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Lipid-based complex injectables are renowned for their effectiveness in delivering drugs, with many approved products. While significant strides have been made in formulating nanosystems for small molecular weight drugs, a pivotal breakthrough emerged with the recognition of lipid nanoparticles as a promising platform for delivering nucleic acids. This finding has paved the way for tackling long-standing challenges in molecular and delivery aspects (e.g., mRNA stability, intracellular delivery) that have impeded the clinical translation of gene therapy, especially in the realm of immunotherapy. Nonetheless, developing and implementing new lipid-based delivery systems pose significant challenges, as industrial manufacturing of these formulations often involves complex, multi-batch processes, giving rise to issues related to scalability, stability, sterility, and regulatory compliance. To overcome these obstacles, embracing the principles of quality-by-design (QbD) is imperative. Furthermore, adopting cutting-edge manufacturing and process analytical tools (PAT) that facilitate the transition from batch to continuous production is essential. Herein, the key milestones and insights derived from the development of currently approved lipid- nanosystems will be explored. Additionally, a comprehensive and critical overview of the latest technologies and regulatory guidelines that underpin the creation of more efficient, scalable, and flexible manufacturing processes for complex lipid-based nanoformulations will be provided. [Display omitted] • Lipid-based complex injectables reliably deliver drugs with many approved products. • Lipid nanoparticles significantly enhance nucleic acid delivery for gene therapy. • Multi-batch processes challenge scalability, stability, and compliance. • Quality-by-Design ensures consistent product quality in complex manufacturing. • Process Analytical Tools enhance efficiency and flexibility in manufacturing. [ABSTRACT FROM AUTHOR]

The aim of the study was to evaluate the outcomes of voriconazole in terms of functional recovery and response on imaging in the management of invasive aspergillosis of orbit. This was a prospective non-comparative interventional study. Diagnosed cases of invasive orbital aspergillosis were studied in a tertiary care hospital. Intravenous voriconazole followed by oral treatment was given. Sinus debridement was done, where needed. The response to treatment was assessed clinically and on radiology. A total of 10 diagnosed cases of invasive orbital aspergillosis were studied. Nine cases (90%) occurred in immunocompetent patients. Predisposing sinus infection was seen in 8 patients (80%). The most common presenting complaint was the protrusion of eye. On voriconazole treatment, there was a statistically significant improvement in vision and extraocular movements from first week onwards (p = 0.01 and p = 0.02, respectively) and reduction in proptosis from second week onwards (p = 0.003). Imaging was done at three months follow-up which revealed a good response to treatment in 90% of patients. All patients tolerated the drug well except one who had transient hepatic dysfunction. The mean follow-up was 5.8 months (range: 3–12 months). There was no recurrence of disease till the last follow-up. Invasive orbital aspergillosis commonly presents as sino-orbital disease, mostly in immunocompetent adult patients. Voriconazole is a safe and effective drug with good short-term clinical outcome. [ABSTRACT FROM AUTHOR]

The purpose of this investigation is to compare Cutibacterium acnes diagnosis using culturing vs. genomic DNA sequencing (NextGen) at various timepoints and locations during primary total shoulder arthroplasty. Additionally, we intend to compare the effects of hydrogen peroxide on standard culture technique results with genomic DNA sequencing. A prospective diagnostic study of 40 patients undergoing primary total shoulder arthroplasty was performed. Intraoperatively, 4 tissue samples were collected per patient: subdermal skin edge following initial skin incision, subdermal skin edge following hydrogen peroxide soak for 5 minutes, glenohumeral joint capsule, and subdermal skin edge prior to wound closure. Each tissue specimen was collected twice (one for culture analysis and the other for genomic (NextGen) DNA sequencing analysis) for a total of 8 specimens per patient and 320 tissue specimens in total. All anaerobic cultures were held for 14 days. Each culture plate was divided into quadrants and the amount of growth was quantified. Tissue samples were collected for genomic sequencing DNA analysis. Genomic sequencing results provided relative percentage of bacteria for each specimen detected. There were 18/40 males (45%) and no postoperative complications. Average age was 72.2 ± 11.8. Overall, 18% (29/160) of standard anaerobic cultures were positive for C. Acnes and 26% (942/160) were positive with genomic (Nextgen) DNA sequencing. When comparing the NextGen results with anaerobic standard cultures, there was a calculated negative predictive value of 85.6% and positive predictive value of 28.6%. Sensitivity of the NextGen was 41.4% and specificity was 77.1%. Bacterial culture rates did not significantly change from the beginning to the end of surgery as demonstrated on standard culturing and the NextGen analysis (P >.05). After treatment with hydrogen peroxide, the standard culturing technique showed no significant difference between the samples; however, there was a significant increase in bacterial burden (12.4%) noted with NextGen analysis (P =.0147). NextGen culturing is a novel technique to help identify shoulder prosthetic joint infections. These results show that, NextGen is better at identifying the absence of infection, but has a high false positive rate indicative of its ability to identify contaminants as compared to standard anaerobic culturing methods. The increase in bacterial burden after peroxide treatment noted with NextGen could also be secondary to the test's increased ability to identify both living and dead bacterial pathogens. [ABSTRACT FROM AUTHOR]

We compared the Institute for Clinical and Economic Review's (ICER) ratings of comparative clinical effectiveness with the German Federal Joint Committee's (G-BA) added benefit ratings, and explored what factors may explain the disagreement between the 2 organizations. We included drugs if they were assessed by ICER under its 2020 to 2023 Value Assessment Framework and had a corresponding assessment by G-BA as of January 2024 for the same indication, patient population, and comparator drug. To compare assessments, we modified ICER's proposed crosswalk between G-BA and ICER benefit ratings to account for G-BA's certainty ratings. We also determined whether each pair was based on similar evidence. Assessment pairs exhibiting disagreement based on the modified crosswalk despite a similar evidence base were qualitatively analyzed to identify reasons for disagreement. Out of 15 drug assessment pairs matched on indication, patient subgroup, and comparator, none showed agreement in their assessments when based on similar evidence. Disagreement was attributed to differences in evidence evaluation, including evaluations of safety, generalizability, and study design, as well as G-BA's rejection of the available evidence in 4 cases as unsuitable. The findings demonstrate that even under conditions where populations and comparators are identical and the evidence base is consistent, different assessors may arrive at divergent conclusions about comparative effectiveness, thus underscoring the presence of value judgments within assessments of clinical effectiveness. To support initiatives that seek to facilitate the exchange of value assessments between countries, these value judgments should always be transparently presented and justified in assessment summaries. • Several studies have documented disagreement in the comparative effectiveness assessments of the same drugs by different national health technology assessment (HTA) bodies. However, we are not aware of any studies that compare Institute for Clinical and Economic Review's (ICER) comparative effectiveness assessments with those of other HTA bodies. Furthermore, existing studies have matched and compared comparative effectiveness assessments at the drug level or the indication and patient subgroup level only. • We identified 15 drug assessment pairs matched on indication, patient subgroup, and comparator treatment. Seven assessment pairs were based on similar evidence. Using a novel crosswalk to translate G-BA ratings into ICER ratings that accounts for G-BA's assessment of certainty, G-BA and ICER did not agree in their assessment for any of these 7 drugs. • The findings demonstrate that even when populations and comparators are identical and the evidence base is similar, different assessors may arrive at divergent conclusions about comparative effectiveness, thus underscoring the role of value judgments. To support initiatives seeking to facilitate exchange of value assessments between jurisdictions, value judgments should be transparently presented and justified in assessment summaries. A recently published framework is 1 tool HTA bodies could use to organize and justify value judgments. [ABSTRACT FROM AUTHOR]

The Inflation Reduction Act (IRA), enacted in 2022, brings substantial reforms to the US healthcare system, particularly regarding Medicare. A key aspect includes the introduction of Medicare price negotiation. The objective of this commentary is to explore the implications of the IRA for US pharmaceutical companies, with a specific focus on the role of real-world evidence (RWE) in the context of Medicare reforms. This commentary uses a qualitative analysis of the IRA's provisions related to healthcare and pharmaceutical regulation, focusing on how these reforms change the evidence requirements for pharmaceutical companies. It discusses the methodological aspects of generating and using RWE, including techniques such as target trial emulation and quantitative bias analysis methods to address biases inherent in RWE. This commentary highlights that the IRA introduces a unique approach to value assessment in the United States by evaluating drug value several years after launch, as opposed to at launch, similar to health technology assessments in other regions. It underscores the central role of RWE in comparing drug effectiveness across diverse clinical scenarios to improve the accuracy of real-world data comparisons. Furthermore, this article identifies key methodologies for managing the inherent biases in RWE, which are crucial for generating credible evidence for IRA price negotiations. This article underscores the importance of these methodologies in ensuring credible evidence for IRA price negotiations. It advocates for an integrated approach in evidence generation, positioning RWE as pivotal for informed pricing discussions in the US healthcare landscape. • The Inflation Reduction Act introduces Medicare price negotiation and reform. This Act affects how US pharmaceutical companies present evidence for their products. The integration of real-world evidence (RWE) and health technology assessments has been important in evaluating drug value and effectiveness, and there has been a notable gap in tailored methodologies that align with the unique healthcare landscape and regulatory requirements of the United States. • This article sheds light on the Act's innovative approach toward value assessment and the strategic importance of generating evidence throughout a drug's life cycle. It elaborates on the application of target trial emulation and quantitative bias analysis. These methodologies are presented as important tools for enhancing the reliability and applicability of RWE, meticulously addressing inherent biases and facilitating more accurate comparisons of drug effectiveness. • This article advocates for a holistic strategy in RWE evidence generation in Medicare price negotiations under the Inflation Reduction Act framework. It suggests that these methodological advancements can significantly influence healthcare policy and pricing strategies, offering a pathway toward optimizing therapeutic outcomes for Medicare beneficiaries. This approach not only aims to streamline the negotiation process but also contributes to the broader goal of ensuring access to cost-effective and high-quality healthcare solutions. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the effects of opioid-free anesthesia (OFA) in laparoscopic gastrectomy and identify the psychological factors that could influence the efficacy of OFA. 120 patients undergoing laparoscopic gastrectomy were allocated to either the opioid-based anesthesia group (OA) (n = 60) or the OFA (n = 60) group. Remifentanil was administered to the OA group intraoperatively, whereas dexmedetomidine and lidocaine were administered to the OFA group. The interaction effect of the psychological factors on OFA was analyzed using the aligned rank transform for nonparametric factorial analyses. The opioid requirement for 24 h after surgery was lower in the OFA group than in the OA group (fentanyl equivalent dose 727 vs. 650 μg, p = 0.036). The effect of OFA was influenced by the pain catastrophizing scale (p = 0.041), temporal pain summation (p = 0.046), and pressure pain tolerance (p = 0.034). This indicates that patients with pain catastrophizing or high pain sensitivity significantly benefited from OFA, whereas patients without these characteristics did not. This study demonstrated that OFA with dexmedetomidine and lidocaine effectively reduced the postoperative 24-h opioid requirements following laparoscopic gastrectomy, which was modified by baseline pain catastrophizing and pain sensitivity. The study protocol was approved by the Institutional Review Board of Yonsei University Health System Gangnam Severance Hospital (#3–2021-0295) and registered at ClinicalTrials.gov (NCT05076903). [ABSTRACT FROM AUTHOR]

Antipsychotic drug efficacy may vary in placebo-controlled and active-controlled trials. The study aims to investigate the performance of antipsychotics in these two different study designs using single-arm meta-analysis. We included randomized controlled trials (RCTs) comparing second-generation antipsychotics with placebo or other antipsychotics from our previous systematic reviews and updated the results with the search on Cochrane Schizophrenia Group register until March 06, 2022. The outcomes were the differences in the change of overall, positive and negative symptoms of schizophrenia, and the difference in study discontinuation between placebo-controlled and head-to-head trials. Random-effects single-arm meta-analysis and subgroup test were conducted to examine the differences in each outcome. A total of 208 RCTs (n = 42,159) were included in the analysis. Of these, 85 trials with 17,056 participants were placebo-controlled, while the remaining were head-to-head trials. Antipsychotics in head-to-head trials demonstrated a significantly greater improvement in overall symptoms (MC −23.58; 95 % CI −25.33, −21.83) compared to antipsychotics in placebo-controlled trials (MC −16.74; 95 % CI −17.80, −15.69; p < 0.0001). Similar findings were observed for positive symptoms, negative symptoms, study discontinuation and sensitivity analyses. Notably, when assessing antipsychotics individually, the same antipsychotic consistently demonstrated superior performance in head-to-head trials compared to placebo-controlled trials. In conclusion, antipsychotics in head-to-head trials presented a considerable efficacy superiority compared to those in placebo-controlled trials. Moreover, the efficacy of the same antipsychotics varied depending on the study design. Future trials should carefully consider the methodology and employ strategies to mitigate the potential for overestimation or underestimation of treatment efficacy. [ABSTRACT FROM AUTHOR]

• Alirocumab improves cardiovascular outcomes after ACS irrespective of sex. • Reduction of total cardiovascular events was greater at higher baseline Lp(a). The ODYSSEY OUTCOMES trial (NCT01663402) compared the effects of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo on major adverse cardiovascular events (MACE) in patients with recent acute coronary syndrome (ACS). We assessed efficacy and safety of alirocumab versus placebo according to sex and lipoprotein(a) level. This prespecified analysis compared the effects of alirocumab versus placebo on lipoproteins, MACE (coronary heart disease death, non-fatal myocardial infarction, fatal/non-fatal ischemic stroke, unstable angina requiring hospitalization), death, total cardiovascular events, and adverse events in 4762 women and 14,162 men followed for a median of 2.8 years. In post-hoc analysis, we evaluated total cardiovascular events according to sex, baseline lipoprotein(a), and treatment. Women were older, had higher baseline low-density lipoprotein cholesterol (LDL-C) levels (89.6 vs 85.3 mg/dL) and lipoprotein(a) (28.0 vs 19.3 mg/dL) and had more co-morbidities than men. At 4 months, alirocumab lowered LDL-C by 49.4 mg/dL in women and 54.0 mg/dL in men and lipoprotein(a) by 9.7 and 8.1 mg/dL, respectively (both p < 0.0001). Alirocumab reduced MACE, death, and total cardiovascular events similarly in both sexes. In the placebo group, lipoprotein(a) was a risk factor for total cardiovascular events in women and men. In both sexes, reduction of total cardiovascular events was greater at higher baseline lipoprotein(a), but this effect was more evident in women than men (p interaction =0.08). Medication adherence and adverse event rates were similar in both sexes. Alirocumab improves cardiovascular outcomes after ACS irrespective of sex. Reduction of total cardiovascular events was greater at higher baseline lipoprotein(a). [Display omitted] [ABSTRACT FROM AUTHOR]

• Only 27% patients with Non-Alcoholic Fatty Liver Disease (NFALD) received statins. • Statin therapy was not associated with elevated liver enzyme levels. • ALT, total cholesterol, and LDL were significantly lower in statin users. • Findings demonstrate statin use in patients with NAFLD can reduce CVD risks. • Findings were generalized to the US population. Non-alcoholic fatty liver disease (NAFLD) is an independent risk factor for cardiovascular disease (CVD). Statins are recommended for treatment of dyslipidemia to reduce the overall cardiovascular risk in patients with NAFLD. However, statin treatment was underutilized and the effect of statins on liver enzymes remained unclear in this patient population. This study aimed to provide real-world evidence of the safety and effect of statin use in patients with NAFLD. We conducted a cross-sectional survey study of adults with NAFLD using pooled data from the US NHANES database 2009–2018. NAFLD was defined by Fatty Liver Index (FLI) ≥ 60 and United States Fatty Liver Index (USFLI) ≥ 30. Multivariate regression analyses adjusted for baseline clinical and demographic characteristics were performed to compare the liver enzymes and lipid profile between statin and non-statin users. The study included 2,533 adults with NAFLD, representing 22.6 million individuals in the US, with 27% receiving statin treatment between 2009 and 2018. The mean differences of liver enzymes for AST, ALT, ALP, and GGT between statin and non-statin users were -0.86 (p=0.539), -3.49 (p=0.042), -0.25 (p=0.913), and 0.57 (p=0.901), respectively. In individuals with NAFLD and dyslipidemia, total cholesterol and LDL levels were significantly lower in statin users compared to non-statin users (mean difference, -28.9; p<0.001 and -27.7; p<0.001). The use of statins was not associated with elevated liver enzymes in patients with NAFLD. Significantly lower levels of ALT, total cholesterol, and LDL were observed in statin users compared to non-statin users. [ABSTRACT FROM AUTHOR]

The emergence of biological agents and small molecule drugs has revolutionized the treatment landscape for psoriasis, yet there remains a lack of systematic reviews elucidating the efficacy and safety of drugs for patients with psoriasis and mental disorders (MDs). The aim was to systemically evaluate the efficacy and safety of FDA-approved psoriasis drugs on MD symptoms and MD drugs on psoriasis symptoms. We conducted comprehensive literature searches of the PubMed, Embase, and Cochrane Library from inception to March 24, 2024, identifying 116 relevant studies for inclusion. Our review encompasses 62 clinical trials and 54 case reports/series. Analyses of clinical trials revealed a positive impact of psoriasis drugs on MD, with notable exceptions including lithium and benzodiazepine receptor agonists, which exhibited adverse effects on psoriasis. Furthermore, analysis of case reports/series highlighted the efficacy of drugs such as apremilast, etanercept, infliximab, and secukinumab in ameliorating MD symptoms, contrasting with detrimental effects observed with methotrexate (MTX), cyclosporine, adalimumab, and secukinumab. Notably, tumor necrosis factor alpha (TNF-α) inhibitors and interleukin inhibitors demonstrated superior efficacy compared to conventional treatments. In the anxiety group, secukinumab showed the largest effective size as assessed by the Hospital Anxiety and Depression Scale - Anxiety (HADS-A) index; In the depression group, ixekizumab showed the largest effective size assessed by the 16-item Quick Inventory of Depressive Symptomology – Self-Report (QIDS-SR16) index. The extracted data cannot be meta-analyzed, as the measurement scale is not uniform. This systematic review provides robust evidence regarding treatment options for individuals with psoriasis and MD, emphasizing the potential benefits of specific drugs in managing both conditions concurrently. • In general, psoriasis drugs (conventional drugs, small molecule drugs, TNF-α inhibitors, IL inhibitors) all have a positive effect on MD. • TNF-α and IL inhibitors demonstrated superior efficacy compared to conventional treatments, particularly in patients with highly inflammatory conditions. • In the anxiety group, secukinumab showed the largest effective size as assessed by the HADS-A index; In the depression group, ixekizumab showed the largest effective size assessed by the QIDS-SR16 index. • MD drugs included gabapentin and paroxetine showed positive effect on psoriasis while lithium and BZRAs were reported to induce psoriasis. [ABSTRACT FROM AUTHOR]

The relationship between depression and gut microbiota remains unclear, but an important role of gut microbiota has been verified. The relationship between gut microbiota and antibiotic resistance genes (ARGs) may be a potential new explanatory pathway. We collected samples from 63 depressed patients and 30 healthy controls for metagenomic sequencing. The two groups' microbiota characteristics, functional characteristics, and ARG differences were analyzed. We obtained 30 differential KEGG orthologs (KOs) and their producers in 5 genera and 7 species by HUMAnN3. We found 6 KOs from Weissella_cibaria and Lactobacillus_plantaru are potentially coring functional mechanism of gut microbiota. Different metabolites including sphingolipids, pyrans, prenol lipids, and isoflavonoids also showed significance between MDD and HC. We detected 48 significantly different ARGs: 5 ARGs up-regulated and 43 ARGs down-regulated in MDD compared to HC. Based on Cox model results, Three ARGs significantly affected drug efficacy (ARG29, ARG105, and ARG111). Eggerthella, Weissella, and Lactobacillus were correlated with different core ARGs, which indicated different mechanisms in affecting MDD. The present study needs to be replicated in different ethnic groups. At the same time, a larger Chinese cohort study and detailed experimental verification are also the key to further discussion. Our findings suggest that ARGs play a role in the interplay between major depressive disorder and gut microbiota. The role of ARGs should be taken into account when understanding the relationship between depression and gut microbiota. • We detected 48 significantly different ARGs: 5 ARGs up-regulated and 43 ARGs down-regulated in MDD compared to HC. • Based on Cox model results, Three ARGs significantly affected drug efficacy (ARG29, ARG105, and ARG111). • Eggerthella, Weissella, and Lactobacillus were correlated with different core ARGs to affect MDD. [ABSTRACT FROM AUTHOR]

Solid cancer remains a serious threat to global health despite decades of progress. Traditional chemotherapy treatment has been used to curb the disease despite its inability to reach cancer cells at high enough quantities leading to adverse toxicity on healthy cells, producing severe side effects, and exacerbating patient suffering. Active targeted nano-drugs (ATNDs) acting as transporter systems have become a viable solution to this shortcoming, offering the possibility of more precise cancer targeting. Therefore, in the present study, we develop a numerical model of capturing ATNDs, incorporating movements within and outside the tumor spheroid and the magnetic forces guiding the nanoparticles. By combining a model of ATNDs transport with a tumor-effector dynamic model based on porous media phenomena, we demonstrate how the models may be combined to model drug-loaded nanoparticle transport in an external magnetic field. We analyze the controlled drug delivery against traditional chemotherapy based on the combined effect of immunotherapy and chemotherapy with the dispersion of nano-drugs to lead a solute cloud toward the tumor. We found that the amalgamation of immune and chemotherapy delivered by ATNDs enhances cancer therapy efficacy compared with conventional chemotherapy. Increased drug convection toward the tumor region presented by ascending values of the Peclet number inhibits the growth of tumor cells and prolongs progression-free survival. Increases in source term and vessel permeability also increase the likelihood of tumor suppression, while raising the hematocrit and magnetic number results in reduced tumor cell killing. Sensitivity analysis of the dynamic model parameters has been discussed. This work demonstrates that ATND-delivery systems can improve therapeutic agent delivery to the tumor tissue, and promote tumor cell killing. • Analyze the impact of drug dispersion on the dynamical systems of tumor-effectors with conventional and targeted therapy. • Incorporate drug dispersion phenomena to describing targeted nano-drugs delivery with hematocrit and drug source term. • Numerical and sensitivity simulation shows the impact of the flow and dynamical control parameters on therapy treatment. • Targeted nano-drug delivery shows more prominent in drug accumulation in the tumor than the conventional treatment. • Outcomes demonstrate the effectiveness of targeted drug delivery to the tumor tissue and enhance tumor cell kill. [ABSTRACT FROM AUTHOR]

Safety and efficacy are the most critical factors for the development of modern medications. For oral drugs, evaluating drug exposure under various conditions is one of the most important outcomes for clinical trials. These data will help to better understand the safety and efficacy of new drugs. Studies involving potential drug-drug interactions, proton pump inhibitors, and intake of food are often conducted to assess the above. Among the above, the influence of food on exposure to the drug is one of the key data sets for regulatory submission. Since food may have either a positive or negative effect on drug exposure, it is important to obtain an early assessment of the food effect. To better forecast and plan for clinical studies, substantial efforts have been made in the industry to develop modeling and in-vitro and in–vivo assays. Despite the efforts, predicting the effect of food on exposure without integrating the dynamic of the gastrointestinal tract in the assessment remains challenging. In this study, we evaluated the utilization of the dynamic Gastro-Intestinal Model (Tiny-TIM) for the food effect of over 20 drugs/formulations in development or on the market that covers all BCS classes. In general, the Tiny-TIM predicted food effects were in good agreement with the reported data in humans. This suggests that Tiny-TIM can successfully capture the impact of physicochemical properties on absorption under the influence of food. [ABSTRACT FROM AUTHOR]

Sinonasal teratocarcinosarcomas (SNTCS) are rare sinonasal malignancies, the incidence of which is less than 1% of all tumors. There is limited data available on SNTCS's, often as case reports and small case series. The management of SNTCS is complicated because of its location, locally aggressive biology, difficulty in achieving complete resection, and limited data on chemotherapy in these malignancies. This audit was performed to understand the role of neoadjuvant chemotherapy (NACT) in SNTCS's, its ability to downstage the disease, achieve complete resection, and impact on long-term survival outcomes. This was a retrospective analysis of a prospectively maintained database approved by the Institutional Ethics Committee (IEC). The baseline characteristics, the extent of tumor, Kadish stage, NACT regimen, and adverse events were extracted from the Electronic Medical Records and the patient's case file. Patients with baseline extensive/inoperable disease were referred for NACT from the multidisciplinary joint clinic followed by response assessment (RECIST v1.1). Patients underwent skull-base surgery if respectable post-completion of NACT, however, if deemed unresectable were treated with non-surgical modalities or palliative therapies. The data of 27 patients were evaluated from the year 2015–2022. The median age was 42 years (IQR:30–56) and 85.2% (n = 23) were males. The ECOG-PS was 0–1 in 88.8% (n = 24) patients. All 27 patients received NACT in view of extensive disease at presentation. 74.1% (n = 20) patients received Cisplatin-Etoposide and 25.9% (n = 7) received other chemotherapy regimens. The median number of chemotherapy cycles was 2(IQR:2–3). 96.3% patients (n = 26) completed the planned NACT cycles. 70.4% (n = 19) patients achieved a partial response in post-NACT imaging. 77.8% (n = 18) underwent surgery, 18.5% (n = 5) received CTRT, and 7.4% (n = 2) received definitive-RT alone. The median PFS and OS of the cohort was 19months (95%CI:12.0–25.6) and 23months (95%CI:5.94–40.06) respectively. NACT is safe, feasible, and effective with significant response rates, leading to effective downstaging, resectability and improved survival in patients with locally advanced SNTCS's. • Sinonasal teratocarcinosarcomas (SNTCS) are rare sinonasal malignancies, the incidence of which is approximately less-than 1% of all tumors. This audit was performed to understand the role of neoadjuvant chemotherapy (NACT) in SNTCS's, its ability to downstage the disease, achieve complete resection, and impact on long-term survival outcomes. • The median PFS and OS of the cohort was 19 months (95%CI:12.0–25.6) and 23 months (95%CI:5.94–40.06), respectively. • NACT is safe, feasible, and effective with significant response rates, leading to effective downstaging, resectability, and improved survival in patients with locally advanced SNTCS's. [ABSTRACT FROM AUTHOR]

Evidence shows stereotactic ablative body radiotherapy (SABR) is used as a non-invasive ablative therapy in the treatment of multisite oligometastatic (OM) and oligoprogressive (OP) diseases originating from metastatic breast cancer. This study aims to report the treatment outcomes and to investigate what factors that are prognostic in terms of local control, progression-free survival (PFS) and overall survival (OS) in patients receiving SABR for extracranial OM and OP diseases originating from metastatic breast cancer. A retrospective review on treatment records of patients with OM and OP from metastatic breast cancer who underwent SABR at a single was carried out. SABR was performed with daily image-guided radiotherapy (IGRT) using a dedicated robotic SABR machine. Local control, PFS and OS were calculated using Kaplan-Meier statistics and the post-treatment toxicity data was scored following the CTCAE v4.0 protocol. Univariate and multivariate Cox regression tests were used in the subgroup analysis of prognostic factors on PFS and OS including patients' age, types of follow-up imaging (staging CT only vs whole-body MR/PET), metastases status (OM vs OP), primary breast cancer tumour grade, hormone receptors (ER/PR/HER2) status, change of systemic treatments at SABR, number of metastases, SABR treatment sites and doses. 56 metastatic breast cancer patients (38 patients with OM and 18 patients with OP) were involved in this retrospective review. The median follow-up was 35.6 months (range 4.0–132.9 months). The estimated local control at 1 , 2 and 5 years were 90.9%, 88.7% and 88.7%, respectively. The estimated median PFS was 19.2 months (95%CI 10.3–28.1 months); the PFS at 1, 2 and 5 years were 63.3%, 44.4% and 33.2%. The estimated OS at 1, 2 and 5 years were 98.0%, 91.9% and 74.3%, respectively with the estimated median OS of 105.1 months (95%CI 51.5–158.7 months). The vast majority of patients tolerated the treatment well with the commonest acute side effects as grade 1 fatigue. There were no statistically significant factors found in OS regression analysis. The types of follow-up imaging, metastases status, oestrogen receptor status, and number of metastases for SABR were statistically significant factors (p < 0.05) in the multivariate Cox regression analysis on PFS. There are limited studies published on the efficacy and post-treatment toxicities of metastatic breast cancer OM and OP SABR with adequate length of follow-up. This study confirmed that SABR was a safe, non-invasive treatment option for patients with extracranial OM and OP diseases originated from primary breast cancer in terms of the acceptable post-treatment toxicities. • This study reported SABR treatment outcomes for multisite OM and OP diseases originating from metastatic breast cancer • It showed modest local control and post-treatment toxicities on the SABR of extracranial OM and OP from metastatic breast cancer. • The types of follow-up imaging, OM vs OP, oestrogen receptor status, and number of metastases for SABR can be used as PFS prognostic factors. [ABSTRACT FROM AUTHOR]

The benefits in survivorship gained with anthracycline (ANT)-based chemotherapies for breast cancer are unfortunately mitigated for some patients by irreversible cardiotoxicity. Randomised controlled trials (RCTs) have explored multiple cardioprotection options, however, it remains unclear which drug is most effective in preserving left ventricular ejection fraction (LVEF). This study aimed to perform a systematic review and network meta-analysis, using Bayesian and frequentist approaches, of RCTs evaluating cardioprotective agents. Two authors searched four databases (CENTRAL, Cochrane Reviews, MEDLINE, SCOPUS), to find RCTs evaluating cardioprotective agents. Trial populations were limited to patients with breast cancer without prior ANT exposure. The primary outcome was mean LVEF change pre and post ANT dosing. Our primary analysis utilised a Bayesian approach, while our sensitivity analysis used frequentist methodology (Prospero registration number CRD42020199580). From 4,007 search results, we identified 12 RCTs, with their various trial arms considered separately—nine beta-blocker (BB), two angiotensin-converting enzyme inhibitor /angiotensin receptor blockers [(AA)+BB=AABB], one AA, one spironolactone, one statin—evaluating 1,126 patients (age 50.5 years). Bayesian network meta-analysis showed no difference in LVEF preservation between AA (1.3%, 95% credible interval [-0.20, 2.9]), BB (0.77, [-0.21, 1.8]), AABB (0.84 [-1.1, 2.8]), spironolactone (0.72, [-2.3, 3.7]) or statin (0.60, [-2.4, 3.6]) when compared against placebo. However, the frequentist analysis showed benefits from using AA (mean difference, 1.32% [0.32, 2.33]) and BB (mean difference, 0.76% [0.12, 1.4]). There is insufficient evidence to support prophylactic cardioprotection to prevent EF reduction. However, frequentist analysis suggested that AA or BBs provide cardioprotection. Thus, for those already on other anti-hypertensives, switching to AA or BBs could be considered. [ABSTRACT FROM AUTHOR]

In the ongoing battle against antimicrobial resistance, phenotypic drug tolerance poses a formidable challenge. This adaptive ability of microorganisms to withstand drug pressure without genetic alterations further complicating global healthcare challenges. Microbial populations employ an array of persistence mechanisms, including dormancy, biofilm formation, adaptation to intracellular environments, and the adoption of L-forms, to develop drug tolerance. Moreover, molecular mechanisms like toxin-antitoxin modules, oxidative stress responses, energy metabolism, and (p)ppGpp signaling contribute to this phenomenon. Understanding these persistence mechanisms is crucial for predicting drug efficacy, developing strategies for chronic bacterial infections, and exploring innovative therapies for refractory infections. In this comprehensive review, we dissect the intricacies of drug tolerance and persister formation, explore their role in acquired drug resistance, and highlight emerging therapeutic approaches to combat phenotypic drug tolerance. Furthermore, we outline the future landscape of interventions for persistent bacterial infections. • Phenotypic drug tolerance and its significance for healthcare challenges. • Diverse active molecular mechanisms involved in drug tolerance. • Extending concept of persistence beyond bacteria to fungi, parasites, and cancer. • Evolutionary significance of phenotypic drug tolerance in acquired drug resistance. • Evolving therapies for persistent infections and future landscape of interventions. [ABSTRACT FROM AUTHOR]

• To evaluate the efficacy of localized delivery of drugs in the treatment of HSIL. • In patients with recurrence after surgery, drug treatment can avoid secondary conization. • For HSIL patients, drug treatment can reduce adverse outcomes during pregnancy. • For HSIL, drug therapy can be used as a supplement to surgery. The present study aims to evaluate the efficacy and effect of localized delivery of drugs in the treatment of high-grade squamous intraepithelial lesion (HSIL) based on a meta -analysis. Databases including Cochrane Library, PubMed, Embase, Scopus, CNKI, and Wanfang were searched from their inception till August 2022. Randomized controlled trials (RCTs) that compared the efficacy of drugs and surgery in the treatment of HSIL were collected. A meta -analysis was performed using the software of Review Manager (version 5.4.1). Eight RCTs involving 523 patients were included in the meta -analysis. For HSIL, the rate of cervical lesions histological regression was 69.85 % in the surgery group and 59.88 % in the drug group, there was no significant difference between the two groups [OR = 0.45, 95 % CI (0.07, 3.03), P = 0.41]. The histological regression rate of cervical lesions in the placebo group was 37.76 %, and the difference between the drug group and the placebo group was statistically significant [OR = 4.94, 95 % CI (2.65, 9.20), P < 0.00001]. A total of four drugs were involved in the eight RCTS included in this study, which were imiquimod, 5-fluorouracil (5-FU), cidofovir and interferon. The results showed that although drug administration was effective in the histological regression of HSIL, the efficacy was less than about 10% of surgical treatment. Considering the recurrence of the disease after surgery and the problems of abortion, premature delivery and premature rupture of membranes after cervical conization in reproductive women, drug therapy can be used as a supplement to surgery or conservative treatment to promote the histological regression of cervical lesions in patients with HSIL. [ABSTRACT FROM AUTHOR]

To evaluate the efficacy of real-time continuous glucose monitoring (rt-CGM) in adjusting insulin therapy in long-term care facilities (LTCF). Prospective randomized clinical trial. Insulin-treated patients with type 2 diabetes (T2D) admitted to LTCF. Participants in the standard of care wore a blinded CGM with treatment adjusted based on point-of-care capillary glucose results before meals and bedtime (POC group). Participants in the intervention (CGM group) wore a Dexcom G6 CGM with treatment adjusted based on daily CGM profile. Treatment adjustment was performed by the LTCF medical team, with a duration of intervention up to 60 days. The primary endpoint was difference in time in range (TIR 70-180 mg/dL) between treatment groups. Among 100 participants (age 74.73 ± 11 years, 80% admitted for subacute rehabilitation and 20% for nursing home care), there were no significant differences in baseline clinical characteristics between groups, and CGM data were compared for a median of 17 days. There were no differences in TIR (53.38% ± 30.16% vs 48.81% ± 28.03%, P =.40), mean daily mean CGM glucose (184.10 ± 43.4 mg/dL vs 190.0 ± 45.82 mg/dL, P =.71), or the percentage of time below range (TBR) <70 mg/dL (0.83% ± 2.59% vs 1.18% ± 3.54%, P =.51), or TBR <54 mg/dL (0.23% ± 0.85% vs 0.56% ± 2.24%, P =.88) between rt-CGM and POC groups. The use of rtCGM is safe and effective in guiding insulin therapy in patients with T2D in LTCF resulting in a similar improvement in glycemic control compared to POC-guided insulin adjustment. [ABSTRACT FROM AUTHOR]

Anti-inflammatory activities of catechin-rich green tea extract (GTE) in obese rodents protect against metabolic endotoxemia by decreasing intestinal permeability and absorption of gut-derived endotoxin. However, translation to human health has not been established. We hypothesized that GTE would reduce endotoxemia by decreasing gut permeability and intestinal and systemic inflammation in persons with metabolic syndrome (MetS) compared with healthy persons. A randomized, double-blind, placebo-controlled, crossover trial in healthy adults (n = 19, 34 ± 2 years) and adults with MetS (n = 21, 40 ± 3 years) examined 4-week administration of a decaffeinated GTE confection (890 mg/d total catechins) on serum endotoxin, intestinal permeability, gut and systemic inflammation, and cardiometabolic parameters. Compared with the placebo, the GTE confection decreased serum endotoxin (P =.023) in both healthy persons and those with MetS, while increasing concentrations of circulating catechins (P <.0001) and γ-valerolactones (P =.0001). Fecal calprotectin (P =.029) and myeloperoxidase (P =.048) concentrations were decreased by GTE regardless of health status. Following the ingestion of gut permeability probes, urinary lactose/mannitol (P =.043) but not sucralose/erythritol (P >.05) was decreased by GTE regardless of health status. No between-treatment differences (P >.05) were observed for plasma aminotransferases, blood pressure, plasma lipids, or body mass nor were plasma tumor necrosis factor-α, interleukin-6, or the ratio of lipopolysaccharide-binding protein/soluble cluster of differentiation-14 affected. However, fasting glucose in both study groups was decreased (P =.029) by the GTE confection compared with within-treatment arm baseline concentrations. These findings demonstrate that catechin-rich GTE is effective to decrease circulating endotoxin and improve glycemic control in healthy adults and those with MetS, likely by reducing gut inflammation and small intestinal permeability but without affecting systemic inflammation. • A novel green tea extract (GTE) confection was provided to healthy adults and adults with metabolic syndrome. • GTE increased circulating catechins and valerolactones regardless of health status. • GTE decreased intestinal inflammation and small intestinal permeability. • GTE decreased circulating endotoxin. • GTE decreased fasting glucose without affecting systemic inflammation. • Gut-level benefits by GTE support research translation for cardioprotection by green tea. Healthy adults and adults with metabolic syndrome were randomized to a placebo or GTE (1 g; 890 mg catechins) confection for 1 month and then crossed-over to the alternative treatment following a 1-month washout. Regardless of health status, the GTE confection decreased fecal biomarkers of intestinal inflammation (calprotectin and myeloperoxidase) and small intestinal permeability based on a differential sugar absorption test while decreasing serum endotoxin. Abbreviations: GTE, green tea extract; MetS, metabolic syndrome [Display omitted] [ABSTRACT FROM AUTHOR]

We aimed to clarify whether clinical outcomes following immune checkpoint inhibitor-based combination therapy differed according to the baseline kidney function of patients with advanced renal cell carcinoma. CKD did not affect the efficacy of IO-IO and IO-TKI regiments. In contrast, the risks of adverse events might be increased depending on the CKD severity, especially among those receiving IO-TKI regimens. Background: It remains unclear whether kidney function affects outcomes following immune checkpoint inhibitor (ICI)- based combination therapy for advanced renal cell carcinoma (RCC). Methods: We retrospectively evaluated data of 167 patients with advanced RCC, including 98 who received ICI dual combination therapy (ie, immunotherapy [IO]-IO) and 69 who received ICI combined with tyrosine kinase inhibitor (TKI) (ie, IO-TKI). In each regimen, treatment profiles were assessed according to the grade of chronic kidney disease (CKD) as defined by the KDIGO 2012 cr iter ia. Results: Of the 98 patients who received IO-IO, 31 (32%), 30 (31%), 15 (15%), and 22 (22%) had CKD G1/2, G3a, G3b, and G4/5, respectively. Of the 69 patients who received IO-TKI, 18 (26%), 25 (36%), and 26 (38%) had G1/2, G3a, and G3b/4/5, respectively. Regarding efficacy, progression-free survival, overall survival, or objective response rate was not different according to the CKD grade in both treatment groups (P > .05). Regarding safety, the rate of adverse events, treatment interruption, or corticosteroid administration was not different according to the CKD grade in the IO-IO group (P > .05), whereas in the IO-TKI group, the incidence of grade = 3 adverse events were significantly higher (P = .0292), and the rates of ICI interruption (P = .0353) and corticosteroid administration (P = .0685) increased, according to the CKD grade. Conclusion: There is a differential safety but comparable efficacy profile between the IO-IO and IO-TKI regimens in patients with CKD. Further prospective studies are required to confirm these findings. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) have limited efficacy in prostate cancer (PCa) and better biomarkers are needed to predict responses to ICIs. In this study, we found that SigMA detects additional cases of mismatch repair deficiency as compared to microsatellite testing in PCa and identifies patients likely to experience durable response to pembrolizumab. Introduction/Background: Immune checkpoint inhibitors (ICIs) have limited efficacy in prostate cancer (PCa). Better biomarkers are needed to predict responses to ICIs. We sought to demonstrate that a panel-based mutational signature identifies mismatch repair (MMR) deficient (MMRd) PCa and is a biomarker of response to pembrolizumab. Patients and Methods: Clinico-genomic data was obtained for 2664 patients with PCa sequenced at Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering (MSK). Clinical outcomes were collected for patients with metastatic castration-resistant PCa (mCRPC) treated with pembrolizumab at DFCI. SigMA was used to characterize tumors as MMRd or MMR proficient (MMRp). The concordance between MMRd with microsatellite instability (MSI-H) was assessed. Radiographic progression-free survival (rPFS) and overall survival (OS) were collected for patients treated with pembrolizumab. Event-time distributions were estimated using Kaplan-Meier methodology. Results: Across both cohorts, 100% (DFCI: 12/12; MSK: 43/43) of MSI-H tumors were MMRd. However, 14% (2/14) and 9.1% (6/66) of MMRd tumors in the DFCI and MSK cohorts respectively were microsatellite stable (MSS), and 26% (17/66) were MSI-indeterminate in the MSK cohort. Among patients treated with pembrolizumab, those with MMRd (n = 5) versus MMRp (n = 14) mCRPC experienced markedly improved rPFS (HR = 0.088, 95% CI: 0.011-0.70; P = .0064) and OS (HR = 0.11, 95% CI: 0.014-0.80; P = .010) from start of treatment. Four patients with MMRd experienced remissions of > = 2.5 years. Conclusion: SigMA detects additional cases of MMRd as compared to MSI testing in PCa and identifies patients likely to experience durable response to pembrolizumab. [ABSTRACT FROM AUTHOR]

Castration resistant prostate cancer (CRPC) is a challenging subset of prostate cancer associated with an extensive metastatic profile and high mortality. Ketoconazole is a nonselective steroid 17 a-hydroxylase/17,20 lyase (CYP17A1) inhibitor and is employed as a second line treatment option for CRPC with an established efficacy profile in patients. The aim of this study is to assess the efficacy of ketoconazole containing regimens for CRPC in terms of prostate specific antigen (PSA) decline rate using a systematic review and meta-analysis. In this review, an electronic search was carried out on PubMed, Cochrane CENTRAL, Scopus, and Google Scholar to find relevant literature. Random effects model was used to assess pooled PSA decline rate and 95% CIs. Publication bias was assessed using the funnel plot symmetry and one-tailed Egger's and Begg's test. In all cases, P -value < .05 was indicative of significant results. The review is registered with PROSPERO: CRD42023466536. A total of 483 articles were retrieved after database searching, out of which 23 studies (having a total of 1315 patients) were included in the review based on prespecified cr iter ia. The PSA decline rate was reported in the 14 observational studies (having 964 patients) and 9 experimental studies (having 351 patients). Pooled results revealed that 48.6% (95% CI 43.1-54.2; P -value < .001; I2 = 73.24%) of participants achieved more than 50% decline in PSA (602/1315 participants). Sensitivity analysis using the leave-one-out method revealed no substantial change in pooled effect estimates; (Risk Ratio) RR 47.2% to RR 49.8% demonstrating the robustness of our results. There was no evidence of publication bias as assessed from the funnel plot symmetry. Ketoconazole containing regimens have shown moderate efficacy in high risk CRPC patients as demonstrated by the pooled results. Hence, a ketoconazole based chemotherapy can be added to patients' regimen if there is a persistent rise in PSA levels after androgen deprivation therapy. [ABSTRACT FROM AUTHOR]

Poly (ADP-ribose) polymerase inhibitors (PARPi) represent an option in selected cases of metastatic castration-resistant prostate cancer (mCRPC). The aim of the present systematic review and meta-analysis is to evaluate the efficacy and safety of approved (Olapar ib, Rucapar ib) and investigational (Talazopar ib, Nirapar ib, Velipar ib) PARPi in mCRPC patients. Three databases were queried for studies analyzing oncological outcomes and adverse events of mCRPC patients receiving PARPi. Primary outcome was a PSA decline ≥ 50% from baseline. Secondary outcomes were objective response rate, progression-free survival (PFS), radiological PFS, overall survival (OS), conversion of circulating tumor cell count, and time to PSA progression. The number and rate of any grade adverse events (AEs), grade ≥ 3 AEs, and most common grade ≥ 3 AEs were registered. A subanalysis of outcomes per mutation type, prospective trials, and studies adopting combination therapies was performed. Overall, 31 studies were included in this systematic review, 28 of which are available for meta-analysis. The most frequently investigated dr ug was Olapar ib. The most frequent mutation was BRCA2. A PSA decline rate of 43% (95% CI 0.32-0.54) was observed in the overall population. Mean OS was 15.9 (95% CI 12.9-19.0) months. In BRCA2 patients, PSA decline rate was 66% (95% CI 0.57-0.7) and OS 23.4 months (95% CI 22.8-24.1). Half of the patients suffered from grade 3 and 4 AEs (0.50 [95% CI 0.39-0.60]). Most common AEs were hematological, the most frequent being anemia (21.5%). PARP inhibitors represent a viable option for mCRPC patients. Current evidence suggests an increased effectiveness in homologous recombination repair (HRR) gene mutation carriers, especially BRCA2. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma is the predominant histological type of kidney cancer with historically poor patient outcomes. Lenvatinib in combination with pembrolizumab is an approved first-line regimen for people with advanced renal cell carcinoma that showed clinically meaningful improvements in efficacy over sunitinib in the CLEAR trial; however, reduced patient exposure to treatment (often stemming from adverse reactions) is a potential therapeutic barrier that must be addressed. Here, we present management strategies for adverse reactions associated with this treatment combination: fatigue, diarrhea, musculoskeletal pain, hypertension, stomatitis, decreased appetite, rash, nausea, and proteinuria. Dosing modification of lenvatinib and pembrolizumab should be made according to the prescribing information for each medication. Clinicians should consider that some adverse reactions, such as diarrhea, may be attributable to lenvatinib, or may be a symptom of immune-related adverse reactions to pembrolizumab (such as colitis). Adverse reactions can generally be managed by: (1) advising the patient on precautionary measures (eg, for stomatitis, practice dental hygiene, avoid irritating foods, and maintain adequate hydration), (2) monitoring for changes in symptoms from baseline (eg, changes in bowel movements, blood pressure or level of fatigue), (3) interrupting/dose reducing lenvatinib or interrupting pembrolizumab, if warranted, and advising the patient to manage their current symptoms via self-care (managing diarrhea with antidiarrheal agents and hydration), and (4) implementing medical interventions (eg, thyroid replacement or antihypertensive therapy) when needed. Through successful management of adverse reactions, oncology clinicians can improve the well-being of their patients and likely enhance adherence rates to treatment with lenvatinib and pembrolizumab. [ABSTRACT FROM AUTHOR]

As most patients with metastatic urothelial carcinoma will be treated with immune checkpoint inhibitors (ICI), familiarity with their toxicities is fundamental to clinical management. Our single-institution experience demonstrated a high rate of immune-related adverse events (irAEs) in patients undergoing ICI rechallenge following an initial irAE, while a durable clinical benefit off treatment was seen in those requiring permanent ICI discontinuation. Introduction: As most patients with metastatic urothelial carcinoma (mUC) will be treated with immune checkpoint inhibitors (ICI), familiarity with their associated immune-related adverse events (irAEs) is cr itical. We descr ibe the characteristics and outcomes of ICI-treated mUC patients who experienced irAEs requiring treatment interruption (TI) or permanent discontinuation. Materials and Methods: ICI-treated mUC patients who developed grade ≥2 irAEs were reviewed. Clinical-, treatment-, and toxicity-related data were evaluated. Toxicity was graded per common terminology for categorization of adverse events v5.0. Cohorts were divided into patients who underwent ICI rechallenge and those who required permanent ICI discontinuation. Time to treatment interruption (TTI), time to next treatment, and duration of clinical benefit were assessed descriptively. Progression-free survival and overall survival (OS) were estimated using Kaplan-Meier methodology. Results: Of 200 ICI-treated mUC patients at Cleveland Clinic between October 2015 and October 2020, 16 (8%) experienced ≥ grade 2 irAEs necessitating TI. Median TTI among all patients was 6.5 months (range, 1-19). Eleven patients (69%) required corticosteroids. ICI were held and rechallenged in 10 patients (62%) and permanently discontinued in 6 patients (38%). Of the 10 ICI-rechallenged patients, 7 (70%) experienced another irAE upon rechallenge with median time to irAE recurrence of 2.9 months (range, 0.1-10.9); 3 (30%) eventually discontinued ICI due to recrudescent irAEs. Four (40%) of the 10 ICI-rechallenged patients received subsequent therapy. Five (83%) of the 6 patients who permanently discontinued ICI demonstrated durable clinical benefit off therapy with median duration of clinical benefit 17.7 months (range, 14.2-55.2). Two-year OS was 40% (95% CI: 19%-86%) in the ICI rechallenge cohort and 67% (95% CI: 38%-100%) in the permanent discontinuation cohort. Conclusion: ICI-treated mUC patients who developed irAEs requiring TI had a high rate of subsequent irAEs upon ICI rechallenge. Importantly, patients who permanently discontinued ICI due to irAE demonstrated durable clinical benefit off treatment. [ABSTRACT FROM AUTHOR]

This study assessed second-line therapy options for metastatic non-clear cell renal cell carcinoma (nccRCC) patients following first-line tyrosine kinase inhibitor (TKI) treatment. Among 65 patients, combination therapy (TKI plus anti-PD1) showed improved response rates (ORR 50.0%, DCR 70.5%) compared to TKI monotherapy (ORR 14.3%, DCR 28.6%). Median progression-free survival (PFS) for combination therapy was 9.2 months vs. 5.4 months for TKI monotherapy, with similar adverse event rates. Anti-PD-1 plus TKI therapy appears effective and safe for nccRCC patients who progressed after initial TKI treatment. Objectives: Guidelines recommend clinical trials or tyrosine kinase inhibitor (TKI) as the first-line option for systemic therapy for non-clear cell renal cell carcinoma (nccRCC) with limited efficacy. However, the preferred subsequent options remain unclear when patients progress after first-line treatment. This study aimed to evaluate the efficacy and safety of anti-PD-1 plus TKI therapy as the second-line regimen in nccRCC. Patients and Methods: We conducted a retrospective analysis of patients with metastatic nccRCC who failed first-line TKI therapy between October 2011 and September 2020. The baseline characteristics of the patients and adverse events (AEs) were collected. Efficacy measures included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Results: The current study enrolled 65 patients, with a median age of 48 (interquartile 37-60) years. Among all patients, 21 received TKI monotherapy while 44 patients received combination therapy (TKI plus anti-PD1). The ORR and DCR for the whole cohort were 38.5% and 56.9%, respectively. ORR (50.0% vs. 14.3%, P = .006) and DCR (70.5% vs. 28.6%, P = .001) were improved in the combination group compared with the TKI group. The overall second-line PFS was 7.7 (95% CI: 6.1-9.3) months and OS was 25.2 (19.5-30.8) months. Patients receiving combination therapy had a longer PFS compared with those receiving TKI monotherapy [median PFS (95% CI): 9.2 (5.9-12.4) vs. 5.4 (2.6-8.2) m, Log-rank P = .002]. The incidence of treatment-related AEs of grade 3 or higher was comparable between the 2 groups (56.8% vs. 52.4%). Conclusion: Anti-PD-1 plus TKI therapy appeared effective and safe in the treatment of patients with metastatic nccRCC who progressed after first-line TKIs. [ABSTRACT FROM AUTHOR]

Cabozantinib is a widely used multikinase-inhibitor for the treatment of metastatic renal cell carcinoma (mRCC). This study analyzed the efficacy of cabozantinib in real world, including heavily pretreated patients. Antitumor activity was observed in various treatment lines; moreover, we observed that an alternative treatment schedule improves PFS when compared to continuous dosing. No new safety signals emerged from our analysis. Background: The multikinase-inhibitor Cabozantinib is a widely used treatment strategy in metastatic renal cell carcinoma (mRCC), either in combination with the programmed cell death protein-1 (PD-1) inhibitor nivolumab or as monotherapy. Cabozantinib is given continuously at a dose of 60 mg once daily when used as a single agent and at 40 mg when combined with nivolumab. Treatment-related adverse events (TRAE's) were shown to occur frequently. Objective: We aimed to assess the safety and efficacy of cabozantinib in patients with mRCC. Patients were treated in various lines. Furthermore, we analyzed the impact of an alternative treatment schedule in patients not able to maintain continuous dosing. Patients: This is a single center retrospective study from the Medical University of Vienna. Outcome Measurements and Statistical Analysis: Overall response rates (ORR), progression free survival (PFS) and overall survival (OS) were evaluated for the entire cohort, by treatment line and by treatment schedule. Results: Between January 2014 until April 2021, 71 patients received cabozantinib. Sixty-seven patients were eligible for full evaluation. By IMDC cr iter ia, 32.4%, 59.2%, and 8.5% were classified as favorable, intermediate and poor risk respectively. Cabozantinib was offered as a 2nd-line or 3rd-line treatment in 38.0% and 32.4% of patients, respectively. An alternative treatment schedule was offered in 39.1% of patients. Objective responses were found in 43.3% (CR 6%) of patients and the median PFS was 10.8 months (95% CI: 5.5-16.2). When compared to continuous dosing, an alternative treatment schedule was associated with longer PFS (12.2 months (95% CI: 0-25.5) vs. 6.1 months (95% CI: 0.37-11.8) (P = .014, HR 0.46 (95% CI: 0.24-0.86), respectively) and a lower frequency and severity of TRAE's. Conclusions: Safety and efficacy of cabozantinib in real world is comparable to what has been observed in the pivotal trials, irrespective of the treatment line. An alternative schedule may further improve efficacy and safety. [ABSTRACT FROM AUTHOR]

Metastatic hormone-sensitive prostate cancer benefits from upfront treatment intensification. To date, we do not have a validated prognostic model to guide treatment choice. In our study, docetaxel-treated patients with high Gleason score, high disease burden, pain or unfavorable laboratory parameters at baseline had worse outcomes. These results may be useful in tailoring treatment in this setting. Background: Treatment of metastatic hormone-sensitive prostate cancer (mHSPC) dramatically changed. PEACE-1 and ARASENS trials established triplet therapy efficacy. Identifying prognostic factors supporting treatment choice is pivotal. Methods: TEAM is an observational, retrospective study to evaluate prognostic role of variables in mHSPC patients receiving upfront docetaxel in 11 Italian centers. Outcome measures were progression-free survival (PFS) and overall-survival (OS). Results: From September 2014 to December 2020, 147 patients were included. Median PFS and OS were 11.6 and 37.4 months. At univariate analysis, PFS-related variables were Gleason Score (GS) (P = .001), opioid use (P = .004), bone metastases number (P < .001), baseline PSA (P = .006), Hb (P < .001), ALP (P < .001) and LDH (P = .002), time between ADT and docetaxel start (P = .018), 3-month PSA (P < .001) and ALP (P < .001), and number of docetaxel cycles (P < .001). OS-related variables were PSA at diagnosis (P = .024), primary tumor treatment (P = .022), baseline pain (P = .015), opioid use (P < .001), bone metastases number (P <. 001), baseline Hb (P < .001), ALP (P < .001) and LDH (P = .001), NLR ratio (P = .039), 3-month PSA (P < .001) and ALP (P < .001) and docetaxel cycles number (P < .001). At multivariate analysis, independent prognostic variables were GS, opioid use, baseline LDH and time between ADT and docetaxel initiation for PFS, and baseline Hb and LDH for OS. Conclusion: Patients receiving upfront docetaxel with high GS, high disease burden, pain or opioid use, baseline unfavorable laboratory values had worse outcomes. Patients had greater docetaxel benefit when initiated early after ADT start. These parameters could be taken into account when selecting candidates for triplet therapy. [ABSTRACT FROM AUTHOR]

• Stiripentol performs best in reducing convulsive seizure frequency in DS patients. • Fenfluramine performs best in reducing at least 75 % convulsive seizure frequency. • Stiripentol performs best in reducing at least 50 % convulsive seizure frequency. • Stiripentol need further study in reducing at least 75 % convulsive seizure frequency. Numerous anti-seizure medications (ASMs) have been developed to treat Dravet syndrome (DS). This network meta-analysis aimed to comprehensively analyse the efficacy of ASMs in DS patients, especially in non-seizure-free patients after treatment. PubMed, EMBASE, Cochrane Library, and Chinese National Knowledge Infrastructure databases were searched. The treatment efficacy was assessed by the percentage reduction in monthly convulsive seizure frequency (MCSF) from baseline or individuals who achieved at least a 50 % or 75 % reduction from baseline in convulsive seizure frequency (CSF). Six randomised controlled trials with 633 participants and seven regimens based on four add-on ASMs—fenfluramine (FFA), stiripentol (STP), cannabidiol (CBD), and soticlestat—were included. All drug regimens were superior to the placebo at achieving at least 50 % and 75 % reductions in CSF, but only STP, 0.4 mg/kg/d FFA (FFA0.4), and 0.7 mg/kg/d FFA (FFA0.7) reduced MCSF. STP (50 mg/kg/d) had the highest correlation with reducing MCSF and achieving at least a 50 % reduction from baseline in CSF, followed by FFA0.4 and FFA0.7. Soticlestat and CBD may also be effective in reducing seizures in DS patients. STP can be recommended as the first choice among the included drug regimens for reducing seizures in DS patients, while FFA0.4 may be considered the second choice. Other drug regimens can be used as alternative treatments. STP, FFA0.4, and FFA0.7 may consistently present favourable efficacy in most DS patients, while other regimens may present prominent inter-individual variability. Appropriate dose selection and intense monitoring are necessary when treating DS using these drugs. [ABSTRACT FROM AUTHOR]

The evidence of treatment options' efficacy on acute bipolar manic episodes is relatively less in youths than adults. We aimed to compare and rank the drug's efficacy, acceptability, tolerability, and safety for acute mania in children and adolescents. We systematically reviewed the double-blinded, randomized controlled trials (RCTs) comparing drugs or placebo for acute manic episodes of bipolar disorder in children and adolescents using PRISMA guidelines. We searched PubMed/MEDLINE, EMBASE, Web of Science, EBSCO, Scopus, the Cochrane Central Register of Controlled Trials, and https://clinicaltrials.gov from inception until November 20, 2022. Response to treatment was the primary outcome, and random-effects network meta-analyses were conducted (PROSPERO 2022: CRD42022367455). Of 10,134 citations, we included 15 RCTs, including 2372 patients (47 % female), 15 psychotropic drugs, and the placebo. Risperidone 0.5–2.5 mg/day, aripiprazole 30 mg/day olanzapine, quetiapine 400 mg/day, quetiapine 600 mg/day, asenapine 5 mg/day, asenapine 10 mg, ziprasidone, and aripiprazole 10 mg were found to be effective (in comparison with placebo) in children and adolescents, respectively (τ2 = 0.0072, I2 = 10.2 %). The tolerability of aripiprazole 30 mg/day was lower than risperidone 0.5–2.5 mg/day and olanzapine. Oxcarbazepine had the highest discontinuation due to the adverse effects risk ratio. Efficacy ranking of the treatments could be performed by evaluating relatively few RCT results, and only monotherapies were considered. Efficacy, acceptability, tolerability, and safety are changing with the doses of antipsychotics for children and adolescents with acute bipolar manic episodes. Drug selection and optimum dosage should be carefully adjusted in children and adolescents. • In this systematic review and network meta-analysis of 15 RCTs, risperidone 0.5-2.5 mg/day, aripiprazole 30 mg/day, and olanzapine were associated with higher efficacy and acceptability. • Oxcarbazepine, aripiprazole 30 mg/day, and ziprasidone were associated with lower tolerability. • This study suggests that antipsychotics have higher efficacy in treatment of bipolar mania in children and adolescents. • Efficacy and tolerability are changing with the doses of antipsychotics for children and adolescents. [ABSTRACT FROM AUTHOR]

Forced degradation, also known as stress testing, is used throughout pharmaceutical development for many purposes including assessing the comparability of biopharmaceutical products according to ICH Guideline Q5E. These formal comparability studies, the results of which are submitted to health authorities, investigate potential impacts of manufacturing process changes on the quality, safety, and efficacy of the drug. Despite the wide use of forced degradation in comparability assessments, detailed guidance on the design and interpretation of such studies is scarce. The BioPhorum Development Group is an industry-wide consortium enabling networking and sharing of common practices for the development of biopharmaceuticals. The BioPhorum Development Group Forced Degradation Workstream recently conducted several group discussions and a benchmarking survey to understand current industry approaches for the use of forced degradation studies to assess comparability of protein-based biopharmaceuticals. The results provide insight into the design of forced degradation studies, analytical characterization and testing strategies, data evaluation criteria, as well as some considerations and differences for non-platform modalities (e.g., non-traditional mAbs). This article presents survey responses from several global companies of various sizes and provides an industry perspective and experience regarding the practicalities of using forced degradation to assess comparability. [ABSTRACT FROM AUTHOR]

Postherpetic pain (PHP) is difficult to control. Although Neurotropin® (NTP) and methylcobalamin (MCB) are often prescribed to treat the pain, the efficacy of combined treatment for PHP remains imcompletely understood. In this study, we investigate the combined effects of NTP and MCB on PHP in mice. NTP and MCB were administered from day 10–29 after herpes simplex virus type-1 (HSV-1) infection. The pain-related responses were evaluated using a paint brush. The expression of neuropathy-related factor (ATF3) and nerve repair factors (GAP-43 and SPRR1A) in the dorsal root ganglion (DRG) and neurons in the skin were evaluated by immunohistochemical staining. Nerve growth factor (NGF) and neurotrophin-3 (NT3) mRNA expression levels were evaluated using real-time PCR. Repeated treatment with NTP and MCB after the acute phase inhibited PHP. Combined treatment with these drugs inhibited PHP at an earlier stage than either treatment alone. In the DRG of HSV-1-infected mice, MCB, but not NTP, decreased the number of cells expressing ATF3 and increased the number of cells expressing GAP-43- and SPRR1A. In addition, MCB, but not NTP, also increased and recovered non-myelinated neurons decreased in the lesional skin. NTP increased the mRNA levels of NTF3 in keratinocytes, while MCB increased that of NGF in Schwann cells. These results suggest that combined treatment with NTP and MCB is useful for the treatment of PHP. The combined effect may be attributed to the different analgesic mechanisms of these drugs. • Neurotropin® and methylcobalamin to postherpetic pain (PHP) were evaluated in mice. • Combined treatment with these drugs to PHP showed faster efficacy than either drug. • Methylcobalamin effected the expression of the factors on neuropathy or nerve repair. • These drugs induced the gene expression on neurotropic factors. • Combined treatment with these drugs is more effective to PHP than each drug alone. [ABSTRACT FROM AUTHOR]

The routine use of tranexamic acid (TXA) in shoulder arthroplasty has grown in popularity due to the perceived benefits of reduction in intra-operative blood loss and the related adverse sequelae. Both intravenous (IV) and oral (PO) formulations of TXA exist and there is minimal data regarding the optimal route of administration. This study aimed to assess whether there was a significant difference in efficacy between the administration of PO vs. IV TXA prior to total shoulder arthroplasty. We hypothesized equivalence in preoperative (preop) to postoperative change in hemoglobin (Hg) and hematocrit (Hct) as well as the length of stay (LOS), 90-day readmission, transfusion rates and adverse events between the two routes. A single-center retrospective chart review was conducted between May 2022 and January 2023. All patients undergoing primary anatomic or reverse total shoulder arthroplasty during this period were included. Patients undergoing revision shoulder arthroplasty or arthroplasty for fracture were excluded. The primary outcome of interest was the change (Δ) in preop to postoperative day 1 Hg and Hct reported as ΔHg and ΔHct. Intraoperative estimated blood loss (EBL), transfusion rates, patient demographics, LOS, and adverse event data were also collected. Two hundred and thirty patients who underwent shoulder arthroplasty met the inclusion criteria. A total of 176 patients received preoppreop IV TXA and 54 patients received preop PO TXA. There was no significant difference between groups in the mean ΔHg (1.69 in the IV group and 2.52 in the PO group, P =.11) or ΔHct (5.19 in the IV group and 5.04 in the PO group, P =.42). There was no significant difference in LOS, transfusion rates, or 90-day readmission between groups. There was a significant difference in the mean EBL between the two groups (123.78cc in the IV group and 173.06cc in the PO group, P <.001). Our study was adequately powered at 0.95. There was no statistically significant difference between the IV and PO TXA groups when comparing preop to postoperative day 1 change in Hg and Hct, LOS, transfusion rates, surgical site infections, and 90-day readmission indicating similar efficacy between the two routes of administration. EBL was found to be significantly higher in the PO TXA group, though the clinical significance of this finding is indeterminate. Given these findings, however, PO TXA may be a reliable alternative to IV TXA in primary shoulder arthroplasty. [ABSTRACT FROM AUTHOR]

We present for the first-time efficacy and tolerability of GLP-1-RA (Semaglutide) in Smith-Kingsmore syndrome (SKS). SKS is a rare genetic disorder characterized by intellectual disability, macrocephaly, seizures and distinctive facial features due to MTOR gene mutation. We present a 22-year-old woman with mosaic SKS and severe obesity (Body Mass Index ≥40 kg/m²), treated with semaglutide. She achieved a 9 kg (7.44%) weight loss over 12 months without adverse effects.This case highlights semaglutide's potential in managing obesity in SKS patients, emphasizing the need for further research in this rare genetic disorder. • Smith-Kingsmore syndrome (SKS) is a rare genetic disorder due to MTOR gene mutation. • Obesity has been sporadically reported among SKS individuals. • The use of GLP-1 analogs has never been described in SKS individuals. • Semaglutide emerges as a promising therapeutic for obesity in mTORopathies. • Digestive tolerance was excellent and no side effects have been observed. [ABSTRACT FROM AUTHOR]

• Post hoc study using pooled data from two phase 3 bempedoic acid clinical trials. • Patients with and without heterozygous familial hypercholesterolemia were included. • In both groups, bempedoic acid lowered LDL-C and other lipid parameters vs. placebo. • Bempedoic acid was generally well tolerated in both patient groups. • No new safety findings in patients with heterozygous familial hypercholesterolemia. Patients with heterozygous familial hypercholesterolemia (HeFH) often cannot reach guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals despite multidrug therapy. To evaluate the efficacy and safety of bempedoic acid as an add-on therapy for lowering LDL-C in patients with HeFH. Pooled data from two 52-week phase 3 clinical trials of patients with atherosclerotic cardiovascular disease and/or HeFH receiving maximally tolerated statin therapy (randomized 2:1 to bempedoic acid or placebo) were analyzed by HeFH status. Endpoints included changes from baseline to week 12 (and up to week 52) in LDL-C and other lipid parameters, achievement of LDL-C goals, and safety. A total of 217 (bempedoic acid, 146; placebo, 71) patients with HeFH and 2,792 (bempedoic acid, 1,864; placebo, 928) without HeFH were included (mean baseline LDL-C, 172.8 mg/dL and 102.6 mg/dL, respectively). Bempedoic acid significantly lowered LDL-C at week 12 vs. placebo regardless of HeFH status (with HeFH, −21.2%; without HeFH, −18.2% [both P <0.0001]). Bempedoic acid significantly reduced other lipid parameters and high-sensitivity C-reactive protein vs. placebo regardless of HeFH status (all P ≤0.01). Among patients with HeFH treated with bempedoic acid, 32% and 27% achieved LDL-C <100 mg/dL at weeks 12 and 52, respectively. Overall treatment-emergent adverse event incidence was comparable across all four groups (74.7–77.5%). Bempedoic acid significantly lowered LDL-C levels vs. placebo and was generally well tolerated in all patients, with no new safety findings in patients with HeFH, despite more intensive lipid-lowering therapy in patients with vs. without HeFH. [Display omitted] [ABSTRACT FROM AUTHOR]

Cisplatin is an effective chemotherapy drug widely used in the treatment of various solid tumors. However, the clinical usage of cisplatin is limited by its nephrotoxicity. Isorhamnetin, a natural flavanol compound, displays remarkable pharmacological effects, including anti-inflammatory and anti-oxidation. In this study, we aimed to investigate the potential of isorhamnetin in alleviating acute kidney injury induced by cisplatin. In vitro study showed that isorhamnetin significantly suppressed the cytotoxic effects of cisplatin on human tubular epithelial cells. Furthermore, isorhamnetin exerted significantly inhibitory effects on cisplatin-induced apoptosis and inflammatory response. In acute kidney injury mice induced by a single intraperitoneal injection with 20 mg/kg cisplatin, oral administration of isorhamnetin two days before or 2 h after cisplatin injection effectively ameliorated renal function and renal tubule injury. Transcriptomics RNA-seq analysis of the mice kidney tissues suggested that isorhamnetin treatment may protect against cisplatin-induced nephrotoxicity via PGC-1α mediated fatty acid oxidation. Isorhamnetin achieved significant enhancements in the lipid clearance, ATP level, as well as the expression of PGC-1α and its downstream target genes PPARα and CPT1A, which were otherwise impaired by cisplatin. In addition, the protection effects of isorhamnetin against cisplatin-induced nephrotoxicity were abolished by a PGC-1α inhibitor, SR-18292. In conclusion, our findings indicate that isorhamnetin could protect against cisplatin-induced acute kidney injury by inducing PGC-1α-dependent reprogramming of fatty acid oxidation, which highlights the clinical potential of isorhamnetin as a therapeutic approach for the management of cisplatin-induced nephrotoxicity. [Display omitted] • Isorhamnetin ameliorated cisplatin-induced acute kidney injury. • Isorhamnetin attenuated cisplatin-induced fatty acid oxidation dysregulation. • PGC-1α-dependent fatty acid oxidation played an essential role in the protection effect of isorhamnetin on AKI. [ABSTRACT FROM AUTHOR]

Quantitative gait analysis (QGA) has the potential to support clinician decision-making. However, it is not yet widely accepted in practice. Evidence for clinical efficacy (i.e., efficacy and effectiveness), as well as a users' perspective on using the technology in clinical practice (e.g., ease of use and usefulness) can help impact their widespread adoption. To synthesize the literature on the clinical efficacy and clinician perspectives on the use of gait analysis technologies in the clinical care of adult populations. This scoping review followed the Joanna Briggs Institute (JBI) methodology for scoping reviews. We included peer-reviewed and gray literature (i.e., conference abstracts). A search was conducted in MEDLINE (Ovid), CENTRAL (Ovid), EMBASE (Ovid), CINAHL (EBSCO) and SPORTDiscus (EBSCO). Included full-text studies were critically appraised using the JBI critical appraisal tools. A total of 15 full-text studies and two conference abstracts were included in this review. Results suggest that QGA technologies can influence decision-making with some evidence to suggest their role in improving patient outcomes. The main barrier to ease of use was a clinician's lack of data expertise, and main facilitator was receiving support from staff. Barriers to usefulness included challenges finding suitable reference data and data accuracy, while facilitators were enhancing patient care and supporting clinical decision-making. This review is the first step to understanding how QGA technologies can optimize clinical practice. Many gaps in the literature exist and reveal opportunities to improve the clinical adoption of gait analysis technologies. Further research is needed in two main areas: 1) examining the clinical efficacy of gait analysis technologies and 2) gathering clinician perspectives using a theoretical model like the Technology Acceptance Model to guide study design. Results will inform research aimed at evaluating, developing, or implementing these technologies. This work was supported by the Walter and Maria Schroeder Institute for Brain Innovation and Recovery and AGE-WELL Graduate Student Award in Technology and Aging [2021,2022]. • Quantitative gait analysis technologies can influence decision-making. • Some evidence suggests the role of gait technologies in improving patient outcomes. • A barrier to ease of use was a clinician's lack of data expertise and a facilitator was receiving support from staff. • A barrier to usefulness was challenges finding suitable reference data and a facilitator was enhancing patient care. [ABSTRACT FROM AUTHOR]

Enterococci facilitate polymicrobial infections, leading to more complicated pathogenesis and poorer prognoses, and compromise the efficacy of antimicrobial agents by promoting the colonization, proliferation, and persistence of diverse pathogenic bacteria. The elucidation of synergistic interactions between enterococci and pathogens is expected to accelerate the discovery and development of novel therapies against polymicrobial infections. Multitargeted or combinatorial therapies provide promising alternative strategies to treat polymicrobial infections by simultaneously targeting pathogens and enterococci, thereby mitigating or eliminating both the causative agents and pathobionts. Enterococci are ubiquitous members of the gut microbiota in human beings and animals and are among the most important nosocomial organisms. Due to their opportunistic pathogenicity, enterococci are referred to as pathobionts and play decisive roles in a diverse array of polymicrobial infections. Enterococci can promote the colonization, pathogenesis, and persistence of various pathogens, compromise the efficacy of drugs, and pose a severe threat to public health. Most current treatments tend to focus on the sole pathogenic bacteria, with insufficient attention to the driving role of enterococci. In this review, we summarize the characteristics of enterococci in infections, the factors facilitating their outgrowth, as well as the sites and types of enterococci-associated polymicrobial infections. We present an overview of the underlying mechanisms of enterococci-mediated pathogenesis in polymicrobial infections. Furthermore, we discuss alternative strategies and potential intervention approaches to restrict such infections, shedding light on the discovery and development of new therapies against polymicrobial infections. [ABSTRACT FROM AUTHOR]

The therapeutic efficacy of anticancer drugs loaded in liposomes composed of rigid phosphatidylcholine (PC) is hindered by the limited release of these drugs at the tumor site, which in turn hampers delivery of the drug to its intracellular target. In an attempt to improve the therapeutic efficacy of liposomal anticancer drugs, we here explored the use of empty liposomes as "trigger" vehicles to induce drug release from drug-loaded liposomes through liposome-liposome interactions. Empty liposomes containing PC in which omega-3 fatty acids comprised both fatty acid strands (Omega-L) showed a triggering effect on drug release from doxorubicin (DOX)-loaded liposomes (Caelyx). The effectiveness of this triggered-release effect was dependent on the Omega-L composition as well as the mixing ratio of Omega-L to Caelyx. Cryo-TEM and differential calorimetry studies revealed that the Omega-L effect was associated with liposome-liposome interactions that led to loosened membrane packing and increased fluidity of Caelyx. In cultured cells, the intracellular/intranuclear DOX uptake and anticancer efficacy of Caelyx was greatly improved by Omega-L pre-mixing. Intravenous injection of rats with Caelyx, premixed with Omega-L, decreased the area under the plasma concentration-time curve from time zero to time infinity and increased clearance without significantly changing the mean residence time or terminal half-life of DOX compared with Caelyx alone. Ex vivo bioimaging showed that DOX fluorescence in tumors, but not in other organs, was significantly increased by Omega-L premixing. In the mouse xenograft model, premixing of Omega-L with Caelyx suppressed tumor growth 2.5-fold compared with Caelyx. Collectively, the data provide preliminary evidence that the Omega-L–triggered drug release that occurs before and after dosing, particularly at tumor site, improved the therapeutic efficacy of Caelyx. The simple approach described here could enhance the therapeutic value of Caelyx and other anticancer drug-loaded liposomes. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • A method was developed for 20 min fluorescent staining of Haemonchus contortus eggs in faecal samples. • Automated counts correlated and were concordant with coproculture and manual counts. • We have provided a method for a rapid, in-clinic faecal egg count reduction test for H. contortus. Haemonchus contortus is one of the most pathogenic nematodes affecting small ruminants globally and is responsible for large economic losses in the sheep and goat industry. Anthelmintic resistance is rampant in this parasite and thus parasite control programs must account for drug efficacy on individual farms and, sometimes, whether H. contortus is the most prevalent trichostrongylid. Historically, coproculture has been the main way to determine the prevalence of H. contortus in faecal samples due to the inability to morphologically differentiate between trichostrongylid egg types, but this process requires a skilled technician and takes multiple days to complete. Fluoresceinated peanut agglutinin (PNA) has been shown to specifically bind H. contortus and thus differentiate eggs based on whether they fluoresce, but this method has not been widely adopted. The ParasightTM System (PS) fluorescently stains helminth eggs in order to identify and quantify them, and the H. contortus PNA staining method was therefore adapted to this platform using methodology requiring only 20 min to obtain results. In this study, 74 fecal samples were collected from sheep and analyzed for PNA-stained H. contortus, using both PS and manual fluorescence microscopy. The percentage of H. contortus was determined based on standard total strongylid counts with PS or brightfield microscopy. Additionally, 15 samples were processed for coproculture with larval identification, and analyzed with both manual and automated PNA methods. All methods were compared using the coefficient of determination (R2) and the Lin's concordance correlation coefficient (ρc). ParasightTM and manual PNA percent H. contortus results were highly correlated with R2 = 0.8436 and ρc = 0.9100 for all 74 fecal samples. Coproculture versus PS percent H. contortus were also highly correlated with R2 = 0.8245 and ρc = 0.8605. Overall, this system provides a rapid and convenient method for determining the percentage of H. contortus in sheep and goat fecal samples without requiring specialized training. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is an intractable disease requiring long-term treatment. S-adenosyl-L-methionine (SAMe), a natural substance, has antidepressant effects, but the exact effect remains unclear. This study examines the evidence concerning the efficacy of SAMe as a monotherapy or in combination with antidepressants. The PubMed, EMBASE, and Cochrane electronic databases were searched for meta-analyses of randomized controlled clinical trials (RCTs) until June 30, 2023. We performed a systematic review and meta-analysis of the enrolled trials that met the inclusion criteria, with the aim to compare the effects of SAMe to those of a placebo or active agents, or SAMe combined with other antidepressants in the treatment of MDD. Fourteen trials, with a total of 1522 subjects, were included in this review. The daily dose of SAMe varied from 200 to 3200 mg and the study duration ranged between 2 and 12 weeks. The results of SAMe versus placebo as a monotherapy, SAMe versus imipramine or escitalopram as a monotherapy, and SAMe versus placebo as an adjunctive therapy, showed no significant difference in depression with SAMe compared to the comparison treatment. SAMe may provide relief of depression symptoms similar to imipramine or escitalopram. However, the results of the comparisons should be interpreted with caution due to the small number of studies and the large range of SAMe doses that were used in the included trials. Therefore, we recommend that patients discuss treatment options with their doctor before taking SAMe. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) has a high prevalence worldwide. Although the economic burden of depression increases annually, the proportion of patients with MDD receiving treatment did not increase between 2010 and 2018, suggesting an unmet treatment need. The burden of long-term treatment for depression is borne by patients. In this context, biomarkers associated with drug-treatment responses can be used as reference indicators to reduce unnecessary treatment and costs. Changes in biomolecules in response to drug treatment for depression and drug-treatment response markers have been studied extensively. The Hamilton Depression Rating Scale (HAM-D) is mainly used as an indicator of response and remission; however, it is difficult to determine whether the medication contributes to recovery when evaluating the effect of drug treatment for depression based on this assessment. Therefore, it is necessary to monitor the effect of medication compared to normal health conditions. Here, serum protein levels were compared using liquid chromatography-tandem mass spectrometry among a group of patients with depression who did not receive medication, a group of patients receiving medication, and a control group. Eight selected biomarkers, including Apolipoproteins A-I, Complement factor H, Complement C5, Complement C1q subcomponent subunit B, Alpha-2-HS-glycoprotein, Complement C1q subcomponent subunit C, Vitamin D-binding protein and Corticosteroid-binding globulin were distinguished between disease states, and protein levels in the drug-treated group were similar to those in the control group. These markers can be used to monitor the effectiveness of drug treatment. [Display omitted] • Evaluating recovery using the Hamilton Depression Rating Scale is difficult. • Biomarkers that indicate a recovery tendency can be used to monitor the effectiveness of drug treatment in MDD. • Several biological processes are associated with drug treatments for depression. [ABSTRACT FROM AUTHOR]

The aim of this systematic review with meta-analysis was to evaluate the efficacy and safety of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) checkpoint inhibitors in patients with metastatic castration-resistant prostate cancer (mCRPC). We searched PubMed, Embase and Cochrane Library until 1 July 2022 for mCRPC trials testing PD-1/PD-L1 checkpoint inhibitors. We measured the efficacy and safety using overall survival, progression-free survival (PFS), overall response rates (ORR), prostate-specific antigen (PSA) response rate or treatment-related adverse events (TRAEs). When possible, data were meta-analysed. Thirteen studies involving 2533 participants were included in this meta-analysis. The pooled hazard ratio for overall survival was 0.81 (95% confidence interval 0.42–1.20, I2 = 80.3%, P Heterogeneity ＜0.001) and for PFS was 0.65 (95% confidence interval 0.38–0.92, I2 = 72.2%, P Heterogeneity = 0.013). Furthermore, better ORR (relative risk = 2.77, 95% confidence interval 1.25–6.13, I2 = 0%, P Heterogeneity = 0.699) was found in PD-L1-expressing tumours. However, no statistical trends between PD-L1 status on PSA response rate (relative risk = 0.79, 95% confidence interval 0.5–1.25, I2 = 0%, P Heterogeneity = 0.953) and tumour mutational burden on ORR (relative risk = 2.53, 95% confidence interval 0.49–13.12, I2 = 74.5%, P Heterogeneity = 0.02) were observed. The pooled proportions of TRAEs and ≥ grade 3 TRAEs were 85.1% (95% confidence interval = 71.7–98.5%) and 31.6% (95% confidence interval = 18.9–44.4%), respectively. This meta-analysis showed that among selected populations of men with mCRPC, anti-PD-1/PD-L1 combination treatment may significantly increase the PFS benefits. However, overall survival in mCRPC warrants further testing. • Efficacy and safety of PD-1/PD-L1 inhibitors in mCRPC patients was evaluated. • Thirteen studies involving 2533 participants were included in the meta-analysis. • Anti-PD-1/PD-L1 treatment may significantly increase the PFS benefits. [ABSTRACT FROM AUTHOR]

Transformed small cell lung cancer (T-SCLC) is a highly aggressive clinical disease with a notably poor prognosis. It most often arises from epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) following treatment. To date, no standard treatment has been established for T-SCLC. Platinum-etoposide was the most commonly used regimen, but progression-free survival remains unsatisfactory. Therefore, there is an urgent unmet need to develop novel and effective strategies for this population. Our study, a multicentre, open-label, single-arm phase II clinical trial (NCT05957510), aims to evaluate the efficacy and safety of serplulimab plus chemotherapy in untreated T-SCLC patients after histological transformation. In total, 36 eligible participants experiencing SCLC transformation from EGFR -mutant NSCLC will be enrolled to receive combination therapy of serplulimab, etoposide and carboplatin for four to six cycles, followed by maintenance therapy with serplulimab for up to 2 years. The primary endpoint is progression-free survival; secondary endpoints include objective response rate, overall survival and safety. Enrolment started in July 2023 and is ongoing, with an estimated completion date of December 2025. This study aims to provide valuable insights into the efficacy and safety of combining serplulimab with chemotherapy for treating patients with T-SCLC originating from EGFR -mutant NSCLC. • T-SCLC is a highly aggressive disease with a poor prognosis and lacks standard treatment. • Adding immunotherapy to chemotherapy might improve outcomes for T-SCLC but lacks clinical evidence. • The first prospective trial to investigate the efficacy of serplulimab plus chemotherapy for T-SCLC. • The exploratory analysis aims to identify potential biomarkers for immunotherapy in T-SCLC. [ABSTRACT FROM AUTHOR]

To compare the clinical efficacy and safety of first-line treatments for advanced unresectable oesophageal squamous cell cancer. A systematic review and network meta-analysis was carried out by retrieving and retaining relevant literature from databases. The studies were randomised controlled trials comparing first-line treatments for advanced unresectable oesophageal squamous cell cancer. A Bayesian network meta-analysis was used to assess clinical outcomes. Nine studies including 4499 patients receiving first-line treatments were analysed. For all populations, toripalimab plus chemotherapy tended to provide the best overall survival (hazard ratio 0.58, 95% confidence intervals 0.43–0.78) and sintilimab plus chemotherapy provided the best progression-free survival (0.56, 0.46–0.68). Nivolumab plus chemotherapy presented the best objective response rate (odds ratio 2.45, 1.78–3.42) and camrelizumab plus chemotherapy (0.47, 0.29–0.74) appeared to be the safest. Sintilimab plus chemotherapy (0.55, 0.40–0.75) and nivolumab (0.54, 0.37–0.80) plus chemotherapy had the best overall survival in programmed death ligand 1 (PD-L1) tumour proportion score <1% and ≥1% subgroups. Toripalimab plus chemotherapy (0.61, 0.40–0.93) and pembrolizumab (0.57, 0.43–0.75) were the best in overall survival in combined positive score <10 and ≥10 subgroups, respectively. Toripalimab plus chemotherapy showed the best overall survival in the Asian group; pembrolizumab presented better overall survival in the Asian population than the non-Asian group. Most immunotherapy combined with chemotherapy showed superior clinical benefits and sintilimab plus chemotherapy, toripalimab plus chemotherapy and tislelizumab plus chemotherapy had better comprehensive clinical efficacy. PD-L1 expression detection and ethnicity differences are still of great significance and most suitable regimens varied from each subgroup. • Current first-line treatments, including immunotherapy, chemotherapy and monoclonal antibody, were compared in this study. • Immunotherapy, such as sintilimab, toripalimab and tislelizumab, combining with chemotherapy has showed their superiority. • Efficacy still differs in PD-L1 expression level and region subgroups. • Epidermal growth factor receptor targeted monoclonal antibody and chemotherapy didn't show their advantages. [ABSTRACT FROM AUTHOR]

The main protease (Mpro) of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle. The covalent Mpro inhibitor nirmatrelvir (in combination with ritonavir, a pharmacokinetic enhancer) and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic use. Effective antiviral drugs are needed to fight the pandemic, while non-covalent Mpro inhibitors could be promising alternatives due to their high selectivity and favorable druggability. Numerous non-covalent Mpro inhibitors with desirable properties have been developed based on available crystal structures of Mpro. In this article, we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent Mpro inhibitors, followed by a general overview and critical analysis of the available information. Prospective viewpoints and insights into current strategies for the development of non-covalent Mpro inhibitors are also discussed. This graphical abstract is centered by co–crystal structure of SARS-CoV-2 Mpro, highlighting the theme of "non-covalent inhibitors targeting Mpro". The surrounding boxes display some representative medicinal chemistry strategies and active compounds concluded in the article. [Display omitted] [ABSTRACT FROM AUTHOR]

Advanced 3D breast cancer models offer a promising, clinically relevant in vitro tool for researchers. By closely mimicking the interaction between tumor cells and the extracellular matrix compartment, these models could be used to help screen drug efficacy and tailor personalised treatments. Clinical translation remains challenging because these models are often biologically underevaluated and do not consider the models' diversity at the genomic, transcriptomic, proteomic, or epigenomic level in relation to matched patients. Multiomics technologies applied to bioengineered 3D breast cancer models could be game changing to unravel the detailed mechanisms of interaction between cancer cells and stroma for each specific breast cancer subtype and to foster their validation and translation into clinics. Great effort is being made in using spatial multiomics. However, the highly demanding costs of sequencing and informatic analysis are still bottlenecks that need to be overcome. The fields of tissue bioengineering, -omics, and spatial biology are advancing rapidly, each offering the opportunity for a paradigm shift in breast cancer research. However, to date, collaboration between these fields has not reached its full potential. In this review, we describe the most recently generated 3D breast cancer models regarding the biomaterials and technological platforms employed. Additionally, their biological evaluation is reported, highlighting their advantages and limitations. Specifically, we focus on the most up-to-date -omics and spatial biology techniques, which can generate a deeper understanding of the biological relevance of bioengineered 3D breast cancer in vitro models, thus paving the way towards truly clinically relevant microphysiological systems, improved drug development success rates, and personalised medicine approaches. [ABSTRACT FROM AUTHOR]

Blueberries are rich in nutrients and (poly)phenols, popular with consumers, and a major agricultural crop with year-round availability supporting their use in food-based strategies to promote human health. Accumulating evidence indicates blueberry consumption has protective effects on cardiovascular health including vascular dysfunction (i.e., endothelial dysfunction and arterial stiffening). This narrative review synthesizes evidence on blueberries and vascular function and provides insight into underlying mechanisms with a focus on oxidative stress, inflammation, and gut microbiota. Evidence from animal studies supports beneficial impacts on vascular function. Human studies indicate acute and chronic blueberry consumption can improve endothelial function in healthy and at-risk populations and may modulate arterial stiffness, but that evidence is less certain. Results from cell, animal, and human studies suggest blueberry consumption improves vascular function through improving nitric oxide bioavailability, oxidative stress, and inflammation. Limited data in animals suggest the gut microbiome mediates beneficial effects of blueberries on vascular function; however, there is a paucity of studies evaluating the gut microbiome in humans. Translational evidence indicates anthocyanin metabolites mediate effects of blueberries on endothelial function, though this does not exclude potential synergistic and/or additive effects of other blueberry components. Further research is needed to establish the clinical efficacy of blueberries to improve vascular function in diverse human populations in a manner that provides mechanistic information. Translation of clinical research to the community/public should consider feasibility, social determinants of health, culture, community needs, assets, and desires, barriers, and drivers to consumption, among other factors to establish real-world impacts of blueberry consumption. Vascular dysfunction contributes to cardiovascular disease. Evidence indicates major mediators include oxidative stress, inflammation, and the gut microbiome. Chronic disease risk factors accelerate vascular dysfunction and cardiovascular disease risk. Preclinical and clinical evidence supports that blueberries improve vascular function, particularly endothelial function. Effects are mediated through modulation of oxidative stress and inflammation and, potentially, the gut microbiome. [Display omitted] [ABSTRACT FROM AUTHOR]