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BACKGROUND: Due to encouraging pre-clinical data and supportive observational studies, there has been growing interest in applying cardiovascular drugs (including aspirin, angiotensin-converting enzyme [ACE] inhibitors, statins, and metformin) approved to treat diseases such as hypertension, hyperlipidemia, and diabetes mellitus to the field of oncology. Moreover, given growing costs with cancer care, these medications have offered a potentially more affordable avenue to treat or prevent recurrence of cancer. We sought to investigate the anti-cancer effects of drugs repurposed from cardiology or anti-inflammatories to treat cancer. We specifically evaluated the following drug classes: HMG-CoA reductase inhibitors (statins), cyclo-oxygenase inhibitors, aspirin, metformin, and both angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors. We also included non-steroidal anti-inflammatory drugs (NSAIDs) because they exert a similar mechanism to aspirin by blocking prostaglandins and reducing inflammation that is thought to promote the development of cancer. METHODS: We performed a systematic literature review using PubMed and Web of Science with search terms including aspirin, NSAID, statin (including specific statin drug names), metformin, ACE inhibitors, and ARBs (including specific anti-hypertensive drug names) in combination with cancer. Searches were limited to human studies published between 2000 and 2023. MAIN OUTCOMES AND MEASURES: The number and percentage of studies reported positive results and pooled estimates of overall survival, progression-free survival, response, and disease-free survival. RESULTS: We reviewed 3094 titles and included 67 randomized clinical trials. The most common drugs that were tested were metformin (n = 21; 30.9%), celecoxib (n = 20; 29.4%), and simvastatin (n = 8; 11.8%). There was only one study that tested cardiac glycosides and none that studied ACE inhibitors. The most common tumor types were non-small-cell lung cancer (n = 19; 27.9%); breast (n = 8; 20.6%), colorectal (n = 7; 10.3%), and hepatocellular (n = 6; 8.8%). Most studies were conducted in a phase II trial (n = 38; 55.9%). Most studies were tested in metastatic cancers (n = 49; 72.1%) and in the first-line setting (n = 36; 521.9%). Four studies (5.9%) were stopped early because of difficulty with accrual. The majority of studies did not demonstrate an improvement in either progression-free survival (86.1% of studies testing progression-free survival) or in overall survival (94.3% of studies testing overall survival). Progression-free survival was improved in five studies (7.4%), and overall survival was improved in three studies (4.4%). Overall survival was significantly worse in two studies (3.8% of studies testing overall survival), and progression-free survival was worse in one study (2.8% of studies testing progression-free survival). CONCLUSIONS AND RELEVANCE: Despite promising pre-clinical and population-based data, cardiovascular drugs and anti-inflammatory medications have overall not demonstrated benefit in the treatment or preventing recurrence of cancer. These findings may help guide future potential clinical trials involving these medications when applied in oncology.

Highlighting concerns about the acceptance of oncologic therapies with no proven benefit, this article compares the interpretation of the clinical trial results of several studies conducted to identify a better therapy for patients with biliary tract cancer.

Abstract Background Motor competence (MC) is a key component reflecting one’s ability to execute motor tasks and is an important predictor of physical fitness. For adolescents, understanding the factors affecting MC is pertinent to their development of more sophisticated sporting skills. Previous studies considered the influence of poor proprioceptive ability on MC, however, the relationship between lower limb joint position sense, kinematic control, and MC is not well understood. Therefore, the aim of this study was to determine the relation between joint position sense and kinematic control with MC in adolescents during a lower limb movement reproduction task. Methods This study was a cross-sectional design. Young people (n = 427, 196 girls and 231 boys) aged 13 to 14 years were recruited. A movement reproduction task was used to assess joint position sense and kinematic control, while the Movement Assessment Battery for Children (mABC-2) was used to assess MC. In this study, participants were categorized into the Typically Developed (TD, n = 231) and Probable Developmental Coordination Disorder (DCD, n = 80) groups for further analysis of joint position sense, kinematic control, and MC between groups. Results Kinematic data, specifically normalized jerk, showed a significant correlation with MC. There was no correlation between knee joint position sense and MC, and no group differences between DCD and TD were found. Conclusions Joint position sense should not be used as a measure to distinguish TD and DCD. Rather than joint position sense, control of kinematic movement has a greater influence on the coordination of the lower limbs in adolescents. Movement control training should be implemented in the clinical setting to target kinematic control, rather than focus on joint position sense practice, to improve motor competency. Trial Registration Identifier NCT03150784. Registered 12 May 2017, https://clinicaltrials.gov/study/NCT03150784 .

Background: Postpartum hemorrhage (PPH) is a leading cause of maternal morbidity and mortality worldwide. Effective management of PPH heavily relies on adherence to clinical guidelines. Mentorship programs aim to enhance healthcare providers' (HCPs) knowledge, skills, and guideline adherence, but their impact on guideline adherence needs evaluation. Objective: To evaluate the effect of a clinical mentorship program on HCPs' adherence to PPH clinical guidelines and patient outcomes at Muhima District Hospital (DH) and its associated health centers (HCs). Methods: A quasi-experimental design was used to compare HCPs' adherence to clinical guidelines before and after mentorship. Maternal outcomes were also analyzed in relation to guideline adherence. Standardized medical records provided data, and consecutive sampling included cases sequentially from medical registers. The Wilcoxon test was used to assess the effect of mentorship on adherence to guidelines. Multivariate regression analysis was performed to explore the relationship between mentorship, guideline adherence, and maternal outcomes. Results: The study included 384 women with PPH. Adherence to clinical guidelines before (96.4%) and after (95.8%) the mentorship program showed no significant change (P-value = 0.25). However, adherence to guidelines was significantly associated with better maternal outcomes (P-value < 0.001). Multivariate logistic regression indicated significantly lower odds of no complications in cases where guidelines were not followed. Adherence to guidelines (AOR = 0.061, 95% CI: 0.001- 0.026), prolonged labor (AOR = 187.25, 95% CI: 13.07- 2683.14), blood loss (AOR = 0.004 95% CI: 0.000 - 0.0008), and specific causes of PPH (AOR = 0.013, 95% CI: 0.000- 0.068) had significant associations with maternal outcomes. Conclusion: Adherence to clinical guidelines is critical for high-quality care and improved maternal outcomes in PPH cases. The study confirms the positive impact of guideline adherence on maternal outcomes, emphasizing the importance of promoting and strengthening adherence. While the mentorship program supported high adherence rates among HCPs, it alone may not be sufficient to ensure adherence, suggesting the influence of additional factors, such as training from other institutions.

Non-small cell lung cancer (NSCLC) is a leading cause of death, but over the past decade, there has been tremendous progress in the field with new targeted therapies. The mesenchymal-epithelial transition factor (MET) proto-oncogene has been implicated in multiple solid tumors, including NSCLC, and dysregulation in NSCLC from MET can present most notably as MET exon 14 skipping mutation and amplification. From this, MET tyrosine kinase inhibitors (TKIs) have been developed to treat this dysregulation despite challenges with efficacy and reliable biomarkers. Capmatinib is a Type Ib MET TKI first discovered in 2011 and was FDA approved in August 2022 for advanced NSCLC with MET exon 14 skipping mutation. In this narrative review, we discuss preclinical and early-phase studies that led to the GEOMETRY mono-1 study, which showed beneficial efficacy in MET exon 14 skipping mutations, leading to FDA approval of capmatinib along with Foundation One CDx assay as its companion diagnostic assay. Current and future directions of capmatinib are focused on improving the efficacy, overcoming the resistance of capmatinib, and finding approaches for new indications of capmatinib such as acquired MET amplification from epidermal growth factor receptor (EGFR) TKI resistance. Clinical trials now involve combination therapy with capmatinib, including amivantamab, trametinib, and immunotherapy. Furthermore, new drug agents, particularly antibody-drug conjugates, are being developed to help treat patients with acquired resistance from capmatinib and other TKIs.

Appendectomy is the most common emergency abdominal surgery in the United States. Open appendectomy has been the standard procedure for decades, whereas laparoscopic appendectomy is a newer, less-invasive method of removing the appendix. This review intends to elucidate the similarities and differences between these two procedures as well as explore the advantages and disadvantages of each approach. Socioeconomic factors, associated costs, preoperative imaging, operative time and methods, length of hospital stay, recovery time, and complications associated with open and laparoscopic appendectomy are discussed. Overall, laparoscopic appendectomy has shorter hospital stays and recovery times, requires less analgesics, and results in better postoperative outcomes. Although such an analysis/comparison involves several perspectives, a review of the available literature suggests that laparoscopic appendectomy is the operation of choice in most cases.

Abstract Recent studies have identified a previously uncharacterized protein C11orf53 (now named POU2AF2/OCA-T1), which functions as a robust co-activator of POU2F3, the master transcription factor which is critical for both normal and neoplastic tuft cell identity and viability. Here, we demonstrate that POU2AF2 dictates opposing transcriptional regulation at distal enhance elements. Loss of POU2AF2 leads to an inhibition of active enhancer nearby genes, such as tuft cell identity genes, and a derepression of Polycomb-dependent poised enhancer nearby genes, which are critical for cell viability and differentiation. Mechanistically, depletion of POU2AF2 results in a global redistribution of the chromatin occupancy of the SWI/SNF complex, leading to a significant 3D genome structure change and a subsequent transcriptional reprogramming. Our genome-wide CRISPR screen further demonstrates that POU2AF2 depletion or SWI/SNF inhibition leads to a PTEN-dependent cell growth defect, highlighting a potential role of POU2AF2-SWI/SNF axis in small cell lung cancer (SCLC) pathogenesis. Additionally, pharmacological inhibition of SWI/SNF phenocopies POU2AF2 depletion in terms of gene expression alteration and cell viability decrease in SCLC-P subtype cells. Therefore, impeding POU2AF2-mediated transcriptional regulation represents a potential therapeutic approach for human SCLC therapy.

IntroductionThere is a paucity of data on immune checkpoint inhibitors (ICIs) plus doublet chemotherapy (C) in patients with advanced lung cancer whose tumor harbors an actionable mutation. We sought to provide insight into the role of this combination in relation to chemotherapy alone in this patient population.MethodsWe conducted a retrospective study at the five University of California National Cancer Institute-designated Comprehensive Cancer Centers. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS) and significant adverse events. Adverse events in patients who received a tyrosine kinase inhibitor (TKI) post-ICI were also captured.ResultsA total of 246 patients were identified, 170 treated with C plus ICI and 76 treated with C alone. Driver alterations included EGFR (54.9%), KRAS (32.9%), ALK (5.3%), HER2/ERBB2 (2.9%), ROS1 (1.2%), MET (1.2%), RET (0.8%), and BRAF non-V600 (0.8%). The overall PFS and OS hazard ratios were not significant at 1.12 (95% confidence interval 0.83-1.51; p = 0.472) and 0.86 (95% confidence interval: 0.60-1.24, p = 0.429), respectively. No significant differences in PFS or OS were observed in the mutational subgroups. Grade 3 or greater adverse events were lower in the C plus ICI group. The multivariate analysis for PFS and OS revealed a performance status (Eastern Cooperative Oncology Group) score of 2, and previous TKI treatment was associated with poorer outcomes with C plus ICI.ConclusionsOur study suggests that patients with oncogenic-driven NSCLC, primarily those with EGFR-driven tumors, treated with a TKI should not subsequently receive C plus ICI. Analysis from prospective clinical trials will provide additional information on the role of ICIs in this group of patients.

Mental disorders impact a large proportion of individuals worldwide, with young adults being particularly susceptible to poor mental health. Past research shows that help-seeking self-stigma plays a vital role in deterring help-seeking among young adults; however, this relationship has primarily been examined in the context of human-delivered psychotherapy. The present study aimed to understand how young adults’ perceptions of help-seeking self-stigma associated with different modes of psychotherapy, specifically human-delivered and artificial intelligence (AI)-delivered, influence attitudes towards using AI chatbots for psychotherapy. This study employed a cross-sectional survey design to measure perceived help-seeking self-stigma and attitudes towards both human- and AI-delivered psychotherapy. The results demonstrated that high help-seeking self-stigma associated with human-delivered psychotherapy was linked to more negative attitudes towards human-delivered psychotherapy but more positive attitudes towards AI-delivered psychotherapy. Moreover, high help-seeking self-stigma associated with AI-delivered psychotherapy was linked to more negative attitudes towards AI-delivered psychotherapy but more positive attitudes towards human-delivered psychotherapy. These findings have important real-world implications for future clinical practice and mental health service delivery. The results indicate that young adults who are reluctant to engage with human-delivered psychotherapy due to help-seeking self-stigma may be more inclined to seek help through alternative modes of psychotherapy, such as AI chatbots. Limitations and future directions are discussed.

Aims Introduction: Second-generation antipsychotics are widely used in psychiatry but are associated with weight gain. Obesity is more prevalent in mental illness and may contribute to the mortality gap. Non-pharmacological management of antipsychotic-induced weight gain (AIWG) has limited success whilst pharmacological treatment typically involves antidiabetic medications that psychiatrists have less experience with. Recent developments in the field have shown promise with using centrally-acting opioid receptor antagonists (CORAs) at treating AIWG. Objective: Review and synthesise the available RCT evidence on the efficacy of CORAs at treating AIWG. Methods Methodology: Four databases (Medline, Embase, PsycINFO, Cochrane) were searched, from database inception to present, for RCTs using CORAs (naloxone, naltrexone, samidorphan) to reduce AIWG. Our primary outcome sought was weight change in kilograms, with secondary outcomes of change in percentage of body weight, waist circumference and 7% or 10% weight change thresholds. We used random-effects meta-analysis due to study heterogeneity. Results A total of 450 articles were found (319 post-deduplication), of which seven met criteria (samidorphan = 4, naltrexone = 3, naloxone = 0) including n = 1,416 patients. On meta-analysis, change in body weight (kg) for CORAs as a class was statistically significant (RE = 1.37 kg; 95% CI: 0.51, 2.24). However, change in BMI was not statistically significant (RE = 0.61kg/m2; 95% CI: −0.56, 1.78). Remaining analysis was only available for samidorphan, which showed statistically significant improvement in change in body weight (%) (RE = 1.81%; 95% CI: 1.07, 2.55), absolute risk of weight gain ≥7% (RE = 12.41%; 95% CI: 6.55, 18.27), absolute risk of weight gain ≥10% (RE = 10.83%; 95% CI: 5.46, 16.21), and change in waist circumference (RE = 1.50 cm; 95% CI: 0.32, 2.67). Conclusion Evidence is strongest for samidorphan, though CORAs as a class remains poorly researched and the benefits are modest. Additionally, samidorphan is currently only available in the combination medication olanzapine-samidorphan and the literature reflects this. Further research is needed to examine its efficacy in AIWG from other antipsychotics.

PurposePatients with non-small cell lung cancer (NSCLC) that harbor driver mutations are associated with a cancer diagnosis at a younger age. While targeted therapies provide deep remissions and durable benefit in a subset of patients, it is unclear whether targeted therapies bridge the gap in years of life lost (YLL) in these younger NSCLC patients with targetable mutations in comparison to generally older NSCLC patients without actionable driver mutations.Materials and methodsRetrospective cross-sectional study using landmark trials leading to the approval of targeted therapies in NSCLC with actionable mutations. We evaluated all targeted therapies as well as chemotherapy and IO regimens for the treatment of NSCLC through FDA Oncology Announcements and NCCN Guidelines for NSCLC (version 4.2021).ResultsWe estimated the YLL for each driver mutation, cumulative median duration of response (DOR) with targeted therapies by mutation type, and percentage of estimated improvement in YLL from NSCLC targeted therapies. The median ages at diagnosis (in years) for patients whose tumors express targetable mutations were: 47.6 (NTRK); 52.0 (ALK); 62.0 (HER2); 57.0 (ROS1); 61.4 (RET); 63.0 (BRAF); 69.0 (EGFR); and 72.0 (MET). For comparison, the median age at diagnosis for patients without driver mutations, regardless of PD-L1 status was 71 years. The median DOR (in years) for patients whose tumors express the same mutations include: 0.9 (NTRK); 3.9 (ALK); 0.6 (HER2); 6.2 (ROS1); 2.2 (RET); 1.5 (BRAF); 3.1 (EGFR); and 2.4 (MET). The median DOR for patients without driver mutations was 1.2 years. The cumulative estimated survival time (years; median age at diagnosis plus the median DOR or OS) for patients whose tumors express targetable mutations were: 48.5 (NTRK); 55.9 (ALK); 62.6 (HER2); 63.2 (ROS1); 63.6 (RET); 64.5 (BRAF); 72.1 (EGFR); and 74.4 (MET). The cumulative estimated survival time for patients without driver mutations, regardless of PD-L1 status, was 72.2 years of age. We calculated the number of years NSCLC is diagnosed earlier in patients with targetable mutations as follows: 23.4 (NTRK), 19 (ALK), 14 (ROS1), 11 (EGFR), 9.6 (RET), 9 (HER2), and 8 (BRAF). The percent difference (%) ameliorated in YLL by mutation type is as follows: 44.3 (ROS1), 28.2 (EGFR), 22.9 (RET), 20.5 (ALK), 18.8 (BRAF), 6.4 (HER2), and 3.7 (NTRK).ConclusionAlthough targeted therapies have paved the way for significant progress toward providing a survival benefit to many young patients with advanced NSCLC with actionable mutations, it is evident that these therapies still leave a wide gap in the YLL in these younger patients compared to generally older individuals with advanced NSCLC without targetable mutations.

ImportanceAlthough several cancer drugs receive US Food and Drug Administration (FDA) approval each month, it is unclear how many of these cancer drugs transform the treatment landscape significantly by tumor group. Specifically, it remains unclear how many of these newly approved cancer drugs displace the existing standard-of-care therapies for their indication vs being added to existing therapies.ObjectiveTo examine how many cancer drugs displace the standard-of-care therapies vs being added to existing therapy or filling breaks in systemic treatments in the metastatic setting, adjuvant setting, or maintenance setting.Design, setting, and participantsRetrospective cross-sectional study using landmark trials leading to FDA approval of cancer drugs between May 1, 2016, and May 31, 2021. The study evaluated all FDA approvals for cancer drugs between May 1, 2016, and May 31, 2021, using the FDA Oncology (Cancer)/Hematologic Malignancies Approval Notifications website. All clinical trials leading to FDA approval of cancer drugs during this period were examined.Main outcomes and measuresA drug was determined to have displaced the prior standard-of-care therapy by evaluating the comparator arm (or lack thereof) in the clinical trial leading to the drug's approval and also by reviewing National Comprehensive Cancer Network Guidelines. Cancer drug approvals were categorized as first-line displacing if a drug was approved for use in the first-line setting and displaced the prior standard-of-care drug for an indication, first-line drug alternatives/new if a drug was approved for use in the first-line setting but did not displace the standard of care at the time of approval or was a new drug that was first of its class for an approved indication, add on if a drug was approved in combination with a previously approved therapy for a disease or if a drug was approved for use in the adjuvant or maintenance settings, and later line if a drug was approved for use in the second-, third-, or later-line settings.ResultsBetween May 1, 2016, and May 31, 2021, there were 207 FDA cancer drug approvals in oncology and malignant hematology. Of these 207 approvals, 28 drugs (14%) were first-line displacing therapies. A total of 32 drugs (15%) were first-line drug alternatives/new drugs. A total of 61 drugs (29%) were add-on therapies. Finally, 86 drugs (42%) were approved as later-line therapies.Conclusions and relevanceIn this study, most cancer drug approvals between 2016 and 2021 were in the later-line settings as opposed to displacing the current standard-of-care therapy for the approved indication. These later-line drugs may benefit patients with few alternatives but add to the cost of care because competition in the drug markets is a key factor in leading to lower drug prices.

In classical autonomous racing, a perception, planning, and control pipeline is employed to navigate vehicles around a track as quickly as possible. In contrast, neural network controllers have been used to replace either part of or the entire pipeline. This paper compares three deep learning architectures for F1Tenth autonomous racing: full planning, which replaces the global and local planner, trajectory tracking, which replaces the local planner and end-to-end, which replaces the entire pipeline. The evaluation contrasts two reward signals, compares the DDPG, TD3 and SAC algorithms and investigates the generality of the learned policies to different test maps. Training the agents in simulation shows that the full planning agent has the most robust training and testing performance. The trajectory tracking agents achieve fast lap times on the training map but low completion rates on different test maps. Transferring the trained agents to a physical F1Tenth car reveals that the trajectory tracking and full planning agents transfer poorly, displaying rapid side-to-side swerving (slaloming). In contrast, the end-to-end agent, the worst performer in simulation, transfers the best to the physical vehicle and can complete the test track with a maximum speed of 5 m/s. These results show that planning methods outperform end-to-end approaches in simulation performance, but end-to-end approaches transfer better to physical robots.