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Abstract In this single‐center study, we aimed to describe the characteristics, treatment patterns, and outcomes of patients with multiple myeloma (MM) following treatment with bortezomib, carfilzomib, daratumumab, ixazomib, lenalidomide or pomalidomide‐based regimens. Data were collected retrospectively from a study cohort of patients receiving a MM treatment in the Hospital District of Helsinki and Uusimaa (HUS) in Finland between 2016–2020. In total, 472 patients were included in the study. Median age was 68.2 years and nearly 25% had a high cytogenetic risk according to the International Myeloma Working Group categorization. In 2018–2020, the spectrum of regimens used as third‐ or later‐line therapy was notably broader than in 2016–2017. The overall response rates for patients who received the most novel regimens (available ≤ 5 years) in second or third line of therapy (n = 67/430) and fourth line or later (n = 78/151) were 53.3% and 25.0%, respectively. In this real‐world MM patient cohort, the response rates for these novel agents were lower compared to those reported in clinical trials. Given the higher cytogenetic risk profile and more advanced disease stage at the time when treated with novel agents, patients could have benefited from effective novel therapies earlier in their treatment pathway. What is the NEW aspect of your work? (ONE sentence) This study characterized the treatment of Finnish multiple myeloma patients during the era of most novel therapies (after 2016) and also included information on the cytogenetic risk profile of this real‐world population. What is the CENTRAL finding of your work? (ONE sentence) There are clear differences between real‐world populations treated with most novel combinations and those of randomized controlled trials (RCTs), which is reflected by the poorer treatment outcomes in the real‐world setting. What is (or could be) the SPECIFIC clinical relevance of your work? (ONE sentence) Given the high cytogenetic risk profile and advanced disease stage at the time when treated with novel agents, patients could have benefited from effective novel therapies earlier in their treatment pathway.

Abstract Fermentation of dietary fiber by gut microbes produces short-chain fatty acids (SCFA), but fermentation outcomes are affected by dietary fiber source and microbiota composition. The aim of this study was to investigate the effect of two different fecal microbial compositions on in vitro fermentation of a standardized amount of oat, rye, and wheat breads. Two human fecal donors with different microbial community composition were recruited. Bread samples were digested enzymatically. An in vitro fermentation model was used to study SCFA production, dietary fiber degradation, pH, and changes in microbiota. Feces from donor I had high relative abundance of Bacteroides and Escherichia/Shigella, whereas feces from donor II were high in Prevotella and Subdoligranulum. Shifts in microbiota composition were observed during fermentation. SCFA levels were low in the samples with fecal microbiota from donor I after 8 h of fermentation, but after 24 h acetate and propionate levels were similar in the samples from the different donors. Butyrate levels were higher in the fermentation samples from donor II, especially with rye substrate, where high abundance of Subdoligranulum was observed. Dietary fiber degradation was also higher in the fermentation samples from donor II. In conclusion, fermentation capacity and substrate utilization differed between the two different microbiota compositions.

Taito Niemelä,1 Hannu Kankaanranta,1– 3 Iida Vähätalo,2 Juho Loponen,1,2 Leena E Tuomisto,2 Onni Niemelä,1,4 Mari Hämäläinen,5 Eeva Moilanen,5 Pinja Ilmarinen1,2 1Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; 2Department of Respiratory Medicine, Seinäjoki Central Hospital, Seinäjoki, Finland; 3Krefting Research Centre, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden; 4Department of Laboratory Medicine, Seinäjoki Central Hospital, Seinäjoki, Finland; 5The Immunopharmacology Research Group, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, Tampere, FinlandCorrespondence: Pinja Ilmarinen, Department of Respiratory Medicine, Seinäjoki Central Hospital, Seinäjoki, Finland, Tel +35 850 420 0596, Email pinja.ilmarinen@epshp.fiBackground: Soluble urokinase plasminogen activator receptor (suPAR) has emerged as a novel biomarker for various inflammatory conditions and has been proposed to associate with the severity of asthma. However, the relationship between suPAR and clinical asthma features is poorly understood.Objective: To examine associations of serum suPAR levels with clinical characteristics of asthma and to define the phenotype with high suPAR levels in patients with adult-onset asthma.Methods: Serum suPAR levels were measured with ELISA from patients with adult-onset asthma participating in the 12-year follow-up visit in the Seinäjoki Adult Asthma Study.Results: In total, 201 patients were divided into quartiles according to suPAR values. High suPAR patients had more severe asthma symptoms and poorer asthma control. They also had higher levels of interleukin 8 (IL-8), interleukin 6 (IL-6), matrix metalloproteinase 9 (MMP-9), and blood neutrophil counts than those with low suPAR levels. The use of high-dose inhaled and oral corticosteroids was more common in patients with elevated suPAR. Such patients also had visited healthcare more frequently during the follow-up period, had more comorbidities, and were physically less active than those with low suPAR levels. The above-mentioned results remained similar after excluding the patients with co-existing COPD; only association to hospitalizations was lost. In multivariable binary regression analyses, the highest suPAR quartile was associated with higher cumulative dispensed oral corticosteroid use, more severe symptoms, and uncontrolled asthma.Conclusion: High suPAR levels occur in uncontrolled adult-onset asthma patients characterized by neutrophilic inflammation, high corticosteroid use, frequent healthcare visits, and multimorbidity with unhealthy lifestyle. This biomarker could be useful in determining asthma phenotypes and target new asthma treatments.Keywords: asthma, adult-onset, neutrophil, phenotypes, suPAR, uncontrolled

Abstract Objectives We conducted this retrospective study to characterize the change in chronic lymphocytic leukemia (CLL) treatment patterns between 2005 and 2019, to understand the treatment sequencing across the course of the disease, and to investigate how targeted agents and prognostic testing were implemented into the patient care. Methods This study included adult patients with CLL treated at the Hospital District of Southwest Finland during the study period. Data were collected from the Turku University Hospital data lake. Results In total, 122 and 60 patients received first‐ and second‐line treatments for CLL, respectively. The shift from conventional chemoimmunotherapy to targeted treatments in recent years (2014–2019) was observed. The median overall survival times were not reached in patients treated with targeted agents compared to conventional standard treatments in first‐ and second‐line settings and improved toward the end of the study period. Prognostic testing increased during the study follow‐up and patients with unmutated immunoglobulin heavy‐chain variable showed significantly poorer overall survival and time‐to‐next‐treatment outcomes than patients with mutated immunoglobulin heavy‐chain variable. Conclusions This real‐world study implicated added value of targeted chemo‐free therapies as reported in randomized clinical trials, and highlighted the necessity of prognostic testing in order to improve treatment selection and patient outcomes.

Abstract Background A low intake of Fermentable, Oligo-, Di-, Mono-saccharides and Polyols (FODMAPs) is effective in the symptom control of irritable bowel syndrome (IBS) patients but may exert negative effects on the intestinal microbiota. The microbial effects of increasing regular or non-FODMAP fibre sources are largely unknown. Furthermore, it is not known if the baseline microbiota composition is associated with individual symptom control during the consumption of different rye products in IBS patients. Our objective was to evaluate whether increased consumption of low-FODMAP rye bread or regular rye bread for 4 weeks would alter the intestinal microbiota composition of IBS patients following their habitual diet, and whether these changes associate to symptoms and/or the baseline microbiota. Methods The study was conducted as a randomized double blind controlled cross-over study (n = 50). Microbiota was analysed by 16S rRNA gene sequencing and associated with gastrointestinal symptoms. Both microbial changes and their associations to symptoms were secondary outcomes. Results The consumption of the test breads did not alter microbiota diversity. Compared to baseline, consumption of the low FODMAP rye bread decreased the abundance of Bacteroides, Flavonifractor, Holdemania, Parasutterella and Klebsiella and showed a trend towards increased bifidobacteria, whereas the regular rye bread decreased the abundance of Flavonifractor. When comparing between the two test breads, Klebsiella was decreased after low-FODMAP rye bread intake. Patients whose symptoms decreased during the low-FODMAP rye bread displayed more Blautia and less Barnesiella at baseline. Conclusions Consumption of low-FODMAP rye bread had modest, potentially beneficial effects on patients’ microbiota while increasing their intake of fibre substantially. The baseline microbiota composition was associated with the variable degrees of symptom relief experienced by the patients. Consumption of a low-FODMAP rye bread might be one way to increase dietary fibre intake and improve the mild dysbiosis often observed among patients with IBS. Trial registration ClinicalTrials.gov: NCT02161120. Retrospectively registered 11 June 2014.

Abstract Background Type 1 neurofibromatosis (NF1) is a genetic tumor predisposing Rasopathy. NF1 patients have an increased risk for developing benign and malignant tumors, but the occurrence of intestinal tumors has not been investigated at the population level. Methods In this retrospective register‐based total population study, diagnoses of gastrointestinal tract tumors were retrieved from the Finnish Care Register for Health Care for 1,410 NF1 patients and 14,030 reference persons. We also reviewed the death certificates of 232 NF1 patients who died during years 1987–2013, and specifically searched for diagnosis of gastrointestinal stromal tumor (GIST). Results The register analysis revealed an increased overall hazard ratio (HR) of 2.6 (95% CI 1.9–3.6) for intestinal tumors in NF1 compared to general population. The highest HR of 15.6 (95% CI 6.9–35.1) was observed in the small intestine. The focused analysis of NF1 death certificates and GISTs demonstrated that the GIST was the primary cause of death in seven patients. Conclusion This study emphasizes the need for careful evaluation of NF1 patients with gastrointestinal complaints. The challenge in diagnosis is that the tumors preferably occur at the small intestine, which is difficult target for diagnostic procedures. We also show that the NF1 GISTs may lead to fatal outcome despite of benign histopathological findings at the time of the diagnosis.

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The ingestion of gluten-containing foods can cause wheat-related disorders in up to 15% of wheat consuming populations. Besides the role of gluten, α-amylase/trypsin inhibitors (ATI) have recently been identified as inducers of an innate immune response via toll-like receptor 4 in celiac disease and non-celiac wheat sensitivity. ATI are involved in plant self-defense against insects and possibly in grain development. Notably, they are largely resistant to gastrointestinal proteases and heat, and their inflammatory activity affects not only the intestine, but also peripheral organs. The aim of this study was to understand the changes of ATI throughout the sourdough and yeast-fermented bread-making processes. ATI tetramers were isolated, fluorescein-labelled, and added to a mini-dough bread-making system. When the pH decreased below 4.0 in sourdough fermentation, the ATI tetramers were degraded due to the activation of aspartic proteases, whilst in yeast fermentation, ATI tetramers remained intact. The amylase inhibitory activity after sourdough fermentation decreased significantly, while the concentration of free thiol groups increased. The glutathione reductase activity of Fructilactobacillus sanfranciscensis did not contribute to the reduction of ATI tetramers. Compared to the unfermented wheat, sourdough fermentation was able to decrease the release of pro-inflammatory cytokines monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor alpha (TNF-α) in quantitative ATI extracts added to the human monocytic cell line THP-1. The current data suggest that sourdough fermentation can degrade ATI structure and bioactivity, and point to strategies to improve product development for wheat sensitivity patients.

Background: There is a lack of knowledge on the association between daily physical activity and lung function in patients with asthma. Objective: This study aims to examine the association between daily physical activity and asthma control, lung function, and lung function decline in patients with adult-onset asthma. Design: This study is part of Seinäjoki Adult Asthma Study (SAAS), where 201 patients were followed for 12 years after asthma diagnosis. Daily physical activity was assessed at follow-up by a structured questionnaire and used to classify the population into subgroups of low (≤240 min) or high (>240 min) physical activity. Three spirometry evaluation points were used: 1. diagnosis, 2. the maximum lung function during the first 2.5 years after diagnosis (Max0-2.5), 3. follow-up at 12 years. Results: High physical activity group had slower annual FEV1 (p

A low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet allows most irritable bowel syndrome (IBS) patients to manage their gastrointestinal symptoms by avoiding FODMAP-containing foods, such as onions, pulses, and products made from wheat or rye. The downside of a low FODMAP diet is the reduced intake of dietary fiber. Applying sourdoughs—with specific FODMAP-targeting metabolic properties—to wholegrain bread making can help to remarkably reduce the content of FODMAPs in bread without affecting the content of the slowly fermented and well-tolerated dietary fiber. In this review, we outline the metabolism of FODMAPs in conventional sourdoughs and outline concepts related to fructan and mannitol metabolism that allow development of low FODMAP sourdough bread. We also summarize clinical studies where low FODMAP but high fiber, rye sourdough bread was tested for its effects on gut fermentation and gastrointestinal symptoms with very promising results. The sourdough bread-making process offers a means to develop natural and fiber-rich low FODMAP bakery products for IBS patients and thereby help them to increase their dietary fiber intake.

Sensory hair cells and supporting cells of the mammalian inner ear are quiescent cells, which do not regenerate. In contrast, non-mammalian supporting cells have the ability to re-enter the cell cycle and produce replacement hair cells. Earlier studies have demonstrated cyclin D1 expression in the developing mouse supporting cells and its downregulation along maturation. In explant cultures of the mouse utricle, we have here focused on the cell cycle control mechanisms and proliferative potential of adult supporting cells. These cells were forced into the cell cycle through adenoviral-mediated cyclin D1 overexpression. Ectopic cyclin D1 triggered robust cell cycle re-entry of supporting cells, accompanied by changes in p27(Kip1) and p21(Cip1) expressions. Main part of cell cycle reactivated supporting cells were DNA damaged and arrested at the G2/M boundary. Only small numbers of mitotic supporting cells and rare cells with signs of two successive replications were found. Ectopic cyclin D1-triggered cell cycle reactivation did not lead to hyperplasia of the sensory epithelium. In addition, a part of ectopic cyclin D1 was sequestered in the cytoplasm, reflecting its ineffective nuclear import. Combined, our data reveal intrinsic barriers that limit proliferative capacity of utricular supporting cells.

Angiotensin converting enzyme (ACE) regulates blood pressure (BP) by hydrolytic actions. ACEinhibitors are widely used in the pharmacological treatment of hypertension. Certain food-derived peptides can also inhibit the activity of ACE. This study shows the occurrences of known ACE-inhibitory peptides in cereal storage protein structures. A literature search yielded thirty-nine candidate peptides. Of these, twenty-two peptides were found to occur in the cereal storage proteins. For instance, of the tripeptides (isoleucine-proline-proline or valine-proline-proline) that lower BP in fermented milk products either one appears in cereal prolamins. In addition, oat globulins possess seven of the candidate peptides in their structures, whereas tripeptides leucine-glutamine-proline (LQP) and valine-serine-proline (VSP) occur repeatedly in C-hordeins and ù-secalins (LQP), and D-hordeins (VSP). Cereal storage proteins, thus, appeared as potential sources of ACE-inhibitory peptides. Novel cereal products with BP-lowering effects may be developed by liberation of the target peptides.;

Abstract Background Lack of suitable mouse models has hindered the studying of diabetic macrovascular complications. We examined the effects of type 2 diabetes on coronary artery disease and cardiac function in hypercholesterolemic low-density lipoprotein receptor-deficient apolipoprotein B100-only mice (LDLR-/-ApoB100/100). Methods and results 18-month-old LDLR-/-ApoB100/100 (n = 12), diabetic LDLR-/-ApoB100/100 mice overexpressing insulin-like growth factor-II (IGF-II) in pancreatic beta cells (IGF-II/LDLR-/-ApoB100/100, n = 14) and age-matched C57Bl/6 mice (n = 15) were studied after three months of high-fat Western diet. Compared to LDLR-/-ApoB100/100 mice, diabetic IGF-II/LDLR-/-ApoB100/100 mice demonstrated more calcified atherosclerotic lesions in aorta. However, compensatory vascular enlargement was similar in both diabetic and non-diabetic mice with equal atherosclerosis (cross-sectional lesion area ~60%) and consequently the lumen area was preserved. In coronary arteries, both hypercholesterolemic models showed significant stenosis (~80%) despite positive remodeling. Echocardiography revealed severe left ventricular systolic dysfunction and anteroapical akinesia in both LDLR-/-ApoB100/100 and IGF-II/LDLR-/-ApoB100/100 mice. Myocardial scarring was not detected, cardiac reserve after dobutamine challenge was preserved and ultrasructural changes revealed ischemic yet viable myocardium, which together with coronary artery stenosis and slightly impaired myocardial perfusion suggest myocardial hibernation resulting from chronic hypoperfusion. Conclusions LDLR-/-ApoB100/100 mice develop significant coronary atherosclerosis, severe left ventricular dysfunction with preserved but diminished cardiac reserve and signs of chronic myocardial hibernation. However, the cardiac outcome is not worsened by type 2 diabetes, despite more advanced aortic atherosclerosis in diabetic animals.

The article discusses the improvement of the baking properties of oats through the prevention by tryptophanin proteins of the lipid-induced destabilization of foam structures. It notes that the quality of foam has declined in the water extraction of kilned oats with nonpolar triglycerides. It mentions that gas retention in oat dough is attained through stable surface properties of the aqueous phase of the baking process.

Background: Current guidelines recommend [beta]-blockers as the first-line preventive treatment of atrial fibrillation (AF) after cardiac surgery. Despite this, 19% of physicians report using amiodarone as first-line prophylaxis of postoperative AF. Data directly comparing the efficacy of these agents in preventing postoperative AF are lacking. Objective: To determine whether intravenous metoprolol and amiodarone are equally effective in preventing postoperative AF after cardiac surgery. Design: Randomized, prospective, equivalence, open-label, multicenter study. (ClinicalTrials.gov registration number: NCT00784316) Setting: 3 cardiac care referral centers in Finland. Patients: 316 consecutive patients who were hemodynamically stable and free of mechanical ventilation and AF within 24 hours after cardiac surgery. Intervention: Patients were randomly assigned to receive 48-hour infusion of metoprolol, 1 to 3 mg/h, according to heart rate, or amiodarone, 15 mg/kg of body weight daily, with a maximum daily dose of 1000 mg, starting 15 to 21 hours after cardiac surgery. Measurements: The primary end point was the occurrence of the first AF episode or completion of the 48-hour infusion. Results: Atrial fibrillation occurred in 38 of 159 (23.9%) patients in the metoprolol group and 39 of 157 (24.8%) patients in the amiodarone group (P = 0.85). However, the difference (-0.9 percentage point [90% CI, -8.9 to 7.0 percentage points]) does not meet the prespecified equivalence margin of 5 percentage points. The adjusted hazard ratio of the metoprolol group compared with the amiodarone group was 1.09 (95% CI, 0.67 to 1.76). Limitations: Caregivers were not blinded to treatment allocation, and the trial evaluated only stable patients who were not at particularly elevated risk for AF. The withdrawal of preoperative [beta]-blocker therapy may have increased the risk for AF in the amiodarone group. Conclusion: The occurrence of AF was similar in the metoprolol and amiodarone groups. However, because of the wide range of the CIs, the authors cannot conclude that the 2 treatments were equally effective. Primary Funding Source: The Finnish Foundation for Cardiovascular Research and the Kuopio University EVO Foundation. [ABSTRACT FROM AUTHOR]

Background: We have reviewed our experience with octogenarians undergoing coronary artery bypass grafting. Methods: A consecutive series of 274 patients age 80 years or greater out of 3,474 patients who underwent isolated coronary artery bypass grafting. We have assessed the intrinsic risk aged 80 years or greater by comparing them with a propensity score-matched cohort of younger patients with similar operative risk (other than age). Results: Thirty-day mortality (4.7% vs 1.3%, p < 0.0001), combined adverse event rates (13.1% vs 6.6%, p < 0.0001), and five-year survival (76.6% vs 90.4%, p < 0.0001) were significantly poorer among patients aged 80 years or greater as compared with younger patients. These figures were, however, better than estimates of a recent systematic review by McKellar and colleagues (McKellar SH, Brown ML, Frye RL, Schaff HV, Sundt TM III. Comparison of coronary revascularization procedures in octogenarians: a systematic review and meta-analysis. Nat Clin Pract Cardiovasc Med 2008;5:738–46) (30-day mortality 7.2%, and five-year survival, 68%). When octogenarians were compared with 273 propensity score-matched patients aged less than 80 years, the 30-day mortality (4.8% vs 2.6%, p = 0.17) and combined adverse event rates (13.2% vs 10.6%, p = 0.36) did not significantly differ. Five-year survival, despite statistical significance, was not remarkably lower than that of propensity-matched patients aged less than 80 years (77.0% vs 81.3%, p = 0.009). The decrease in survival of octogenarians was evident only during the first few months after surgery, but not later on. Conclusions: The results of this study suggest that immediate and five-year survival of octogenarians undergoing coronary artery bypass grafting may be even better than previously estimated. Survival of octogenarians may be suboptimal only during the first few months after surgery, whereas at five years may not differ remarkably from younger patients with otherwise similar operative risk. [Copyright &y& Elsevier]