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IMPORTANCE: Age-related macular degeneration (AMD) is a serious and common ophthalmologic disorder that is hypothesized to result, in part, from inflammatory reactions in the macula. Alzheimer disease (AD) treatment, acetylcholinesterase inhibitors (AChEIs), have anti-inflammatory effects and it remains unclear if they modify the risk of AMD. OBJECTIVE: To investigate the association between AChEI medications and the incidence of AMD. DESIGN, SETTING, AND PARTICIPANTS: This propensity score–matched retrospective cohort study took place at health care facilities within the US Department of Veterans Affairs (VA) health care system from January 2000 through September 2023. Participants included patients diagnosed with AD between ages 55 and 80 years with no preexisting diagnosis of AMD in the VA database. EXPOSURE: AChEIs prescription dispensed as pharmacologic treatments for AD. MAIN OUTCOMES AND MEASURE: The first diagnosis of AMD. RESULTS: A total of 21 823 veterans with AD (mean [SD] age, 72.3 [6.1] years; 21 313 male participants [97.7%] and 510 female participants [2.3%]) were included. Propensity score–matched Cox model reveals each additional year of AChEI treatment was associated with a 6% lower hazard of AMD (hazard ratio, 0.94; 95% CI, (0.89-0.99). CONCLUSIONS AND RELEVANCE: This observational study reports a small reduction in the risk of AMD among veterans with AD receiving AChEIs. Randomized clinical trials would be needed to determine if there is a cause-and-effect relationship and further research is required to validate these findings across diverse populations.

ABSTRACTIntroductionCardiovascular disease (CVD) is one of the global leading causes of morbidity and mortality in chronic kidney disease (CKD) patients. Vascular calcification (VC) is a major cause of CVD in this population and is the consequence of complex interactions between inhibitor and promoter factors leading to pathological deposition of calcium and phosphate in soft tissues. Different pathological landscapes are associated with the development of VC, such as endothelial dysfunction, oxidative stress, chronic inflammation, loss of mineralization inhibitors, release of calcifying extracellular vesicles (cEVs) and circulating calcifying cells.Areas coveredIn this review, we examined the literature and summarized the pathophysiology, biomarkers and focused on the treatments of VC.Expert opinionEven though there is no consensus regarding specific treatment options, we provide the currently available treatment strategies that focus on phosphate balance, correction of vitamin D and vitamin K deficiencies, avoidance of both extremes of bone turnover, normalizing calcium levels and reduction of inflammatory response and the potential and promising therapeutic approaches liketargeting cellular mechanisms of calcification (e.g. SNF472, TNAP inhibitors).Creating novel scores to detect in advance VC and implementing targeted therapies is crucial to treat them and improve the future management of these patients.

ABSTRACTEvidence suggests that Ras-related C3 botulinum toxin substrate 1 (Rac1) might be a target in atherosclerotic disease (AD). We hypothesize that due to their ability to inhibit Rac1, thiopurines are associated with a lower risk of AD. We fit a time-dependent cox proportional hazards model estimating the hazard of AD among a national cohort of US veterans with inflammatory bowel disease. Patients exposed to thiopurines had a 7.5% lower risk of AD (HR = 0.925; 95% CI = (0.87–0.984)) compared to controls. The propensity score weighted analysis reveals thiopurine exposure reduces the risk of AD by 6.6% (HR = 0.934; 95% CI = (0.896–0.975)), compared to controls. Further exploration and evaluation of Rac1 inhibition as a target for AD is warranted.

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ABSTRACTIntroduction:Secondary hyperparathyroidism (SHPT) represents a complication of chronic kidney disease (CKD). Vitamin D system is altered since early CKD, and vitamin D deficiency is an established trigger of SHPT. Although untreated SHPT may degenerate into tertiary hyperparathyroidism with detrimental consequences in advanced CKD, best treatments for counteracting SHPT from stage 3 CKD are still debated. Enthusiasm on prescription of vitamin D receptor activators (VDRA) in non-dialysis renal patients, has been mitigated by the risk of low bone turnover and positive calcium-phosphate balance. Nutritional vitamin D is now suggested as first-line therapy to treat SHPT with low 25(OH)D insufficiency. However, no high-grade evidence supports the best choice between ergocalciferol, cholecalciferol, and calcifediol (in its immediate or extended-release formulation).Areas covered:The review discusses available data on safety and efficacy of nutritional vitamin D, VDRA and nutritional therapy in replenishing 25(OH)D deficiency and counteracting SHPT in non-dialysis CKD patients.Expert opinion:Best treatment for low 25(OH)D and SHPT remains unknown, due to incomplete understanding of the best homeostatic, as mutable, adaptation of mineral metabolism to CKD progression. Nutritional vitamin D and nutritional therapy appear safest interventions, whenever contextualized with single-patient characteristics. VDRA should be restricted to uncontrolled SHPT by first-line therapy.

To evaluate adherence after treatment switch from a multiple-tablet regimen (MTR) to a single-tablet regimen (STR) in a national cohort of human immunodeficiency virus (HIV) patients.

Ewing sarcoma (EWS) is an aggressive bone and soft tissue tumor of children and young adults in which the principal driver is a fusion gene, EWSR1-FLI1. Although the essential role of EWSR1-FLI1 protein in the regulation of oncogenesis, survival, and tumor progression processes has been described in-depth, little is known about the regulation of chimeric fusion-gene expression. Here, we demonstrate that the active nuclear HDAC6 in EWS modulates the acetylation status of specificity protein 1 (SP1), consequently regulating the SP1/P300 activator complex binding to EWSR1and EWSR1-FLI1promoters. Selective inhibition of HDAC6 impairs binding of the activator complex SP1/P300, thereby inducing EWSR1-FLI1downregulation and significantly reducing its oncogenic functions. In addition, sensitivity of EWS cell lines to HDAC6 inhibition is higher than other tumor or non-tumor cell lines. High expression of HDAC6 in primary EWS tumor samples from patients correlates with a poor prognosis in two independent series accounting 279 patients. Notably, a combination treatment of a selective HDAC6 and doxorubicin (a DNA damage agent used as a standard therapy of EWS patients) dramatically inhibits tumor growth in two EWS murine xenograft models. These results could lead to suitable and promising therapeutic alternatives for patients with EWS.

We sought to examine the progression from abdominal aortic aneurysm (AAA) diagnosis to surgery and death among diabetics with and without exposure to metformin as well as non-diabetics. We conducted a retrospective cohort study (January 2000 to July 2019) comparing 3 transitions (AAA surgery, death, and death after AAA surgery) among propensity score-matched metformin-exposed and unexposed diabetic veterans and non-diabetic veterans using the VA Informatics and Computing Infrastructure database. We fit an adjusted Cox proportional hazards model with transition-specific effects. There were 43,073 metformin-unexposed diabetics, 24,361 metformin-exposed diabetics and 56,006 non-diabetics. Compared with the non-diabetic cohort, both diabetic cohorts have a lower risk of surgery (no metformin (HR=0.740, 95% CI 0.706 to 0.776); with metformin (HR=0.770, 95% CI 0.730 to 0.813)). However, the non-metformin diabetic cohort has a higher risk of death (HR=1.024, 95% CI 1.004 to 1.045) and death after surgery (HR=1.086, 95% CI 1.013 to 1.165). The metformin-exposed diabetic cohort has a lower risk of death in the first 10 years after AAA diagnosis (HR=0.877, 95% CI 0.855 to 0.899), yet a higher risk of death 10 years after AAA diagnosis (HR=1.177, 95% CI 1.092 to 1.270) compared with non-diabetic cohort. Non-diabetics have the highest rate of AAA surgery compared with both diabetic cohorts. However, diabetics without metformin have the highest risk of death prior to, and after surgery. This research provides novel findings for patients diagnosed with AAA. The use of metformin after both AAA diagnosis and surgery should be further investigated.

Aims/patients & methods:To evaluate the risk of acute kidney injury (AKI) in patients with HIV receiving proton pump inhibitors (PPI) a cohort study was conducted utilizing the Veterans Affairs Informatics and Computing Infrastructure (VINCI) database. Patients were followed from the index date until the earliest date of AKI, 120 days or end of study period, or death. Statistical analyses utilized a Cox proportional hazards model. Results:A total of 21,643 patients (6000 PPI and 15,643 non-PPI) met all study criteria. The PPI cohort had twice the risk of AKI compared with controls (2.12, hazard ratio: 1.46–3.1). Conclusion:A nationwide cohort study supported the relationship of an increased risk of AKI in patients receiving PPIs.

ABSTRACTIntroduction: Current treatment of conventional and non-conventional high-grade osteosarcoma (HGOS) is based on the surgical removal of primary tumor and, when possible, of metastases and local reccurrence, together with systemic pre- and post-operative chemotherapy with drugs that have been used since decades.Areas covered: This review is intended to summarize the new agents and therapeutic strategies that are under clinical evaluation in HGOS, with the aim to increase the cure probability of this highly malignant bone tumor, which has not significantly improved during the last 30–40 years. The list of drugs, compounds and treatment modalities presented and discussed here has been generated by considering only those that are included in presently ongoing and recruiting clinical trials, or which have been completed in the last 2 years with reported results, on the basis of the information obtained from different and continuously updated databases.Expert opinion: Despite HGOS is a rare tumor, several clinical trials are presently evaluating different treatment strategies, which may hopefully positively impact on the outcome of patients who experience unfavorable prognosis when treated with conventional therapies.Trial registration:ClinicalTrials.gov identifier: NCT01459484.Trial registration:ClinicalTrials.gov identifier: NCT01669369.Trial registration:ClinicalTrials.gov identifier: NCT00134030.Trial registration:ClinicalTrials.gov identifier: NCT00180908.Trial registration:ClinicalTrials.gov identifier: NCT00470223.Trial registration:ClinicalTrials.gov identifier: NCT01532687.Trial registration:ClinicalTrials.gov identifier: NCT02357810.Trial registration:ClinicalTrials.gov identifier: NCT03163381.Trial registration:ClinicalTrials.gov identifier: NCT02432274.Trial registration:ClinicalTrials.gov identifier: NCT02048371.Trial registration:ClinicalTrials.gov identifier: NCT02389244.Trial registration:ClinicalTrials.gov identifier: NCT02243605.Trial registration:ClinicalTrials.gov identifier: NCT02867592.Trial registration:ClinicalTrials.gov identifier: NCT03210714.Trial registration:ClinicalTrials.gov identifier: NCT03526250.Trial registration:ClinicalTrials.gov identifier: NCT03213678.Trial registration:ClinicalTrials.gov identifier: NCT03718091.Trial registration:ClinicalTrials.gov identifier: NCT03233204.Trial registration:ClinicalTrials.gov identifier: NCT03698994.Trial registration:ClinicalTrials.gov identifier: NCT03220035.Trial registration:ClinicalTrials.gov identifier: NCT03220035.Trial registration:ClinicalTrials.gov identifier: NCT02689336.Trial registration:ClinicalTrials.gov identifier: NCT03678883.Trial registration:ClinicalTrials.gov identifier: NCT01962103.Trial registration:ClinicalTrials.gov identifier: NCT02945800.Trial registration:ClinicalTrials.gov identifier: NCT01669369.Trial registration:ClinicalTrials.gov identifier: NCT03598595.Trial registration:ClinicalTrials.gov identifier: NCT02644460.Trial registration:ClinicalTrials.gov identifier: NCT02517918.Trial registration:ClinicalTrials.gov identifier: NCT03002805.Trial registration:ClinicalTrials.gov identifier: NCT02013336.Trial registration:ClinicalTrials.gov identifier: NCT02536183.Trial registration:ClinicalTrials.gov identifier: NCT02557854.Trial registration:ClinicalTrials.gov identifier: NCT02390843.Trial registration:ClinicalTrials.gov identifier: NCT03643133.Trial registration:ClinicalTrials.gov identifier: NCT03006848.Trial registration:ClinicalTrials.gov identifier: NCT03676985.Trial registration:ClinicalTrials.gov identifier: NCT03277924.Trial registration:ClinicalTrials.gov identifier: NCT03190174.Trial registration:ClinicalTrials.gov identifier: NCT02304458.Trial registration:ClinicalTrials.gov identifier: NCT02406781.Trial registration:ClinicalTrials.gov identifier: NCT02502786.Trial registration:ClinicalTrials.gov identifier: NCT03860207.Trial registration:ClinicalTrials.gov identifier: NCT03320330.Trial registration:ClinicalTrials.gov identifier: NCT03610490.Trial registration:ClinicalTrials.gov identifier: NCT02100891.Trial registration:ClinicalTrials.gov identifier: NCT02508038.Trial registration:ClinicalTrials.gov identifier: NCT03356782.Trial registration:ClinicalTrials.gov identifier: NCT01953900.Trial registration:ClinicalTrials.gov identifier: NCT03618381.Trial registration:ClinicalTrials.gov identifier: NCT03462316.Trial registration:ClinicalTrials.gov identifier: NCT02487979.

ABSTRACTIntroduction: DNA damaging drugs are widely used for the chemotherapeutic treatment of high-grade osteosarcoma (HGOS). In HGOS patients, several germline polymorphisms have been reported to impact on the development of adverse toxic events related to DNA damaging drugs treatment. Some of these polymorphisms, when present in tumor cells, may also influence treatment response and prognosis of HGOS patients.Area covered: In this review, the authors have focused on pharmacogenetic markers (mainly germline polymorphisms) described in patients with HGOS, which have proved or indicated to be related to the susceptibility to adverse toxic reactions and/or to influence response to DNA damaging drugs. The concordant and discordant results reported in different studies have also been discussed.Expert opinion: Response and toxicity predisposition to DNA damaging drugs are influenced by genes encoding proteins involved in their uptake, efflux, activation, inactivation, and in DNA repair, activity of which may vary according to specific gene variations. In HGOS, there is a substantial medical need for biomarkers predictive for individual response and toxicity predisposition to DNA-targeting drugs, which may be used to tailor therapy in order to decrease the occurrence of adverse side effects and increase treatment efficacy and safety.

Ras-related C3 botulinum toxin substrate 1 (Rac1), a member of the Rho-GTPase family of proteins, could be an Alzheimer's disease (AD) triggering co-factor due to its effect on both amyloid precursor protein (APP) and tau. Thiopurine medications, such as azathioprine and mercaptopurine, are immunosuppressants that suppress Rac1 activation. We hypothesize that due to their ability to suppress Rac1, thiopurines are associated with a lower risk of AD.