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Abstract: Measurements for determining the activity of 89Sr and 90Sr in reactor coolant water are associated with limitations due to interferences from radionuclides with similar chemical properties and β−-energies. From a measurement bias point-of-view these interferences would result mainly in an overestimated activity concentration of 90Sr. In order to address the interference problem, a common and well-known method was used in order to show the need for sufficient decontamination. An improvement was achieved by taking the sample through two initial strontium separations in order to increase the decontamination factor. This method determines the activity concentration of 89Sr and 90Sr, via its daughter nuclide 90Y, by Cherenkov counting. This work is primarily based on theoretical calculations of strontium-, yttrium- and other potential interfering radionuclide ratios after instant fission. The work done to confirm the theoretical calculations were carried through on spiked strontium standard solutions and fresh reactor coolant water. The reactor coolant water was known to contain interferences at a composition resembling that of instant fission. The detection limit for double separation was calculated to 0.17Bq/kg for 90Sr and 0.38Bq/kg for 89Sr. When using methods that solely rely on strontium resins, this paper shows that the decontamination factor (DF) is significantly higher when using double separation than that of a single separation. The paper also shows that the DF of an initial double strontium separation is as effective when it comes to removing high ratio interferences as separations done with both Sr- and Ln-resin (EiChrom Technologies, Inc., 2003; Tovedal et al., 2009b). However, ‘old’ samples, where e.g. 140Ba and 89Sr has decayed, does not benefit from double separation. Furthermore, samples with low ratios of interfering radionuclides does not benefit from using this method either, seeing as this is a more time consuming method due to the double separations. [Copyright &y& Elsevier]

Abstract: Oxidative degradation is a well-known problem for UHMWPE used in prostheses. The aim of the present study has been to find suitable techniques to study the spatial distribution of this oxidation in 8 retrieved acetabular cups. The techniques used were visual examination using an optical microscope and computer scanner, FTIR mapping, imaging chemiluminescence, and staining with SO2 and HCl. The staining technique is based on a previous study which showed that by treating oxidized UHMWPE with SO2 followed by heat treatment, the hydroperoxides present in the sample react with the SO2 and discolor the sample. The intensity of this discoloring is, at low levels of oxidation, proportional to the amount of hydroperoxides and accordingly to the level of the oxidation. The same study also showed that staining a sample with hot HCl resulted in a brown discoloration which was proportional to the amount of carbonyls. It was found that the staining techniques do not give as much information about the chemical and physical changes in the material as FTIR mapping but have a great advantage in better spatial resolution of the oxidation and are also much quicker and easier to use. Imaging chemiluminescence turned out not to be a suitable method to use, compared to the other two, since it gives less information and is more difficult to interpret. When interpreting the results from the different techniques used, it was found that all cups showed the typical oxidation behavior of gamma sterilized UHMWPE. All cups but one showed substantial wear of the articulating surface but very little backside wear. Examination of the oxidation and whitening profile suggests that at least some of the oxidation must have occurred in vivo. [Copyright &y& Elsevier]

Objective: To investigate associations between physical activity and risk factors for cardiovascular disease (CVD), subclinical atherosclerosis, and disease activity in patients with early and long-standing rheumatoid arthritis (RA).Method: This cross-sectional study included 84 patients with early and 37 with long-standing RA (disease duration, mean ± sd: 1.4 ± 0.4 and 16.3 ± 2.3 years, respectively). Physical activity was measured using a combined accelerometer and heart-rate monitor. Further assessments were disease activity (erythrocyte sedimentation rate, Disease Activity Score in 28 joints), functional ability (Health Assessment Questionnaire), risk factors for CVD (blood lipids, i.e. triglycerides, high-density lipoprotein, low-density lipoprotein; blood glucose, blood pressure, sleeping heart rate, waist circumference, body mass index, and body fat), and subclinical atherosclerosis (pulse-wave velocity, augmentation index, and carotid intima-media thickness).Results: Physical activity variables did not differ between patients with early and long-standing RA. However, 37% of the patients with early and 43% of those with long-standing RA did not reach the World Health Organization's recommended levels of moderate to vigorous physical activity (MVPA). In a final multiple regression model, adjusted for age, gender, disease duration, and activity monitor wear time, higher total physical activity was associated with lower body fat and higher functional ability. With the same adjustments, more time spent in MVPA was associated with lower high-density lipoprotein and lower sleeping heart rate.Conclusions: Physical activity was associated with more favourable risk factors for CVD. However, many patients were physically inactive, stressing the importance of promoting physical activity in RA. [ABSTRACT FROM AUTHOR]

Objectives: With the emergence of targeted cell transplantation and gene therapy, there is a need for minimally invasive tissue access to facilitate delivery of therapeutic substrate. The objective of this study was to demonstrate the suitability of an endovascular device which is able to directly access tissue and deliver therapeutic agent to the heart, kidney and pancreas without need to seal the penetration site.Methods: In vivo experiments were performed in 30 swine, including subgroups with follow-up to evaluate complications. The previously described trans-vessel wall (VW) device was modified to be sharper and not require tip detachment to seal the VW. Injections into targets in the heart (n = 13, 24-h follow-up n = 5, 72-h follow-up n = 3), kidney (n = 8, 14-day follow-up n = 3) and pancreas (n = 5) were performed. Some animals were used for multiple organ injections. Follow-up consisted of clinical monitoring, angiography and necropsy. Transvenous (in heart) and transarterial approaches (in heart, kidney and pancreas) were used. Injections were targeted towards the subepicardium, endomyocardium, pancreas head and tail, and kidney subcapsular space and cortex.Results: Injections were successful in target organs, visualized by intraparenchymal contrast on fluoroscopy and by necropsy. No serious complications (defined as heart failure or persistent arrhythmia, haemorrhage requiring treatment or acute kidney injury) were encountered over a total of 157 injections.Conclusions: The trans-VW device can achieve superselective injections to the heart, pancreas and kidney for delivery of therapeutic substances without tip detachment. All parts of these organs including the subepicardium, pancreas tail and renal subcapsular space can be efficiently reached. [ABSTRACT FROM AUTHOR]

Introduction:Lobectomy is the standard curative treatment for non-small cell carcinoma (NSCLC) of the lung. Most studies on lobectomy have focused on short-term outcome and 30-day mortality. The aim of this study was to determine both short-term and long-term surgical outcome in all patients who underwent lobectomy for NSCLC in Iceland over a 24-year period. Material and methods:The study involved 489 consecutive patients with NSCLC who underwent lobectomy with curative intent in Iceland, 1991–2014. Patient demographics, pTNM stage, rate of perioperative complications, and 30-day mortality were registered. Overall survival was analyzed with the Kaplan?Meier method. The Cox proportional hazards model was used to evaluate factors that were prognostic of overall mortality. To study trends in survival, the study period was divided into six 4-year periods. The median follow-up time was 42 months and no patients were lost to follow-up. Results:The average age of the patients was 67 years and 53.8% were female. The pTNM disease stage was IA in 148 patients (30.0%), IB in 125 patients (25.4%), IIA in 96 patients (19.5%), and IIB in 50 patients (10.1%), but 74 (15.0%) were found to be stage IIIA, most often diagnosed perioperatively. The total rate of major complications was 4.7%. Thirty-day mortality was 0.6% (three patients). One- and 5-year overall survival was 85.0% and 49.2%, respectively, with 3-year survival improving from 48.3% to 72.8% between the periods 1991–1994 and 2011–2014 (p = .0004). Advanced TNM stage and age were independent negative prognostic factors for all-cause mortality, and later calendar year and free surgical margins were independent predictors of improved survival. Conclusions:The short-term outcome of lobectomy for NSCLC in this population-based study was excellent, as reflected in the low 30-day mortality and low rate of major complications. The long-term survival was acceptable and the overall 3-year survival had improved significantly during the study period. [ABSTRACT FROM PUBLISHER]

Gamma spectrometric measurements to determine the isotopic composition and total uranium mass in UO 2 pellets (D = 7.5 mm; H = 3.5 mm, ρ = 10 g/cm3) were carried out. The required efficiency curve was obtained by applying the efficiency transfer method from a calibration standard (D = 65 mm; H = 20 mm) of a slightly acidified water solution. The average isotopic composition of ten UO 2 pellets was consistent with values of natural uranium given by IUPAC. The average relative bias for the 235U/238U amount ratio was −0.73% using the 1001 keV gamma line for 238U and 0.50% using the 63 keV gamma line (186 keV was always used for 235U). For the total uranium mass, the mean deviation as compared to mass determinations using a balance was 5.5% using the 1001 keV gamma line for 238U and 4.3% using the 63 keV gamma line. • Uranium isotopic composition and mass were measured via activity measurements using a semi-empirical calibrated HPGe detector. • Both measurands were measured using either the 1001 keV or the 63 keV gamma lines for 238U. • Average bias of the 235U/238U ratio was less than 1%, and around 5% for the uranium mass. [ABSTRACT FROM AUTHOR]

The isotopic composition of uranium was measured using high resolution gamma spectrometry. Two acid solutions and two samples in the form of UO 2 pellets were measured. The measurements were done in close geometries, i.e. directly on the endcap of the high purity germanium detector (HPGe). Applying no corrections for count losses due to true coincidence summing (TCS) resulted in up to about 40% deviation in the abundance of 235 U from the results obtained with mass spectrometry. However, after correction for TCS, excellent agreement was achieved between the results obtained using two different measurement methods, or a certified value. Moreover, after corrections, the fitted relative response curves correlated excellently with simulated responses, for the different geometries, of the HPGe detector. [ABSTRACT FROM AUTHOR]

Nicotine addiction is one of the leading contributors to the global burden of disease, and early onset smokers report a more severe addiction with lower chance of cessation than those with a late onset. Preclinical research supports an age-dependent component to the rewarding and reinforcing properties of nicotine, and the aim of this study was to define behavioral adaptations and changes in accumbal neurotransmission that arise over 15 days of intermittent nicotine treatment (0.36 mg/kg/day) in rats of three different ages (5 weeks, 10 weeks, 36 weeks old). Repeated treatment increased the locomotor stimulatory response to nicotine in all age groups, but significantly faster in the two younger groups. In addition, nicotine decreased rearing activity in a way that sustained even after repeated administration in aged rats but not in the younger age groups. Electrophysiological field potential recordings revealed a decline in input/output function in the nucleus accumbens (NAc) of animals intermittently treated with nicotine starting at 5 weeks of age, but not in older animals. In drug naïve rats, acute administration of nicotine modulated both accumbal dopamine output and excitatory transmission in a partially age-dependent manner. Fifteen days of intermittent nicotine treatment did not alter the acute effect displayed by nicotine on dopamine levels or evoked field potentials. The data presented here show that both acute and repeated nicotine administration modulates accumbal neurotransmission and behavior in an age-contingent manner and that these age-dependent differences could reflect important neurobiological underpinnings associated with the increased vulnerability for nicotine-addiction in adolescents. [ABSTRACT FROM AUTHOR]

Abstract: Our aim was to compare udder health in groups of organically and conventionally managed cows, using data from a longitudinal study in a Swedish dairy-research farm. Management of the groups was identical except for feed composition and the feeding regimen. Our dataset included all lactating cows calving from 1 September 1990 to 31 August 2001 (145 organically and 151 conventionally managed cows). Udder health was assessed by the geometric average somatic-cell count (SCC) within 150 days after calving, by the number of monthly SCC tests >200,000cells/ml within 150 days after calving and by presence of lactations with veterinary-treated cases of clinical mastitis. The effect of animal group was analysed by multivariable linear, Poisson and logistic-regression models, controlling for factors such as lactation number, breed, year, season and milk yield. The groups did not differ in any measure of udder health. We had power to rule out differences of at least 33,000cells/ml in the geometric average somatic-cell count, an incidence rate ratio of 0.65 in the incidence of high-SCC milk-testing occasions, and an odds ratio of 0.43 in veterinary treated cases of mastitis. [Copyright &y& Elsevier]

A method for the measurement of the isotopic composition and time since last chemical separation (age) of plutonium is presented. The method includes alpha spectrometric measurement of 238Pu, 239Pu and 240Pu where the ratio of 239Pu and 240Pu was determined using spectral deconvolution, and liquid scintillation counting of 241Pu, after chemical separation of plutonium and americium. For the age determination, the 241Pu determined using liquid scintillation counting was combined with alpha spectrometric measurement of 241Am. The results of the isotopic composition were compared with certified reference materials with known isotopic composition, and the results of the age determination were compared with literature values of the separation dates. • Measurement of plutonium isotopic composition with alpha spectrometry and LSC. • Deconvolution of alpha peaks from 239Pu and 240Pu. • Age determination of plutonium using alpha spectrometry and LSC. [ABSTRACT FROM AUTHOR]

Discovery of cancer risk variants in the sequence of the germline genome can shed light on carcinogenesis. Here we describe gene burden association analyses, aggregating rare missense and loss of function variants, at 22 cancer sites, including 130,991 cancer cases and 733,486 controls from Iceland, Norway and the United Kingdom. We identified four genes associated with increased cancer risk; the pro-apoptotic BIK for prostate cancer, the autophagy involved ATG12 for colorectal cancer, TG for thyroid cancer and CMTR2 for both lung cancer and cutaneous melanoma. Further, we found genes with rare variants that associate with decreased risk of cancer; AURKB for any cancer, irrespective of site, and PPP1R15A for breast cancer, suggesting that inhibition of PPP1R15A may be a preventive strategy for breast cancer. Our findings pinpoint several new cancer risk genes and emphasize autophagy, apoptosis and cell stress response as a focus point for developing new therapeutics., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: Hydroxychloroquine (HCQ) exerts a large reduction of cardiovascular risk in patients with inflammatory diseases, but the mechanisms are not fully known. The aim of this study was to study potential mechanisms for this., Methods: This interventional study (EudraCT 2014-005418-45) in 30 patients (23 with rheumatoid arthritis, 7 with systemic lupus erythematosus) investigates the effects of HCQ on cardiovascular risk factors and arterial stiffness in patients with inflammatory disease. Blood lipids, blood pressure, blood glucose, glycated haemoglobin (HbA1c) and arterial stiffness was assessed at initiation, after four weeks of treatment and after eight weeks of treatment with 200 mg HCQ daily., Results: After four weeks of treatment with HCQ, total cholesterol had decreased from 5.4 mmol/L to 5.1 mmol/L (p<0.001), low-density lipoproteins from 3,0 mmol/L to 2.7 mmol/L (p<0.001) and apolipoprotein B from 0.96 g/L to 0.90 g/L (p<0.01). Those levels remained unchanged after eight weeks of treatment with HCQ. Levels of triglycerides, high-density lipoproteins and apolipoprotein A1 remained unchanged during the study. HbA1c decreased in most patients, especially in patients with high levels at start of HCQ, but increased HbA1c was seen in patients with low levels at start of treatment with HCQ. No significant effect was seen on blood pressure or any measure of arterial stiffness., Conclusion: This study does not identify the mechanisms of cardiovascular risk reduction from HCQ. Arterial stiffness is not affected by HCQ. The impact of HCQ on HbA1c and blood lipids is rapid, but of modest magnitude, and these effects do not fully explain the reduced risk of cardiovascular disease seen in observational studies. The mechanisms of cardiovascular risk reduction from HCQ are yet not completely known., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wahlin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The resemblance between fallopian tube cells and serous borderline ovarian tumors (BOTs) suggests a potential origin link, with salpingitis proposed as a contributing factor in the pathogenesis of BOT. This study aimed to explore the potential association between pelvic inflammatory disease (PID) and the risk of developing BOT. A national population-based case-control study in Sweden included women with BOT between 1999 and 2020 and 10 matched controls. Data from nationwide registers were analyzed using conditional logistic regression, adjusting for age, residential district, educational level and parity. Among 4782 cases and 45,167 controls, 2.0% of cases and 1.3% of controls had a history of PID. Previous PID was associated with an increased risk of BOT overall (aOR, 1.48; 95% CI, 1.19-1.85). Significant association was observed with serous tumors (aOR, 1.76; 95% CI, 1.36-2.29), while not with mucinous tumors (aOR, 0.95; 95% CI, 0.60-1.49). A dose-response relationship between number of PID episodes and serous BOT risk was noted (P trend  < .001). This study demonstrates that PID is associated with increased risk of serous BOT, with a dose response relationship. The study highlights the potential serious implications of upper reproductive tract infections and inflammation. This underscores the need for further investigation of biological mechanisms and possible impact of PID on serous BOT development., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Immunoglobulin G (IgG) is the main isotype of antibody in human blood. IgG consists of four subclasses (IgG1 to IgG4), encoded by separate constant region genes within the Ig heavy chain locus (IGH). Here, we report a genome-wide association study on blood IgG subclass levels. Across 4334 adults and 4571 individuals under 18 years, we discover ten new and identify four known variants at five loci influencing IgG subclass levels. These variants also affect the risk of asthma, autoimmune diseases, and blood traits. Seven variants map to the IGH locus, three to the Fcγ receptor (FCGR) locus, and two to the human leukocyte antigen (HLA) region, affecting the levels of all IgG subclasses. The most significant associations are observed between the G1m (f), G2m(n) and G3m(b*) allotypes, and IgG1, IgG2 and IgG3, respectively. Additionally, we describe selective associations with IgG4 at 16p11.2 (ITGAX) and 17q21.1 (IKZF3, ZPBP2, GSDMB, ORMDL3). Interestingly, the latter coincides with a highly pleiotropic signal where the allele associated with lower IgG4 levels protects against childhood asthma but predisposes to inflammatory bowel disease. Our results provide insight into the regulation of antibody-mediated immunity that can potentially be useful in the development of antibody based therapeutics., (© 2024. The Author(s).)

Objective: To investigate the time to first childbirth and to compare the prevalence of assisted reproductive treatment (ART) in women with congenital heart disease (CHD) compared with women without CHD., Methods: All women in the national register for CHD who had a registered first childbirth in the Swedish Pregnancy Register between 2014 and 2019 were identified. These individuals (cases) were matched by birth year and municipality to women without CHD (controls) in a 1:5 ratio. The time from the 18th birthday to the first childbirth and the prevalence of ART was compared between cases and controls., Results: 830 first childbirths in cases were identified and compared with 4137 controls. Cases were slightly older at the time for first childbirth (28.9 vs 28.5 years, p=0.04) and ART was more common (6.1% vs 4.0%, p<0.01) compared with controls. There were no differences in ART when stratifying for the complexity of CHD. For all women, higher age was associated with ART treatment (OR 1.24, 95% CI 1.20 to 1.28)., Conclusions: Women with and without CHD who gave birth to a first child did so at similar ages. ART was more common in women with CHD, but disease severity did not influence the need for ART. Age was an important risk factor for ART also in women with CHD and should be considered in consultations with these patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

A major hypothesis for the etiology of type 1 diabetes (T1D) postulates initiation by viral infection, leading to double-stranded RNA (dsRNA)-mediated interferon response and inflammation; however, a causal virus has not been identified. Here, we use a mouse model, corroborated with human islet data, to demonstrate that endogenous dsRNA in beta cells can lead to a diabetogenic immune response, thus identifying a virus-independent mechanism for T1D initiation. We found that disruption of the RNA editing enzyme adenosine deaminases acting on RNA (ADAR) in beta cells triggers a massive interferon response, islet inflammation, and beta cell failure and destruction, with features bearing striking similarity to early-stage human T1D. Glycolysis via calcium enhances the interferon response, suggesting an actionable vicious cycle of inflammation and increased beta cell workload., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Climate change driven increases in permafrost thaw and terrestrial runoff are expected to facilitate the mobilization and transport of mercury (Hg) from catchment soils to coastal areas in the Arctic, potentially increasing Hg exposure of marine food webs. The main aim of this study was to determine the impacts of seasonal riverine inputs on land-ocean Hg transport, zooplankton diet and Hg bioaccumulation in an Arctic estuary (Adventfjorden, Svalbard). The Adventelva River was a source of dissolved and particulate Hg to Adventfjorden, especially in June and July during the river's main discharge period. Stable isotope and fatty acid analyses suggest that zooplankton diet varied seasonally with diatoms dominating during the spring phytoplankton bloom in May and with increasing contributions of dinoflagellates in the summer months. In addition, there was evidence of increased terrestrial carbon utilization by zooplankton in June and July, when terrestrial particles contributed substantially to the particulate organic matter pool. Total (TotHg) and methyl Hg (MeHg) concentrations in zooplankton increased from April to August related to increased exposure to riverine inputs, and to shifts in zooplankton diet and community structure. Longer and warmer summer seasons will probably increase riverine runoff and thus Hg exposure to Arctic zooplankton., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Highly impaired individuals stand to benefit greatly from cutting-edge bionic technology, however concurrent functional deficits may complicate the adaptation of such technology. Here, we present a case in which a visually impaired individual with bilateral burn injury amputation was provided with a novel transradial neuromusculoskeletal prosthesis comprising skeletal attachment via osseointegration and implanted electrodes in nerves and muscles for control and sensory feedback. Difficulties maintaining implant hygiene and donning and doffing the prosthesis arose due to his contralateral amputation, ipsilateral eye loss, and contralateral impaired vision necessitating continuous adaptations to the electromechanical interface. Despite these setbacks, the participant still demonstrated improvements in functional outcomes and the ability to control the prosthesis in various limb positions using the implanted electrodes. Our results demonstrate the importance of a multidisciplinary, iterative, and patient-centered approach to making cutting-edge technology accessible to patients with high levels of impairment.

Background: Epithelial ovarian cancer is an insidious disease, and women are often diagnosed when the disease is beyond curative treatment. Accordingly, identifying modifiable risk factors is of paramount importance. Inflammation predisposes an individual to cancer in various organs, but whether pelvic inflammatory disease is associated with an increased risk of epithelial ovarian cancer has not been fully determined., Objective: This study aimed to investigate a possible association between clinically verified pelvic inflammatory disease and the risk of epithelial ovarian cancer., Study Design: In this national population-based case-control study, all women in Sweden diagnosed with epithelial ovarian cancer between 1999 and 2020 and 10 controls for each were identified, matched for age and residential district. Using several Swedish nationwide registers, data on previous pelvic inflammatory disease and potential confounding factors (age, parity, educational level, and previous gynecologic surgery) were retrieved. Adjusted odds ratios and 95% confidence intervals were estimated using conditional logistic regression. Histotype-specific analyses were performed for the subgroup of women diagnosed with epithelial ovarian cancer between 2015 and 2020. Moreover, hormonal contraceptives and menopausal hormone therapy were adjusted in addition to the aforementioned confounders., Results: This study included 15,072 women with epithelial ovarian cancer and 141,322 controls. Most women (9102 [60.4%]) had serous carcinoma. In a subgroup of cases diagnosed between 2015 and 2020, high-grade serous carcinoma (2319 [60.0%]) was identified. A total of 168 cases (1.1%) and 1270 controls (0.9%) were diagnosed with pelvic inflammatory disease. Previous pelvic inflammatory disease was associated with an increased risk of epithelial ovarian cancer (adjusted odds ratio, 1.39; 95% confidence interval, 1.17-1.66) and serous carcinoma (adjusted odds ratio, 1.46; 95% confidence interval, 1.18-1.80) for the entire study population. For the subgroup of women diagnosed in 2015-2020, pelvic inflammatory disease was associated with high-grade serous carcinoma (adjusted odds ratio, 1.43; 95% confidence interval, 1.01-2.04). The odds ratios of the other histotypes were as follows: endometrioid (adjusted odds ratio, 0.13; 95% confidence interval, 0.02-1.06), mucinous (adjusted odds ratio, 1.55; 95% confidence interval, 0.56-4.29), and clear cell carcinoma (adjusted odds ratio, 2.30; 95% confidence interval, 0.90-5.86). A dose-response relationship was observed between the number of pelvic inflammatory disease episodes and the risk of epithelial ovarian cancer (P trend <.001)., Conclusion: A history of pelvic inflammatory disease is associated with an increased risk of epithelial ovarian cancer and a dose-response relationship is evident. Histotype-specific analyses show an association with increased risk of serous epithelial ovarian cancer and high-grade serous carcinoma and potentially also with clear cell carcinoma, but there is no significant association with other histotypes. Infection and inflammation of the upper reproductive tract might have serious long-term consequences, including epithelial ovarian cancer., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Bronchial squamous carcinoma in situ (CIS) is a preinvasive lesion that is thought to precede invasive carcinoma. We conducted prospective autofluorescence and white light bronchoscopy trials between 1992 and 2016 to assess the prevalence, molecular markers, and outcome of individuals with CIS and other preneoplastic bronchial lesions. Biopsies were evaluated at multiple levels and selected biopsies were tested for aneuploidy and DNA sequenced for TP53 mutation. Thirty-one individuals with CIS were identified. Twenty-two cases of CIS occurred in association with concurrent invasive carcinomas. Seven of the invasive tumors were radiographically occult. In two cases, CIS spread from the focus of invasive carcinoma into contralateral lung lobes, forming secondary invasive tumors. In nine cases, CIS occurred as isolated lesions and one progressed to invasive squamous carcinoma at the same site 40 months after discovery. In a second case, CIS was a precursor of carcinoma at a separate site in a different lobe. In seven cases CIS regressed to a lower grade or disappeared. High level chromosomal aneusomy was often associated with TP53 mutation and with invasive carcinoma. CIS most often occurs in association with invasive squamous carcinoma and may extend along the airways into distant lobes. In rare cases, CIS may be observed to directly transform into invasive carcinoma. CIS may be indicative of invasive tumor at a separate distant site. Isolated CIS may regress. Molecular changes parallel histological changes in CIS and may be used to map clonal expansion in the airways., (© 2023 The Authors. APMIS published by John Wiley & Sons Ltd on behalf of Scandinavian Societies for Pathology, Medical Microbiology and Immunology.)

Non-typeable Haemophilus influenzae (NTHi) is a Gram-negative human pathogen that causes a wide range of airway diseases. NTHi has a plethora of mechanisms to colonize while evading the host immune system for the establishment of infection. We previously showed that the outer membrane protein P5 contributes to bacterial serum resistance by the recruitment of complement regulators. Here, we report a novel role of P5 in maintaining bacterial outer membrane (OM) integrity and protein composition important for NTHi-host interactions. In silico analysis revealed a peptidoglycan-binding motif at the periplasmic C-terminal domain (CTD) of P5. In a peptidoglycan-binding assay, the CTD of P5 (P5 CTD ) formed a complex with peptidoglycan. Protein profiling analysis revealed that deletion of CTD or the entire P5 changed the membrane protein composition of the strains NTHi 3655Δ p5 CTD and NTHi 3655 Δp5 , respectively. Relative abundance of several membrane-associated virulence factors that are crucial for adherence to the airway mucosa, and serum resistance were altered. This was also supported by similar attenuated pathogenic phenotypes observed in both NTHi 3655Δ p5 CTD and NTHi 3655Δ p5 . We found (i) a decreased adherence to airway epithelial cells and fibronectin, (ii) increased complement-mediated killing, and (iii) increased sensitivity to the β-lactam antibiotics in both mutants compared to NTHi 3655 wild-type. These mutants were also more sensitive to lysis at hyperosmotic conditions and hypervesiculated compared to the parent wild-type bacteria. In conclusion, our results suggest that P5 is important for bacterial OM stability, which ultimately affects the membrane proteome and NTHi pathogenesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Su, Kadari, Straw, Janoušková, Jonsson, Thofte, Jalalvand, Matuschek, Sandblad, Végvári, Zubarev and Riesbeck.)

Concern about residential long-term care quality and safety is a critical issue in developed countries internationally, often fueled by media scandals exposing riveting accounts of resident-to-resident aggression/responsive behaviours. These scandals raise questions about standards of care set through long-term care regulation. Using a participatory action research approach and document analysis method, we analyzed incidents related to responsive behaviours documented in three types of public version inspection reports posted for 535 Ontario, Canada long-term care homes from 2016 through 2018. Creation of an Individual Home Data Collection and Analysis Tool facilitated data collation and descriptive statistical analysis of seven long-term care service areas in the province of Ontario. Results highlight several combined service areas differences between for-profit and not-for-profit home documentation related to responsive behaviours in (a) resident quality inspection means; (b) total complaint and critical incident proportions and means; (c) total enforcement actions proportions; and (d) enforcement penalties. We discovered that documented evidence of incidents related to responsive behaviours was instead represented by other sections of the legislation. The highest proportion of enforcement actions related to responsive behaviours involved no follow-up by inspectors and only four enforcement penalties over three years. Recommendations include revision of the inspection report judgement matrix tool to produce separate enforcement actions specific to responsive behaviours. We submit that attending to this will contribute to protecting long-term care residents from harm and improving their quality of care through more effective connection of long-term care regulation to responsive behaviour care management., Competing Interests: Conflicts of InterestThe authors declare they have no conflicts of interest., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Wetland area in agricultural landscapes has been heavily reduced to gain land for crop production, but in recent years there is increased societal recognition of the negative consequences from wetland loss on nutrient retention, biodiversity and a range of other benefits to humans. The current trend is therefore to re-establish wetlands, often with an aim to achieve the simultaneous delivery of multiple ecosystem services, i.e., multifunctionality. Here we review the literature on key objectives used to motivate wetland re-establishment in temperate agricultural landscapes (provision of flow regulation, nutrient retention, climate mitigation, biodiversity conservation and cultural ecosystem services), and their relationships to environmental properties, in order to identify potential for tradeoffs and synergies concerning the development of multifunctional wetlands. Through this process, we find that there is a need for a change in scale from a focus on single wetlands to wetlandscapes (multiple neighboring wetlands including their catchments and surrounding landscape features) if multiple societal and environmental goals are to be achieved. Finally, we discuss the key factors to be considered when planning for re-establishment of wetlands that can support achievement of a wide range of objectives at the landscape scale., Competing Interests: Declaration of competing interest There are no financial or personal interests affecting the contents of this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene-drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed., Methods: We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK). Patients aged 18 years or older receiving a first prescription for a drug clinically recommended in the guidelines of the Dutch Pharmacogenetics Working Group (ie, the index drug) as part of routine care were eligible for inclusion. Exclusion criteria included previous genetic testing for a gene relevant to the index drug, a planned duration of treatment of less than 7 consecutive days, and severe renal or liver insufficiency. All patients gave written informed consent before taking part in the study. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant (ie, a drug-gene interaction test result for which the Dutch Pharmacogenetics Working Group [DPWG] recommended a change to standard-of-care drug treatment) were treated according to DPWG recommendations. Patients in the control group received standard treatment. To prepare clinicians for pre-emptive pharmacogenetic testing, local teams were educated during a site-initiation visit and online educational material was made available. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were irrespective of patient adherence to the DPWG guidelines. The primary analysis was done using a gatekeeping analysis, in which outcomes in people with an actionable drug-gene interaction in the study group versus the control group were compared, and only if the difference was statistically significant was an analysis done that included all of the patients in the study. Outcomes were compared between the study and control groups, both for patients with an actionable drug-gene interaction test result (ie, a result for which the DPWG recommended a change to standard-of-care drug treatment) and for all patients who received at least one dose of index drug. The safety analysis included all participants who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03093818 and is closed to new participants., Findings: Between March 7, 2017, and June 30, 2020, 41 696 patients were assessed for eligibility and 6944 (51·4 % female, 48·6% male; 97·7% self-reported European, Mediterranean, or Middle Eastern ethnicity) were enrolled and assigned to receive genotype-guided drug treatment (n=3342) or standard care (n=3602). 99 patients (52 [1·6%] of the study group and 47 [1·3%] of the control group) withdrew consent after group assignment. 652 participants (367 [11·0%] in the study group and 285 [7·9%] in the control group) were lost to follow-up. In patients with an actionable test result for the index drug (n=1558), a clinically relevant adverse drug reaction occurred in 152 (21·0%) of 725 patients in the study group and 231 (27·7%) of 833 patients in the control group (odds ratio [OR] 0·70 [95% CI 0·54-0·91]; p=0·0075), whereas for all patients, the incidence was 628 (21·5%) of 2923 patients in the study group and 934 (28·6%) of 3270 patients in the control group (OR 0·70 [95% CI 0·61-0·79]; p <0·0001)., Interpretation: Genotype-guided treatment using a 12-gene pharmacogenetic panel significantly reduced the incidence of clinically relevant adverse drug reactions and was feasible across diverse European health-care system organisations and settings. Large-scale implementation could help to make drug therapy increasingly safe., Funding: European Union Horizon 2020., Competing Interests: Declaration of interests MP received partnership funding from the UK Medical Research Council (MRC) Clinical Pharmacology Training Scheme (cofunded by MRC, Roche, Union Chimique Belge [UCB] Pharma, Eli Lilly, and Novartis); a PhD studentship jointly funded by the UK Engineering and Physical Sciences Research Council and AstraZeneca; unrestricted educational grant support for the UK Pharmacogenetics and Stratified Medicine Network from Bristol Myers Squibb; and human leucocyte antigen genotyping panel with MC Diagnostics but does not benefit financially from this, outside of the submitted work. JCS received speaker honoraria from Novartis for lectures on CYP2C9 pharmacogenetics and siponimod metabolism, outside of the submitted work. MS was partly supported by the Robert Bosch Stiftung and German Research Foundation (DFG) under Germany's Excellence Strategy (EXC 2180—390900677); and outside of the submitted work received support from Green Cross WellBeing, Gilead Sciences, Robert Bosch, CORAT Therapeutics, and Agena Bioscience. ES was partly supported by the Robert Bosch Stiftung and the German Research Foundation (DFG) under Germany's Excellence Strategy (EXC 2180—390900677). RT was partly supported by the Robert Bosch Stiftung. MK received research funding from Bayer and Roche, educational grants from Novartis and Servier, and consultancy fees from Pharmetheus, outside of the submitted work. SJ received consultancy fees from Pharmetheus, outside of the submitted work. All other authors declare no competing interests., (Crown Copyright © 2023 Published by Elsevier Ltd. All rights reserved.)

Anthropogenic mercury (Hg) undergoes long-range transport to the Arctic where some of it is transformed into methylmercury (MeHg), potentially leading to high exposure in some Arctic inhabitants and wildlife. The environmental exposure of Hg is determined not just by the amount of Hg entering the Arctic, but also by biogeochemical and ecological processes occurring in the Arctic. These processes affect MeHg uptake in biota by regulating the bioavailability, methylation and demethylation, bioaccumulation and biomagnification of MeHg in Arctic ecosystems. Here, we present a new budget for pools and fluxes of MeHg in the Arctic and review the scientific advances made in the last decade on processes leading to environmental exposure to Hg. Methylation and demethylation are key processes controlling the pool of MeHg available for bioaccumulation. Methylation of Hg occurs in diverse Arctic environments including permafrost, sediments and the ocean water column, and is primarily a process carried out by microorganisms. While microorganisms carrying the hgcAB gene pair (responsible for Hg methylation) have been identified in Arctic soils and thawing permafrost, the formation pathway of MeHg in oxic marine waters remains less clear. Hotspots for methylation of Hg in terrestrial environments include thermokarst wetlands, ponds and lakes. The shallow sub-surface enrichment of MeHg in the Arctic Ocean, in comparison to other marine systems, is a possible explanation for high MeHg concentrations in some Arctic biota. Bioconcentration of aqueous MeHg in bacteria and algae is a critical step in the transfer of Hg to top predators, which may be dampened or enhanced by the presence of organic matter. Variable trophic position has an important influence on MeHg concentrations among populations of top predator species such as ringed seal and polar bears distributed across the circumpolar Arctic. These scientific advances highlight key processes that affect the fate of anthropogenic Hg deposited to Arctic environments., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sofi Jonsson reports financial support was provided by the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (2020-01868). Sofi Jonsson reports financial support was provided by the Swedish Research Council (2017-05275). John Chetelat reports was provided by Environment and Climate Change Canada. Lars-Eric Heimburger-Boavida reports was provided by the AXA Research Fund. Lars-Eric Heimburger-Boavida reports was provided by Chantier Arctique Francais (Pollution in the Arctic System)., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The human pathogen Haemophilus influenzae causes respiratory tract infections and is commonly associated with prolonged carriage in patients with chronic obstructive pulmonary disease. Production of outer membrane vesicles (OMVs) is a ubiquitous phenomenon observed in Gram-negative bacteria including H. influenzae . OMVs play an important role in various interactions with the human host; from neutralization of antibodies and complement activation to spread of antimicrobial resistance. Upon vesiculation certain proteins are found in OMVs and some proteins are retained at the cell membrane. The mechanism for this phenomenon is not fully elucidated. We employed mass spectrometry to study vesiculation and the fate of proteins in the outer membrane. Functional groups of proteins were differentially distributed on the cell surface and in OMVs. Despite its supposedly periplasmic and outer membrane location, we found that the peptidoglycan synthase-activator Lipoprotein A (LpoA) was accumulated in OMVs relative to membrane fractions. A mutant devoid of LpoA lost its fitness as revealed by growth and electron microscopy. Furthermore, high-pressure liquid chromatography disclosed a lower concentration (55%) of peptidoglycan in the LpoA-deficient H. influenzae compared to the parent wild type bacterium. Using an LpoA-mNeonGreen fusion protein and fluorescence microscopy, we observed that LpoA was enriched in "foci" in the cell envelope, and further located in the septum during cell division. To define the fate of LpoA, C-terminally truncated LpoA-variants were constructed, and we found that the LpoA C-terminal domain promoted optimal transportation to the OMVs as revealed by flow cytometry. Taken together, our study highlights the importance of LpoA for H. influenzae peptidoglycan biogenesis and provides novel insights into cell wall integrity and OMV production., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jalalvand, Su, Manat, Chernobrovkin, Kadari, Jonsson, Janousková, Rutishauser, Semsey, Løbner-Olesen, Sandblad, Flärdh, Mengin-Lecreulx, Zubarev and Riesbeck.)

Retention of logging residue as dead wood could be a method to simultaneously increase biodiversity and predation rates of pest insects, in managed forests. Managed forests are generally low in diversity, and dead wood has been demonstrated to increase species diversity. Moreover, managed forests are predicted to suffer from higher frequency of insect outbreaks in the future, particularly in the northern hemisphere. In this study, we explore the effect of dead wood removal and addition in managed pine forest stands in Sweden on arthropod diversity and abundance and predation rates. We performed a controlled field experiment, focusing on logging residue type of dead wood. We used pitfall traps and sticky traps to measure arthropod diversity and abundance and plasticine larvae to assess predation rates. We specifically targeted generalist arthropods (i.e. non-wood living species), and predation rate on tree-dwelling larvae (corresponding to defoliating outbreak pests). We found no effect of dead wood addition on arthropod abundance or diversity, neither did we find an effect on predation rate. Despite the lack of effects in our study, we argue that dead wood can be an important component for both biodiversity of generalist arthropod and for pest control, but the effect may depend on both the specific arthropod group targeted and the specific life stage of the pest insect as well as on inherent components of the dead wood, such as age., Competing Interests: The authors have declared that no competing interests exist.

Increasing terrestrial run-off from melting glaciers and thawing permafrost to Arctic coastal areas is expected to facilitate re-mobilization of stored legacy persistent organic pollutants (POPs) and mercury (Hg), potentially increasing exposure to these contaminants for coastal benthic organisms. We quantified chlorinated POPs and Hg concentrations, lipid content and multiple dietary markers, in a littoral deposit-feeding amphipod Gammarus setosus and sediments during the melting period from April to August in Adventelva river estuary in Svalbard, a Norwegian Arctic Aarchipelago. There was an overall decrease in concentrations of ∑POPs from April to August (from 58 ± 23 to 13 ± 4 ng/g lipid weight; lw), Hg (from 5.6 ± 0.7 to 4.1 ± 0.5 ng/g dry weight; dw) and Methyl Hg (MeHg) (from 5 ± 1 to 0.8 ± 0.7 ng/g dw) in G. setosus. However, we observed a seasonal peak in penta- and hexachlorobenzene (PeCB and HCB) in May (2.44 ± 0.3 and 23.6 ± 1.7 ng/g lw). Sediment concentrations of POPs and Hg (dw) only partly correlated with the contaminant concentrations in G. setosus. Dietary markers, including fatty acids and carbon and nitrogen stable isotopes, indicated a diet of settled phytoplankton in May-July and a broader range of carbon sources after the spring bloom. Phytoplankton utilization and chlorobenzene concentrations in G. setosus exhibited similar seasonal patterns, suggesting a dietary uptake of chlorobenzenes that is delivered to the aquatic environment during spring snowmelt. The seasonal decrease in contaminant concentrations in G. setosus could be related to seasonal changes in dietary contaminant exposure and amphipod ecology. Furthermore, this decrease implies that terrestrial run-off is not a significant source of re-mobilized Hg and legacy POPs to littoral amphipods in the Adventelva river estuary during the melt season., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Sediments represent the main reservoir of mercury (Hg) in aquatic environments and may act as a source of Hg to aquatic food webs. Yet, accumulation routes of Hg from the sediment to benthic organisms are poorly constrained. We studied the bioaccumulation of inorganic and methylmercury (Hg II and MeHg, respectively) from different geochemical pools of Hg into four groups of benthic invertebrates (amphipods, polychaetes, chironomids, and bivalves). The study was conducted using mesocosm experiments entailing the use of multiple isotopically enriched Hg tracers and simulation of estuarine systems with brackish water and sediment. We applied different loading regimes of nutrients and terrestrial organic matter and showed that the vertical localization and the chemical speciation of Hg II and MeHg in the sediment, in combination with the diet composition of the invertebrates, consistently controlled the bioaccumulation of Hg II and MeHg into the benthic organisms. Our results suggest a direct link between the concentration of MeHg in the pelagic planktonic food web and the concentration of MeHg in benthic amphipods and, to some extent, in bivalves. In contrast, the quantity of MeHg in benthic chironomids and polychaetes seems to be driven by MeHg accumulation via the benthic food web. Accounting for these geochemical and dietary drivers of Hg bioaccumulation in benthic invertebrates will be important to understand and predict Hg transfer between the benthic and the pelagic food web, under current and future environmental scenarios.

Photochemical demethylation of dimethylmercury (DMHg) could potentially be an important source of monomethylmercury (MMHg) in sunlit water. Whether or not DMHg is photochemically degraded when dissolved in water is, however, debated. While an early study suggested DMHg dissolved in natural waters to readily degrade, later work claimed DMHg to be stable in seawater under natural sunlight and that early observations may be due to experimental artifacts. Here, we present experimental data showing that DMHg is readily degraded by photochemical processes in different natural waters (including water from a DOC-rich stream, the Baltic Sea, and the Arctic Ocean) as well as in artificial seawater and purified water. For most of the waters, the degradation rate constant ( k d ) for DMHg measured in indoor experiments exceeded, or was close to, the k d observed for MMHg. Outdoor incubations of DMHg in purified water and Arctic Ocean surface water further confirmed that DMHg is photochemically degraded under natural sunlight. Our study shows that DMHg is photochemically degraded in a range of natural waters and that this process may be a source of MMHg in sunlit waters where the supply or formation of DMHg is sufficient.

Lung cancer is the second and third most common cancer in Iceland for females and males, respectively. Although the incidence is declining, lung cancer still has the highest mortality of all cancers in Iceland. Symptoms of lung cancer can be specific and localized to the lungs, but more commonly they are unspecific and result in significant diagnostic delay. Therefore, majority of lung cancer patients are diagnosed with non-localized disease. In recent years, major developments have been made in the diagnosis and treatment of lung cancer. Positive emission scanning (PET) and both transbroncial (EBUS) or transesophageal ultrasound (EUS) biopsy techniques have resulted in improved mediastinal staging of the disease and minimal invasive video-assisted thoracic surgery (VATS) has lowered postoperative complications and shortened hospital stay. Technical developments in radiotherapy have benefitted those patients who are not candidates for curative surgery. Finally, and most importantly, recent advances in targeted chemotherapeutics and development of immunomodulating agents have made individual tailoring of treatment possible. Recent screening-trials with low-dose computed tomography show promising results in lowering mortality. This evidence-based review focuses on the most important developments in the diagnosis and treatment of lung cancer, and includes Icelandic studies in the field.

Purpose: The aim of this study was to assess the role of the patient's background and perceived healthcare-related factors in symptoms of acute stress after lung cancer diagnosis., Methods: The study population consisted of 89 individuals referred for diagnostic work-up at Landspitali National University Hospital in Iceland and subsequently diagnosed with lung cancer. Before diagnosis, the patients completed questionnaires on sociodemographic characteristics, pre-diagnostic distress (Hospital Anxiety and Depression Scale), social support, and resilience. At a median of 16 days after diagnosis, the patients reported symptoms of acute stress on the Impact of Event Scale-Revised (IES-R) and experience of communication and support from healthcare professionals and family during the diagnostic period., Results: Patients were on average 68 years and 52% reported high levels of post-diagnostic acute stress (IES-R > 23) while 24% reported symptoms suggestive of clinical significance (IES-R > 32). Prior history of cancer (β = 6.7, 95% CI: 0.1 to 13.3) and pre-diagnostic distress were associated with higher levels of post-diagnostic acute stress (β = 8.8, 95% CI: 2.7 to 14.9), while high educational level (β = - 7.9, 95% CI: - 14.8 to - 1.1) was associated with lower levels. Controlling for the abovementioned factors, the patients' perception of optimal doctor-patient (β = - 9.1, 95% CI: - 14.9 to - 3.3) and family communication (β = - 8.6, 95% CI: - 14.3 to - 2.9) was inversely associated with levels of post-diagnostic acute stress after lung cancer diagnosis., Conclusions: A high proportion of patients with newly diagnosed lung cancer experience high levels of acute traumatic stress of potential clinical significance. Efforts to improve doctor-patient and family communication may mitigate the risk of these adverse symptoms., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Patients with rheumatoid arthritis (RA) have an accelerated progression of atherosclerosis. The aim of this study was to examine the associations between subclinical atherosclerosis, assessed by intima-media thickness (IMT), and regulators of bone formation, markers of bone turnover and bone mineral density (BMD) in patients with RA., Methods: Patients with new-onset RA (n=79), aged ≤60 years at diagnosis, were consecutively included in a study of development of atherosclerosis. Ultrasound measurement of IMT of the common carotid artery was undertaken at inclusion (T0) and after 11 years (T11) (n=54). Bone turnover biomarkers were examined in samples collected at T0 and T11. BMD was assessed at T11., Results: In patients with RA, osteocalcin (OCN) and osteoprotegerin (OPG) measured at T11 were significantly associated with IMT at T11, adjusted for systolic blood pressure (SBP) and age. BMD at T11 and the bone turnover markers procollagen type 1 N-terminal propeptide (P1NP) and carboxy-terminal crosslinked C-terminal telopeptide (CTX) were not associated with IMT. OPG, OCN and sclerostin at T0 were significantly associated with IMT at T11, and OPG and OCN at T0 were associated with change in IMT from T0 to T11. The associations between IMT and bone biomarkers were stronger in patients with joint erosions at onset of RA, than in patients with non-erosive disease., Conclusions: Atherosclerosis in patients with RA is associated with OPG and OCN, but not with BMD or markers reflecting ongoing bone turnover, indicating that atherosclerosis is not associated with bone turnover per se.

Thousands of dams are currently under construction or planned worldwide to meet the growing need for electricity. The creation of reservoirs could, however, lead to conditions that promote the accumulation of mercury (Hg) in surface sediments and the subsequent production of methylmercury (MeHg). Once produced, MeHg can bioaccumulate to harmful levels in organisms. It is unclear to what extent variations in physical features and biogeochemical factors of the reservoir impact Hg accumulation. The objective of this study was to identify key drivers of the accumulation of total Hg (THg) in tropical reservoir sediments. The concentration of THg in all analyzed depth intervals of 22 sediment cores from the five contrasting reservoirs investigated ranged from 16 to 310 ng g -1 ( n = 212, in the different sediment cores, the maximum depth varied from 18 to 96 cm). Our study suggests reservoir size to be an important parameter determining the concentration of THg accumulating in tropical reservoir sediments, with THg ranging up to 50 ng g -1 in reservoirs with an area exceeding 400 km 2 and from 100 to 200 ng g -1 in reservoirs with an area less than 80 km 2 . In addition to the reservoir size, the role of land use, nutrient loading, biome and sediment properties ( e.g. , organic carbon content) was tested as potential drivers of THg levels. The principal component analysis conducted suggested THg to be related to the properties of the watershed (high degree of forest cover and low degree of agricultural land use), size and age of the reservoir, water residence time and the levels of nutrients in the reservoir. A direct correlation between THg and tested variables was, however, only observed with the area of the reservoir.

Nontypeable Haemophilus influenzae (NTHi) is a Gram-negative human pathogen that causes infections mainly in the upper and lower respiratory tract. The bacterium is associated with bronchitis and exacerbations in patients suffering from chronic obstructive pulmonary disease and frequently causes acute otitis media in preschool children. We have previously demonstrated that the binding of C4b binding protein (C4BP) is important for NTHi complement evasion. In this study, we identified outer membrane protein 5 (P5) of NTHi as a novel ligand of C4BP. Importantly, we observed significantly lower C4BP binding and decreased serum resistance in P5-deficient NTHi mutants. Surface expression of recombinant P5 on Escherichia coli conferred C4BP binding and consequently increased serum resistance. Moreover, P5 expression was positively correlated with C4BP binding in a series of clinical isolates. We revealed higher levels of P5 surface expression and consequently more C4BP binding in isolates from the lower respiratory tract of chronic obstructive pulmonary disease patients and tonsil specimens compared with isolates from the upper respiratory tract and the bloodstream (invasive strains). Our results highlight P5 as an important protein for protecting NTHi against complement-mediated killing., (Copyright © 2021 The Authors.)

Screening for severe combined immunodeficiency (SCID) was introduced into the Swedish newborn screening program in August 2019 and here we report the results of the first year. T cell receptor excision circles (TRECs), kappa-deleting element excision circles (KRECs), and actin beta (ACTB) levels were quantitated by multiplex qPCR from dried blood spots (DBS) of 115,786 newborns and children up to two years of age, as an approximation of the number of recently formed T and B cells and sample quality, respectively. Based on low TREC levels, 73 children were referred for clinical assessment which led to the diagnosis of T cell lymphopenia in 21 children. Of these, three were diagnosed with SCID. The screening performance for SCID as the outcome was sensitivity 100%, specificity 99.94%, positive predictive value (PPV) 4.11%, and negative predictive value (NPV) 100%. For the outcome T cell lymphopenia, PPV was 28.77%, and specificity was 99.95%. Based on the first year of screening, the incidence of SCID in the Swedish population was estimated to be 1:38,500 newborns.

Mercury (Hg) pollution is a global environmental problem. The abiotic formation of dimethylmercury (DMeHg) from monomethylmercury (MMeHg) may account for a large portion of DMeHg in oceans. Previous experimental work has shown that abiotic formation of DMeHg from MMeHg can be facilitated by reduced sulfur groups on sulfide mineral surfaces. In that work, a mechanism was proposed in which neighboring MMeHg moieties bound to sulfide sites on a mineral surface react through an S N 2-type mechanism to form DMeHg and incorporate the remaining Hg atoms into the mineral surface. Here, we perform density functional theory calculations to explore the mechanisms of DMeHg formation on the 110 surface of a CdS(s) (hawleyite) nanoparticle. We show that coordination of MMeHg substituents to adjacent reduced sulfur groups protruding from the surface indeed facilitates DMeHg formation and that the reaction proceeds through direct transmethylation from one MMeHg substituent to another. Coordination of Hg by multiple S atoms provides a transition-state stabilization and activates a C-Hg bond for methyl transfer. In addition, solvation effects play an important role in the surface reconstruction of the nanoparticle and in decreasing the energetic barrier for DMeHg formation relative to the corresponding reaction in vacuo.

Aims: The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development., Methods and Results: We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1-1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10-20), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05)., Conclusion: We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Methylmercury (MeHg) forms in anoxic environments and can bioaccumulate and biomagnify in aquatic food webs to concentrations of concern for human and wildlife health. Mercury (Hg) pollution in the Arctic environment may worsen as these areas warm and Hg, currently locked in permafrost soils, is remobilized. One of the main concerns is the development of Hg methylation hotspots in the terrestrial environment due to thermokarst formation. The extent to which net methylation of Hg is enhanced upon thaw is, however, largely unknown. Here, we have studied the formation of Hg methylation hotspots using existing thaw gradients at five Fennoscandian permafrost peatland sites. Total Hg (HgT) and MeHg concentrations were analyzed in 178 soil samples from 14 peat cores. We observed 10 times higher concentrations of MeHg and 13 times higher %MeHg in the collapse fen (representing thawed conditions) as compared to the peat plateau (representing frozen conditions). This suggests significantly greater net methylation of Hg when thermokarst wetlands are formed. In addition, we report HgT to soil organic carbon ratios representative of Fennoscandian permafrost peatlands (median and interquartile range of 0.09 ± 0.07 μg HgT g -1 C) that are of value for future estimates of circumpolar HgT stocks.