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Listening to music and perceiving and understanding a music piece are complex processes that depend on many factors. How a music piece of work will be accepted and understood is greatly influenced by the age, music experience, preparation before listening, as well as the actual realization of the given activity, that is, the methodical procedures used in the field of music education. Perceiving and understanding the music form is an abstract and one of a more difficult tasks facing children and students, if there is no preparation before listening to music, explanation, or correlation with other areas. Also, the perception of a music form, in itself, is the most complex mental activity, which includes, in addition to the ability of music perception of children/pupils, the cognitive data processing, that is, the ability of abstract musical thinking. The aim of the paper is to explore how children at preschool and younger school age perceive and understand the musical form of certain compositions with prior preparation before listening to music. The research was carried out on a sample of children of pre-school age and children of the first and second grade of elementary school. The results showed that children with more hands-on experience and those who had interdisciplinary content involved before music activities were better in recognizing the music form.

Tourism is one of the most important industries in Montenegro, having several multiplier effects. Direct contribution of tourism to economic growth and development of Montenegro became even more important in the period after the outbreak of the global economic crisis. Due to low export competitiveness and high dependence of its economy on import, Montenegro has been facing high deficit in foreign trade and balance of payments for years. The article aims to analyze the trend of revenue from foreign tourists and to assess the effects of such revenue on overall changes to the current account of Montenegro's balance of payment. The results of the study show that in the period from 2008 onwards, growth of tourism revenue has lead to increased deficit in balance of payments. Since needs of tourists cannot be met from own sources, Montenegro has increased import of goods and services in the same period, which reduced total effects of tourism. In the years after the outbreak of the global economic crisis, the direct influence of tourism on increased surplus on the services subaccount within the current account of the balance of payments becomes even more important. Growth of tourism revenue leads to significantly higher surplus in the services subaccount, and therefore reduces the balance of payments deficit. Negative effects of tourism on goods import have been significantly reduced over the period, which allowed for a higher degree of coverage of trade deficit by tourism revenue. Increased revenue from foreign tourists at the same time causes higher growth of revenues from transport services, which has indirect positive effect on general changes in the current account of Montenegro's balance of payments.

Creating a satisfied and loyal customer base is one of the prerequisites for a long-term survival of the bank in a competitive market, such it is today. Considering that, to achieve a client satisfaction as well as to establish loyalty, it is necessary to have competent, satisfied and motivated employees. That is the reason why banks tend to increasingly shift their attention from traditional to internal marketing. Therefore, the aim of this research is to determine the key internal marketing activities which are crucial for the bank employees' perception of overall quality of internal marketing. Besides, it is necessary to find out are there correlations between all of the extracted key internal marketing activities and all forms of employee satisfaction. The research was conducted in eight branch offices of two banks in Belgrade and Novi Sad and includes 165 respondents employed in said banks. Based on the provided results, a scientific confirmation was given of the importance of internal marketing for the employees' satisfaction in banks. Also, managerial implications are given which internal marketing activities are crucial for achieving the overall employees' satisfaction.

The problems of environment and evaluation of natural capital belong to the phenomenology of externalities, and the requirements of environmental economics are ever more oriented towards the elaboration of the ecological–economic category of the externalization of internal expenses, wherefrom reasons for the introduction of ecological–economic instruments, before all payments for pollutions, ensue. Demystification of the negative conviction relating ecological payments as taxes is very important, since it must be shown that ecological payments correct, mitigate or remove externalities. Environmental protection is a complex system and it consists in a set of rules, measures and instruments that are applied for the surveillance of pollution sources, and shaping of instruments for environmental protection is a complex process intended for the accomplishment of established ecological goals. Among all instruments available for bridging the gap of internalization and exerting a significant effect on polluters to diminish their emissions of pollution, the ecological and economic ones are most important. The results of our investigation have demonstrated that it is necessary to reshape the current set of instruments regarding protection of vital functions of nature and an efficient environmental protection, and one of the key cognitions is that the scientific and professional public must not be excluded from the appraisals of creating and redesigning the instruments of environmental protection. These assertions have their foundation in the premise that the significance of elements of the social dimension in sustainable development is to a great extent determined by the level of environmental degradation and reduction in capacity of renewable sources. The paper, approach and data processing of the conducted research offer a new model and new elements of methodology for establishing the state and quality of the environment, whereby social-economic criteria of research (a socio–economic laboratory) are introduced into the fundamental analysis of the condition of crucial media of the environment, but also into shaping a more efficacious instrument set of protection. In such a way, a substantial contribution is given to the affirmation of a holistic and inter-disciplinary approach in the investigation and understanding the phenomenon of contemporary environmental reality, especially the central media of the environment (water, air, soil).

The Language of hatred in its basic war inciting sense has almost disappeared from media. However, its mutants still may come out into public though intolerance or political settlements. There is no community insensitive to some kinds of hatred. Neither developed democratic nor, even less communities in new Balkan states. Members of minority groups are specially under impact - from ethnic via religious to those specially vulnerable community groups such as handicapped, with specific diseases and juveniles and alike. This paper is about that tolerance and hatred which still exists in media on Balkan. The writer points to the relationship of journalists to those minority groups and offers some of possible ways for improving the relationship between them.

Due to constantly increasing competition in the higher education market, customer or user satisfaction should be made the focal point of all higher education institutions. Creating happier, satisfied customers, whether they are students, their parents, donors, professors or employers, should be the primary objective which will also contribute to the quality of the educational institutions. In line with that, this paper aims to show the extent to which human factor (as a tool of marketing mix) and all elements associated with it, affect student satisfaction in higher education institutions. The survey was conducted on a sample of 703 respondents, i.e. students of four faculties which are part of the University Business Academy in Novi Sad. A questionnaire created specially for research purposes was used as an instrument for data collection. The analysis of collected data included correlation and regression analysis. The obtained results indicate a statistically significant correlation between the human factor and the satisfaction of students in higher education institutions. The paper touches upon the impact of each element on the satisfaction of students. Such analysis provides us with important indicators in terms of specific elements of human factor which should be improved if we want to improve the overall satisfaction of students in higher education institutions. Finally, the paper outlines possible conclusions and recommendations for further research on the basis of the obtained results.

The paper deals with the particular naming units for plant species of the genus Scilla characteristic for the Balkan languages that have not been sufficiently discussed in previous phytonomastical researches.

Objectives: We aimed to investigate age- and sex-specific effects of obesity, metabolic syndrome (MetS) and its components on back pain in middle-aged and older English individuals.Methods: We used data from the English Longitudinal Study of Ageing, wave 2 (2004-2005). Body mass index (BMI) expressed the obesity, while MetS was defined according to revised Adult Treatment Panel (ATP) III criteria. We assessed associations between obesity, MetS and its components with presence and severity of back pain and provided estimates per strata, middle-aged (50-64years) and older (65-79years), women and men.Results: The study sample included 3328 participants, 1021 and 835 middle-aged women and men and 773 and 699 older women and men, respectively. We found that BMI (OR=1.07, 95% CI 1.05-1.09), MetS (OR=1.47, 95% CI 1.22-1.77), high waist circumference (WC), high triglycerides (TG), and high fasting blood glucose were associated with the presence of back pain. Effects of BMI were consistent across the strata. However, MetS was associated with back pain only in women, middle-aged (OR=1.59, 95% CI 1.14-2.21) and older (OR=1.43, 95% CI 1.01-2.05). The MetS component driving this association was high WC, supported by high TG in older women. Higher BMI, presence of MetS, high blood pressure and TG were associated with back pain severity.Conclusions: We found that obesity was associated with the presence and severity of back pain, irrespective of age and sex. However, we found women-specific effects of MetS driven by high WC, indicating that metabolic dysregulation contributes to back pain pathophysiology in women. [ABSTRACT FROM AUTHOR]

Clostridioides difficile is a One Health pathogen found in humans, animals, and environment, with food representing a potential transmission route. One Health studies are often limited to single country or selected reservoirs and ribotypes. This study provides a varied and accessible collection of C. difficile isolates and sequencing data derived from human, animal, and food sources across thirteen European countries. A total of 441 strains (human hospital and community associated cases n = 280, animal n = 96, food n = 65) were analysed by ribotyping, toxinotyping and whole genome sequencing (WGS). We detected 83 sequence types (STs), with ST11 (n = 80 isolates) and ST1 (n = 54 isolates) being the most represented. Several STs included strains originating from all source combinations. Further genomic analysis confirmed close genetic relatedness in some of the STs. Additionally, genomic analysis identified ten strains from cryptic clades (C-I to C-III) and four of them were mono-toxigenic possessing only a variant form of tcd A gene. Amongst 106 ribotypes, ten were shared between all three sources and 68 were source specific. Some ribotypes were only found at intersection of human and food source (RT023, RT027), or between human and animal source (RT009, RT045, RT046). C. difficile ribotypes and STs in Europe were diverse. In this collection some ribotypes showed potential association with food or animal transmission routes. C. difficile strains from divergent clades CI-III, currently emerging in human population, were rare and mostly food associated.

Purpose: Here, we evaluate a PET displacement model with a Single-step and Numerical solution in healthy individuals using the synaptic vesicle glycoprotein (SV2A) PET-tracer [ 11 C]UCB-J and the anti-seizure medication levetiracetam (LEV). We aimed to (1) validate the displacement model by comparing the brain LEV-SV2A occupancy from a single PET scan with the occupancy derived from two PET scans and the Lassen plot and (2) determine the plasma LEV concentration-SV2A occupancy curve in healthy individuals., Methods: Eleven healthy individuals (five females, mean age 35.5 [range: 25-47] years) underwent two 120-min [ 11 C]UCB-J PET scans where an LEV dose (5-30 mg/kg) was administered intravenously halfway through the first PET scan to partially displace radioligand binding to SV2A. Five individuals were scanned twice on the same day; the remaining six were scanned once on two separate days, receiving two identical LEV doses. Arterial blood samples were acquired to determine the arterial input function and plasma LEV concentrations. Using the displacement model, the SV2A-LEV target engagement was calculated and compared with the Lassen plot method. The resulting data were fitted with a single-site binding model., Results: SV2A occupancies and V ND estimates derived from the displacement model were not significantly different from the Lassen plot (p = 0.55 and 0.13, respectively). The coefficient of variation was 14.6% vs. 17.3% for the Numerical and the Single-step solution in Bland-Altman comparisons with the Lassen plot. The average half maximal inhibitory concentration (IC 50 ), as estimated from the area under the curve of the plasma LEV concentration, was 12.5 µg/mL (95% CI: 5-25) for the Single-Step solution, 11.8 µg/mL (95% CI: 4-25) for the Numerical solution, and 6.3 µg/mL (95% CI: 0.08-21) for the Lassen plot. Constraining Emax to 100% did not significantly improve model fits., Conclusion: Plasma LEV concentration vs. SV2A occupancy can be determined in humans using a single PET scan displacement model. The average concentration of the three computed IC 50 values ranges between 6.3 and 12.5 µg/mL. The next step is to use the displacement model to evaluate LEV occupancy and corresponding plasma concentrations in relation to treatment efficacy., Clinical Trial Registration: NCT05450822. Retrospectively registered 5 July 2022 https://clinicaltrials.gov/ct2/results? term=NCT05450822&Search=Search., (© 2024. The Author(s).)

RBFOX1 is a highly pleiotropic gene that contributes to several psychiatric and neurodevelopmental disorders. Both rare and common variants in RBFOX1 have been associated with several psychiatric conditions, but the mechanisms underlying the pleiotropic effects of RBFOX1 are not yet understood. Here we found that, in zebrafish, rbfox1 is expressed in spinal cord, mid- and hindbrain during developmental stages. In adults, expression is restricted to specific areas of the brain, including telencephalic and diencephalic regions with an important role in receiving and processing sensory information and in directing behaviour. To investigate the contribution of rbfox1 to behaviour, we used rbfox1 sa15940 , a zebrafish mutant line with TL background. We found that rbfox1 sa15940 mutants present hyperactivity, thigmotaxis, decreased freezing behaviour and altered social behaviour. We repeated these behavioural tests in a second rbfox1 mutant line with a different genetic background (TU), rbfox1 del19 , and found that rbfox1 deficiency affects behaviour similarly in this line, although there were some differences. rbfox1 del19 mutants present similar thigmotaxis, but stronger alterations in social behaviour and lower levels of hyperactivity than rbfox1 sa15940 fish. Taken together, these results suggest that mutations in rbfox1 lead to multiple behavioural changes in zebrafish that might be modulated by environmental, epigenetic and genetic background effects, and that resemble phenotypic alterations present in Rbfox1-deficient mice and in patients with different psychiatric conditions. Our study, thus, highlights the evolutionary conservation of rbfox1 function in behaviour and paves the way to further investigate the mechanisms underlying rbfox1 pleiotropy on the onset of neurodevelopmental and psychiatric disorders., (© 2024. The Author(s).)

RBFOX1 functions as a master regulator of thousands of genes, exerting a pleiotropic effect on numerous neurodevelopmental and psychiatric disorders. A potential mechanism by which RBFOX1 may impact these disorders is through its modulation of serotonergic neurotransmission, a common target for pharmacological intervention in psychiatric conditions linked to RBFOX1 . However, the precise effects of RBFOX1 on the serotonergic system remain largely unexplored. Here we show that homozygous rbfox1 sa15940 zebrafish, which express a shorter, aberrant rbfox1 mRNA, have significantly reduced serotonin levels in telencephalon and diencephalon. We observed that the acute administration of fluoxetine partially reverses the associated behavioural alterations. The hyperactive phenotype and altered shoaling behaviour of the rbfox1 sa15940/sa15940 zebrafish could be reversed with acute fluoxetine exposure in the Open Field and the Shoaling test, respectively. However, in the other paradigms, hyperactivity was not diminished, suggesting a distinct intrinsic motivation for locomotion in the different paradigms. Acute fluoxetine exposure did not reverse the alterations observed in the aggression and social novelty tests, suggesting the involvement of other neurological mechanisms in these behaviours. These findings underscore the importance of investigating the intricate working mechanisms of RBFOX1 in neurodevelopmental and psychiatric disorders to gain a better understanding of the associated disorders along with their pharmacological treatment.

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: Population data that examines recent national trends in the prevalence of fractures are lacking in the United States (US)., Materials and Methods: Analyses were based on 1999-2020 data from the National Health and Nutrition Examination Survey (NHANES). Primary outcomes included the prevalence of hip, wrist, and vertebral fractures among adults aged greater than or equal to 50 years. Changes in the prevalence over time were determined by joinpoint regression analysis. The authors also described the variation by fracture subtypes, sociodemographic characteristics, and their combination., Results: For adults aged greater than or equal to 50 years in NHANES 2017-March 2020, the authors estimated that there was 2.6 million Americans with hip fractures, 14.6 million Americans with wrist fractures, and 5.2 million Americans with vertebral fractures. The prevalence of wrist fractures significantly increased from 8.7% (7.4-9.9%) in 1999-2000 to 12.8% (11.6-14.1%) in 2017-March 2020 among adults aged greater than or equal to 50 years ( P for trend=0.04); significant increases were also observed in fractures that occurred at age less than 50 years, non-Hispanic White, high family income groups, and several combination subgroups (e.g. fractures occurred at age <50 years among women). The prevalence of vertebral fractures increased from 2.2% (1.7-2.8%) in 1999-2000 to 4.6% (3.7-5.5%) in 2017-March 2020 among adults aged greater than or equal to 50 years ( P for trend=0.02); significant increases were also observed in 50-64 years, women, non-Hispanic White, high family income groups and several combination subgroups (e.g. fractures that occurred at age <50 years among women). The authors did not observe significant trend changes in the prevalence of hip fractures among adults aged greater than or equal to 50 years between 1999 and 2020., Conclusion: The estimated prevalence of wrist and vertebral fractures significantly increased among US adults aged greater than or equal to 50 years from 1999 to 2020, although hip fractures did not significantly change., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Studies have reported an increase in the prevalence of depression during the COVID-19 pandemic. The accuracy of screening tools may change with the prevalence and distribution of a disease in a population or sample: the "Spectrum Effect"., Methods: First, we selected commonly used screening tools and developed search strategies for the inclusion of original studies during the pandemic. Second, we searched PsycINFO, EMBASE, and MEDLINE from March 2020 to September 2022 to obtain original studies that investigated the accuracy of depression screening tools during the pandemic. We then searched these databases to identify meta-analyses summarizing the accuracy of these tools conducted before the pandemic and compared the optimal cut-offs for depression screening tools during the pandemic with those before., Result: Four original studies evaluating the optimal cut-offs for four screening tools (Beck Depression Inventory [BDI-II], Hospital Anxiety and Depression Scale-Depression [HADS-D], Patient Health Questionnaire-9 [PHQ-9], and Geriatric Depression Scale-4 [GDS-4]) were published during the pandemic. Four meta-analyses summarizing these tools before the pandemic. We found that the optimal cut-off of BDI-II was 14 during the pandemic (23.8% depression prevalence, screening patients with Type 2 diabetes) and 14.5 before the pandemic (17.6% depression prevalence, screening psychiatric, primary care, and healthy populations); HADS-D was 10 during the pandemic (23.8% depression prevalence, screening patients with type 2 diabetes) and 7 before the pandemic (15.0% depression prevalence, screening medically ill patients); PHQ-9 was 11 during the pandemic (14.5% depression prevalence, screening university students) and 8 before the pandemic (10.9% depression prevalence, screening the unrestricted population), and GDS-4 was 1.8 during the pandemic (29.0% depression prevalence, screening adults seen in a memory clinic setting) and 3 before the pandemic (18.5% depression prevalence, screening older adults)., Conclusion: The optimal cut-off for different screening tools may be sensitive to changes in study populations and reference standards. And potential spectrum effects that should be considered in post-COVID time which aiming to improve diagnostic accuracy., (© 2023. The Author(s).)

Background: There are increasing concerns that participants in health research in the UK are not representative of the UK population, risking widening health inequities. However, detailed information on the magnitude of the problem is limited. Therefore, we evaluated if the health research conducted in the Greater Manchester region was broadly representative of its diverse population., Methods: We conducted an audit of all health  research studies conducted exclusively in Greater Manchester, using data from a national research network. Two researchers selected studies that were (1) an interventional or observational study of a health outcome; (2) 'closed' for recruitment between May 2016 and May 2021 and (3) human research. They extracted study information (dates, contacts, sample recruited, clinical speciality). Participant characteristics were sourced from published and unpublished manuscripts and requested directly from principal investigators and named study contacts. Data were extracted, summarised and compared to the Greater Manchester population for the following metrics: ethnicity, sex, age, deprivation and smoking status. A weighted mean age estimate was calculated to account for variation in age reporting. Too few studies provided patient-level deprivation data so, using the area code of the recruitment site, the area level multiple deprivation, health deprivation and disability index and decile was derived. These data were geo-mapped using QGIS 3.26., Results: Overall, 145/153 (95%) studies met inclusion criteria and participant information was sourced for 85/145 (59%) studies, representing 21,797 participants. Participant information was incomplete for all metrics. Where ethnicity (N = 10,259) data were available and compared to Greater Manchester estimates there was evidence that ethnic minorities were under-represented (6% versus 16%). Most of the recruitment occurred in central Manchester (50%) and with NHS hospital settings (74%)., Conclusions: Greater Manchester health research in 2016-2021 was centralised and under-represented ethnic minorities. We could not report which ethnic minority group was least represented because sourcing detailed participant information was challenging. Recommendations to improve the reporting of key participant characteristics with which to monitor representativeness in health research are discussed., (© 2023. The Author(s).)

Aims: Serum insulin-like growth factor binding protein-2 (IGFBP-2) is low in persons with type 2 diabetes mellitus (T2D) and possibly regulated by metformin. Counter-intuitively, high IGFBP-2 associates with mortality. We investigated the association between IGFBP-2, metformin-treatment, and indices of insulin sensitivity, and assessed IGFBP-2 in relation to prior comorbidity and mortality during five-year follow-up., Methods: The study included 859 treatment-naive and 558 metformin-treated persons enrolled in the Danish Centre for Strategic Research in T2D and followed for 4.9 (3.9-5.9) years through national health registries. All proteins were determined in serum collected at enrollment., Results: Following adjustment for age, metformin-treated and treatment-naive persons has similar IGFBP-2 levels. Low IGFBP-2 level was associated with increased BMI, fasting glucose, and C-peptide. IGFBP-2 was higher in the 437 persons who had comorbidities at enrollment than in those with T2D only (343 (213;528) vs. 242 (169;378) ng/mL). During follow-up, 87 persons died, and IGFBP-2 predicted mortality with an unadjusted HR (95% CI) per doubling in IGFBP-2 concentration of 2.62 (2.04;3.37) and a HR of 2.21 (1.61;3.01) following full adjustment., Conclusions: In T2D, high IGFBP-2 associates with low glucose and insulin secretion, is unaffected by metformin treatment, and associates with risk of prior comorbidity and mortality., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Throughout the literature, pain burden has been assessed by asking different questions, often cross-sectionally, different populations of interest. We know little about pain re-occurrence and how to translate knowledge between pain questions within the population of interest. We aimed to estimate the burden of musculoskeletal pain by estimating prevalence, incidence rates, and re-occurrence risk of back, hand, hip, knee, and foot pain using different questions from UK population-based samples and predict the number of affected individuals in the UK in 2030., Methods: We used two UK population-representative studies, with two eight-year-apart follow-ups and two pain questions assessing recent pain episodes and often troubled pain when walking. We estimated prevalence, 8-year incidence rates, and 8-year pain re-occurrence risk for women and men aged 50 years and older and the relation between the two pain questions., Results: Among UK individuals older than 50 years, the prevalence of musculoskeletal pain episode was 20%-50%, and the incidence was 20-40/1,000 person-years, while the prevalence of pain when walking was 10%-25%, and the incidence was 6-12/1,000 person-years. The most prevalent musculoskeletal pain types were back and knee pain; of five women experiencing back or knee pain episodes, three are expected to be often troubled by pain. Hip and foot pain had similar estimates in both questions. Hand pain peaked in women aged 50-65 years. Women had higher prevalence and incidence rates, but men had higher 8-year re-occurrence risk of all types of musculoskeletal pain. Reporting a pain episode was associated with two times higher risk, but often troubled by pain when walking was associated with four to seven times times higher risk of the same pain in 8 years. Women and men with a body mass index (BMI) of ≥27 kg/m 2 were twice as likely to experience musculoskeletal pain than those with BMI<27 kg/m 2 . In 2030, we expect 2-7 million people older than 50 years in the United Kingdom to seek site-specific musculoskeletal pain-focused healthcare., Conclusions: In individuals older than 50 years, the experience of musculoskeletal pain at least doubles the chance of experiencing it again. Women report musculoskeletal pain more often, but men report more persistent pain. Musculoskeletal pain presents a significant burden to public health., Competing Interests: TDS reported serving as a scientific consultant for Zoe Global Ltd. NKA reported receiving personal fees from Bristows LLP outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, (© 2023 Radojčić, Perera, Hart, Spector and Arden.)

Background: Immune dysregulation and associated inefficient anti-viral immunity during Coronavirus Disease 2019 (COVID-19) can cause tissue and organ damage which shares many similarities with pathogenetic processes in systemic autoimmune diseases. In this study, we investigate wide range autoimmune and immunoserological markers in hospitalized patients with COVID-19., Methods: Study included 51 patients with confirmed Severe Acute Respiratory Syndrome Coronavirus 2 infection and hospitalized due to COVID-19 pneumonia. Wide spectrum autoantibodies associated with different autoimmune inflammatory rheumatic diseases were analyzed and correlated with clinical and laboratory features and pneumonia severity., Results: Antinuclear antibodies (ANA) positivity was found in 19.6%, anti-cardiolipin IgG antibodies (aCL IgG) in 15.7%, and anti-cardiolipin IgM antibodies (aCL IgM) in 7.8% of patients. Positive atypical x anti-neutrophil cytoplasmic antibodies (xANCA) were detected in 10.0% (all negative for Proteinase 3 and Myeloperoxidase) and rheumatoid factor was found in 8.2% of patients. None of tested autoantibodies were associated with disease or pneumonia severity, except for aCL IgG being significantly associated with higher pneumonia severity index ( p = 0.036). Patients with reduced total serum IgG were more likely to require non-invasive mechanical ventilation (NIMV) ( p < 0.0001). Serum concentrations of IgG ( p = 0.003) and IgA ( p = 0.032) were significantly lower in this group of patients. Higher total serum IgA ( p = 0.009) was associated with mortality, with no difference in serum IgG ( p = 0.115) or IgM ( p = 0.175). Lethal outcome was associated with lower complement C4 ( p = 0.013), while there was no difference in complement C3 concentration ( p = 0.135)., Conclusion: Increased autoimmune responses are present in moderate and severe COVID-19. Severe pneumonia is associated with the presence of aCL IgG, suggesting their role in disease pathogenesis. Evaluation of serum immunoglobulins and complement concentration could help assess the risk of non-invasive mechanical ventilation NIMV and poor outcome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewers IJ and VC declared a shared affiliation with the authors MRS, MIS, SD-J, SP, IB, DJ, MS-L, IS, BB-N, RM, and SS to the handling editor at the time of review., (Copyright © 2022 Stjepanovic, Stojanovic, Stankovic, Cvejic, Dimic-Janjic, Popevic, Buha, Belic, Djurdjevic, Stjepanovic, Jovanovic, Stojkovic-Laloševic, Soldatovic, Bonaci-Nikolic and Miskovic.)

Objective: We aimed to study 19-year body mass index (BMI) patterns and their (1) bidirectional relationship with musculoskeletal pain and (2) mortality risk., Study Design and Setting: We used data from the Chingford study and group-based trajectory modelling to define 19-year BMI patterns. We investigated whether baseline back, hand, hip, and knee pain (as single- and multi-site) predicted 19-year BMI trajectory, and whether 19-year BMI patterns predicted pain in year 20. We explored BMI trajectories and mortality risk over 25 years (life expectancy)., Results: We included 938 women (mean age: year-1=54, year-20=72) and found seven distinct 19-year BMI trajectories: two normal-weighted (reference), slightly overweight, lower and upper overweight-to-obese, lower and upper obese. BMI patterns capturing the increase overweight-to-obese (BMI 27-34 overtime) were bidirectionally related to knee and multi-site pain. The lower obese pattern (BMI 33-38) was unidirectionally associated with lower limb pain. Women with BMI above 40 had an increased all-cause and cardiovascular mortality risk., Conclusion: For most postmenopausal women, the overweight WHO category was a transition. Two patterns capturing increase overweight-to-obese were mutually related to musculoskeletal pain, i.e., knee and multi-site pain contributed to becoming obese, and trajectories of becoming obese increased the odds of experiencing pain later., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Rugby football (Union and League) provides physical activity (PA) with related physical and mental health benefits. However, as a collision sport, rugby research and media coverage predominantly focus on injuries in elite players while the overall impact on health and well-being remains unclear. This study aims to provide a greater understanding of the risks and benefits of rugby participation in a diverse sample of men and women, current and former rugby Union and League players from recreational to the elite level of play. We will explore: (1) joint-specific injuries and concussion; (2) joint pain and osteoarthritis (OA); (3) medical and mental health conditions; (4) PA and sedentary behaviour and (5) well-being (quality of life, flourishing and resilience)., Methods and Analysis: The Rugby Health and Well-being Study is designed in two phases: (1) a UK-wide cross-sectional survey and (2) cross-validation using health register data from Scotland. Participants will be at least 16 years old, current or former rugby players who have played rugby for at least one season. We will report standardised, level of play-, sex- and age-stratified prevalence of joint injury, concussion, medical conditions and PA. We will describe injury/concussion prevention expectations and protective equipment use. Rugby-related factors associated with injury, pain, OA, PA, health and well-being will be explored in regression models. We will compare joint pain intensity and duration, elements of pain perception and well-being between recreational and elite players and further investigate these associations in regression models while controlling for confounding variables. In the second phase, we will validate self-reported with health register data, and provide further information on healthcare use., Ethics and Dissemination: The Yorkshire and the Humber-Leeds East Research Ethics Committee (REC reference: 19/HY/0377) has approved this study (IRAS project ID 269424). The results will be disseminated through scientific publications, conferences and social media., Competing Interests: Competing interests: NKPP, MRR, SRF, LG, RH and NKA declare no competing interests. SAG works as a Sports Medicine Training Fellow for the Rugby Football Union and receives remuneration for clinical work in the sport. AM receives remuneration from Scottish Rugby Union for clinical work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Knee osteoarthritis (OA) is a heterogeneous disease, and identification of its subgroups/phenotypes can improve patient treatment and drug development. We aimed to identify homogeneous OA subgroups/phenotypes using pain development over time; to understand the interplay between pain and functional limitation in time course; and to investigate subgroups' responses to available pharmacological and surgical treatments. We used group-based trajectory modelling to identify pain trajectories in the phase-3 VIDEO trial (n = 474, 3-year follow-up) and also in the Osteoarthritis Initiative cohort study (n = 4796, 9-year follow-up). We extended trajectory models by (1) fitting dual trajectories to investigate the interplay between pain and functional limitation over time, and (2) including analgesic use as a time-varying covariate. Also, we investigated the relationship between trajectory groups and knee replacement in regression models. We identified 4 pain trajectory groups in the trial and 6 in the cohort. These overlapped and led us to define 4 OA phenotypes: low-fluctuating, mild-increasing, moderate-treatment-sensitive, and severe-treatment-insensitive pain. Over time, functional knee limitation followed the same trajectory as pain with almost complete concordance (94.3%) between pain and functional limitation trajectory groups. Notably, we identified a phenotype with severe pain that did not benefit from available treatments, and another one most likely to benefit from knee replacement. Thus, knee OA subgroups/phenotypes can be identified based on patients' pain experiences in studies with long and regular follow-up. We provided a robust approach, reproducible between different study designs, which informs clinicians about symptom development and delivery of treatment options and opens a new avenue toward personalized medicine in OA.

Little is known about local and systemic biomarkers in relation to synovitis and pain in end-stage osteoarthritis (OA) patients. We investigated the associations between the novel extracellular matrix biomarker, C1M, and local and systemic interleukin 6 (IL-6) with synovitis and pain. Serum C1M, plasma, and synovial fluid IL-6 (p-IL-6, sf-IL-6) were measured in 104 end-stage knee OA patients. Contrast-enhanced magnetic resonance imaging was used to semiquantitatively assess an 11-point synovitis score; pain was assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Neuropathic Pain Questionnaire (NPQ). Linear regression was used to investigate associations between biomarkers and synovitis, and biomarkers and pain while controlling for age, sex, and body mass index. We also tested whether associations between biomarkers and pain were confounded by synovitis. We found sf-IL-6 was associated with synovitis in the parapatellar subregion (B = 0.006; 95% confidence interval [CI] 0.003-0.010), and no association between p-IL-6 and synovitis. We also observed an association between C1M and synovitis in the periligamentous subregion (B = 0.013; 95% CI 0.003-0.023). Furthermore, sf-IL-6, but not p-IL-6, was significantly associated with pain, WOMAC (B = 0.022; 95% CI 0.004-0.040), and NPQ (B = 0.043; 95% CI 0.005-0.082). There was no association between C1M and WOMAC pain, but we did find an association between C1M and NPQ (B = 0.229; 95% CI 0.036-0.422). Lastly, synovitis explained both biomarker-NPQ associations, but not the biomarker-WOMAC association. These results suggest that C1M and IL-6 are associated with synovitis and pain, and synovitis is an important confounding variable when studying biomarkers and neuropathic features in OA patients.

Benzodiazepines and benzodiazepine-related medications (BBRMs) are anxiolytics and hypnotics acting on γ-amino butyric acid (GABA) A receptors. BBRMs are assumed to have a low potential for major congenital malformations, but research on more subtle and protracted developing symptoms of these medications is lacking. Therefore, we prospectively investigated the association between BBRM use in pregnancy and long-term effects on child behavior in a large population-based cohort study. The study population consisted of 104 children prenatally exposed to BBRM, 527 children exposed to maternal prenatal anxiety or phobic anxiety symptoms (without exposure to BBRM), and 5609 control children. At child age, 6years, Oppositional Defiant Disorder (ODD), Aggressive Behavior and Anxiety Problems were assessed by the Child Behavior Checklist (CBCL) reported by the mother and the Teacher Report Form (TRF). Children prenatally exposed to BBRM had higher scores of ODD and aggressive behavior, but not of anxiety. However, these associations were explained by maternal anxiety symptoms during pregnancy. Moreover, prenatal exposure to anxiety (without exposure to BBRM) was associated with increased scores of child ODD, aggressive behavior, and anxiety. In conclusion, the current study demonstrates that prenatal BBRM exposure was not independently associated with ODD and aggressive behavior in childhood when prenatal anxiety symptoms were taken into account., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This study investigated the function of the cruciate ligaments during a forward lunge movement. The mechanical roles of the anterior and posterior cruciate ligament (ACL, PCL) during sagittal plane movements, such as forward lunging, are unclear. A forward lunge movement contains a knee joint flexion and extension that is controlled by the quadriceps muscle. The contraction of the quadriceps can cause anterior tibial translation, which may strain the ACL at knee joint positions close to full extension. However, recent findings suggest that it is the PCL rather than the ACL which is strained during forward lunging. Thus, the purpose of the present study was to establish a musculoskeletal model of the forward lunge to computationally investigate the complete mechanical force equilibrium of the tibia during the movement to examine the loading pattern of the cruciate ligaments. A healthy female was selected from a group of healthy subjects who all performed a forward lunge on a force platform, targeting a knee flexion angle of 90°. Skin-markers were placed on anatomical landmarks on the subject and the movement was recorded by five video cameras. The three-dimensional kinematic data describing the forward lunge movement were extracted and used to develop a biomechanical model of the lunge movement. The model comprised two legs including femur, crus, rigid foot segments and the pelvis. Each leg had 35 independent muscle units, which were recruited according to a minimum fatigue criterion. This approach allowed a full understanding of the mechanical equilibrium of the knee joint, which revealed that the PCL had an important stabilizing role in the forward lunge movement. In contrast, the ACL did not have any significant mechanical function during the lunge movement. Furthermore, the results showed that m. gluteus maximus may play a role as a knee stabilizer in addition to the hamstring muscles., (© 2012 The Authors. Journal of Anatomy © 2012 Anatomical Society.)