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The use of relative abundance data from next generation sequencing (NGS) can lead to misinterpretations of microbial community structures, as the increase of one taxon leads to the concurrent decrease of the other(s) in compositional data. Although different DNA- and cell-based methods as well as statistical approaches have been developed to overcome the compositionality problem, and the biological relevance of absolute bacterial abundances has been demonstrated, the human microbiome research has not yet adopted these methods, likely due to feasibility issues. Here, we describe how quantitative PCR (qPCR) done in parallel to NGS library preparation provides an accurate estimation of absolute taxon abundances from NGS data and hence provides an attainable solution to compositionality in high-throughput microbiome analyses. The advantages and potential challenges of the method are also discussed.

Publisher Copyright: © 1964-2012 IEEE. Joint tissue mechanics (e.g., stress and strain) are believed to have a major involvement in the onset and progression of musculoskeletal disorders, e.g., knee osteoarthritis (KOA). Accordingly, considerable efforts have been made to develop musculoskeletal finite element (MS-FE) models to estimate highly detailed tissue mechanics that predict cartilage degeneration. However, creating such models is time-consuming and requires advanced expertise. This limits these complex, yet promising, MS-FE models to research applications with few participants and makes the models impractical for clinical assessments. Also, these previously developed MS-FE models have not been used to assess activities other than gait. This study introduces and verifies a semi-automated rapid state-of-the-art MS-FE modeling and simulation toolbox incorporating an electromyography- (EMG) assisted MS model and a muscle-force driven FE model of the knee with fibril-reinforced poro(visco)elastic cartilages and menisci. To showcase the usability of the pipeline, we estimated joint- and tissue-level knee mechanics in 15 KOA individuals performing different daily activities. The pipeline was verified by comparing the estimated muscle activations and joint mechanics to existing experimental data. To determine the importance of the EMG-assisted MS analysis approach, results were compared to those from the same FE models but driven by static-optimization-based MS models. The EMG-assisted MS-FE pipeline bore a closer resemblance to experiments compared to the static-optimization-based MS-FE pipeline. Importantly, the developed pipeline showed great potential as a rapid MS-FE analysis toolbox to investigate multiscale knee mechanics during different activities of individuals with KOA.

Background Knowledge of the adverse effects of drugs with anticholinergic properties (DAPs) has increased in recent decades. However, research on the temporal trends of the clinical use of DAPs is still sparse. Objectives The aim of this study was to investigate the temporal trends of DAP use over two decades in the older community-dwelling population and to explore the medication classes contributing to the use of DAPs. Methods The study involved random samples of >= 75-year-old community-dwelling Helsinki citizens in 1999, 2009, and 2019 from the Helsinki Ageing Study. A postal questionnaire inquired about their health, functioning, and medications. The medications were categorized as DAPs according to Duran's list. In addition, we grouped DAPs into various medication groups. Results The prevalence and burden of DAPs on Duran's list showed a decreasing trend over the years. In 1999 the prevalence was 20% and the burden 0.35, in 2009 they were 22% and 0.35, respectively, and in 2019 they were 16% and 0.23, respectively. There were no differences in how the 75- and 80-year-olds used DAPs compared with those aged 85 years and older. The proportion of typical antipsychotics, benzodiazepines, hypnotics, urinary antispasmodics, and asthma/chronic obstructive pulmonary disease medications decreased, whereas the proportion of atypical antipsychotics, antidepressants, strong opioids, and antihistamines increased. In particular the use of mirtazapine increased-to 3.9% in 2019. In 2019 the three most prevalent groups of DAPs were antidepressants (7.4%), opioids (2.7%), and antihistamines (2.4%). Conclusions The decrease in the use of DAPs on Duran's list is a welcome change. Although the use of old, strong DAPs has decreased, new DAPs have simultaneously emerged. Physicians need continuous education in prescribing DAPs and more recent information on the use and effects of DAPs is needed in order to decrease their exposure among the rapidly growing older population.

Background & Aims: Current screening strategies for chronic liver disease focus on detection of subclinical advanced liver fibrosis but cannot identify those at high future risk of severe liver disease. Our aim was to develop and validate a risk pre-diction model for incident chronic liver disease in the general population based on widely available factors. Methods: Multivariable Cox regression analyses were used to develop prediction models for liver-related outcomes with and without laboratory measures (Modellab and Modelnon-lab) in 25,760 individuals aged 40-70 years. Their data were sourced from the Finnish population-based health examination surveys FINRISK 1992-2012 and Health 2000 (derivation cohort). The models were externally validated in the Whitehall II (n = 5,058) and Copenhagen City Heart Study (CCHS) (n = 3,049) cohorts. Results: The absolute rate of incident liver outcomes per 100,000 person-years ranged from 53 to 144. The final prediction model included age, sex, alcohol use (drinks/week), waist-hip ratio, diabetes, and smoking, and Modellab also included gamma-glutamyltransferase values. Internally validated Wolbers' C -sta-tistics were 0.77 for Modellab and 0.75 for Modelnon-lab, while apparent 15-year AUCs were 0.84 (95% CI 0.75-0.93) and 0.82 (95% CI 0.74-0.91). The models identified a small proportion (< 2%) of the population with > 10% absolute 15-year risk for liver events. Of all liver events, only 10% occurred in participants in the lowest risk category. In the validation cohorts, 15-year AUCs were 0.78 (Modellab) and 0.65 (Modelnon-lab) in the CCHS cohort, and 0.78 (Modelnon-lab) in the Whitehall II cohort. Conclusions: Based on widely available risk factors, the Chronic Liver Disease (CLivD) score can be used to predict risk of future advanced liver disease in the general population. Lay summary: Liver disease often progresses silently without symptoms and thus the diagnosis is often delayed until severe complications occur and prognosis becomes poor. In order to identify individuals in the general population who have a high risk of developing severe liver disease in the future, we developed and validated a Chronic Liver Disease (CLivD) risk prediction score, based on age, sex, alcohol use, waist-hip ratio, diabetes, and smoking, with or without measurement of the liver enzyme gamma-glutamyltransferase. The CLivD score can be used as part of health counseling, and for planning further liver investigations and follow-up. (C) 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

Introduction: The aim of this study was to estimate the potential cost-effectiveness of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) program. Methods: A life-time Markov model with societal perspective, simulating a cohort of people at risk of dementia reflecting usual care and the FINGER program. Results: Costs were 1,653,275 and 1,635,346 SEK and quality-adjusted life years (QALYs) were 8.636 and 8.679 for usual care and the FINGER program, respectively, resulting in savings of 16,928 SEK (2023 US$) and 0.043 QALY gains per person, supporting extended dominance for the FINGER program. A total of 1623 dementia cases were avoided with 0.17 fewer person-years living with dementia. The sensitivity analysis confirmed the conclusions in most scenarios. Discussion: The model provides support that programs like FINGER have the potential to be cost-effective in preventing dementia. Results at the individual level are rather modest, but the societal benefits can be substantial because of the large potential target population. publishedVersion

Objective IL-17A and TNF act in synergy to induce proinflammatory mediators in synovial fibroblasts thus contributing to diseases associated with chronic arthritis. Many of these factors are regulated by transcription factor E74-like factor-3 (ELF3). Therefore, we sought to investigate ELF3 as a downstream target of IL-17A and TNF signalling and to characterize its role in the molecular mechanism of synergy between IL-17A and TNF. Methods Regulation of ELF3 expression by IL-17A and TNF was studied in synovial fibroblasts of RA and OA patients and RA synovial explants. Signalling leading to ELF3 mRNA induction and the impact of ELF3 on the response to IL-17A and TNF were studied using siRNA, transient overexpression and signalling inhibitors in synovial fibroblasts and HEK293 cells. Results ELF3 was marginally affected by IL-17A or TNF alone, but their combination resulted in high and sustained expression. ELF3 expression was regulated by the nuclear factor-κB (NF-κB) pathway and CCAAT/enhancer-binding protein β (C/EBPβ), but its induction required synthesis of the NF-κB co-factor IκB (inhibitor of NF-κB) ζ. siRNA-mediated depletion of ELF3 attenuated the induction of cytokines and matrix metalloproteinases by the combination of IL-17A and TNF. Overexpression of ELF3 or IκBζ showed synergistic effect with TNF in upregulating expression of chemokine (C-C motif) ligand 8 (CCL8), and depletion of ELF3 abrogated CCL8 mRNA induction by the combination of IκBζ overexpression and TNF. Conclusion Altogether, our results establish ELF3 as an important mediator of the synergistic effect of IL-17A and TNF in synovial fibroblasts. The findings provide novel information of the pathogenic mechanisms of IL-17A in chronic arthritis and implicate ELF3 as a potential therapeutic target.

Key Points Question Are alcohol-induced loss of consciousness and heavy weekly alcohol consumption associated with increased risk of future dementia? Findings In this multicohort study of 131 415 adults, a 1.2-fold excess risk of dementia was associated with heavy vs moderate alcohol consumption. Those who reported having lost consciousness due to alcohol consumption, regardless of their overall weekly consumption, had a 2-fold increased risk of dementia compared with people who had not lost consciousness and were moderate drinkers. Meaning The findings of this study suggest that alcohol-induced loss of consciousness is a long-term risk factor for dementia among both heavy and moderate drinkers., Importance Evidence on alcohol consumption as a risk factor for dementia usually relates to overall consumption. The role of alcohol-induced loss of consciousness is uncertain. Objective To examine the risk of future dementia associated with overall alcohol consumption and alcohol-induced loss of consciousness in a population of current drinkers. Design, Setting, and Participants Seven cohort studies from the UK, France, Sweden, and Finland (IPD-Work consortium) including 131 415 participants were examined. At baseline (1986-2012), participants were aged 18 to 77 years, reported alcohol consumption, and were free of diagnosed dementia. Dementia was examined during a mean follow-up of 14.4 years (range, 12.3-30.1). Data analysis was conducted from November 17, 2019, to May 23, 2020. Exposures Self-reported overall consumption and loss of consciousness due to alcohol consumption were assessed at baseline. Two thresholds were used to define heavy overall consumption: greater than 14 units (U) (UK definition) and greater than 21 U (US definition) per week. Main Outcomes and Measures Dementia and alcohol-related disorders to 2016 were ascertained from linked electronic health records. Results Of the 131 415 participants (mean [SD] age, 43.0 [10.4] years; 80 344 [61.1%] women), 1081 individuals (0.8%) developed dementia. After adjustment for potential confounders, the hazard ratio (HR) was 1.16 (95% CI, 0.98-1.37) for consuming greater than 14 vs 1 to 14 U of alcohol per week and 1.22 (95% CI, 1.01-1.48) for greater than 21 vs 1 to 21 U/wk. Of the 96 591 participants with data on loss of consciousness, 10 004 individuals (10.4%) reported having lost consciousness due to alcohol consumption in the past 12 months. The association between loss of consciousness and dementia was observed in men (HR, 2.86; 95% CI, 1.77-4.63) and women (HR, 2.09; 95% CI, 1.34-3.25) during the first 10 years of follow-up (HR, 2.72; 95% CI, 1.78-4.15), after excluding the first 10 years of follow-up (HR, 1.86; 95% CI, 1.16-2.99), and for early-onset (, This cohort study examines the association of overall consumption of alcohol and resultant loss of consciousness with risk for dementia.

Background There are several national and international criteria available for identifying potentially inappropriate medications (PIMs) for older people. The prevalence of PIM use may vary depending on the criteria used. The aim is to examine the prevalence of potentially inappropriate medication use in Finland according to the Meds75+ database, developed to support clinical decision-making in Finland, and to compare it with eight other PIM criteria. Methods This nationwide register study consisted of Finnish people aged 75 years or older (n = 497,663) who during 2017–2019 purchased at least one prescribed medicine considered as a PIM, based on any of the included criteria. The data on purchased prescription medicines was collected from the Prescription Centre of Finland. Results The annual prevalence of 10.7–57.0% was observed for PIM use depending on which criteria was used. The highest prevalence was detected with the Beers and lowest with the Laroche criteria. According to the Meds75+ database, annually every third person had used PIMs. Regardless of the applied criteria, the prevalence of PIM use decreased during the follow-up. The differences in the prevalence of medicine classes of PIMs explain the variance of the overall prevalence between the criteria, but they identify the most commonly used PIMs quite similarly. Conclusion PIM use is common among older people in Finland according to the national Meds75+ database, but the prevalence is dependent on the applied criteria. The results indicate that different PIM criteria emphasize different medicine classes, and clinicians should consider this issue when applying PIM criteria in their daily practice.

Background The red cell distribution width (RDW) reflects the degree of heterogeneity of red blood cells. Elevated RDW is associated both with frailty and with increased mortality in hospital-admitted patients. In this study we evaluate whether high RDW values are associated with mortality in older emergency department (ED) patients with frailty, and if the association is independent of the degree of frailty. Methods We included ED patients with the following criteria: ≥ 75 years of age, Clinical Frailty Scale (CFS) score of 4 to 8, and RDW % measured within 48 h of ED admission. Patients were allocated to six classes by their RDW value: ≤ 13%, 14%, 15%, 16%, 17%, and ≥ 18%. The outcome was death within 30 days of ED admission. Crude and adjusted odds ratios (OR) with 95% confidence intervals (CI) for a one-class increase in RDW for 30-day mortality were calculated via binary logistic regression analysis. Age, gender and CFS score were considered as potential confounders. Results A total of 1407 patients (61.2% female), were included. The median age was 85 with an inter-quartile range (IQR) of 80–89, median CFS score 6 (IQR: 5–7), and median RDW 14 (IQR: 13–16). Of the included patients, 71.9% were admitted to hospital wards. A total of 85 patients (6.0%) died during the 30-day follow-up. Mortality rate was associated with RDW increase (p for trend p p Conclusion Higher RDW values had a significant association with increased 30-day mortality risk in frail older adults in the ED, and this risk was independent of degree of frailty. RDW is a readily available biomarker for most ED patients. It might be beneficial to include it in risk stratification of older frail ED patients to identify those who could benefit from further diagnostic assessment, targeted interventions, and care planning.

C9orf72 hexanucleotide repeat expansion is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 locus may harbor residual risk outside the hexanucleotide repeat expansion, but the evidence is conflicting. Here, we first compared 683 unrelated amyotrophic lateral sclerosis cases and 3,196 controls with Finnish ancestry to find best single nucleotide polymorphisms that tag the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles. Rs2814707 was the best tagging single nucleotide polymorphisms for intermediate-length alleles with ≥7 repeats (p = 5 × 10−307) and rs139185008 for the hexanucleotide repeat expansion (p = 7 × 10−114) as well as alleles with ≥20 repeats. rs139185008*C associated with amyotrophic lateral sclerosis after removing cases with the hexanucleotide repeat expansion, especially in the subpopulation homozygous for the rs2814707*T (p = 0.0002, OR = 5.06), which supports the concept of residual amyotrophic lateral sclerosis risk at the C9orf72 haplotypes other than the hexanucleotide repeat expansion. We then leveraged Finnish biobank data to test the effects of rs2814707*T and rs139185008*C on longevity after removing individuals with amyotrophic lateral sclerosis / frontotemporal dementia diagnoses. In the discovery cohort (n = 230,006), the frequency of rs139185008*C heterozygotes decreased significantly with age in the comparisons between 50 and 80 years vs. >80 years (p = 0.0005) and 80 years (p = 0.0001). The findings were similar but less significant in a smaller replication cohort (2-sided p = 0.037 in 50–80 years vs. >80 years and 0.061 in 80 years). Analysis of the allele frequencies in 5-year bins demonstrated that the decrease of rs139185008*C started after the age of 70 years. The hexanucleotide repeat expansion tagging single nucleotide polymorphisms decreasing frequency with age suggests its’ association with age-related diseases probably also outside amyotrophic lateral sclerosis / frontotemporal dementia.

OBJECTIVE Understanding mechanisms underlying rapid estimated glomerular filtration rate (eGFR) decline is important to predict and treat kidney disease in type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS We performed a case-control study nested within four T1D cohorts to identify urinary proteins associated with rapid eGFR decline. Case and control subjects were categorized based on eGFR decline ≥3 and RESULTS The cohort study included 1,270 participants followed a median 8 years. In the discovery set, only cathepsin D peptide and protein were significant on full adjustment for clinical and laboratory variables. In the validation set, associations of cathepsin D with eGFR decline were replicated in minimally adjusted models but lost significance with adjustment for albuminuria. In a meta-analysis with combination of discovery and validation sets, the odds ratio for the association of cathepsin D with rapid eGFR decline was 1.29 per SD (95% CI 1.07–1.55). In complementary human cohorts, urine cathepsin D was associated with tubulointerstitial injury and tubulointerstitial cathepsin D expression was associated with increased cortical interstitial fractional volume. In mouse proximal tubular epithelial cell cultures, advanced glycation end product–BSA increased cathepsin D activity and inflammatory and tubular injury markers, which were further increased with cathepsin D siRNA. CONCLUSIONS Urine cathepsin D is associated with rapid eGFR decline in T1D and reflects kidney tubulointerstitial injury.

25 páginas, 6 figuras, 2 tablas, Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele., This work was funded by a grant (EADB) from the EU Joint Programme – Neurodegenerative Disease Research. INSERM UMR1167 is also funded by the INSERM, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine and French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Full consortium acknowledgements and funding are in the Supplementary Not

Background and aims Online interventions for problem gambling are increasingly popular, but not everyone benefits from them. We describe 12 years of real-world data from an online intervention for gambling problems and aim to find out the extent to which depression, alcohol use, and sense of financial control influence the effectiveness of the program. Methods We analyzed treatment effectiveness and moderators in the Finnish “Peli Poikki” program (2007–2018)—an 8-week cognitive behavioral therapy and follow-up program for problem gambling. Participants were Finnish-speaking adults over 18 years of age (N = 2011, 66.9% males). We measured the self-reported level of problem gambling, depression, alcohol use, and sense of financial control across four treatment phases (baseline, post-treatment, 6-month follow-up, and 12-month follow-up), as well as the presence of gambling debt, psychological and physiological health, years suffered from gambling problems, and demographic variables. Results Participation grew across years with retention rates of 55%, 30%, and 19% for post-treatment and the two follow-ups, respectively. The average problem gambling scores declined significantly following treatment and remained low throughout the follow-ups. However, this decline (the beneficial treatment effect) was reversed after the follow-ups for those with high depression scores and those who felt they had no control over their finances. Discussion and Conclusions The Peli Poikki program is a well-functioning online intervention but less effective in the long term for participants with persisting symptoms of depression or without a sense of financial control. More attention is needed to screen and direct people with comorbidities to the appropriate services.

Purpose We compared the prevalence of COVID-19 and related mortality in nursing homes (NHs) in 14 countries until October 2021. We explored the relationship between COVID-19 mortality in NHs with the average size of NHs and with the COVID-19 deaths at a population level. Methods The total number of COVID-19 cases and COVID-19-related deaths in all NHs as well as the total number of NHs and NH beds were provided by representatives of 14 countries. The population level respective figures in each country were provided up to October 2021. Results There was a wide variation in prevalence of COVID-19 cases and deaths between countries. We observed a significant correlation between COVID-19 deaths in NHs and that of the total population and between the mean size of NHs and COVID-19 deaths. Conclusion Side-by-side comparisons between countries allow international sharing of good practice to better enable future pandemic preparedness.

Purpose The aim of this study was to assess the association between low body temperature and mortality in frail older adults in the emergency department (ED). Methods Inclusion criteria were: ≥ 75 years of age, Clinical Frailty Scale (CFS) score of 4–8, and temperature documented at ED admission. Patients were allocated to three groups by body temperature: low ≤ 36.0 °C, normal 36.1–38.0 and high ≥ 38.1. Odds ratios (OR) for 30-day and 90-day mortality were analysed. Results 1577 patients, 61.2% female, were included. Overall mortalities were 85/1577 (5.4%) and 144/1557 (9.2%) in the 30-day and 90-day follow-ups, respectively. The ORs for low body temperature were 3.03 (1.72–5.35; P P Conclusions Low body temperature in frail older ED patients was associated with significantly higher 30- and 90-day mortality.

Publisher Copyright: © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Objectives: The development of intestinal failure-related complications in Finnish adults is unknown. This study aimed to investigate the incidence of catheter-related bloodstream infections (CRBSI), and the longitudinal changes in biochemical liver and kidney tests in a nationwide cohort. Materials and methods: The search for Finnish adults with intestinal failure (IF) utilized a survey to Finnish health-care providers (n = 111) with the potential to provide long-term parenteral support (PS) for adult IF. Our nationwide, cross-sectional cohort included all IF patients aged ≥ 18 years who had received PS for ≥ 120 d in 2017. Data regarding CRBSI and biochemical liver and kidney tests were collected from patient records at the start of PS up to the latest available measurement in 2017. Results: In the nationwide cohort of 52 patients, the CRBSI incidence was 1.35/1000 catheter days. Seventy-three percent of CRBSI in a long-term catheter led to catheter replacement. During a median PS duration of 27.5 (interquartile range [IQR] 11.3–57.3) months, a statistically significant median change occurred in estimated glomerular filtration rate (eGFR; −8.5 ml/min/1.73 m2, IQR −30–7, p =.005) and alkaline phosphatase (ALP; 26 U/l, IQR −11–95, p =.019). In a multiple regression model for eGFR at data collection, baseline eGFR and age were strong explanatory variables. Conclusions: Incidence of CRBSI, but not treatment strategies, in this nationwide adult IF population correspond well to those reported from specialized centers. Decreased kidney function and abnormal liver test results are frequent findings, and even more so over time, emphasizing the importance of regular monitoring.

Tissue-level mechanics (e.g., stress and strain) are important factors governing tissue remodeling and development of knee osteoarthritis (KOA), and hence, the success of physical rehabilitation. To date, no clinically feasible analysis toolbox has been introduced and used to inform clinical decision making with subject-specific in-depth joint mechanics of different activities. Herein, we utilized a rapid state-of-the-art electromyography-assisted musculoskeletal finite element analysis toolbox with fibril-reinforced poro(visco)elastic cartilages and menisci to investigate knee mechanics in different activities. Tissue mechanical responses, believed to govern collagen damage, cell death, and fixed charge density loss of proteoglycans, were characterized within 15 patients with KOA while various daily activities and rehabilitation exercises were performed. Results showed more inter-participant variation in joint mechanics during rehabilitation exercises compared to daily activities. Accordingly, the devised workflow may be used for designing subject-specific rehabilitation protocols. Further, results showed the potential to tailor rehabilitation exercises, or assess capacity for daily activity modifications, to optimally load knee tissue, especially when mechanically-induced cartilage degeneration and adaptation are of interest.

Background The success of antiretroviral therapy has normalized pregnancy among women living with HIV (WWH) with a very low risk of perinatal transmission of HIV. Despite these advances, WWH still face complex medical and psychosocial issues during pregnancy and postpartum. The aim of this study was to assess differences in psychosocial health outcomes between pregnant WWH, non-pregnant WWH, and pregnant women without HIV, and further identify factors associated with probable depression in the third trimester and postpartum. Methods In a longitudinal survey study, participants were included from sites in Denmark, Finland, and Sweden during 2019–2020. Data was collected in the 3rd trimester, 3 and 6 months postpartum using standardized questionnaires assessing depression, perceived stress, loneliness, and social support. Mixed regression models were used to assess changes over time within and between groups. Logistic regression models were used to identify factors associated with depression in pregnancy and postpartum. Results A total of 47 pregnant WWH, 75 non-pregnant WWH, and 147 pregnant women without HIV were included. The prevalence of depression was high among both pregnant and non-pregnant WWH. There was no significant difference between pregnant and non-pregnant WWH in depression scores, perceived stress scores, or social support scores at any time point. Compared to pregnant women without HIV, pregnant WWH reported worse outcomes on all psychosocial scales. Social support and loneliness were associated with an increased odds of depressive symptoms in the adjusted analysis. Conclusions A high burden of adverse psychosocial outcomes was observed in both pregnant and non-pregnant women living with HIV compared to pregnant women without HIV. Loneliness and inadequate social support were associated with increased odds of depression in pregnancy and should be a focus in future support interventions.

Oral health and declining cognition may have a bi-directional association. We characterized the subgingival microbiota composition of subjects from normal cognition to severe cognitive decline in two cohorts. Memory and Periodontitis (MINOPAR) include 202 home-living participants (50-80 years) in Sweden. Finnish Oral Health Studies in Older Adults (FINORAL) include 174 participants (>= 65 years) living in long-term care in Finland. We performed oral examination and assessed the cognitive level with Mini Mental State Examination (MMSE). We sequenced the 16S-rRNA gene (V3-V4 regions) to analyse the subgingival bacterial compositions. The microbial diversities only tended to differ between the MMSE categories, and the strongest determinants were increased probing pocket depth (PPD) and presence of caries. However, abundances of 101 taxa were associated with the MMSE score. After adjusting for age, sex, medications, PPD, and caries, only eight taxa retained the significance in the meta-analyses of the two cohorts. Especially Lachnospiraceae [XIV] at the family, genus, and species level increased with decreasing MMSE. Cognitive decline is associated with obvious changes in the composition of the oral microbiota. Impaired cognition is accompanied with poor oral health status and the appearance of major taxa of the gut microbiota in the oral cavity. Good oral health-care practices require special deliberations among older adults.

Background Recent data on the rate and risk factors of induced abortion among women living with HIV (WLWH) are limited. Our aim was to use Finnish national health register data to 1) determine the nationwide rate of induced abortions of WLWH in Finland during 1987–2019, 2) compare the rates of induced abortions before and after HIV diagnosis over different time periods, 3) determine the factors associated with terminating a pregnancy after HIV diagnosis, and 4) estimate the prevalence of undiagnosed HIV at induced abortions to see whether routine testing should be implemented. Methods A retrospective nationwide register study of all WLWH in Finland 1987–2019 (n = 1017). Data from several registers were combined to identify all induced abortions and deliveries of WLWH before and after HIV diagnosis. Factors associated with terminating a pregnancy were assessed with predictive multivariable logistic regression models. The prevalence of undiagnosed HIV at induced abortion was estimated by comparing the induced abortions among WLWH before HIV diagnosis to the number of induced abortions in Finland. Results Rate of induced abortions among WLWH decreased from 42.8 to 14.7 abortions/1000 follow-up years from 1987–1997 to 2009–2019, more prominently in abortions after HIV diagnosis. After 1997 being diagnosed with HIV was not associated with an increased risk of terminating a pregnancy. Factors associated with induced abortion in pregnancies that began after HIV diagnosis 1998–2019 were being foreign-born (OR 3.09, 95% CI 1.55–6.19), younger age (OR 0.95 per year, 95% CI 0.90–1.00), previous induced abortions (OR 3.36, 95% CI 1.80–6.28), and previous deliveries (OR 2.13, 95% CI 1.08–4.21). Estimated prevalence of undiagnosed HIV at induced abortion was 0.008–0.029%. Conclusions Rate of induced abortions among WLWH has decreased. Family planning should be discussed at every follow-up appointment. Routine testing of HIV at all induced abortions is not cost-effective in Finland due to low prevalence.

Background Symptom burden causes suffering amongst older adults and is associated with healthcare visits and prognosis. Aims We evaluated the prevalence of 10 symptoms and changes in symptom burden amongst home-dwelling older adults in 2019 and 2021 using Finnish cohort data. We analysed factors associated with symptom burden increase during follow-up. Methods Altogether 1,637 people aged 75+ participated in the Helsinki Ageing Study postal survey in 2019, where they reported the presence of 10 common symptoms over the past 2 weeks. Of them, 785 participated in a follow-up in 2021, where the same symptoms were queried. We compared the prevalence of various symptoms and symptom burden scores in the 2-year interval and evaluated factors associated with increased symptom burden during this time. Results Of participants, 33% reported at least one daily symptom in 2019 versus 44% in 2021. Symptom burden increased by a mean ratio of 1.29 between 2019 and 2021. The most common symptoms were joint pain, back pain, urinary incontinence and fatigue. The prevalence of four symptoms increased between 2019 and 2021: joint pain, urinary incontinence, dizziness and shortness of breath. Higher age, reduced functional capacity and comorbidities were associated with higher odds of symptom burden increase during follow-up. Psychological well-being (PWB) was strongly associated with lower odds of symptom burden increase in the logistic regression model. Conclusions Symptom burden increased in our cohort aged 75+ between 2019 and 2021 before and during the COVID-19 pandemic. PWB was associated with lower odds of acquiring additional symptoms over time.

Objectives Our objective was to study mortality related to different obstructive lung diseases, occupational exposure, and their potential joint effect in a large, randomized population-based cohort. Methods We divided the participants based on the answers to asthma and chronic obstructive pulmonary disease (COPD) diagnoses and occupational exposure and used a combined effects model and compared the results to no asthma or COPD with no occupational exposure. Results High exposure had a hazards ratio (HR) of 1.34 (1.11-1.62) and asthma and COPD coexistence of 1.58 (1.10-2.27). The combined effects of intermediate exposure and coexistence had an HR of 2.20 (1.18-4.09), high exposure with coexistence of 1.94 (1.10-3.42) for overall mortality, and sub-HR for respiratory-related mortality of 3.21 (1.87-5.50). Conclusions High occupational exposure increased overall but not respiratory-related mortality hazards, while coexisting asthma and COPD overall and respiratory-related hazards of mortality. publishedVersion

Context Guidelines recommend blood-based fibrosis biomarkers to identify advanced nonalcoholic fatty liver disease (NAFLD), which is particularly prevalent in patients with obesity. Objective To study whether the degree of obesity affects the performance of liver fibrosis biomarkers in NAFLD. Design Cross-sectional cohort study comparing simple fibrosis scores [Fibrosis-4 Index (FIB-4); NAFLD Fibrosis Score (NFS); aspartate aminotransferase to platelet ratio index; BARD (body mass index, aspartate-to-alanine aminotransferase ratio, diabetes); Hepamet Fibrosis Score (HFS)] and newer scores incorporating neo-epitope biomarkers PRO-C3 (ADAPT, FIBC3) or cytokeratin 18 (MACK-3). Setting Tertiary referral center. Patients We recruited overweight/obese patients from endocrinology (n = 307) and hepatology (n = 71) clinics undergoing a liver biopsy [median body mass index (BMI) 40.3 (interquartile range 36.0-44.7) kg/m2]. Additionally, we studied 859 less obese patients with biopsy-proven NAFLD to derive BMI-adjusted cutoffs for NFS. Main Outcome Measures Biomarker area under the receiver operating characteristic (AUROC), sensitivity, specificity, and predictive values to identify histological stage ≥F3 fibrosis or nonalcoholic steatohepatitis with ≥F2 fibrosis [fibrotic nonalcoholic steatohepatitis (NASH)]. Results The scores with an AUROC ≥0.85 to identify ≥F3 fibrosis were ADAPT, FIB-4, FIBC3, and HFS. For fibrotic NASH, the best predictors were MACK-3 and ADAPT. The specificities of NFS, BARD, and FIBC3 deteriorated as a function of BMI. We derived and validated new cutoffs for NFS to rule in/out ≥F3 fibrosis in groups with BMIs Conclusions In obese patients, the best-performing fibrosis biomarkers are ADAPT and the inexpensive FIB-4, which are unaffected by BMI. The widely used NFS loses specificity in obese individuals, which may be corrected with BMI-adjusted cutoffs.

Background: Literature suggests that different risks of mortality could influence physicians in prescribing or not anticoagulants in older patients with atrial fibrillation (AF). The Multidimensional Prognostic Index (MPI) can be considered a tool for the detection of multidimensional frailty. The aim of this cross-sectional study was to evaluate whether prescription patterns of oral anticoagulants exist, based on MPI values. Methods: Older hospitalised patients (age >= 65 years) with non-valvular AF were included across 24 European centres. MPI was calculated using validated and standardised tools derived from a comprehensive geriatric assessment. Other functional and clinical information were collected to calculate indexes specific for haemorrhagic and thromboembolic risk in AF. Results: Altogether, 2,012 participants affected by AF (mean age was 83.2 +/- 7.5, range: 65-104 years), with a higher presence of women (57.0%), were included. Overall, 440 took vitamin K antagonists VKAs (22.0%), 667 (33.4%) direct oral anticoagulants (DOACs), whilst 44.6% did not take any anticoagulant treatment. Prescription of anticoagulants was associated with MPI values, with people taking anticoagulants having lower mean MPI values. Anticoagulant therapy was not used in 53.1% of the group with the highest risk of mortality, compared with 32.3% of those in the group with the lowest mortality risk. People with higher scores in MPI were less frequently treated with anticoagulant therapy, after adjusting for several potential confounders. Conclusions: The EURopean study of Older Subjects with Atrial Fibrillation (EUROSAF) suggested that almost half of the older persons with AF do not receive anticoagulants and that MPI is an important determinant in prescribing or not anticoagulants.

Type 1 diabetes affects over nine million individuals globally, with approximately 40% developing diabetic kidney disease. Emerging evidence suggests that epigenetic alterations, such as DNA methylation, are involved in diabetic kidney disease. Here we assess differences in blood-derived genome-wide DNA methylation associated with diabetic kidney disease in 1304 carefully characterised individuals with type 1 diabetes and known renal status from two cohorts in the United Kingdom-Republic of Ireland and Finland. In the meta-analysis, we identify 32 differentially methylated CpGs in diabetic kidney disease in type 1 diabetes, 18 of which are located within genes differentially expressed in kidneys or correlated with pathological traits in diabetic kidney disease. We show that methylation at 21 of the 32 CpGs predict the development of kidney failure, extending the knowledge and potentially identifying individuals at greater risk for diabetic kidney disease in type 1 diabetes.

Background: Although periodontitis is associated with increased risk of hypertension, studies based on new periodontal disease classification is limited. We investigated whether periodontitis severity and progression rate are linked with self-reports on doctor-diagnosed hypertension in a large cohort of patients attending the periodontology clinic at the faculty of dentistry. Methods: Archived patient files, including radiographic image records and results from full-mouth clinical periodontal examination were screened for inclusion. Data on socioeconomic factors, smoking and oral hygiene habits, and medical history were collected with a questionnaire. Results: Diagnosis and background data were available for 7008 patients. The median (IQR) age was 31.0 (21.0) years; 60.1% (n = 4211) were female. Hypertension was diagnosed in 6.2% (n = 435) of patients. Both periodontitis stage and grade differed (p < 0.001) between patients with or without hypertension. Increased periodontal disease severity was associated with a 20% increasing risk for hypertension; the odds ratio (OR) was 2.63 (95% confidence interval [CI] 1.48–4.68, p < 0.001) in stage IV periodontitis. Increasing periodontitis progression rate was associated with a 35% increased risk for hypertension; the OR was 2.22 (95% CI 1.45–3.40, p < 0.001) in grade C periodontitis. Conclusion: Severity and progression rate of periodontitis may be independent risk factors for hypertension in this large cohort of patients attending the university periodontal department. © 2022, The Author(s)., Eskişehir Osmangazi Üniversitesi, ESOGU: 202045A221, This work was supported by Eskisehir Osmangazi University Research Fund, Turkey (no: 202045A221). Open access funded by Helsinki University Library.

Park, MacLean, et al. conduct an exome-wide association study of liver fat content in the Penn Medicine BioBank. By leveraging machine learning-assisted analysis of clinical CT scans to quantify steatosis, they uncover previously undescribed liver fat-associated genetic variants. Non

Sixteen patients with active rheumatoid arthritis, despite conventional synthetic disease-modifying antirheumatic drugs, started additional tofacitinib treatment. Blood samples were drawn at baseline and at 3-month follow-up visits, and plasma levels of 92 inflammation-related proteins were measured with proximity extension assay. Levels of 21 proteins changed substantially (>20%) and statistically significantly upon tofacitinib treatment, and the baseline levels of interleukin-6, C-C motif chemokine 11 and Delta and Notch-like epidermal growth factor-related receptor associated with the treatment response. The data on the effects of tofacitinib on soluble proteins in patients with rheumatoid arthritis (RA) is currently very limited. We analyzed how tofacitinib treatment and thus inhibition of the Janus kinase-signal transducer and activation of transcription pathway affects the in vivo levels of inflammation-related plasma proteins in RA patients. In this study, 16 patients with active RA [28-joint disease activity score (DAS28) >3.2] despite treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) started tofacitinib treatment 5 mg twice daily. Levels of 92 inflammation-related plasma proteins were determined by proximity extension assay at baseline and at 3 months. Tofacitinib treatment for 3 months, in csDMARD background, decreased the mean DAS28 from 4.4 to 2.6 (P < 0.001). Marked (>20%) and statistically significant (P < 0.05) changes were found in the levels of 21 proteins, 18 of which decreased and 3 increased. Of these proteins, 17 are directly involved in inflammatory responses or in the cellular response to cytokines. The highest (>50%) decrease was observed for interleukin-6 (IL-6), C-X-C motif chemokine ligand 1, matrix metalloproteinase-1, and AXIN1. Higher baseline levels of IL-6 and lower levels of C-C motif chemokine 11 and Delta and Notch-like epidermal growth factor-related receptors were associated with DAS28 improvement. Our results indicate that tofacitinib downregulates several proinflammatory plasma proteins that may contribute to the clinical efficacy of tofacitinib. In addition, soluble biomarkers may predict the treatment response to tofacitinib.

Publisher Copyright: © 2022 The Authors Background and aims: The susceptibility of low-density lipoprotein (LDL) to aggregation predicts atherosclerotic cardiovascular disease. However, causes of interindividual variation in LDL lipid composition and aggregation susceptibility remain unclear. We examined whether the lipid composition and aggregation susceptibility of LDL reflect the lipid composition of the human liver. Methods: Liver biopsies and blood samples for isolation of LDL particles were obtained from 40 obese subjects (BMI 45.9 ± 6.1 kg/m2, age 43 ± 8 years). LDL was isolated using sequential ultracentrifugation and lipidomic analyses of liver and LDL samples were determined using ultra-high performance liquid chromatography–mass spectrometry. LDL aggregation susceptibility ex vivo was analyzed by inducing aggregation by human recombinant secretory sphingomyelinase and following aggregate formation. Results: The composition (acyl carbon number and double bond count) of hepatic triglycerides, phosphatidylcholines, and sphingomyelins (SMs) was closely associated with that of LDL particles. Hepatic dihydroceramides and ceramides were positively correlated with concentrations of the corresponding SM species in LDL as well with LDL aggregation. These relationships remained statistically significant after adjustment for age, sex, and body mass index. Conclusions: Lipid composition of LDL reflects that of the human liver in obese patients. Changes in hepatic sphingolipid metabolism may contribute to interindividual variation of LDL lipid composition and susceptibility to aggregation.

Aim Inflammatory signals in the sacroiliac (SI) joints and the aorta of patients with axial spondyloarthritis (axSpA) were graded by positron emission tomography/computed tomography (PET/CT) imaging before and after treatment with sulfasalazine (SSZ) or adalimumab (ADA). Methods Patients with axSpA, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4, were recruited. Disease‐modifying antirheumatic drug‐naïve patients started SSZ for 12 weeks, whereas those with prestudy treatment with or contraindication to SSZ commenced ADA for 16 weeks. In addition, those patients in the SSZ group with insufficient response commenced ADA for 16 weeks. 18F‐fluorodeoxyglucose PET/CT was performed after inclusion and after treatment with SSZ and ADA. Maximum standardized uptake value (SUVmax) was assessed for the aorta and the SI joints, and maximal target‐to‐blood‐pool ratio (TBRmax) only for the aorta. Results Among five SSZ patients, mean ± SD BASDAI was 4.7 ± 1.6 before and 3.5 ± 1.4 after treatment (p = .101). In 13 ADA patients, the BASDAI decreased from 5.4 ± 1.6 to 2.8 ± 2.2 (p, We launched this small open‐label study to test the hypothesis that axial spondyloarthritis (axSpA) induces positron emission tomography (PET)‐detectable inflammation in the sacroiliac (SI) joints and cardiovascular tissues and that the effects of treatment with sulfasalazine and adalimumab (ADA) for axSpA can be visualized and confirmed by PET. Our results imply that sulfasalazine may reduce PET‐computed tomography‐detectable inflammation in the SI joints, with a trend towards a reduction in the aorta. In the ADA group, however, we did not observe any change in the PET signals in the SI joints nor in the aorta.

Supplemental Digital Content is available in the text., Objective: We recently showed that measurement of the susceptibility of LDL (low-density lipoprotein) to aggregation is an independent predictor of cardiovascular events. We now wished to compare effects of overfeeding different dietary macronutrients on LDL aggregation, proteoglycan-binding of plasma lipoproteins, and on the concentration of oxidized LDL in plasma, 3 in vitro parameters consistent with increased atherogenicity. Approach and Results: The participants (36 subjects; age, 48±10 years; body mass index, 30.9±6.2 kg/m2) were randomized to consume an extra 1000 kcal/day of either unsaturated fat, saturated fat, or simple sugars (CARB) for 3 weeks. We measured plasma proatherogenic properties (susceptibility of LDL to aggregation, proteoglycan-binding, oxidized LDL) and concentrations and composition of plasma lipoproteins using nuclear magnetic resonance spectroscopy, and in LDL using liquid chromatography mass spectrometry, before and after the overfeeding diets. LDL aggregation increased in the saturated fat but not the other groups. This change was associated with increased sphingolipid and saturated triacylglycerols in LDL and in plasma and reduction of clusterin on LDL particles. Proteoglycan binding of plasma lipoproteins decreased in the unsaturated fat group relative to the baseline diet. Lipoprotein properties remained unchanged in the CARB group. Conclusions: The type of fat during 3 weeks of overfeeding is an important determinant of the characteristics and functional properties of plasma lipoproteins in humans. Registration: URL: http://www.clinicaltrials.gov; Unique identifier NCT02133144.

Publisher Copyright: © 2021 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd. Background: The clinical significance of respiratory syncytial virus (RSV) among adults remains underinvestigated. We compared the characteristics and population-based attack rates of RSV and influenza hospitalizations. Methods: During 2018–2020, we recruited hospitalized adults with respiratory infection to our prospective substudy at a tertiary care hospital in Finland and compared the characteristics of RSV and influenza patients. In our retrospective substudy, we calculated the attack rates of all RSV and influenza hospitalizations among adults in the same geographic area during 2016–2020. Results: Of the 537 prospective substudy patients, 31 (6%) had RSV, and 106 (20%) had influenza. Duration of hospitalization, need for intensive care or outcome did not differ significantly between RSV and influenza patients. RSV was more often missed or its diagnosis omitted from medical record (13% vs. 1%, p = 0.016 and 52% vs. 85%, p < 0.001). In the retrospective substudy, the mean attack rates of RSV, influenza A, and influenza B hospitalizations rose with age from 4.1 (range by season 1.9–5.9), 15.4 (12.3–23.3), and 4.7 (0.5–16.2) per 100,000 persons among 18- to 64-year-olds to 58.3 (19.3–117.6), 204.1 (31.0–345.0), and 60.4 (0.0–231.0) per 100,000 persons among 65+-year-olds and varied considerably between seasons. Discussion: While the attack rates of influenza hospitalizations were higher compared with RSV, RSV and influenza hospitalizations were similar in severity. Missing or underreporting of RSV infections may lead to underestimating its disease burden. Both RSV and influenza caused a substantial amount of hospitalizations among the elderly, stressing the need for more effective interventions.

Background and aims: Clinical practice before 2019 suggests a substantial proportion of high and very high CV risk patients taking lipid-lowering therapy (LLT) would not achieve the new LDL-C goals recommended in the 2019 ESC/EAS guidelines (18 years of age with high and very high CV risk (as assigned by the investigators) requiring LLT, with no formal patient or comparator groups. The primary objective is to document, in the real-world setting, the effectiveness of current treatment modalities in managing plasma levels of LDL-C in high-and very high-risk patients requiring LLT. Key secondary effectiveness objectives include documenting the relationship between LLT and levels of other plasma lipids, high sensitivity C-reactive protein (hsCRP) and overall predicted CV risk over one year. Health economics and patient-relevant parameters will also be assessed. Conclusions: The SANTORINI study, which commenced after the 2019 ESC/EAS guidelines were published, is ideally placed to provide important contemporary insights into the evolving management of LLT in Europe and highlight factors contributing to the low levels of LDL-C goal achievement among high and very high CV risk patients. It is hoped the findings will help enhance patient management and reduce the burden of ASCVD in Europe. ' (c) 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Background Dyslipidemia is a major risk factor for cardiovascular disease, and diabetes impacts the lipid metabolism through multiple pathways. In addition to the standard lipid measurements, apolipoprotein concentrations provide added awareness of the burden of circulating lipoproteins. While common genetic variants modestly affect the serum lipid concentrations, rare genetic mutations can cause monogenic forms of hypercholesterolemia and other genetic disorders of lipid metabolism. We aimed to identify low-frequency protein-altering variants (PAVs) affecting lipoprotein and lipid traits. Methods We analyzed whole-exome (WES) and whole-genome sequencing (WGS) data of 481 and 474 individuals with type 1 diabetes, respectively. The phenotypic data consisted of 79 serum lipid and apolipoprotein phenotypes obtained with clinical laboratory measurements and nuclear magnetic resonance spectroscopy. Results The single-variant analysis identified an association between the LIPC p.Thr405Met (rs113298164) and serum apolipoprotein A1 concentrations (p=7.8×10−8). The burden of PAVs was significantly associated with lipid phenotypes in LIPC, RBM47, TRMT5, GTF3C5, MARCHF10, and RYR3 (p−6). The RBM47 gene is required for apolipoprotein B post-translational modifications, and in our data, the association between RBM47 and apolipoprotein C-III concentrations was due to a rare 21 base pair p.Ala496-Ala502 deletion; in replication, the burden of rare deleterious variants in RBM47 was associated with lower triglyceride concentrations in WES of >170,000 individuals from multiple ancestries (p=0.0013). Two PAVs in GTF3C5 were highly enriched in the Finnish population and associated with cardiovascular phenotypes in the general population. In the previously known APOB gene, we identified novel associations at two protein-truncating variants resulting in lower serum non-HDL cholesterol (p=4.8×10−4), apolipoprotein B (p=5.6×10−4), and LDL cholesterol (p=9.5×10−4) concentrations. Conclusions We identified lipid and apolipoprotein-associated variants in the previously known LIPC and APOB genes, as well as PAVs in GTF3C5 associated with LDLC, and in RBM47 associated with apolipoprotein C-III concentrations, implicated as an independent CVD risk factor. Identification of rare loss-of-function variants has previously revealed genes that can be targeted to prevent CVD, such as the LDL cholesterol-lowering loss-of-function variants in the PCSK9 gene. Thus, this study suggests novel putative therapeutic targets for the prevention of CVD.

AimThis study aimed to determine the prevalence of malnutrition in a head and neck cancer (HNC) population according to the Global Leadership Initiative on Malnutrition (GLIM) criteria and to assess its relation to survival. The secondary aim was to compare GLIM criteria to Patient–Generated Subjective Global Assessment (PG–SGA) and Nutritional Risk Screening 2002 (NRS 2002) methods.MethodsThe assessment was performed in a series of 65 curative patients with newly diagnosed HNC in a nutrition intervention study. Malnutrition was defined as PG-SGA classes BC and nutritional risk as NRS 2002 score ≥3 and was retrospectively diagnosed with GLIM criteria in prospectively collected data at diagnosis. Sensitivity, specificity, and kappa (κ) were analyzed. Predictive accuracy was assessed by calculating the area under curve (AUC) b y receiver operating characteristic (ROC) analysis. Kaplan–Meier and Cox regression analyses were used to evaluate association between malnutrition and overall survival (OS), and disease-free survival (DFS).ResultsGLIM-defined malnutrition was present in 37% (24/65) of patients. The GLIM showed 77% sensitivity and 84% specificity with agreement of κ = 0.60 and accuracy of AUC = 0.80 (p < 0.001) with PG-SGA and slightly higher sensitivity (83%) with NRS 2002 (κ = 0.58). Patients with GLIM-defined malnutrition had shorter OS (56 vs. 72 months, HR 2.26, 95% CI 1.07–4.77, p = 0.034) and DFS (37 vs. 66 months, HR 2.01, 95% CI 0.99–4.09, p = 0.054), than well-nourished patients. The adjusted HR was 2.53 (95% CI 1.14–5.47, p = 0.023) for OS and 2.10 (95% CI 0.98–4.48, p = 0.056) for DFS in patients with GLIM-defined malnutrition.ConclusionA substantial proportion of HNC patients were diagnosed with malnutrition according to the GLIM criteria and this showed a moderate agreement with NRS 2002- and PG–SGA-defined malnutrition. Even though the GLIM criteria had strong association with OS, its diagnostic value was poor. Therefore, the GLIM criteria seem potential for malnutrition diagnostics and outcome prediction in the HNC patient population. Furthermore, NRS 2002 score ≥3 indicates high nutritional risk in this patient group.

Background Dysbiotic intestinal and oral microbiota have been implicated in the pathogenesis of rheumatoid arthritis (RA), but the mechanisms how microbiota could impact disease activity have remained elusive. The aim of this study was to assess the association of the biological activity of serum lipopolysaccharides (LPS) with disease activity and likelihood of achieving remission in RA patients. Methods We measured Toll-like receptor (TLR) 4-stimulating activity of sera of 58 RA patients with a reporter cell line engineered to produce secreted alkaline phosphatase in response to TLR4 stimulation. Levels of LPS-binding protein, CD14, and CD163 were determined by ELISA assays. Results The patient serum-induced TLR4 activation (biological activity of LPS) was significantly associated with inflammatory parameters and body mass index at baseline and at 12 months and with disease activity (DAS28-CRP, pp=0.031) and, in 28 early RA patients, the likelihood of achieving remission at 12 months (p=0.009). The level of LPS bioactivity was similar at baseline and 12-month visits, suggesting that LPS bioactivity is an independent patient-related factor. Neutralization of LPS in serum by polymyxin B abrogated the TLR4 signaling, suggesting that LPS was the major contributor to TLR4 activation. Conclusion We describe a novel approach to study the biological activity of serum LPS and their impact in diseases. The results suggest that LPS contribute to the inflammatory burden and disease activity on patients with RA and that serum-induced TLR4 activation assays can serve as an independent prognostic factor. Graphical Abstract A graphical summary of the conclusions of the study.

One-year data from EXPLORE Part A showed high disease burden and impaired quality of life (QOL) in patients with acute hepatic porphyria (AHP) with recurrent attacks. We report baseline data of patients who enrolled in EXPLORE Part B for up to an additional 3 years of follow-up. EXPLORE B is a long-term, prospective study evaluating disease activity, pain intensity, and QOL in patients with AHP with ≥1 attack in the 12 months before enrollment or receiving hemin or gonadotropin-releasing hormone prophylaxis. Data were evaluated in patients with more (≥3 attacks or on prophylaxis treatment) or fewer (

Objective: To explore work participation and the health-related factors affecting work participation among the Finnish Spinal Cord injury (FinSCI) study population (n = 884).Methods: A cross-sectional explorative observational study in the FinSCI community survey applying Patient-Reported Outcomes Measurement Information System (PROMIS®) forms on Social Health and Global Health. Analyses of socio-demographic and injury-related data were performed.Results: Employment among the study population (n = 452) was 26.5%. Physical, Mental, Social and General Health were better in the employed group compared with work-age persons not working. Logistic regression showed that work participation was related to all health domains, but Physical Health and Ability to Participate in Social Roles and Activities in Social Health were the strongest indicators of likelihood of being at work. Paraplegia and young age were associated with increased likelihood of work participation. Conclusion: The first national survey among people with spinal cord injury in Finland shows low level of employment. The results suggest that pain, physical function, and ability to participate in social roles should be monitored by health and vocational professionals when assessing a person’s likelihood of being in work. Lay abstractThe data source for this study was the Finnish Spinal Cord Injury Study (FinSCI), which collected extensive information from people with spinal cord injury about their health and employment status. A total of 452 responders from the FinSCI survey were included in the current study. The employment rate in the FinSCI study population was low (26.5%) and the majority of those not in work (73.5%) were receiving a disability pension. The analysis of health factors showed that all health aspects were better in the employed group compared with the group who were not working. Physical Health, Ability to Participate in Social Roles and Activities, less severe injury, and young age were associated with likelihood of work participation. This study provides up-to-date self-reported data for the spinal cord injury population and health professionals, helping to identify health-related problems that could be barring employment.

BackgroundJAK-inhibitors (JAKi), recently approved in rheumatoid arthritis (RA), have changed the landscape of treatment choices. We aimed to compare the effectiveness of four current second-line therapies of RA with different modes of action, since JAKi approval, in an international collaboration of 19 registers.MethodsIn this observational cohort study, patients initiating tumour necrosis factor inhibitors (TNFi), interleukin-6 inhibitors (IL-6i), abatacept (ABA) or JAKi were included. We compared the effectiveness of these treatments in terms of drug discontinuation and Clinical Disease Activity Index (CDAI) response rates at 1 year. Analyses were adjusted for patient, disease and treatment characteristics, including lines of therapy and accounted for competing risk.ResultsWe included 31 846 treatment courses: 17 522 TNFi, 2775 ABA, 3863 IL-6i and 7686 JAKi. Adjusted analyses of overall discontinuation were similar across all treatments. The main single reason of stopping treatment was ineffectiveness. Compared with TNFi, JAKi were less often discontinued for ineffectiveness (adjusted HR (aHR) 0.75, 95% CI 0.67 to 0.83), as was IL-6i (aHR 0.76, 95% CI 0.67 to 0.85) and more often for adverse events (aHR 1.16, 95% CI 1.03 to 1.33). Adjusted CDAI response rates at 1 year were similar between TNFi, JAKi and IL-6i and slightly lower for ABA.ConclusionThe adjusted overall drug discontinuation and 1 year response rates of JAKi and IL-6i were similar to those observed with TNFi. Compared with TNFi, JAKi were more often discontinued for adverse events and less for ineffectiveness, as were IL-6i.

Funding Information: Funding Sources: Dr Koponen was supported by a research grant from the Aarne Koskelo Foundation. Publisher Copyright: © 2022 Heart Rhythm Society Background: Long QT syndrome (LQTS) is an inherited arrhythmia disorder characterized by ventricular repolarization abnormalities and a risk of sudden cardiac death. The electrophysiological components generating the high risk of arrhythmias in LQTS are prolonged repolarization, increased dispersion of repolarization, and early afterdepolarizations, which are clinically estimated as QT interval, T-wave peak to T-wave end (TPE) interval, and T2/T1-wave amplitude ratio, respectively. In experimental LQTS type 2 (LQT2) models, β-blockers decrease dispersion of repolarization and prevent early afterdepolarizations. In clinical studies in patients with LQT2, β-blockers are more effective against exercise-induced than arousal-induced cardiac events. Objectives: The aim of the study was to investigate the effects of β-blocker therapy on repolarization properties in LQT2. Methods: QT and TPE intervals and maximal T2/T1-wave amplitude ratios recorded by 24-hour electrocardiograms before and during β-blocker therapy were evaluated in 25 patients with LQT2. Results: β-Blocker therapy decreased the maximal T2/T1-wave amplitude ratio from 2.9 ± 1.1 to 1.8 ± 0.7 (P < .001), but did not change the pause-induced T2/T1-wave amplitude ratio. Under medication, abrupt maximal TPE intervals were shorter at heart rates of ≥75 beats/min and maximal QT intervals were shorter at a heart rate of 100 beats/min. Conclusion: β-Blockers stabilize ventricular repolarization in LQT2 by reducing electrocardiographic early afterdepolarizations and by reducing abrupt prolongation of electrocardiographic dispersion of repolarization and ventricular repolarization duration at elevated heart rates. The effect of β-blockers on pause-induced electrocardiographic early afterdepolarizations is weak. The findings provide electrocardiographic explanation for the protective effects of β-blockers against exercise-induced cardiac events in LQT2.

Objective To assess whether aerosol generation occurs during otologic surgery, to define which instruments are aerosol generating, and to identify factors that enhance safety in protection against airborne pathogens, such as severe acute respiratory syndrome coronavirus 2. Study Design An observational prospective study on aerosol measurements during otologic operations recorded between August and December 2020. Setting Aerosol generation was measured with an Optical Particle Sizer as part of otologic operations with anesthesia. Particles with a size range of 0.3 to 10 mu m were quantified. Aerosol generation was measured during otologic operations to analyze aerosols during drilling in transcanal and transmastoid operations and when using the following instruments: bipolar electrocautery, laser, suction, and cold instruments. Coughing is known to produce significant concentration of aerosols and is commonly used as a reference for high-risk aerosol generation. Thus, the operating room background concentration and coughing were chosen as reference values. Patients Thirteen otologic operations were included. The average drilling time per surgery was 27.00 minutes (range, 2.00-71.80 min). Intervention Different rotation speeds during drilling and other instruments were used. Main Outcome Measures Aerosol concentrations during operations were recorded and compared with background and cough aerosol concentrations. Results Total aerosol concentrations during drilling were significantly higher than background (p < 0.0001, d = 2.02) or coughing (p < 0.0001, d = 0.50). A higher drilling rotation speed was associated with higher particle concentration (p = 0.037, eta(2) = 0.01). Aerosol generation during bipolar electrocautery, drilling, and laser was significantly higher than with cold instruments or suction (p < 0.0001, eta(2) = 0.04). Conclusion High aerosol generation is observed during otologic surgery when drill, laser, or bipolar electrocautery is used. Aerosol generation can be reduced by using cold instruments instead of electric and keeping the suction on during aerosol-generating procedures. If drilling is required, lower rotation speeds are recommended. These measures may help reduce the spread of airborne pathogens during otologic surgery.

We investigated the effect of a multidomain lifestyle intervention on the risk of dementia estimated using the validated CAIDE risk score (post-hoc analysis). The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is a 2-year randomized controlled trial among 1,260 at-risk older adults (60–77 years). Difference in the estimated mean change in CAIDE score at 2 years in the intervention compared to the control group was –0.16 (95 %CI –0.31 to 0.00) (p = 0.013), corresponding to a relative dementia risk reduction between 6.04–6.50%. This could be interpreted as a reflection of the prevention potential of the intervention.

Background Pain is undertreated in older populations. At the same time, increased use of opioids is of concern in the Western world. Aims We sought to analyze temporal trends in musculoskeletal pain and prescribed analgesic treatment among community-dwelling people aged 75-95 years using cross-sectional cohort data spanning 20 years. Methods The Helsinki Aging Study recruited random samples of people aged 75, 80, 85, 90, and 95 years in 1999, 2009, and 2019. In total, 5707 community-dwelling persons participated in the study. The participants reported their medical diagnoses, regular prescription medications, and the presence of back pain or joint pain within the last 2 weeks (never, sometimes, or daily). We compared analgesic use among participants reporting and not reporting musculoskeletal pain in 1999, 2009, and 2019. Results Of the participants, 57-61% reported intermittent or daily musculoskeletal pain. The percentage receiving a prescribed daily analgesic increased from 9% in 1999 to 16% in 2019. The use of non-steroidal anti-inflammatory drugs (NSAIDs) decreased from 1999 to 2019, while the use of paracetamol increased from 2 to 11%. Opioids were taken by 2% in 1999 and 3% in 2019. Of those reporting daily musculoskeletal pain, 20%, 35%, and 32% received regular pain medication in 1999, 2009, and 2019, respectively. Conclusions Pain remains undertreated in the community-dwelling older population, although the use of regular prescribed analgesics increased between 1999 and 2019. The use of NSAIDs has decreased, while the use of paracetamol has increased. Daily opioid use has remained modest.

Key messages Considerable proportion of patients with SpA have been immunized to the subcutaneous anti-TNF drug they are using. Concomitant use of MTX protects from immunization, whereas SASP does not. Patients with SpA using subcutaneous anti-TNF drugs can benefit from monitoring of the drug trough levels. Abstract Immunization to biological drugs can lead to decreased efficacy and increased risk of adverse effects. The objective of this cross-sectional study was to assess the extent and significance of immunization to subcutaneous tumor necrosis factor (TNF) inhibitors in axial spondyloarthritis (axSpA) patients in real-life setting. A serum sample was taken 1–2 days before the next drug injection. Drug trough concentrations, anti-drug antibodies (ADAb) and TNF-blocking capacity were measured in 273 patients with axSpA using subcutaneous anti-TNF drugs. The clinical activity of SpA was assessed using the Bath AS Disease Activity Index (BASDAI) and the Maastricht AS Entheses Score (MASES). ADAb were found in 11% of the 273 patients: in 21/99 (21%) of patients who used adalimumab, in 0/83 (0%) of those who used etanercept, in 2/79 (3%) of those who used golimumab and in 6/12 (50%) of those who used certolizumab pegol. Use of methotrexate reduced the risk of formation of ADAb, whereas sulfasalazine did not. Presence of ADAb resulted in decreased drug concentration and reduced TNF-blocking capacity. However, low levels of ADAb had no effect on TNF-blocking capacity and did not correlate with disease activity. The drug trough levels were below the consensus target level in 36% of the patients. High BMI correlated with low drug trough concentration. Patients with low drug trough levels had higher disease activity. The presence of anti-drug antibodies was associated with reduced drug trough levels, and the patients with low drug trough levels had higher disease activity. The drug trough levels were below target level in significant proportion of patients and, thus, measuring the drug concentration and ADAb could help to optimize the treatment in SpA patients.

The neuropeptide urocortin 3 (UCN3) has a beneficial effect on metabolic disorders, such as obesity, diabetes, and cardiovascular disease. It has been reported that UCN3 regulates insulin secretion and is dysregulated with increasing severity of obesity and diabetes. However, its function in the adipose tissue is unclear. We investigated the overexpression of UCN3 in 3T3-L1 preadipocytes and differentiated adipocytes and its effects on heat shock response, ER stress, inflammatory markers, and glucose uptake in the presence of stress-inducing concentrations of palmitic acid (PA). UCN3 overexpression significantly downregulated heat shock proteins (HSP60, HSP72 and HSP90) and ER stress response markers (GRP78, PERK, ATF6, and IRE1α) and attenuated inflammation (TNFα) and apoptosis (CHOP). Moreover, enhanced glucose uptake was observed in both preadipocytes and mature adipocytes, which is associated with upregulated phosphorylation of AKT and ERK but reduced p-JNK. Moderate effects of UCN3 overexpression were also observed in the presence of 400 μM of PA, and macrophage conditioned medium dramatically decreased the UCN3 mRNA levels in differentiated 3T3-L1 cells. In conclusion, the beneficial effects of UCN3 in adipocytes are reflected, at least partially, by the improvement in cellular stress response and glucose uptake and attenuation of inflammation and apoptosis.

Introduction We studied the costs of formal and informal care in relation to Alzheimer’s disease (AD) progression. Methods 231 persons with AD with a family caregiver were followed up for 5 years. The Clinical Dementia Rating Scale—Sum of Boxes (CDR-SB) was used to measure AD progression. Health and social care unit costs were used for formal care costs. An opportunity cost method for lost leisure time was applied to analyse the cost of informal care. Results Total cost of care in early stage AD (CDR-SB ≤ 4) was 16,448€ (95% CI 13,722–19,716) annually. In mild (CDR-SB 4.5–9), moderate (CDR-SB 9.5–15.5) and severe (CDR-SB ≥ 16) AD, the total costs were 2.3, 3.4 and 4.4 times higher, respectively. A one-unit increase in CDR-SB increased the total, formal and informal costs by 15, 11 and 18%, respectively. Conclusions Compared to early AD, the costs of total, formal and informal care are remarkably higher already in mild AD. This finding emphasises early diagnosis, interventions and family support for persons with AD and their caregivers.

Fatty-acid binding protein 4 (FABP4) is implicated in the pathogenesis of cardiometabolic disorders. Pharmacological inhibition or genetic deletion of FABP4 improves cardiometabolic health and protects against atherosclerosis in preclinical models. As cardiovascular disease (CVD) is common in type 1 diabetes, we examined the role of FABP4 for the development of complications in type 1 diabetes, focusing on a functional, low-expression, variant (rs77878271) in the promoter of the FABP4 gene. For this, we assessed the risk of CVD, stroke, coronary artery disease (CAD), end-stage kidney disease (ESKD), and mortality using Cox proportional-hazard models for the FABP4 rs77878271 in 5,077 Finnish individuals with type 1 diabetes. The low-expression G-allele of rs77878271 increased the risk of CVD, independently of confounders. Findings were tested for replication in 852 Danish and 3,678 Finnish individuals with type 1 diabetes. In the meta-analysis, each G-allele increased the risk of stroke by 26% (p=0.04), CAD by 26% (p=0.006), and CVD by 17% (p=0.003). In Mendelian Randomization, a decrease in FABP4 increased CAD 2.4-fold. Hence, in contrast to the general population, the low-expression G-allele of rs77878271 increased CVD risk in type 1 diabetes, suggesting that genetically low FABP4 levels may be detrimental in the context of type 1 diabetes.

Background Changes in older people’s symptoms across recent decades have not been investigated. Aims We analyzed temporal trends in symptom burden by comparing data from independent, cross-sectional cohorts retrieved in 1989, 1999, 2009, and 2019. Furthermore, we compared the association between symptom burden and psychological wellbeing (PWB) in older men and women. Methods The Helsinki Aging Study recruited a random sample of people aged 75, 80, and 85 in 1989, and random samples aged 75, 80, 85, 90, and 95 in 1999, 2009, and 2019 (four study waves). Altogether, 6263 community-dwelling people answered the questions concerning symptoms in the questionnaire surveys. The symptoms inquired in all study waves were dizziness, back pain, joint pain, chest pain, shortness of breath, and loss of appetite. Symptom burden was calculated according to the number of symptoms and their frequency (score range: 0–6). PWB and the Charlson comorbidity index were calculated. Results Symptom burden decreased in both men and women aged 75 and 80 from 1989 to 2019. Changes in cohorts aged 85 + were nonsignificant. There was a significant difference in symptom burden between men and women in all ages with men having fewer symptoms. PWB decreased with increasing symptom burden. Men had greater PWB than women up to severe levels of symptom burden. Conclusions Symptom burden decreased from 1989 to 2019 in cohorts aged 75–80, whereas changes remained nonsignificant in cohorts aged 85 +. To our knowledge, this is the first study to examine temporal trends in symptom burden.

Background Idiopathic normal pressure hydrocephalus (iNPH) is a neurodegenerative disease with a characteristic symptom triad of gait disturbance, cognitive decline, and incontinence. Recently, also dysfunctions in upper limbs have been described in iNPH and reported to improve after shunt surgery. We aim to describe the role of upper limb motor function in the clinical assessment of iNPH patients and its influence on activities of daily living (ADL). Methods Seventy-five consecutive patients with probable iNPH were studied pre-operatively and at 3 and 12 months after shunt surgery. The pre-operative evaluation included lumbar drainage of cerebrospinal fluid (tap test). Motor functions were assessed in upper and lower limbs with Grooved Pegboard Test (GPT), Box & Block Test (BBT), Total Score of Gait (TSG), and balance test. ADL was assessed with Barthel’s index and cognition in accordance with the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Results Patients showed improvement in all motor tests and ADL at 3 months after shunt surgery. The improvement remained stable during the 12-month post-operative follow-up. The motor function tests correlated with each other and with ADL. Conclusions A 3-month follow-up period after shunt surgery is adequate to show improvement in motor tasks, and a positive outcome will last for at least 12 months. A shunt-responsive dysfunction of upper limb motor performance plays a major role in ADL of iNPH patients. Therefore, we suggest an evaluation of upper limb motor performance to be included in routine evaluation of iNPH patients.