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Solid organ transplant recipients (SOTRs) are on lifelong immunosuppression, which may interfere with adaptive immunity to COVID-19. The data on dynamics and duration of antibody response in SOTRs are limited. This longitudinal study examined the longevity of both anti-spike (S)- and anti-nucleocapsid (N)-specific IgG antibodies after COVID-19 in SOTRs compared to matched immunocompetent persons. SOTRs (n = 65) were matched with controls (n = 65) for COVID-19 disease severity, age, and sex in order of priority. Serum-IgG antibodies against N and S antigens of SARS-CoV-2 were analyzed. At 1 and 9 months after COVID-19, anti-S-IgG detectability decreased from 91% to 82% in SOTRs versus 100% to 95% in controls, whereas the anti-N-IgG decreased from 63% to 29% in SOTRs versus 89% to 46% in controls. A matched paired analysis showed SOTRs having significantly lower levels of anti-N-IgG at all time points (1 month p = .007, 3 months p .001, 6 months p = .019, and 9 months p = .021) but not anti-S-IgG at any time points. A mixed-model analysis confirmed these findings except for anti-S-IgG at 1 month (p = .005) and identified severity score as the most important predictor of antibody response. SOTRs mount comparable S-specific, but not N-specific, antibody responses to SARS-CoV-2 infection compared to immunocompetent controls.

Alzheimer’s disease (AD) is a neurodegenerative disease that eventually affects memory and behavior. The identification of biomarkers based on risk factors for AD provides insight into the disease since the exact cause of AD remains unknown. Several studies have proposed microRNAs (miRNAs) in blood as potential biomarkers for AD. Exposure to heavy metals is a potential risk factor for onset and development of AD. Blood cells of subjects that are exposed to lead detected in the circulatory system, potentially reflect molecular responses to this exposure that are similar to the response of neurons. In this study we analyzed blood cell-derived miRNAs derived from a general population as proxies of potentially AD-related mechanisms triggered by lead exposure. Subsequently, we analyzed these mechanisms in the brain tissue of AD subjects and controls. A total of four miRNAs were identified as lead exposure-associated with hsa-miR-3651, hsa-miR-150-5p and hsa-miR-664b-3p being negatively and hsa-miR-627 positively associated. In human brain derived from AD and AD control subjects all four miRNAs were detected. Moreover, two miRNAs (miR-3651, miR-664b-3p) showed significant differential expression in AD brains versus controls, in accordance with the change direction of lead exposure. The miRNAs’ gene targets were validated for expression in the human brain and were found enriched in AD-relevant pathways such as axon guidance. Moreover, we identified several AD relevant transcription factors such as CREB1 associated with the identified miRNAs. These findings suggest that the identified miRNAs are involved in the development of AD and might be useful in the development of new, less invasive biomarkers for monitoring of novel therapies or of processes involved in AD development.

OBJECTIVE The objective is to characterize the presence of malnutrition, examine the association between malnutrition and baseline functional capacity (FC), and the extent to which patients benefit from preoperative multimodal prehabilitation in patients undergoing lung resection for cancer. METHODS Data from 162 participants enrolled in multimodal prehabilitation or control before lung cancer surgery were analyzed. Malnutrition was measured using the Patient-Generated Subjective Global Assessment (PG-SGA) according to triage levels: low-nutrition-risk (PG-SGA 0-3), moderate-nutrition-risk (4-8) and high-nutrition-risk (≥9). Baseline differences in FC, measured by the 6-minute walk test (6MWT), were compared. Factorial analysis of covariance (ANCOVA) was conducted to examine the effect of nutrition status and intervention on mean change in 6MWT preoperatively. RESULTS 51.2% patients were considered low-nutrition-risk, 37.7% moderate-nutrition-risk, and 11.1% high-nutrition-risk. Low-nutrition-risk patients had significantly higher 6MWT at baseline (mean of 484 m [standard deviation (SD) = 88]) compared with moderate-nutrition-risk (432 m [SD = 107], P = .005) and high-nutrition-risk groups (416 m [SD = 90], P = .022). The adjusted mean change in 6MWT between prehabilitation vs control was 18.1 (95% confidence interval, 3.8 to 32.3) vs 5.6 m (-14.1 to 25.4) in low-nutrition-risk (P = .309), 28.5 (11 to 46) vs -4 m (-31.3 to 23.4) in moderate-nutrition-risk (P = .053), and 58.9 (16.7 to 101.2) vs -39.7 m (-80.2 to 0.826) in high-nutrition-risk group (P = .001). CONCLUSIONS Lung cancer patients at high-nutrition-risk awaiting surgery had significantly lower baseline FC compared with low-nutrition-risk patients but experienced significant improvements in preoperative FC upon receiving multimodal prehabilitation.

BACKGROUND Multimodal prehabilitation, including exercise training, nutritional therapy and anxiety reduction, has been shown to attenuate functional decline associated with surgery. Due to the growing interest in functional status as a targeted surgical outcome, a better understanding of the optimal prescription of exercise is critical. OBJECTIVE The objective is to compare peri-operative functional trajectory in response to two different exercise training protocols within a 4-week, supervised, multimodal prehabilitation programme. DESIGN This was a single blinded, single centre, randomised controlled study. Participants performed four assessments: at baseline, after prehabilitation (just before surgery), and at 1 and 2 months after surgery. PATIENTS Adult patients scheduled for elective resection of nonmetastatic colorectal cancer were included provided there were no absolute contraindications to exercise nor poor language comprehension. INTERVENTION Patients followed either high-intensity interval training (HIIT), or moderate intensity continuous training (MICT), as part of a 4-week multimodal prehabilitation programme. Both groups followed the same supervised resistance training, nutritional therapy and anxiety reduction interventions. All patients followed standardised peri-operative management. MAIN OUTCOME MEASURE Changes in oxygen consumption at anaerobic threshold, measured with sequential cardio-pulmonary exercise testing, were assessed and compared between groups. RESULTS Forty two patients were included in the primary analysis (HIIT n = 21 vs. MICT n = 21), with mean ± SD age 64.5 ± 11.2 years and 62% were men. At 2 months after surgery, 13/21 (62%) in HIIT and 11/21 (52%) in MICT attended the study visits. Both protocols significantly enhanced pre-operative functional capacity, with no difference between groups: mean (95% confidence interval) oxygen consumption at anaerobic threshold 1.97 (0.75 to 3.19) ml kg min in HIIT vs. 1.71 (0.56 to 2.85) in MICT, P = 0.753. At 2 months after surgery, the HIIT group showed a higher improvement in physical fitness: 2.36 (0.378 to 4.34) ml kg min, P = 0.021. No adverse events occurred during the intervention. CONCLUSION Both MICT and HIIT enhanced pre-operative functional capacity. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03361150.

Purpose Approximately, 50 persons per 100,000 per year sustain a tibial fracture. There is, however, a lack of large cohort studies that describe the treatment and re-operation frequencies of tibial fractures. The aim of this study was to describe the treatment and re-operation rates of tibial fractures in all segments of the tibia. Methods Data related to all patients aged 16 and above treated for tibial fractures (ICD-10 S82.10-31) at Sahlgrenska University Hospital in 2011–2015 were extracted from the Swedish Fracture Register. To make sure all re-operations were included in the study, the operation planning system was checked for all patients included in the study. Results The study comprised 1371 tibial fractures − 712 proximal, 417 diaphyseal and 242 distal tibial fractures. Among the proximal and distal tibial fractures, plate fixation was the most commonly used surgical method, whereas among tibial shaft fractures, an intramedullary nail was the most commonly used surgical method. Almost 30% (29.8%) of all surgically treated tibial fractures underwent re-operation. Among proximal tibial fractures, 24.0% underwent re-operation; tibial shaft fractures 37.0% and distal tibial fractures 26.8%. Re-operations due to infection were more or less equally common in all segments (3.9–5.4%). Conclusion This study describes the treatment and re-operation rates after tibial fractures in a cohort of 1371 tibial fractures at Sahlgrenska University Hospital during a period of 5 years. The study shows an overall re-operation rate of 29.8% for fractures in all segments of the tibia.

N‐Acetyltransferases play critical roles in the deactivation and clearance of xenobiotics, including clinical drugs. NAT2 has been classified as an arylamine N‐acetyltransferase that mainly converts aromatic amines, hydroxylamines, and hydrazines. Herein, we demonstrate that the human arylamine N‐acetyltransferase NAT2 also acetylates aliphatic endogenous amines. Metabolomic analysis and chemical synthesis revealed increased intracellular concentrations of mono‐ and diacetylated spermidine in human cell lines expressing the rapid compared to the slow acetylator NAT2 phenotype. The regioselective N 8‐acetylation of monoacetylated spermidine by NAT2 answers the long‐standing question of the source of diacetylspermidine. We also identified selective acetylation of structurally diverse alkylamine‐containing drugs by NAT2, which may contribute to variations in patient responses. The results demonstrate a previously unknown functionality and potential regulatory role for NAT2, and we suggest that this enzyme should be considered for re‐classification., Same NAT2, new substr8: NAT2 has been classified as an arylamine N‐acetyltransferase that mainly converts aromatic amines, hydroxylamines, and hydrazines. Through a combination of metabolomics, chemical synthesis, and mass spectrometry it is demonstrated that unknown endogenous, aliphatic metabolites, and aliphatic amine‐containing commonly used drugs also act as substrates for NAT2.

Frailty is a state of vulnerability as a result of decreased reserves. Prehabilitation may increase reserve and improve postoperative outcomes. Our objective was to determine if home-based prehabilitation improves postoperative functional recovery in older adults with frailty having cancer surgery.This double blind randomised trial enrolled people ≥60 yr having elective cancer surgery and ≥3 weeks from enrolment to surgery as eligible. Participation in a remotely supported, home-based exercise prehabilitation program plus nutritional guidance was compared with standard care plus written advice on age-appropriate activity and nutrition. The primary outcome was 6-min walk test (6MWT) distance at the first postoperative clinic visit. Secondary outcomes included physical performance, quality of life, disability, length of stay, non-home discharge, and 30-day readmission.Of 543 patients assessed, 254 were eligible and 204 (80%) were randomised (102 per arm); 182 (94 intervention and 88 control) had surgery and were analysed. Mean age was 74 yr and 57% were female. Mean duration of participation was 5 weeks, mean adherence was 61% (range 0%-100%). We found no significant difference in 6MWT at follow-up (+14 m, 95% confidence interval -26-55 m, P=0.486), or for secondary outcomes. Analyses using a prespecified adherence definition of ≥80% supported improvements in 6MWT distance, complication count, and disability.A home-based prehabilitation program did not significantly improve postoperative recovery or other outcomes in older adults with frailty having cancer surgery. Program adherence may be a key mediator of prehabilitation efficacy.NCT02934230.

Introduction/aim:Young patients with Fontan circulation may have low serum 25-hydroxyvitamin D levels, an affected liver, and unhealthy body compositions. This study aimed to explore the association between vitamin D intake/levels, liver biomarkers, and body composition in young Fontan patients.Method:We collected prospective data in 2017 to 2018, obtained with food-frequency questionnaires, biochemical analyses of liver biomarkers, and dual-energy X-ray absorptiometry scans in 44 children with Fontan circulation. Body compositions were compared to matched controls (n = 38). Linear regression analyses were used to investigate associations of biomarkers, leg pain, and lean mass on serum levels of 25-hydroxyvitamin D. Biomarkers were converted to z scores and differences were evaluated within the Fontan patients.Results:Our Fontan patients had a daily mean vitamin D intake of 9.9 µg and a mean serum 25-hydroxyvitamin D of 56 nmol/L. These factors were not associated with fat or lean mass, leg pain, or biomarkers of liver status. The Fontan patients had significantly less lean mass, but higher fat mass than controls. Male adolescents with Fontan circulation had a greater mean abdominal fat mass than male controls and higher cholesterol levels than females with Fontan circulation.Conclusion:Vitamin D intake and serum levels were not associated with body composition or liver biomarkers in the Fontan group, but the Fontan group had lower lean mass and higher fat mass than controls. The more pronounced abdominal fat mass in male adolescents with Fontan circulation might increase metabolic risks later in life.

Background Positive associations have been reported between persistent organic pollutants (POPs) and type 2 diabetes mellitus (T2DM); however, causality has not been established. Over the last decades, environmental exposure to legacy POPs has decreased, complicating epidemiological studies. In addition, physiological risk factors for T2DM may also influence POP concentrations, contributing to a complex network of factors that could impact associations with T2DM. Longitudinal studies on this topic are lacking, and few have assessed prospective and cross-sectional associations between repeated POP measurements and T2DM in the same individuals, which may shed light on causality. Objectives To compare longitudinal trends in concentrations of polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) in T2DM cases and controls, and to examine prospective and cross-sectional associations between PCBs, OCPs and T2DM at different time-points before and after T2DM diagnosis in cases. Methods We conducted a longitudinal, nested case-control study (1986–2016) of 116 T2DM cases and 139 controls from the Tromso Study. All participants had three blood samples collected before T2DM diagnosis in cases, and up to two samples thereafter. We used linear mixed-effect models to assess temporal changes of POPs within and between T2DM cases and controls, and logistic regression models to investigate the associations between different POPs and T2DM at different time-points. Results PCBs, trans-nonachlor, cis-nonachlor, oxychlordane, cis-heptachlor epoxide, p,p’-DDE, and p,p’-DDT declined more slowly in cases than controls, whereas β-HCH and HCB declined similarly in both groups. Most POPs showed positive associations between both pre- and post-diagnostic concentrations and T2DM, though effect estimates were imprecise. These associations were most consistent for cis-heptachlor epoxide. Discussion The observed positive associations between certain POPs and T2DM may be because of higher POP concentrations within prospective T2DM cases, due to slower temporal declines as compared to controls.

The wide-spread environmental pollutants per- and polyfluoroalkyl substances (PFAS) have repeatedly been associated with elevated serum cholesterol in humans. However, underlying mechanisms are still unclear. Furthermore, we have previously observed inverse associations with plasma triglycerides. To better understand PFAS-induced effects on lipid pathways we investigated associations of PFAS-related metabolite features with plasma cholesterol and triglyceride concentrations. We used 290 PFAS-related metabolite features that we previously discovered from untargeted liquid chromatography-mass spectometry metabolomics in a case-control study within the Swedish Västerbotten Intervention Programme cohort. Herein, we studied associations of these PFAS-related metabolite features with plasma cholesterol and triglyceride concentrations in plasma samples from 187 healthy control subjects collected on two occasions between 1991 and 2013. The PFAS-related features did not associate with cholesterol, but 50 features were associated with triglycerides. Principal component analysis on these features indicated that one metabolite pattern, dominated by glycerophospholipids, correlated with longer chain PFAS and associated inversely with triglycerides (both cross-sectionally and prospectively), after adjustment for confounders. The observed time-trend of the metabolite pattern resembled that of the longer chain PFAS, with higher levels during the years 2004-2010. Mechanisms linking PFAS exposures to triglycerides may thus occur via longer chain PFAS affecting glycerophospholipid metabolism. If the results reflect a cause-effect association, as implied by the time-trend and prospective analyses, this may affect the general adult population.

Purpose Multimodal prehabilitation programs (exercise, nutrition, and anxiety reduction) have been shown to be successful for enhancing patients' physical function prior to surgery, although adherence remains a challenge. Given the short pre-operative period, maintaining adherence is critical to maximize program effectiveness. This study was designed to better understand patients' perspectives of prehabilitation and to identify factors related to program adherence.Methods A qualitative descriptive study was conducted based on 52 cancer patients enrolled in a prehabilitation program at the Montreal General Hospital, Montreal, Canada. Data was collected with a structured questionnaire designed to evaluate the program.Results Patients enjoyed their experience in prehabilitation, especially the exercise program and training sessions. The primary motivating factor for participation was to be physically prepared for the surgery. The most challenging exercise component was resistance training, while the most enjoyed was the aerobic training. Approximately 50% of patients were interested in group fitness classes as opposed to supervised individual training sessions for reasons related to social support. The preferred methods for exercise program delivery were home-based and one supervised exercise session per week. The biggest barrier to participation was related to transportation.Conclusions These findings highlight the need to make prehabilitation programs more patient-centered. This is critical when designing more effective therapeutic strategies tailored to meet patients' specific needs while overcoming program non-adherence.

Background Alcohol is an established risk factor for several cancers, but modest alcohol-cancer associations may be missed because of measurement error in self-reported assessments. Biomarkers of habitual alcohol intake may provide novel insight into the relationship between alcohol and cancer risk. Methods Untargeted metabolomics was used to identify metabolites correlated with self-reported habitual alcohol intake in a discovery dataset from the European Prospective Investigation into Cancer and Nutrition (EPIC; n = 454). Statistically significant correlations were tested in independent datasets of controls from case-control studies nested within EPIC (n = 280) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC; n = 438) study. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations of alcohol-associated metabolites and self-reported alcohol intake with risk of pancreatic cancer, hepatocellular carcinoma (HCC), liver cancer, and liver disease mortality in the contributing studies. Results Two metabolites displayed a dose-response association with self-reported alcohol intake: 2-hydroxy-3-methylbutyric acid and an unidentified compound. A 1-SD (log2) increase in levels of 2-hydroxy-3-methylbutyric acid was associated with risk of HCC (OR = 2.54, 95% CI = 1.51 to 4.27) and pancreatic cancer (OR = 1.43, 95% CI = 1.03 to 1.99) in EPIC and liver cancer (OR = 2.00, 95% CI = 1.44 to 2.77) and liver disease mortality (OR = 2.16, 95% CI = 1.63 to 2.86) in ATBC. Conversely, a 1-SD (log2) increase in questionnaire-derived alcohol intake was not associated with HCC or pancreatic cancer in EPIC or liver cancer in ATBC but was associated with liver disease mortality (OR = 2.19, 95% CI = 1.60 to 2.98) in ATBC. Conclusions 2-hydroxy-3-methylbutyric acid is a candidate biomarker of habitual alcohol intake that may advance the study of alcohol and cancer risk in population-based studies.

The certainty that prehabilitation improves postoperative outcomes is not clear. The objective of this umbrella review (i.e. systematic review of systematic reviews) was to synthesise and evaluate evidence for prehabilitation in improving health, experience, or cost outcomes.We performed an umbrella review of prehabilitation systematic reviews. MEDLINE, Embase, Cochrane, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, Joanna Briggs Institute's database, and Web of Science were searched (inception to October 20, 2020). We included all systematic reviews of elective, adult patients undergoing surgery and exposed to a prehabilitation intervention, where health, experience, or cost outcomes were reported. Evidence certainty was assessed using Grading of Recommendations Assessment, Development and Evaluation. Primary syntheses of any prehabilitation were stratified by surgery type.From 1412 titles, 55 systematic reviews were included. For patients with cancer undergoing surgery who participate in any prehabilitation, moderate certainty evidence supports improvements in functional recovery. Low to very low certainty evidence supports reductions in complications (mixed, cardiovascular, and cancer surgery), non-home discharge (orthopaedic surgery), and length of stay (mixed, cardiovascular, and cancer surgery). There was low to very low certainty evidence that exercise prehabilitation reduces the risk of complications, non-home discharge, and length of stay. There was low to very low certainty evidence that nutritional prehabilitation reduces risk of complications, mortality, and length of stay.Low certainty evidence suggests that prehabilitation may improve postoperative outcomes. Future low risk of bias, randomised trials, synthesised using recommended standards, are required to inform practice. Optimal patient selection, intervention design, and intervention duration must also be determined.

Aims Impaired renal function is a major contributor to the low proportion of mineralocorticoid receptor antagonist (MRA) treatment in patients with heart failure with reduced ejection fraction (HFrEF). Our aims were to investigate the impact of MRA treatment on all-cause mortality and worsening renal function (WRF) in patients with HFrEF and moderately impaired renal function. Methods Retrospective data between 2010–2018 on HFrEF patients from a single-centre hospital with estimated glomerular renal function (eGFR) < 60 ml/min/1.73 m2 were analysed. WRF was defined as a decline of by eGFR ≥ 20%. Results 416 patients were included, 131 patients on MRA and 285 without MRA, mean age was 77 years (SD ± 9) and 82 years (SD ± 9), respectively. Median follow-up was 2 years. 128 patients (32%) experienced WRF, 25% in the MRA group and 30% in patients without MRA (p = 0.293). In multivariable analysis, hospitalization for heart failure and systolic blood pressure were associated with WRF (p = 0.015 and p = Conclusion In this cohort of elderly HFrEF patients with moderately impaired renal function, MRA did not increase risk for WRF or all-cause mortality.

Background In research on co-creation in nursing, a caring manner can be used to create opportunities for the patient to reach vital goals and thereby increase the patient’s quality of life in palliative home care. This can be described as an ethical cornerstone and the goal of palliative care. Nurses must be extra sensitive to patients’ and their relatives’ needs with regard to ethical and existential issues and situations in home care encounters, especially at the end of life. Aim The aim of this study was to explore nurses’ experiences of dealing with ethical and existential issues through co-creation at the end of life in palliative home care. Research design, participants, and research context The material consisted of texts from interviews with 12 nurses in a home care context. A hermeneutical approach was used, and the method was inspired by a thematic analysis. Ethical considerations Informed consent was sought from the participants regarding study participation and the storage and handling of data for research purposes. Ethical permission to conduct the study was given from organizations that participated in this study. Findings A main theme and four subthemes emerged. The main theme was “Deep co-creative relationships are needed to manage ethical and existential issues at the end of life.” A model was created to display the findings and relations between ethical issues and situations and the need for a deep trustful caring relationship to solve problems in palliative home care. Discussion Together, the themes can be considered as a tool for learning and dealing with ethical and existential issues at the end of life in home care. The themes can also be seen as a part of nurses’ ethical competence within this context. Conclusion The quality of life at the end of life can be improved through co-creation, despite difficult ethical and existential issues. Future research should focus on co-creation from the patients’ perspective.

Background The enhancement of post-operative care is under constant evolution and, with the addition of enhanced recovery programs, is changing the traditional in-hospital paradigm. Despite these advances, there is a clear lack of focus regarding early post-surgical mobilization, which has been identified as an important aspect of recovery. This pilot study investigates the feasibility of initiating resistance exercise to promote early mobilization in colorectal cancer patients during the in-hospital period. Method Patients participated in a supervised progressive resistance exercise program, adapted to their physical ability (either in bed, seated or standing), within the first 24 h following surgery. They were seen each day during the hospital stay and encouraged to continue exercising upon discharge. All patients were asked to return to the lab at four weeks after surgery for re-evaluation to establish recovery. Results Patient compliance to the in-hospital program was high, with 90% of patients engaging in exercise on the first post-operative day (POD 1) and no adverse effects reported during study. By POD 2, over 70% of patients met enhanced recovery after surgery (ERAS) recommendations. Conclusion It is feasible to initiate a progressive post-operative resistance exercise program in patients undergoing colorectal resection. The results suggest the positive aspects of incorporating resistance exercise into post-operative care. This may facilitate a clear and easy to implement exercise intervention that can take into consideration patient physical status and limited facility space in the hospital environment.

There is conflicting evidence regarding the association between fish intake and type 2 diabetes (T2D) incidence, possibly owing to measurement errors in self-reported intake and coexposure to persistent organic pollutants (POPs) present in fish.The aim of this study was to identify plasma metabolites associated with fish intake and to assess their association with T2D risk, independently of POPs, in Swedish adults.In a case-control study nested in the Swedish Västerbotten Intervention Programme, fasting plasma samples from 421 matched T2D case-control pairs of men and women aged 30-60 y at baseline and 10-y follow-up samples from a subset of 149 pairs were analyzed using untargeted metabolomics. Moreover, 16 plasma POPs were analyzed for the 149 pairs who had repeated samples available. Fish-related plasma metabolites were identified using multivariate modelling and partial correlation analysis. Reproducibility of metabolites and metabolite patterns, derived via principal component analysis (PCA), was assessed by intraclass correlation. A unique component of metabolites unrelated to POPs was dissected by integrating metabolites and POPs using 2-way orthogonal partial least squares regression. ORs of T2D were estimated using conditional logistic regression.We identified 31 metabolites associated with fish intake that had poor to good reproducibility. A PCA-derived metabolite pattern strongly correlated with fish intake (ρ = 0.37, P 0.001) but showed no association with T2D risk. Integrating fish-related metabolites and POPs led to a unique metabolite component independent of POPs, which tended to be inversely associated with T2D risk (OR: 0.75; 95% CI: 0.54, 1.02, P = 0.07). This component mainly consisted of metabolites reflecting fatty fish intake.Our results suggest that fatty fish intake may be beneficial for T2D prevention, after removing the counteractive effects of coexposure to POPs in Swedish adults. Integrating metabolite markers and POP exposures appears a promising approach to advance the understanding of associations between fish intake and T2D incidence.

Background: Perfluoroalkyl substances (PFAS) are persistent synthetic chemicals that may affect components of metabolic risk through the peroxisome proliferator-activated receptor but epidemiological data remain scarce and inconsistent. Objective: To estimate associations between repeated measurements of the main PFAS in plasma and total cholesterol, triglycerides and hypertension among the control subjects from a population-based nested case-control study on diabetes type 2 in middle-aged women and men. Methods: Participants (n = 187) were free of diabetes at both baseline and follow-up visits to the Västerbotten Intervention Programme, 10 years apart: during 1990 to 2003 (baseline) and 2001 to 2013 (follow-up). Participants left blood samples, completed questionnaires on diet and lifestyle factors, and underwent medical examinations, including measurement of blood pressure. PFAS and lipids were later determined in stored plasma samples. Associations for the repeated measurements were assessed using generalized estimating equations. Results: Six PFAS exceeded the limit of quantitation. Repeated measures of PFAS in plasma, cardiometabolic risk factors and confounders, showed an average decrease of triglycerides from −0.16 mmol/l (95% confidence interval [CI]: −0.33, 0.02 for PFOA) to −0.26 mmol/l (95% CI: −0.50, −0.08 for PFOS), when comparing the highest tertile of PFAS plasma levels with the lowest. Associations based on average PFAS measurements and follow-up triglycerides revealed similar inverse associations, although attenuated. The estimates for cholesterol and hypertension were inconsistent and with few exception non-significant. Conclusions: This study found inverse associations between PFAS and triglycerides, but did not support any clear link with either cholesterol or hypertension. Keywords: Plasma perfluoroalkyl substances, Cardiometabolic risk factors, Lipids, Hypertension, Environmental epidemiology, Repeated measurements, Prospective assessment

Patients palliated with Total Cavopulmonary Connection have a lower muscle mass and a lower exercise capacity. We assessed calf muscle oxidative metabolism during and after heel raise exercise to exhaustion in young patients with TCPC compared to healthy peers. Near-infrared spectroscopy was used for measuring oxygen metabolism in the medial portion of the gastrocnemius muscle. Forty-three patients with TCPC, aged 6–18 years, were compared with 43 age and sex-matched healthy control subjects. Subgroups were formed to include children (6–12 years) and adolescents (13–18 years) to determine if these age groups influenced the results. During exercise, for the patients compared to controls there was a lower increase in deoxygenated hemoglobin (oxygen extraction) (5.13 ± 2.99au vs. 7.75 ± 4.15au, p = 0.001) and a slower rate of change in total hemoglobin (blood volume) (0.004 ± 0.015au vs 0.016 ± 0.01au, p = 0.001). Following exercise, patients exhibited a slower initial increase in tissue oxygenation saturation index (0.144 ± 0.11au vs 0.249 ± 0.226au, p = 0.007) and a longer half-time to maximum hyperemia (23.7 ± 11.4 s vs 16.8 ± 7.5 s, p = 0.001). On the subgroup level, the adolescents differed compared to healthy peers, whereas the children did not. Young patients with TCPC had impaired oxidative metabolism during exercise and required a longer time to recover. In that the differences were seen in the adolescent group and not in the children group may indicate a declining function with age.

Background Distal radial fractures (DRF) are one of the most common fractures with a small peak in incidence among young males and an increasing incidence with age among women. The reliable classification of fractures is important, as classification provides a framework for communicating effectively on clinical cases. Fracture classification is also a prerequisite for data collection in national quality registers and for clinical research. Since its inception in 2011, the Swedish Fracture Register (SFR) has collected data on more than 490,000 fractures. The attending physician classifies the fracture according to the AO/OTA classification upon registration in the SFR. Previous studies regarding the classification of distal radial fractures (DRF) have shown difficulties in inter- and intra-observer agreement. This study aims to assess the accuracy of the registration of DRF in adults in the SFR as it is carried out in clinical practice. Methods A reference group of three experienced orthopaedic trauma surgeons classified 128 DRFs, randomly retrieved from the SFR, at two classification sessions 6 weeks apart. The classification the reference group agreed on was regarded as the gold standard classification for each fracture. The accuracy of the classification in the SFR was defined as the agreement between the gold standard classification and the classification in the SFR. Inter- and intra-observer agreement was evaluated and the degree of agreement was calculated as Cohen’s kappa. Results The accuracy of the classification of DRF in the SFR was kappa = 0.41 (0.31–0.51) for the AO/OTA subgroup/group and kappa = 0.48 (0.36–0.61) for the AO/OTA type. This corresponds to moderate agreement. Inter-observer agreement ranged from kappa 0.22–0.48 for the AO/OTA subgroup/group and kappa 0.48–0.76 for the AO/OTA type. Intra-observer agreement ranged from kappa 0.52–0.70 for the AO/OTA subgroup/group and kappa 0.71–0.76 for the AO/OTA type. Conclusions The study shows moderate accuracy in the classification of DRF in the SFR. Although the degree of accuracy for DRF appears to be lower than for other fracture locations, the accuracy shown in the current study is similar to that in previous studies of DRF.

Background Findings and limitations of previous studies on persistent organic pollutants (POPs) and pancreatic cancer risk support conducting further research in prospective cohorts. Methods We conducted a prospective case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Participants were 513 pancreatic cancer cases and 1020 matched controls. Concentrations of 22 POPs were measured in plasma collected at baseline. Results Some associations were observed at higher concentrations of p, p’-DDT, trans-nonachlor, β-hexachlorocyclohexane and the sum of six organochlorine pesticides and of 16 POPs. The odds ratio (OR) for the upper quartile of trans-nonachlor was 1.55 (95% confidence interval 1.06-2.26; P for trend = 0.025). Associations were stronger in the groups predefined as most valid (participants having fasted >6 h, with microscopic diagnostic confirmation, normal weight, and never smokers), and as most relevant (follow-up ≥10 years). Among participants having fasted >6 h, the ORs were relevant for 10 of 11 exposures. Higher ORs were also observed among cases with microscopic confirmation than in cases with a clinical diagnosis, and among normal-weight participants than in the rest of participants. Among participants with a follow-up ≥10 years, estimates were higher than in participants with a shorter follow-up (for trans-nonachlor: OR = 2.14, 1.01 to 4.53, P for trend = 0.035). Overall, trans-nonachlor, three PCBs and the two sums of POPs were the exposures most clearly associated with pancreatic cancer risk. Conclusions Individually or in combination, most of the 22 POPs analysed did not or only moderately increased the risk of pancreatic cancer.

Prehabilitation has been previously shown to be more effective in enhancing postoperative functional capacity than rehabilitation alone. The purpose of this study was to determine whether a weekly supervised exercise session could provide further benefit to our current prehabilition program, when comparing to standard post-surgical rehabilitation.A parallel-arm single-blind randomized control trial was conducted in patients scheduled for non-metastatic colorectal cancer resection. Patients were assigned to either a once weekly supervised prehabilitation (PREHAB+, n = 41) or standard rehabilitation (REHAB, n = 39) program. Both multimodal programs were home-based program and consisted of moderate intensity aerobic and resistance exercise, nutrition counseling with daily whey protein supplementation and anxiety-reduction strategies. Perioperative care was standardized for both groups as per enhanced recovery after surgery (ERASBoth groups were comparable for baseline walking capacity (PREHAB+: 448 m [IQR 375-525] vs. REHAB: 461 m [419-556], p=.775) and included a similar proportion of patients who improved walking capacity (20 m) during the preoperative period (PREHAB+: 54% vs. REHAB: 38%, p = .222). After surgery, changes in 6MWD were also similar in both groups. In PREHAB+, however, there was a significant association between physical activity energy expenditure and 6MWD (p .01). Previously inactive patients were more likely to improve functional capacity due to PREHAB+ (OR 7.07 [95% CI 1.10-45.51]).The addition of a weekly supervised exercise session to our current prehabilitation program did not further enhance postoperative walking capacity when compared to standard REHAB care. Sedentary patients, however, seemed more likely to benefit from PREHAB+. An association was found between energy spent in physical activity and 6MWD. This information is important to consider when designing cost-effective prehabilitation programs.

Objective To investigate, in lung cancer patients awaiting elective surgery, the feasibility of delivering a novel four-week multimodal prehabilitation intervention and its effects on preoperative functional capacity and health-related quality of life (HRQoL), compared to standard hospital care. Methods Adult patients awaiting elective thoracotomy for lung cancer stages I, II or IIIa, were approached to participate in an open-label, randomized controlled trial of two parallel arms: multimodal prehabilitation combining a mixed-nutrient supplement with structured supervised and home-based exercise training, and relaxation-strategies (Prehab) or standard hospital care (Control). Feasibility was assessed based on recruitment and adherence rates to the intervention and study outcome assessment. Functional capacity, measured by the 6-min walk test (6MWT), and HRQoL were measured at baseline and after four weeks (preoperative). Results Within 5 months, 34 patients were enrolled and randomized (2:1) to Prehab (n = 24; median age = 67 years) or Control (n = 10; median age = 69 years); recruitment rate of 58.6%. The study was interrupted by the COVID-19 pandemic. Adherence to the prescribed intensity of the supervised exercise program was 84.1% (SD 23.1). Self-reported adherence to the home-based exercise program was 88.2% (SD 21) and to the nutritional supplement, 93.2% (SD 14.2). Adherence to patients’ preoperative assessment was 82% and 88% in Prehab and Control, respectively. The mean adjusted difference in 4-week preoperative 6MWT between groups was 37.7 m (95% CI, −6.1 to 81.4), p = 0.089. There were no differences in HRQoL between groups. Conclusion Within a preoperative timeframe, it was feasible to deliver this novel multimodal prehabilitation intervention in lung cancer patients awaiting surgery.

New guidelines from the European Society of Cardiology (ESC) for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation (NSTEMI-ACS) stress the importance of more individualized diagnostics and therapy based on the patients' initial risk profile balancing risk of ischemia with risk of bleeding. In this commentary, the Working Group on Coronary Artery Disease of the Swedish Society of Cardiology points out what is new in the 2020 NSTEMI guidelines.

Perfluoroalkyl substances (PFAS) are widespread persistent environmental pollutants. There is evidence that PFAS induce metabolic perturbations in humans, but underlying mechanisms are still unknown. In this exploratory study, we investigated PFAS-related plasma metabolites for their associations with type 2 diabetes (T2D) to gain potential mechanistic insight in these perturbations. We used untargeted LC-MS metabolomics to find metabolites related to PFAS exposures in a case-control study on T2D (n = 187 matched pairs) nested within the Västerbotten Intervention Programme cohort. Following principal component analysis (PCA), six PFAS measured in plasma appeared in two groups: 1) perfluorononanoic acid, perfluorodecanoic acid and perfluoroundecanoic acid and 2) perfluorohexane sulfonic acid, perfluorooctane sulfonic acid and perfluorooctanoic acid. Using a random forest algorithm, we discovered metabolite features associated with individual PFAS and PFAS exposure groups which were subsequently investigated for associations with risk of T2D. PFAS levels correlated with 171 metabolite features (0.16 ≤ |r| ≤ 0.37, false discovery rate (FDR) adjusted p

Background The risk of heart failure among diabetic individuals is high, even under tight glycemic control. The correlates and mediators of heart failure risk in individuals with diabetes need more elucidation in large population-based cohorts with long follow-up times and a wide panel of biologically relevant biomarkers. Methods In a population-based sample of 3834 diabetic and 90,177 non-diabetic individuals, proportional hazards models and mediation analysis were used to assess the relation of conventional heart failure risk factors and biomarkers with incident heart failure. Results Over a median follow-up of 13.8 years, a total of 652 (17.0%) and 5524 (6.1%) cases of incident heart failure were observed in participants with and without diabetes, respectively. 51.4% were women and the mean age at baseline was 48.7 (standard deviation [SD] 12.5) years. The multivariable-adjusted hazard ratio (HR) for heart failure among diabetic individuals was 2.70 (95% confidence interval, 2.49–2.93) compared to non-diabetic participants. In the multivariable-adjusted Cox models, conventional cardiovascular disease risk factors, such as smoking (diabetes: HR 2.07 [1.59–2.69]; non-diabetes: HR 1.85 [1.68–2.02]), BMI (diabetes: HR 1.30 [1.18–1.42]; non-diabetes: HR 1.40 [1.35–1.47]), baseline myocardial infarction (diabetes: HR 2.06 [1.55–2.75]; non-diabetes: HR 2.86 [2.50–3.28]), and baseline atrial fibrillation (diabetes: HR 1.51 [0.82–2.80]; non-diabetes: HR 2.97 [2.21–4.00]) had the strongest associations with incident heart failure. In addition, biomarkers for cardiac strain (represented by nT-proBNP, diabetes: HR 1.26 [1.19–1.34]; non-diabetes: HR 1.43 [1.39–1.47]), myocardial injury (hs-TnI, diabetes: HR 1.10 [1.04–1.16]; non-diabetes: HR 1.13 [1.10–1.16]), and inflammation (hs-CRP, diabetes: HR 1.13 [1.03–1.24]; non-diabetes: HR 1.29 [1.25–1.34]) were also associated with incident heart failure. In general, all these associations were equally strong in non-diabetic and diabetic individuals. However, the strongest mediators of heart failure in diabetes were the direct effect of diabetes status itself (relative effect share 43.1% [33.9–52.3] and indirect effects (effect share 56.9% [47.7-66.1]) mediated by obesity (BMI, 13.2% [10.3–16.2]), cardiac strain/volume overload (nT-proBNP, 8.4% [-0.7–17.4]), and hyperglycemia (glucose, 12.0% [4.2–19.9]). Conclusions The findings suggest that the main mediators of heart failure in diabetes are obesity, hyperglycemia, and cardiac strain/volume overload. Conventional cardiovascular risk factors are strongly related to incident heart failure, but these associations are not stronger in diabetic than in non-diabetic individuals. Active measurement of relevant biomarkers could potentially be used to improve prevention and prediction of heart failure in high-risk diabetic patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12933-021-01378-4.

Exposure to mercury (Hg) is a global concern, particularly among Arctic populations that rely on the consumption of marine mammals and fish which are the main route of Hg exposure for Arctic populations. The MercuNorth project was created to establish baseline Hg levels across several Arctic regions during the period preceding the Minamata Convention. Blood samples were collected from 669 pregnant women, aged 18–44 years, between 2010 and 2016 from sites across the circumpolar Arctic including Alaska (USA), Nunavik (Canada), Greenland, Iceland, Norway, Sweden, Northern Lapland (Finland) and Murmansk Oblast (Russia). Descriptive statistics were calculated, multiple pairwise comparisons were made between regions, and unadjusted linear trend analyses were performed. Geometric mean concentrations of total Hg were highest in Nunavik (5.20 µg/L) and Greenland (3.79 µg/L), followed by Alaska (2.13 µg/L), with much lower concentrations observed in the other regions (ranged between 0.48 and 1.29 µg/L). In Nunavik, Alaska and Greenland, blood Hg concentrations have decreased significantly since 1992, 2000 and 2010 respectively with % annual decreases of 4.7%, 7.5% and 2.7%, respectively. These circumpolar data combined with fish and marine mammal consumption data can be used for assessing long-term Hg trends and the effectiveness of the Minamata Convention.

To determine the effect of preoperative nutrition and multimodal prehabilitation on clinical and functional outcomes in surgical lung cancer patients.We searched MEDLINE, Cochrane Library and CENTRAL, EMBASE, Scopus, and clinical trial registries ( clinicaltrials.gov , International Clinical Trials Registry Platform and Google Scholar) to identify studies involving a preoperative nutrition-based intervention or multimodal prehabilitation (nutrition with exercise) of at least 7 days, in lung cancer patients awaiting surgery. Studies must have reported results on at least one of the following outcomes: functional capacity, pulmonary function, postoperative complications, and length of hospital stay. The quality of included studies was assessed using the Cochrane risk of bias assessment tool for randomized trials and the modified Newcastle-Ottawa scale for non-controlled trials.Five studies were included (1 nutrition-only and 4 multimodal prehabilitation studies). Due to substantial heterogeneity in the interventions across studies, a meta-analysis was not conducted. Findings suggest that multimodal prehabilitation, compared with standard hospital care, is associated with improvements in both functional walking capacity and pulmonary function during the preoperative period; however it does not appear to have an effect on postoperative outcomes. Rather, the finding of significantly lower rates of postoperative complications in the intervention group was unique to the nutrition-only study.Multimodal prehabilitation programs that combine nutrition and exercise may have beneficial effects on various physical function outcomes in patients with lung cancer awaiting surgery. Optimizing preoperative nutrition may have postoperative benefits which remain to be confirmed.

Background The distribution of retroperitoneal lymph node metastases for patients with nonseminoma and a residual tumour of 10–49 mm in a population-based setting is unknown. This information is needed to justify selection of patients for a unilateral template resection. Objective To describe the location of retroperitoneal metastases and recurrences in patients with nonseminoma germ cell tumour (NSGCT) with a residual tumour of 10–49 mm. Design, setting, and participants RETROP is a population-based prospective observational mapping study of 213 patients in Sweden and Norway with a retroperitoneal residual tumour of 10–49 mm who underwent postchemotherapy retroperitoneal lymph node dissection for metastatic NSGCT during 2007–2014 with median follow-up of 100 mo. Patients were classified according to the testis primary tumour and the distribution of unilateral or bilateral lymph node metastases (with reference to the aorta) present on pre- and/or postchemotherapy computed tomography (CT) scans. Outcome measurements and statistical analysis The distribution and rate of teratoma or cancer in unilateral or bilateral retroperitoneal fields and the location and rate of retroperitoneal recurrence were measured. Results and limitations In total, 65% of the patients had unilateral retroperitoneal lymph node metastases (RLNMs) on CT scans. Patients with unilateral RLNMs had a low risk of contralateral teratoma or cancer (1.6% for right- and 2.6% for left-sided NSGCT) or retroperitoneal recurrence (0% for right- and 4% for left-sided NSGCT). A weakness of the study is that the pathology specimen could not be fully designated to one specific area for some of the patients. Conclusions Men with postchemotherapy residual disease of 10–49 mm and unilateral metastases on pre- and postchemotherapy CT scans have a low risk of contralateral disease and should be considered for a unilateral template resection. Patient summary The surgeon can use computed tomography (CT) scans in deciding on the extent of lymph node dissection in patients with testicular cancer.

Stapylococcus aureus is a common infectious agent in e.g. sepsis, associated with both high mortality rates and severe long-term effects. The cytolytic protein α-hemolysin has repeatedly been shown to enhance the virulence of S. aureus. Combined with an unhindered spread of multi drug-resistant strains, this has triggered research into novel anti virulence (i.e. anti α-hemolysin) drugs. Their functionality will depend on our ability to identify infections that might be alleviated by such. We therefore saw a need for detection methods that could identify individuals suffering from S. aureus infections where α-hemolysin was a major determinant. Molecular imprinted polymers were subsequently prepared on gold coated sensor chips. Used in combination with a surface plasmon resonance biosensor, α-hemolysin could therethrough be quantified from septic blood samples (n = 9), without pre-culturing of the infectious agent. The biosensor recognized α-hemolysin with high affinity (KD = 2.75 x 10-7 M) and demonstrated a statistically significant difference (p < 0.0001) between the α-hemolysin response and potential sample contaminants. The detection scheme proved equally good, or better, when compared to antibody-based detection methods. This novel detection scheme constitutes a more rapid, economical, and user-friendly alternative to many methods currently in use. Heightening both reproducibility and sensitivity, molecular imprinting in combination with surface plasmon resonance (SPR)-technology could be a versatile new tool in clinical- and research-settings alike.

Alzheimer's disease (AD) is a neurodegenerative disease which is manifested by a progressive and irreversible decline of cognition, memory loss, a shortened attention span, and changes in personality. Aging and genetic pre-dispositions, particularly the presence of a specific form of apolipoprotein E (APOE), are main risk factors of sporadic AD; however, a large body of evidence has shown that multiple environmental factors, including exposure to toxic metals, increase the risk for late onset AD. Lead (Pb) and cadmium (Cd) are ubiquitous toxic metals with a wide range of applications resulting in global distribution in the environment and exposure of all living organisms on earth. In addition to being classified as carcinogenic (Cd) and possibly carcinogenic (Pb) to humans by the International Agency for Research on Cancer, both compounds disrupt metal homeostasis and can cause toxic responses at the cellular and organismal levels. Pb toxicity targets the central nervous system and evidence for that has emerged also for Cd. Recent epidemiological studies show that both metals possibly are etiological factors of multiple neurodegenerative diseases, including Alzheimer's disease (AD). To further explore the association between metal exposure and AD risk we applied whole transcriptome gene expression analysis in peripheral blood leukocytes (PBLs) from 632 subjects of the general population, taken from the EnviroGenomarkers project. We used linear mixed effect models to associate metal exposure to gene expression after adjustment for gender, age, BMI, smoking, and alcohol consumption. For Pb exposure only few associations were identified, including a downregulation of the human eukaryotic translation initiation factor 5 (eIF5). In contrast, Cd exposure, particularly in males, revealed a much stronger transcriptomic response, featuring multiple pathways related to pathomolecular mechanisms of AD, such as endocytosis, neutrophil degranulation, and Interleukin-7 signaling. A gender stratified analysis revealed that the Cd responses were male-specific and included a downregulation of the APOE gene in men. This exploratory study revealed novel hypothetical findings which might contribute to the understanding of the neurotoxic effects of chronic Pb and Cd exposure and possibly improve our knowledge on the molecular mechanisms linking metal exposure to AD risk.

The aims of this study were to investigate the mortality following a proximal humeral fracture. Data from a large population-based fracture register were used to quantify 30-day, 90-day, and one-year mortality rates after a proximal humeral fracture. Associations between the risk of mortality and the type of fracture and its treatment were assessed, and mortality rates were compared between patients who sustained a fracture and the general population.All patients with a proximal humeral fracture recorded in the Swedish Fracture Register between 2011 and 2017 were included in the study. Those who died during follow-up were identified via linkage with the Swedish Tax Agency population register. Age- and sex-adjusted controls were retrieved from Statistics Sweden and standardized mortality ratios (SMRs) were calculated.A total of 18,452 patients who sustained a proximal humeral fracture were included. Their mean age was 68.8 years (16 to 107) and the majority (13,729; 74.4%) were women. A total of 310 (1.68%) died within 30 days, 615 (3.33%) within 90 days, and 1,445 (7.83%) within one year after the injury. The mortality in patients sustaining a fracture and the general population was 1,680/100,000 and 326/100,000 at 30 days, 3,333/100,000 and 979/100,000 at 90 days, and 7,831/100,000 and 3,970/100,000 at one year, respectively. Increasing age, male sex, low-energy trauma, type A fracture, concomitant fractures, and non-surgical treatment were all independent factors associated with an increased risk of mortality.Compared with the general population, patients sustaining a proximal humeral fracture have a significantly higher risk of mortality up to one year after the injury. The risk of mortality is five times higher during the first 30 days, diminishing to two times higher at one year, suggesting that these patients constitute a strikingly frail group, in whom appropriate immediate management and medical optimization are required. Cite this article

Objective - Several risk factors for type 2 diabetes mellitus (T2DM) are also associated with blood concentrations of persistent organic pollutants (POPs), and factors related to the disease may affect POP concentrations, and subsequent associations between POPs and T2DM. The purpose of this pilot study was to investigate the change in concentrations of lipids, hormones and POPs pre- and post-diagnosis in T2DM cases compared to healthy controls and their associations with T2DM. Methods - We measured POPs, lipids, and thyroid and steroid hormones in plasma from 44 female cases collected prior to (pre-diagnostic) and following (post-diagnostic) T2DM diagnosis, and in 44 healthy female age-matched controls. We compared cross-sectional differences and longitudinal changes within and between matched cases and controls with t-tests and multivariable linear regression models. Associations between POP concentrations and T2DM were investigated using conditional logistic regression. Results - Between the pre- and post-diagnostic measurement, cases developed more favorable lipid profiles and the longitudinal changes in lipid-normalized concentrations of non-dioxin-like polychlorinated biphenyls (PCBs), dioxin-like PCBs, beta-hexachlorocyclohexane (HCH), HCB, and 1,1,1-trichloro-2,2-bis(4-chlorophenyl) ethane (p,p'-DDE) differed significantly between cases and controls. The longitudinal changes in POPs were mainly driven by changes in bodyweight, total lipids and T2DM status. Cases had significantly higher pre-diagnostic concentrations of POPs and triglycerides, and lower concentrations of high-density lipoprotein cholesterol and free thyroxin than controls. Pre-diagnostic POP concentrations were not significantly associated with incident T2DM, whereas several post-diagnostic POP concentrations were significantly positively associated with prevalent T2DM. Conclusions - This pilot study suggests that factors related to T2DM affect blood concentrations of POPs and may partly explain the positive associations between POPs and T2DM.

Streptococcus pyogenes (Group A streptococcus; GAS) is an important human pathogen responsible for mild to severe, life-threatening infections. GAS expresses a wide range of virulence factors, including the M family proteins. The M proteins allow the bacteria to evade parts of the human immune defenses by triggering the formation of a dense coat of plasma proteins surrounding the bacteria, including IgGs. However, the molecular level details of the M1-IgG interaction have remained unclear. Here, we characterized the structure and dynamics of this interaction interface in human plasma on the surface of live bacteria using integrative structural biology, combining cross-linking mass spectrometry and molecular dynamics (MD) simulations. We show that the primary interaction is formed between the S-domain of M1 and the conserved IgG Fc-domain. In addition, we show evidence for a so far uncharacterized interaction between the A-domain and the IgG Fc-domain. Both these interactions mimic the protein G-IgG interface of group C and G streptococcus. These findings underline a conserved scavenging mechanism used by GAS surface proteins that block the IgG-receptor (FcγR) to inhibit phagocytic killing. We additionally show that we can capture Fab-bound IgGs in a complex background and identify XLs between the constant region of the Fab-domain and certain regions of the M1 protein engaged in the Fab-mediated binding. Our results elucidate the M1-IgG interaction network involved in inhibition of phagocytosis and reveal important M1 peptides that can be further investigated as future vaccine targets., Author summary Streptococcus pyogenes is a human specific pathogen causing both mild and invasive infections. It employs sophisticated mechanisms to evade and circumvent parts of the host’s immune defenses, in part via its major surface associated virulence factor, the family of M proteins. Of these, the M1 protein is the most prevalent serotype. The M1 protein creates a dense coat-like structure with multiple host proteins on the bacterial surface to disguise itself from opsonizing antibodies. It specifically interacts in a non-immune way with human immunoglobulin G (IgG) Fc-domains to disarm their receptor binding site. The molecular level details of this interaction have not been characterized. Here, we describe these interactions from minimally perturbed samples of human plasma adsorbed onto living bacteria using an integrative structural biology approach including cross-linking mass spectrometry, molecular modeling, and molecular dynamics simulations. We identify two distinct M1-peptides that bind IgGs and reveal the stability of these interactions. We show that both peptides block the Fc-receptor binding sites through capturing IgGs via their Fc-domains. These results highlight the importance of describing novel pathogen-derived peptides mediating host immune evasion as potential vaccine targets in future studies.

Just as there is growing interest in enhancing recovery after surgery, prehabilitation is becoming a recognised means of preparing the patient physically for their operation and/or subsequent treatment. Exercise training is an important stimulus for improving low cardiovascular fitness and preserving lean muscle mass, which are critical factors in how well the patient recovers from surgery. Despite the usual focus on exercise, it is important to recognise the contribution of nutritional optimisation and psychological wellbeing for both the adherence and the response to the physical training stimulus. This article reviews the importance of a multi-modal approach to prehabilitation in order to maximise its impact in the pre-surgical period, as well as critical future steps in its development and integration in the healthcare system.

There is a lack of epidemiological studies of fractures in all segments of the tibia classified by orthopaedic surgeons according to the AO/OTA classification. Since 2011, the Swedish Fracture Register (SFR) has provided prospectively collected, population-based data on fractures of all types, treated both surgically and non-surgically. The aim of this study was to describe the epidemiology and incidence of fractures in all segments of the tibia in a cohort of consecutive tibia fractures over a period of five years at Sahlgrenska University Hospital, Gothenburg, Sweden.Information on age, gender, date and mechanism of injury, fracture classification according to AO/OTA, affected side and high- or low-energy trauma was extracted from the SFR for all patients, aged 16 years and above, with tibia fractures treated at Sahlgrenska University Hospital, Gothenburg, during the five-year period 1 January 2011 to 31 December 2015.1325 patients sustained 1371 tibia fractures. There were 712 proximal tibia fractures, 417 tibial shaft fractures and 242 distal tibia fractures. Patients with proximal tibia fractures had a higher mean age (54.3) and 58% were women, whereas patients with shaft and distal fractures had a slightly lower mean age (47.0 and 48.7 respectively) and a dominance of men (59% and 54% respectively). The overall incidence of tibia fractures was 51.7 per 100,000 and year. The incidence of proximal, diaphyseal and distal tibia fractures was 26.9, 15.7 and 9.1 respectively per 100,000 and year. Among women, tibia fractures showed an increasing incidence with age in all segments, whereas men had a fairly flat incidence curve, except for tibial shaft fractures, which displayed a peak among young males. The incidence of tibia fractures and graphs for age-specific incidence for each segment of the tibia are presented.This study describes the epidemiology and incidence of fractures in the whole of the tibia classified by orthopaedic surgeons according to the AO/OTA classification.

Objectives: The aim was to study self-image and the level of psychological symptoms in patients with symptoms attributed to their dental restorative materials. Materials and methods: A questionnaire containing questions regarding dental and medical history was answered by 257 participants, one group with local oral symptoms only (LSO), and one group with multi-symptoms (M-S). A reference group was randomly selected from a research database at the Department of Psychology, Umeå University, Sweden. The self-image was assessed using the Structural Analysis of Social Behavior (SASB). Psychological symptoms such as somatization, depression, and anxiety were assessed using the Symptom Check List 90 (SCL-90) and the Global Severity Index (GSI) was used to determine the level of psychological symptoms. Results: SASB showed that the M-S group and the LSO-group scored significantly higher on the Bspontaneous^ and Bpositive self-image^ than the reference group. In the SCL-90, the M-S group scored significantly higher than the LSO-group and the references on the somatization subscales. On depression, anxiety, and the GSI scale, the M-S group scored significantly higher than the reference group. Conclusions: The two subgroups scored significantly higher on the SASB Spontaneous and Positive clusters which indicates that these patients have an excessively positive self-image, are very spontaneous and have an overconfidence in themselves compared to the reference group. In the M-S group there was a clear tendency to somatization, depression, and anxiety and they were more psychologically stressed than the reference group. Clinical relevance: Among the patients with illness attributed to their dental materials, the M-S-patients had a significantly higher level of general psychological distress and somatization than the control group which may lead to mental stress. Originally included in thesis in manuscript form with titel "Psychological symptoms and self-image of patients with complaints attributed to dental restorative materials: Psychological symptoms in patients with environmental intolerance".

To explore and derive new conceptual understanding of nurse leaders' experiences and perceptions of caring in nursing. Research question: What is caring in nursing leadership from the nurse leaders' perspectives? There is a paucity of theoretical studies of caring in nursing leadership. Noblit and Hares interpretative meta-ethnography was chosen because of its interpretative potential for theory development. Caring in nursing leadership is a conscious movement between different “rooms” in the leader's “house” of leadership. This emerged as the metaphor that illustrates the core of caring in nursing leadership, presented in a tentative model. There are 5 relation-based rooms: The “patient room,” where nurse leaders try to avoid patient suffering through their clinical presence; the “staff room,” where nurse leaders trust and respect each other and facilitate dialogue; the “superior's room,” where nurse leaders confirm peer relationships; the “secret room,” where the leaders' strength to hang on and persist is nurtured; and the “organizational room,” where limited resources are continuously being balanced. Caring in nursing leadership means nurturing and growing relationships to safeguard the best nursing care. This presupposes that leaders possess a consciousness of the different “rooms.” If rooms are not given equal attention, movement stops, symbolizing that caring in leadership stops as well. One room cannot be given so much attention that others are neglected. Leaders need solid competence in nursing leadership to balance multiple demands in organizations; otherwise, their perceptiveness and the priority of “ministering to the patients” can be blurred.

BACKGROUND: Epidemiologic evidence on the association of a healthy Nordic diet and future type 2 diabetes (T2D) is limited. Exploring metabolites as biomarkers of healthy Nordic dietary patterns may facilitate investigation of associations between such patterns and T2D. OBJECTIVES: We aimed to identify metabolites related to a priori-defined healthy Nordic dietary indexes, the Baltic Sea Diet Score (BSDS) and Healthy Nordic Food Index (HNFI), and evaluate associations with the T2D risk in a case-control study nested in a Swedish population-based prospective cohort. DESIGN: Plasma samples from 421 case-control pairs at baseline and samples from a subset of 151 healthy controls at a 10-y follow-up were analyzed with the use of untargeted liquid chromatography-mass spectrometry metabolomics. Index-related metabolites were identified through the use of random forest modelling followed by partial correlation analysis adjustment for lifestyle confounders. Metabolite patterns were derived via principal component analysis (PCA). ORs of T2D were estimated via conditional logistic regression. Reproducibility of metabolites was assessed by intraclass correlation (ICC) in healthy controls. Associations were also assessed for 10 metabolites previously identified as linking a healthy Nordic diet with T2D. RESULTS: In total, 31 metabolites were associated with BSDS and/or HNFI (−0.19 ≤ r ≤ 0.21, 0.10 ≤ ICC ≤ 0.59). Two PCs were determined from index-related metabolites: PC1 strongly correlated to the indexes (r = 0.27 for BSDS, r = 0.25 for HNFI, ICC = 0.45) but showed no association with T2D risk. PC2 was weakly associated with the indexes, but more strongly with foods not part of the indexes, e.g., pizza, sausages, and hamburgers. PC2 was also significantly associated with T2D risk. Predefined metabolites were confirmed to be reflective of consumption of whole grains, fish, or vegetables, but not related to T2D risk. CONCLUSIONS: Our study did not support an association between healthy Nordic dietary indexes and T2D. However, foods such as hamburger, sausage, and pizza not covered by the indexes appeared to be more important for T2D risk in the current population.

Background: Aortic valve stenosis (AS) is the most common indication for cardiac valve surgery; untreated AS is linked to high mortality. The etiological background of AS is unknown. Previous human studies were typically based on case-control studies. Biomarkers identified in prospective studies could lead to novel mechanistic insights. Methods: Within a large population survey with blood samples obtained at baseline, 334 patients were identified who later underwent surgery for AS (median age [interquartile range], 59.9 [10.4] years at survey and 68.3 [12.7] at surgery; 48% female). For each case, 2 matched referents were allocated. Plasma was analyzed with the multiplex proximity extension assay for screening of 92 cardiovascular candidate proteins. Conditional logistic regression models were used to assess associations between each protein and AS, with correction for multiple testing. A separate set of 106 additional cases with 212 matched referents was used in a validation study. Results: Six proteins (growth differentiation factor 15, galectin-4, von Willebrand factor, interleukin 17 receptor A, transferrin receptor protein 1, and proprotein convertase subtilisin/kexin type 9) were associated with case status in the discovery cohort; odds ratios ranged from 1.25 to 1.37 per SD increase in the protein signal. Adjusting the multivariable models for classical cardiovascular risk factors at baseline yielded similar results. Subanalyses of case-referent triplets (n=133) who showed no visible coronary artery disease at the time of surgery in the index person supported associations between AS and growth differentiation factor 15 (odds ratio, 1.40; 95% confidence interval, 1.10-1.78) and galectin-4 (odds ratio, 1.27; 95% confidence interval, 1.02-1.59), but these associations were attenuated after excluding individuals who donated blood samples within 5 years before surgery. In triplets (n=201), which included index individuals with concurrent coronary artery disease at the time of surgery, all 6 proteins were robustly associated with case status in all sensitivity analyses. In the validation study, the association of all but 1 (interleukin 17 receptor A) of these proteins were replicated in patients with AS with concurrent coronary artery disease but not in patients with AS without coronary artery disease. Conclusions: We provide evidence that 5 proteins were altered years before AS surgery and that the associations seem to be driven by concurrent atherosclerotic disease.

Supplemental Digital Content is available in the text., Persistent organochlorine pollutants (POPs) have shown to be involved in the atherosclerotic process and to cause endothelial cell dysfunction. To assess longitudinally whether plasma concentrations of different POPs were associated with blood pressure and risk of hypertension in middle-aged women and men. Study subjects were 850 participants in the VIP (Västerbotten Intervention Programme) with 2 blood samples and blood pressure measurements, 10 years apart, during 1990 to 2003 (baseline) and during 2000 to 2013 (follow-up). Dioxin-like and nondioxin-like polychlorinated biphenyls (DL-PCBs, NDL-PCBs) and p,p′-dichlorodiphenyldichloroethylene (DDE) were measured. Associations were assessed using generalized estimating equations. At baseline sampling 49% and at follow-up 64% had hypertension. DL-PCBs and DDE, but not NDL-PCBs or hexachlorobenzene, were associated with hypertension. Only the association for DL-PCBs remained statistically significant after lipid-standardization and adjustment for body mass index and total serum lipids. The multivariable-adjusted odds ratio of hypertension based on repeated measurements were 1.52 (95% confidence interval, 1.08–2.13) for DL-PCBs (third versus first tertile of lipid-standardized POPs). In stratified adjusted analyses, odds ratio for those born after 1950 increased to 3.99 (95% confidence interval, 2.15–7.43), whereas no association was observed among those born earlier. Based on repeated measurements, the accumulated exposure to DL-PCBs and DDE, although less clear for the latter, may disrupt the normal blood pressure levels and increase the odds of hypertension. Moreover, individuals experiencing early-life POP exposure may be at elevated risk of vascular POP effects.

High complication rates following colorectal surgery render many patients unable to fully regain functional capacity, thus seriously compromising quality of life. The aim of this study was to assess whether a 4-week trimodal prehabilitation program (exercise, nutritional supplementation, and counseling on relaxation techniques), implemented during the preoperative period, is sufficient to modify exercise behaviors and improve functional capacity of elderly patients scheduled for colorectal cancer surgery. Patients were assigned to either a prehabilitation (PREHAB; n = 57) or matched time control group (CTRL; n = 59). Over the 4-week period prior to surgery, patients in PREHAB participated in a trimodal prehabilitation program. Patients in CTRL received the same program but only postoperatively. The Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire was used to measure physical activity levels, while the 6-min walk test (6MWT) was used for assessment of functional walking capacity. Measurements were collected at baseline and at the time of surgery. Over the preoperative period, patients in PREHAB significantly increased the amount of moderate- and vigorous-intensity physical activities that they performed. PREHAB patients also demonstrated a greater improvement in 6MWT compared to CTRL. At the time of surgery, a greater proportion of patients in PREHAB met current physical activity guidelines, as compared to CTRL. These findings highlight the positive effects of a trimodal prehabilitation program on patients’ physical activity levels and functional walking capacity and demonstrate that modifying exercise behaviors and improving physical function within the 4-week preoperative period are an achievable goal.

Background: Poor functional capacity (FC) is an independent predictor of postoperative morbidity. However, there is still a lack of evidence as to whether enhancing FC before surgery has a protective effect on postoperative complications. The purpose of this study was to determine whether an improvement in preoperative FC impacted positively on surgical morbidity. Methods: This was a secondary analysis of a cohort of patients who underwent colorectal resection for cancer under Enhanced Recovery After Surgery care. FC was assessed with the 6-min walk test, which measures the distance walked in 6 min (6MWD), at 4 weeks before surgery and again the day before. The study population was classified into two groups depending on whether participants achieved a significant improvement in FC preoperatively (defined as a preoperative 6MWD change ≥19 meters) or not (6MWD change Results: A total of 179 eligible adults were studied: 80 (44.7%) improved in 6MWD by ≥19 m preoperatively, and 99 (55.3%) did not. Subjects whose FC increased had lower CCI (0 [0–8.7] versus 8.7 [0–22.6], p = .022). Furthermore, they were less likely to have a severe complication (adjusted OR 0.28 (95% CI 0.11–0.74), p = .010), and to have an ED visit. Conclusion: Improved preoperative FC was independently associated with a lower risk of severe postoperative complications. Further investigation is required to establish a causative relationship conclusively.

Aims This study aims to investigate the eligibility of the Prospective Comparison of Angiotensin Receptor–Neprilysin Inhibitor (ARNI) with ACE inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM‐HF) study to a real‐world heart failure population. Methods and results Medical records of all heart failure patients living within the catchment area of Umeå University Hospital were reviewed. This district consists of around 150 000 people. Out of 2029 patients with a diagnosis of heart failure, 1924 (95%) had at least one echocardiography performed, and 401 patients had an ejection fraction of ≤35% at their latest examination. The major PARADIGM‐HF criteria were applied, and 95 patients fulfilled all enrolment criteria and thus were eligible for sacubitril–valsartan. This corresponds to 5% of the overall heart failure population and 24% of the population with ejection fraction ≤ 35%. The eligible patients were significantly older (73.2 ± 10.3 vs. 63.8 ± 11.5 years), had higher blood pressure (128 ± 17 vs. 122 ± 15 mmHg), had higher heart rate (77 ± 17 vs. 72 ± 12 b.p.m.), and had more atrial fibrillation (51.6% vs. 36.2%) than did the PARADIGM‐HF population. Conclusions Only 24% of our real‐world heart failure and reduced ejection fraction population was eligible for sacubitril–valsartan, and the real‐world heart failure and reduced ejection fraction patients were significantly older than the PARADIGM‐HF population. The lack of data on a majority of the patients that we see in clinical practice is a real problem, and we are limited to extrapolation of results on a slightly different population. This is difficult to address, but perhaps registry‐based randomized clinical trials will help to solve this issue.

Recent prospective studies have shown that dysregulation of the immune system may precede the development of B‐cell lymphomas (BCL) in immunocompetent individuals. However, to date, the studies were restricted to a few immune markers, which were considered separately. Using a nested case–control study within two European prospective cohorts, we measured plasma levels of 28 immune markers in samples collected a median of 6 years before diagnosis (range 2.01–15.97) in 268 incident cases of BCL (including multiple myeloma [MM]) and matched controls. Linear mixed models and partial least square analyses were used to analyze the association between levels of immune marker and the incidence of BCL and its main histological subtypes and to investigate potential biomarkers predictive of the time to diagnosis. Linear mixed model analyses identified associations linking lower levels of fibroblast growth factor‐2 (FGF‐2 p = 7.2 × 10−4) and transforming growth factor alpha (TGF‐α, p = 6.5 × 10−5) and BCL incidence. Analyses stratified by histological subtypes identified inverse associations for MM subtype including FGF‐2 (p = 7.8 × 10−7), TGF‐α (p = 4.08 × 10−5), fractalkine (p = 1.12 × 10−3), monocyte chemotactic protein‐3 (p = 1.36 × 10−4), macrophage inflammatory protein 1‐alpha (p = 4.6 × 10−4) and vascular endothelial growth factor (p = 4.23 × 10−5). Our results also provided marginal support for already reported associations between chemokines and diffuse large BCL (DLBCL) and cytokines and chronic lymphocytic leukemia (CLL). Case‐only analyses showed that Granulocyte‐macrophage colony stimulating factor levels were consistently higher closer to diagnosis, which provides further evidence of its role in tumor progression. In conclusion, our study suggests a role of growth‐factors in the incidence of MM and of chemokine and cytokine regulation in DLBCL and CLL., What's new? B‐cell lymphomas (BCL) are frequent in immunocompromised individuals, but most BCL cases are thought to occur as a consequence of minor immune perturbations in otherwise immunocompetent individuals. Here the authors prospectively examined a panel of immune markers in the blood from 268 patients afflicted with BCL and paired controls. The data uncover a functional role for growth factors (i.e. FGF‐2, TGF‐alpha) in the incidence and progression of multiple myeloma, a BCL subtype, and underscore the importance of chemokine and cytokine regulation in diffuse large B‐cell lymphoma and chronic lymphocytic leukemia.

Numerous conceptual models of health literacy have been proposed in the literature, but very few have been empirically validated in clinical contexts. The aim of this study was to test the effects of the conceptual model of health literacy as a risk in a clinical dental context. A convenience sample of 133 Norwegian-speaking adults was recruited. Participants were randomly allocated to an intervention group (n = 64, 54% women, mean age = 50 years) and a control group (n = 69, 49% women, mean age = 46 years). Clinical measurements were conducted pre-intervention and six months post-intervention. In the intervention group, communication regarding patients&rsquo, oral health was tailored to their health literacy levels using recommended communication techniques, whereas the control group received brief information not tailored to health literacy levels. The ANCOVA showed significant between-group effects, finding reduced post-intervention mean gingival (p &lt, 0.000) and mean plaque (p &lt, 0.000) indices in the intervention group when controlling for baseline index scores. The adjusted Cohen&rsquo, s d indicated large effect sizes between the intervention group and the control group for both the mean gingival index (&minus, 0.98) and the mean plaque index (&minus, 1.33). In conclusion, the conceptual model of health literacy as a risk had a large effect on important clinical outcomes, such as gingival status and oral hygiene. The model may be regarded as a suitable supplement to patient education in populations.

Chronic inflammation may be involved in cancer development and progression. Using 28 inflammatory-related proteins collected from prospective blood samples from two case-control studies nested in the Italian component of the European Prospective Investigation into Cancer and nutrition (n = 261) and in the Northern Sweden Health and Disease Study (n = 402), we tested the hypothesis that an inflammatory score is associated with breast cancer (BC) and Β-cell Non-Hodgkin Lymphoma (B-cell NHL, including 68 multiple myeloma cases) onset. We modelled the relationship between this inflammatory score and the two cancers studied: (BC and B-cell NHL) using generalised linear models, and assessed, through adjustments the role of behaviours and lifestyle factors. Analyses were performed by cancer types pooling both populations, and stratified by cohorts, and time to diagnosis. Our results suggested a lower inflammatory score in B-cell NHL cases (β = −1.28, p = 0.012), and, to lesser, extent with BC (β = −0.96, p = 0.33) compared to controls, mainly driven by cancer cases diagnosed less than 6 years after enrolment. These associations were not affected by subsequent adjustments for potential intermediate confounders, notably behaviours. Sensitivity analyses indicated that our findings were not affected by the way the inflammatory score was calculated. These observations call for further studies involving larger populations, larger variety of cancer types and repeated measures of larger panel of inflammatory markers.

BackgroundObesity is an established risk factor for several common chronic diseases such as breast and colorectal cancer, metabolic and cardiovascular diseases; however, the biological basis for these relationships is not fully understood. To explore the association of obesity with these conditions, we investigated peripheral blood leucocyte (PBL) DNA methylation markers for adiposity and their contribution to risk of incident breast and colorectal cancer and myocardial infarction.MethodsDNA methylation profiles (Illumina Infinium® HumanMethylation450 BeadChip) from 1941 individuals from four population-based European cohorts were analysed in relation to body mass index, waist circumference, waist-hip and waist-height ratio within a meta-analytical framework. In a subset of these individuals, data on genome-wide gene expression level, biomarkers of glucose and lipid metabolism were also available. Validation of methylation markers associated with all adiposity measures was performed in 358 individuals. Finally, we investigated the association of obesity-related methylation marks with breast, colorectal cancer and myocardial infarction within relevant subsets of the discovery population.ResultsWe identified 40 CpG loci with methylation levels associated with at least one adiposity measure. Of these, one CpG locus (cg06500161) in ABCG1 was associated with all four adiposity measures (P = 9.07×10−8 to 3.27×10−18) and lower transcriptional activity of the full-length isoform of ABCG1 (P = 6.00×10−7), higher triglyceride levels (P = 5.37×10−9) and higher triglycerides-to-HDL cholesterol ratio (P = 1.03×10−10). Of the 40 informative and obesity-related CpG loci, two (in IL2RB and FGF18) were significantly associated with colorectal cancer (inversely, P P ConclusionOur results suggest that epigenetic changes, in particular altered DNA methylation patterns, may be an intermediate biomarker at the intersection of obesity and obesity-related diseases, and could offer clues as to underlying biological mechanisms.