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Background The increased risk of fractures associated with aromatase inhibitors (AIs) therapy has been well established in clinical trials; however, data on Asian populations remain limited. Furthermore, the impact of AIs on fracture risk across different age groups and breast cancer stages has not been thoroughly investigated. This study aimed to assess the association between AIs therapy and major osteoporotic fractures (MOFs) in postmenopausal Taiwanese women with breast cancer using real-world data. Methods We used Taiwan’s National Health Insurance and Cancer Registry databases to identify women aged  ≥  50 years with newly diagnosed breast cancer who received continuous AIs ( N  = 1,835) or tamoxifen (TAM) ( N  = 1,868) treatment. MOFs requiring hospitalization were tracked through 2019. The mean follow-up duration was 47.49 months (SD = 29.73) for the AIs group and 72.49 months (SD = 37.22) for the TAM group. Cox regression analysis was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). MOFs incidence in AIs users compared to TAM users, with secondary outcomes including fractures of the spine, hip, humerus, and forearm. Results AIs users had a higher incidence of MOFs than TAM users. After adjustment, AIs therapy significantly increased forearm fracture risk [adjusted hazard ratios (aHR) = 2.16, 95% CI = 1.24–3.76)]. In age-stratified analyses, women aged 50–65 years had a notably higher risk of hip fractures (aHR = 5.65, 95% CI: 1.55–20.68) and forearm fractures (aHR = 3.14, 95% CI: 1.55–6.36) compared with TAM users, while no significant difference was observed in women over 65 years. Among early-stage (0–1) patients, AIs use was associated with a higher risk of hip fractures (aHR = 3.14, 95% CI: 1.10–8.97). In later-stage (2–3) patients, AIs use was linked to a higher risk of forearm fractures (aHR = 2.41, 95% CI: 1.11–5.20). Additionally, even among low-risk groups, AIs users had a significantly higher fracture risk than TAM users ( p  = 0.040). Conclusion AIs therapy significantly increased the risk of hip and forearm fractures compared to TAM, particularly in women aged 50–65 years and in specific cancer stages. Regular bone mineral density monitoring and personalized bone-protective strategies are recommended.

PurposeChemotherapy-induced nausea and vomiting (CINV) commonly occurs after chemotherapy, adversely affecting patients’ quality of life. Recently, studies have shown inconsistent antiemetic effects of two common 5-hydroxytryptamine 3 receptor antagonists, namely, palonosetron and granisetron. Therefore, we conducted a meta-analysis to evaluate the effectiveness of palonosetron versus granisetron in preventing CINV.MethodsRelevant studies were obtained from PubMed, Embase, and Cochrane databases. The primary outcome was the complete response (CR) rate. Secondary outcomes were headache and constipation events.ResultsIn total, 12 randomized controlled trials and five retrospective studies were reviewed. Palonosetron was consistently statistically superior to granisetron in all phases in terms of the CR rate (acute phases: odds ratio [OR] = 1.28, 95% confidence interval [CI] = 1.06–1.54; delayed phases: OR = 1.38, 95% CI = 1.13–1.69; and overall phases: OR = 1.37, 95% CI = 1.17–1.60). Moreover, a non-significant difference was found between the two groups in terms of the headache event, but the occurrence of the constipation event was lower in the granisetron group than in the palonosetron group.ConclusionPalonosetron showed a higher protective efficacy in all phases of CINV prevention, especially in delayed phases, and no relatively severe adverse effects were observed.

Inflammation have been linked to bone diseases such as osteoporosis or bone destruction. However, whether M1 inflammatory stimuli exert a stimulatory or inhibitory effect on the differentiation of osteoclasts remained controversial. Also, how inflammatory milieu influence cell proliferation and survival during osteoclastogenesis have not been determined. Here we reported the molecular repertoire alterations of RANKL-stimulated osteoclastogenesis from RAW264.7 at different stages in the inflammatory environments. Adding conditioned medium collected from LPS-stimulated macrophage, which are the primary source of extracellular inflammatory mediators, resulted in a biphasic change in cell number among differentiating preosteoclasts. The inflammatory milieu induced a transient proliferation of preosteoclasts during the initial 48 h, which was followed by a significant decline in cell numbers from the fourth day onwards. Proliferation-related AKT and ERK were transiently activated in the inflammatory environments, which also upregulated the expressions of c-myc , a major transcription factor for osteoclast differentiation, and pro-inflammatory genes, such as Tnf-a and Nos2 . Following prolonged exposure to an inflammatory environment, undifferentiated osteoclast precursors undergo apoptosis. Our findings suggest that short-term inflammatory exposure transiently promotes the proliferation and differentiation of preosteoclasts, whereas long-term exposure leads to apoptosis, potentially due to the enhancement of inflammatory signals.

Background Availability of next generation sequencing data, allows low-frequency and rare variants to be studied through strategies other than the commonly used genome-wide association studies (GWAS). Rare variants are important keys towards explaining the heritability for complex diseases that remains to be explained by common variants due to their low effect sizes. However, analysis strategies struggle to keep up with the huge amount of data at disposal therefore creating a bottleneck. This study describes CLIN_SKAT, an R package, that provides users with an easily implemented analysis pipeline with the goal of (i) extracting clinically relevant variants (both rare and common), followed by (ii) gene-based association analysis by grouping the selected variants. Results CLIN_SKAT offers four simple functions that can be used to obtain clinically relevant variants, map them to genes or gene sets, calculate weights from global healthy populations and conduct weighted case–control analysis. CLIN_SKAT introduces improvements by adding certain pre-analysis steps and customizable features to make the SKAT results clinically more meaningful. Moreover, it offers several plot functions that can be availed towards obtaining visualizations for interpretation of the analyses results. CLIN_SKAT is available on Windows/Linux/MacOS and is operative for R version 4.0.4 or later. It can be freely downloaded from https://github.com/ShihChingYu/CLIN_SKAT , installed through devtools::install_github(\"ShihChingYu/CLIN_SKAT\", force=T) and executed by loading the package into R using library(CLIN_SKAT). All outputs (tabular and graphical) can be downloaded in simple, publishable formats. Conclusions Statistical association analysis is often underpowered due to low sample sizes and high numbers of variants to be tested, limiting detection of causal ones. Therefore, retaining a subset of variants that are biologically meaningful seems to be a more effective strategy for identifying explainable associations while reducing the degrees of freedom. CLIN_SKAT offers users a one-stop R package that identifies disease risk variants with improved power via a series of tailor-made procedures that allows dimension reduction, by retaining functionally relevant variants, and incorporating ethnicity based priors. Furthermore, it also eliminates the requirement for high computational resources and bioinformatics expertise.

Background Empathy is an important factor in the doctor-patient relationship, but mental illness is more difficult to understand than other diseases. Besides traditional skills, virtual reality (VR) has been identified as a promising tool in empathy education. This study aimed to investigate the ability of empathy enhancement, the feasibility of depression education, and the changes in thoughts and attitudes in medical students through a single VR experience. Methods We recruited medical students and randomly assigned them to two groups based on their completed Interpersonal Response Index scores. Two sets of VR systems were provided; the intervention group experienced the daily life of the depressed medical student, while the control group experienced the general medical student scenario. The improvement of empathy was assessed using the Jefferson Scale of Empathy-Health Professional Students (JSE-HPS), and the change of attitude was assessed through the Implicit Association Test. In addition, other questionnaires were used to evaluate the user experience of this VR system, and correlation analysis was conducted to examine the association between the use of VR and changes in the JSE and IAT scores. Results A total of 59 medical students were enrolled in this study. The intervention group showed a significant increase in the perspective-taking (pre: mean 5.817, SD 0.536; post: mean 5.947, SD 0.620; P  = .03) and compassionate care (pre: mean 5.546, SD 0.581; post: mean 5.721, SD 0.629; P  = .01) domains of the JSE score and a significant decrease in the standing in the patient’s shoes (SP) domain (pre: mean 3.583, SD 1.253; post: mean 2.967, SD 1.252; P  = .002). The Pearson correlation analysis found a significant positive correlation between the JSE score with immersion aspect ( r  = .308, P  = .049) and presence aspect ( r  = .415, P  = .01), and we also found a significant negative correlation between the IAT score and presence aspect ( r =-.333, P  = .04). Conclusions This study is the first randomized case-control study to investigate the effect of two different versions of VR on empathy development toward depression for medical students. Although the single VR experience was unable to induce a great improvement in empathy or attitude, the VR system could help medical students enhance their understanding of depressive disorders. Trial registration This trial was retrospectively registered in the Australian New Zealand Clinical Trials Registry (ANZCTR) (21/03/2024, ACTRN12624000297527). https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=386683&isReview=true .

Background Coexistence of a catecholamine-secreting tumor and an adrenal cortical tumor is quite rare which makes both diagnosis and management challenging. The purpose of this article is to describe the presence of this condition, share a stepwise approach for preoperative evaluation, and review the related literature. Case presentation A 44-year-old male patient had a history of hypertension and aggravating hypokalemia for years. Abdominal computed tomography incidentally found concomitant bilateral adrenal and left para-aortic tumors. Comprehensive adrenal hormone tests revealed a high aldosterone renin ratio and mildly elevated 24-h urine vanillylmandelic acid and norepinephrine levels. Subsequently, a metaiodobenzylguanidine scan showed uptake over the left para-aortic tumor, and NP-59 adrenal scintigraphy showed uptake over the left adrenal tumor. Further confirmatory tests, including captopril suppression, irbesartan suppression, and saline infusion, all confirmed the diagnosis of hyperaldosteronism. Adrenal venous sampling following 2 months of preparation with an alpha blocker demonstrated a left aldosterone-producing adrenal adenoma. Combining hormonal analysis, imaging studies, and adrenal venous sampling, the patient was diagnosed with left adrenal aldosteronoma, right adrenal nonfunctional tumor, and left para-aortic paraganglioma (PGL). Accordingly, laparoscopic left adrenalectomy and left PGL excision were performed smoothly under alpha blocker maintenance. The pathology report confirmed left adrenal cortical adenoma and left para-aortic PGL. Postoperatively, the blood pressure, biochemical tests, and adrenal hormone assays returned to normal, and related symptoms disappeared and were relatively stable during the follow-up period of two years. Conclusions This is the first case of left para-aortic PGL coexisting with an ipsilateral aldosterone-producing adenoma presenting as a left para-aortic tumor associated with bilateral adrenal tumors. Awareness of the rarity of this coexistence can avoid unexpected disasters during the process of evaluation and management.

The reducing and capping sites along with their local structure impact photo properties of the red bovine serum albumin-capped Au nanocluster (BSA-AuNC), however, they are hard to identify. We developped a workflow and relevant techniques using mass spectrometry (MS) to identify the reducing and capping sites of BSA-AuNCs involved in their formation and fluorescence. Digestion without disulfide cleavages yielded an Au core fraction exhibiting red fluorescence and [AunSm] ion signals and a non-core fraction exhibiting neither of them. The core fraction was identified to mainly be comprised of peptides containing cysteine residues. The fluorescence and [AunSm] signals were quenched by tris(2-carboxyethyl)phosphine, confirming that disulfide groups were required for nanocluster stabilization and fluorescence. By MS sequencing, the disulfide pairs, C75–C91/C90–C101 in domain IA, C315–C360/C359–C368 in domain IIB, and C513–C558/C557–C566 in domain IIIB, were identified to be main capping sites of red AuNCs. Peptides containing oxidized cysteines (sulfinic or cysteic acid) were identified as reducing sites mainly in the non-core fraction, suggesting that disulfide cleavages by oxidization and conformational changes contributed to the subsequent growth of nanoclusters at nearby intact disulfide pairs. This is the first report on precise identification of the reducing and capping sites of BSA-AuNCs.

Cross-strand interactions are important for the stability of β-sheet structures. Accordingly, cross-strand diagonal interactions between glutamate and arginine analogs with varying side-chain lengths were studied in a series of β-hairpin peptides. The peptides were analyzed by homonuclear two-dimensional nuclear magnetic resonance methods. The fraction folded population and folding free energy of the peptides were derived from the chemical shift data. The fraction folded population trends could be rationalized using the strand propensity of the constituting residues, which was not the case for the peptides with lysine analogs, highlighting the difference between the arginine analogs and lysine analogs. Double-mutant cycle analysis was used to derive the diagonal ion-pairing interaction energetics. The most stabilizing diagonal cross-strand interaction was between the shortest residues (i.e., Asp2–Agp9), most likely due to the least side-chain conformational penalty for ion-pair formation. The diagonal interaction energetics in this study involving the arginine analogs appears to be consistent with and extend beyond our understanding of diagonal ion-pairing interactions involving lysine analogs. The results should be useful for designing β-strand-containing molecules to affect biological processes such as amyloid formation and protein-protein interactions.

Introduction Intraoperative radiotherapy (IORT) is more convenient than standard whole breast external beam radiotherapy (EBRT) as a sole adjuvant radiotherapy for breast cancer. The impact of age on breast cancer course and treatment strategy is still under investigation, and the peak age for breast cancer in Taiwan is much younger than that in Western countries. We aimed to review the oncological outcomes of sole IORT compared with standard EBRT in a country with younger breast cancer patients. Patients and methods We reviewed patients with invasive breast cancer who received breast-conserving surgery (BCS) from September 2014 to December 2016. The clinicopathologic characteristics and oncological outcomes of eligible patients who received EBRT or IORT as sole adjuvant radiotherapy after BCS were collected and reviewed. Results A total of 170 patients were enrolled with a mean follow-up time of 3.53 ± 0.82 years. The risk of locoregional recurrence was 2.44% for EBRT versus 10.64% for IORT ( p  = 0.024). IORT was a significant risk factor of locoregional recurrence ( p  = 0.005). The hazard ratios (HRs) for locoregional recurrence in the IORT group compared with the EBRT group were significantly higher in non-suitable risk group patients (HR = 7.02, p  = 0.009) and in patients under 50 years old (HR = 10.42, p  = 0.011). Conclusions Locoregional recurrence was significantly higher in patients who received IORT than in those who underwent EBRT. IORT should not be used alone in patients under 50 years old who do not belong to a suitable group.

The growing demand for plastic products has led to an increase in human exposure to microplastics (MPs). MPs have been shown to have detrimental effects on reproductive function, while probiotics have demonstrated promise in enhancing fertility. This study aimed to determine the protective effects of Lactobacillus brevis GKJOY against reproductive damage induced by polystyrene microplastics (PS-MPs) in male rats. In the cell study, LC540 cells were treated with L. brevis GKJOY postbiotic (PGK), gamma-aminobutyric acid (GABA), and PS-MPs to evaluate their effects on cell viability and reactive oxygen species (ROS) production. In the animal experiment, rats were treated with a low dose of L. brevis GKJOY (GK1X, 50 mg/kg), a medium dose (GK2X, 100 mg/kg), or a high dose (GK4X, 200 mg/kg). The results showed that PGK and GABA reduced the levels of ROS and protected against oxidative stress. In contrast, PS-MPs increased ROS levels and had harmful effects on cell viability. In the animal study, testicular injuries caused by PS-MPs led to disruption of the hypothalamic–pituitary–gonadal (HPG) axis and a decrease in reproductive hormone levels. However, treatment with L. brevis GKJOY reduced oxidative stress and pro-inflammatory cytokine levels, restored hormonal imbalances, and led to significant improvements. L. brevis GKJOY effectively mitigated reproductive damage in male rats due to its dual function as a probiotic and neurotransmitter modulator. In conclusion, L. brevis GKJOY, which functions as both a probiotic and a GABA producer, may offer superior protection against male reproductive damage.