Global RNA modifications to the MALAT1 triple helix differentially affect thermostability and weaken binding to METTL16.

Therapeutic mRNAs are generated using modified nucleotides, namely N1-methylpseudouridine (m1Ψ) triphosphate, so that the mRNA evades detection by the immune system. RNA modifications, even at a single-nucleotide position, perturb RNA structure, although it is not well understood how structure and function is impacted by globally modified RNAs. Therefore, we examined the metastasis-associated lung adenocarcinoma transcript 1 triple helix, a highly structured stability element that includes single-, double-, and triple-stranded RNA, globally modified with N6-methyladenosine (m6A), pseudouridine (Ψ), or m1Ψ. UV thermal denaturation assays showed that m6A destabilizes both the Hoogsteen and Watson-Crick faces of the RNA by ∼20 °C, Ψ stabilizes the Hoogsteen and Watson-Crick faces of the RNA by ∼12 °C, and m1Ψ has minimal effect on the stability of the Hoogsteen face of the RNA but increases the stability of the Watson-Crick face by ∼9 °C. Native gel-shift assays revealed that binding of the methyltransferase-like protein 16 to the metastasis-associated lung adenocarcinoma transcript 1 triple helix was weakened by at least 8-, 99-, and 23-fold, respectively, when RNA is globally modified with m6A, Ψ, or m1Ψ. These results demonstrate that a more thermostable RNA structure does not lead to tighter RNA-protein interactions, thereby highlighting the regulatory power of RNA modifications by multiple means.

Recommendations for asthma monitoring in children: A PeARL document endorsed by APAPARI, EAACI, INTERASMA, REG, and WAO.

Monitoring is a major component of asthma management in children. Regular monitoring allows for diagnosis confirmation, treatment optimization, and natural history review. Numerous factors that may affect disease activity and patient well-being need to be monitored: response and adherence to treatment, disease control, disease progression, comorbidities, quality of life, medication side-effects, allergen and irritant exposures, diet and more. However, the prioritization of such factors and the selection of relevant assessment tools is an unmet need. Furthermore, rapidly developing technologies promise new opportunities for closer, or even "real-time," monitoring between visits. Following an approach that included needs assessment, evidence appraisal, and Delphi consensus, the PeARL Think Tank, in collaboration with major international professional and patient organizations, has developed a set of 24 recommendations on pediatric asthma monitoring, to support healthcare professionals in decision-making and care pathway design.

The link between early childhood lower airway symptoms, airway hyperresponsiveness, and school-age lung function.

BACKGROUND: The role of early airway hyperresponsiveness (AHR) in the lung function of school-age children is currently unclear. OBJECTIVE: To conduct a prospective follow-up study of lung function in schoolchildren with a history of lower airway symptoms and AHR to methacholine in early childhood and to compare the findings to schoolchildren with no previous or current lung diseases. We also explored symptoms and markers of type 2 inflammation. METHODS: In 2004 to 2011, data on atopic markers, lung function, and AHR to methacholine were obtained from 193 symptomatic children under 3 years old. In 2016 to 2018, a follow-up sample of 84 children (median age, 11 years; IQR, 11-12) underwent measurements of atopic parameters, lung function, and AHR to methacholine. Moreover, in 2017 to 2018, 40 controls (median age, 11 years; IQR, 9-12) participated in the study. RESULTS: Schoolchildren with early childhood lower airway symptoms and increased AHR had more frequent blood eosinophilia than their peers without increased AHR and lower prebronchodilator forced expiratory volume in 1 second (FEV1) and FEV1/forced vital capacity Z-scores than those without increased AHR and controls. Post-bronchodilator values were not significantly different between the two AHR groups. Atopy in early childhood (defined as atopic eczema and at least 1 positive skin prick test result) was associated with subsequent lung function and atopic markers, but not AHR. CONCLUSION: In symptomatic young children, increased AHR was associated with subsequent obstructive lung function, which appeared reversible by bronchodilation, and blood eosinophilia, indicative of type 2 inflammation.

The Finnish versions of food allergy quality of life questionnaires including parent form 10.

AIM: Examining health-related quality of life (HRQoL) is important to improve patient care. In this study, we translate and evaluate the Finnish versions of the Food Allergy Specific Quality of Life Questionnaires (FAQLQs) from a Finnish perspective and undertake a detailed evaluation of the 10-question Parent Form Questionnaire (FAQLQ-PF10). METHODS: This validation study was performed to evaluate the Finnish versions of the FAQLQs. Validation was performed by analysing clinical characteristics, factor loadings and Cronbach's α reliability estimates. The inclusion criteria for participants in this study were having a doctor-diagnosed food allergy or being a parent of a child with a doctor-diagnosed food allergy and being able to answer the questionnaire in Finnish. RESULTS: Altogether, 247 questionnaires were completed in this study. Most of the respondents had multiple food allergies (77%, 189/247). Spearman's correlations related to the 10-question parent form (FAQLQ-PF10), the 30-question parent form (FAQLQ-PF) and the Food Allergy Severity Measurement-Parent Form (FAIM-PF) were statistically significant (p value = 0.000-0.007). The reliability of the Finnish versions of the FAQLQs measured by Cronbach's α was overall good (0.75-0.981). CONCLUSION: The Finnish versions of the FAQLQs are reliable and suitable to use, and the FAQLQ-PF10 has good usability.

Long-term changes in milk component immunoglobulins reflect milk oral immunotherapy outcomes in Finnish children.

BACKGROUND: Milk oral immunotherapy (OIT) may increase the amount of milk protein that can be ingested without triggering an allergic reaction. It is important to understand why some patients benefit from the treatment while others do not. OBJECTIVE: The aim was to define the differences in the milk allergen component-specific (casein, α-lactalbumin, ß-lactoglobulin) immunoglobulin (sIg [sIgE, sIgG4, and sIgA]) levels relative to the long-term outcomes of milk OIT. METHODS: In this long-term, open-label follow-up study, 286 children started milk OIT between 2005 and 2015. Follow-up data were collected at two points: the post-buildup phase and long term (range 1-11 years, median 6 years). Comparisons of sIg levels were made among three outcome groups of self-reported long-term milk consumption (high-milk dose, low-milk dose, and avoidance). RESULTS: A total of 168 (59%) of the 286 patients on OIT participated. Most patients (57%) were in the high-dose group; here, 80% of these patients had a baseline casein sIgE value less than 28 kUA/L, they had the lowest casein sIgE levels at all time (p < .001), their casein sIgG4/IgE levels increased, and long-term casein sIgA was highest compared with the low-dose and avoidance groups (p = .02). Low-milk dose group had the highest casein sIgG4/IgE levels in long term (p = .002). CONCLUSION: The baseline Ig profiles and responses to milk OIT differed depending on long-term milk consumption. Lower casein sIgE levels were associated with better outcome. Milk casein sIgA differed in the long term among high-milk consumers.

Interaction of mediators and effector cells in cashew nut-induced anaphylaxis.

BACKGROUND: The underlying mechanisms of an immediate food-induced allergic reaction involve mast cell degranulation and recruitment of other effector cells, such as lymphocytes, eosinophils, and basophils. How the interaction of various mediators and cells results in anaphylaxis is not fully understood. OBJECTIVE: To evaluate changes in platelet-activating factor (PAF), platelet-activating factor acetylhydrolase (PAF-AH), tryptase, eosinophils, basophils, and eosinophil cationic protein (ECP) in cashew nut-induced anaphylaxis. METHODS: Open cashew nut challenges were performed on 106 children (aged 1-16 years), sensitized to cashew nut, with earlier allergic reaction to cashew nut or no known exposure. PAF, PAF-AH, tryptase, ECP, eosinophils, and basophils were measured at 4 time points. RESULTS: Of 72 challenges with positive results, 34 were defined as anaphylactic. Eosinophil count decreased progressively during an anaphylactic reaction at all 4 time points (P < .005*) compared with baseline. Although significant PAF elevation was observed 1 hour from moderate-to-severe reaction (P = .04*), PAF seemed to peak especially in anaphylaxis but did not achieve statistical significance. PAF peak ratio (peak PAF/baseline PAF) was significantly greater in anaphylactic reactions compared with the no-anaphylaxis group (P = .008*). Maximal percentage change in eosinophils revealed negative correlation to severity score and PAF peak ratio (Spearman's rho -0.424 and -0.516, respectively). Basophils decreased significantly in moderate-to-severe reactions and in anaphylaxis (P < .05*) compared with baseline. Delta-tryptase (peak tryptase minus baseline) did not differ significantly between anaphylaxis and the no-anaphylaxis subgroups (P = .05). CONCLUSION: PAF is a specific anaphylaxis biomarker. Marked decline of eosinophils during anaphylaxis may be related to robust secretion of PAF reflecting migration of eosinophils to target tissues.

Topical tacrolimus versus corticosteroids in childhood moderate-to-severe atopic dermatitis and the impact on airway inflammation: a long-term randomized open-label study.

BACKGROUND: Childhood atopic dermatitis (AD) is often followed by other atopic comorbidities such as asthma. AIM: To compare the effectiveness of topical tacrolimus (TAC) and topical corticosteroids (TCSs) and their impact on airway inflammation and bronchial hyperresponsiveness in patients with paediatric AD. METHODS: This was a 3-year randomized open-label comparative follow-up study of 152 1-3-year-old children with moderate-to-severe AD (trial registration: EudraCT2012-002412-95). Frequent study visits including clinical examinations, laboratory investigations (total IgE, specific IgEs, blood eosinophils), skin prick and respiratory function tests to assess airway inflammation and bronchial hyperresponsiveness (exhaled nitric oxide, airway responsiveness to exercise and methacholine) were performed. RESULTS: Changes in eczema parameters at 36 months were similar in the TCS and TAC groups for mean body surface area (BSA) difference 1.4 [95% confidence interval (CI) -1.48 to 4.19); P = 0.12], mean Eczema Area and Severity Index (EASI) difference 0.2 (95% CI -1.38 to 1.82; P = 0.2), mean Investigator's Global Assessment (IGA) difference, 0.3 (95% CI -0.12 to 0.67; P = 0.12) and mean transepidermal water loss (TEWL) difference at the eczema site, -0.3 (95% CI -4.93 to 4.30; P = 0.96) and at the control site, 1.4 (95% CI -0.96 to 3.60, P = 0.19). The control-site TEWL increased more towards the end of follow-up in the TCS vs. TAC group (mean change difference -4.2, 95% CI -8.14 to -0.29; P = 0.04). No significant impact on development of airway inflammation or bronchial hyperresponsiveness occurred in early effective eczema-treatment responders vs. others ('early' vs. 'other' response was defined as the difference in treatment response to airway outcomes in BSA, EASI or IGA at 3 months). CONCLUSION: Children with moderate-to-severe AD benefit from long-term treatment with TCS or TAC. There were no significant differences in treatment efficacy. No differences in the impact on airways occurred between early effective treatment responders vs. others.

Impact of a digital web-based asthma platform, a real-life study.

BACKGROUND: Digital health technology (DHT) is a growing area in the treatment of chronic diseases. Study results on DHT's effect on asthma control have been mixed, but benefits have been seen for adherence, self-management, symptoms, and quality of life. The aim was to evaluate the impact of an interactive web-based asthma treatment platform on asthma exacerbations and health care visits. METHODS: In this real-life study, we retrospectively collected data on adult patients registered on a web-based interactive asthma treatment platform between December 2018 and May 2021. Patients who activated their accounts were active users, and patients who did not were inactive users and considered as controls. We compared the number of exacerbations, total number of exacerbation events defined as the sum of oral corticosteroid (OCS) and antimicrobial courses, emergency room visits, hospitalizations, and asthma-related health care visits before and one year after the registration on the platform. Statistical tests used included the t-test, Pearson's chi-square test and Poisson regression models. RESULTS: Of 147 patients registered on the platform, 106 activated their accounts and 41 did not. The active users had significantly fewer total number of exacerbation events (2.56 per person years, relative decline 0.78, 95% CI 0.6 to 1.0) and asthma-related health care visits (2.38 per person years, relative decline 0.84, 95% CI 0.74 to 0.96) than before registration to the platform, whereas the reductions in health care visits and the total number of exacerbation events were not significant in the inactive users. CONCLUSIONS: An interactive web-based asthma platform can reduce asthma-related health care visits and exacerbations when used actively.

Managing the allergy and asthma epidemic in 2020s-Lessons from the Finnish experience.

In Finland, a systematic public health programme was implemented from 2008 to 2018 to mitigate the burden of allergic disorders by revisiting the prevention strategy. Allergy health and contacts with natural environment were emphasized to promote immunological and psychological resilience instead of poorly justified avoidance. Allergy management practices were improved and low-valued recommendations for care, for example for food allergy, were revised. Patients and families were empowered to use guided self-management to proactively stop symptom exacerbations. A professional non-governmental organization implemented the nationwide education for healthcare and patient NGOs for patients, families and lay public. In healthcare, the work supporting allergic patients and families was organized towards common goals and integrated into everyday work without extra costs. Reaching the predefined goals was followed by employing the national healthcare registers and questionnaire surveys. Governmental bodies contributed with kick-off funding, which was supplemented by private funding. International collaboration, for example with the European patient organization (EFA), increased awareness of the Finnish action and predisposed it for peer review. The 10-year results are favourable, patients are less disabled, practices and attitudes in healthcare have changed, and major cost savings have been obtained. Views of the lay public and patients are slow to move, however. Local multidisciplinary allergy teams were set up to continue the activities also after the Programme. Changes in environment and lifestyle in the last 50 years are the main reasons for the allergy rise. The Finnish experience may help to manage allergic diseases, improve nature relatedness in the fast-urbanizing world, combat nature loss and reduce the disease burden.

Optimizing tools for evaluating challenge outcomes in children with cashew nut allergy.

BACKGROUND: The incidence of cashew nut anaphylaxis is increasing and there is a need for accurate diagnostic tests. Age-specific cutoffs in children are lacking. Changes in serum tryptase levels are not well documented in pediatric food allergy, except in anaphylaxis. OBJECTIVE: To evaluate the ability of various tests to diagnose cashew nut allergy and to predict reaction severity. We also investigated changes in tryptase and their correlation to reaction severity. METHODS: We performed an open cashew nut challenge on 106 children (aged 1-16 years), who were sensitized to cashew nut with either previous allergic reaction to cashew nut or no known exposure. We analyzed the accuracy of Ana o 3 immunoglobulin E (IgE), cashew nut IgE, skin prick test, basophil activation test (BAT), and combinations thereof to diagnose cashew nut allergy and to predict reaction severity. Tryptase level was measured at the baseline and during an allergic reaction. RESULTS: A total of 72 children had positive challenge outcomes. Ana o 3 IgE seemed to be the best single test to diagnose cashew allergy, with a 0.97 kU/L cutoff exhibiting 94.1% specificity and 61.1% sensitivity. Though BAT values of at least 22.8% best predicted reaction severity, with 91.7% specificity and 60.7% sensitivity, the cutoffs were age-specific. Tryptase levels increased substantially 1 to 2 hours after the first allergic symptoms compared with baseline. CONCLUSION: Ana o 3 IgE seems to be the best diagnostic test in pediatric cashew nut allergy, and test combinations do not seem to improve the diagnostics. Cutoffs are age-specific. BAT is promising in predicting reaction severity. Tryptase levels should be measured 1 to 2 hours after initiation of an allergic reaction.

Allergic sensitisation did not affect bronchial hyper-responsiveness in children without respiratory tract symptoms.

AIM: The potential for immunotherapy to prevent asthma development has become a hot topic. This prompted us to revisit data from an early study that examined allergic sensitisation on bronchial hyperresponsiveness (BHR) in children with and without respiratory symptoms. Unlike previous studies, it used both indirect and direct test methods. METHODS: The study was conducted in Kuopio, Finland, in 1994 and 247 children (55.1% boys) with a mean age 10.5 ± 1.7 years were recruited using a school survey: 165 with lower respiratory symptoms and 82 healthy controls. Each child underwent a 6-min free-running test and a methacholine test with a cumulative dose of 4900 µg. All participants underwent skin-prick tests: 127were sensitised and 120 were non-sensitised. RESULTS: There were no significant differences in lung function between the sensitised and non-sensitised children. However, sensitisation was associated with BHR which was measured by both the methacholine test (2400 µg versus >4900 µg, p < 0.001) and the free-running test (-3.5% versus -2.6%, p = 0.042). No such differences were observed among the healthy controls. Sensitisation was a predictor of allergic diseases, and only multisensitisation to a minimum of four allergens increased the incidence of asthma. CONCLUSION: Allergic sensitisation did not affect BHR in children without respiratory symptoms.

The Finnish Allergy Program 2008-2018: Society-wide proactive program for change of management to mitigate allergy burden.

A 10-year national program to improve prevention and management of allergic diseases and asthma was implemented in Finland (population 5.5. million) in 2008-2018. The main aim was to reduce the long-term burden of these conditions. The strategy was changed from traditional avoidance to tolerance and resilience of the population. Health was endorsed instead of medicalization of mild symptoms. Disease severity was reevaluated, and disabling clinical manifestations were given high priority. For health care, 5 quantitative goals and 1 qualitative goal were set. For each of the goals, specific tasks, tools, and outcome evaluation were stipulated. During the program, 376 educational sessions gathered 24,000 health care participants. An information campaign targeted the lay public, and social media was used to contact people. In the 10 years of the program, the prevalence of allergic diseases and asthma leveled off. Asthma caused fewer symptoms and less disability, and 50% fewer hospital days. Food allergy diets in day care and schools decreased by half. Occupational allergies were reduced by 45%. In 2018, the direct and indirect costs of allergic diseases and asthma ranged from €1.5 billion to €1.8 billion, with the 2018 figures being 30% less than in the respective figures in 2007. The Finnish proactive and real-world intervention markedly reduced the public health burden of allergic disorders. The allergy paradigm was revisited to improve management with systematic education.

Impact of Nordic Arthroplasty Register Association (NARA) collaboration on demographics, methods and revision rates in knee arthroplasty: a register-based study from NARA 2000-2017.

BACKGROUND AND PURPOSE: We have previously observed differences in treatment and outcome of knee arthroplasties in the Nordic countries. To evaluate the impact of Nordic collaboration in the last 15 years we aimed to compare patient demographics, methods, and revision rates in primary knee arthroplasties among the 4 Nordic countries. PATIENTS AND METHODS: We included 535,051 primary knee arthroplasties reported 2000-2017 from the Nordic Arthroplasty Register Association (NARA) database. Kaplan-Meier analysis (KM) and restricted mean survival time (RMST) analysis were used to evaluate the cumulative revision rate (CRR) and RMST estimates with 95% confidence intervals (CI) and to compare countries in relation to risk of revision for any reason. RESULTS: After 2010, the increase in incidence of knee arthroplasty plateaued in Sweden and Denmark but continued to increase in Finland and Norway. In 2017 the incidence was highest in Finland with 226 per 105 person-years, while it was less than 150 per 105 in the 3 other Nordic countries. In total knee arthroplasties performed for osteoarthritis (OA), overall CRR at 15 years for revision due to any reason was higher in Denmark (CRR 9.6%, 95% CI 9.2-10), Norway (CRR 9.1%, CI 8.7-9.5), and Finland (CRR 7.0%, CI 6.8-7.3) compared with Sweden (CRR 6.6%, CI 6.4-6.8). There were differences among the countries in use of implant brand and type, fixation, patellar component, and use of unicompartmental knee arthroplasty. INTERPRETATION: We evinced a slowing growth of incidence of knee arthroplasties in the Nordic countries after 2010 with Finland having the highest incidence. We also noted substantial differences among the 4 Nordic countries, with Sweden having a lower risk of revision than the other countries. No impact of NARA could be demonstrated and CRR did not improve over time.

Early Onset Rapidly Progressive Osteoarthritis of the Hip in a Young Athlete.

We report and discuss a very rare case of early-stage rapidly progressive osteoarthritis (RPO) in a 33-year-old female athlete. The etiopathology of RPO remained unclear, although in this case mechanical overloading due to constant joint overuse appeared to be the only significant contributing factor to the very early development of RPO. Key words: rapidly progressive osteoarthritis, rapid destructive arthrosis, hip arthrosis, total hip arthroplasty, athlete, osteoarthritis.

Immunological resilience and biodiversity for prevention of allergic diseases and asthma.

Increase of allergic conditions has occurred at the same pace with the Great Acceleration, which stands for the rapid growth rate of human activities upon earth from 1950s. Changes of environment and lifestyle along with escalating urbanization are acknowledged as the main underlying causes. Secondary (tertiary) prevention for better disease control has advanced considerably with innovations for oral immunotherapy and effective treatment of inflammation with corticosteroids, calcineurin inhibitors, and biological medications. Patients are less disabled than before. However, primary prevention has remained a dilemma. Factors predicting allergy and asthma risk have proven complex: Risk factors increase the risk, while protective factors counteract them. Interaction of human body with environmental biodiversity with micro-organisms and biogenic compounds as well as the central role of epigenetic adaptation in immune homeostasis have given new insight. Allergic diseases are good indicators of the twisted relation to environment. In various non-communicable diseases, the protective mode of the immune system indicates low-grade inflammation without apparent cause. Giving microbes, pro- and prebiotics, has shown some promise in prevention and treatment. The real-world public health programme in Finland (2008-2018) emphasized nature relatedness and protective factors for immunological resilience, instead of avoidance. The nationwide action mitigated the allergy burden, but in the lack of controls, primary preventive effect remains to be proven. The first results of controlled biodiversity interventions are promising. In the fast urbanizing world, new approaches are called for allergy prevention, which also has a major cost saving potential.

Overweight and exercise-induced bronchoconstriction - Is there a link?

BACKGROUND: The objective of this study was to evaluate the role of body mass index with regard to exercise performance, exercise-induced bronchoconstriction (EIB), and respiratory symptoms in 7- to 16-year-old children. METHODS: A total of 1120 outdoor running exercise challenge test results of 7- to 16-year-old children were retrospectively reviewed. Lung function was evaluated with spirometry, and exercise performance was assessed by calculating distance per 6 minutes from the running time and distance. Respiratory symptoms in the exercise challenge test were recorded, and body mass index modified for children (ISO-BMI) was calculated for each child from height, weight, age, and gender according to the national growth references. RESULTS: Greater ISO-BMI and overweight were associated with poorer exercise performance (P < .001). In addition, greater ISO-BMI was independently associated with cough (P = .002) and shortness of breath (P = .012) in the exercise challenge. However, there was no association between ISO-BMI and EIB or with wheeze during the exercise challenge. CONCLUSION: Greater ISO-BMI may have a role in poorer exercise performance and appearance of respiratory symptoms during exercise, but not in EIB in 7- to 16-year-old children.

Impulse oscillometry and free-running tests for diagnosing asthma and monitoring lung function in young children.

BACKGROUND: Separating individuals with viral-induced wheezing from those with asthma is challenging, and there are no guidelines for children under 6 years of age. Impulse oscillometry, however, is feasible in 4-year-old children. OBJECTIVE: To explore the use of impulse oscillometry in diagnosing and monitoring asthma in young children and evaluating treatment response to inhaled corticosteroid (ICS). METHODS: A total of 42 children (median age 5.3 years, range 4.0-7.9 years) with physician-diagnosed asthma and lability in oscillometry were followed for 6 months after initiation of ICS treatment. All children performed the 6-minute free-running test and impulse oscillometry at 3 time points. After the baseline, they attended a second visit when they had achieved good asthma control and a third visit approximately 60 days after the second visit. A positive ICS response was defined as having greater than 19 points in asthma control test and no hyperreactivity on the third visit. RESULTS: In total, 38 of 42 children responded to ICS treatment. Exercise-induced increases of resistance at 5 Hz decreased after ICS treatment (61% vs 18% vs 13.5%, P < .001), and running distance during the 6-minute test was lengthened (800 m vs 850 m vs 850 m, P = .001). Significant improvements in childhood asthma control scores occurred between the baseline and subsequent visits (21 vs 24 vs 24, P < .001) and acute physicians' visits for respiratory symptoms (1, (0-6) vs 0, (0-2), P = .001). Similar profiles were observed in children without aeroallergen sensitization and among those under 5 years of age. CONCLUSION: Impulse oscillometry is a useful tool in diagnosing asthma and monitoring lung function in young children.

Optimal administration of bronchodilators with valved holding chambers in preschool children: a review of literature.

Our aim was to synthesize the published literature on factors that potentially affect the delivery of bronchodilators using valved holding chambers (VHC) in preschool children. We also aimed to identify those attributes that are not yet incorporated or clearly stated in the guidelines and those topics that are still lacking sufficient data. There is strong evidence supporting several recommendations in current guidelines. Based on present knowledge, bronchodilators should be delivered by VHC administering each puff separately. Face mask should be omitted as soon as the child can hold the mouthpiece of the VHC tightly between the lips and teeth. Based on the review, we suggest adding a specific note to current guidelines about the effect of chamber volume and the impact of co-operation during drug administration. Calming the child and securing a tight face-to-mask seal is critical for successful drug delivery. There is not enough evidence to make specific recommendations on the most reliable VHC and face mask for children. There is an urgent need for studies that evaluate and compare the effectiveness of VHCs in various clinical settings in wide age-groups and respiratory patterns. In addition, there is insufficient data on ideal chamber volume, material, and effective antistatic treatment. What is Known: • Valved holding chambers (VHC) should not be considered interchangeable when used with pressurized metered dose inhalers (pMDI). • Drug delivery is influenced by VHC volume, aerodynamic and electrostatic properties; mask fit; respiratory pattern and co-operation during inhalation; and the number of puffs actuated. What is New: • The impact of co-operation, VHC volume, and good mask-to-face fit during drug inhalation is not stressed enough in the guidelines. • Studies are urgently needed to evaluate the effectiveness of different VHCs in various clinical settings focusing on VHC electrostatic properties, respiratory patters, face masks, and ideal pMDI+VHC combinations.

Heterogeneity of emergency treatment practices in wheezing preschool children.

AIM: Our aim was to survey treatment practices used for preschool children with wheezing in emergency rooms (ER) focussing on inhalation device choice and handling, face mask use, salbutamol dosing and written instructions. We sought to assess whether current protocols are in line with published evidence and guidelines. METHODS: This is a cross-sectional survey done in paediatric ER units located in Finnish municipalities with more than 10 000 inhabitants. RESULTS: Of the 100 units contacted, 50% responded. More than 50% of the units used nebulisers. Only 13% of the units administered salbutamol in single puffs. More than 30% of the units lacked criteria on face mask use. Poor co-operation had no effect on the dose of salbutamol in 62% of the units. Ensuring tight mask-to-face seal was included in the training in 20% of the units. A written action plan was provided to the caregivers in 28% of the units. CONCLUSION: ER treatment guidelines for preschool children with wheezing are poorly endorsed. Research is needed to identify approaches to guideline implementation that are specific for primary care. Clinical research should focus on strengthening recommendations that are currently not embraced. ER treatment protocols need to be updated and adherence to guidelines should be re-evaluated.

Association between fixation type and revision risk in total knee arthroplasty patients aged 65 years and older: a cohort study of 265,877 patients from the Nordic Arthroplasty Register Association 2000-2016.

Background and purpose - The population of the Nordic countries is aging and the number of elderly patients undergoing total knee arthroplasty (TKA) is also expected to increase. Reliable fixation methods are essential to avoid revisions. We compared the survival of different TKA fixation concepts with cemented fixation as the gold standard.Patients and methods - We used data from the Nordic Arthroplasty Register Association (NARA) database of 265,877 unconstrained TKAs performed for patients aged ≥ 65 years with primary knee osteoarthritis between 2000 and 2016. Kaplan-Meier (KM) survival analysis with 95% confidence intervals (CI) and the Cox multiple-regression model were used to compare the revision risk of the fixation methods.Results - Cemented fixation was used in 243,166 cases, uncemented in 8,000, hybrid (uncemented femur with cemented tibia) in 14,248, and inverse hybrid (cemented femur with uncemented tibia) fixation in 463 cases. The 10-year KM survivorship (95% CI) of cemented TKAs was 96% (96 - 97), uncemented 94% (94 - 95), hybrid 96% (96 - 96), and inverse hybrid 96% (94 - 99), respectively. Uncemented TKA was associated with increased risk of revision compared with the cemented TKA; the adjusted hazard ratio was 1.3 (95% CI 1.1 - 1.4).Interpretation - Cemented, hybrid, and inverse hybrid TKAs showed 10-year survival rates exceeding 95%. Uncemented fixation was associated with an increased risk of revision in comparison with cemented fixation. As both hybrid and inverse hybrid fixation were used in only a limited number of TKAs, indicating possibility of selection bias in their favor, cemented TKA still remains the gold standard, as it works reliably in the hands of many.