Background: and Purpose In the ESCAPE-NA1 (Efficacy and Safety of Nerinetide for the Treatment of Acute Ischaemic Stroke) trial, treatment with nerinetide was associated with improved outcomes in patients who did not receive intravenous alteplase. We compared the effect of nerinetide on clinical outcomes in patients without concurrent intravenous alteplase treatment within different patient subgroups. Methods: ESCAPE-NA1 was a multicenter randomized trial in which acute stroke patients with baseline Alberta Stroke Program Early CT Score (ASPECTS) >4 undergoing endovascular treatment (EVT) were randomized to intravenous nerinetide or placebo. The primary outcome was independence (modified Rankin Scale [mRS] score 0–2) at 90 days. We assessed baseline, clinical, and imaging variables as predictors of outcome and for evidence of treatment effect modification. We constructed two multivariable models using variables known prior to randomization and variables known immediately post-EVT procedure to provide adjusted estimates of effect. We assessed for evidence of treatment effect modification using multiplicative interaction terms within each model. Results: Four hundred forty-six patients were included in the analysis. Clinical outcomes were better in patients randomized to the nerinetide arm (mRS 0–2: 59.4% vs. 49.8%). There was possible treatment effect modification by ASPECTS score; patients with ASPECTS 8–10 showed a larger treatment effect compared to those with lower ASPECTS score. Younger age, lower NIHSS score, lower baseline serum glucose, absence of atrial fibrillation at baseline, higher ASPECTS score, middle cerebral artery (vs. internal carotid artery) occlusion, use of conscious or no sedation (vs. general anesthesia), and faster treatment were all predictors of favorable outcome. Conclusion Patients in the nerinetide arm who were not treated with concurrent alteplase showed improved clinical outcomes and the treatment effect was larger among patients with favorable ASPECTS profiles.

Purpose: Breast cancer is one of the most common cancers globally, with an increasing incidence rate. It is a heterogeneous disease, and early metastasis remains a challenge. Tumor budding, defined as single tumor cells or small clusters at the invasive front, has been suggested as a prognostic marker in various cancers, including breast cancer. This study aims to evaluate tumor budding in invasive breast carcinoma using the International Tumor Budding Consensus Conference (ITBCC) scoring system and explore its association with pathological characteristics and prognosis. Methods: A retrospective study was conducted on 100 mastectomy specimens of histopathologically confirmed invasive breast carcinoma, excluding cases that underwent chemotherapy or radiotherapy. Tumor budding was classified as low, intermediate, or high based on the ITBCC scoring method, and associations with clinicopathological features were analyzed using appropriate statistical tests. Results: Tumor budding was classified as high in 52% of cases. A significant association was found between high tumor budding and higher tumor grade (P<0.001), negative estrogen receptor and progesterone receptor status (P<0.001), positive HER2neu status (P=0.003), and high Ki-67 levels (P<0.001). High tumor budding was also linked to higher T stage, and dermal lymphovascular invasion (P=0.001). Our findings support previous studies showing that high tumor budding is associated with poor prognostic factors such as higher tumor grade, negative hormone receptor status, and higher T stage. Conclusion Tumor budding is a potential prognostic marker in breast cancer, associated with more aggressive tumor characteristics.

The pharmaceutical research sector is highly interested in oral gastro-retentive dose formulations. The significance of gastro-retentive drug delivery systems (GRDDS) has grown as these systems enhance patient compliance and improve the therapeutic indices of medications. Various technical advancements in the design and production of gastro-retentive dosage forms can overcome physiological limitations, such as short gastric retention time and fluctuations in stomach emptying. Medications with shorter half-lives, instability or poor solubility at alkaline pH, or inadequate absorption in the lower gastrointestinal tract can greatly benefit from GRDDS. To achieve the desired retention period and release pattern, these systems can be developed using a range of innovative methods, including magnetic, bioadhesive, expandable, and floating systems. The use of GRDDS for oral drug administration has significantly increased in recent years, with innovative design strategies—such as the widely used floating drug delivery system—playing a major role. GRDDS offer several advantages, including the ability to provide drugs with a narrow absorption window, improved pharmacological effects, reduced dosing frequency, enhanced bioavailability, and prolonged drug residence in the stomach for local effects such as the treatment of peptic ulcer disease. This study provides a brief introduction to gastro-retentive drug delivery, covering its necessity, advantages, disadvantages, influencing factors, approaches, and applications.

Purpose: Breast cancer is one of the most common cancers globally, with an increasing incidence rate. It is a heterogeneous disease, and early metastasis remains a challenge. Tumor budding, defined as single tumor cells or small clusters at the invasive front, has been suggested as a prognostic marker in various cancers, including breast cancer. This study aims to evaluate tumor budding in invasive breast carcinoma using the International Tumor Budding Consensus Conference (ITBCC) scoring system and explore its association with pathological characteristics and prognosis. Methods: A retrospective study was conducted on 100 mastectomy specimens of histopathologically confirmed invasive breast carcinoma, excluding cases that underwent chemotherapy or radiotherapy. Tumor budding was classified as low, intermediate, or high based on the ITBCC scoring method, and associations with clinicopathological features were analyzed using appropriate statistical tests. Results: Tumor budding was classified as high in 52% of cases. A significant association was found between high tumor budding and higher tumor grade (P<0.001), negative estrogen receptor and progesterone receptor status (P<0.001), positive HER2neu status (P=0.003), and high Ki-67 levels (P<0.001). High tumor budding was also linked to higher T stage, and dermal lymphovascular invasion (P=0.001). Our findings support previous studies showing that high tumor budding is associated with poor prognostic factors such as higher tumor grade, negative hormone receptor status, and higher T stage. Conclusion Tumor budding is a potential prognostic marker in breast cancer, associated with more aggressive tumor characteristics.

Background: Parkinson’s disease is a debilitating and the second most common neurodegenerative disorder with a high prevalence. Parkinson’s disease has a multifaceted etiology characterized by an altered redox state and an excessive inflammatory response. In this study, we investigated the potential neuroprotective properties of carvacrol in a haloperidol-induced Parkinson’s model. In female Sprague-Dawley rats, the animal Parkinson model was induced by intraperitoneally administering 1 mg / kg of haloperidol once daily for fifteen days. Carvacrol was administered at a dose of 25 and 50 mg / kg once daily for fifteen days before haloperidol administration. In order to further illustrate the vital role of the tumor necrosis factor (TNF-α) pathway, we administered 50 mg / kg of the TNF-α inhibitor thalidomide once daily for 15 days. Results: Our results showed that haloperidol-induced motor deficits, changed endogenous antioxidant enzymes, along with higher levels of inflammasome (NLRP3) and other inflammatory mediators. Moreover, increased levels of lipid peroxidase (LPO) indicated a significant rise in oxidative stress due to haloperidol. Moreover, carvacrol reduced these effects by preventing pyroptosis mediated by the inflammasome (NLRP3) and TNF-α. The administration of thalidomide mitigated oxidative stress and suppresses inflammatory pathways through the augmentation of the intrinsic antioxidant system. Further, co-treatment of carvacrol with thalidomide synergized the neuroprotective effect of carvacrol as demonstrated by various immunoassays and histology analyses. Conclusions Taken together, our findings suggest that carvacrol mitigated haloperidol-induced Parkinson-like symptoms, partially through the downregulation of TNF-α and NLRP3.

Purpose: In this systematic review and meta-analysis, we investigated assisted reproductive technology (ART) success in infertile men with clinical varicocele and abnormal semen parameters who underwent varicocele repair (VR) before the ART procedure as compared to those who did not. Materials and Methods: A comprehensive search of the Scopus, PubMed, Embase, and Cochrane Library databases was conducted using a specific query string to identify studies examining the impact of VR on ART outcomes, including fertilization rate, clinical pregnancy, pregnancy loss, and live-birth rate, until October 2023. Outcomes were analyzed based on the type of ART. Studies on VR in infertile men with non-obstructive azoospermia and those who underwent ART only due to female factor infertility were excluded from the study. Results: Out of 1,554 articles reviewed, only 9 met the inclusion criteria for the study. All the included articles were observational studies. The variability in study quality in the included literature resulted in a moderate overall risk of bias. Data analysis showed that for intrauterine insemination, there was no difference in the clinical pregnancy rate (odds ratio [OR] 1.01, 95% confidence interval [CI]: 0.42, 2.45; p=0.97). However, for intracytoplasmic sperm injection (ICSI), men with VR showed a significant improvement in fertilization rate (mean difference 10.9, 95% CI: 5.94, 15.89; p<0.01), clinical pregnancy rate (OR 1.38, 95% CI: 1.07, 1.78; p=0.01) and live-birth rate (OR 2.07, 95% CI: 1.45, 2.97; p<0.01), compared to men who did not undergo VR. Conclusions The findings of this systematic review and meta-analysis suggest that VR has a positive impact on pregnancy and live birth rates after ICSI. However, biases like small sample sizes and heterogeneous populations highlight the need for larger, well-designed prospective studies to validate these findings.

Purpose: This study aimed to examine current global practices in regenerative therapy (RT) for erectile dysfunction (ED) and to establish expert recommendations for its use, addressing the current lack of solid evidence and standardized guidelines. Materials and Methods: A 39-question survey was developed by senior Global Andrology Forum (GAF) experts to comprehensively cover clinical aspects of RT. This was distributed globally via a secure online Google Form to ED specialists through the GAF website, international professional societies, and social media, the responses were analyzed and presented for frequencies as percentages. Consensus on expert recommendations for RT use was achieved using the Delphi method. Results: Out of 479 respondents from 62 countries, a third reported using RT for ED. The most popular treatment was low-intensity shock wave therapy (54.6%), followed by platelet-rich plasma (24.5%) and their combination (14.7%), with stem cell therapy being the least used (3.7%). The primary indication for RT was the refractory or adverse effects of PDE5 inhibitors, with the best effectiveness reported in middle-aged and mild-to-moderate ED patients. Respondents were confident about its overall safety, with a significant number expressing interest in RT’s future use, despite pending guidelines support. Conclusions This inaugural global survey reveals a growing use of RT in ED treatment, showcasing its diverse clinical applications and potential for future widespread adoption. However, the lack of comprehensive evidence and clear guidelines requires further research to standardize RT practices in ED treatment.

Purpose: Despite the significant role of varicocele in the pathogenesis of male infertility, its association with anti-sperm antibodies (ASA) remains controversial. This systematic review and meta-analysis (SRMA) aims to investigate the frequency of ASA positivity in men with varicocele. Materials and Methods: This SRMA is conducted in accordance with the Meta-analysis of Observational Studies in Epidemiology guidelines. We investigated the frequency of ASA positivity in ejaculates or serum of men with varicocele as compared to men without varicocele (controls). A literature search was performed using the Scopus and PubMed databases following the Population Exposure Comparison Outcome, Study Design model. Data extracted from eligible studies were meta-analyzed and expressed as odds ratios (ORs) and confidence intervals (CIs). Results: Out of 151 abstracts identified during the initial screening, 6 articles met the inclusion criteria and were included in the meta-analysis. Using mixed antiglobulin reaction (MAR) assay, 61 out of the 153 (39.8%) patients with varicocele tested positive for ASA in their ejaculates as compared to 22 out of the 129 control subjects (17%, OR=4.34 [95% CI: 1.09–17.28]; p=0.04). Using direct or indirect immunobead test, 30 out of 60 cases diagnosed with varicocele (50%) had shown ASA positivity in their ejaculates as compared to 16 out of 104 controls (15.4%, OR=3.57 [95% CI: 0.81–15.68]; p=0.09). Using enzyme-linked immunosorbent assay (ELISA), out of 89 varicocele patients, 33 (37.1%) tested positive for serum ASA as compared to 9 out of 57 participants in the control group (15.8%, OR=7.87 [95% CI: 2.39–25.89]; p<0.01). Conclusions This SRMA indicates that ASA positivity is significantly higher among men with varicocele when tested by direct method (MAR) or indirect method (ELISA). This data suggests an immunological pathology in infertile men with varicocele and may have implications for the management of these patients.