P-selectin and C-reactive protein in relation to home blood pressure and coronary calcification: a SCAPIS substudy.

BACKGROUND: Soluble P-selectin (sP-selectin) and high-sensitivity C-reactive protein (hsCRP) have previously been associated with hypertension, but the relation with out-of-office blood pressure (BP) and coronary artery calcification score is unknown. We aimed to examine the relationship between sP-selectin, hsCRP and home BP, as well as coronary artery calcification score and carotid artery plaques. METHODS: In the Swedish CArdioPulmonary bioImage Study (SCAPIS), 5057 randomly selected participants were evaluated with office and home BP using the semi-automatic Omron M10-IT device. For this cross-sectional study, participants with sP-selectin <4 standard deviations above mean and hsCRP <5 mg/l, representing low-grade inflammation, were included. Using generalized linear models, these inflammatory markers were evaluated in relation to BP classifications, as well as coronary artery calcification score and carotid artery plaques. RESULTS: Of participants, 4548 were included in the analyses. The median age was 57.2 (53.4-61.2) years, and 775 (17.0%) reported taking medication for hypertension. Participants in the highest quartile of sP-selectin [odds ratio (OR) 1.67, 95% confidence interval (CI) 1.40-1.98, P < 0.001] and hsCRP [OR 2.25, (95% CI 1.89-2.60), P < 0.001] were more likely to have sustained hypertension. Participants in the highest quartile of hsCRP were also more likely to have masked hypertension, OR (95% CI) 2.31 (1.72-3.10), P < 0.001 and carotid artery plaques, OR (95% CI) 1.21 (1.05-1.38), P = 0.007. CONCLUSION: Increased sP-selectin and hsCRP were independently associated with sustained hypertension. These findings indicate an association between hypertension and platelet activity, as expressed by sP-selectin.

Current interventional options for palliative care for patients with advanced-stage cholangiocarcinoma.

Primary biliary tract tumors are malignancies that originate in the liver, bile ducts, or gallbladder. These tumors often present with jaundice of unknown etiology, leading to delayed diagnosis and advanced disease. Currently, several palliative treatment options are available for primary biliary tract tumors. They include percutaneous transhepatic biliary drainage (PTBD), biliary stenting, and surgical interventions such as biliary diversion. Systemic therapy is also commonly used for the palliative treatment of primary biliary tract tumors. It involves the administration of chemotherapy drugs, such as gemcitabine and cisplatin, which have shown promising results in improving overall survival in patients with advanced biliary tract tumors. PTBD is another palliative treatment option for patients with unresectable or inoperable malignant biliary obstruction. Biliary stenting can also be used as a palliative treatment option to alleviate symptoms in patients with unresectable or inoperable malignant biliary obstruction. Surgical interventions, such as biliary diversion, have traditionally been used as palliative options for primary biliary tract tumors. However, biliary diversion only provides temporary relief and does not remove the tumor. Primary biliary tract tumors often present in advanced stages, making palliative treatment the primary option for improving the quality of life of patients.

Is asthma in children still increasing? 20-year prevalence trends in northern Sweden.

BACKGROUND: In the present study, we describe prevalence trends of asthma and investigate the association with asthma symptoms, use of asthma medication, and asthma severity among 8-year-old children in Norrbotten, Sweden in 1996, 2006, and 2017. METHODS: Within the Obstructive Lung Disease in Northern Sweden (OLIN) studies, three pediatric cohorts were recruited in 1996, 2006, and 2017 respectively. Identical methods were used; all children in first and second grade (median age 8 years) in three municipalities were invited to a parental questionnaire survey, completed by n = 3430 in 1996 (97% participation), n = 2585 in 2006 (96%), and n = 2785 in 2017 (91%). The questionnaire included questions about respiratory symptoms and diagnosis, treatment, and severity of asthma. RESULTS: The prevalence of wheezing was stable during the study, 10.1% in 1996; 10.8% in 2006; and 10.3% in 2017, p = .621, while physician-diagnosed asthma increased: 5.7%, 7.4%, and 12.2%, p < .001. The use of asthma medication in the last 12 months increased: 7.1%, 8.7%, and 11.5%, p < .001. Among children diagnosed with asthma, the prevalence of asthma symptoms, the impact on daily life, and severe asthma decreased, while the use of inhaled corticosteroids increased from 1996 until 2017. CONCLUSION: The prevalence of wheezing was stable among 8-year-old in this area from 1996 to 2017, while the prevalence of physician-diagnosed asthma doubled but without an increase in asthma morbidity. The increase of physician-diagnosed asthma without a coincident increase in asthma morbidity can partly be explained by more and earlier diagnosis among those with mild asthma.

Progressive changes in pulmonary gas exchange during invasive respiratory support for COVID-19 associated acute respiratory failure: A retrospective study of the association with 90-day mortality.

BACKGROUND: Ratio of arterial pressure of oxygen and fraction of inspired oxygen (P/F ratio) together with the fractional dead space (Vd/Vt) provides a global assessment of pulmonary gas exchange. The aim of this study was to assess the potential value of these variables to prognosticate 90-day survival in patients with COVID-19 associated ARDS admitted to the Intensive Care Unit (ICU) for invasive ventilatory support. METHODS: In this single-center observational, retrospective study, P/F ratios and Vd/Vt were assessed up to 4 weeks after ICU-admission. Measurements from the first 2 weeks were used to evaluate the predictive value of P/F ratio and Vd/Vt for 90-day mortality and reported by the adjusted hazard ratio (HR) and 95% confidence intervals [95%CI] by Cox proportional hazard regression. RESULTS: Almost 20,000 blood gases in 130 patients were analyzed. The overall 90-day mortality was 30% and using the data from the first ICU week, the HR was 0.85 [0.77-0.94] for every 10 mmHg increase in P/F ratio and 1.61 [1.20-2.16] for every 0.1 increase in Vd/Vt. In the second week, the HR for 90-day mortality was 0.82 [0.75-0.89] for every 10 mmHg increase in P/F ratio and 1.97 [1.42-2.73] for every 0.1 increase in Vd/Vt. CONCLUSION: The progressive changes in P/F ratio and Vd/Vt in the first 2 weeks of invasive ventilatory support for COVID-19 ARDS were significant predictors for 90-day mortality.

Acquisition Duration Optimization Using Visual Grading Regression in [68Ga]FAPI-46 PET Imaging of Oncologic Patients.

Fibroblast activation protein is a promising target for oncologic molecular imaging with radiolabeled fibroblast activation protein inhibitors (FAPI) in a large variety of cancers. However, there are yet no published recommendations on how to set up an optimal imaging protocol for FAPI PET/CT. It is important to optimize the acquisition duration and strive toward an acquisition that is sufficiently short while simultaneously providing sufficient image quality to ensure a reliable diagnosis. The aim of this study was to evaluate the feasibility of reducing the acquisition duration of [68Ga]FAPI-46 imaging while maintaining satisfactory image quality, with certainty that the radiologist's ability to make a clinical diagnosis would not be affected. Methods: [68Ga]FAPI-46 PET/CT imaging was performed on 10 patients scheduled for surgical resection of suspected pancreatic cancer, 60 min after administration of 3.6 ± 0.2 MBq/kg. The acquisition time was 4 min/bed position, and the raw PET data were statistically truncated and reconstructed to represent images with an acquisition duration of 1, 2, and 3 min/bed position, additional to the reference images of 4 min/bed position. Four image quality criteria that focused on the ability to distinguish specific anatomic details, as well as perceived image noise and overall image quality, were scored on a 4-point Likert scale and analyzed with mixed-effects ordinal logistic regression. Results: A trend toward increasing image quality scores with increasing acquisition duration was observed for all criteria. For the overall image quality, there was no significant difference between 3 and 4 min/bed position, whereas 1 and 2 min/bed position were rated significantly (P < 0.05) lower than 4 min/bed position. For the other criteria, all images with a reduced acquisition duration were rated significantly inferior to images obtained at 4 min/bed position. Conclusion: The acquisition duration can be reduced from 4 to 3 min/bed position while maintaining satisfactory image quality. Reducing the acquisition duration to 2 min/bed position or lower is not recommended since it results in inferior-quality images so noisy that clinical interpretation is significantly disrupted.

The Buddy Study: Local reach, adoption and implementation following a randomised controlled trial of conservative management of fifth metacarpal neck fractures.

OBJECTIVE: To understand the reach, adoption and implementation of the evidence that buddy strapping for uncomplicated fifth metacarpal neck fractures is non-inferior to plaster casting. METHODS: Mixed-method study using clinical audit of the years before and after the original randomised controlled study was published (2019) and staff questionnaires/semi-structured interviews. RESULTS: Sixty-nine percent of questionnaire respondents were aware of the original study findings (i.e. reach) and 57% had adopted the research findings. The proportion of patients receiving buddy strapping was 6% in 2014-2016 and 28% in 2019-2021 (implementation). Qualitative data provided insight into ongoing barriers to adoption and implementation including fear of reprisal, the need for permission, opinions of senior decision makers, perceptions about patient preferences, and an overall tendency to 'play it safe'. CONCLUSIONS: Even in a department where primary research is conducted, implementation requires ongoing attention to factors impacting reach and adoption.

The STRAT-PARK cohort: A personalized initiative to stratify Parkinson's disease.

The STRAT-PARK initiative aims to provide a platform for stratifying Parkinson's disease (PD) into biological subtypes, using a bottom-up, multidisciplinary biomarker-based and data-driven approach. PD is a heterogeneous entity, exhibiting high interindividual clinicopathological variability. This diversity suggests that PD may encompass multiple distinct biological entities, each driven by different molecular mechanisms. Molecular stratification and identification of disease subtypes is therefore a key priority for understanding and treating PD. STRAT-PARK is a multi-center longitudinal cohort aiming to recruit a total of 2000 individuals with PD and neurologically healthy controls from Norway and Canada, for the purpose of identifying molecular disease subtypes. Clinical assessment is performed annually, whereas biosampling, imaging, and digital and neurophysiological phenotyping occur every second year. The unique feature of STRAT-PARK is the diversity of collected biological material, including muscle biopsies and platelets, tissues particularly useful for mitochondrial biomarker research. Recruitment rate is ∼150 participants per year. By March 2023, 252 participants were included, comprising 204 cases and 48 controls. STRAT-PARK is a powerful stratification initiative anticipated to become a global research resource, contributing to personalized care in PD.

Improved limit of detection for zoonotic Plasmodium knowlesi and P. cynomolgi surveillance using reverse transcription for total nucleic acid preserved samples or dried blood spots.

Background: Zoonotic P. knowlesi and P. cynomolgi symptomatic and asymptomatic infections occur across endemic areas of Southeast Asia. Most infections are low-parasitemia, with an unknown proportion below routine microscopy detection thresholds. Molecular surveillance tools optimizing the limit of detection (LOD) would allow more accurate estimates of zoonotic malaria prevalence. Methods: An established ultra-sensitive Plasmodium genus quantitative-PCR (qPCR) assay targeting the 18S rRNA gene underwent LOD evaluation with and without reverse transcription (RT) for P. knowlesi, P. cynomolgi and P. vivax using total nucleic acid preserved (DNA/RNA Shield™) isolates and archived dried blood spots (DBS). LODs for selected P. knowlesi-specific assays, and reference P. vivax- and P. cynomolgi-specific assays were determined with RT. Assay specificities were assessed using clinical malaria samples and malaria-negative controls. Results: The use of reverse transcription improved Plasmodium species detection by up to 10,000-fold (Plasmodium genus), 2759-fold (P. knowlesi), 1000-fold (P. vivax) and 10-fold (P. cynomolgi). The median LOD with RT for the Kamau et al. Plasmodium genus RT-qPCR assay was ≤0.0002 parasites/µL for P. knowlesi and 0.002 parasites/µL for both P. cynomolgi and P. vivax. The LODs with RT for P. knowlesi-specific PCRs were: Imwong et al. 18S rRNA (0.0007 parasites/µL); Divis et al. real-time 18S rRNA (0.0002 parasites/µL); Lubis et al. hemi-nested SICAvar (1.1 parasites/µL) and Lee et al. nested 18S rRNA (11 parasites/µL). The LOD for P. vivax- and P. cynomolgi-specific assays with RT were 0.02 and 0.20 parasites/µL respectively. For DBS P. knowlesi samples the median LOD for the Plasmodium genus qPCR with RT was 0.08, and without RT was 19.89 parasites/uL (249-fold change); no LOD improvement was demonstrated in DBS archived beyond 6 years. The Plasmodium genus and P. knowlesi-assays were 100% specific for Plasmodium species and P. knowlesi detection, respectively, from 190 clinical infections and 48 healthy controls. Reference P. vivax-specific primers demonstrated known cross-reactivity with P. cynomolgi. Conclusion: Our findings support the use of an 18S rRNA Plasmodium genus qPCR and species-specific nested PCR protocol with RT for highly-sensitive surveillance of zoonotic and human Plasmodium species infections.

Co-creation of a digital platform for peer support in a community of adolescent and young adult patients during and after cancer.

PURPOSE: Adolescents and young adults (AYAs) diagnosed with cancer report psychological challenges and social isolation. Peer support has been shown to be a valuable resource for coping with these experiences. The aim of this study was through co-creation map the needs for peer support among AYA cancer patients in Sweden; and building on these results to develop and test a prototype of a digital tool for peer support. METHOD: The study was conducted in co-creation in a team consisting of AYA cancer patients, researchers, and a health tech company in Sweden. Through interviews the needs for emotional support were investigated. Based on this information, a prototype of a digital platform for peer support was co-created by the team. The platform was tested and evaluated through an online survey and follow-up interviews as part of the development process. RESULTS: AYAs expressed feelings of loneliness and a desire to process their cancer experiences with peers. A prerequisite for a digital platform for peer support was the assurance of a high degree of security. Piloting the prototype, 87% reported feeling secure, all participants found it valuable to interact with peers on the platform. In the follow-up interviews, AYAs emphasizing the need to simplify this process while maintaining stringent security measures. CONCLUSION: Co-creating tools for support together with AYAs ensures relevance and usability. A secure digital platform for peer support represents a complement to other existing forms of support. The presence of moderators was found to enhance security. Further development of the platform's log-in procedure is necessary.

Dietary adherence is not dependent on the mode of diagnosis in children with coeliac disease.

AIM: To compare the adherence to gluten-free diet between children with serology-based and biopsy-proven coeliac disease. METHODS: Medical records were retrospectively reviewed in 257 Swedish children diagnosed with coeliac disease between 2012 and 2019 at a tertiary hospital. Adherence to a gluten-free diet was systematically assessed by trained dietitians at follow-up. Mixed models were used to analyse the dietary adherence by mode of diagnosis (serology-based vs. biopsy-proven). RESULTS: After mean 6.3 (SD 2.4) years, there was neither a difference in the dietary adherence over time depending on the mode of diagnosis (OR 0.64 [95% confidence interval (CI) 0.26, 1.60], p = 0.342), nor if coeliac disease was detected in screening studies (OR 0.74 [95% CI 0.25, 2.17], p = 0.584) or in risk-groups (OR 1.01 [95% CI 0.26, 3.91], p = 0.991) compared to clinically detected diagnosis. Non-adherence to a gluten-free diet increased with age (OR 1.19 [95% CI 1.06, 1.33], p = 0.003). There was no difference in the proportion of patients improving their dietary adherence from non-adherent to adherent over time (p = 0.322). CONCLUSION: Mode of diagnosis did not influence the dietary adherence in Swedish children with coeliac disease, although adherence to a gluten-free diet was inversely associated with increasing age.

Affinity chromatography reveals direct binding of the GATA4-NKX2-5 interaction inhibitor (3i-1000) with GATA4.

Heart failure is a serious medical condition with a poor prognosis. Current treatments can only help manage the symptoms and slow the progression of heart failure. However, there is currently no cure to prevent and reverse cardiac remodeling. Transcription factors are in a central role in various cellular processes, and in the heart, GATA4 and NKX2-5 transcription factors mediate hypertrophic responses and remodeling. We have identified compounds that modulate the synergistic interaction of GATA4 and NKX2-5 and shown that the most promising compound (1, 3i-1000) is cardioprotective in vitro and in vivo. However, direct evidence of its binding site and mechanism of action has not been available. Due to the disordered nature of transcription factors, classical target engagement approaches cannot be utilized. Here, we synthesized a small-molecule ligand-binding pulldown probe of compound 1 to utilize affinity chromatography alongside CETSA, AlphaScreen, and molecular modeling to study ligand binding. These results provide the first evidence of direct physical binding of compound 1 selectively to GATA4. While developing drugs that target transcription factors presents challenges, advances in technologies and knowledge of intrinsically disordered proteins enable the identification of small molecules that can selectively target transcription factors.

Cochlear implantation outcomes in children with multiple disabilities: a topic that's worth revisiting.

OBJECTIVES: To determine the benefits of cochlear implantation in hearing loss children with multiple disabilities (MD) in terms of auditory outcomes, speech performance, and their quality of life. METHODS: This was a cross sectional study from January 2019 to December 2020 in which thirty-one children with hearing loss and multiple disabilities were evaluated. Their improvement in auditory and speech performances were assessed using Categories of Auditory Performance version II (CAP-II) and the Speech Intelligibility Rating (SIR) scales. The assessment was done at 6-month intervals, with the baseline evaluation done at least six months after activation of the implant. Parents were asked to fill the Parents Evaluation of Aural/Oral Performance of Children (PEACH) diary and Perceived Benefit Questionnaire (PBQ) to evaluate the child's quality of life. RESULTS: All 31 children have Global Developmental Delay (GDD), with 11 having an additional disability. Both mean CAP-II and SIR scores showed significant improvement with increased hearing age (p < 0.05) after 6-month intervals. In addition, 20 out of 31 children (64.5%) have achieved verbal communication after implantation. The mean PEACH score in quiet was significantly better than in noise (p = 0.007) and improved with the increased of hearing age. The majority of parents (96%‒100%) perceived a cochlear implant as beneficial to their child in terms of auditory response, awareness, interaction, communication, and speech development. CONCLUSIONS: Cochlear implantation had shown benefits in children with multiple disabilities. Outcome measures should not only focus on auditory and speech performances but the improvement in quality of life. Hence, individualized each case with realistic expectation from families must be emphasized in this group of children. LEVEL OF EVIDENCE: Level 3.

Benefits and challenges of 18F-FDG PET/CT in patients with Takayasu arteritis.

AIM: To evaluate the diagnostic performance of 2-[18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron-emission tomography (PET)/computed tomography (CT) in TA diagnosis and Takayasu arteritis (TA) activity assessment. MATERIALS AND METHODS: This retrospective study included patients with TA diagnosed according to the American College of Rheumatology (ACR) criteria and undergoing 18F-FDG PET/CT imaging from October 2010 to July 2022. TA activity was assessed through 18F-FDG PET/CT (maximum standard uptake value [SUVmax], vascular SUVmax/mean standard uptake value [SUVmean] of liver (SUV ratio), and PET vascular activity score [PETVAS]) using physician global assessment (PGA) as the reference standard, and the results of these assessments were compared against the clinical activity scores (National Institutes of Health [NIH] and Indian Aortitis Disease Activity [ITAS-A] scores), acute-phase reactants (APR), and white blood cell and platelet counts. RESULTS: Twenty 18F-FDG PET/CT examinations from 19 patients were included in the study, nine were performed in the active phase and 11 in the inactive phase. The involved vessels showed segmental and tubular FDG uptake in the active group. The average SUVmax, SUV ratio, and PETVAS was 6.3 ± 2.7 (range 3.4-12), 4.2 ± 1.7 (range 2.1-7.5), and 22.7 ± 11.2 (range 6-39), respectively, in the active group and 1.7 ± 0.9 (0.9-3.1), 1.1 ± 0.6 (range 0.6-2.4), and 3.5 ± 5.5 (range 0-18), respectively, in the inactive group. The sensitivity, specificity of SUVmax, SUV ratio, and PETVAS for TA activity assessment were 100%, 100%; 100%, 90.9%; and 88.9, 90.9%, respectively. After ROC curve analysis, a new SUVmax cut-off was obtained. Based on the new cut-off value, SUVmax 3.3 and SUV ratio 1.9 had a more perfect assessment performance. CONCLUSION: 18F-FDG PET/CT is an alternative imaging technique for TA.

Human Epidermal Growth Factor Receptor 2 (HER2) PET Imaging of HER2-Low Breast Cancer with [68Ga]Ga-ABY-025: Results from a Pilot Study.

Patients with HER2-low metastatic breast cancer (mBC), defined as an immunohistochemistry (IHC) score of 1+ or 2+ without HER2 gene amplification, may benefit from HER2 antibody-drug conjugates. Identifying suitable candidates is a clinical challenge because of spatial and temporal heterogeneity in HER2 expression and discrepancies in pathologic reporting. We aimed to investigate the feasibility and safety of HER2-specific PET imaging with [68Ga]Ga-ABY-025 for visualization of HER2-low mBC. Methods: A prospective pilot study was done with 10 patients who had HER2-low mBC, as part of a phase 2 basket imaging study with [68Ga]Ga-ABY-025 in HER2-expressing solid tumors. Patients were recruited at the Breast Clinic at the Karolinska University Hospital, Stockholm, Sweden. PET/CT images were acquired 3 h after injection of 200 MBq of [68Ga]Ga-ABY-025. The SUVmax was used to quantify tracer uptake. Ultrasound-guided tumor biopsies were guided by results from the HER2 PET. The main outcome-the safety and feasibility of HER2 PET in patients with HER2-low mBC, measured the occurrence of possible procedure-related adverse events. Results: Ten patients with HER2-low mBC underwent [68Ga]Ga-ABY-025 PET/CT with paired tumor biopsies. No adverse events occurred. In all patients, [68Ga]Ga-ABY-025-avid lesions with substantial intra- and interindividual heterogeneity in tracer uptake were noted. In 8 of 10 patients with ABY-025-avid lesions, the HER2-low status of the corresponding lesions was confirmed by IHC or in situ hybridization. Two patients had an IHC score of 0 in the tumor biopsies:1 in a cutaneous lesion with a low SUVmax and 1 in a liver metastasis with a high SUVmax but a "cold" core. Conclusion: The visualization of HER2-low mBC with [68Ga]Ga-ABY-025 PET/CT was feasible and safe. Areas of tracer uptake showed varying levels of HER2 expression on IHC. The observed intra- and interindividual heterogeneity in [68Ga]Ga-ABY-025 uptake suggested that HER2 PET might be used as a tool for the noninvasive assessment of disease heterogeneity and has the potential to identify patients in whom HER2-targeted drugs can have a clinical benefit.

N-acetylcysteine increases dopamine release and prevents the deleterious effects of 6-OHDA on the expression of VMAT2, α-synuclein, and tyrosine hydroxylase.

OBJECTIVES: Current treatments for Parkinson's disease using pharmacological approaches alleviate motor symptoms but do not prevent neuronal loss or dysregulation of dopamine neurotransmission. In this article, we have explored the molecular mechanisms underlying the neuroprotective effect of the antioxidant N-acetylcysteine (NAC) on the damaged dopamine system. METHODS: SH-SY5Y cells were differentiated towards a dopaminergic phenotype and exposed to 6-hydroxydopamine (6-OHDA) to establish an in vitro model of Parkinson's disease. We examined the potential of NAC to restore the pathological effects of 6-OHDA on cell survival, dopamine synthesis as well as on key proteins regulating dopamine metabolism. Specifically, we evaluated gene- and protein expression of tyrosine hydroxylase (TH), vesicle monoamine transporter 2 (VMAT2), and α-synuclein, by using qPCR and Western blot techniques. Moreover, we quantified the effect of NAC on total dopamine levels using a dopamine ELISA assay. RESULTS: Our results indicate that NAC has a neuroprotective role in SH-SY5Y cells exposed to 6-OHDA by maintaining cell proliferation and decreasing apoptosis. Additionally, we demonstrated that NAC treatment increases dopamine release and protects SH-SY5Y cells against 6-OHDA dysregulations on the proteins TH, VMAT2, and α-synuclein. CONCLUSIONS: Our findings contribute to the validation of compounds capable to restore dopamine homeostasis and shed light on the metabolic pathways that could be targeted to normalize dopamine turnover. Furthermore, our results highlight the effectiveness of the antioxidant NAC in the prevention of dopaminergic neurodegeneration in the present model. ABBREVIATIONS: DAT, dopamine transporter; 6-OHDA, 6-hydroxydopamine; NAC, N-acetylcysteine; PARP, poly (ADP-ribose) polymerase; RA; retinoic acid; ROS, reactive oxygen species; TH, tyrosine hydroxylase; TPA, 12-O-tetradecanoyl-phorbol-13-acetate; VMAT2, vesicle monoamine transporter 2.

The effects of Electronic Stability Control (ESC) on fatal crash rates in the United States.

PROBLEM: Electronic Stability Control (ESC) is believed to be among the most efficient vehicle safety interventions with reported effects around 50% for fatal single and rollover crashes. However, such estimates have used sample data, which have not controlled for the possibilities of self-selection, behavioral adaptation, increased access to the technology by less safe drivers, and the calculation of effects on very specific categories of crashes. Effects of ESC in the population can therefore be expected to be smaller than is currently believed. METHOD: National U.S. data for fatal crashes, driving exposure and other control factors, and market penetration of ESC over 1991-2021 were used to calculate whether the trends in fatalities over time in crash rates for singles, rollovers, and fatal crashes in general matched projections from estimates of effectiveness. RESULTS: It was found that downward trends in the relevant crash types were generally present before ESC was introduced, and that the trends thereafter were weaker. Although some trends were consistent with effects of ESC, they were markedly smaller than the projected ones, and could be explained by other factors such as the number of vehicles per capita. At best, the effect for rollovers could be up to two-thirds of previous estimates, no effect was detected for singles, while for all fatal crashes results depended upon the type of analysis performed. These results conflict with conclusions in all published ESC crash sample studies, which have compared vehicles with and without ESC. This discrepancy can be explained by methodological errors in the previous studies using induced exposure methods and self-selected samples. PRACTICAL APPLICATIONS: Traffic safety may not be as much improved by technological interventions as believed. Alternative approaches to traffic safety are needed, which do not rely on technology that interferes with driver behavior.

Identification of early risk factors for anti-citrullinated-protein-antibody positive rheumatoid arthritis-a prospective cohort study.

OBJECTIVE: Individuals positive for anti-cyclic-peptide-antibodies (anti-CCP) and musculoskeletal complaints (MSK-C) are at risk for developing rheumatoid arthritis (RA). In this study we aimed to investigate factors involved in arthritis progression. METHODS: Anti-CCP2-positive individuals with MSK-C referred to a rheumatologist were recruited. Individuals lacked arthritis at clinical and ultrasound examination and were followed for ≥three years or until clinical arthritis diagnosis. Blood samples from inclusion were analyzed for; nine anti-citrullinated-protein-antibody (ACPA) reactivities (citrullinated α-1-enolase, fibrinogen, filaggrin, histone, vimentin and tenascin peptides); 92 inflammation-associated proteins; and HLA-shared epitope alleles. Cox regression was applied to the data to identify independent predictors in a model. RESULTS: 267 individuals were included with median follow up of 49 months (IQR: 22-60). 101 (38%) developed arthritis after median 14 months (IQR: 6-27). The analysis identified that presence of at least one ACPA reactivity (HR 8.0, 95% CI 2.9-22), ultrasound detected tenosynovitis (HR 3.4, 95% CI 2.0-6.0), IL6 levels (HR 1.5, 95% CI 1.2-1.8) and IL15-Rα levels (HR 0.6, 95% CI 0.4-0.9) are significant independent predictors for arthritis progression in a prediction model (Harrell's C 0.76 [SE 0.02], AUC 0.82 [95% CI 0.76-0.89], cross-validated AUC 0.70 [95% CI 0.56-0.85]). CONCLUSION: We propose a high-Risk-RA phase characterized by presence of ACPA reactivity, tenosynovitis, IL6, and IL15-Rα and suggest that these factors need to be further investigated for their biological effects and clinical values, to identify individuals at particular low risk and high risk for arthritis progression.

Investigating the link between frailty and outcomes in geriatric patients with isolated rib fractures.

Background: Studies have shown an increased risk of morbidity in elderly patients suffering rib fractures from blunt trauma. The association between frailty and rib fractures on adverse outcomes is still ill-defined. In the current investigation, we sought to delineate the association between frailty, measured using the Orthopedic Frailty Score (OFS), and outcomes in geriatric patients with isolated rib fractures. Methods: All geriatric (aged 65 years or older) patients registered in the 2013-2019 Trauma Quality Improvement database with a conservatively managed isolated rib fracture were considered for inclusion. An isolated rib fracture was defined as the presence of ≥1 rib fracture, a thorax Abbreviated Injury Scale (AIS) between 1 and 5, an AIS ≤1 in all other regions, as well as the absence of pneumothorax, hemothorax, or pulmonary contusion. Based on patients' OFS, patients were classified as non-frail (OFS 0), pre-frail (OFS 1), or frail (OFS ≥2). The prevalence ratio (PR) of composite complications, in-hospital mortality, failure-to-rescue (FTR), and intensive care unit (ICU) admission between the OFS groups was determined using Poisson regression models to adjust for potential confounding. Results: A total of 65 375 patients met the study's inclusion criteria of whom 60% were non-frail, 29% were pre-frail, and 11% were frail. There was a stepwise increased risk of complications, in-hospital mortality, and FTR from non-frail to pre-frail and frail. Compared with non-frail patients, frail patients exhibited a 87% increased risk of in-hospital mortality [adjusted PR (95% CI): 1.87 (1.52-2.31), p<0.001], a 44% increased risk of complications [adjusted PR (95% CI): 1.44 (1.23-1.67), p<0.001], a doubling in the risk of FTR [adjusted PR (95% CI): 2.08 (1.45-2.98), p<0.001], and a 17% increased risk of ICU admission [adjusted PR (95% CI): 1.17 (1.11-1.23), p<0.001]. Conclusion: There is a strong association between frailty, measured using the OFS, and adverse outcomes in geriatric patients managed conservatively for rib fractures.

Targeting the ACOD1-itaconate axis stabilizes atherosclerotic plaques.

Inflammatory macrophages are key drivers of atherosclerosis that can induce rupture-prone vulnerable plaques. Skewing the plaque macrophage population towards a more protective phenotype and reducing the occurrence of clinical events is thought to be a promising method of treating atherosclerotic patients. In the current study, we investigate the immunomodulatory properties of itaconate, an immunometabolite derived from the TCA cycle intermediate cis-aconitate and synthesised by the enzyme Aconitate Decarboxylase 1 (ACOD1, also known as IRG1), in the context of atherosclerosis. Ldlr-/- atherogenic mice transplanted with Acod1-/- bone marrow displayed a more stable plaque phenotype with smaller necrotic cores and showed increased recruitment of monocytes to the vessel intima. Macrophages from Acod1-/- mice contained more lipids whilst also displaying reduced induction of apoptosis. Using multi-omics approaches, we identify a metabolic shift towards purine metabolism, in addition to an altered glycolytic flux towards production of glycerol for triglyceride synthesis. Overall, our data highlight the potential of therapeutically blocking ACOD1 with the aim of stabilizing atherosclerotic plaques.

Clinical benefit of anti-PD-(L)1 immunotherapies in advanced cancer in France: a population-based estimate from 2014 to 2021.

BACKGROUND: In France, the potential benefit of new treatments is initially evaluated by the Haute Autorité de Santé to determine reimbursement and pricing, but rarely afterwards. Although immunotherapies (ITs) have considerably improved the survival of patients, few data are available on their long-term benefit at a population-treated level. The present retrospective study aimed to assess the clinical benefit of ITs compared to the previous standards of care (SoCs) in France from 2014 to 2021. MATERIALS AND METHODS: To do this, we analyzed all ITs from the anti-programmed cell death protein 1/programmed death-ligand 1 [anti-PD-(L)1] class used in monotherapy or in association with another treatment available in early access or reimbursed in France between 2014 and 2021, regardless of indication. The number of patients initiating an IT was retrieved by year, drug and indication. Using extrapolated Kaplan-Meier curves, utility scores and the population treated, the clinical benefit was expressed as the number of deaths prevented (DP), life-years (LYs) and quality-adjusted life years (QALYs) gained compared to previous SoC. RESULTS: Across the period, five ITs were marketed in 21 indications related to eight primary tumor sites. Between 2014 and 2021, 132 924 patients initiated an IT. By December 2021, 16 173 (13 804-17 141) deaths were delayed compared to previous SoC, mainly in lung cancer. Compared to their SoC, ITs provided a gain of 37 316 (33 581-41 048) additional LYs and 27 709 (23 784-30 450) additional QALYs. Lung cancer was the driver indication with 70.6% of LYs and 68.4% of QALYs gained followed by melanoma with 18.7% and 20.4% of the gain, respectively. CONCLUSIONS: Significant gains in DP, LYs and QALYs have been observed in France following the introduction of ITs.