Generative Pre-trained Transformer 4 makes cardiovascular magnetic resonance reports easy to understand.

BACKGROUND: Patients are increasingly using Generative Pre-trained Transformer 4 (GPT-4) to better understand their own radiology findings. PURPOSE: To evaluate the performance of GPT-4 in transforming cardiovascular magnetic resonance (CMR) reports into text that is comprehensible to medical laypersons. METHODS: ChatGPT with GPT-4 architecture was used to generate three different explained versions of 20 various CMR reports (n = 60) using the same prompt: "Explain the radiology report in a language understandable to a medical layperson". Two cardiovascular radiologists evaluated understandability, factual correctness, completeness of relevant findings, and lack of potential harm, while 13 medical laypersons evaluated the understandability of the original and the GPT-4 reports on a Likert scale (1 "strongly disagree", 5 "strongly agree"). Readability was measured using the Automated Readability Index (ARI). Linear mixed-effects models (values given as median [interquartile range]) and intraclass correlation coefficient (ICC) were used for statistical analysis. RESULTS: GPT-4 reports were generated on average in 52 s ± 13. GPT-4 reports achieved a lower ARI score (10 [9-12] vs 5 [4-6]; p < 0.001) and were subjectively easier to understand for laypersons than original reports (1 [1] vs 4 [4,5]; p < 0.001). Eighteen out of 20 (90%) standard CMR reports and 2/60 (3%) GPT-generated reports had an ARI score corresponding to the 8th grade level or higher. Radiologists' ratings of the GPT-4 reports reached high levels for correctness (5 [4, 5]), completeness (5 [5]), and lack of potential harm (5 [5]); with "strong agreement" for factual correctness in 94% (113/120) and completeness of relevant findings in 81% (97/120) of reports. Test-retest agreement for layperson understandability ratings between the three simplified reports generated from the same original report was substantial (ICC: 0.62; p < 0.001). Interrater agreement between radiologists was almost perfect for lack of potential harm (ICC: 0.93, p < 0.001) and moderate to substantial for completeness (ICC: 0.76, p < 0.001) and factual correctness (ICC: 0.55, p < 0.001). CONCLUSION: GPT-4 can reliably transform complex CMR reports into more understandable, layperson-friendly language while largely maintaining factual correctness and completeness, and can thus help convey patient-relevant radiology information in an easy-to-understand manner.

Deep Learning Super-Resolution Reconstruction for Fast and Motion-Robust T2-weighted Prostate MRI.

Background Deep learning (DL) reconstructions can enhance image quality while decreasing MRI acquisition time. However, DL reconstruction methods combined with compressed sensing for prostate MRI have not been well studied. Purpose To use an industry-developed DL algorithm to reconstruct low-resolution T2-weighted turbo spin-echo (TSE) prostate MRI scans and compare these with standard sequences. Materials and Methods In this prospective study, participants with suspected prostate cancer underwent prostate MRI with a Cartesian standard-resolution T2-weighted TSE sequence (T2C) and non-Cartesian standard-resolution T2-weighted TSE sequence (T2NC) between August and November 2022. Additionally, a low-resolution Cartesian DL-reconstructed T2-weighted TSE sequence (T2DL) with compressed sensing DL denoising and resolution upscaling reconstruction was acquired. Image sharpness was assessed qualitatively by two readers using a five-point Likert scale (from 1 = nondiagnostic to 5 = excellent) and quantitatively by calculating edge rise distance. The Friedman test and one-way analysis of variance with post hoc Bonferroni and Tukey tests, respectively, were used for group comparisons. Prostate Imaging Reporting and Data System (PI-RADS) score agreement between sequences was compared by using Cohen κ. Results This study included 109 male participants (mean age, 68 years ± 8 [SD]). Acquisition time of T2DL was 36% and 29% lower compared with that of T2C and T2NC (mean duration, 164 seconds ± 20 vs 257 seconds ± 32 and 230 seconds ± 28; P < .001 for both). T2DL showed improved image sharpness compared with standard sequences using both qualitative (median score, 5 [IQR, 4-5] vs 4 [IQR, 3-4] for T2C and 4 [IQR, 3-4] for T2NC; P < .001 for both) and quantitative (mean edge rise distance, 0.75 mm ± 0.39 vs 1.15 mm ± 0.68 for T2C and 0.98 mm ± 0.65 for T2NC; P < .001 and P = .01) methods. PI-RADS score agreement between T2NC and T2DL was excellent (κ range, 0.92-0.94 [95% CI: 0.87, 0.98]). Conclusion DL reconstruction of low-resolution T2-weighted TSE sequences enabled accelerated acquisition times and improved image quality compared with standard acquisitions while showing excellent agreement with conventional sequences for PI-RADS ratings. Clinical trial registration no. NCT05820113 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Turkbey in this issue.

A novel and simple cardiac magnetic resonance score (PE2RT) predicts outcome in takotsubo syndrome.

OBJECTIVES: To find simple imaging-based features on cardiac magnetic resonance (CMR) that are associated with major adverse cardiovascular events (MACE) in takotsubo syndrome (TTS). METHODS: Patients with TTS referred for CMR between 2007 and 2021 were retrospectively evaluated. Besides standard CMR analysis, commonly known complications of TTS based on expert knowledge were assessed and summarised via a newly developed PE2RT score (one point each for pleural effusion, pericardial effusion, right ventricular involvement, and ventricular thrombus). Clinical follow-up data was reviewed up to three years after discharge. The relationship between PE2RT features and the occurrence of MACE (cardiovascular death or new hospitalisation due to acute myocardial injury, arrhythmia, or chronic heart failure) was examined using Cox regression analysis and Kaplan-Meier estimator. RESULTS: Seventy-nine patients (mean age, 68 ± 14 years; 72 women) with TTS were included. CMR was performed in a median of 4 days (IQR, 2-6) after symptom onset. Over a median follow-up of 13.3 months (IQR, 0.4-36.0), MACE occurred in 14/79 (18%) patients: re-hospitalisation due to acute symptoms (9/79, 11%) or chronic heart failure symptoms (4/79, 5%), and cardiac death (1/79, 1%). Patients with MACE had a higher PE2RT score (median [IQR], 2 [2-3] vs 1 [0-1]; p < 0.001). PE2RT score was associated with MACE on Cox regression analysis (hazard ratio per PE2RT feature, 2.44; 95%CI: 1.62-3.68; p < 0.001). Two or more PE2RT complications were strongly associated with the occurrence of MACE (log-rank p < 0.001). CONCLUSIONS: The introduced PE2RT complication score might enable an easy-to-assess outcome evaluation of TTS patients by CMR. KEY POINTS: • Complications like pericardial effusion, pleural effusion, right ventricular involvement, and ventricular thrombus (summarised as PE2RT features) are relatively common in takotsubo syndrome. • The proposed PE2RT score (one point per complication) was associated with the occurrence of major adverse cardiac events on follow-up. • Complications easily detected by cardiac magnetic resonance imaging can help clinicians derive long-term prognostic information on patients with takotsubo syndrome.

Analysis of associations between dietary patterns, genetic disposition, and cognitive function in data from UK Biobank.

PURPOSE: Research suggests that diet influences cognitive function and the risk for neurodegenerative disease. The present study aimed to determine whether a recently developed diet score, based on recommendations for dietary priorities for cardio metabolic health, was associated with fluid intelligence, and whether these associations were modified by individual genetic disposition. METHODS: This research has been conducted using the UK Biobank Resource. Analyses were performed using self-report data on diet and the results for the verbal-numerical reasoning test of fluid intelligence of 104,895 individuals (46% male: mean age at recruitment 57.1 years (range 40-70)). For each participant, a diet score and a polygenic score (PGS) were constructed, which evaluated predefined cut-offs for the intake of fruit, vegetables, fish, processed meat, unprocessed meat, whole grain, and refined grain, and ranged from 0 (unfavorable) to 7 (favorable). To investigate whether the diet score was associated with fluid intelligence, and whether the association was modified by PGS, linear regression analyses were performed. RESULTS: The average diet score was 3.9 (SD 1.4). After adjustment for selected confounders, a positive association was found between baseline fluid intelligence and PGS (P < 0.001). No association was found between baseline fluid intelligence and diet score (P = 0.601), even after stratification for PGS, or in participants with longitudinal data available (n = 9,482). CONCLUSION: In this middle-aged cohort, no evidence was found for an association between the investigated diet score and either baseline or longitudinal fluid intelligence. However, as in previous reports, fluid intelligence was strongly associated with a PGS for general cognitive function.

Association between urinary iodine excretion, genetic disposition and fluid intelligence in children, adolescents and young adults: the DONALD study.

PURPOSE: Iodine deficiency increases the risk of cognitive impairment and delayed physical development in children. It is also associated with cognitive impairment in adults. Cognitive abilities are among the most inheritable behavioural traits. However, little is known about the consequences of insufficient postnatal iodine intake and whether the individual genetic disposition modifies the association between iodine intake and fluid intelligence in children and young adults. METHODS: The cultural fair intelligence test was used to assess fluid intelligence in the participants of the DONALD study (n = 238; mean age, 16.5 [SD = 7.7] years). Urinary iodine excretion, a surrogate iodine intake marker, was measured in 24-h urine. Individual genetic disposition (n = 162) was assessed using a polygenic score, associated with general cognitive function. Linear regression analyses were conducted to determine whether Urinary iodine excretion was associated with fluid intelligence and whether this association was modified by individual genetic disposition. RESULTS: Urinary iodine excretion above the age-specific estimated average requirement was associated with a five-point higher fluid intelligence score than that below the estimated average requirement (P = 0.02). The polygenic score was positively associated with the fluid intelligence score (ß = 2.3; P = 0.03). Participants with a higher polygenic score had a higher fluid intelligence score. CONCLUSION: Urinary iodine excretion above the estimated average requirement in childhood and adolescence is beneficial for fluid intelligence. In adults, fluid intelligence was positively associated with a polygenic score for general cognitive function. No evidence showed that the individual genetic disposition modifies the association between Urinary iodine excretion and fluid intelligence.

High prevalence of peripheral and carotid artery disease in patients with interstitial lung diseases.

Background: Interstitial lung diseases (ILD) are a heterogenous group of diseases, which have pulmonary fibrosis, restrictive lung disease, and decreased diffusion capacity as a common final path. Premature death frequently results not from ILD itself but from comorbidities. Peripheral artery disease (PAD) is a common comorbid disease in different chronic lung diseases. The focus of the present study is to clarify the prevalence of PAD in ILD. Patients and methods: A total of 97 patients with ILD and 30 controls were included in the study. Patients with ILD were subdivided into two groups according to the progression of pulmonary fibrosis: progressive fibrosing and non-progressive fibrosing ILD (PF-ILD and nPF-ILD, respectively). All participants underwent standard angiological and pneumological diagnostic procedures including six-minute walking test, measurement of ankle-brachial-index, and colour-coded duplex sonography. Results: We observed no relevant differences in the baseline characteristics except age. Both, PF-ILD and nPF-ILD patients, presented with a highly increased incidence of atherosclerotic lesions compared to the control group (p<0.001). PAD was present in all patients with PF-ILD and in 73% of patients with nPF-ILD. These results were confirmed by age-adjusted regression analyses. Conclusions: The present results indicate that ILD is an independent risk factor for atherosclerosis. Patients with PF-ILD are more severely affected than nPF-ILD patients with age as a confounding variable. Atherogenesis in ILD may be mediated by increased cardiovascular risk, systemic inflammation and chronic hypoxemia.

Levels of Alzheimer's disease blood biomarkers are altered after food intake-A pilot intervention study in healthy adults.

INTRODUCTION: Blood biomarkers accurately identify Alzheimer's disease (AD) pathophysiology and axonal injury. We investigated the influence of food intake on AD-related biomarkers in cognitively healthy, obese adults at high metabolic risk. METHODS: One-hundred eleven participants underwent repeated blood sampling during 3 h after a standardized meal (postprandial group, PG). For comparison, blood was sampled from a fasting subgroup over 3 h (fasting group, FG). Plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), amyloid-beta (Aß) 42/40, phosphorylated tau (p-tau) 181 and 231, and total-tau were measured via single molecule array assays. RESULTS: Significant differences were found for NfL, GFAP, Aß42/40, p-tau181, and p-tau231 between FG and PG. The greatest change to baseline occurred for GFAP and p-tau181 (120 min postprandially, p < 0.0001). CONCLUSION: Our data suggest that AD-related biomarkers are altered by food intake. Further studies are needed to verify whether blood biomarker sampling should be performed in the fasting state. HIGHLIGHTS: Acute food intake alters plasma biomarkers of Alzheimer's disease in obese, otherwise healthy adults. We also found dynamic fluctuations in plasma biomarkers concentration in the fasting state suggesting physiological diurnal variations. Further investigations are highly needed to verify if biomarker measurements should be performed in the fasting state and at a standardized time of day to improve the diagnostic accuracy.

Influence of Intraoperative Nociception during Hip or Knee Arthroplasty with Supplementary Regional Anaesthesia on Postoperative Pain and Opioid Consumption.

Background and Objectives: Early postoperative mobilization is central for postoperative outcomes after lower extremity joint replacement surgery. By providing adequate pain control, regional anaesthesia plays an important role for postoperative mobilization. It was the objective of this study to investigate the use of the nociception level index (NOL) to determine the effect of regional anaesthesia in hip or knee arthroplasty patients undergoing general anaesthesia with additional peripheral nerve block. Materials and Methods: Patients received general anaesthesia, and continuous NOL monitoring was established before anaesthesia induction. Depending on the type of surgery, regional anaesthesia was performed with a Fascia Iliaca Block or an Adductor Canal Block. Results: For the final analysis, 35 patients remained, 18 with hip and 17 with knee arthroplasty. We found no significant difference in postoperative pain between hip or knee arthroplasty groups. NOL increase at the time of skin incision was the only parameter associated with postoperative pain measured using a numerical rating scale (NRS > 3) after 24 h in movement (-12.3 vs. +119%, p = 0.005). There was no association with intraoperative NOL values and postoperative opioid consumption, nor was there an association between secondary parameters (bispectral index, heart rate) and postoperative pain levels. Conclusions: Intraoperative NOL changes may indicate regional anaesthesia effectiveness and could be associated with postoperative pain levels. This remains to be confirmed in a larger study.

Lymphocyte transformation test for drug allergy detection: When does it work?

BACKGROUND: The lymphocyte transformation test (LTT) is an in vitro test system for the detection of a sensitization in the context of allergies to drugs. Its reported sensitivity varies largely and seems to be affected by different parameters. In review articles, the average LTT performance was often calculated by combining overall mean sensitivities of various published studies, but without considering different patient characteristics or varying patient numbers per publication. OBJECTIVE: To investigate the impact of different patient-specific and methodological parameters on the sensitivity of the LTT based on data on the level of the individual patient extracted from single studies. METHODS: We performed an advanced literature search in PubMed and screened the identified publications according to previously defined inclusion criteria. In total, individual patient data from 721 patients were extracted from 30 studies. Random-effects meta-regression analyses were performed. RESULTS: The analysis indicate that the enzyme-linked immunosorbent assay-based read-out is more sensitive compared with the classical radioactivity method (enzyme-linked immunosorbent assay: 80% vs radioactivity: 66%; P = .08). Interestingly, drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome is associated with a higher probability of a positive LTT test result compared with other investigated clinical phenotypes ("drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome" vs "bullous reaction"; odds ratio, 2.52; P value = .003). Our analysis also revealed an impact of the time to testing period after the occurrence of the allergic event ("< 2 weeks" vs "2 weeks-2 months"; odds ratio, 2.12; P value = .03). CONCLUSION: The read-out method and relevant clinical parameters affect the sensitivity of the LTT. These findings are based on a meta-analysis providing a higher level of evidence than a single study or previous reviews not considering individual patient data.

Perioperative red blood cell transfusion is associated with poor functional outcome and overall survival in patients with newly diagnosed glioblastoma.

The influence of perioperative red blood cell (RBC) transfusion on prognosis of glioblastoma patients continues to be inconclusive. The aim of the present study was to evaluate the association between perioperative blood transfusion (PBT) and overall survival (OS) in patients with newly diagnosed glioblastoma. Between 2013 and 2018, 240 patients with newly diagnosed glioblastoma underwent surgical resection of intracerebral mass lesion at the authors' institution. PBT was defined as the transfusion of RBC within 5 days from the day of surgery. The impact of PBT on overall survival was assessed using Kaplan-Meier analysis and multivariate regression analysis. Seventeen out of 240 patients (7%) with newly diagnosed glioblastoma received PBT. The overall median number of blood units transfused was 2 (95% CI 1-6). Patients who received PBT achieved a poorer median OS compared to patients without PBT (7 versus 18 months; p < 0.0001). Multivariate analysis identified "age > 65 years" (p < 0.0001, OR 6.4, 95% CI 3.3-12.3), "STR" (p = 0.001, OR 3.2, 95% CI 1.6-6.1), "unmethylated MGMT status" (p < 0.001, OR 3.3, 95% CI 1.7-6.4), and "perioperative RBC transfusion" (p = 0.01, OR 6.0, 95% CI 1.5-23.4) as significantly and independently associated with 1-year mortality. Perioperative RBC transfusion compromises survival in patients with glioblastoma indicating the need to minimize the use of transfusions at the time of surgery. Obeying evidence-based transfusion guidelines provides an opportunity to reduce transfusion rates in this population with a potentially positive effect on survival.

Comparison of the Newborn Infant Parasympathetic Evaluation (NIPE™) index to changes in heart rate to detect intraoperative nociceptive stimuli in healthy and critically ill children below 2 years: An observational study.

BACKGROUND: The validity of current tools for intraoperative objective assessment of nociception/antinociception balance during anesthesia in young and very young surgery children is unknown. AIM: Primary aim of the study was to test the hypothesis that the Newborn Infant Parasympathetic Evaluation (NIPE) index performs better in indicating nociception in anesthetized children below 2 years than changes in heart rate. Secondary aims were to evaluate associations between intraoperative changes in NIPE index values and postoperative pain and emergence delirium. METHODS: Fifty-one children aged <2 years who underwent surgery were included in this prospective observational study. Patients were assigned to either group 1 (healthy children, n = 31) or group 2 (critically ill, ventilated premature infants and neonates, n = 20). The NIPE index and heart rate in response to three defined nociceptive stimuli were continuously recorded. Two different scales, Kindliche Unbehagens- und Schmerzskala (KUS) and Pediatric Anesthesia Emergence Delirium (PAED) as well as a Pain Questionnaire were used to assess postoperative pain levels and emergence delirium. RESULTS: In total, 110 nociceptive events were evaluated. The analysis revealed a statistically significant association between a decrease in the NIPE index and all nociceptive stimuli, with a sensitivity of 92% and a specificity of 96%. The mean percentage decrease ranged from approx. 15%-30% and was highly statistically significant in both groups and for each of the nociceptive events except for venous puncture (p = .004). In contrast, no consistent change in heart rate was demonstrated. The KUS and PAED scale scores were significantly associated with the duration of anesthesia (p = .04), but not with intraoperative NIPE depression. CONCLUSION: The NIPE index was reliable for assessing intraoperative nociception in children aged <2 years and was more reproducible for detecting specific nociceptive stimuli during general anesthesia than heart rate. An effect on postoperative outcome is still elusive.

Validation of the web-based self-administered 24-h dietary recall myfood24-Germany: comparison with a weighed dietary record and biomarkers.

PURPOSE: We aimed to validate myfood24-Germany, a web-based 24-h dietary recall (24HDR), by comparing its performance with a weighed dietary record (WDR) and biomarkers. METHODS: 97 adults (77% female) completed a 3-day WDR with a 24-h urine collection on day 3, followed by at least one 24HDR with myfood24-Germany (corresponding to day 3 of the WDR). Intake of energy and 32 nutrients assessed by myfood24-Germany and the WDR for the same day were compared (method comparison). Intakes of protein and potassium assessed by myfood24-Germany/WDR were compared with intake estimated from urinary biomarkers for protein and potassium (biomarker comparison). RESULTS: In the method comparison, significant correlations were found for energy and all tested nutrients (range 0.45-0.87). There was no significant difference between both methods in the assessed mean energy and macronutrient intake. However, myfood24-Germany underestimated mean intake of 15 nutrients. In the biomarker comparison, protein intake reported by myfood24-Germany/WDR was on average 10%/8% lower than estimated by biomarker. There was no significant difference in mean potassium intake assessed by myfood24-Germany/WDR and biomarker. However, a shared bias in the assessment of potassium intake was observed for both instruments. Concordance correlation coefficients (pc) and weighted Kappa coefficients (κ) confirmed good agreement with the biomarker estimates for myfood24-Germany/WDR in case of protein (pc = 0.58/0.66, κ = 0.51/0.53) and moderate agreement in case of potassium (pc = 0.44/0.51; κ = 0.30/0.33). CONCLUSION: Our results suggest that myfood24-Germany is of comparable validity to traditional dietary assessment methods.

Drug-related problems in head and neck cancer patients identified by repeated medication reviews on consecutive therapy cycles.

BACKGROUND: Head and neck cancer (HNC) patients are particularly vulnerable to drug-related problems (DRPs) given the toxicity of concomitant chemoradiotherapy (CCRT). OBJECTIVE: To investigate the number and type of potential DRPs (pDRPs) in HNC outpatients undergoing five consecutive cycles of CCRT. METHODS: A single-centre, non-randomized, non-interventional, observational study was conducted at the Oncological Outpatient Clinic of the Center for Integrated Oncology at the University Hospital Bonn, Germany. Clinical pharmacists took a comprehensive medication history, documented laboratory data, assessed patients' symptom burden, and retrospectively performed medication reviews at study entry and on the first day of each therapy cycle without any clinical intervention. RESULTS: In 26 patients, the mean number of pDRPs continuously increased during therapy course, from 4.8 (SD 2.7, range 2-12) at cycle 1 to 6.9 (SD 2.6, range 2-12) at cycle 5, with drug-drug interactions, adverse drug reactions, inappropriate durations of use, and inappropriate dosage intervals being the most common. Considering only new and recurrent pDRPs, the mean number was 4.3 (SD 2.3, range 2-9) at cycle 1 and lower in the further therapy course with an average of 1.3 (SD 1.7, range 0-7) at cycle 2 and 1.9 (SD 1.5, range 0-5) at cycle 5. The number of pDRPs was found to be associated with medication regimen complexity and health-related quality of life assessed in the first therapy cycle. CONCLUSION: pDRPs frequently occurred in HNC outpatients demonstrating the need for pharmaceutical care. A methodological framework for repeated medication reviews was established, facilitating implementation into routine healthcare practice.

Digitomotography in children with oro-facial dysfunction (OFD, oro-facial myofunctional disorders) and childhood apraxia of speech (CAS).

BACKGROUND: Oro-facial dysfunctions (OFDs; oro-facial myofunctional disorders) in children and childhood apraxia of speech (CAS) often cause severe problems in articulation, chewing, swallowing and oral posture. OBJECTIVES: Pathognomonic symptoms could yet not be identified, but central problems in planning, programming, timing and automating oro-facial, as well as other fine motor skills, are assumed to be affected. METHODS: To investigate the nature of motor and coordinative deficits in OFD and CAS, digitomotography was applied. The testing focused on recording frequency, force, rhythm and regularity of the index finger including speeded and metronome tapping tasks. 25 children with OFD (7 girls and 18 boys, age 7.9 ± 2.3) and 5 children with CAS (0 girls and 5 boys, age 7.6 ± 2.3), and 31 healthy controls (12 girls and 19 boys, age 9.3 ± 2.2) were tested. Statistical significance was accepted at α = 0.05. ANOVA test, non-parametric Mann-Whitney U test, Kruskal-Wallis test and Spearman's rank correlation coefficient were used. RESULTS: Cross-sectional data revealed consistent significant differences between children with OFD and healthy controls concerning frequency, force, rhythm and regularity of index finger tapping. Individuals with CAS showed particularly low results. Tapping results correlated with disease burden. CONCLUSION: These findings support that underlying superordinated sensorimotor deficits exist. This may help phenotyping and influence diagnostical and therapeutical approaches.

PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment.

A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer's disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau181, total tau, and Aß1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aß1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.

Longitudinal Course of Short-Term Variation and Doppler Parameters in Early Onset Growth Restricted Fetuses.

PURPOSE: To evaluate the longitudinal pattern of fetal heart rate short term variation (STV) and Doppler indices and their correlation to each other in severe growth restricted (IUGR) fetuses. MATERIALS AND METHODS: In this retrospective study, pregnancies with a birth weight below the 10th percentile, born between 24 and 34 gestational weeks with serial Doppler measurements in combination with a computerized CTG (cCTG) with calculated STV were included. Longitudinal changes of both Doppler indices and STV values were evaluated with generalized additive models, adjusted for gestational age and the individual. For all measurements the frequency of abnormal values with regard to the time interval before delivery and Pearson correlations between Doppler indices and STV values were calculated. RESULTS: 41 fetuses with a total of 1413 observations were included. Over the course of the whole study period, regression analyses showed no significant change of STV values (p = 0.38). Only on the day of delivery, a prominent decrease was observed (mean STV d28-22: 7.97 vs. mean STV on day 0: 6.8). Doppler indices of UA and MCA showed a continuous, significant deterioration starting about three weeks prior to delivery (p = 0.007; UA and p < 0.001, MCA). Correlation between any Doppler index and STV values was poor. CONCLUSION: Fetal heart rate STV does not deteriorate continuously. Therefore, cCTG monitoring should be performed at least daily in these high-risk fetuses. Doppler indices of umbilical artery (UA) and middle cerebral artery (MCA), however, showed continuous deterioration starting about 3 weeks prior to delivery.

Circulating metabolites and general cognitive ability and dementia: Evidence from 11 cohort studies.

INTRODUCTION: Identifying circulating metabolites that are associated with cognition and dementia may improve our understanding of the pathogenesis of dementia and provide crucial readouts for preventive and therapeutic interventions. METHODS: We studied 299 metabolites in relation to cognition (general cognitive ability) in two discovery cohorts (N total = 5658). Metabolites significantly associated with cognition after adjusting for multiple testing were replicated in four independent cohorts (N total = 6652), and the associations with dementia and Alzheimer's disease (N = 25,872) and lifestyle factors (N = 5168) were examined. RESULTS: We discovered and replicated 15 metabolites associated with cognition including subfractions of high-density lipoprotein, docosahexaenoic acid, ornithine, glutamine, and glycoprotein acetyls. These associations were independent of classical risk factors including high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, and apolipoprotein E (APOE) genotypes. Six of the cognition-associated metabolites were related to the risk of dementia and lifestyle factors. DISCUSSION: Circulating metabolites were consistently associated with cognition, dementia, and lifestyle factors, opening new avenues for prevention of cognitive decline and dementia.

Comparison of two-stage revision arthroplasty and intramedullary arthrodesis in patients with failed infected knee arthroplasty.

BACKGROUND: Failed total knee arthroplasty (TKA) with significant bone loss and compromised soft-tissues is challenging and the final results are often inferior to patient's expectation. The objective of this study was to present a comparison of outcomes in patients with failed infected TKA treated with two-stage revision TKA or knee arthrodesis and to assess clinical and functional results, implant survival and infection recurrence. The hypothesis was that an arthrodesis may result in beneficial effects on patients' outcome. METHODS: Clinical data of 81 patients with periprosthetic joint infection (PJI) of the knee joint were collected and analyzed retrospectively. Between 2008 and 2014, a total of 36 patients had been treated within a two-stage exchange procedure and reimplantation of a modular intramedullary arthodesis nail and 45 patients with revision TKA. Patients were treated according to the same structured treatment algorithm. Clinical and functional evaluation was performed using the Oxford knee score (OKS) and the visual analogue scale (VAS). RESULTS: The mean follow-up was 32.9 ± 14.0 months. The rate of definitely free of infection at last follow-up in the arthrodesis group was 32 of 36 (88.9%) and 36 of 45 (80.0%) in the revision TKA group (p = 0.272). Mean VAS for pain in the arthrodesis group was 3.1 ± 1.4 compared to 3.2 ± 1.6 in the revision TKA group (p = 0.636). The OKS in the arthrodesis group was 38.7 ± 8.9 and 36.5 ± 8.9 (p = 0.246) in patients with revision TKA. Rate of revisions in the revision-TKA group was 2.8 ± 3.7 compared to 1.2 ± 2.4 in the arthrodesis group (p = 0.021). CONCLUSION: Treatment of PJI needs a distinct therapy with possible fallback strategies in case of failure. A knee arthrodesis is a limb salvage procedure that showed no significant benefits on the considered outcome factors compared to revision TKA but is associated with significantly lower revision rate. After exhausted treatment modalities, a knee arthrodesis should be considered as an option in selected patients. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

A statistical model for the analysis of beta values in DNA methylation studies.

BACKGROUND: The analysis of DNA methylation is a key component in the development of personalized treatment approaches. A common way to measure DNA methylation is the calculation of beta values, which are bounded variables of the form M/(M+U) that are generated by Illumina's 450k BeadChip array. The statistical analysis of beta values is considered to be challenging, as traditional methods for the analysis of bounded variables, such as M-value regression and beta regression, are based on regularity assumptions that are often too strong to adequately describe the distribution of beta values. RESULTS: We develop a statistical model for the analysis of beta values that is derived from a bivariate gamma distribution for the signal intensities M and U. By allowing for possible correlations between M and U, the proposed model explicitly takes into account the data-generating process underlying the calculation of beta values. Using simulated data and a real sample of DNA methylation data from the Heinz Nixdorf Recall cohort study, we demonstrate that the proposed model fits our data significantly better than beta regression and M-value regression. CONCLUSION: The proposed model contributes to an improved identification of associations between beta values and covariates such as clinical variables and lifestyle factors in epigenome-wide association studies. It is as easy to apply to a sample of beta values as beta regression and M-value regression.

Impact of interstitial lung disease on left ventricular myocardial function.

BACKGROUND: Interstitial lung disease (ILD) comprises a wide variety of pulmonary parenchymal disorders within which progressive fibrosing ILD (PF-ILD) constitutes a phenotypic subset. By use of speckle tracking-based strain analysis we aimed to evaluate the degree of left ventricular (LV) dysfunction in progressive vs. non-progressive fibrosing ILD (non-PF-ILD). METHODS: A total of 99 ILD patients (mean age 63.7 ± 13.5 years, 37.4% female), composed of 50 PF-ILD and 49 non-PF-ILD patients, and 33 controls were prospectively enrolled and underwent conventional and speckle tracking echocardiography. Additional laboratory and pulmonary function testing, as well as six-minute walk test were performed. RESULTS: As compared to the non-PF-ILD cohort, PF-ILD patients exhibited a significantly impaired forced vital capacity (2.4 ± 1.0l vs. 3.1 ± 0.9l, p = 0.002), diffusion capacity for carbon monoxide (DLCO, 25.6 ± 16.3% predicted vs. 43.6 ± 16.67% predicted, p <0.001) and exercise capacity response as measured by the six-minute walk test distance (268.1 ± 178.2m vs. 432.6 ± 94.2m, p <0.001). Contrary to conventional echocardiographic LV parameters, both regional and global longitudinal LV strain measurements were significantly altered in ILD patients as compared to controls. No differences in LV strain were found between both patient groups. Significant correlations were observed between global longitudinal strain, on the one hand, and systemic inflammation markers, total lung capacity (TLC) and DLCO, on the other hand (high-sensitivity C-reactive protein: Pearson´s r = -0.30, p< 0.001; interleukin-6: Pearson´s r = -0.26, p = 0.007; TLC % predicted: Pearson´s r = 0.22, p = 0.02; DLCO % predicted: Pearson´s r = 0.21, p = 0.02). CONCLUSIONS: ILD is accompanied by LV dysfunction. LV functionality inversely correlates with the severity of the restrictive ventilatory defect and inflammation marker levels. These observations support the assumption of persistent low-grade systemic inflammation that may link systemic cardiovascular function to ILD status.