Extending Activation Steering to Broad Skills and Multiple Behaviours

Current large language models have dangerous capabilities, which are likely to become more problematic in the future. Activation steering techniques can be used to reduce risks from these capabilities. In this paper, we investigate the efficacy of activation steering for broad skills and multiple behaviours. First, by comparing the effects of reducing performance on general coding ability and Python-specific ability, we find that steering broader skills is competitive to steering narrower skills. Second, we steer models to become more or less myopic and wealth-seeking, among other behaviours. In our experiments, combining steering vectors for multiple different behaviours into one steering vector is largely unsuccessful. On the other hand, injecting individual steering vectors at different places in a model simultaneously is promising.Comment: Code is available at: https://github.com/TeunvdWeij/extending-activation-additio

A rare cause of acute ST-elevation myocardial infarction:case report of native aortic valve thrombosis

Background One to 13% of all patients with the clinical diagnosis of an acute coronary syndrome (ACS) show no evidence of significant obstructive coronary artery disease on angiography. Less common causes should be considered in those situations. A very rare cause of ACS is native aortic valve thrombosis. Case summary A 69-year-old previously healthy woman presented with acute chest pain. The electrocardiogram showed an anterolateral ST-elevation myocardial infarction (STEMI). She was immediately transferred for primary percutaneous coronary intervention. Shortly after arriving in hospital her condition deteriorated, with development of cardiogenic shock necessitating cardiopulmonary resuscitation. A coronary angiogram was performed during resuscitation that did not reveal any obstructive coronary artery disease. Echocardiography showed no pericardial effusion, no significant left-sided valve pathology, no signs of an aortic dissection or pulmonary embolism. She died of cardiogenic shock of unknown cause. Permission for autopsy was obtained. Pathologic examination revealed a large anterolateral myocardial infarction caused by a mass attached to the bottom of the left coronary cusp of the native aortic valve, which was large enough to occlude the ostium of the left main coronary artery. Microscopic analysis showed a thrombus of unknown origin. The aortic valve itself showed no signs of pathology. Discussion An ST-elevation myocardial infarction due to native aortic valve thrombosis is a rare condition, especially when there are no significant valvular abnormalities. This case demonstrates that thrombosis can develop in an apparently healthy middle-aged woman without any history of thrombotic disease

Association of quantifiable prostate MRI parameters with any and large cribriform pattern in prostate cancer patients undergoing radical prostatectomy

Purpose: Cribriform pattern has recently been recognized as an important independent risk factor for prostate cancer (PCa) outcome. This study aimed to identify the association of quantifiable prostate magnetic resonance imaging (MRI) parameters with any and large cribriform pattern at radical prostatectomy (RP) specimens. Methods: Preoperative prostate MRI's from 188 men undergoing RP between 2010 and 2018 were retrospectively acquired. RP specimens of the patients were revised for Gleason score (GS), and presence of any and large cribriform pattern. MRI parameters such as MRI visibility, PI-RADS score, lowest apparent diffusion coefficient (ADC) value, lesion size, and radiologic extra-prostatic extension (EPE) were reviewed. The association of prostate MRI parameters for presence of any and large cribriform pattern at RP was analysed using logistic regression. Results: 116/188 (61.7%) PCa patients had any cribriform and 36/188 (19.1%) large cribriform pattern at RP. 171/188 (91.0%) men had MRI-visible lesions; 111/116 (95.7%) tumours with any and 36/36 (100%) with large cribriform pattern were visible at MRI. PCa with any and large cribriform pattern both had lower ADC values than those without (p &lt; 0.001). In adjusted analysis, lowest ADC value was as an independent predictor for any cribriform (Odds Ratio (OR) 0.2, 95% Confidence Interval (CI) 0.1–0.8; p = 0.01) and large cribriform pattern (OR 0.2, 95% CI 0.1–0.7; p = 0.01), while other parameters were not. Conclusions: The majority of PCa with cribriform pattern at RP were visible at MRI, and lowest ADC value was an independent predictor for both any and large cribriform pattern.</p

Drug protein binding in chronic renal failure: Evaluation of nine drugs

Drug protein binding in chronic renal failure: Evaluation of nine drugs. In this study, changes of protein binding of nine drugs were evaluated. In addition, theophylline and phenytoin, the two drugs with the most substantial and progressive decrease in protein binding, were further studied by high performance liquid chromatography (HPLC)-fractions of ultrafiltrate of normal and uremic serum, in an attempt to identify substances causing drug protein binding inhibition. There was a marked decline of the protein binding of theophylline, phenytoin and methotrexate (dialyzed patients vs. normals: -20.1, -16.0 and -15.1%, respectively). There was a rise in the protein binding of propranolol, cimetidine and clonidine. The changes observed for diazepam, prazosin and imipramine were less marked. For phenytoin, theophylline, methotrexate and diazepam, protein binding was inversely correlated to the serum creatinine (r = 0.87, 0.80, 0.79 and 0.67, P < 0.001), and a less pronounced but still significant positive correlation was found for clonidine (r = 0.46, P < 0.01). Ultrafiltrate, obtained during a hemofiltration session, inhibited protein binding of theophylline and phenytoin in a dose dependent way. After separation of this ultrafiltrate by HPLC, it appeared that for both theophylline and phenytoin at least a part of this inhibitory activity corresponded to the elution zone of hippuric acid. For theophylline two other inhibitory zones were further recognized: one corresponding to the elution zone of NaCl and one in which the responsible substance remained unidentified. Hippuric acid in solution inhibited protein binding of theophylline and phenytoin in a dose dependent way. In conclusion, protein binding of several drugs currently used in renal failure is affected in parallel with renal function, which might affect the therapeutic effectiveness of the drugs. Furthermore, hippuric acid appears to play an important role in the defect of the protein binding of theophylline and phenytoin

Membranous urethral length measurement on preoperative MRI to predict incontinence after radical prostatectomy:a literature review towards a proposal for measurement standardization

Objectives: To investigate the membranous urethral length (MUL) measurement and its interobserver agreement, and propose literature-based recommendations to standardize MUL measurement for increasing interobserver agreement. MUL measurements based on prostate MRI scans, for urinary incontinence risk assessment before radical prostatectomy (RP), may influence treatment decision-making in men with localised prostate cancer. Before implementation in clinical practise, MRI-based MUL measurements need standardization to improve observer agreement. Methods: Online libraries were searched up to August 5, 2022, on MUL measurements. Two reviewers performed article selection and critical appraisal. Papers reporting on preoperative MUL measurements and urinary continence correlation were selected. Extracted information included measuring procedures, MRI sequences, population mean/median values, and observer agreement. Results: Fifty papers were included. Studies that specified the MRI sequence used T2-weighted images and used either coronal images (n = 13), sagittal images (n = 18), or both (n = 12) for MUL measurements. ‘Prostatic apex’ was the most common description of the proximal membranous urethra landmark and ‘level/entry of the urethra into the penile bulb’ was the most common description of the distal landmark. Population mean (median) MUL value range was 10.4–17.1 mm (7.3–17.3 mm), suggesting either population or measurement differences. Detailed measurement technique descriptions for reproducibility were lacking. Recommendations on MRI-based MUL measurement were formulated by using anatomical landmarks and detailed descriptions and illustrations. Conclusions: In order to improve on measurement variability, a literature-based measuring method of the MUL was proposed, supported by several illustrative case studies, in an attempt to standardize MRI-based MUL measurements for appropriate urinary incontinence risk preoperatively. Clinical relevance statement: Implementation of MUL measurements into clinical practise for personalized post-prostatectomy continence prediction is hampered by lack of standardization and suboptimal interobserver agreement. Our proposed standardized MUL measurement aims to facilitate standardization and to improve the interobserver agreement. Key Points: • Variable approaches for membranous urethral length measurement are being used, without detailed description and with substantial differences in length of the membranous urethra, hampering standardization. • Limited interobserver agreement for membranous urethral length measurement was observed in several studies, while preoperative incontinence risk assessment necessitates high interobserver agreement. • Literature-based recommendations are proposed to standardize MRI-based membranous urethral length measurement for increasing interobserver agreement and improving preoperative incontinence risk assessment, using anatomical landmarks on sagittal T2-weighted images.</p

Altered Levels of Decidual Immune Cell Subsets in Fetal Growth Restriction, Stillbirth, and Placental Pathology

Immune cells are critically involved in placental development and functioning, and inadequate regulation of the maternal immune system is associated with placental pathology and pregnancy complications. This study aimed to explore numbers of decidual immune cells in pregnancies complicated with fetal growth restriction (FGR) and stillbirth (SB), and in placentas with histopathological lesions: maternal vascular malperfusion (MVM), fetal vascular malperfusion (FVM), delayed villous maturation (DVM), chorioamnionitis (CA), and villitis of unknown etiology (VUE). Placental tissue from FGR (n = 250), SB (n = 64), and healthy pregnancies (n = 42) was included. Histopathological lesions were classified according to criteria developed by the Amsterdam Placental Workshop Group. Tissue slides were stained for CD68 (macrophages), CD206 (M2-like macrophages), CD3 (T cells), FOXP3 [regulatory T (Treg) cells], and CD56 [natural killer (NK) cells]. Cell numbers were analyzed in the decidua basalis using computerized morphometry. The Mann-Whitney U-test and Kruskal Wallis test with the Dunn's as post-hoc test were used for statistical analysis. Numbers of CD68+ macrophages were higher in FGR compared to healthy pregnancies (p &lt; 0.001), accompanied by lower CD206+/CD68+ ratios (p &lt; 0.01). In addition, in FGR higher numbers of FOXP3+ Treg cells were seen (p &lt; 0.01) with elevated FOXP3+/CD3+ ratios (p &lt; 0.01). Similarly, in SB elevated FOXP3+ Treg cells were found (p &lt; 0.05) with a higher FOXP3+/CD3+ ratio (p &lt; 0.01). Furthermore, a trend toward higher numbers of CD68+ macrophages was found (p &lt; 0.1) in SB. Numbers of CD3+ and FOXP3+ cells were higher in placentas with VUE compared to placentas without lesions (p &lt; 0.01 and p &lt; 0.001), accompanied by higher FOXP3+/CD3+ ratios (p &lt; 0.01). Elevated numbers of macrophages with a lower M2/total macrophage ratio in FGR suggest a role for a macrophage surplus in its pathogenesis and could specifically indicate involvement of inflammatory macrophages. Higher numbers of FOXP3+ Treg cells with higher Treg/total T cell ratios in VUE may be associated with impaired maternal-fetal tolerance and a compensatory response of Treg cells. The abundant presence of placental lesions in the FGR and SB cohorts might explain the increase of Treg/total T cell ratios in these groups. More functionality studies of the observed altered immune cell subsets are needed.</p

Oxidative stress biomarkers in fetal growth restriction with and without preeclampsia

INTRODUCTION: Oxidative stress as observed in fetal growth restriction (FGR) and preeclampsia (PE) can be identified by decreased levels of systemic free thiols (FT) and increased levels of plasma ischemia-modified albumin (IMA), which may serve as biomarkers in maternal blood for pregnancy complications. We evaluate the performance of oxidative stress-associated potential biomarkers for FGR and PE, and their relationship with clinical characteristics.METHODS: A prospective clinical pilot study was performed in healthy controls and women with pregnancies complicated by severe FGR with or without PE. Blood samples were taken directly after inclusion and analyzed for FT; IMA; soluble FMS-like tyrosine kinase-1 (sFlt-1); placenta growth factor (PlGF); and biomarkers like leptin and soluble receptors for advanced glycation end products (sRAGE). Placentas were examined microscopically. Descriptive statistics and receiver operating characteristics statistics were performed.RESULTS: Mothers with both severe FGR and PE had significantly reduced FT levels (p &lt; 0.001) and PlGF levels (p &lt; 0.001), and increased levels of plasma IMA (p &lt; 0.05), sFlt (p &lt; 0.001), leptin (p &lt; 0.05) and sRAGE (p &lt; 0.01) compared to women with FGR only. Systemic FT levels were significantly inversely associated with blood pressure (p &lt; 0.01) and plasma IMA (p &lt; 0.001), leptin (p = 0.01) and sRAGE (p &lt; 0.001). Systemic FT and leptin showed significant discriminative ability to differentiate mothers with both FGR and PE from mothers with uncomplicated pregnancies or pregnancies complicated by FGR only.DISCUSSION: There is a significant discriminative capacity of FT, IMA, leptin and sRAGE that harbor potential as biomarkers of pregnancies complicated by combined FGR and PE.</p

The influence of the dietary exposome on oxidative stress in pregnancy complications

Pregnancy complications including fetal growth restriction, preeclampsia, and preterm birth, as well as gestational diabetes, affect one in every four to five pregnancies. Accumulating evidence indicates that increased production of reactive oxygen species accompanies these complications. Given that reactive oxygen species are cell stress-inducing agents, they may have a causal role in disease pathophysiology, although the exact mechanisms by which they contribute to pregnancy complications are not completely understood. Since many environmental and lifestyle factors and exposures are known to modulate reactive oxygen species production, the exposome of pregnant women could contribute to increased generation of reactive oxygen species. The objective of this review is to provide a comprehensive overview of the endogenous and exogenous exposome factors that regulate reactive species in healthy and complicated pregnancies. We also provide a description of dietary interventions aimed at the reduction of reactive species in order to attenuate adverse pregnancy outcome. Dietary interventions in general hold minimal risk in pregnancy and could therefore be considered a promising therapeutic approach

Distribution of decidual mast cells in fetal growth restriction and stillbirth at (near) term

Introduction: Placental pathology and pregnancy complications are associated with unfavorable regulation of the maternal immune system. Although much research has been performed towards the role of immune cells like macrophages and T cells in this context, little is known about the presence and function of mast cells (MC). MC can be sub classified in tryptase-positive (MCT) and tryptase- and chymase-positive (MCTC). This study investigates the presence of MC in the decidua of pregnancies complicated by fetal growth restriction (FGR) and stillbirth (SB). Methods: Placental tissue from FGR (n = 250), SB (n = 64) and healthy pregnancies (n = 42) was included. Histopathological lesions were classified according to the Amsterdam Placental Workshop Group criteria. Tissue sections were stained for tryptase and chymase. Decidual MC were counted manually, and the results were expressed as number of cells/mm2 decidual tissue. Results: A significant lower median number of MCTC was found in the decidua of FGR (0.40 per mm2; p < 0.001) and SB (0.51 per mm2; p < 0.05) compared to healthy controls (1.04 per mm2). No difference in MCT number (1.19 per mm2, 1.88 per mm2 and 1.37 per mm2 respectively) was seen between the groups. There was no difference in number of MCT and MCTC between placental pathological lesions. Discussion: Our findings suggest a shift in decidual MC balance towards MCT in pregnancy complications. No difference in numbers of MC subtypes was found to be related to histopathologic lesions