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Prenatal adversity has been linked to later psychopathology. Yet, research on cumulative prenatal adversity, as well as its interaction with offspring genotype, on brain and behavioral development is scarce. With this study, we aimed to address this gap. In Finnish mother–infant dyads, we investigated the association of a cumulative prenatal adversity sum score (PRE-AS) with (a) child emotional and behavioral problems assessed with the Strengths and Difficulties Questionnaire at 4 and 5 years (N = 1568, 45.3% female), (b) infant amygdalar and hippocampal volumes (subsample N = 122), and (c) its moderation by a hippocampal-specific coexpression polygenic risk score based on the serotonin transporter (SLC6A4) gene. We found that higher PRE-AS was linked to greater child emotional and behavioral problems at both time points, with partly stronger associations in boys than in girls. Higher PRE-AS was associated with larger bilateral infant amygdalar volumes in girls compared to boys, while no associations were found for hippocampal volumes. Further, hyperactivity/inattention in 4-year-old girls was related to both genotype and PRE-AS, the latter partially mediated by right amygdalar volumes as preliminary evidence suggests. Our study is the first to demonstrate a dose-dependent sexually dimorphic relationship between cumulative prenatal adversity and infant amygdalar volumes.

Research on the longitudinal courses of child social–emotional symptoms and sleep during the COVID-19 pandemic within societies would be of key value for promoting child well-being in global crises. We characterized the course of children’s social–emotional and sleep symptoms before and throughout the pandemic in a Finnish longitudinal cohort of 1825 5- to 9-year-old children (46% girls) with four follow-up points during the pandemic from up to 695 participants (spring 2020–summer 2021). Second, we examined the role of parental distress and COVID-related stressful events in child symptoms. Child total and behavioral symptoms increased in spring 2020 but decreased thereafter and remained stable throughout the rest of the follow-up. Sleep symptoms decreased in spring 2020 and remained stable thereafter. Parental distress was linked with higher child social–emotional and sleep symptoms. The cross-sectional associations between COVID-related stressors and child symptoms were partially mediated by parental distress. The findings propose that children can be protected from the long-term adverse influences of the pandemic, and parental well-being likely plays a mediating role between pandemic-related stressors and child well-being. Further research focusing on the societal and resilience factors underlying family and child responses to the pandemic is warranted.

Prenatal stress exposure (PSE) has been observed to exert a programming effect on the developing infant brain, possibly with long-lasting consequences on temperament, cognitive functions and the risk for developing psychiatric disorders. Several prior studies have revealed that PSE associates with alterations in neonate functional connectivity in the prefrontal regions and amygdala. In this study, we explored whether maternal psychological symptoms measured during the 24th gestational week had associations with neonate resting-state network metrics. 21 neonates (9 female) underwent resting-state fMRI scanning (mean gestation-corrected age at scan 26.95 days) to assess fractional amplitude of low-frequency fluctuation (fALFF) and regional homogeneity (ReHo). The ReHO/fALFF maps were used in multiple regression analysis to investigate whether maternal self-reported anxiety and/or depressive symptoms associate with neonate functional brain features. Maternal psychological distress (composite score of depressive and anxiety symptoms) was positively associated with fALFF in the neonate medial prefrontal cortex (mPFC). Anxiety and depressive symptoms, assessed separately, exhibited similar but weaker associations. Post hoc seed-based connectivity analyses further showed that distal connectivity of mPFC covaried with PSE. No associations were found between neonate ReHo and PSE. These results offer preliminary evidence that PSE may affect functional features of the developing brain during gestation.

The aim of this study was to investigate (1) if there are differences in training load and intensity between the different training days within a microcycle and (2) if training load and intensity within the different training days are stable over the course of a season. Data were collected over a full season from a team in the women’s premier division in Norway. External load (total distance, high-speed-running distance, sprint distance, and the combined number of accelerations and decelerations [ACCDEC]) was assessed using a 10-Hz GPS system with a built-in accelerometer. Internal load was assessed through session rating of perceived exertion, which was multiplied with session duration (session rating of perceived exertion-load). Training days were classified in relation to their proximity to the upcoming match day (MD): MD − 4, MD − 3, MD − 2, and MD − 1. Contents on these days were standardized according to a weekly periodization model followed by the coaching staff. Differences between training days were analyzed using a linear mixed-effects model. All training days were significantly different from each other across multiple variables. ACCDEC values were highest on MD − 4 (147.5 [13.0] ACCDEC count), and all distance variables were highest on MD − 3. All measures of training load were significantly reduced from MD − 3 to MD − 2 (effect size [ES] = 1.0–4.1) and from MD − 2 to MD − 1 (ES = 1.6-4.3). A significant negative effect across the season was observed for session rating of perceived exertion-load and ACCDEC (ES = 0.8–2.1). These results provide evidence that elite female football teams can be successful in differentiating training load between training days when implementing a weekly periodization approach.

In contemporary society, visual information is influential, not least when businesses are communicating with potential customers. It represents and influences how people understand phenomena. In sports, much attention is directed toward how media represent elite sports and sport stars. Less attention is directed toward children’s sports. The aim of this article is to explore and analyze visual representations of children on sport businesses’ websites. The sample contained 697 images of sporting children, on which an interpretative content and discourse analysis was conducted. The study shows that the ideal customer emerging on these sites is a White, physically active, able, and slim boy or girl. Consumer culture seems to reproduce and preserve existing normative frameworks rather than producing alternative norms and ideas in children’s sport. Moreover, dilemmatic images of children both as competent and as innocent develop, displaying a childhood that should be both joyful and active but also safeguarded.

Den kanadensiska sociologen och feministen Dorothy Edith Smith avled den 2 juni 2022. Under sina 95 år i livet hann hon göra flera betydelsefulla bidrag till bland annat arbetsvetenskap, etnografi, familjesociologi, psykologi och utbildningsvetenskap. Den här essän kommer dock främst att rikta uppmärksamheten mot Smiths bidrag till feministisk teori och metodologi. I synnerhet kommer jag att diskutera Smiths bidrag till att utveckla en feministisk ståndpunktsteori som inte tar kvinnan – i bestämd form singularis – som en homogen utgångspunkt för sitt projekt. Den sociologi som Smith utvecklade riktade fokus bort från att göra den marginaliserade gruppen till ett objekt för forskning till att i stället studera hur maktstrukturer runt omkring marginaliserade grupper formar deras levnadsvillkor. Med utgångspunkt från människors levda erfarenheter utformade Smith Institutionell etnografi, en sociologi för att förstå de styranderelationer som formar människors vardagliga liv. I den essän kommer jag börja med att beskriva Smiths liv och gärning för att därifrån ge en överblick över vad jag anser vara hennes främsta intellektuella bidrag till eftervärlden: feministisk ståndpunktsteori och institutionell etnografi. För att konkretisera begreppen Smith introducerade kommer jag att ta exempel från min egen och andras forskning och därigenom även visa vad arvet efter Smith kan ha för betydelse för samhällsvetenskapen framöver.

Purpose: Patients with metastatic uveal melanoma have limited therapeutic options and high mortality rate so new treatment options are needed. Patients and Methods: We previously reported that patients treated with the PD-1 inhibitor pembrolizumab and the histone deacetylase inhibitor entinostat in the PEMDAC trial, experienced clinical benefits if their tumor originated from iris or was wildtype for BAP1 tumor suppressor gene. Here we present the 2-year follow-up of the patients in the PEMDAC trial and identify additional factors that correlate with response or survival. Results: Durable responses were observed in 4 patients, with additional 8 patients exhibiting a stable disease. The median overall survival was 13.7 months. Grade 3 adverse events were reported in 62% of the patients, but they were all manageable. No fatal toxicity was observed. Activity of thymidine kinase 1 in plasma was higher in patients with stable disease or who progressed on treatment, compared with those with partial response. Chemokines and cytokines were analyzed in plasma. Three chemokines were significantly different when comparing patients with and without response. One of the factors, CCL21, was higher in the plasma of responding patients before treatment initiation but decreased in the same patients upon treatment. In tumors, CCL21 was expressed in areas resembling tertiary lymphoid structures (TLS). High plasma levels of CCL21 and presence of TLS-like regions in the tumor correlated with longer survival. Conclusions: This study provides insight into durable responses in the PEMDAC trial, and describes dynamic changes of chemokines and cytokines in the blood of these patients. Significance: The most significant finding from the 2-year follow-up study of the PEMDAC trial was that high CCL21 levels in blood was associated with response and survival. CCL21 was also expressed in TLS-like regions and presence of these regions was associated with longer survival. These analyses of soluble and tumor markers can inform on predictive biomarkers needing validation and become hypothesis generating for experimental research.

A critical book review of Osagie Obasogie's book Blinded by Sight: Seeing Race through the Eyes of the Blind discussed its methodological, analytical, and theoretical choices whilst also analyzing its relevance in a contemporary setting.

Background and purpose: Scheuermann’s disease is characterized by kyphosis and frequently mild back pain. As the level of kyphosis may progress over time, also the level of pain may increase. We evaluated the prevalence of Scheuermann’s disease, and their pain, in Swedish elderly men.Patients and methods: The Osteoporotic Fractures in Men (MrOS) Study Sweden (n = 3,014) is a population-based prospective observational study of community-living men aged 69–81 years. At baseline, participants answered a questionnaire including history of neck/back pain during the preceding year and characteristics of any pain (severity, sciatica, and neurological deficits). Lateral thoracic/lumbar spine radiographs were taken of 1,453 men. We included the 1,417 men with readable radiographs. Scheuermann’s disease was defined as 3 or more consecutive vertebrae with > 5° wedging with no other explanation for the deformity.Results: 92 of the 1,417 men (6.5%, 95% confidence interval 5.3–7.9) had Scheuermann’s disease. 31% of men with and 31% without Scheuermann’s disease reported neck pain (P = 0.90) and 51% with and 55% without the disease reported back pain (P = 0.4). Among men with Scheuermann’s disease and back pain, none reported severe pain, 57% moderate, and 43% mild, compared with 7%, 50%, and 44% in those without Scheuermann’s disease (P = 0.2). In those with Scheuermann’s disease 63% reported no sciatica, 15% sciatica without neurological deficits, and 22% sciatica with neurological deficits, compared with 56%, 16%, and 28% in those without the disease (P = 0.6).Conclusion: The prevalence of Scheuermann’s disease in elderly Swedish men is between 5.3% and 7.9%. The condition seems at this age not to be associated with neck or back pain.

Performing risk assessments (RA) on household use of flexible polyurethane (PU) foams requires access to reliable data about emission and migration of potential diamine impurities. A toluene diisocyanate (TDI) and a methylene diphenyl diisocyanate (MDI) based foam were thermally treated to enable measurements on samples with defined concentrations of the corresponding diamines, toluene diamine (TDA), and methylene dianiline (MDA). The thermally treated foams used for emission testing contained up to 15 mg.kg−1 of TDA and 27 mg.kg−1 of MDA. Those used for migration testing contained 5.1 mg.kg−1 of TDA and 14.1 mg.kg−1 of MDA. Stability of the thermally generated diamines was sufficient for testing over a 37-day period. Analytical techniques that did not decompose the polymer matrix were applied. Emission rates for TDA and MDA isomers were less than the limit of quantitation (LOQ) of 0.008–0.07 μg.m−2.h−1. Migration was studied using samples of the same thermally treated foams over a 35-day period. Quantifiable migration of MDA from the MDI-based foam was only observed on Days 1 and 2. From Day 3 onward, migration rates were less than the LOQ. Quantifiable migration of TDA from the TDI-based foam rapidly decreased with time and was only observed on Days 1 thru 3. From Day 4 onward, migration rates were less than the LOQ. Theoretically, the migration rate should be inversely proportional to the square root of time (t) as t−0.5. This relationship was confirmed by the experimental data and enables extrapolating migration values to more extended time periods to conduct RAs.

A sampling chamber was developed for emission testing of diisocyanates, methylene diphenyl diisocyanate (MDI), toluene diisocyanate (TDI), and corresponding diamines, methylene diphenyl diamine (MDA), and toluene diamine (TDA) from polyurethane (PU) product surfaces. In addition, a methodology for validation of the sampling chamber was presented, based on the introduction of generated standard atmospheres of the different diisocyanates and diamines to the sampling chamber system. Sampling of diisocyanates and diamines was performed on a circular glass fiber filter (150 mm diameter) impregnated with dihexyl amine (DHA) and acetic acid (AA) positioned inside a cylindrical stainless steel sampling chamber. The diisocyanates were immediately derivatized to DHA derivatives, and the amines were derivatized in a subsequent work-up procedure with ethyl chloroformate (ECF). The design of the sampling chamber and the presented methodology allowed for simultaneous sampling and analysis of diisocyanates and diamines of emission from a large surface area with minimal interior wall interaction in the sampling chamber. Performance characteristics of the sampling chamber for different sampling times and air humidity were obtained by determining collected amounts of the diisocyanates and diamines in the different parts of the sampling chamber. The repeatability of the collected amount on the impregnated filters in the sampling chamber was 15% with an overall recovery for 8 h of sampling in the range of 61% to 96%. The performance of the sampling chamber was not affected by air humidity (5%–75% RH), and no breakthrough during sampling was observed. LC-MS/MS determinations allowed for emission testing of diisocyanates and diamines on product surfaces as low as 10–30 ng m−2 h−1.

Purpose: The local immune infiltrate's influence on tumor progression may be closely linked to tumor-intrinsic factors. The study aimed to investigate whether integrating immunologic and tumor-intrinsic factors can identify patients from a low-risk cohort who may be candidates for radiotherapy (RT) de-escalation. Experimental Design: The SweBCG91RT trial included 1,178 patients with stage I to IIA breast cancer, randomized to breast-conserving surgery with or without adjuvant RT, and followed for a median of 15.2 years. We trained two models designed to capture immunologic activity and immunomodulatory tumor-intrinsic qualities, respectively. We then analyzed if combining these two variables could further stratify tumors, allowing for identifying a subgroup where RT de-escalation is feasible, despite clinical indicators of a high risk of ipsilateral breast tumor recurrence (IBTR). Results: The prognostic effect of the immunologic model could be predicted by the tumor-intrinsic model (Pinteraction = 0.01). By integrating measurements of the immunologic- and tumor-intrinsic models, patients who benefited from an active immune infiltrate could be identified. These patients benefited from standard RT (HR, 0.28; 95% CI, 0.09–0.85; P = 0.025) and had a 5.4% 10-year incidence of IBTR after irradiation despite high-risk genomic indicators and a low frequency of systemic therapy. In contrast, high-risk tumors without an immune infiltrate had a high 10-year incidence of IBTR despite RT treatment (19.5%; 95% CI, 12.2–30.3). Conclusions: Integrating tumor-intrinsic and immunologic factors may identify immunogenic tumors in early-stage breast cancer populations dominated by ER-positive tumors. Patients who benefit from an activated immune infiltrate may be candidates for RT de-escalation.

Background Acute high-risk abdominal surgery is common, as are the attendant risks of organ failure, need for intensive care, mortality, or long hospital stay. This study assessed the implementation of standardized management. Methods A prospective study of all adults undergoing emergency laparotomy over an interval of 42 months (2018–2021) was undertaken; outcomes were compared with those of a retrospective control group. A new standardized clinical protocol was activated for all patients including: prompt bedside physical assessment by the surgeon and anaesthetist, interprofessional communication regarding location of resuscitation, elimination of unnecessary factors that might delay surgery, improved operating theatre competence, regular epidural, enhanced recovery care, and frequent early warning scores. The primary endpoint was 30-day mortality. Secondary endpoints were duration of hospital stay, need for intensive care, and surgical complications. Results A total of 1344 patients were included, 663 in the control group and 681 in the intervention group. The use of antibiotics increased (81.4 versus 94.7 per cent), and the time from the decision to operate to the start of surgery was reduced (3.80 versus 3.22 h) with use of the new protocol. Fewer anastomoses were performed (22.5 versus 16.8 per cent). The 30-day mortality rate was 14.5 per cent in the historical control group and 10.7 per cent in the intervention group (P = 0.045). The mean duration of hospital (11.9 versus 10.2 days; P = 0.007) and ICU (5.40 versus 3.12 days; P = 0.007) stays was also reduced. The rate of serious surgical complications (grade IIIb–V) was lower (37.6 versus 27.3 per cent; P = Conclusion Standardized management protocols improved outcomes after emergency laparotomy.

Understanding cellulose hornification provides crucial information regarding drying of pulp, paper, and other cellulosic materials as well as recycling them. By measuring drainage, fiber width, and water retention value of hardwood and softwood pulps before and after sheet forming and after different drying procedures at different achieved levels of solids, the hornification was evaluated. The water retention value was also measured for the pulps when dried from acetone to observe what happens when hydrogen bonds are not available in the liquid phase. The drainage and fiber width decreased with increasing solids content; the fibers became increasingly stiff with increased water removal. Water retention measurements indicated that hornification is a stepwise process with large drops in fiber flexibility as soon as the fibers are being processed and later after a certain amount of water has been removed. In sum, the fibers must achieve a certain solids content to show hornification, and hydrogen bonds in water draw the cellulose surfaces together to create hornification. The mechanism of hornification is believed to be driven by hydrogen bonds and related to the distance between cellulose chains inside the fiber wall. Other types of bonds are probably also present and help with the irreversibility of hornification.

BACKGROUND: Very young premenopausal women diagnosed with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+HER2-) early breast cancer (EBC) have higher rates of recurrence and death for reasons that remain largely unexplained. PATIENTS AND METHODS: Genomic sequencing was applied to HR+HER2- tumours from patients enrolled in the Suppression of Ovarian Function Trial (SOFT) to determine genomic drivers that are enriched in young premenopausal women. Genomic alterations were characterised using next-generation sequencing from a subset of 1276 patients (deep targeted sequencing, n = 1258; whole-exome sequencing in a young-age, case-control subsample, n = 82). We defined copy number (CN) subgroups and assessed for features suggestive of homologous recombination deficiency (HRD). Genomic alteration frequencies were compared between young premenopausal women (

Diffusion tensor imaging (DTI) has provided great insights into the microstructural features of the developing brain. However, DTI images are prone to several artifacts and the reliability of DTI scalars is of paramount importance for interpreting and generalizing the findings of DTI studies, especially in the younger population. In this study, we investigated the intrascan test-retest repeatability of four DTI scalars: fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) in 5-year-old children (N = 67) with two different data preprocessing approaches: a volume censoring pipeline and an outlier replacement pipeline. We applied a region of interest (ROI) and a voxelwise analysis after careful quality control, tensor fitting and tract-based spatial statistics. The data had three subsets and each subset included 31, 32, or 33 directions thus a total of 96 unique uniformly distributed diffusion encoding directions per subject. The repeatability of DTI scalars was evaluated with intraclass correlation coefficient (ICC(3,1)) and the variability between test and retest subsets. The results of both pipelines yielded good to excellent (ICC(3,1) 0.75) reliability for most of the ROIs and an overall low variability (10%). In the voxelwise analysis, FA and RD had higher ICC(3,1) values compared to AD and MD and the variability remained low (12%) across all scalars. Our results suggest high intrascan repeatability in pediatric DTI and lend confidence to the use of the data in future cross-sectional and longitudinal studies.

The gut microbiota has been suggested to influence neurodevelopment in rodents. Preliminary human studies have associated fecal microbiota composition with features of emotional and cognitive development as well as differences in thalamus-amygdala connectivity. Currently, microbiota-gut-brain axis studies cover heterogenous set of infant and child brain developmental phenotypes, while microbiota associations with more fine-grained aspects of brain development remain largely unknown. Here (N = 122, 53% boys), we investigated the associations between infant fecal microbiota composition and infant attention to emotional faces, as bias for faces is strong in infancy and deviations in early processing of emotional facial expressions may influence the trajectories of social-emotional development. The fecal microbiota composition was assessed at 2.5 months of age and analyzed with 16S rRNA gene sequencing. Attention to emotional faces was assessed with an age-appropriate face-distractor paradigm, using neutral, happy, fearful, and scrambled faces and salient distractors, at 8 months of age. We observed an association between a lower abundance of Bifidobacterium and a higher abundance of Clostridium with an increased "fear bias," that is, attention toward fearful versus happy/neutral faces. This data suggests an association between early microbiota and later fear bias, a well-established infant phenotype of emotionally directed attention. However, the clinical significance or causality of our findings remains to be assessed. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

The human brain develops dynamically during early childhood, when the child is sensitive to both genetic programming and extrinsic exposures. Recent studies have found links between prenatal and early life environmental factors, family demographics and the cortical brain morphology in newborns measured by surface area, volume and thickness. Here in this magnetic resonance imaging study, we evaluated whether a similar set of variables associates with cortical surface area and volumes measured in a sample of 170 healthy 5-year-olds from the FinnBrain Birth Cohort Study. We found that child sex, maternal pre-pregnancy body mass index, 5 min Apgar score, neonatal intensive care unit admission and maternal smoking during pregnancy associated with surface areas. Furthermore, child sex, maternal age and maternal level of education associated with brain volumes. Expectedly, many variables deemed important for neonatal brain anatomy (such as birth weight and gestational age at birth) in earlier studies did not associate with brain metrics in our study group of 5-year-olds, which implies that their effects on brain anatomy are age-specific. Future research may benefit from including pre- and perinatal covariates in the analyses when such data are available. Finally, we provide evidence for right lateralization for surface area and volumes, except for the temporal lobes which were left lateralized. These subtle differences between hemispheres are variable across individuals and may be interesting brain metrics in future studies.

Purpose: To provide normative data on swallowing capacity (mL/s) in people older than 60 years using the Timed Water Swallow Test (TWST), stratified by sex. Intra- and inter-rater reliability for swallowing time in TWST was further investigated. Method: A total of 165 participants, aged 60 years and above, were included in the study. The time taken to consume 150 mL of tap water and the swallowing capacity (mL/s) was observed in a clinical context using the TWST. Video recordings of the performances were collected for 118 of the 165 participants for inter-rater reliability testing, of which a random set of 25 performances were assessed for intra-rater reliability. Analysis of the agreement between TWST rated by an in-person clinician and rated from a video recording was further evaluated. Result: There were significant age and sex effects observed for swallowing capacity. The average reduction in swallowing capacity in the investigated age range (60-92 years) was 8.8 and 7.3 mL/s for women and men respectively. The results showed high inter-and intra-rater reliability and agreement between the clinical assessment and the video recording. Conclusion: The presented measurements indicate a clear effect of age on swallowing capacity and that women may be expected to have lower capacity scores than men when tested using TWST. The provided norms can be used as reference points in the clinical identification of people at risk of dysphagia in the older population.

Aim. To determine whether adolescents with type 1 diabetes (T1D) have morphological changes of the corneal nerve fibers and reduced smell and taste function compared to healthy control subjects as a sign of cranial nerve affection and to evaluate possible associated risk factors for cranial nerve affection. Methods. The study was a part of the T1DANES study including 60 adolescents (15–Results. The adolescents with T1D (mean diabetes duration 9.8 years, mean HbA1c 61 mmol/mol) had lower CCM parameters (corneal nerve fiber density, corneal nerve branch density, corneal nerve fiber length, and corneal nerve fiber fractal dimension) compared to control subjects (all p Conclusion. Up to 29% of adolescents with T1D had abnormal test scores indicating cranial nerve affection. Lower corneal nerve fiber density and reduced ability to taste sweet were found in adolescents with T1D compared to control subjects. Clinical attention to smell and taste function seems important because it requires intervention for advising adolescents with impaired smell and taste function. Aim. To determine whether adolescents with type 1 diabetes (T1D) have morphological changes of the corneal nerve fibers and reduced smell and taste function compared to healthy control subjects as a sign of cranial nerve affection and to evaluate possible associated risk factors for cranial nerve affection.Methods. The study was a part of the T1DANES study including 60 adolescents (15–Results. The adolescents with T1D (mean diabetes duration 9.8 years, mean HbA1c 61 mmol/mol) had lower CCM parameters (corneal nerve fiber density, corneal nerve branch density, corneal nerve fiber length, and corneal nerve fiber fractal dimension) compared to control subjects (all p Conclusion. Up to 29% of adolescents with T1D had abnormal test scores indicating cranial nerve affection. Lower corneal nerve fiber density and reduced ability to taste sweet were found in adolescents with T1D compared to control subjects. Clinical attention to smell and taste function seems important because it requires intervention for advising adolescents with impaired smell and taste function.

Sex-driven immune differences can affect tumor progression and the landscape of the tumor microenvironment. Deeper understanding of these differences in males and females can inform patient selection to improve sex-optimized immunotherapy treatments. In this study, single-cell RNA sequencing and protein analyses uncovered a subpopulation of myeloid cells in pancreatic lesions associated with an immune-excluded tumor phenotype and effector T-cell exhaustion exclusively in females. This myeloid subpopulation was positively correlated with poor survival and genetic signatures of M2-like macrophages and T-cell exhaustion in females. The G-protein coupled receptor formyl peptide receptor 2 (FPR2) mediated these immunosuppressive effects. In vitro, treatment of myeloid cells with a specific FPR2 antagonist prevented exhaustion and enhanced cytotoxicity of effector cells. Proteomic analysis revealed high expression of immunosuppressive secretory proteins PGE2 and galectin-9, enriched integrin pathway, and reduced proinflammatory signals like TNFα and IFNγ in female M2-like macrophages upon FPR2 agonist treatment. In addition, myeloid cells treated with FPR2 agonists induced TIM3 and PD-1 expression only in female T cells. Treatment with anti-TIM3 antibodies reversed T-cell exhaustion and stimulated their ability to infiltrate and kill pancreatic spheroids. In vivo, progression of syngeneic pancreatic tumors was significantly suppressed in FPR2 knockout (KO) female mice compared with wild-type (WT) female mice and to WT and FPR2 KO male mice. In female mice, inoculation of tumors with FPR2 KO macrophages significantly reduced tumor growth compared with WT macrophages. Overall, this study identified an immunosuppressive function of FPR2 in females, highlighting a potential sex-specific precision immunotherapy strategy. Significance: FPR2 is a sex-dependent mediator of macrophage function in pancreatic cancer and can be targeted to reprogram macrophages and stimulate antitumor immunity in females.

The exterior application of fire-retardant (FR) timber necessitates it to have high durability because of the possibility to be exposed to rainfall. In this study, water-leaching resistance of FR wood has been imparted by grafting phosphate and carbamate groups of the water-soluble FR additives ammonium dihydrogen phosphate (ADP)/urea onto the hydroxyl groups of wood polymers via vacuum-pressure impregnation, followed by drying/heating in hot air. A darker and more reddish wood surface was observed after the modification. Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, solid-state 13C cross-polarization magic-angle-spinning nuclear magnetic resonance (13C CP-MAS NMR), and direct-excitation 31P MAS NMR suggested the formation of C–O–P covalent bonds and urethane chemical bridges. Scanning electron microscopy/energy-dispersive X-ray spectrometry suggested the diffusion of ADP/urea into the cell wall. The gas evolution analyzed by thermogravimetric analysis coupled with quadrupole mass spectrometry revealed a potential grafting reaction mechanism starting with the thermal decomposition of urea. Thermal behavior showed that the FR-modified wood lowered the main decomposition temperature and promoted the formation of char residues at elevated temperatures. The FR activity was preserved even after an extensive water-leaching test, confirmed by the limiting oxygen index (LOI) and cone calorimetry. The reduction of fire hazards was achieved through the increase of the LOI to above 80%, reduction of 30% of the peak heat release rate (pHRR2), reduction of smoke production, and a longer ignition time. The modulus of elasticity of FR-modified wood increased by 40% without significantly decreasing the modulus of rupture. Validerad;2023;Nivå 2;2023-04-21 (joosat);Funder: OP RDE (Grant no.CZ.02.1.01/0.0/0.0/16_019/0000803); CT WOOD, Luleå University of TechnologyLicens fulltext: CC BY License

Laser ablation multi-collector mass spectrometry (LA-MC-ICP-MS) has emerged as the technique of choice for in situ measurements of Sr isotopes in geological minerals. However, the method poses analytical challenges and there is no widely adopted standardised approach to collecting these data or correcting the numerous potential isobaric inferences. Here, we outline practical analytical procedures and data reduction strategies to help establish a consistent framework for collecting and correcting Sr isotope measurements in geological materials by LA-MC-ICP-MS. We characterise a new set of plagioclase reference materials, which are available for distribution to the community, and present a new data reduction scheme for the Iolite software package to correct isobaric interferences for different materials and analytical conditions. Our tests show that a combination of Kr-baseline subtraction, Rb-peak-stripping using βRb derived from a bracketing glass reference material, and a CaCa or CaAr correction for plagioclase and CaCa or CaAr + REE 2+ correction for rock glasses, yields the most accurate and precise 87Sr/ 86Sr measurements for these materials. Using the analytical and correction procedures outlined herein, spot analyses using a beam diameter of 100 μm or rastering with a 50–65 μm diameter beam can readily achieve 87Sr/ 86Sr measurements for materials with -1 Sr.

Background: The de novo drug development process is expensive and challenging, with a high risk of failure. Drug repurposing can ideally identify novel therapeutic indications for FDA-approved drugs with pre-existing pre-clinical and clinical evidence. Both aspirin and tamoxifen drugs are good examples of successful drug repurposing in oncology. Although proteasome inhibitors such as bortezomib and carfilzomib are currently only used to treat multiple myeloma and basal cell lymphoma, we and others have shown that triple-negative breast cancer (TNBC) is particularly sensitive to proteasome inhibition. TNBC is an aggressive form of breast cancer with an urgent need for novel treatment options. Here, we evaluate the potency of proteasome inhibitors and other clinically relevant chemotherapeutic agents on TNBC cell lines. Methods: We performed a high-throughput drug sensitivity screen with eight cell lines representing the four TNBC subtypes (basal-like 1: HCC70 and MDA-MB-468; basal-like 2: HCC1806 and MDA-MB-436; mesenchymal-like: BT-549 and HCC38; luminal androgen receptor: CAL-148 and MDA-MB-435) and MCF-7 as control (estrogen and progesterone receptor-positive) exposed to 18 drugs (11 proteasome inhibitors, 2 mitosis inhibitors, 2 topoisomerase inhibitors, and 3 platinum agents) for 24 hours. Drug potency was determined using the IC50, GR50, GRmax drug metrics. IDACombo was then used to predict efficacious drug combinations, followed by calculation of synergistic drug combinations with SynergyFinder. Results: TNBC cell lines were generally more sensitive to proteasome inhibitors with significantly reduced cell viability than clinically relevant drugs, e.g. paclitaxel. Although the potency of different proteasome inhibitors varied, the most potent proteasome inhibitors included bortezomib, carfilzomib, delanzomib, epoxomicin, and MLN-2238. According to the GR50 values, HCC38 (range, 8.2-382.7 nM) and MDA-MB-468 (range, 10.8-110.6 nM) were most sensitive to proteasome inhibition, whereas the least sensitive TNBC cell lines were HCC1806 (range, 289.9-Inf nM) and BT-549 (range, 101.0-Inf nM). Using the drug sensitivity screening results for single drugs, IDACombo predicted potent drug combinations for different combinations of bortezomib, carboplatin, carfilzomib, delanzomib, docetaxel, doxorubicin, epirubicin, epoxomicin, MLN-2238, MLN-9708, and nedaplatin. Conclusions: In summary, some proteasome inhibitors (e.g. bortezomib) had a substantial impact on TNBC cell survival. These findings indicate that proteasome inhibitors, together with other forms of chemotherapy, may be further explored as a novel complement treatment for TNBC. Citation Format: Peter Larsson, Daniella Pettersson, Maxim Olsson, Eva Forssell-Aronsson, Anikó Kovács, Per Karlsson, Khalil Helou, Toshima Z. Parris. Repurposing proteasome inhibitors for improved treatment of triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-17.

Introduction: The European Working Group on Sarcopenia in Older People (EWGSOP) published a revised definition of sarcopenia in 2018. There are few incidence studies of sarcopenia following the latest definition. Objective: To study prevalence, incidence proportion and incidence rate of sarcopenia in a simple random sample of older Swedish men using the EWGSOP2 definition. Methods: Men aged 69-81 were invited to participate in the Osteoporotic Fractures in Men (MrOs) Sweden study. Of 2,004 included participants, 1,266 participants (mean age 75.1, SD 3.1 years) completed baseline and 5-year follow-up measurements. We assessed muscle strength by measuring grip strength and chair stands test, lean mass by dual energy X-ray absorptiometry and physical performance by gait speed at baseline and follow-up. Sarcopenia prevalence and incidence were calculated according to the EWGSOP2 definition.Results: Sarcopenia prevalence increased from 5.6% at baseline to 12.0% at follow-up. During the mean 5.2year follow-up period, 9.1% developed sarcopenia (incidence proportion), corresponding to an incidence rate of 1.8 per 100 person-years at risk while 39.4% of the participants with sarcopenia at baseline participating in follow-up reversed to no longer having confirmed sarcopenia at 5-year follow-up.Conclusion: The prevalence of sarcopenia defined along EWGSOP2 criteria doubled within 5 years in older men, and more than a third of the study participants with sarcopenia at baseline did not have sarcopenia at follow-up. We conclude that sarcopenia is not a static condition.(c) 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)