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APOE Polymorphism Is Associated with Changes in the Kynurenine Pathway
Full text linkAbstract: Background: APOE polymorphism and the Kynurenine pathway (KP) are associated with many disorders, but little is known about associations between APOE polymorphism and the KP. This study explored the associations between the KP and APOE polymorphism in disorders associated with APOE polymorphism and changes in the KP. Methods: Subjects with morbid obesity before and after bariatric surgery (numbers 139 and 95, respectively), depression (number 49), and unspecified neurological symptoms (number 39) were included. The following grouping of the APOE genotypes was used: E2 = ε2ε2 + ε2ε3, E3 = ε3ε3 + ε2ε4, and E4 = ε3ε4 + ε4ε4. The KP metabolites Tryptophan, Kynurenine, Kynurenic acid, Quinolinic acid, and Xanthurenic acid were quantified in serum. Results: The main findings were a significant positive association between E3 and Quinolinic acid (difference between E3 and E2E4: 12.0 (3.5; 18.6) ng/mL); p = 0.005), and a negative association between E4 and Kynurenine (difference between E4 and E2E3: −31.3 (−54.2; −3.2) ng/mL; p = 0.008). Quinolinic acid has been ascribed neurotoxic and inflammatory effects, and Kynurenine is a marker of inflammation. Conclusions: The findings indicate that APOE polymorphism might cause changes in the KP that contribute to the disease. Inflammation could be the link between APOE and the KP.The study was funded by Innlandet Hospital Trust, Brumunddal, Norway and Department of Medical Biochemistry,
Oslo University Hospital, Oslo, Norway.publishedVersio
Respectful Caring for the Agitated Elderly (ReCAGE): A Multicentre, Prospective, Observational Study to Evaluate the Effectiveness of Special Care Units for People with Dementia
Full text linkBehavioral and psychological symptoms of dementia (BPSD) bring complexity in the clinical management of people with dementia; therefore, it is important to evaluate different models of care, such as Special Care Units (SCU-B).∥Objective:To evaluate the SCU-B effectiveness toward alleviating BPSD and improving the quality of life (QoL) of patients and their caregivers.∥Methods:ReCAGE was a multicenter, controlled, longitudinal study where 508 patients with BPSD were enrolled in two cohorts: 262 patients from centers endowed with a SCU-B, and 246 from centers without SCU-B. Statistical analyses included factorial ANCOVA for comparison among centers. The primary endpoint was effectiveness of the SCU-B, measured through the Neuropsychiatric Inventory (NPI) changes. Secondary endpoints were change in QoL of patients and caregivers, and the tertiary endpoint was time to nursing home admission.∥Results:The NPI scores decreased in both arms, with a statistically significant difference from baseline to 36 months (p < 0.0001) in both cohorts. Over time, NPI decreased more steeply during the first year in the SCU-B arm, but in the following two years the slope was clearly in favor of the control arm. This different pattern of the two cohorts reached statistical significance at the interaction "cohort by time" (p < 0.0001). Conflicting results were found regarding the outcomes of quality of life, while there were no differences in time to institutionalization in both cohorts.∥Conclusion:The RECage study did not confirm the long-term superiority of the pathway comprising a SCU-B. A post-hoc analysis revealed data supporting their acute effectiveness during behavioral crises.acceptedVersio
Functional orthosis versus cast immobilization for weightbearing stable Weber B ankle fractures with concomitant unstable gravity stress tests
Full text linkAims: Treatment of Weber B ankle fractures that are stable on weightbearing radiographs but unstable on concomitant stress tests (classified SER4a) is controversial. Recent studies indicate that these fractures should be treated nonoperatively, but no studies have compared alternative nonoperative options. This study aims to evaluate patient-reported outcomes and the safety of fracture treatment using functional orthosis versus cast immobilization. Methods: A total of 110 patients with Weber B/SER4a ankle fractures will be randomized (1:1 ratio) to receive six weeks of functional orthosis treatment or cast immobilization with a two-year follow-up. The primary outcome is patient-reported ankle function and symptoms measured by the Manchester-Oxford Foot and Ankle Questionnaire (MOxFQ); secondary outcomes include Olerud-Molander Ankle Score, radiological evaluation of ankle congruence in weightbearing and gravity stress tests, and rates of treatment-related adverse events. The Regional Committee for Medical and Health Research (approval number 277693) has granted ethical approval, and the study is funded by South-Eastern Norway Regional Health Authority (grant number 2023014). Discussion: Randomized controlled trials are needed to evaluate alternative nonoperative treatment options for Weber B/SER4a ankle fractures, as current clinical guidelines are based on biomechanical reasoning. The findings will be shared through publication in peer-reviewed journals and presentations at conferences.The authors disclose receipt of the following financial or material support for the research, authorship, and/or publication of this article: South-Eastern Norway Regional Health Authority (Helse Sør-Øst RHF), grant number 2023014.publishedVersio
The Bone Cement Hypercoagulation Syndrome: Pathophysiology, Mortality, and Prevention
Full text linkSince Charnley introduced acrylic cement to seal metallic hip prostheses in the 1950s, reports of perioperative fatal cardiorespiratory and vascular dysfunctions have been published. Studies on humans and animals have shown neurogenic stimulation and substantial local and systemic activation of coagulation are caused by surgical bone marrow damage and chemical cell destruction by toxic monomeric methyl methacrylate from the implanted cement and other tissue-released substances. Venous blood-borne cell fragments and conjugates of activated cells from the surgical site are sequestered and trapped in the pulmonary microcirculation. A substantial hypercoagulation occurs in the lung circulation. Hypercoagulable blood is passed over to the arterial side and may cause vessel obliteration and organ damage. This process may affect the brain, heart, and kidneys and, through the release of vasoactive substances, introduce hemodynamic imbalances that can lead to fatal outcomes in susceptible populations such as elderly patients with hip fractures. The main underlying pathophysiologic processes leading to these occasionally devastating outcomes are a substantial activation of coagulation and cell destruction caused by the toxic substance released by curing bone cement and several vasoactive substances.publishedVersio
Factors associated with time to first dialysis-associated peritonitis episode: Data from the Peritonitis Prevention Study (PEPS)
Full text linkIntroduction: Peritonitis remains a potentially serious complication of peritoneal dialysis (PD) treatment. It is therefore important to identify risk factors in order to reduce the incidence of peritonitis. The aim of the present analysis was to identify factors associated with time to first peritonitis episode. Methods: Incident PD patients from 57 centres in Europe participated in the prospective randomised controlled Peritonitis Prevention Study (PEPS) from 2010 to 2015. Peritonitis-free, self-care PD patients ≥18 years were randomised to a retraining or a control group and followed for 1-36 months after PD initiation. The association of biochemical, clinical and prescription data with time to first peritonitis episode was studied. Results: A first peritonitis episode was experienced by 33% (223/671) of participants. Univariable Cox proportional hazard regression showed a strong association between the time-updated number of PD bags connected per 24 h (PD bags/24 h) and time to first peritonitis episode (HR 1.35; 95% confidence interval (CI) 1.17-1.57), even after inclusion of PD modalities in the same model. Multivariable Cox regression revealed that the factors independently associated with time to first peritonitis episode included age (HR 1.16 per 10 years; 95% CI 1.05-1.28), PD bags/24 h (HR 1.32; 95% CI 1.13-1.54), serum albumin 35 g/L (HR 1.39; 95% CI 1.06-1.82) and body weight per 10 kg (HR 1.10; 95% CI 1.01-1.19). Conclusion: This study of incident PD patients indicates that older age, greater number of PD bags connected/24 h, higher body weight and hypoalbuminaemia are independently associated with a shorter time to first peritonitis episode.The author(s) received financial support for the research, authorship, and/or publication of this article: The trial was supported by The Health & Medical Care Committee of The Regional Executive Board, Region West of Sweden (VGFOUREG-78061, 226521 and 383641), Baxter Healthcare Corporation (McGaw Park, IL, USA; Clinical Evidence Council grant number 10CECEU1004), Swedish Society of Nephrology, The Swedish Kidney Association, The Society of Kidney Patients in West of Sweden, The John and Brit Wennerström Foundation, The Bertil and Berit Adström Foundation, The Foundation for Kidney Failure (Sweden), The Swedish Kidney Foundation and Norwegian Society of Kidney Patients. The funders did not have any role in the study design, data collection, analysis, reporting, or the decision to submit the manuscript for publication.publishedVersio
Exacerbated Neuropathy in POLAR A and M Trials Due to Redox Interaction of PledOx-Associated Mn<sup>2+</sup> and Oxaliplatin-Associated Pt<sup>2+</sup>
No full textDisappointing results from the POLAR A and M phase III trials involving colorectal cancer patients on chemotherapy with FOLFOX6 in curative (A) and palliative (M) settings have been reported by the principal investigators and the sponsor (PledPharma AB/Egetis Therapeutics AB). FOLFOX6, oxaliplatin in combination with 5-fluorouracil (5-FU), possesses superior tumoricidal activity in comparison to 5-FU alone, but suffers seriously from dose-limiting platinum-associated Chemotherapy-Induced Peripheral Neuropathy (CIPN). The aim of the POLAR trials was to demonstrate that PledOx [calmangafodipir; Ca4Mn(DPDP)5] reduced the incidence of persistent CIPN from 40% to 20%. However, this assumption was based on "explorative" data in the preceding PLIANT phase II trial, which did not mirror the expected incidence of unwanted toxicity in placebo patients. In POLAR A and M, the assessment of PledOx efficacy was conducted in patients that received at least six cycles of FOLFOX6, enabling analyses of efficacy in 239 A and 88 M patients. Instead of a hypothesized improvement from 40% to 20% incidence of persistent CIPN in the PledOx group, i.e., a 50% improvement, the real outcome was the opposite, i.e., an about 50% worsening in this bothersome toxicity. Mechanisms that may explain the disastrous outcome, with a statistically significant number of patients being seriously injured after having received PledOx, indicate interactions between two redox active metal cations, Pt2+ (oxaliplatin) and Mn2+ (PledOx). A far from surprising causal relationship that escaped prior detection by the study group and the sponsor. Most importantly, recently published data (ref 1) unequivocally indicate that the PLIANT study was not suited to base clinical phase III studies on. In conclusion, the POLAR and PLIANT trials show that PledOx and related manganese-containing compounds are unsuited for co-treatment with platinum-containing compounds. For use as a therapeutic adjunct in rescue treatment, like in ischemia-reperfusion of the heart or other organs, or in acetaminophen (paracetamol)-associated liver failure, there is little or nothing speaking against the use of PledOx or other PLED compounds. However, this must be thoroughly documented in more carefully designed clinical trials. Keywords: POLAR A and M trials; calmangafodipir (PledOx); chemotherapy-induced peripheral neuropathy; clinical phase III trials; drug interaction; manganese; oxaliplatin; platinum; redox active cations.This work was supported by Karlsson-Tuner Invest AS, Norway.publishedVersio
Childhood executive function predicts internalizing and externalizing symptoms in emerging adults with and without autism: A 10-year longitudinal study
Full text linkIndividuals with autism spectrum disorder (ASD) and typically developing individuals were assessed on three neuropsychological tests of executive function (EF) and on scales of autism symptoms and co-occurring internalizing and externalizing symptoms at baseline (T1; N = 88, Mage = 11.8 years, 73% males), 2-year (T2; 99% retention, Mage = 13.9 years), and 10-year follow-ups (T3; 75% retention, Mage = 21.4 years). An EF composite score from T1 significantly predicted internalizing symptoms at T2 (β = .228) and internalizing and externalizing symptoms at T3 (β = .431 and .478, respectively), when controlling for age and autism symptoms. OThe findings suggest that EF difficulties are a long-term risk factor for more co-occurring symptoms.Childhood executive function predicts internalizing and externalizing symptoms in emerging adults with and without autism: A 10-year longitudinal studyThis work was supported by grants from the Innlandet Hospital Trust (grant numbers: 150663, 150610, 150624, and 150648) and from the Norwegian Centre of Expertise for Neurodevelopmental Disorders and Hypersomnias, Department of Rare Disorders and Disabilities, Oslo University Hospital (grant number: 150616)publishedVersio
Elite professional online poker players: factors underlying success in a gambling game usually associated with financial loss and harm
Full text linkMost gamblers lose money, and this means that a behavioral dependence to gambling can cause harm. However, some professional gamblers win consistently, and there is little academic literature on their psychology and how they differ from disordered gamblers. To contribute to this understudied area, we qualitatively analyzed interviews with 19 elite online professional poker players, by examining factors from the disordered gambling and decision-making literatures. Like disordered gamblers, participants displayed aspects of a behavioral dependence to gambling, but contrastingly did not generally experience harm. Other contrasts included their rational approach to statistical thinking, a general selfreported tendency to not be impulsive, and their social connections with other experts. One factor that did not yield clear contrasting results was whether or not they experienced early big wins. Parallels with the decision-making literature included their assessment of decision quality based on expected value rather than realized outcomes, their reluctance to take risks outside of their ‘circle of competence,’ and their ‘active open-minded’ thinking style. This study contributes to gambling psychology via an in-depth exploration of an understudied group.The author(s) reported there is no funding associated with the workfeatured in this article.publishedVersio
Edmonton Frail Scale predicts mortality in older patients with cancer undergoing radiotherapy-A prospective observational study
Full text linkBackground: Several screening tools are developed to identify frailty in the increasing number of older patients with cancer. Edmonton Frail Scale (EFS) performs well in geriatric settings but is less studied in oncology. We aimed to investigate if EFS score (continuous and categorical) predicts survival in patients referred for radiotherapy, and to assess the concurrent validity of EFS compared with a modified geriatric assessment (mGA). Methods: Prospective observational, single-center study including patients ≥65 years, referred for curative or palliative radiotherapy for confirmed cancer. Patients underwent mGA (assessment of cognition, mobility, falls, comorbidity, polypharmacy, depression, nutrition, and activities of daily living) and screening with EFS prior to radiotherapy. The predictive value of EFS score of two-year overall survival (OS) was assessed by Kaplan-Meier plots and compared by log-rank test. Cox proportional hazards regression model was estimated to adjust the associations for major cancer-related factors. Concurrent validity of EFS in relation to mGA was estimated by Spearman`s correlation coefficient and ordinal regression. Sensitivity and specificity for different cut-offs was assessed. Results: Patients' (n = 301) mean age was 73.6 (SD 6.3) years, 159 (52.8%) were men, 54% received curative-intent treatment, breast cancer (32%) was the most prevalent diagnosis. According to EFS≥6, 101 (33.7%) were classified as frail. EFS score was predictive of OS [hazard ratio (HR) 1.20 (95% confidence interval (CI) 1.10-1.30)], as was increasing severity assessed by categorical EFS (p<0.001). There was a strong correlation between EFS score and number of geriatric impairments (Spearman`s correlation coefficient 0.77). EFS cut-off ≥6 had a sensitivity of 0.97 and specificity of 0.57 for identifying patients with minimum two geriatric impairments. Conclusion: EFS predicts mortality in older patients with cancer receiving radiotherapy, and it is a quick (<5 minutes) and sensitive screening tool to identify patients who may benefit from a geriatric assessment. Copyright: © 2023 Røyset et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.publishedVersio
Increased SIRT1 Concentration Following Four Years of Selenium and Q<inf>10</inf> Intervention Associated with Reduced Cardiovascular Mortality at 10-Year Follow-Up—Sub-Study of a Previous Prospective Double-Blind Placebo-Controlled Randomized Clinical Trial
Full text linkBackground: Selenium and coenzyme Q10 (SeQ10) possess antioxidant and anti-inflammatory properties, potentially mediated via Sirtuin1 (SIRT1). We aimed to investigate the influence of a SeQ10 intervention on SIRT1 concentration, with potential interactions with microRNAs. Methods: In this sub-study of a prospective double-blind placebo-controlled clinical trial, healthy subjects (mean age 76 years) were randomized to receive an active treatment (n = 165, combined 200 µg/day of Se and 200 mg/day of Q10) or a placebo (n = 161). SIRT1 concentration and microRNAs were measured with ELISA and PCR, respectively. Results: After four years, SIRT1 concentration was increased in the active treatment group, with mean (SD) ng/mL of 469 (436) vs. 252 (162), p < 0.001, and decreased in the placebo group, 190 (186) vs. 269 (172), p = 0.002, and the differences between the groups were significant (p = 0.006, adjusted). Those who suffered CV death during a 10-year follow-up (n = 25 and n = 52 in the active treatment and placebo groups, respectively) had significantly lower baseline SIRT1 concentrations compared to the survivors (p < 0.001). MiR-130a-3p was significantly downregulated during the intervention and correlated inversely with SIRT1 at baseline (r = -0.466, p = 0.007). Conclusion: The increased SIRT1 concentration after the SeQ10 intervention associated with reduced CV mortality, partly mediated via miR-1303a-3p, suggests that SIRT1 is an additional mediator of the intervention, preventing vascular ageing.This research was funded by the Stein Erik Hagen Foundation for Clinical Heart Research, Oslo, Norway. Part of the analysis cost was funded by grants from Pharma Nord Aps, Vejle, Denmark, and the County Council of Östergötland, Linköping University, Sweden. The selenium and coenzyme Q10 tablets were provided by Pharma Nord Aps, Vejle, Denmark.publishedVersio