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The drugs activity at the target tissue could help to define the minimal effective dose to promote cancer preventive therapy. Here we present exemestane and sex hormone concentrations within breast tissue from a presurgical study of alternative exemestane schedules. Postmenopausal women candidates for breast surgery for estrogen receptor-positive breast cancer were randomly assigned to exemestane 25 mg once daily (QD), 25 mg 3 times/week (TIW), or 25 mg per week (QW) for 4-6 weeks before surgery. Drug and sex hormones were analyzed from homogenized frozen tissue using a QTRAP 6500+ LC-MS/MS System. Tissue drug concentrations were detectable only in the QD arm with higher concentrations in nonmalignant tissue. Estradiol was nearly suppressed in all groups in the nonmalignant tissue (QD vs TIW P = .364 and QD vs QW P = .693). In contrast, a dose-response trend was observed in cancer tissue. Based on estradiol suppression in nonmalignant tissue, lower exemestane schedules should be explored for breast cancer preventive therapy. Trial Registration: Clinical Trials.gov NCT02598557 and EudraCT 2015-005063-1.

Abstract Research suggests that nature promotes psychological and behavioral health among children. However, children living in low-income urban communities often have less access to green spaces compared to their counterparts living in high-income neighborhoods, and limited research has investigated the impact of nature on well-being and social connectedness in children experiencing marginalization. To address this gap, this mixed-methods study examined the impact of a one-week immersive nature camp on the well-being and social connectedness of 27 children aged 6–12 years referred to a community hub in Ottawa, Canada, for complex psychosocial difficulties. One week prior to and one week after the camp, caregivers completed a survey inquiring about their child’s personal well-being, social contact, loneliness, positive emotional state, and positive outlook. On the first and last days of the camp, children completed the same survey. Children also engaged in an audio-recorded focus group about their experience in the camp to inform the quantitative findings. Quantitative and qualitative responses were analyzed using paired samples t-tests and thematic analysis, respectively. Although not statistically significant, small to medium effect sizes for improved positive emotional state and positive outlook were reported by children (p =.26, d = 0.24; p =.14, d = 0.31) and their caregivers (p =.12, d = 0.37; p =.89, d = 0.03). Qualitative thematic analyses of focus groups revealed nine themes including making friends, acquiring new skills, and connecting with nature. Within the Canadian child health context, exposure to green spaces for children with complex psychological difficulties living in low-income urban communities may be associated with perceived enhancements in social connections and skills. Future research with larger sample sizes is needed.

Abstract Background In conjunction with other antiviral medicines, sofosbuvir (SOF) is an essential therapy for chronic hepatitis C. There is some debate over its influence on hepatic fibrosis. The use of nanotechnology in treatment has gained popularity, with the goal of delivering therapeutic substances to the liver to increase efficacy and decrease adverse effects. The aim of this study was to demonstrate the protective effect of sofosbuvir and the efficacy of incorporating nanoparticle galactosylated taurocholate bilosomal formula to SOF on thioacetamide-induced liver fibrosis. Methods Rats were divided into 7 groups: normal control, SOF, SOF encapsulated in galactosylated taurocholate bilosomal formula (nano-SOF), galactosylated taurocholate bilosomal formula (nanoparticle), thioacetamide (TAA), TAA-SOF and TAA-nano-SOF. Liver fibrosis was induced by TAA (200 mg/kg) intraperitoneal injection twice per week for 8 weeks. SOF, nanoparticle and nano-SOF were given (40 mg/Kg/day) orally from day one of the study. Serum activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and tissue transforming growth factor beta (TGF-β) were assessed. Also, histopathological assessment of hepatic tissue was done. Results Administration of SOF and TAA to normal rats resulted in significant increase in serum AST, ALT, ALP and tissue TGF-β1 levels with variable degree of liver fibrosis. Additionally, rats in TAA group that received SOF therapy did not exhibit improved liver functions, TGF-β1 level and liver fibrosis score. However, administering nano-sofosbuvir prophylactically to TAA-treated rats resulted in a considerable improvement in liver function tests, TGF-1 levels, with liver fibrosis score regression. Conclusion In contrast to free sofosbuvir, SOF encapsulated in galactosylated taurocholate bilosomal formula (nano-SOF) displayed hepatoprotective effects in rat with thioacetamide-induced hepatic fibrosis. These findings strongly support the concept that galactoylatedbilosomes are promising nanocarrier for the targeted delivery of sofosbuvir to the liver.

In a 3-arm presurgical trial, four-six weeks exemestane 25 mg three times/week (TIW) was non-inferior to 25 mg/day (QD) in suppressing circulating estradiol in postmenopausal women with ER-positive breast cancer. Since obesity may decrease exemestane efficacy, we analyzed changes in sex steroids, adipokines, Ki-67, and drug levels in relation to obesity. Postmenopausal women with early-stage ER-positive breast cancer were randomized to either exemestane 25 mg QD (n = 57), 25 mg TIW (n = 57), or 25 mg/week (QW, n = 62) for 4-6 weeks before breast surgery. Serum and tissue pre- and post-treatment biomarkers were stratified by body mass index (BMI)< or ≥30 kg/m2. Post-treatment median exemestane and 17-OH exemestane levels were 5-6 times higher in the QD arm compared to the TIW arm. For obese women, TIW maintained comparable reductions to QD in systemic estradiol levels, although the reduction in estrone was less with the TIW regimen. There was less suppression of SHBG with the TIW versus the QD dose schedule in obese women which should result in less systemic bioavailable estrogens. Metabolically, the effect of the TIW regimen was similar to the QD regimen for obese women in terms of leptin suppression and increase in the adiponectin-leptin ratio. Reduction in tissue Ki-67 was less for obese women on the TIW regimen than QD, although changes were similar for non-obese women. Our findings suggest that TIW exemestane should be explored further for primary cancer prevention in both normal weight and obese cohorts.

PURPOSE: To guide clinicians and policymakers in three global resource-constrained settings on treating patients with metastatic breast cancer (MBC) when Maximal setting-guideline recommended treatment is unavailable. METHODS: A multidisciplinary, multinational panel reviewed existing ASCO guidelines and conducted modified ADAPTE and formal consensus processes. RESULTS: Four published resource-agnostic guidelines were adapted for resource-constrained settings; informing two rounds of formal consensus; recommendations received ≥75% agreement. RECOMMENDATIONS: Clinicians should recommend treatment according to menopausal status, pathological and biomarker features when quality results are available. In first-line, for hormone receptor (HR)-positive MBC, when a non-steroidal aromatase inhibitor and CDK 4/6 inhibitor combination is unavailable, use hormonal therapy alone. For life-threatening disease, use single-agent chemotherapy or surgery for local control. For premenopausal patients, use ovarian suppression or ablation plus hormone therapy in Basic settings. For human epidermal growth factor receptor 2 (HER2)-positive MBC, if trastuzumab, pertuzumab, and chemotherapy are unavailable, use trastuzumab and chemotherapy; if unavailable, use chemotherapy. For HER2-positive, HR-positive MBC, use standard first-line therapy, or endocrine therapy if contraindications. For triple-negative MBC with unknown PD-L1 status, or if PD-L1-positive and immunotherapy unavailable, use single-agent chemotherapy. For germline BRCA1/2 mutation-positive MBC, if poly(ADP-ribose) polymerase inhibitor is unavailable, use hormonal therapy (HR-positive MBC) and chemotherapy (HR-negative MBC). In second-line, for HR-positive MBC, Enhanced setting recommendations depend on prior treatment; for Limited, use tamoxifen or chemotherapy. For HER2-positive MBC, if trastuzumab deruxtecan is unavailable, use trastuzumab emtansine; if unavailable, capecitabine and lapatinib; if unavailable, trastuzumab and/or chemotherapy (hormonal therapy alone for HR-positive MBC).Additional information is available at www.asco.org/resource-stratified-guidelines. It is ASCOs view that healthcare providers and system decision-makers should be guided by the recommendations for the highest stratum of resources available. The guideline is intended to complement but not replace local guidelines.

Abstract Background As the healthcare field is undergoing a paradigm shift, the role of interprofessional education (IPE) is being widely accepted and recognized. Despite this, IPE interventions are not employed globally and the use of such interventions is variable. Additionally, there is an ongoing debate over how and when to employ IPE interventions. This qualitative study was conducted at Royal College of Surgeons in Ireland – Bahrain (RCSI Bahrain) to understand medical and nursing students’ attitudes, expectations, perspectives and experiences in relation to IPE. Methods Medical and nursing students from all cycles and levels of the medical and nursing programs at RCSI Bahrain participated in Focus Group Discussions (FGDs) and interviews where they discussed issues and opinions related to IPE. These discussions were then transcribed for analysis. Thematic analysis of the data using a grounded theory approach was carried out using a four-staged process of reading transcripts, identifying possible themes and structures and building theory. Results 16 elected class representatives participated in the study. The comprehensive process of thematic analysis led to the emergence of five themes and associated subthemes: integrated curriculum (realistic interventions, idealistic interventions, varied perspectives), role recognition (communication, task division), understanding of team dynamics (harmonious collaboration, amplification of strengths, team management), cultural practices (organizational culture, interpersonal culture), and social conditioning (identity navigation, stereotype persistence, varied mindsets). The sequential relationship between these themes provides an approach for integrated IPE in healthcare curricula. Conclusion This qualitative study investigated medical and nursing students’ perspectives on IPE at RCSI Bahrain. The identified themes provide a valuable framework for policymakers and medical educators to design and implement effective IPE interventions, thereby enhancing interprofessional collaboration and improving patient outcomes in healthcare settings.

Abstract Among the various classes of fast-adapting (FA) tactile afferents found in hairy and glabrous skin, FA2 afferents, associated with Pacinian corpuscles (PC), preferentially signal high-frequency sinusoidal events corresponding with vibration percepts, in contrast to other classes associated with lower frequency flutter percepts. The FA2-PC complex is also uniquely sensitive to distant sources of vibration mechanically transmitted through anatomical structures. In the present study, we used a pulsatile waveform to assess the contribution of FA2 afferents to the perception of flutter-range frequency stimuli (~ 20 Hz) in combination with two methods to abolish local FA inputs and force a dependence on FA2 via transmission from adjacent structures. Firstly, we examined frequency discrimination and perception of vibration applied to the hairy skin overlying the ulnar styloid before and during the blockade of intradermal receptors by local anaesthesia. Secondly, we tested frequency discrimination on the digital glabrous skin before and during the blockade of myelinated fibres by ulnar nerve compression. Despite reliance on vibration transmission to activate remote PCs, we found that flutter-range frequency discrimination was unimpeded across both skin types. Comparisons with stimuli applied to the contralateral side also indicated that perceived frequency was unaffected. This confirms that flutter-range frequency perception can be encoded by the FA2-PC system. Our results demonstrate that input from receptors specialised for low-frequency signalling is not mandatory for flutter-range frequency perception. This explains how the constancy of frequency perception might be achieved across different skin regions, irrespective of the afferent type activated for transmitting these signals.

Cranial retained surgical sponges, known as “gossypiboma” or “textiloma”, represent a rare but potentially severe complication following surgical procedures. While it is infrequent, it poses a significant risk, particularly in delicate surgical settings such as neurosurgery. The inadvertent retention of cotton balls or surgical gauzes may cause localized inflammation, infection, abscess, or neurologic sequelae.In the realm of neurosurgery, where precision is paramount, the occurrence of postoperative brain gossypibomas is particularly concerning.This case report contributes to the radiological literature by presenting a distinctive instance of postoperative brain gossypiboma. By delving into the radiological intricacies and potential contributing factors to the retention of surgical materials in neurosurgical procedures, our aim is to underscore the significance of a collaborative approach between neurosurgeons and radiologists for enhanced detection and prevention of such complication.

Abstract A straightforward and sensitive spectrofluorimetric approach was established for the determination of heptaminol hydrochloride (HTM-HCl) based on the derivatization of the drug through its reaction with 5-dimethylaminonaphthalene-1-sulfonyl chloride (Dansyl chloride). The reagent underwent a nucleophilic substitution of its chlorine atom with HTM to give N-(5-dimethylaminonaphthalene-1-sulfonyl)-6-amino-2-methylheptan-2-ol. The highly luminescent derivative was extracted using methylene chloride and subjected to analysis at an excitation wavelength of 345 nm and an emission wavelength of 490 nm. The chemical reaction occurred within an aqueous environment buffered with a 0.1 M borate buffer solution adjusted to pH 10.5. Experimental findings indicate that the proposed method displays sensitivity and linearity across a concentration range from 0.03 to 2 µg mL− 1. The method achieves lower detection and quantification limits of 0.016 and 0.048 µg mL− 1, respectively. The analytical validation of this method followed the guidelines outlined by the International Council of Harmonization (ICH). This approach was applied effectively for quantifying the medication in both tablet and oral drops formulations available on the market, demonstrating excellent recovery of 98.95 ± 0.45 for tablets and 99.37 ± 0.24 for oral drops with no interference from excipients.

One of the hallmarks of Alzheimer’s disease (AD) is the deposition of amyloid-β (Aβ) within the extracellular spaces of the brain as plaques and along the blood vessels in the brain, a condition also known as cerebral amyloid angiopathy (CAA). Clusterin (CLU), or apolipoprotein J (APOJ), is a multifunctional glycoprotein that has a role in many physiological and neurological conditions, including AD. The apolipoprotein E (APOE) is a significant genetic factor in AD, and while the primary physiological role of APOE in the brain and peripheral tissues is to regulate lipid transport, it also participates in various other biological processes, having three basic human forms: APOE2, APOE3, and APOE4. Notably, the APOE4 allele substantially increases the risk of developing late-onset AD. The main purpose of this review is to examine the roles of CLU and APOE in AD pathogenesis in order to acquire a better understanding of AD pathogenesis from which to develop targeted therapeutic approaches.

Abstract Background Radiotherapy is a treatment modality used for head and neck cancer patients. It has a negative influence on bonding strength of adhesives. Little information is available about the effect of radiotherapy on bonding strength of adhesives in primary teeth. Therefore, this in vitro study aimed to detect the best adhesive system and ideal time to apply restorations in primary irradiated teeth regarding adhesive shear bond strength. Methods Dentin samples from primary teeth were randomly assigned to four groups based on restoration application time and radiation exposure, (G1: control, G2: preradiation, G3: 24 h postradiation, and G4: 6 months postradiation) with 20 samples per group. These groups were further divided into 2 subgroups according to the adhesive system used, with 10 samples per subgroup. (1) 3M™ Single Bond Universal Adhesive (SB), (2) 3M AdperSingle Bond 2 (AS). Samples were exposed to gamma radiation from a cobalt-60 machine. One shot of 60 Gy of radiation was delivered. Then samples were subjected to a shear bond strength test. The load was applied until failure and the maximum load was recorded. Numerical data are presented as mean and standard deviation values, then distributed according to Shapiro–Wilk test or Levene's test and analyzed via two-way ANOVA. The significance level was set at p 0.001). However, there was a significant difference between G1, G2, and G3 (p

Smallholder farmers are critical to global food production and natural resource management. Due to increased competition for water resources and variability in rainfall due to climate change, chronic irrigation water scarcity is rising particularly in drought-prone regions. Improving the awareness of climatic risk to yields and incomes is critical to sustainable agricultural intensification. However, adopting a new technology represents a certain level of risk for the farmers, who invest time and economic resources in changing their practices. We have developed a mobile application, currently for cotton, that would allow farmers to actualize the risk of growing cotton. By implementing a sociohydrological dynamic model with a kernel principal component analysis structural error model, the software provides a risk forecast of the yield and profit the user can expect at the end of the season. The mobile app not only processes social and agricultural information provided by the user but also retrieves and continually updates climate datasets from the web, as well as market prices. The users can request the execution of the sociohydrological model to the servers from their own mobile devices. By following an agile methodology, the mobile app has been tested with ∼100 farmers in order to get feedback from real users; this brought the opportunity to redesign the functionality based on the correct understanding of information and, a fast and clear management of the tool and helping in the adoption of the technology. This was combined with existing knowledge around communicating risk by using multiple modes of communication - text, graphics, sound and video - all of which were implemented to reinforce the knowledge communicated and ensure sufficient redundancy. This turned out to be beneficial for farmers with low prior knowledge and higher acceptability of the mobile app by the users as evidenced through feedback rounds with them. This study exemplifies an approach to address the gap in communicating risks in agriculture using a user-friendly mobile application.

The present study investigates EFL educators’ perceptions and experiences in teaching EFL writing skills in large classes, focusing on the problems they face and the techniques they use to minimize these issues and achieve course objectives. Many studies hitherto have investigated the difficulties EFL teachers face in teaching writing in large – sized classes, and they have concluded that for better communication and more individual attention to be given to students, more time and effort are needed. However, this study aims to propose diverse effective, collaborative teaching methods and strategies to upgrade the students' writing skills in large classes. The study adopts a descriptive methodology to analyze a questionnaire of 17 items on a five-point Likert-type scale given to 64 faculty members. The questionnaire includes 17 questions, 14 questions on the challenges faced by teachers and suggested strategies and the last 3 questions on the role of technology in facilitating teaching writing in large classes. The electronic questionnaire was prepared using Google forms, and the data collected was analyzed using Microsoft Excel. The main finding of the study was that the challenges faced by teachers in teaching writing in large classes can be minimized by effective teaching techniques such as collaborative learning, giving personalized feedback, engaging students in pair and group work, and utilizing technology – enhanced teaching and learning methods to facilitate the writing tasks and activities. The study provides practical insights for EFL educators to effectively implement these strategies. Additionally, it encourages further research in this area to enhance pedagogical practices and support EFL teachers in overcoming these common obstacles.