Miracle-dz/UniFAR-FTUs huggingface dataset:
Circulating microRNAs as biomarkers and mediators of platelet activation

Abstract Platelets are essential mediators of physiological hemostasis and pathological thrombosis. Currently available tests and markers of platelet activation did not prove successful in guiding treatment decisions for patients with cardiovascular disease, justifying further research into novel markers of platelet reactivity. Platelets contain a variety of microRNAs (miRNAs) and are a major contributor to the extracellular circulating miRNA pool. Levels of platelet-derived miRNAs in the circulation have been associated with different measures of platelet activation as well as antiplatelet therapy and have therefore been implied as potential new markers of platelet reactivity. In contrast to the ex vivo assessment of platelet reactivity by current platelet function tests, miRNA measurements may enable assessment of platelet reactivity in vivo. It remains to be seen however, whether miRNAs may aid clinical diagnostics. Major limitations in the platelet miRNA research field remain the susceptibility to preanalytical variation, non-standardized sample preparation and data normalization that hampers inter-study comparisons. In this review, we provide an overview of the literature on circulating miRNAs as biomarkers of platelet activation, highlighting the underlying biology, the application in patients with cardiovascular disease and antiplatelet therapy and elaborating on technical limitations regarding their quantification in the circulation.
A qualitative study of services accessibility for indigenous persons who use injection drugs across three communities in the United States

Abstract Aims: This study concerns the perspectives of Indigenous persons who use injection drugs (IPWIDs) and key stakeholders across multiple sectors regarding healthcare service and treatment accessibility in the United States. Methods: Sixty in-depth interviews were undertaken with selected participants (30 people who use injection drugs and 30 stakeholders) across three non-urban locations in the United States. An inductive analytic approach was used to explore perspectives regarding healthcare accessibility gaps. Results: IPWIDs described injecting stimulants, opioids, and diverted medications for opioid use disorder, as well as having unstable access to sterile syringes. Often, the most accessible treatment for IPWID substance use was engagement with punitive aspects of the criminal justice system. While local health and social services were described as providing limited or inadequate services for IPWIDs, human capital deficiencies in those agencies and institutions often reinforced barriers to accessibility for IPWIDs, further aggravating the epidemics of Hepatitis C Virus infection and overdose risk in Indigenous communities. Conclusions: Decolonizing approaches to IPWID-centered services are urgently needed to reduce disparities in transmission of infectious diseases and other health consequences of injection drug use among American Indian people. Potential pathways forward include moving away from punitive treatment of IPWIDs by the criminal justice system and toward local, tribally-centered, culturally appropriate treatment models. We identify an urgent need to provide reliable and local access to sterile injection equipment and opioid substitution treatment on or near reservations.
Efficacy and safety of ofatumumab in recently diagnosed, treatment-naive patients with multiple sclerosis: Results from ASCLEPIOS I and II

Background: In the phase III ASCLEPIOS I and II trials, participants with relapsing multiple sclerosis receiving ofatumumab had significantly better clinical and magnetic resonance imaging (MRI) outcomes than those receiving teriflunomide. Objectives: To assess the efficacy and safety of ofatumumab versus teriflunomide in recently diagnosed, treatment-naive (RDTN) participants from ASCLEPIOS. Methods: Participants were randomized to receive ofatumumab (20 mg subcutaneously every 4 weeks) or teriflunomide (14 mg orally once daily) for up to 30 months. Endpoints analysed post hoc in the protocol-defined RDTN population included annualized relapse rate (ARR), confirmed disability worsening (CDW), progression independent of relapse activity (PIRA) and adverse events. Results: Data were analysed from 615 RDTN participants (ofatumumab: n = 314; teriflunomide: n = 301). Compared with teriflunomide, ofatumumab reduced ARR by 50% (rate ratio (95% confidence interval (CI)): 0.50 (0.33, 0.74); p < 0.001), and delayed 6-month CDW by 46% (hazard ratio (HR; 95% CI): 0.54 (0.30, 0.98); p = 0.044) and 6-month PIRA by 56% (HR: 0.44 (0.20, 1.00); p = 0.049). Safety findings were manageable and consistent with those of the overall ASCLEPIOS population. Conclusion: The favourable benefit–risk profile of ofatumumab versus teriflunomide supports its consideration as a first-line therapy in RDTN patients. ASCLEPIOS I and II are registered at ClinicalTrials.gov (NCT02792218 and NCT02792231).
A multi‐component evaluation framework of a state‐wide preventive health program: My health for life

Abstract Issue Chronic disease is a growing problem affecting approximately half of all Australian adults. In response to growing calls for action on chronic disease, the My health for life program was created, aimed at improving the health of individuals at high risk of developing preventable chronic disease. The preventive health program is multi‐modal, cross‐culturally tailored and contains complex social marketing, community engagement, risk assessment and health promotion components. Therefore, a multi‐component evaluation framework is essential to understand the effectiveness of the My health for life program. This brief report details the evaluation. Methods The evaluation design uses non‐randomised, longitudinal analysis using repeated measures, observational, program goal‐based and pretest‐posttest design features to assess the program, its specific modalities and its program adaptations. To ensure timely and credible evaluation, different evaluative implementation frameworks and methods are considered. Quantitative and qualitative methods collect an array of program data at differing levels to assess the processes, outcomes and impacts of My health for life. Discussion The implemented evaluation framework has allowed measurement of: (i) process impacts including uptake, retention and attrition, participant satisfaction, fidelity and program stakeholder engagement and (ii) outcomes relating to individual participant level changes in health behaviours. So what? This evaluation is an example of an integrated evaluation approach in a large successful preventive health program. Findings from the evaluation will ultimately inform the applicability and transferability of the program and inform policy makers, stakeholders and other health professionals in preventive health practice.
Boosting curcumin activity against human prostatic cancer PC3 cells by utilizing scorpion venom conjugated phytosomes as promising functionalized nanovesicles

Abstract Prostate cancer (PC) is emerging as one of the leading causes of mortality and morbidity worldwide. Curcumin (CUR) is a well-known phytochemical, and scorpion venom (SV) is a natural peptide with proven anticancer properties. However, these natural bioactive agents are limited by low solubility, low bioavailability, poor thermal stability, and short half-lives. Therefore, the aim of this study was to fabricate SV-conjugated CUR phytosomes as promising functionalized nanovesicles and assess their anticancer efficacy in human prostatic cancer PC3 cells. CUR-Phytosome-SV was fabricated using experimental design software in which the zeta potential and particle sizes were used as dependent variables. The anticancer effect of the fabricated formulation was determined by performing a tetrazolium (MTT) assay, cell cycle analysis, annexin V staining, and examining the expression levels of Bcl-associated X-protein (Bax), p53, caspase-3, B-cell lymphoma 2 (Bcl-2), nuclear factor kappa beta (NF-kB), and tumor necrosis factor alpha (TNF-α). The particle size of the nanoconjugates was found to be in the range of 137.5 ± 7.9 to 298.4 ± 11.9 nm, and the zeta potential was 2.9 ± 0.1 to 26.9 ± 1.2 mV. The outcome of the MTT assay showed that curcumin–Phospholipon®–scorpion venom (CUR–PL–SV) exhibited a satisfactory level of cytotoxicity, and the IC50 was found to be lower than CUR and PL-SV individually. Cell cycle analysis showed predominantly cell cycle arrest at the G2-M and pre-G1 phases. In contrast, annexin V staining showed significant early and late apoptosis events in addition to increased necrosis when PC3 cells were treated with CUR–PL–SV. Reverse-transcriptase polymerase chain reaction (RT-PCR) analysis showed a reduction in expression of Bax, p53, caspase-3, NF-kB, TNF-α, and an increase in Bcl-2 expression. Moreover, a MMP analysis showed a reduction in mitochondrial permeability and hence confirmed the superior anticancer potential of CUR–PL–SV. Thus, the present study showed significant anticancer potency of SV-conjugated CUR phytosomes against human prostatic cancer PC3 cells, making it a novel treatment approach for PC.
Holmium: yttrium-aluminum-garnet laser with Moses: does it make a difference?

Purpose of review Moses effect is an inherent physical principle of Ho:YAG laser functioning. Moses Technology is a pulse modulation modality of Ho:YAG laser, which became commercially available for the treatment of two urological conditions: urinary stones and benign prostatic obstruction. The purpose of this narrative review is to distinguish between Moses effect and Moses Technology, as well as to summarize the latest evidence on Moses Technology and its main application in the urological field. Recent findings During laboratory lithotripsy, Moses Technology seems to reduce stone retropulsion and determine higher ablation volume compared with regular lithotripsy. However, this technology presents similar characteristics to long pulse Ho:YAG laser, and several studies showed no significant difference between Moses Technology and standard lasers. When used in prostate enucleation, Moses Technology promises to reduce operating time by increasing the efficiency of prostate resection and improve the hemostasis. Moreover, some studies state that it is possible to reduce the HoLEP morbidity. Despite this, the clinical impact of the time reduction remains uncertain and different studies either present relevant limitations or are burdened by significant bias. Summary Although Moses effect has been extensively described and characterized, and several studies have been published on the usage of Moses Technology for both laser lithotripsy and laser enucleation of the prostate with Holmium YAG, solid clinical evidence on the real improvement of surgical outcomes is still missing.
Examining the role of trauma in alcohol interlock performance: A structural pathway analysis

Abstract Objective Self-medication using alcohol is a common coping response among individuals dealing with trauma as is driving under the influence of alcohol (DUI). A common intervention for drivers convicted of DUI, is an alcohol ignition interlock device (IID)—which requires breath samples before starting the car. If the sample is above a predetermined limit (.025), the car will not start, thus preventing impaired driving. IIDs are an effective intervention to reduce rates of drinking and driving among high risk populations; however, limited research has examined how traumatic experiences may impact performance on IIDs. Methods This study is an archival analysis of the Managing Heavy Drinking (MHD) study of drivers in New York state. The MHD is a comprehensive study of drivers convicted of a DUI from 2015–2020. Participants (N = 121) completed questionnaires and provided consent to retrieve information from interlock providers. Outcome variable included high BAC lockout ratios (number of high BAC lockouts [BAC>.08]/number of clean blows [BAC ≤ .025]). Other variables included demographic variables, alcohol treatment history, trauma experiences, and prior DUI history. Variables were entered into a structural equation model. Results In the final structural model, pathways that demonstrated a p-value of greater than . 10 were dropped from the model. This produced acceptable overall model fit statistics (χ2 = 27.059(10), p=. 003; CFI = . 900; NFI = . 898; RMSEA = . 063). A significant pathway was found from the trauma measure to alcohol use (β = .132), and from alcohol use to interlock performance (β = .636). However, no significant relationship was found between trauma and interlock performance other than through alcohol use. Conclusions The current study provides a useful framework upon which to understand the role traumatic experiences have on alcohol IID performance. Traumatic experiences are in of themselves insufficient to impact IID performance directly, but it may indirectly impact IID performance through increasing alcohol use.
A critical analysis of research methods and experimental models to study the load capacity and clinical behaviour of the root filled teeth

Abstract The prognosis of root‐filled teeth depends not only on a successful root canal treatment but also on the restorative prognosis. This critical review discusses the advantages and limitations of various methodologies used to assess the load capacity or clinical survivability of root‐filled teeth and restorations. These methods include static loading, cyclic loading, finite element analysis and randomized clinical trials. In vitro research is valuable for preclinical screening of new dental materials or restorative modalities. It also can assist investigators or industry to decide whether further clinical trials are justified. It is important that these models present high precision and accuracy, be reproducible, and present adequate outcomes. Although in vitro models can reduce confounding by controlling important variables, the lack of clinical validation (accuracy) is a downside that has not been properly addressed. Most importantly, many in vitro studies did not explore the mechanisms of failure and their results are limited to rank different materials or treatment modalities according to the maximum load capacity. An extensive number of randomized clinical trials have also been published in the last years. These trials have provided valuable insight on the survivability of the root‐filled tooth answering numerous clinical questions. However, trials can also be affected by the selected outcome and by intrinsic and extrinsic biases. For example, selection bias, loss to follow‐up and confounding. In the clinical scenario, hypothesis‐based studies are preferred over observational and retrospective studies. It is recommended that hypothesis‐based studies minimize error and bias during the design phase.
Cross-Disorder Analysis of Shared Genetic Components Between Cortical Structures and Major Psychiatric Disorders.

BACKGROUND AND HYPOTHESIS Although large-scale neuroimaging studies have demonstrated similar patterns of structural brain abnormalities across major psychiatric disorders, the underlying genetic etiology behind these similar cross-disorder patterns is not well understood. STUDY DESIGN We quantified the extent of shared genetic components between cortical structures and major psychiatric disorders (CS-MPD) by using genome-wide association study (GWAS) summary statistics of 70 cortical structures (surface area and thickness of the whole cortex and 34 cortical regions) and five major psychiatric disorders, consisting of attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). Cross-disorder analyses were then conducted to estimate the degree of similarity in CS-MPD shared genetic components among these disorders. STUDY RESULTS The CS-MPD shared genetic components have medium-to-strong positive correlations in ADHD, BD, MDD, and SCZ (r = 0.415 to r = 0.806) while ASD was significantly correlated with ADHD, BD, and SCZ (r = 0.388 to r = 0.403). These pairwise correlations of CS-MPD shared genetic components among disorders were significantly associated with corresponding cross-disorder similarities in cortical structural abnormalities (r = 0.668), accounting for 44% variance. In addition, one latent shared factor consisted primarily of BD, MDD, and SCZ, explaining 62.47% of the total variance in CS-MPD shared genetic components of all disorders. CONCLUSIONS The current results bridge the gap between shared cross-disorder heritability and shared structural brain abnormalities in major psychiatric disorders, providing important implications for a shared genetic basis of cortical structures in these disorders.
Dying in times of COVID-19: Experiences in different care settings – An online questionnaire study among bereaved relatives (the CO-LIVE study)

Background: The COVID-19 pandemic and restricting measures have affected end-of-life care across different settings. Aim: To compare experiences of bereaved relatives with end-of-life care for a family member or friend who died at home, in a hospital, nursing home or hospice during the pandemic. Design: An open observational online survey was developed and disseminated via social media and public fora (March–July 2020). Data were analyzed using descriptive statistics and logistic regression analyses. Participants: Individuals who lost a family member or friend in the Netherlands during the COVID-19 pandemic. Results: The questionnaire was filled out by 393 bereaved relatives who lost a family member or friend at home (n = 68), in a hospital (n = 114), nursing home (n = 176) or hospice (n = 35). Bereaved relatives of patients who died in a hospital most often evaluated medical care (79%) as sufficient, whereas medical care (54.5%) was least often evaluated as sufficient in nursing homes. Emotional support for relatives was most often evaluated as sufficient at home (67.7%) and least often in nursing homes (40.3%). Sufficient emotional support for relatives was associated with a higher likelihood to rate the place of death as appropriate. Bereaved relatives of patients who died at a place other than home and whose care was restricted due to COVID-19 were less likely to evaluate the place of death as appropriate. Conclusion: End-of-life care during the COVID-19 pandemic was evaluated least favourably in nursing homes. The quality of emotional support for relatives and whether care was restricted or not were important for assessing the place of death as appropriate.
Validation of the Questionnaire on Sexual and Reproductive Health Literacy for Adolescents Age 15 to 19 Years in Lao People's Democratic Republic

Background: Beyond sexual and reproductive health (SRH) knowledge, it is sexual and reproductive health literacy (SRHL) that reflects the capacity to deal with sexuality. Many interventions have been conducted to increase SRH knowledge in adolescents, but SRHL has rarely been measured, and a well-validated tool is needed to measure it. Objective: This study aimed to validate a tool to measure adolescent SRHL. Methods: Reliability, validity, and cultural equivalence were investigated using data from expert consultations, cognitive interviews, and two-pilot studies. Then adaptation was made to the SRHL questionnaire for correct use among Southeast Asian adolescents in Lao and in wider groups. Key Results: The SRHL tool was comprised of 39 question items focusing on teenage pregnancy, contraception, and abortion. Conceptual, item, and semantic equivalence were all met. Interviewer-administrated mode was found to be optimal. Each question offers the answer choices very difficult, difficult, easy, and very easy, with a good to excellent Cronbach's alpha (0.8–0.9); there were no missing items and no floor/ceiling effects. Construct validity was high as 6 of 7 hypotheses were confirmed. Conclusion: Validation was completed with good cross-cultural validity. The tool was shown to be effective in determining the level of SRHL in adolescents in Laos and potentially in other countries with similar cultures. [HLRP: Health Literacy Research and Practice. 2022;6(1):e37–e50. ] Plain Language Summary: To find out how much adolescents know about sexual and reproductive health, an appropriate instrument of measurement is needed. Using different methods, we investigated the performance of a new tool, namely the SRHL questionnaire, which has 39 questions and should be used with an interviewer to assist in recording responses. This new tool could be used effectively to determine the level of literacy on sexual and reproductive health among adolescents.
CRISPR/Cas9-Mediated Insertion of HIV Long Terminal Repeat within BACH2 Promotes Expansion of T Regulatory–like Cells

One key barrier to curative therapies for HIV is the limited understanding of HIV persistence. HIV provirus integration sites (ISs) within BACH2 are common, and almost all sites mapped to date are located upstream of the start codon in the same transcriptional orientation as the gene. These unique features suggest the possibility of insertional mutagenesis at this location. Using CRISPR/Cas9-based homology-directed repair in primary human CD4+ T cells, we directly modeled the effects of HIV integration within BACH2. Integration of the HIV long terminal repeat (LTR) and major splice donor increased BACH2 mRNA and protein levels, altered gene expression, and promoted selective outgrowth of an activated, proliferative, and T regulatory–like cell population. In contrast, introduction of the HIV-LTR alone or an HIV-LTR-major splice donor construct into STAT5B, a second common HIV IS, had no functional impact. Thus, HIV LTR-driven BACH2 expression modulates T cell programming and leads to cellular outgrowth and unique phenotypic changes, findings that support a direct role for IS-dependent HIV-1 persistence. Key Points HIV integration frequently targets the intron preceding the first exon of BACH2. Gene editing was used to model the impact of integration in primary CD4+ T cells. BACH2 IS targeting led to selective expansion of a Treg–like population.
Neutralization against Omicron variant in transplant recipients after three doses of mRNA vaccine

The SARS‐CoV‐2 virus Omicron variant has now supplanted wild‐type virus as the dominant circulating strain globally. Three doses of mRNA COVID‐19 vaccine are recommended for transplant recipients as their primary vaccine series. However, the immunogenicity of mRNA vaccines as they specifically relate to the Omicron variant are not well studied. We analyzed Omicron‐specific neutralization in transplant recipients after three‐doses of mRNA‐1273 vaccine. Neutralization was determined using a SARS‐CoV‐2 spike pseudotyped lentivirus assay with constructs for Omicron and Delta variants. A total of 60 transplant patients (kidney, kidney‐pancreas, lung, heart, liver) were analyzed 1 month and 3 months after completion of three doses of mRNA‐1273. At 1 month, 11/60 (18.3%) patients had detectable neutralizing antibody responses to Omicron (log10ID50 of 2.38 [range 1.34–3.57]). At 3 months, 8/51 (15.7%) were positive (median log10ID50 [1.68; range 1.12–3.61; approximate fivefold reduction over time]). The proportion of positive patients was lower for Omicron versus wild‐type, and Omicron vs. Delta (p < .001). No demographic variables were found to be significantly associated with Omicron response. Many patients with a positive anti‐RBD response still had undetectable Omicron‐specific neutralizing antibody. In conclusion, three doses of mRNA vaccine results in poor neutralizing responses against the Omicron variant in transplant patients.