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Introduction Not much is known about the fall risk among the adult population of those who rarely visit doctors. We wanted to determine the prevalence of increased fall risk in a population of family practice non-attenders and the factors associated with it. Methods We included participants from family medicine practices in this cross-sectional study. To be included in the study, the participants had to be adults living in the community (home-dwelling people) who had not visited their chosen family physician in the last five years (non-attenders). The identification of the eligible persons was done through a search of electronic medical records, which yield 2,025 non-attenders. Community nurses collected data in the participants’ homes. The outcome measure was increased fall risk as assessed by the Morse fall scale: increased risk (≥25) vs. no risk. Results The sample consisted of 1,945 patients (96.0% response rate) with a mean age of 60.4 years (range 20.5 to 99.7 years). An increased fall risk was determined in 482 or 24.8% (95% CI: [22.9, 26.8]) of the patients. The multivariate model showed a significant association of increased fall risk with higher age (p Conclusion Non-attenders may have an increased risk of falling which depends on their health status and age. The inclusion of community nurses in primary healthcare teams could be of use not only to identify the non-attenders’ health needs, but also to better manage their health, especially the factors that were identified to be associated with greater fall risk.

Linear mixed effects models (LMMs) are a popular and powerful tool for analysing grouped or repeated observations for numeric outcomes. LMMs consist of a fixed and a random component, which are specified in the model through their respective design matrices. Verifying the correct specification of the two design matrices is important since mis-specifying them can affect the validity and efficiency of the analysis. We show how to use empirical stochastic processes constructed from appropriately ordered and standardized residuals from the model to test whether the design matrices of the fitted LMM are correctly specified. We define two different processes: one can be used to test whether both design matrices are correctly specified, and the other can be used only to test whether the fixed effects design matrix is correctly specified. The proposed empirical stochastic processes are smoothed versions of cumulative sum processes, which have a nice graphical representation in which model mis-specification can easily be observed. The amount of smoothing can be adjusted, which facilitates visual inspection and can potentially increase the power of the tests. We propose a computationally efficient procedure for estimating p-values in which refitting of the LMM is not necessary. Its validity is shown by using theoretical results and a large Monte Carlo simulation study. The proposed methodology could be used with LMMs with multilevel or crossed random effects.

Objectives (1) To develop reference values for health-related fitness in European children and adolescents aged 6–18 years that are the foundation for the web-based, open-access and multilanguage fitness platform (FitBack); (2) to provide comparisons across European countries. Methods This study builds on a previous large fitness reference study in European youth by (1) widening the age demographic, (2) identifying the most recent and representative country-level data and (3) including national data from existing fitness surveillance and monitoring systems. We used the Assessing Levels of PHysical Activity and fitness at population level (ALPHA) test battery as it comprises tests with the highest test–retest reliability, criterion/construct validity and health-related predictive validity: the 20 m shuttle run (cardiorespiratory fitness); handgrip strength and standing long jump (muscular strength); and body height, body mass, body mass index and waist circumference (anthropometry). Percentile values were obtained using the generalised additive models for location, scale and shape method. Results A total of 7 966 693 test results from 34 countries (106 datasets) were used to develop sex-specific and age-specific percentile values. In addition, country-level rankings based on mean percentiles are provided for each fitness test, as well as an overall fitness ranking. Finally, an interactive fitness platform, including individual and group reporting and European fitness maps, is provided and freely available online ( www.fitbackeurope.eu). Conclusion This study discusses the major implications of fitness assessment in youth from health, educational and sport perspectives, and how the FitBack reference values and interactive web-based platform contribute to it. Fitness testing can be conducted in school and/or sport settings, and the interpreted results be integrated in the healthcare systems across Europe., Erasmus+ Sport Programme of the European Union within the project FitBack 13010-EPP-1-2019-1-SI-SPO-SCP, Slovenian Research Agency within the Research programme Bio- psycho-social context of kinesiology P5-0142, Units of Excellence, Unit of Excellence on Exercise, Nutrition and Health, Junta de Andalucia, Investigacion y Universidades, European Commission SOMM17/6107/UGR, CIBERobn Physiopathology of Obesity and Nutrition

Blagus, R, Jurak, G, Starc, G, and Leskošek, B. Centile reference curves of the SLOfit physical fitness tests for school-aged children and adolescents. J Strength Cond Res XX(X): 000-000, 2022-The study provides sex- and age-specific centile norms of Slovenian children and youth. Physical fitness was assessed using the SLOfit test battery on population data, including 185,222 children, aged 6-19 years, measured in April and May 2018. Centile curves for both sexes and 12 test items were constructed using the generalized additive models for location, scale, and shape (GAMLSS). Boys generally achieved higher scores in most of the physical fitness tests, except in stand and reach, but this was not consistent throughout childhood and adolescence, nor did it pertain to the entire range of performance. Girls outperformed boys in the arm-plate tapping test throughout childhood; the poorest performing girls outperformed the poorest performing boys in the 600-m run, 60-m dash, backward obstacle course, and standing broad jump. The shapes and trends of physical fitness curves adequately reflect the effects of growth and development on boys' and girls' physical performance. Comparing the existing reference fitness curves showed that Slovenian children and adolescents display higher fitness levels than their peers from other countries. This study provides the most up-to-date sex- and age-specific reference fitness centile curves of Slovenian children, which can be used as benchmark values for health and fitness monitoring and surveillance systems.

SLOfit Lifelong is a public health initiative which was created to upgrade a well-established, national physical fitness surveillance system for Slovenian schoolchildren that has been collecting annual fitness and health data for over three decades. The ultimate objective of creating SLOfit Lifelong was to build a modern societal infrastructure with the capacity and ability to detect future causal associations between childhood physical fitness trends and future health outcomes based on the lifelong surveillance of one’s own fitness status. By instilling citizens with an ambition to test, understand, and follow-up their own physical fitness and health status (including related health risk factors), this initiative provides the technical support and expert feedback needed to engender greater individual control over understanding (and thus modulating), one’s own physical fitness status as they progress into older adulthood. This perspective paper details the extensive approach taken to devise appropriate fitness test batteries for adults and older adults which can also relate to the student version of the original SLOfit test database, including establishing criterion health risk zones and a public approach to establish this national, citizen-driven health feedback framework. Through its sophisticated online web applications, social media, print media, and outreach workshops, SLOfit Lifelong provides the expert support for public health engagement by fostering positive lifelong physical literacy experiences an individual can enjoy across their aging journey.

Using the population-based data we aim to estimate the general population trends of multiple components of physical fitness of children, identify critical structural changes in these trends, and evaluate the potential changes in differences in the test scores between the children. During the entire study period, 1989–2019, median body mass index and triceps skinfold increased in both genders and all age groups. Muscular fitness, in general, showed negative trends, with some exceptions: during the post-2010 period, children were mostly experiencing the improvement of isometric strength of the upper body. The neuromuscular components of physical fitness showed positive trends, especially in girls. Cardiorespiratory fitness has been declining in all age groups until the last decade, with the largest decreases occurring before 2000. In the last decade, the trends reversed. The flexibility indicator revealed the largest differences between boys and girls, with boys mainly experiencing negative and girls mostly positive trends. The variability of the test scores mostly increased during the study period. This increasing variance suggests that—despite generally favourable trends in the last decade—children in Slovenia have been facing increasing inequalities in their development, which can potentially lead to future inequalities in health.

Supplemental material, sj-docx-1-spo-10.1177_17479541231152548 for Utility of video analysis and expert modelling for technique development in novice sport climbers: A randomized controlled study by Rok Blagus, Bojan Leskošek, Luka Okršlar, Nace Vreček and Tadej Debevec in International Journal of Sports Science & Coaching

Supplemental material, sj-docx-1-spo-10.1177_17479541231152548 for Utility of video analysis and expert modelling for technique development in novice sport climbers: A randomized controlled study by Rok Blagus, Bojan Leskošek, Luka Okršlar, Nace Vreček and Tadej Debevec in International Journal of Sports Science & Coaching

A large proportion of people with diabetes do not receive proper foot screening due to insufficiencies in healthcare systems. Introducing an effective risk prediction model into the screening protocol would potentially reduce the required screening frequency for those considered at low risk for diabetic foot complications. The main aim of the study was to investigate the value of individualised risk assignment for foot complications for optimisation of screening. From 2015 to 2020, 11,878 routine follow-up foot investigations were performed in the tertiary diabetes clinic. From these, 4282 screening investigations with complete data containing all of 18 designated variables collected at regular clinical and foot screening visits were selected for the study sample. Penalised logistic regression models for the prediction of loss of protective sensation (LOPS) and loss of peripheral pulses (LPP) were developed and evaluated. Using leave-one-out cross validation (LOOCV), the penalised regression model showed an AUC of 0.84 (95% CI 0.82, 0.85) for prediction of LOPS and 0.80 (95% CI 0.78, 0.83) for prediction of LPP. Calibration analysis (based on LOOCV) presented consistent recall of probabilities, with a Brier score of 0.08 (intercept 0.01 [95% CI −0.09, 0.12], slope 1.00 [95% CI 0.92, 1.09]) for LOPS and a Brier score of 0.05 (intercept 0.01 [95% CI −0.12, 0.14], slope 1.09 [95% CI 0.95, 1.22]) for LPP. In a hypothetical follow-up period of 2 years, the regular screening interval was increased from 1 year to 2 years for individuals at low risk. In individuals with an International Working Group on the Diabetic Foot (IWGDF) risk 0, we could show a 40.5% reduction in the absolute number of screening examinations (3614 instead of 6074 screenings) when a 10% risk cut-off was used and a 26.5% reduction (4463 instead of 6074 screenings) when the risk cut-off was set to 5%. Enhancement of the protocol for diabetic foot screening by inclusion of a prediction model allows differentiation of individuals with diabetes based on the likelihood of complications. This could potentially reduce the number of screenings needed in those considered at low risk of diabetic foot complications. The proposed model requires further refinement and external validation, but it shows the potential for improving compliance with screening guidelines.

Background For finite samples with binary outcomes penalized logistic regression such as ridge logistic regression has the potential of achieving smaller mean squared errors (MSE) of coefficients and predictions than maximum likelihood estimation. There is evidence, however, that ridge logistic regression can result in highly variable calibration slopes in small or sparse data situations. Methods In this paper, we elaborate this issue further by performing a comprehensive simulation study, investigating the performance of ridge logistic regression in terms of coefficients and predictions and comparing it to Firth’s correction that has been shown to perform well in low-dimensional settings. In addition to tuned ridge regression where the penalty strength is estimated from the data by minimizing some measure of the out-of-sample prediction error or information criterion, we also considered ridge regression with pre-specified degree of shrinkage. We included ‘oracle’ models in the simulation study in which the complexity parameter was chosen based on the true event probabilities (prediction oracle) or regression coefficients (explanation oracle) to demonstrate the capability of ridge regression if truth was known. Results Performance of ridge regression strongly depends on the choice of complexity parameter. As shown in our simulation and illustrated by a data example, values optimized in small or sparse datasets are negatively correlated with optimal values and suffer from substantial variability which translates into large MSE of coefficients and large variability of calibration slopes. In contrast, in our simulations pre-specifying the degree of shrinkage prior to fitting led to accurate coefficients and predictions even in non-ideal settings such as encountered in the context of rare outcomes or sparse predictors. Conclusions Applying tuned ridge regression in small or sparse datasets is problematic as it results in unstable coefficients and predictions. In contrast, determining the degree of shrinkage according to some meaningful prior assumptions about true effects has the potential to reduce bias and stabilize the estimates. Supplementary Information The online version contains supplementary material available at 10.1186/s12874-021-01374-y.

SLOfit Lifelong is a public health initiative which was created to upgrade a well-established, national physical fitness surveillance system for Slovenian schoolchildren that has been collecting annual fitness and health data for over three decades. The ultimate objective of creating SLOfit Lifelong was to build a modern societal infrastructure with the capacity and ability to detect future causal associations between childhood physical fitness trends and future health outcomes based on the lifelong surveillance of one's own fitness status. By instilling citizens with an ambition to test, understand, and follow-up their own physical fitness and health status (including related health risk factors), this initiative provides the technical support and expert feedback needed to engender greater individual control over understanding (and thus modulating), one's own physical fitness status as they progress into older adulthood. This perspective paper details the extensive approach taken to devise appropriate fitness test batteries for adults and older adults which can also relate to the student version of the original SLOfit test database, including establishing criterion health risk zones and a public approach to establish this national, citizen-driven health feedback framework. Through its sophisticated online web applications, social media, print media, and outreach workshops, SLOfit Lifelong provides the expert support for public health engagement by fostering positive lifelong physical literacy experiences an individual can enjoy across their aging journey.

BACKGROUND AND PURPOSE The characteristics and long-term outcome of Lyme neuroborreliosis (LNB) according to diagnostic certainty (definite vs. possible) are incompletely understood. METHODS In this retrospective cohort study of adults with definite or possible LNB, clinical and microbiological characteristics and long-term outcome over 12 months were evaluated at a single medical center. Severity of acute disease and long-term outcome were assessed using a composite clinical score encompassing clinical findings and symptoms and by the probability of incomplete recovery. RESULTS Amongst 311 adult patients enrolled from 2008 to 2017, 139 (44.7%) had definite LNB and 172 (55.3%) had possible LNB. The most frequent LNB manifestation was cranial neuropathy with or without meningitis (53.4%). Patients with definite LNB more often had Bannwarth syndrome (53.2% vs. 18.6%), more severe disease (6 points vs. 4 points), longer pre-treatment duration (median 21 days vs. 13.5 days), higher cerebrospinal fluid pleocytosis (median 139 × 106 /L vs. 11 × 106 /L) and higher rate of Borrelia seropositivity (84.2% vs. 68.6%) than those with possible LNB. Ceftriaxone was prescribed more often than oral doxycycline in definite LNB than in possible LNB (96.4% vs. 65.7%). Unfavorable outcomes decreased during follow-up, being higher in patients with more severe disease at enrollment and in those with possible LNB, but were not associated with antibiotic therapy. CONCLUSIONS Early LNB, most often presenting as cranial neuropathy, was definitively diagnosed in less than half of cases. A better diagnostic approach is needed to confirm borrelial etiology. Ceftriaxone was not superior to doxycycline in the treatment of early LNB, regardless of diagnostic certainty. In this retrospective cohort study of 311 adults with Lyme neuroborreliosis (LNB), allocated according to diagnostic certainty, early LNB was definitively diagnosed in less than half of cases and the most frequent LNB manifestation was cranial neuropathy with or without meningitis. Patients with definite LNB more often had Bannwarth syndrome, more severe disease, longer pre-treatment duration, higher cerebrospinal fluid pleocytosis and higher rate of Borrelia seropositivity than those with possible LNB. A better diagnostic approach is needed to confirm borrelial etiology. Ceftriaxone was not superior to doxycycline in the treatment of early LNB, regardless of diagnostic certainty.

This is the first study aiming to evaluate the reliability of assigning a difficulty grade to a climb. Each of the 70 climbers, divided by their abilities into group A (intermediate) and group B (advanced), climbed 5 different routes, and independently suggested a grade for the routes. Although the reliability was generally high (Kendall W = .89 and .86, intraclass correlation coefficient ICC = .82 and .89 in groups A and B, respectively), the grades proposed by a single climber have too large a standard error of measurement to confidently claim that two routes with different grades are truly of different difficulties. The most important factor associated with the accuracy and bias of grading, was the gap between a climber's ability and a route's difficulty (easier routes were graded less accurate, advanced climbers underestimated the true difficulty of the routes). The following factors were also found important for grading; their effect however, was lower, or was only found in some routes or in one group: success (failed attempts were graded higher), tiredness, sex and body height (but only unadjusted for sex). Surprisingly, no significant effects were found for climbing experience, ability level, and style of climbing (onsight, flash).

To date, few data on how the COVID-19 pandemic and restrictions affected children’s physical activity in Europe have been published. This study examined the prevalence and correlates of physical activity and screen time from a large sample of European children during the COVID-19 pandemic to inform strategies and provide adequate mitigation measures. An online survey was conducted using convenience sampling from 15 May to 22 June, 2020. Parents were eligible if they resided in one of the survey countries and their children aged 6–18 years. 8395 children were included (median age [IQR], 13 [10–15] years; 47% boys; 57.6% urban residents; 15.5% in self-isolation). Approximately two-thirds followed structured routines (66.4% [95%CI, 65.4–67.4]), and more than half were active during online P.E. (56.6% [95%CI, 55.5–57.6]). 19.0% (95%CI, 18.2–19.9) met the WHO Global physical activity recommendation. Total screen time in excess of 2 h/day was highly prevalent (weekdays: 69.5% [95%CI, 68.5–70.5]; weekend: 63.8% [95%CI, 62.7–64.8]). Playing outdoors more than 2 h/day, following a daily routine and being active in online P.E. increased the odds of healthy levels of physical activity and screen time, particularly in mildly affected countries. In severely affected countries, online P.E. contributed most to meet screen time recommendation, whereas outdoor play was most important for adequate physical activity. Promoting safe and responsible outdoor activities, safeguarding P.E. lessons during distance learning and setting pre-planned, consistent daily routines are important in helping children maintain healthy active lifestyle in pandemic situation. These factors should be prioritised by policymakers, schools and parents. HIGHLIGHTS: To our knowledge, our data provide the first multi-national estimates on physical activity and total screen time in European children roughly two months after COVID-19 was declared a global pandemic. Only 1 in 5 children met the WHO Global physical activity recommendations. Under pandemic conditions, parents should set pre-planned, consistent daily routines and integrate at least 2-hours outdoor activities into the daily schedule, preferable on each day. Schools should make P.E. lessons a priority. Decision makers should mandate online P.E. be delivered by schools during distance learning. Closing outdoor facilities for PA should be considered only as the last resort during lockdowns.

Wild carnivores are definitive hosts and potential reservoirs for the tapeworm Echinococcus sp. which can cause cystic and alveolar echinococcosis. Both are considered neglected and important food-borne pandemics. This study is the first to molecularly test Slovenian wild carnivores for Echinococcus species that can cause disease in humans. Fecal samples from 210 red foxes (Vulpes vulpes), 42 wolves (Canis lupus), 39 golden jackals (Canis aureus), 18 martens (Marten sp.), 2 Eurasian lynx (Lynx lynx), 2 European badger (Meles meles), and 1 Eurasian otter (Lutra lutra) were examined for Echinococcus granulosus sensu lato (EGsl: E. granulosus sensu stricto, E. canadensis) and E. multilocularis (EM) using real-time PCR. Red foxes (29.1%) and golden jackals (18%) were positive for EM. All animals examined were negative for EGsl. Univariate analysis showed no significant differences in EM prevalence with respect to animal species (red fox vs., golden jackal) (p = 0.22), age (p = 0.12), and sex (p = 0.18). Prevalence of EM was associated with the region (p < 0.001), with regions in central and southern Slovenia having higher EM prevalence and risk of infection. Due to the increase in population and expansion of habitat, the golden jackal may soon become as important definitive host for EM as the red fox.

Background To date, few data on the quality and quantity of online physical education (P.E.) during the COVID-19 pandemic have been published. We assessed activity in online classes and reported allocated curriculum time for P.E. in a multi-national sample of European children (6–18 years). Methods Data from two online surveys were analysed. A total of 8395 children were included in the first round (May–June 2020) and 24 302 in the second round (January–February 2021). Results Activity levels during P.E. classes were low in spring 2020, particularly among the youngest children and in certain countries. 27.9% of students did not do any online P.E. and 15.7% were hardly ever very active. Only 18.4% were always very active and 14.9% reported being very active quite often. In winter 2020, we observed a large variability in the allocated curriculum time for P.E. In many countries, this was lower than the compulsory requirements. Only 65.7% of respondents had the same number of P.E. lessons than before pandemic, while 23.8% had less P.E., and 6.8% claimed to have no P.E. lessons. Rates for no P.E. were especially high among secondary school students, and in large cities and megapolises. Conclusions During the COVID-19 pandemic, European children were provided much less P.E. in quantity and quality than before the pandemic. Countermeasures are needed to ensure that these changes do not become permanent. Particular attention is needed in large cities and megapolises. The critical role of P.E. for students’ health and development must be strengthened in the school system.

Background To date, few multi-country data on how the COVID-19 pandemic and restrictions affected children’s physical activity have been published, and most reports originate outside Europe. This repeated cross-sectional study investigated the prevalence and correlates of physical activity (PA) and screen time (ST) in a large sample of European children during the COVID-19 pandemic in January-February 2021, and compared the data to the first lockdown in May-June 2020. Methods Data from two online survey rounds were analysed. A total of 8,395 children aged 6-18 years were included in Round 1 (May-June 2020) and 24,302 in Round 2 (Jan-Feb 2021). PA and ST were assessed by 7-day recall measure. Results Overall, 9.3% of children (95%CI, 6.9-11.7) met the WHO PA recommendation, which is half of what was observed in Spring 2020 (19.0% [18.2-19.9]). Exceeding ST recommendations was also prevalent in both data collection rounds. Playing outdoors more than 2 hours/day, following a daily routine and being active in online P.E. increased the odds of healthy levels of physical activity and screen time. We also observed a large variability in curriculum time allocated for P.E. In many countries this was lower than the compulsory requirements. Conclusions Findings suggest that lockdown in winter has greater negative impact than in spring. Promoting safe and responsible outdoor activities, safeguarding P.E. lessons during distance learning and setting pre-planned, consistent daily routines are important in helping children maintain healthy active lifestyle in pandemic situation. These factors should be prioritised by policymakers, schools and parents.

Wild carnivores are definitive hosts and potential reservoirs for the

Using the population-based data we aim to estimate the general population trends of multiple components of physical fitness of children, identify critical structural changes in these trends, and evaluate the potential changes in differences in the test scores between the children. During the entire study period, 1989–2019, median body mass index and triceps skinfold increased in both genders and all age groups. Muscular fitness, in general, showed negative trends, with some exceptions: during the post-2010 period, children were mostly experiencing the improvement of isometric strength of the upper body. The neuromuscular components of physical fitness showed positive trends, especially in girls. Cardiorespiratory fitness has been declining in all age groups until the last decade, with the largest decreases occurring before 2000. In the last decade, the trends reversed. The flexibility indicator revealed the largest differences between boys and girls, with boys mainly experiencing negative and girls mostly positive trends. The variability of the test scores mostly increased during the study period. This increasing variance suggests that—despite generally favourable trends in the last decade—children in Slovenia have been facing increasing inequalities in their development, which can potentially lead to future inequalities in health.

Introduction The role of host immune responses in the pathogenesis of borrelial dissemination in early Lyme borreliosis (LB) in the form of multiple erythema migrans (MEM) or LB‐associated symptoms is incompletely understood. Methods In this study, fifteen cytokine or chemokine levels, representative of innate, Th1, and Th17 immune responses, were assessed using a bead‐based Luminex multiplex assay in acute sera from 76 adult patients with skin culture‐positive Borrelia afzelii solitary erythema migrans (SEM) and 58 patients with MEM at a single‐center university hospital. Differences between the groups were tested by modeling each cytokine or chemokine concentration by means of left‐censored regression using the classic Tobit model. Results Mean serum cytokine or chemokine levels were low. When taking into account the proportion of patients with cytokine or chemokine concentrations below the lowest detectable limit, only levels of CXCL10 (p = .03) and CCL19 (p = .02), representatives of the Th1 immune response, differed between patients with SEM and those with MEM; however, the differences did not reach statistical significance when adjusted for multiple comparisons. In addition, we did not find differences in systemic inflammatory responses when comparing patients with and those without LB‐associated constitutional symptoms. Conclusion No significant differences in systemic immune responses represented by selected cytokines or chemokines in serum samples of patients with EM infected with B. afzelii suggest that systemic mediators are not pivotal in the pathogenesis of dissemination of early infection in the form of MEM or LB‐associated symptoms. Localized immune responses in the skin or other pathogenetic mechanisms may be more important in this regard.

Lyme borreliosis is the most prevalent vector-borne disease in Europe and the USA. Doxycycline for 10 days is the primary treatment recommendation for erythema migrans. To reduce potentially harmful antibiotic overuse by identifying shorter effective treatments, we aimed to assess whether oral doxycycline for 7 days is non-inferior to 14 days in adults with solitary erythema migrans.In this randomised open-label non-inferiority trial, we enrolled patients with a solitary erythema at the University Medical Centre in Ljubljana, Slovenia. Patients were excluded if they were pregnant or lactating, immunosuppressed, allergic to doxycycline, or had received antibiotics with anti-borrelial activity within 10 days preceding enrolment or had additional manifestations of Lyme borreliosis Adults were randomly allocated 1:1 to receive oral doxycycline 100 mg twice a day for 7 days or 14 days. The primary efficacy endpoint was the difference in proportion of patients with treatment failure, defined as persistent erythema, new objective signs of Lyme borreliosis, or borrelial isolation on skin re-biopsy at 2 months, in a per-protocol analysis (the population that completed the assigned doxycycline regimen according to the study protocol and did not receive any other antibiotics with anti-borrelial activity until the 2-month visit). The non-inferiority margin was 6 percentage points. Safety was assessed in all randomly assigned patients who followed the study protocol and were evaluable at the 14-day visit. This study is registered with ClinicalTrials.gov, NCT03153267.Between July 3, 2017, and Oct 2, 2018, we enrolled 300 patients (150 per group: median age 56 years [IQR 47-65]; 126 [45%] of 300 male; skin culture positive 72 [30%] of 239 assessed). 295 patients completed antibiotic therapy as per protocol and 294 (98%) patients were evaluable 2 months post-enrolment. Five (3%) of 147 patients from the 7-day group versus 3 (2%) of 147 patients from the 14-day group (one patient did not attend the 2-month visit and was unreachable by telephone) had treatment failure manifesting as persistence of erythema (difference 1·4 percentage points; upper limit of one-sided 95% CI 5·2 percentage points; p=0·64). No patients developed new objective manifestations of Lyme borreliosis during follow-up or had positive repeat skin biopsies. Two (1%) of 150 patients in the 7-day and one (1%) of 150 patients in the 14-day group discontinued therapy due to adverse events.Our data support 7 days of oral doxycycline for adult European patients with solitary erythema migrans, permitting less antibiotic exposure than current guideline-driven therapy.Slovenian Research Agency and the University Medical Centre Ljubljana.

During the first wave of the COVID-19 pandemic in spring 2020, Slovenia was among the least affected countries, but the situation became drastically worse during the second wave in autumn 2020 with high numbers of deaths per number of inhabitants, ranking Slovenia among the most affected countries. This was true even though strict non-pharmaceutical interventions (NPIs) to control the progression of the epidemic were being enforced. Using a semi-parametric Bayesian model developed for the purpose of this study, we explore if and how the changes in mobility, their timing and the activation of contact tracing can explain the differences in the epidemic progression of the two waves. To fit the model, we use data on daily numbers of deaths, patients in hospitals, intensive care units, etc., and allow transmission intensity to be affected by contact tracing and mobility (data obtained from Google Mobility Reports). Our results imply that though there is some heterogeneity not explained by mobility levels and contact tracing, implementing interventions at a similar stage as in the first wave would keep the death toll and the health system burden low in the second wave as well. On the other hand, sticking to the same timeline of interventions as observed in the second wave and focusing on enforcing a higher decrease in mobility would not be as beneficial. According to our model, the ‘dance’ strategy, i.e., first allowing the numbers to rise and then implementing strict interventions to make them drop again, has been played at too-late stages of the epidemic. In contrast, a 15–20% reduction of mobility compared to pre-COVID level, if started at the beginning and maintained for the entire duration of the second wave and coupled with contact tracing, could suffice to control the epidemic. A very important factor in this result is the presence of contact tracing without it, the reduction in mobility needs to be substantially larger. The flexibility of our proposed model allows similar analyses to be conducted for other regions even with slightly different data sources for the progression of the epidemic the extension to more than two waves is straightforward. The model could help policymakers worldwide to make better decisions in terms of the timing and severity of the adopted NPIs.

Background In binary logistic regression data are ‘separable’ if there exists a linear combination of explanatory variables which perfectly predicts the observed outcome, leading to non-existence of some of the maximum likelihood coefficient estimates. A popular solution to obtain finite estimates even with separable data is Firth’s logistic regression (FL), which was originally proposed to reduce the bias in coefficient estimates. The question of convergence becomes more involved when analyzing clustered data as frequently encountered in clinical research, e.g. data collected in several study centers or when individuals contribute multiple observations, using marginal logistic regression models fitted by generalized estimating equations (GEE). From our experience we suspect that separable data are a sufficient, but not a necessary condition for non-convergence of GEE. Thus, we expect that generalizations of approaches that can handle separable uncorrelated data may reduce but not fully remove the non-convergence issues of GEE. Methods We investigate one recently proposed and two new extensions of FL to GEE. With ‘penalized GEE’ the GEE are treated as score equations, i.e. as derivatives of a log-likelihood set to zero, which are then modified as in FL. We introduce two approaches motivated by the equivalence of FL and maximum likelihood estimation with iteratively augmented data. Specifically, we consider fully iterated and single-step versions of this ‘augmented GEE’ approach. We compare the three approaches with respect to convergence behavior, practical applicability and performance using simulated data and a real data example. Results Our simulations indicate that all three extensions of FL to GEE substantially improve convergence compared to ordinary GEE, while showing a similar or even better performance in terms of accuracy of coefficient estimates and predictions. Penalized GEE often slightly outperforms the augmented GEE approaches, but this comes at the cost of a higher burden of implementation. Conclusions When fitting marginal logistic regression models using GEE on sparse data we recommend to apply penalized GEE if one has access to a suitable software implementation and single-step augmented GEE otherwise.

Background and Objective. Knee osteoarthritis is a serious epidemiological problem that causes severe pain and impairs abilities. We investigated the effects of adductor canal blockade (ACB) on chronic osteoarthritis knee pain, motor function, and mobility. Methods. Seventy-seven patients with chronic knee osteoarthritis pain received ultrasound-guided ACB with 14 ml 0.25% levobupivacaine and 100 mcg clonidine. At baseline and 1 month after the blockade, we assessed maximal and minimal pain intensity in the knee using a numeric rating scale (NRS) and the Knee Injury and Osteoarthritis Outcome Score (KOOS). The range of motion in extension and flexion (ROMext and ROMflex) and quadriceps muscle strength of both knees (QS), Timed Up and Go Test (TUG), and 30-Second Chair Stand Test (30CST) results were determined at baseline, 1 hour, 1 week, and 1 month after the blockade. Results. ACB with levobupivacaine and clonidine appeared to decrease pain severity ( 8.13 to 4.2, and 3.32 to 1.40, ). Similarly, knee ROMext decreased from 3.90 preintervention to 2.89 postintervention at 1 month, ROMflex decreased from 5.70 to 3.29, TUG time decreased from 3.22 to 2.93

BackgroundSevere equine asthma (SEA) is a common chronic respiratory disease and a significant health and well-being problem in horses. Current therapeutic strategies improve pulmonary function and clinical signs in some horses, but in the long-term, return to full athletic function appears to be rare. The aim of this study was to assess the safety and the effect of intrabronchial administration of adipose-derived mesenchymal stem cells (AD-MSC) on pulmonary inflammatory and clinical parameters in horses with SEA.MethodsThis was a randomized controlled trial. Twenty adult horses diagnosed with SEA were randomly divided into two groups (n = 10), and treated either with a single intrabronchial application of autologous AD-MSC or oral dexamethasone for three weeks. A targeted clinical examination with determination of clinical score, maximal change in pleural pressure during the breathing cycle, and an endoscopic examination of the airways were performed at baseline and three weeks after treatment. Bronchoalveolar lavage fluid was analyzed cytologically, and IL-1β, IL-4, IL-8, IL-17, TNFα and IFNγ mRNA and protein concentrations were measured at baseline and three weeks. The horses were then monitored over one year for recurrence of SEA. A non-inferiority analysis and a linear mixed-effects model were performed to assess differences between treatments.ResultsThe non-inferiority of AD-MSC treatment was not established. However, AD-MSC administration significantly ameliorated the clinical score (P = 0.01), decreased the expression of IL-17 mRNA (P = 0.05) and IL-1β (P ≤ 0.001), IL-4 (P ≤ 0.001), TNFα (P = 0.02) protein levels, and had a positive long-term effect on SEA-associated clinical signs (P = 0.02).ConclusionsIntrabronchial administration of AD-MSC had limited short-term anti-inflammatory effects but improved the clinical signs of SEA at one year.

This repeat cross-sectional study investigated the impact of lockdown in Europe in Winter (January and February 2021) on children’s and adolescent’s physical activity (PA) and recreational screen time (RST), and compared PA to the lockdown in Spring 2020. An online survey was administered (n = 24 302; 6–18 years; 51.7% boys) in nine countries. PA and RST were assessed by 7-day recall. In total, 9.3% of children (95% confidence interval: 6.9–11.7) met WHO PA recommendation, which was half of the proportion observed in Spring 2020 [19.0% (18.2–19.9)]. Sixty percent exceeded the RST recommendations. This suggests that winter lockdown could have a more negative impact on PA than in spring.

Background and Objective. Knee osteoarthritis is a serious epidemiological problem that causes severe pain and impairs abilities. We investigated the effects of adductor canal blockade (ACB) on chronic osteoarthritis knee pain, motor function, and mobility. Methods. Seventy-seven patients with chronic knee osteoarthritis pain received ultrasound-guided ACB with 14 ml 0.25% levobupivacaine and 100 mcg clonidine. At baseline and 1 month after the blockade, we assessed maximal and minimal pain intensity in the knee using a numeric rating scale (NRS) and the Knee Injury and Osteoarthritis Outcome Score (KOOS). The range of motion in extension and flexion (ROMext and ROMflex) and quadriceps muscle strength of both knees (QS), Timed Up and Go Test (TUG), and 30-Second Chair Stand Test (30CST) results were determined at baseline, 1 hour, 1 week, and 1 month after the blockade. Results. ACB with levobupivacaine and clonidine appeared to decrease pain severity ( NR S max 8.13 to 4.2, p < 0.001 and NR S min 3.32 to 1.40, p < 0.001 ). Similarly, knee ROMext decreased from 3.90 preintervention to 2.89 postintervention at 1 month, p < 0.001 ; ROMflex decreased from 5.70 to 3.29, p < 0.001 ; TUG time decreased from 3.22 to 2.93, p < 0.001 ; CST increased from 8.23 to 10.74, p < 0.001 . The KOOS for pain (36.40 to 58.34), symptoms (52.55 to 64.32), activities of daily living functions (ADLs, 36.36 to 60.77), and quality of life (QoL, 17.87 to 30.97) also increased, all p < 0.001 . Conclusion. ACB appeared to decrease pain and increase ambulation. If our preliminary results are reproducible in a planned randomized controlled trial, ACB could be a useful adjunctive pain therapy in patients with disabling pain due to knee OA.

Additional file 1.

Additional file 4: List of primer sequences used for qRT-PCR

Sport climbing is a multifaceted sport that also requires appropriate techniques to optimize movements. As augmented feedback is known to facilitate motor learning, we investigated the utility of adding video analysis and expert modelling to standardized verbal feedback for the acquisition of three climbing-specific techniques (drop knee, heel hook and high step). Twenty-six novice climbers (12 women) completed two testing sessions before and after a training intervention that consisted of three coached climbing sessions targeting the three techniques. Participants were randomly assigned to a control group, which solely received standardized verbal feedback or an experimental group that additionally received standardized video analysis and expert modelling using the Dartfish tablet application. Video recordings were subsequently evaluated by two climbing experts on a 7-point scale. The expert scores were higher in the experimental than in the control group for the high step (causal total effect (CTE) 0.38, 95% confidence interval (CI) [0.06, 0.68]). Improvements for the drop knee (CTE = 0.12, 95% CI [−0.24, 0.48]) and heel hook (CTE = −0.05, 95% CI [−0.42, 0.31]) were similar in both groups. For the drop knee, we, however, observed a positive causal direct effect (CDE = 0.38, 95% CI [0.07, 0.68]), which was comparable to that observed for the high step but also a negative causal mediator effect via the perceived difficulty (CME = −0.26, 95% CI [−0.51, −0.04]). Compared to verbal feedback solely, the addition of video analysis and expert modelling might facilitate the acquisition of certain climbing techniques, such as high step, in novice climbers.

In this retrospective cohort study of patients with tick-borne encephalitis (TBE), the clinical outcome in relation to co-infection with B. burgdorferi sensu lato (s.l.) and, specifically, the effect of antibiotic treatment on clinical outcome in patients with TBE who were seropositive for borreliae but who did not fulfil clinical or microbiologic criteria for proven co-infection, were assessed at a single university medical center in Slovenia, a country where TBE and Lyme borreliosis are endemic with high incidence. Among 684 patients enrolled during a seven-year period from 2007 through 2013, 382 (55.8%) had TBE alone, 62 (9.1%) had proven co-infection with borreliae and 240 (35.1%) had possible co-infection. The severity of acute illness was similar in all the groups. The odds for incomplete recovery decreased during a 12-month follow-up but were higher in women, older patients, and in those with more severe acute illness. Incomplete recovery was not associated with either proven (odds ratio (OR) 1.21, 95% confidence interval (CI) 0.49–2.95 p = 0.670) or possible co-infection (OR 0.95, 95% CI 0.55–1.65 p = 0.853). Among patients with possible co-infection, older patients were more likely to be prescribed antibiotics, but the odds for incomplete recovery were similar in those who received antibiotics and those who did not (OR 0.82, 95% CI 0.36–1.87 p = 0.630), suggesting that routine antibiotic treatment in patients with TBE and possible co-infection may not be warranted.

Simple Summary Toxoplasma gondii is a parasite that can cause serious disease in humans, especially in pregnant women. This parasite is found in many animals and people can be infected by eating raw or undercooked meat. Wild boar are known to harbor this parasite; populations and habitats have increased in the past decade, as it also increased the consumption of venison. The European population of wild boar has a mean prevalence of 26%. In our study, we found that the prevalence in the Slovenian wild boar population is 62%, the highest in the world to date. The prevalence was influenced by age and weight, but not by gender. In conclusion, the hunting community should be made aware of the high risk of parasite exposure when dealing with wild boar meat. Abstract Toxoplasma gondii is a zoonotic parasite of great public health concern. Wild boars could be considered an emerging source of toxoplasmosis in humans due to the popularity of venison and their increasing population. The aim of this study was to determine the seroprevalence of T. gondii in the Slovenian wild boar population and evaluate risk factors for human infection. Of 353 samples, 62% were positive for T. gondii using ELISA tests. This is the highest T. gondii seroprevalence reported to date in wild boar worldwide. The increase in prevalence with increasing age (p = 0.003) and weight (p = 0.002) were statistically significant, whereas gender was not (p = 0.781). Odds for being T. gondii-positive increased with age with the largest difference being between 2–3-year-old and 1–2-year-old animals (OR = 2.66, 95%CI: 1.03–6.85). Animals weighing 20–40 kg had a higher risk than animals weighing 0–20 kg (OR = 2.74, 95%CI: 1.21–6.20), whereas a further increase in the weight was not associated with increasing the odds. Due to the high Toxoplasma prevalence, the study concluded that the risk of exposure to T. gondii from handling raw or undercooked wild boar meat is high. Surveillance protocols should be established at the national level together with increased awareness within the hunting community.

During the first wave of the COVID-19 pandemic in spring 2020, Slovenia was among the least affected countries, but the situation became drastically worse during the second wave in autumn 2020 with high numbers of deaths per number of inhabitants, ranking Slovenia among the most affected countries. This was true even though strict non-pharmaceutical interventions (NPIs) to control the progression of the epidemic were being enforced. Using a semi-parametric Bayesian model developed for the purpose of this study, we explore if and how the changes in mobility, their timing and the activation of contact tracing can explain the differences in the epidemic progression of the two waves. To fit the model, we use data on daily numbers of deaths, patients in hospitals, intensive care units, etc., and allow transmission intensity to be affected by contact tracing and mobility (data obtained from Google Mobility Reports). Our results imply that though there is some heterogeneity not explained by mobility levels and contact tracing, implementing interventions at a similar stage as in the first wave would keep the death toll and the health system burden low in the second wave as well. On the other hand, sticking to the same timeline of interventions as observed in the second wave and focusing on enforcing a higher decrease in mobility would not be as beneficial. According to our model, the ‘dance’ strategy, i.e., first allowing the numbers to rise and then implementing strict interventions to make them drop again, has been played at too-late stages of the epidemic. In contrast, a 15–20% reduction of mobility compared to pre-COVID level, if started at the beginning and maintained for the entire duration of the second wave and coupled with contact tracing, could suffice to control the epidemic. A very important factor in this result is the presence of contact tracing; without it, the reduction in mobility needs to be substantially larger. The flexibility of our proposed model allows similar analyses to be conducted for other regions even with slightly different data sources for the progression of the epidemic; the extension to more than two waves is straightforward. The model could help policymakers worldwide to make better decisions in terms of the timing and severity of the adopted NPIs.

Methods for the determination of the postmortem interval (PMI) include methods that monitor the postmortem changes of cells and molecules in different tissues. The rate of pathological degradation of macromolecules in the extracellular matrix (ECM) of hyaline cartilage could be verified by assessing the intensity of collagen and proteoglycan (PG) staining. In the presented in vitro pilot study, this methodology was used for the first time to determine PMI. The osteochondral samples of three donors were stored at 11 °C and 35 °C and analyzed on day 1, day 12, and day 36 postmortem. The intensity of staining using Masson's trichrome and Sirius red for collagen, and Alcian blue and Safranin O dyes for PG was estimated ten times according to the modified Bern grading scale. Statistical analysis showed that the Safranin O without Fast green method is the most appropriate (raters agreement 0.5541) for up to 36 days postmortem, and that the influence of time is more important (p = 0.023) than the influence of temperature (p = 0.061) on the degradation of the ECM macromolecules. The described method, which is simple and can be performed in any histological laboratory, should be verified in corpore conditions, on a large number of donors, and using an objective method for assessing the intensity of cartilage macromolecule staining for PMI determination.

Introduction We tested the hypothesis that individual susceptibility to freezing cold injury might be reflected in an attenuated cold-induced vasodilatation (CIVD) response by comparing the CIVD responses of an elite alpinist with a history of freezing cold injury in the feet (case alpinist) with those of an age- and ability- matched noninjured alpinists control group (controls). According to this hypothesis, the vasomotor responses to a CIVD test of the case alpinist would represent a pathophysiological response when compared with the normal physiological response of a noninjured cohort. Methods The case alpinist and the controls in the cohort group conducted a cold water immersion test comprising sequential immersion of a hand and foot for 5 min in 35°C water, followed by a 30-min immersion in 8°C water and a 10-min recovery period in room air. During this test we monitored the finger and toe skin temperatures. Results The case alpinist had a significantly attenuated CIVD response and a lower skin temperature in all injured and noninjured digits during immersion (∼2°C lower than in the control group) and an attenuated recovery of finger skin temperatures (∼6°C lower than in the control group). Conclusions The attenuated CIVD response of the case alpinist may reflect a previously unrecognized enhanced susceptibility to frostbite. In addition to the poor vasomotor response observed in the injured toes, he also exhibited a poor vasomotor response in his noninjured fingers. The results of the present study indicate that a test of vasomotor activity during thermal stress may identify individuals predisposed to cold injury.

A large proportion of people with diabetes do not receive proper foot screening due to insufficiencies in healthcare systems. Introducing an effective risk prediction model into the screening protocol would potentially reduce the required screening frequency for those considered at low risk for diabetic foot complications. The main aim of the study was to investigate the value of individualised risk assignment for foot complications for optimisation of screening.From 2015 to 2020, 11,878 routine follow-up foot investigations were performed in the tertiary diabetes clinic. From these, 4282 screening investigations with complete data containing all of 18 designated variables collected at regular clinical and foot screening visits were selected for the study sample. Penalised logistic regression models for the prediction of loss of protective sensation (LOPS) and loss of peripheral pulses (LPP) were developed and evaluated.Using leave-one-out cross validation (LOOCV), the penalised regression model showed an AUC of 0.84 (95% CI 0.82, 0.85) for prediction of LOPS and 0.80 (95% CI 0.78, 0.83) for prediction of LPP. Calibration analysis (based on LOOCV) presented consistent recall of probabilities, with a Brier score of 0.08 (intercept 0.01 [95% CI -0.09, 0.12], slope 1.00 [95% CI 0.92, 1.09]) for LOPS and a Brier score of 0.05 (intercept 0.01 [95% CI -0.12, 0.14], slope 1.09 [95% CI 0.95, 1.22]) for LPP. In a hypothetical follow-up period of 2 years, the regular screening interval was increased from 1 year to 2 years for individuals at low risk. In individuals with an International Working Group on the Diabetic Foot (IWGDF) risk 0, we could show a 40.5% reduction in the absolute number of screening examinations (3614 instead of 6074 screenings) when a 10% risk cut-off was used and a 26.5% reduction (4463 instead of 6074 screenings) when the risk cut-off was set to 5%.Enhancement of the protocol for diabetic foot screening by inclusion of a prediction model allows differentiation of individuals with diabetes based on the likelihood of complications. This could potentially reduce the number of screenings needed in those considered at low risk of diabetic foot complications. The proposed model requires further refinement and external validation, but it shows the potential for improving compliance with screening guidelines.

Additional file 1.

BackgroundIndependence in daily activities is defined as the ability to perform functions related to daily living, i.e. the capacity of living independently in the community with little or no help from others.ObjectiveWe focused on non-attenders as a subgroup of patients whose health status is not well known to family practice teams. Our goal was to estimate the prevalence of dependence and its severity level in the daily activities of patients, and to determine the factors that are associated with the occurrence of dependence.DesignCross-sectional observational study.Settings and participantsData was obtained in family medicine settings. Participants in the study were adults living in the community (aged 18 or over) who had not visited their chosen family physician in the last 5 years (non-attenders) and who were able to participate in the study. Through the electronic system, we identified 2,025 non-attenders. Community nurses collected data in the participants’ homes. The outcome measure was dependence in daily activities, assessed through eight items: personal hygiene; eating and drinking; mobility; dressing and undressing; urination and defecation; continence; avoiding hazards in the environment; and communication.ResultsThe final sample consisted of 1,999 patients (98.7% response rate). The mean age was 59.9 (range 20 to 99). Dependence in daily activities was determined in 466 or 23.3% (95% CI: [21.5, 25.2]) of the patients. Older patients (over 60 years), with at least one chronic disease, increased risk of falling, moderate feelings of loneliness and a lower self-assessment of health were statistically significantly more likely to be dependent in their daily activities, according to our multivariate model.ConclusionsA considerable proportion of family practice non-attenders were found to be dependent in daily activities, though at a low level. We identified several factors associated with this dependence. This could help to identify people at risk of being dependent in daily activities in the general adult population, and enable specific interventions that would improve their health status.

Background The efficacy and optimal duration of postexposure influenza prophylaxis with oseltamivir are undetermined in hospital settings, where immediate separation from index cases is not feasible. Methods In an open-label noninferiority randomized clinical trial in a single-center university hospital, the efficacy of 5-day vs 10-day postexposure prophylaxis with oseltamivir was compared in adult patients exposed to influenza who could not be immediately separated from index influenza cases. Influenza incidence was assessed for 10 days after discontinuing prophylaxis. Results Among 222 exposed patients (median age, 75 years; male 119; median Charlson Comorbidity Index, 5), 110 patients were assigned to 5 days of postexposure prophylaxis with oseltamivir, and 112 patients were assigned to the 10-day group. The median duration of exposure to influenza (interquartile range) was 2 (1–3) days. In the intention-to-treat analysis, the incidence of influenza was 2/110 (1.8%) in the 5-day group and 0/112 (0%) in the 10-day group (difference, 1.8 percentage points; 1-sided 95% CI, –1 to 4.9 percentage points; P = .77). Conclusions For patients exposed to influenza in a hospital setting and who were not immediately separated from index cases, postexposure prophylaxis with oseltamivir resulted in low incidence of nosocomial influenza transmission. Five-day postexposure prophylaxis was noninferior to 10-day regimen. ClinicalTrials.gov Registration NCT03899571.

Objectives To evaluate the impact of European Antibiotic Awareness Day (EAAD) on antibiotic consumption, improvements in general public awareness and antibiotic resistance in Slovenia. Methods Outpatient data for the period from 2002 to 2016 and hospital antibiotic consumption data for 2004-16 were collected using the Anatomical Therapeutic Chemical (ATC) classification/DDDs. Outpatient antibiotic consumption data were expressed in DDDs/1000 inhabitants/day (DIDs), number of packages/1000 inhabitant-days and number of prescriptions/1000 inhabitants/year. Hospital consumption data were expressed in DIDs, number of DDDs/100 bed-days and number of DDDs/100 admissions. Segmented regression analysis of interrupted time series was used to estimate the effects of these interventions on antibiotic consumption. Results During the 8 year period since establishing EAAD, a 9%-17% decrease in outpatient antibiotic consumption has been observed, depending on the measurement unit, which was a little more than in the 6 years prior to EAAD (7%-12%). The trend change in hospital consumption after EAAD was established remained small, with a highly non-significant P value. Eurobarometer data did not show an increase in knowledge on antibiotic use. Resistance of Streptococcus pneumoniae to penicillin and macrolides decreased during EAAD activities. Conclusions EAAD activities were associated with a decreasing trend in community consumption. Owing to many other national activities on the prudent use of antimicrobials in outpatients and inpatients it is difficult to analyse the direct effect of EAAD.

Gorjanc, Jurij, Shawnda A. Morrison, Rok Blagus, and Igor B. Mekjavic. Cold susceptibility of digit stumps resulting from amputation after freezing cold injury in elite alpinists. High Alt Med Biol. 19:185-192, 2018.The aim of the study was to assess whether previous freezing cold injury in fingers and/or toes might predispose alpinists to greater risk of further freezing cold injury, primarily due to a greater vasoconstrictor response to cold, resulting in a lower perfusion, reflected in lower skin temperature.Ten elite alpinists (N = 10; 8 male and 2 female) with amputations after freezing cold injury participated in a cold-water (8°C) immersion stress test of the hands and feet. Digit skin temperatures of amputated digits, their noninjured counterparts, noninjured digits of the affected side and noninjured digits of the corresponding side were measured. The skin temperatures were compared during three consecutive phases of the cold stress test: prewarming, cold water immersion, and passive heating.Amputated toes cooled much faster compared to their uninjured counterparts (n = 26, p 0.001), and attained lower skin temperatures during the cold exposure test (n = 26, p 0.001). Higher cooling rate was observed in all the toes on the injured limb compared with the toes on the uninjured limb (n = 40, p 0.001). In contrast to the toes, the fingers on the injured limb after freezing cold injury were warmer during cooling phase compared to uninjured fingers (n = 15, p 0.001).The lower digit temperatures observed in affected toe stumps during the cold stress test compared to the nonamputated toes may indicate a heightened risk of future freezing cold injury with subsequent cold exposures, as a consequence of less perfusion, reflected in the lower skin temperature. This relationship was not confirmed in the fingers.

Background Statins were shown to inhibit borrelial growth in vitro and promote clearance of spirochetes in a murine model of Lyme borreliosis (LB). We investigated the impact of statin use in patients with early LB. Methods In this post-hoc analysis, the association between statin use and clinical and microbiologic characteristics was investigated in 1520 adult patients with early LB manifesting as erythema migrans (EM), enrolled prospectively in several clinical trials between June 2006 and October 2019 at a single-center university hospital. Patients were assessed at enrollment and followed for 12 months. Results Statin users were older than patients not using statins, but statin use was not associated with Borrelia seropositivity rate, Borrelia skin culture positivity rate, or disease severity as assessed by erythema size or the presence of LB-associated symptoms. The time to resolution of EM was comparable in both groups. The odds for incomplete recovery decreased with time from enrollment, were higher in women, in patients with multiple EM, and in those reporting LB-associated symptoms at enrollment, but were unaffected by statin use. Conclusion Statin use was not associated with clinical and microbiologic characteristics or long-term outcome in early LB.

The purpose of the study was to find out whether there is a difference in the early parameters of cardiotoxicity (left ventricular ejection fraction LVEF and N-terminal pro-B-type natriuretic peptide NT-proBNP) between the two groups of patients: the patients treated for left breast cancer (left breast cancer group) and those treated for the right breast cancer (right breast cancer group), after the treatment had been completed. Patients and methods. The study included 175 consecutive patients with human epidermal growth factor receptor- 2 (HER2) positive early breast cancer, treated concurrently with trastuzumab and radiotherapy (RT), between June 2005 and December 2010. Echocardiography with LVEF was performed before adjuvant RT (LVEF0) and in all patients after the concurrent treatment had been completed (LVEF1) as well as we carried out the NT-proBNP measurements. The difference (%) between LVEF0 and LVEF1 was analysed (% LVEF = LVEF0 - LVEF1) and compared between the two groups. Results. There were 84 patients in the left and 91 in the right breast cancer group. Median observation time was 57 (37%71) months. Mean % LVEF (%) was -1.786% in the left and -2.607% in the right breast cancer group (p = 0.562, CI: -2.004 to 3.648). Median NT-proBNP were 111.0 ng/l in the left and 90.0 ng/l in the right breast cancer group (p = 0.545). Echocardiography showed that the patients in the left breast cancer group did not have significantly worse systolic and diastolic left ventricular function in comparison with the patients in the right breast cancer group, but, they had higher incidence of pericardial effusion (9 11% vs. 1 1%) (p = 0.007). Conclusions. We did not find any significant differences in the early parameters of cardiotoxicity (LVEF, NT-proBNP) between the two groups we observed. Those patients who were irradiated on the left breast/chest wall had higher incidence of pericardial effusion. Z raziskavo smo želeli preveriti ali je med bolnicami, ki so ob zdravljenju s trastuzumabom pooperativno obsevale levo (skupina 1) oziroma desno (skupina 2) dojko/prsno steno, po zaključenem zdravljenju pomembna razlika v zgodnjih kazalcih kardiotoksičnosti. To smo merili z iztisnim deležem levega prekata (LVEF) in N-končnim pro-B natriuretičnim peptidom NT-proBNP). Bolniki in metode. V raziskavo smo vključili 175 zaporednih bolnic s pozitivnim HER2 rakom dojke, ki so v okviru dopolnilnega zdravljenja med junijem 2005 in decembrom 2010 prejemale trastuzumab ter smo jim sočasno pooperativno obsevali dojko/prsno steno. Vsem bolnicam smo ob začetku dopolnilnega zdravljenja naredili izhodiščno preiskavo srca, bodisi ehokardiografijo ali radioizotopno ventrikulografijo (LVEF0) ter naredili kontrolne meritve po zaključenem zdravljenju (LVEF1), hkrati pa smo jim določili vrednosti NT-proBNP. Analizirali smo razliko med LVEF0 in LVEF1 (% LVEF = LVEF0 -LVEF1) ter ju primerjali med skupinama. Rezultati. V skupini 1 je sodelovalo 84, v skupini 2 pa 91 bolnic. Mediani čas sledenja bolnic je bil 57 (37%71) mesecev. V skupini 1 je bila srednja vrednost % LVEF (%) -1,786 %, v skupini 2 pa -2,607 % (p = 0,562; interval zaupanja CI: od -2,004 do 3,648). Srednja vrednost NT-proBNP je bila 111,0 ng/l v skupini 1 in 90,0 ng/l v skupini 2 (p = 0,545). Primerjava ehokardiografskih kazalcev je pokazala, da bolnice iz skupine 1 niso imele pomembno slabše sistolične in diastolične funkcije levega prekata kot bolnice iz skupine 2, imele pa so pomembno več perikardnih izlivov (9 11 %) kot bolnice v skupini 2 (1 1 %) (p = 0,007). Zaključki. Med opazovanima skupinama nismo našli značilnih razlik v zgodnjih kazalcih kardiotoksičnosti (LVEF, NTproBNP). Bolnice, pri katerih smo obsevali levo dojko/prsno steno, so imele značilno več perikardnih izlivov.

Background Several guidelines advocate the same treatment approaches for both early disseminated Lyme borreliosis, manifested as multiple erythema migrans (EM), and early localized Lyme borreliosis, manifested as solitary EM. Methods Oral doxycycline (100 mg q12h) was compared on a non-inferiority premise with intravenous ceftriaxone (2 g q24h) for 14 days in 200 adult European patients with multiple EM in an open-label alternate-treatment observational trial performed in a single-centre university hospital. Treatment outcome was assessed at 14 days and at 2, 6 and 12 months post-enrolment. Non-specific symptoms in patients and 192 control subjects without a history of Lyme borreliosis were evaluated and compared. This trial was registered at http://clinicaltrials.gov (identifier NCT01163994). Results At the 12 month visit, 4/82 (4.9%) multiple EM patients prescribed doxycycline and 6/88 (6.8%) multiple EM patients prescribed ceftriaxone showed incomplete response manifested predominantly as post-Lyme symptoms (1.9% difference, upper limit of 95% CI 5.1%). The upper limit of 95% CI for the difference in proportion of patients with incomplete response between doxycycline and ceftriaxone groups did not exceed the predetermined non-inferiority margin of 10%. The frequency of non-specific symptoms in patients was similar to that in controls. Conclusions The 14 day oral doxycycline was not inferior to the 14 day intravenous ceftriaxone in treatment of adult European patients with early disseminated Lyme borreliosis manifested as multiple EM. The frequency of non-specific symptoms in patients was similar to that in controls without a history of Lyme borreliosis.

Background Commercial enteral formulas are generally recommended for gastrostomy feeding in patients with severe neurologic impairment. However, pureed food diets are still widely used and even gaining popularity among certain groups. We tried to compare the effectiveness of gastrostomy feeding for treatment of severe malnutrition with either enteral formulas or pureed feeds. Patients and methods A 6-month nutritional intervention was made with 37 malnourished children, adolescents and young adults (2–26 years old) with severe neurologic impairment (Gross Motor Function Classification system [GMFCS] grade V). The individual needs were calculated. Participants were fed by gastrostomy with either enteral formulas (n = 17) or pureed food (n = 20). Measurements to assess nutritional status were made at the beginning and at the end of intervention. Results The Z scores for weight-for-age and for the body-mass index increased more in enteral formula than in pureed food group (2.07 vs. 0.70, p = 0.0012; and 3.75 vs. 0.63, p = 0.0014, respectively). Fat mass index increased more in enteral formula than in pureed food group (1.12 kg/m2 vs. 0.38 kg/m2; p = 0.0012). Patients in the enteral formula group showed increase in lean body mass expressed as fat-free mass index (0.70 kg/m2), while those in pureed food group did not (-0.06 kg/m2) (p = 0.0487). Conclusions The results suggest that even professionally planned pureed food diet is less effective than commercial enteral formula for nutritional rehabilitation of malnourished patients with severe neurologic impairment. However, larger and if possible randomised clinical studies should be made to confirm our findings.

Animal studies suggest that dynamic predictors remain useful in patients with pneumoperitoneum, but human data is conflicting. Our aim was to determine predictive values of pulse pressure variation (PPV) and stroke volume variation (SVV) in patients with pneumoperitoneum using LiDCORapid™ haemodynamic monitor. Standardised fluid challenges of colloid were administered to patients undergoing laparoscopic procedures, one fluid challenge per patient. Intra-abdominal pressure was automatically held at 12 mmHg. Fluid responsiveness was defined as an increase in nominal stroke index (nSI) ≥ 10%. Linear regression was used to assess the ability of PPV and SVV to track the changes of nSI and logistic regression and area under the receiver operating curve (AUROC) to assess the predictive value of PPV and SVV for fluid responsiveness. Threshold values for PPV and SVV were obtained using the “gray zone” approach. A p

In clinical research the goal is often to correctly estimate the probability of an event. For this purpose several characteristics of the patients are measured and used to develop a prediction model which can be used to predict the class membership for future patients. Ensemble classifiers are combinations of many different classifiers and they can be useful because combining a set of classifiers can result in more accurate predictions. Gradient boosting is an ensemble classifier which was shown to perform well in the setting where the number of variables exceeds the number of samples (high-dimensional data), however it has not been evaluated for the prediction of rare events. It is demonstrated that Gradient boosting suffers from severe rare events bias, correctly classifying only a small proportion of samples from the rare class. The bias can be removed by using subsampling in combination with appropriate amount of shrinkage but only for a specific number of boosting iterations and for binomial loss function. It is shown that the number of boosting iterations where the rare events bias is removed cannot be estimated efficiently from the training data when the sample size is small. Therefore several corrections for the rare events bias of Gradient boosting are proposed and evaluated by using simulated and real high-dimensional data. It is demonstrated that the proposed corrections successfully remove the rare events bias and outperform the other ensemble classifiers that were considered. Large flexibility and high interpretability of the proposed methods is also illustrated.