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Myc 9aaTAD activation domain binds to mediator of transcription with superior high affinity
No full textThe overexpression of MYC genes is frequently found in many human cancers, including adult and pediatric malignant brain tumors. Targeting MYC genes continues to be challenging due to their undruggable nature. Using our prediction algorithm, the nine-amino-acid activation domain (9aaTAD) has been identified in all four Yamanaka factors, including c-Myc. The predicted activation function was experimentally demonstrated for all these short peptides in transactivation assay. We generated a set of c-Myc constructs (1–108, 69–108 and 98–108) in the N-terminal regions and tested their ability to initiate transcription in one hybrid assay. The presence and absence of 9aaTAD (region 100–108) in the constructs strongly correlated with their activation functions (5-, 3- and 67-times respectively). Surprisingly, we observed co-activation function of the myc region 69–103, called here acetyl-TAD, previously described by Faiola et al. (Mol Cell Biol 25:10220–10234, 2005) and characterized in this study as a new domain collaborating with the 9aaTAD. We discovered strong interactions on a nanomolar scale between the Myc-9aaTAD activation domains and the KIX domain of CBP coactivator. We showed conservation of the 9aaTADs in the MYC family. In summary for the c-Myc oncogene, the acetyl-TAD and the 9aaTAD domains jointly mediated activation function. The c-Myc protein is largely intrinsically disordered and therefore difficult to target with small-molecule inhibitors. For the c-Myc driven tumors, the strong c-Myc interaction with the KIX domain represents a promising druggable target.</p
Physiological Assessment with iFR prior to FFR Measurement in Left Main Disease
No full textDespite guideline-based recommendation of the interchangeable use of instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR) to guide revascularization decision-making, iFR/FFR could demonstrate different physiological or clinical outcomes in some specific patient or lesion subsets. Therefore, we sought to investigate the impact of difference between iFR and FFR-guided revascularization decision-making on clinical outcomes in patients with left main disease (LMD). In this international multicenter registry of LMD with physiological interrogation, we identified 275 patients in whom physiological assessment was performed with both iFR/FFR. Major adverse cardiovascular event (MACE) was defined as a composite of death, non-fatal myocardial infarction, and ischemia-driven target lesion revascularization. The receiver-operating characteristic analysis was performed for both iFR/FFR to predict MACE in respective patients in whom revascularization was deferred and performed. In 153 patients of revascularization deferral, MACE occurred in 17.0% patients. The optimal cut-off values of iFR and FFR to predict MACE were 0.88 (specificity:0.74; sensitivity:0.65) and 0.76 (specificity:0.81; sensitivity:0.46), respectively. The area under the curve (AUC) was significantly higher for iFR than FFR (0.74; 95%CI 0.62–0.85 vs. 0.62; 95%CI 0.48–0.75; p = 0.012). In 122 patients of coronary revascularization, MACE occurred in 13.1% patients. The optimal cut-off values of iFR and FFR were 0.92 (specificity:0.93; sensitivity:0.25) and 0.81 (specificity:0.047; sensitivity:1.00), respectively. The AUCs were not significantly different between iFR and FFR (0.57; 95%CI 0.40–0.73 vs. 0.46; 95%CI 0.31–0.61; p = 0.43). While neither baseline iFR nor FFR was predictive of MACE in patients in whom revascularization was performed, iFR-guided deferral seemed to be safer than FFR-guided deferral. Graphical abstract Impact of Physiological Assessment with iFR and FFR on Clinical Outcomes of Patients with LMD. In the present study, physiological assessment, both with iFR and FFR, provided a high predictability of adverse cardiovascular event in LMD patients with revascularization deferral. Furthermore, the iFR-guided deferral strategy was safer as compared to FFR. Conversely, in patients in whom revascularization was performed for LMD, neither iFR nor FFR was predictive of cardiovascular event. AUC: area under the curve; FFR: fractional flow reserve; iFR: instantaneous wave-free ratio; LMD: left main coronary artery disease.</p
Herbal Medicine Associated Casualty And Fatality In South West Nigeria: A Retrospective Analysis
No full textIntroduction: Several studies have indicated that use of herbal medicines (HMs)in Nigeria and other parts of the world may harm human health. Contamination, adulteration, and the likely presence of toxic constituents in HMs have raised serious concerns regarding their safety. As a result, hospital records in Ekiti state, Nigeria, were analyzed to determine the extent to which HMs contribute to the number of hospital admissions (casualties) and deaths (fatalities) in the area.
Methods: A 5-year (2010 to 2014) retrospective analysis of patient data was carried out by examining HM-associated paediatric, adult medical, and obstetric casualty and fatality figures. The findings were then triangulated with available secondary data.
Results: During the studied period, out of 23,363 pediatric cases, 0.5% of casualties and 3.2% of fatalities were associated with HM use. Similarly, among 52,871 adult cases, 0.06% of casualties and 0.2% of fatalities were linked to HM use. Of the 668 obstetric stillbirth cases, 3.9% involved the use of HM. The highest number of casualties and fatalities were observed in male patients aged between 30 to 49 years, who were Christians and self-employed.
Conclusion: While the number of deaths associated with HM is relatively low, the possible complications that can arise from its use make it necessary to test and promote awareness of possible dangers of HM use to prevent hospitalizations and fatalities. Better awareness and documentation of patients' HM use by healthcare providers will help gain a better insight into their usage.</p
Optimizing intrauterine insemination: A systematic review and meta‐analysis of the effectiveness and safety of clinical treatment add‐ons
No full textIntroduction: Intrauterine insemination (IUI) is one of the most widespread fertility treatments. However, IUI protocols vary significantly amongst fertility clinics. Various add‐on interventions have been proposed to boost success rates. These are mostly chosen arbitrarily or empirically. The aim of this systematic review and meta‐analysis is to assess the effectiveness and safety of add‐on interventions to the standard IUI protocol and to provide evidence‐based recommendations on techniques used to optimize the clinical outcomes of IUI treatment.Material and MethodsSystematic review and meta‐analyses were performed in accordance with PRISMA guidelines. A computerized literature search was performed from database inception to May 2023. Randomized controlled trials (RCTs) were included reporting on couples/single women undergoing IUI with any protocol for any indication using partner's or donor sperm. A meta‐analysis based on random effects was performed for each outcome and add‐on. Three authors independently assessed the trials for quality and risk of bias and overall certainty of evidence. Uncertainties were resolved through consensus. Primary outcomes were ongoing pregnancy rate (OPR) or live birth rate (LBR) per cycle/per woman randomized. Registration number PROSPERO: CRD42022300857.ResultsSixty‐six RCTs were included in the analysis (16 305 participants across 20 countries). Vaginal progesterone as luteal phase support in stimulated cycles was found to significantly increase LBR/OPR (RR 1.37, 95% CI 1.09–1.72, I2 = 4.9%) (moderate/low certainty of the evidence). Endometrial scratch prior/during stimulated IUI cycles may increase LBR/OPR (RR 1.44, 95% CI 1.03–2.01, I2 = 1.8%), but evidence is very uncertain. Results from two studies suggest that follicular phase ovarian stimulation increases LBR/OPR (RR 1.39, 95% CI 1.00–1.94, I2 = 0%) (low certainty of evidence). No significant difference was seen for the primary outcome for the other studied interventions.ConclusionsThe findings of this systematic review and meta‐analysis suggest that vaginal luteal phase progesterone support probably improves LBR/OPR in stimulated IUI treatments. In view of moderate/low certainty of the evidence more research is needed for solid conclusions. Further research is also recommended for the use of endometrial scratch and ovarian stimulation. Future studies should report on results according to subfertility background as it is possible that different add‐ons could benefit specific patient groups.</p
Disparities in the prevalence of suicidal ideation according to oral contraceptive pill use among US women: a cross-sectional study
No full textBackground and Aims: The relationship between oral contraceptive pill (OCP) and suicidal ideation remains unclear. This study aims to estimate the prevalence of suicidal ideation among US women and evaluate their associates overall and according to OCP use status.Methods: Data from the National Health and Nutrition Examination Survey (NHANES) 2005−2012 were used to calculate the prevalence and associates of suicidal ideation in women using OCP. Suicidal ideation was assessed using the Patient Health Questionnaire‐9. Overall and OCP‐specific weighted prevalence of suicidal ideation were estimated. Multivariable logistic regressions were used to investigate overall and OCP‐specific associates.Results: The prevalence of suicidal ideation was 3.6% with no evident disparity between OCP groups, suggesting that OCP use is not associated with increased prevalence of suicidal ideation. Smoking was inversely associated with suicidal ideation in the former users of OCP. In the overall population, the prevalence of suicidal ideation was greater in those who were: Black or Hispanic, smoking, taking antidepressants, those with lower educational attainment, and women with low and middle income.Conclusion: Our findings suggest that OCP use was not associated with increased prevalence of suicidal ideation. Unique associates were identified among different OCP groups.</p
The reliability and validity of the Affinity Altitude hypoxic generators in acute and chronic conditions
No full textThis study investigated the reliability of the Affinity Altitude hypoxic generator within-day, between-day and between generator under acute and chronic hypoxic conditions. An additional objective was to assess the validity of the fraction of inspired oxygen (FiO2) values in relation to the claimed manufacture’s reference values to ensure the accuracy and safety of the product. Three altitude generators (Affinity Altitude Ltd., Sussex, UK) were assessed across all available settings during a test–retest design for equivalent FiO2 and output volume. This consisted of two phases: 1) acute exposure (10 min per setting) and 2) chronic exposure (8 h per setting). FiO2 and volume data were calculated from 1 min collection samples using the Douglas bag method for acute and chronic exposures. There were low variations in FiO2 data across all settings within the acute exposure for within-day (coefficient of variation [CV] range: 0.0–2.6%), between-day (0.2–1.3%), and between generator analysis (0.7–1.4%). This was similarly found for volume data within-day (0.1–3.7%), between-day (0.7–5.4%), and between-generator (1.2–3.0%). Equally, for chronic exposure trials, CV for FiO2 (<4.0%) and volume (<5.0%) across each of the generators presented low variations. The FiO2 values were similar to reference values, however, significant differences were found for settings 4 (−0.3% [17.6% vs. 17.9% reference value]) and 5 (−0.1% [15.8% vs. 15.9% reference value], both p<0.05). A ‘good’ level of reliability (CV<5%) and validity were found within and between the Affinity Altitude’s generators. However, a review of the reference values is warranted, and long-term experimental studies are required to determine the efficacy of this device for the purpose of physiological adaptations.</p
The influence of ethnicity on assessments and academic progression in a midwifery degree
No full textBackground/Aims Midwifery degrees require students to study for 3 years, during which they are assessed both academically and in practice placements. This study's aim was to explore year-by-year associations between assessment grades and students' ethnicity as they progressed through their degree. Methods Retrospective data collected at a single university in the UK were analysed using descriptive statistics. The cohort and variables were stratified by student ethnicity, year of study and assessment grades given for academic work and placement practice assessments. Results While Black, Asian and minority ethnic students started with lower practice assessment grades in year 1, this improved such that there was no difference in attainment by year 3. In contrast, university academic grades were consistently lower for Black, Asian and minority ethnic versus White students, and this pattern did not change throughout the degree programme. Conclusions The likely factor in lower final degree outcomes among Black, Asian and minority ethnic students is not from practice assessments but academic performance. Targeted interventions that recognise different learning styles and educational experiences in the university environment may address and improve this inequality in attainment.</p
Response to: "ChatGPT for assessment writing".
No full textResponse to: “ChatGPT for assessment writing”." Medical Teacher, ahead-of-print(ahead-of-print), p. 1 </p
Architectural Materials between Rural and Urban Models of Settlement Principles in the Urban Transformation
No full textThe article focuses on the relationship between urban and rural in architectural transformations. It demonstrates through an analytical process the transposition of the characteristics of rural architecture into urban expansions.</p
Vernacular Architecture Facing a Degrowth Scenario
No full textThe present work explores the possibilities of vernacular architecture in the search for a new construction model that contributes to addressing some of the crises facing civilization, such as the climate crisis, the demographic crisis, and the resource crisis</p
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