 % CI: 4.9 %-6.1 %). Six-month retention was highest for methadone (73.4 %, 95 % CI: 73.0 %-73.8 %), however, followed by buprenorphine (55.7 %, 95 % CI: 55.3 %-57.1 %) and substantially lower for XR-NTX (12.6 %, 95 % CI: 10.6 %-14.6 %). Screening for HIV and HCV was low among OUD enrollees (11.1 %, 14.4 %), slightly higher for MOUD initiators (18.0 %, 21.6 %). Being prescribed MOUD was correlated with HCV infection (AOR: 2.54; 95 % CI: 2.41-2.68), HCV/HIV coinfection (AOR: 1.89; 95 % CI: 1.41-2.53), and hospitalization for OUD-related services (AOR: 1.14; 95 % CI: 1.11-1.17), yet hospitalization for OUD-related services was positively correlated with XR-NTX (AOR: 2.72; 95 % CI: 2.56-2.85) prescription and negatively with methadone (AOR: 0.19; 95 % CI: 0.16-0.23) prescription. Having HIV was negatively correlated with being prescribed methadone (AOR: 0.33; 95 % CI: 0.13-0.86). CONCLUSIONS: Substantial gaps in the OUD cascade persist, underscoring better implementation opportunities for MOUD prescription in hospital-based settings and expanding access to methadone beyond highly regulated sites given its low coverage yet high treatment retention.

Effects of chamomile (Matricaria chamomilla L.) on sleep: A systematic review and meta-analysis of clinical trials.

OBJECTIVE: We aimed to investigate the effects of chamomile (Matricaria chamomilla L.) on sleep in this systematic review and meta-analysis of clinical trials. METHODS: PubMed, Scopus, Web of Science, and Cochrane Library were searched until August 2023. All clinical trials that investigated the effects of chamomile on sleep, either in healthy or diseased adults, were eligible to enter the study. The quality of studies was assessed using the Cochrane tool. Random-effects meta-analysis was used to pool weighted mean differences (WMD) and 95 % CI for the outcomes assessed by at least three studies with relatively consistent participants. RESULTS: The systematic review included ten studies (772 participants). Meta-analysis was conducted for the Pittsburgh Sleep Quality Index (PSQI) score and sleep length. A significant reduction in PSQI score (WMD: -1.88, 95 %CI: -3.46, -0.31, I2: 88.4 %, n = 5) was found. For other outcomes, meta-analysis was not conducted. Sleep onset latency or ease of getting to sleep were improved in three of the four studies. Daytime functioning measures, including fatigue severity index or postpartum fatigue scale, did not change in all three studies. Sleep efficiency did not change in two studies and deteriorated in one. The number of awakenings after sleep or staying asleep was improved in two of the three studies. No adverse events were reported in any of the studies although passive surveillance was used to assess adverse effects except in one study. Only one study surveyed the blinding success and tested the purity and/or potency of the used products. CONCLUSION: Chamomile improved sleep, especially the number of awakenings after sleep or staying asleep; however, it did not lead to an improvement in the duration of sleep, percentage of sleep efficiency, and daytime functioning measures. Future studies are suggested to assess objective measures.

Microsatellite instability at U2AF-binding polypyrimidic tract sites perturbs alternative splicing during colorectal cancer initiation.

BACKGROUND: Microsatellite instability (MSI) due to mismatch repair deficiency (dMMR) is common in colorectal cancer (CRC). These cancers are associated with somatic coding events, but the noncoding pathophysiological impact of this genomic instability is yet poorly understood. Here, we perform an analysis of coding and noncoding MSI events at the different steps of colorectal tumorigenesis using whole exome sequencing and search for associated splicing events via RNA sequencing at the bulk-tumor and single-cell levels. RESULTS: Our results demonstrate that MSI leads to hundreds of noncoding DNA mutations, notably at polypyrimidine U2AF RNA-binding sites which are endowed with cis-activity in splicing, while higher frequency of exon skipping events are observed in the mRNAs of MSI compared to non-MSI CRC. At the DNA level, these noncoding MSI mutations occur very early prior to cell transformation in the dMMR colonic crypt, accounting for only a fraction of the exon skipping in MSI CRC. At the RNA level, the aberrant exon skipping signature is likely to impair colonic cell differentiation in MSI CRC affecting the expression of alternative exons encoding protein isoforms governing cell fate, while also targeting constitutive exons, making dMMR cells immunogenic in early stage before the onset of coding mutations. This signature is characterized by its similarity to the oncogenic U2AF1-S34F splicing mutation observed in several other non-MSI cancer. CONCLUSIONS: Overall, these findings provide evidence that a very early RNA splicing signature partly driven by MSI impairs cell differentiation and promotes MSI CRC initiation, far before coding mutations which accumulate later during MSI tumorigenesis.

A Comprehensive Insight and In Silico Analysis of CircRNAs in Hepatocellular Carcinoma: A Step toward ncRNA-Based Precision Medicine.

Circular RNAs (circRNAs) are cardinal players in numerous physiological and pathological processes. CircRNAs play dual roles as tumor suppressors and oncogenes in different oncological contexts, including hepatocellular carcinoma (HCC). Their roles significantly impact the disease at all stages, including initiation, development, progression, invasion, and metastasis, in addition to the response to treatment. In this review, we discuss the biogenesis and regulatory functional roles of circRNAs, as well as circRNA-protein-mRNA ternary complex formation, elucidating the intricate pathways tuned by circRNAs to modulate gene expression and cellular processes through a comprehensive literature search, in silico search, and bioinformatics analysis. With a particular focus on the interplay between circRNAs, epigenetics, and HCC pathology, the article sets the stage for further exploration of circRNAs as novel investigational theranostic agents in the dynamic realm of HCC.