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PURPOSE: We investigated the effect of metformin and lifestyle intervention on metabolic, inflammatory, and steroid biomarkers of breast cancer (BC) recurrence risk in two intervention trials among BC survivors with overweight or obesity. METHODS: Baseline and follow-up serum samples collected during the two trials were analyzed and data pooled. The USA trial (Reach for Health) included postmenopausal BC survivors (n = 333) randomly assigned to 6-month metformin vs placebo and lifestyle intervention (LSI) vs control (2 × 2 factorial design). The Italian trial (MetBreCS) included BC survivors (n = 40) randomized to 12-month metformin vs placebo. Insulin resistance (HOMA-IR), adipokines, cytokines, and steroids were measured. RESULTS: Metformin compared to placebo showed a favorable decrease in leptin (- 8.8 vs - 3.5 ng/mL; p

In a 3-arm presurgical trial, four-six weeks exemestane 25 mg three times/week (TIW) was non-inferior to 25 mg/day (QD) in suppressing circulating estradiol in postmenopausal women with ER-positive breast cancer. Since obesity may decrease exemestane efficacy, we analyzed changes in sex steroids, adipokines, Ki-67, and drug levels in relation to obesity. Postmenopausal women with early-stage ER-positive breast cancer were randomized to either exemestane 25 mg QD (n = 57), 25 mg TIW (n = 57), or 25 mg/week (QW, n = 62) for 4-6 weeks before breast surgery. Serum and tissue pre- and post-treatment biomarkers were stratified by body mass index (BMI)< or ≥30 kg/m2. Post-treatment median exemestane and 17-OH exemestane levels were 5-6 times higher in the QD arm compared to the TIW arm. For obese women, TIW maintained comparable reductions to QD in systemic estradiol levels, although the reduction in estrone was less with the TIW regimen. There was less suppression of SHBG with the TIW versus the QD dose schedule in obese women which should result in less systemic bioavailable estrogens. Metabolically, the effect of the TIW regimen was similar to the QD regimen for obese women in terms of leptin suppression and increase in the adiponectin-leptin ratio. Reduction in tissue Ki-67 was less for obese women on the TIW regimen than QD, although changes were similar for non-obese women. Our findings suggest that TIW exemestane should be explored further for primary cancer prevention in both normal weight and obese cohorts.

Abstract Background Recent changes in the infant feeding guidelines for women living with HIV from high-income countries recommend a more supportive approach focusing on shared decision-making. Limited information is available on the infant feeding knowledge of women living with HIV and how healthcare providers engage with them in this context. This multicenter, longitudinal, mixed methods study aims to get a comprehensive and nuanced understanding of infant feeding knowledge among women living with HIV of Nordic and non-Nordic origin living in Nordic countries, and their interaction with healthcare providers regarding infant feeding planning. Methods Pregnant women living with HIV in Denmark, Finland, and Sweden were recruited in 2019–2020. The Positive Attitudes Concerning Infant Feeding (PACIFY) questionnaire was completed in the 3rd trimester (T1), three (T2), and six (T3) months postpartum. Women who completed the quantitative survey were also invited to participate in qualitative semi-structured interviews at T1 and T3. Results from the survey and interviews were brought together through merging to assess for concordance, complementarity, expansion, or discordance between the datasets and to draw meta-inferences. Results In total, 44 women living with HIV completed the survey, of whom 31 also participated in the interviews. The merged analyses identified two overarching domains: Knowledge about breastfeeding in the U = U era and Communications with healthcare providers. The women expressed confusion about breastfeeding in the context of undetectable equals untransmittable (U = U). Women of Nordic origin were more unsure about whether breastfeeding was possible in the context of U = U than women of non-Nordic origin. Increased postpartum monitoring with monthly testing of the mother was not seen as a barrier to breastfeeding, but concerns were found regarding infant testing and infant ART exposure. Infant feeding discussions with healthcare providers were welcome but could also question whether breastfeeding was feasible, and many participants highlighted a need for more information. Conclusions Healthcare providers caring for women living with HIV must have up-to-date knowledge of HIV transmission risks during breastfeeding and engage in shared decision-making to optimally support infant feeding choices.

Abstract Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of malignancies with poor outcome. Here, we identify a subgroup, PTCL-NOS SMARCB1- , which is characterized by the lack of the SMARCB1 protein and occurs more frequently in young patients. Human and murine PTCL-NOS SMARCB1- show similar DNA methylation profiles, with hypermethylation of T-cell-related genes and hypomethylation of genes involved in myeloid development. Single-cell analyses of human and murine tumors revealed a rich and complex network of interactions between tumor cells and an immunosuppressive and exhausted tumor microenvironment (TME). In a drug screen, we identified histone deacetylase inhibitors (HDACi) as a class of drugs effective against PTCL-NOS Smarcb1- . In vivo treatment of mouse tumors with SAHA, a pan-HDACi, triggered remodeling of the TME, promoting replenishment of lymphoid compartments and reversal of the exhaustion phenotype. These results provide a rationale for further exploration of HDACi combination therapies targeting PTCL-NOS SMARCB1- within the TME.

Abstract Aims Individuals with congenital heart disease (CHD) are at an increased risk for cancer. As cancer survival rates improve, the prevalence of late side effects, such as heart failure (HF), is becoming more evident. This study aims to evaluate the risk of developing HF following a cancer diagnosis in patients with CHD, compared with those without CHD and with CHD patients who do not have cancer. Methods CHD patients (n = 69 799) and randomly selected non‐CHD controls (n = 650 406), born in Sweden between 1952 and 2017, were identified from the Swedish National Health Registers and Total Population Register (excluding those with syndromes and transplant recipients). CHD patients who developed cancer (n = 1309) were propensity score‐matched with non‐CHD patients who developed cancer (n = 9425), resulting in a cohort of 1232 CHD patients with cancer and 2602 non‐CHD controls with cancer (after exclusion of individuals with HF prior to cancer diagnosis). In a separate analysis, CHD patients with cancer were propensity score‐matched with CHD patients without cancer (n = 68 490). A total of 1233 CHD patients with cancer and 2257 CHD patients without cancer were included in the study. Results Among CHD patients with cancer, 73 (5.9%) developed HF during a mean follow‐up time of 8.5 ± 8.7. Comparatively, in the propensity‐matched control population, 29 (1.1%) non‐CHD cancer patients (mean follow‐up time of 7.3 ± 7.5) and 101 (4.5%) CHD patients without cancer (mean follow‐up time of 9.9 ± 9.2) developed HF. CHD patients exhibited a significantly higher risk of HF post‐cancer diagnosis compared with the non‐CHD control group [hazard ratio (HR) 4.39, 95% confidence interval (CI) 2.83–6.81], after adjusting for age at cancer diagnosis and comorbidities. In the analysis between CHD patients with cancer and those without cancer, the results indicated a significantly higher risk of developing HF in CHD patients with cancer (HR 1.53, 95% CI 1.13–2.07). Conclusions CHD patients face a more than four‐fold increased risk of developing HF after a cancer diagnosis compared with cancer patients without CHD. Among CHD patients, the risk of HF is only modestly higher for those with cancer than for those without cancer. This suggests that the increased HF risk in CHD patients with cancer, relative to non‐CHD cancer patients, may be more attributable to CHD itself than to cancer treatment‐related side effects.

This study investigates public perceptions regarding the prioritization of different areas of police work in Sweden amid growing concerns over crime and public safety. Utilizing a best–worst scaling (BWS) approach, the research aims to discern which police activities citizens deem most and least important, thereby shedding light on public expectations for police resource allocation. The findings reveal a strong public emphasis on the importance of responding to emergency calls and addressing gang criminality. Conversely, administrative tasks and traffic safety are viewed as lower priorities. The article offers insights into the alignment (or misalignment) between public expectations and police practices, emphasizing the role of public opinion in shaping police strategies and the importance of balancing crime fighting with social service functions to maintain public trust and legitimacy in law enforcement.

This article aims to explore the conditions for children's language and literacy learning in 153 Swedish preschools with children one to five years. The Early Childhood Environment Rating Scale (ECERS-3) is used to evaluate preschool quality, focusing on the subscale of Language and literacy activities. The study draws on Bronfenbrenner's ecological systems theory to highlight the conditions for children's language and literacy learning in preschool. Significant differences were found in the quality of the 153 preschools as a whole and the five subscales in ECERS-3, giving children unequal conditions for learning and development in the studied areas. Within the Language and literacy subscale, items related to children's oral language development scored a higher average quality compared with written language-related items. Individualized teaching, Staff-child interaction, and Whole-group activities were moderately correlated with activities supporting language development. The results are discussed in terms of an ecological perspective on preschool quality in which intentional teaching needs to be directed at language and literacy learning in both individual, small, and whole-group interactions.

We aimed to investigate to what extent small fiber tests were abnormal in an unselected retrospective patient material with symptoms suggesting that small fiber neuropathy (SFN) could be present, and to evaluate possible gender differences.

Abstract A large proportion of patients with severe obesity remain with left ventricular (LV) dysfunction after bariatric surgery. We assessed whether preoperative evaluation by echocardiography and inflammatory proteins can identify this high-risk group. In the Bariatric Surgery on the West Coast of Norway study, 75 patients (44 ± 10 years, body mass index [BMI] 41.5 ± 4.7 kg/m2) were prospectively evaluated by echocardiography and inflammatory proteins (high-sensitivity C-reactive protein [hsCRP], serum amyloid A [SAA] and calprotectin) before and one year after Roux-en-Y gastric bypass surgery. LV mechanics was assessed by the midwall shortening (MWS) and global longitudinal strain (GLS). Bariatric surgery improved BMI and GLS, and lowered hsCRP, calprotectin and SAA (p

Abstract In a 3-arm presurgical trial, four-six weeks exemestane 25 mg three times/week (TIW) was non-inferior to 25 mg/day (QD) in suppressing circulating estradiol in postmenopausal women with ER-positive breast cancer. Since obesity may decrease exemestane efficacy, we analyzed changes in sex steroids, adipokines, Ki-67, and drug levels in relation to obesity. Postmenopausal women with early-stage ER-positive breast cancer were randomized to either exemestane 25 mg QD (n = 57), 25 mg TIW (n = 57), or 25 mg/week (QW, n = 62) for 4–6 weeks before breast surgery. Serum and tissue pre- and post-treatment biomarkers were stratified by body mass index (BMI)< or ≥30 kg/m2. Post-treatment median exemestane and 17-OH exemestane levels were 5–6 times higher in the QD arm compared to the TIW arm. For obese women, TIW maintained comparable reductions to QD in systemic estradiol levels, although the reduction in estrone was less with the TIW regimen. There was less suppression of SHBG with the TIW versus the QD dose schedule in obese women which should result in less systemic bioavailable estrogens. Metabolically, the effect of the TIW regimen was similar to the QD regimen for obese women in terms of leptin suppression and increase in the adiponectin-leptin ratio. Reduction in tissue Ki-67 was less for obese women on the TIW regimen than QD, although changes were similar for non-obese women. Our findings suggest that TIW exemestane should be explored further for primary cancer prevention in both normal weight and obese cohorts.

The following article is an adapted and abridged excerpt from The Language Immersion Life: A Guide for Families by Millie Park Mellgren (2017). This book features answers to the most common questions Dr. Mellgren was asked as an elementary immersion principal. The volume features commentary and data gleaned from surveys given to hundreds of former students, parents and educators. This input combined with Dr. Mellgren's years of immersion experience, creates a comprehensive guide offering insight on selecting an immersion program and navigating through the K-12 immersion years with success. While most of the quotes from survey participants have been deleted from this excerpt, that additional commentary can be found in the full text.

Objective Patients with congenital heart disease (CHD) have an increased cancer risk. The aim of this study was to determine cancer-related mortality in CHD patients compared with non-CHD controls, compare ages at cancer diagnosis and death, and explore the most fatal cancer diagnoses.Design Registry-based cohort study.Setting and participants CHD patients born between 1970 and 2017 were identified using Swedish Health Registers. Each was matched by birth year and sex with 10 non-CHD controls. Included were those born in Sweden with a cancer diagnosis.Results Cancer developed in 758 out of 67814 CHD patients (1.1%), with 139 deaths (18.3%)—of which 41 deaths occurred in patients with genetic syndromes. Cancer was the cause of death in 71.9% of cases. Across all CHD patients, cancer accounted for 1.8% of deaths. Excluding patients with genetic syndromes and transplant recipients, mortality risk between CHD patients with cancer and controls showed no significant difference (adjusted HR 1.17; 95% CI 0.93 to 1.49). CHD patients had a lower median age at cancer diagnosis—13.0 years (IQR 2.9–30.0) in CHD versus 24.6 years (IQR 8.6–35.1) in controls. Median age at death was 15.1 years (IQR 3.6–30.7) in CHD patients versus 18.5 years (IQR 6.1–32.7) in controls. The top three fatal cancer diagnoses were ill-defined, secondary and unspecified, eye and central nervous system tumours and haematological malignancies.Conclusions Cancer-related deaths constituted 1.8% of all mortalities across all CHD patients. Among CHD patients with cancer, 18.3% died, with cancer being the cause in 71.9% of cases. Although CHD patients have an increased cancer risk, their mortality risk post-diagnosis does not significantly differ from non-CHD patients after adjustements and exclusion of patients with genetic syndromes and transplant recipients. However, CHD patients with genetic syndromes and concurrent cancer appear to be a vulnerable group.

Abstract Purpose Adjuvant endocrine treatment is essential for treating luminal subtypes of breast cancer, which constitute 75% of all breast malignancies. However, the detrimental side effects of treatment make it difficult for many patients to complete the guideline-required treatment. Such non-adherence may jeopardize the lifesaving ability of anti-estrogen therapy. In this systematic review, we aimed to assess the consequences of non-adherence and non-persistence from available studies meeting strict statistical and clinical criteria. Methods A systematic literature search was performed using several databases, yielding identification of 2,026 studies. After strict selection, 14 studies were eligible for systematic review. The review included studies that examined endocrine treatment non-adherence (patients not taking treatment as prescribed) or non-persistence (patients stopping treatment prematurely), in terms of the effects on event-free survival or overall survival among women with non-metastatic breast cancer. Results We identified 10 studies measuring the effects of endocrine treatment non-adherence and non-persistence on event-free survival. Of these studies, seven showed significantly poorer survival for the non-adherent or non-persistent patient groups, with hazard ratios (HRs) ranging from 1.39 (95% CI, 1.07 to 1.53) to 2.44 (95% CI, 1.89 to 3.14). We identified nine studies measuring the effects of endocrine treatment non-adherence and non-persistence on overall survival. Of these studies, seven demonstrated significantly reduced overall survival in the groups with non-adherence and non-persistence, with HRs ranging from 1.26 (95% CI, 1.11 to 1.43) to 2.18 (95% CI, 1.99 to 2.39). Conclusion The present systematic review demonstrates that non-adherence and non-persistence to endocrine treatment negatively affect event-free and overall survival. Improved follow-up, with focus on adherence and persistence, is vital for improving health outcomes among patients with non-metastatic breast cancer.

Abstract Objectives Paediatric Burkitt's lymphoma (pBL) is the most common childhood non‐Hodgkin B‐cell lymphoma. Despite the encouraging survival rates for most children, treating cases with relapse/resistance to current therapies remains challenging. CD38 is a transmembrane protein highly expressed in pBL. This study investigates the effectiveness of CD38‐targeting monoclonal antibodies (mAbs), daratumumab and isatuximab, in impairing crucial cellular processes and survival pathways in pBL malignant cells. Methods In silico analyses of patient samples, combined with in vitro experiments using the Ramos cell line, were conducted to assess the impact of daratumumab and isatuximab on cellular proliferation, apoptosis and the phosphoinositide 3‐kinase (PI3K) pathway. Results Isatuximab was found to be more effective than daratumumab in disrupting B‐cell receptor signalling, reducing cellular proliferation and inducing apoptosis. Additionally, isatuximab caused a significant impairment of the PI3K pathway and induced metabolic reprogramming in pBL cells. The study also revealed a correlation between CD38 and MYC expression levels in pBL patient samples, suggesting CD38 involvement in key oncogenic processes. Conclusion The study emphasises the therapeutic potential of CD38‐targeting mAbs, particularly isatuximab, in pBL.

This study investigates preschool student teachers' views on how early writing should be supported in preschool. The sample consists of 66 preschool student teachers from Finland, Norway, and Sweden, who participated in the study by responding to open-ended questions on a written questionnaire. Results show that the respondents' answers were underpinned by holistic views on children's learning; they value children's own initiative as a decisive learning factor. Further, the responses underscore the importance of a writing-inviting environment and the preschool teachers acting as role models. The respondents rarely offered explicit theoretical reasons and arguments for why they would encourage early writing. Based on the findings, it appears critical to discuss within the profession the issue why early writing should be encouraged.

Abstract Background Epidemiological studies often investigate amino acids and their metabolites as biomarkers, but do not always consistently use fasting or non-fasting blood samples, or may lack information on the prandial status of the study participants. Since little information is available on the effects of the prandial status on many biomarkers, and since blood is typically sampled early in the day with participants in a fasting state or after having consumed a light meal in many trials, the main purpose of this study was to investigate the short-term effects of a light breakfast on serum concentrations of amino acids and related metabolites. Methods Blood was collected from sixty-three healthy adults (36 women) in the fasting state and at set times for 120 min after intake of a light breakfast with low protein content (14 g protein, 2218 kJ). Relative changes in serum biomarker concentrations from fasting to postprandial serum concentrations were tested using T test. Results The serum concentrations of 13 of the 20 measured amino acids were significantly changed 60 min following breakfast intake, with the most marked effects seen as increases in alanine (34%) and proline (45%) concentrations. The response did not reflect the amino acid composition of the breakfast. The concentrations of seven kynurenine metabolites were significantly decreased after breakfast. Conclusion Consumption of a light breakfast affected serum concentrations of several amino acids and related metabolites, underlining the importance of having information regarding the participants’ prandial state at the time of blood sampling in studies including these biomarkers. Trial registration This trial was registered at clinicaltrials.gov as NCT02350595 (registered January 2015).

Driving simulators are a common tool for researching and practicing driver behaviors. Despite this, research on the use of driving simulators within the basic police training in Nordic countries is sparse. Therefore, the purpose of this quasi-experimental study was to evaluate and compare studentsʼ driving ability regarding low-speed maneuvering in tight spaces, during a limited part of their education, based on the type of training (simulator only, courtyard only, or 50/50) they receive. 83 Swedish police students, divided into four classes, attending their second semester at the police program, participated in the study. These four classes were divided into three different experimental groups. The simulation group (two classes, n = 41) only practiced driving using a driving simulator. The 50/50 group (one class, n = 22) practiced driving a vehicle in the courtyard and in the simulator. The courtyard group (one class, n = 20) only practiced driving a vehicle in a courtyard. The results showed that there were no statistically significant differences between type of training and performance on the examination regarding low-speed maneuvering in tight spaces. The findings are discussed in terms of their implications for the use of driving simulators in higher education, more specifically in police basic training programs.

Abstract Background Excess adipose tissue is associated with increased cardiovascular and metabolic risk, but the volume of visceral and subcutaneous adipose tissue poses different metabolic risks. MRI with fat suppression can be used to accurately quantify adipose depots. We have developed a new semi-automatic method, RAdipoSeg, for MRI adipose tissue segmentation and quantification in the free and open source statistical software R. Methods MRI images were obtained from wild-type mice on high- or low-fat diet, and from 20 human subjects without clinical signs of metabolic dysfunction. For each mouse and human subject, respectively, 10 images were segmented with RAdipoSeg and with the commercially available software SliceOmatic. Jaccard difference, relative volume difference and Spearman’s rank correlation coefficients were calculated for each group. Agreement between the two methods were analysed with Bland–Altman plots. Results RAdipoSeg performed similarly to the commercial software. The mean Jaccard differences were 10–29% and the relative volume differences were below ( ±) 20%. Spearman’s rank correlation coefficient gave p-values below 0.05 for both mouse and human images. The Bland–Altman plots indicated some systematic and proporitional bias, which can be countered by the flexible nature of the method. Conclusion RAdipoSeg is a reliable and low cost method for fat segmentation in studies of mice and humans.

Summary: Cholesterol-to-coprostanol conversion by the intestinal microbiota has been suggested to reduce intestinal and serum cholesterol availability, but the relationship between intestinal cholesterol conversion and the gut microbiota, dietary habits, and serum lipids has not been characterized in detail. We measured conserved proportions of cholesterol high and low-converter types in individuals with and without obesity from two distinct, independent low-carbohydrate high-fat (LCHF) dietary intervention studies. Across both cohorts, cholesterol conversion increased in previous low-converters after LCHF diet and was positively correlated with the fecal relative abundance of Eubacterium coprostanoligenes. Lean cholesterol high-converters had increased serum triacylglycerides and decreased HDL-C levels before LCHF diet and responded to the intervention with increased LDL-C, independently of fat, cholesterol, and saturated fatty acid intake. Our findings identify the cholesterol high-converter type as a microbiome marker, which in metabolically healthy lean individuals is associated with increased LDL-C in response to LCHF.

BackgroundClinical studies on effects of marine-derived omega-3 (n-3) polyunsaturated fatty acids (PUFAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and the plant-derived omega-6 (n-6) PUFA linoleic acid (LA) on lipoprotein-lipid components and glucose-insulin homeostasis have shown conflicting results, which may partly be explained by differential responses in females and males. However, we have lacked data on sexual dimorphism in the response of cardiometabolic risk markers following increased consumption of n-3 or n-6 PUFAs.ObjectiveTo explore sex-specific responses after n-3 (EPA + DHA) or n-6 (LA) PUFA supplementation on circulating lipoprotein subfractions, standard lipids, apolipoproteins, fatty acids in red blood cell membranes, and markers of glycemic control/insulin sensitivity among people with abdominal obesity.MethodsThis was a randomized double-blind crossover study with two 7-week intervention periods separated by a 9-week washout phase. Females (n = 16) were supplemented with 3 g/d of EPA + DHA (fish oil) or 15 g/d of LA (safflower oil), while males (n = 23) received a dose of 4 g/d of EPA + DHA or 20 g/d of LA. In fasting blood samples, we measured lipoprotein particle subclasses, standard lipids, apolipoproteins, fatty acid profiles, and markers of glycemic control/insulin sensitivity.ResultsThe between-sex difference in relative change scores was significant after n-3 for total high-density lipoproteins (females/males: −11%*/−3.3%, p = 0.036; *: significant within-sex change), high-density lipoprotein particle size (+2.1%*/−0.1%, p = 0.045), and arachidonic acid (−8.3%*/−12%*, p = 0.012), and after n-6 for total (+37%*/+2.1%, p = 0.041) and small very-low-density lipoproteins (+97%*/+14%, p = 0.021), and lipoprotein (a) (−16%*/+0.1%, p = 0.028). Circulating markers of glucose-insulin homeostasis differed significantly after n-3 for glucose (females/males: −2.1%/+3.9%*, p = 0.029), insulin (−31%*/+16%, p

Summary: Background: The valine (branched-chain amino acid) metabolite 3-hydroxyisobutyrate (3-HIB), produced by 3-Hydroxyisobutyryl-CoA Hydrolase (HIBCH), is associated with insulin resistance and type 2 diabetes, but implicated tissues and cellular mechanisms are poorly understood. We hypothesized that HIBCH and 3-HIB regulate hepatic lipid accumulation. Methods: HIBCH mRNA in human liver biopsies (“Liver cohort”) and plasma 3-HIB (“CARBFUNC” cohort) were correlated with fatty liver and metabolic markers. Human Huh7 hepatocytes were supplemented with fatty acids (FAs) to induce lipid accumulation. Following HIBCH overexpression, siRNA knockdown, inhibition of PDK4 (a marker of FA β-oxidation) or 3-HIB supplementation, we performed RNA-seq, Western blotting, targeted metabolite analyses and functional assays. Findings: We identify a regulatory feedback loop between the valine/3-HIB pathway and PDK4 that shapes hepatic FA metabolism and metabolic health and responds to 3-HIB treatment of hepatocytes. HIBCH overexpression increased 3-HIB release and FA uptake, while knockdown increased cellular respiration and decreased reactive oxygen species (ROS) associated with metabolic shifts via PDK4 upregulation. Treatment with PDK4 inhibitor lowered 3-HIB release and increased FA uptake, while increasing HIBCH mRNA. Implicating this regulatory loop in fatty liver, human cohorts show positive correlations of liver fat with hepatic HIBCH and PDK4 expression (Liver cohort) and plasma 3-HIB (CARBFUNC cohort). Hepatocyte 3-HIB supplementation lowered HIBCH expression and FA uptake and increased cellular respiration and ROS. Interpretation: These data implicate the hepatic valine/3-HIB pathway in mechanisms of fatty liver, reflected in increased plasma 3-HIB concentrations, and present possible targets for therapeutic intervention. Funding: Funding was provided by the Research Council of Norway (263124/F20), the University of Bergen, the Western Norway Health Authorities, Novo Nordisk Scandinavia AS, the Trond Mohn Foundation and the Norwegian Diabetes Association.

Abstract Background Anal squamous cell carcinoma (SCC) generally carries a favorable prognosis, as most tumors are highly sensitive to standard of care chemoradiation. However, outcomes are poor for the 20–30% of patients who are refractory to this approach, and many will require additional invasive procedures with no guarantee of disease resolution. Methods To identify the patients who are unlikely to respond to the current standard of care chemoradiation protocol, we explored a variety of objective clinical findings as a potential predictor of treatment failure and/or mortality in a single center retrospective study of 42 patients with anal SCC. Results Patients with an increase in total peripheral white blood cells (WBC) and/or neutrophils (ANC) had comparatively poor clinical outcomes, with increased rates of death and treatment failure, respectively. Using pre-treatment biopsies from 27 patients, tumors with an inflamed, neutrophil dominant stroma also had poor therapeutic responses, as well as reduced overall and disease-specific survival. Following chemoradiation, we observed uniform reductions in nearly all peripheral blood leukocyte subtypes, and no association between peripheral white blood cells and/or neutrophils and clinical outcomes. Additionally, post-treatment biopsies were available from 13 patients. In post-treatment specimens, patients with an inflamed tumor stroma now demonstrated improved overall and disease-specific survival, particularly those with robust T-cell infiltration. Conclusions Combined, these results suggest that routinely performed leukocyte subtyping may have utility in risk stratifying patients for treatment failure in anal SCC. Specifically, pre-treatment patients with a high WBC, ANC, and/or a neutrophil-dense tumor stroma may be less likely to achieve complete response using the standard of care chemoradiation regimen, and may benefit from the addition of a subsequent line of therapy.

The drug's activity at the target tissue could help to define the minimal effective dose to promote cancer preventive therapy. Here we present exemestane and sex hormone concentrations within breast tissue from a presurgical study of alternative exemestane schedules. Postmenopausal women candidates for breast surgery for estrogen receptor-positive breast cancer were randomly assigned to exemestane 25 mg once daily (QD), 25 mg 3 times/week (TIW), or 25 mg per week (QW) for 4-6 weeks before surgery. Drug and sex hormones were analyzed from homogenized frozen tissue using a QTRAP 6500+ LC-MS/MS System. Tissue drug concentrations were detectable only in the QD arm with higher concentrations in nonmalignant tissue. Estradiol was nearly suppressed in all groups in the nonmalignant tissue (QD vs TIW P  = .364 and QD vs QW P  = .693). In contrast, a dose-response trend was observed in cancer tissue. Based on estradiol suppression in nonmalignant tissue, lower exemestane schedules should be explored for breast cancer preventive therapy. Trial Registration : Clinical Trials.gov NCT02598557 and EudraCT 2015-005063-1 [ABSTRACT FROM AUTHOR]

Purpose Methods Results Conclusion To report the results of strabismus surgery in a series of patients with Graves' orbitopathy (GO), using topical anaesthesia with intraoperative suture adjustment.All first‐time strabismus surgeries in patients with GO in our department during the years 2014–2021 (n = 45) were assessed retrospectively. Among these, 31% came from outside our health region due to increased complexity of the strabismus condition. Orbital decompression surgery had been carried out in 58% of the patients prior to strabismus surgery. Patients with less than 2 months of follow‐up were excluded from the study. Median follow‐up time was 22 months.Among the total patient material, 37 (82%) could be operated with topical anaesthesia with intraoperative suture adjustment. There were no cases with triggering of the oculo‐cardiac reflex during the procedure. Among the 36 patients operated with topical anaesthesia and follow‐up time ≥2 months, 11 (31%) needed further surgery. Late overcorrection after recession of the inferior rectus was seen in 19%. At the last control examination, 32 (89%) were diplopia‐free in primary and down‐gaze position, either with or without weak prisms.Strabismus surgery in topical anaesthesia with intraoperative suture adjustment appears to be a suitable and safe procedure in most patients with GO, including difficult and complex cases. The patients should be informed about the possibility of additional surgery and/or post‐operative need for prism glasses. [ABSTRACT FROM AUTHOR]