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Background: The increased comorbidity and mortality in rheumatoid arthritis (RA) patients are largely due to cardiovascular disease (CVD). Previously, we demonstrated increased frequencies of risk factors for CVD (elevated body mass index (BMI), elevated apoliprotein (Apo) B:ApoA1 ratio, and smoking) in pre-RA individuals compared with matched controls. Objectives: Assess the impact of traditional CV risk factors present before the onset of RA on the risk of CV events (CVE) after diagnosis in comparison with matched controls. Methods: A case–control study including 521 pre-symptomatic individuals and 1566 controls identified within the Health Surveys of the Medical Biobank was performed. CVD risk factors were hypertension, elevated ApoB:A1 ratio, BMI, diabetes, and smoking. Information on comorbidities was requested from the Swedish National Patient Register and Cause of Death Register. Results: Pre-RA individuals had a higher risk of future CVE compared with matched controls (HR [95% CI] 1.70 [1.31–2.21]), which remained after adjustments for risk factors for CVD (HR [95% CI] 1.73 [1.27–2.35]). Most risk factors were associated with CVE after diagnosis, and a combination resulted in a higher risk in RA compared with controls; two risk factors, HR [95% CI] 2.70 [1.19–6.13] vs. 1.26 [0.75–2.13]; and three to four risk factors, HR [95% CI] 6.32 [2.92–13.68] vs. 3.77 [2.34–6.00]. Conclusions: Risk factors for CVD present in pre-RA individuals were associated with future CVE, and even after adjustments for these risk factors and treatments after RA onset, pre-RA individuals had a higher risk of CVE compared with controls. These findings further highlight the importance of the early assessment of risk for CVD.

Background: Proteins and lipids of milk fat globule membrane (MFGM) and probiotics are immunomodulatory. We hypothesized that Lactobacillus paracasei ssp. paracasei strain F19 (F19) would augment vaccine antibody and T helper 1 type immune responses whereas MFGM would produce an immune response closer to that of breastfed (BF) infants.

Objective: To compare the effects of supplementing formula with F19 or bovine MFGM on serum cytokine and vaccine responses of formula-fed (FF) and BF infants.

Design: FF infants were randomized to formula with F19 (n = 195) or MFGM (n = 192), or standard formula (SF) (n = 194) from age 21±7 days until 4 months. A BF group served as reference (n = 208). We analyzed seven cytokines (n = 398) in serum at age 4 months using magnetic bead-based multiplex technology. Using ELISA, we analyzed anti-diphtheria IgG (n = 258) and anti-poliovirus IgG (n = 309) concentrations in serum before and after the second and third immunization, respectively.

Results: Compared with SF, the F19 group had greater IL-2 and lower IFN-γ concentrations (p<0.05, average effect size 0.14 and 0.39). Compared with BF, the F19 group had greater IL-2, IL-4 and IL-17A concentrations (p<0.05, average effect size 0.42, 0.34 and 0.26, respectively). The MFGM group had lower IL-2 and IL-17A concentrations compared with SF (p<0.05, average effect size 0.34 and 0.31). Cytokine concentrations were comparable among the MFGM and BF groups. Vaccine responses were comparable among the formula groups.

Conclusions: Contrary to previous studies F19 increased IL-2 and lowered IFN-γ production, suggesting that the response to probiotics differs across populations. The cytokine profile of the MFGM group approached that of BF infants, and may be associated with the previous finding that infectious outcomes for the MFGM group in this cohort were closer to those of BF infants, as opposed to the SF group. These immunomodulatory effects support future clinical evaluation of infant formula with F19 or MFGM.

The auditory apparatus of the inner ear does not show turnover of sensory hair cells (HCs) in adult mammals; in contrast, there are many observations supporting low-level turnover of vestibular HCs within the balance organs of mammalian inner ears. This low-level renewal of vestibular HCs exists during normal conditions and it is further enhanced after trauma-induced loss of these HCs. The main process for renewal of HCs within mammalian vestibular epithelia is a conversion/transdifferentiation of existing supporting cells (SCs) into replacement HCs.In earlier studies using long-term organ cultures of postnatal rat macula utriculi, HC loss induced by gentamicin resulted in an initial substantial decline in HC density followed by a significant increase in the proportion of HCs to SCs indicating the production of replacement HCs. In the present study, using the same model of ototoxic damage to study renewal of vestibular HCs, we focus on the ultrastructural characteristics of SCs undergoing transdifferentiation into new HCs. Our objective was to search for morphological signs of SC plasticity during this process. In the utricular epithelia, we observed immature HCs, which appear to be SCs transdifferentiating into HCs. These bridge SCs have unique morphological features characterized by formation of foot processes, basal accumulation of mitochondria, and an increased amount of connections with nearby SCs. No gap junctions were observed on these transitional cells. The tight junction seals were morphologically intact in both control and gentamicin-exposed explants. 

Purpose: To evaluate effects on growth and infection rates of supplementing infant formula with the probiotic Lactobacillus paracasei ssp. paracasei strain F19 (F19) or bovine milk fat globule membrane (MFGM).

Methods: In a double-blind, randomized controlled trial, 600 infants were randomized to a formula supplemented with F19 or MFGM, or to standard formula (SF). A breastfed group was recruited as reference (n = 200).The intervention lasted from age 21 ± 7 days until 4 months, and infants were followed until age one year.

Results: Both experimental formulas were well tolerated and resulted in high compliance. The few reported adverse events were not likely related to formula, with the highest rates in the SF group, significantly higher than for the F19-supplemented infants (p = 0.046). Weight or length gain did not differ during or after the intervention among the formula-fed groups, with satisfactory growth. During the intervention, overall, the experimental formula groups did not have more episodes of diarrhea, fever, or days with fever than the breastfed infants. However, compared to the breastfed infants, the SF group had more fever episodes (p = 0.021) and days with fever (p = 0.036), but not diarrhea. Compared with the breastfed group, the F19-supplemented infants but not the other two formula groups had more visits/unscheduled hospitalizations (p = 0.015) and borderline more episodes of upper respiratory tract infections (p = 0.048).

Conclusions: Both the MFGM- and F19-supplemented formulas were safe and well-tolerated, leading to few adverse effects, similar to the breastfed group and unlike the SF group. During the intervention, the MFGM-supplemented infants did not differ from the breastfed infants in any primary outcome.

An evaluation of Vasterbotten Intervention Programme (VIP) was recently conducted by San Sebastian et al. (BMC Public Health 19:202, 2019). Evaluation of health care interventions of this kind require 1) an understanding of both the design and the nature of the intervention, 2) correct definition of the target population, and 3) careful choice of the appropriate evaluation method. In this correspondence, we review the approach used by San Sebastian et al. as relates to these three criteria. Within this framework, we suggest important explanations for why the conclusions drawn by these authors contradict a large body of research on the effectiveness of the VIP.

Background: Several large scale community-based cardiovascular disease prevention programs were initiated in the 80s, and one was the Västerbotten Intervention Programme, Sweden. As an initial step in 1985, a pilot study was introduced in the Norsjö municipality that combined individual disease prevention efforts among the middle-aged population with community-oriented health promotion activities. All citizens at 30, 40, 50, and 60 years of age were invited to a physical examination combined with a healthy dialogue at the local primary health care centre. Västerbotten Intervention Program is still running following the same lines and is now a part of the ordinary public health in the county. The purpose of this study is to estimate the costs of running Västerbotten Intervention Programme from 1990 to 2006, versus the health gains and savings reasonably attributable to the program during the same time period. Methods: A previous study estimated the number of prevented deaths during the period 1990-2006 which can be attributed to the programme. We used this estimate and calculated the number of QALYs gained, as well as savings in resources due to prevented non-fatal cases during the time period 1990 to 2006. Costs for the programmes were based on previously published scientific articles as well as current cost data from the county council, who is responsible for the programme. Result: The cost per QALY gained from a societal perspective is SEK 650 (Euro 68). From a health care sector perspective, the savings attributable to the VIP exceeded its costs. Conclusion: Our analysis shows that Västerbotten Intervention Programme is extremely cost-effective in relation to the Swedish threshold value (SEK 500000 per QALY gained or Euro 53,000 per QALY gained). Other research has also shown a favorable effect of Västerbotten Intervention Programme on population health and the health gap. We therefore argue that all health care organizations, acting in settings reasonably similar to Sweden, have good incentive to implement programs like Västerbotten Intervention Programme.

Introduction and hypothesis: Stress urinary incontinence is common among women. First-line treatment includes pelvic floor muscle training (PFMT) and lifestyle advice, which can be provided via a mobile app. The efficacy of app-based treatment has been demonstrated in a randomized controlled trial (RCT). In this study, we aimed to analyze factors associated with successful treatment.

Methods: Secondary analysis of data from the RCT. At baseline and 3-month follow-up, participants (n = 61) answered questions about symptoms, quality of life, background, and PFMT. Success was defined as rating the condition as much or very much better according to the validated Patient Global Impression of Improvement questionnaire. Factors possibly associated with success were analyzed with univariate logistic regression; if p < 0.20, the factor was entered into a multivariate model that was adjusted for age. Variables were then removed stepwise.

Results: At follow-up, 34 out of 61 (56%) of participants stated that their condition was much or very much better. Three factors were significantly associated with success: higher expectations for treatment (odds ratio [OR] 11.38, 95% confidence interval [CI] 2.02-64.19), weight control (OR 0.44 per kg gained, 95% CI 0.25-0.79), and self-rated improvement of pelvic floor muscle strength (OR 35.54, 95% CI 4.96-254.61). Together, these factors accounted for 61.4% (Nagelkerke R-2) of the variability in success.

Conclusion: These results indicate that app-based treatment effects are better in women who are interested in and have high expectations of such treatment. Also, the findings underline the importance of strengthening the pelvic floor muscles and offering lifestyle advice.

Background: Patients with rheumatoid arthritis (RA) are at increased risk of developing cardiovascular disease (CVD). Our aim was to evaluate the impact of factors related to CVD, such as smoking, lipid levels, hypertension, body mass index (BMI) and diabetes, in individuals prior to the onset of symptoms of RA. Methods: A nested case-control study was performed including data from 547 pre-symptomatic individuals (i.e. individuals who had participated in population surveys in northern Sweden prior to onset of symptoms of RA, median time to symptom onset 5.0 (interquartile range 2.0-9.0) years) and 1641 matched controls. Within the survey, health examinations prior to symptom onset were performed, blood samples were analysed for plasma glucose and lipids, and data on lifestyle factors had been collected with a questionnaire. CVD risk factors were extracted and further analysed with conditional logistic regression models for association with subsequent RA development, including hypertension, apolipoprotein (Apo) B/ApoA1 ratio, BMI, diabetes and smoking habits. Results: Smoking and BMI >= 25 (odds ratio (OR) (95% confidence interval (CI)) = 1.86 (1.48-2.35) and OR = 1.28 (1.01-1.62), respectively) were associated with increased risk for future RA development. In women, elevated ApoB/ApoA1 ratio (OR = 1.36 (1.03-1.80)) and smoking (OR = 1.82 (1.37-2.41)) were significantly associated with being pre-symptomatic for RA, whilst in men smoking (OR = 1.92 (1.26-2.92)) and diabetes (OR = 3.62 (95% CI 1.13-11.64)) were significant. In older (> 50.19 years) individuals, only smoking (OR = 1.74 (1.24-2.45)) was significantly associated with increased risk of future RA, whereas in younger individuals the significant factors were elevated ApoB/ApoA1 ratio (OR = 1.39 (1.00-1.93)), BMI >= 25.0 (OR = 1.45 (1.04-2.02)) and smoking (OR = 2.11 (1.51-2.95)). Pre-symptomatic individuals had a higher frequency of risk factors: 41.5% had >= 3 compared with 30.4% among matched controls (OR = 2.81 (1.78-4.44)). Conclusions: Several risk factors for CVD were present in pre-symptomatic individuals and significantly associated with increased risk for future RA. These factors differed in women and men. The CVD risk factors had a greater impact in younger individuals. These results urge an early analysis of cardiovascular risk factors for proposed prevention in patients with early RA.

Background/Purpose: Individuals who later developed rheumatoid arthritis (RA) have increased levels and frequencies of risk factors for cardiovascular disease (CVD), years before onset of RA. The relationships between CVD risk factors and inflammatory markers, i.e., cytokines and chemokines, were analysed in individuals prior to onset of symptoms and compared with controls. Methods: A case-control study was based on population surveys from The Västerbotten Intervention Programme (VIP) and the WHO Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) with data collected on socioeconomic and lifestyle factors, BMI, waist, blood pressure, and blood samples by a nurse. The register of patients with RA (ARA criteria) was co-analysed with the registers from the Medical Biobank and 469 pre-symptomatic individuals (median age 50.2 years; 67.8% women, median predating time 5.0 (IQR; 2.0-8.0) years), and 234 controls (median age 50.3 years; 67.1% women) were identified. CVD risk factors were defined as: hypertension (treatment or systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg), elevated ApoB/ApoA1 ratio (women ≥0.7, men ≥0.8, including lipid lowering treatment), BMI ≥25kg/m2, diabetes, and ever being smoker. Concentrations of eotaxin, interferon gamma-induced protein (IP-10), monocyt-chemoattractant protein 1 (MCP1), macrophage derived chemokine (MDC), interleukin (IL) 2, IL-4, IL-6, IL-8, and IL-10, were analysed in plasma using R&D systems' assays (Minneapolis, MN) according to the manufacturer's instructions. Results: Pre-symptomatic individuals had significantly higher levels of IL-6 compared with controls, both in women and men. IL-10 was significantly higher in pre-symptomatic men compared with controls. Cytokines/chemokines were significantly associated with the CVD risk factors in the cases e.g. IL-6 with each of the risk factors, eotaxin with smoking, IP-10 with increased BMI, being diabetes or having hypertension, whilst MDC was associated significantly with smoking and BMI≥25 kg/m2. After adjustments for sex and age only eotaxin concentrations were significantly associated with being ever smoker. In women, MDC was significantly associated with smoking, BMI≥25 kg/m2 and diabetes. Having the combination of several CVD risk factors was associated with significantly higher concentrations of MCP-1, MDC, and IL-6 in pre-symptomatic women. IL-6 increased further the relative risk in combinations with all CVD risk factors for the pre-symptomatic cases compared with controls. Conclusion: Increased concentrations of cytokines/chemokines were associated with CVD risk factors to a higher extent among the pre-symptomatic RA cases compared with controls. The pattern of association varied between the risk factors and the sex of the cases.