Optimum take-off angle in the standing long jump

The aim of this study was to identify and explain the optimum projection angle that maximises the distance achieved in a standing long jump. Five physically active males performed maximum-effort jumps over a wide range of take-off angles, and the jumps were recorded and analysed using a 2-D video analysis procedure. The total jump distance achieved was considered as the sum of three component distances (take-off, flight, and landing), and the dependence of each component distance on the take-off angle was systematically investigated. The flight distance was strongly affected by a decrease in the jumper’s take-off speed with increasing take-off angle, and the take-off distance and landing distance steadily decreased with increasing take-off angle due to changes in the jumper’s body configuration. The optimum take-off angle for the jumper was the angle at which the three component distances combined to produce the greatest jump distance. Although the calculated optimum take-off angles (19–27º) were lower than the jumpers’ preferred take-off angles (31–39º), the loss in jump distance through using a sub-optimum take-off angle was relatively small

Therapeutic potential of extracellular vesicles

Extracellular vesicles (EVs) are nanometer-sized, lipid membrane enclosed, vesicles that are secreted by most, if not all, cells and contain macromolecular material of the source cell including lipids, proteins and various nucleic acid species. Over the last two decades, EVs have been recognized as important mediators of cell-to-cell communication that influence both physiological and pathological conditions. Owing to their ability to transfer bioactive components and surpass biological barriers, EVs are increasingly explored as therapeutics, both as natural delivery vectors and in its own right, as improved cell based therapies. In paper I, the great potential of EVs as therapeutic entities is explored by equipping EVs with the brain targeting rabies viral glycoprotein peptide and load them with siRNA against alpha-synuclein (a-Syn). The findings demonstrate that EVs efficiently deliver the siRNA to the target with subsequent reduction of a-Syn pathology in vitro as well as in the brains of a- Syn overexpressing transgenic mice. Thus, this indicates that targeted EVs can be employed as efficient vectors for siRNA therapy against Parkinson’s disease and other a-Syn related pathological conditions. In pursuance of using EVs for therapeutic purposes, the fate of injected EVs must be understood. Consequently, the aim of paper II was to elucidate the biodistribution of injected EVs and to investigate factors that may influence the tissue distribution of exogenous EVs. The use of the fluorescent lipophilic dye DiR was thoroughly assessed and found to be a suitable labelling method for biodistribution studies that allowed for in vivo EV tracing with high sensitivity. EVs displayed a general distribution pattern with high accumulation in liver, lung and spleen, which is in line with previous findings of mononuclear phagocyte system (MPS)-associated EV uptake. In addition, the biodistribution profile of EVs was, to a varying degree, influenced by the administration route, cell source, dosing and targeting. These variables may thus be adopted for future EV-based therapies to reflect the preferred biodistribution and/or pharmacokinetic profile for a given therapeutic approach. Furthermore, EVs have been found to convey the beneficial immunomodulatory effects of mesenchymal stromal cell (MSC)-based cell therapy. Based on these findings and studies demonstrating that EVs can be engineered to display surface moieties, the objective of paper III was to produce MSC-derived EVs that express therapeutic proteins. A chimeric construct, with an EV sorting domain fused to a non-signalling cytokine receptor, was introduced to the parental cell to produce EVs that can sequester cytokines, termed decoy EVs. By targeting the central inflammatory pathways of TNFa and IL-6 trans-signalling, these decoy EVs significantly ameliorate systemic inflammation and neuroinflammation in vivo. This novel concept thus combines the beneficial effects of stem cell therapy, EVs as delivery agents and cytokine targeted biologics. Taken together, the findings in this thesis suggest that EVs have the potential to be utilized as a future platform of highly potent multifaceted biopharmaceutical

Psychometric properties of a short version of the HIV stigma scale, adapted for children with HIV infection

Background: HIV is a stigmatizing medical condition. The concept of HIV stigma is multifaceted, with personalized stigma (perceived stigmatizing consequences of others knowing of their HIV status), disclosure concerns, negative self-image, and concerns with public attitudes described as core aspects of stigma for individuals with HIV infection. There is limited research on HIV stigma in children. The aim of this study was to test a short version of the 40-item HIV Stigma Scale (HSS-40), adapted for 8–18 years old children with HIV infection living in Sweden. Methods: A Swedish version of the HSS-40 was adapted for children by an expert panel and evaluated by think aloud interviews. A preliminary short version with twelve items covering the four dimensions of stigma in the HSS-40 was tested. The psychometric evaluation included inspection of missing values, principal component analysis (PCA), internal consistency, and correlations with measures of health-related quality of life (HRQoL). Results: Fifty-eight children, representing 71% of all children with HIV infection in Sweden meeting the inclusion criteria, completed the 12-item questionnaire. Four items concerning participants’ experiences of others’ reactions to their HIV had unacceptable rates of missing values and were therefore excluded. The remaining items constituted an 8-item scale, the HIV Stigma Scale for Children (HSSC-8), measuring HIV-related disclosure concerns, negative self-image, and concerns with public attitudes. Evidence for internal validity was supported by a PCA, suggesting a three factor solution with all items loading on the same subscales as in the original HSS-40. The scale demonstrated acceptable internal consistency, with exception for the disclosure concerns subscale. Evidence for external validity was supported in correlational analyses with measures of HRQoL, where higher levels of stigma correlated with poorer HRQoL. Conclusion: The results suggest feasibility, reliability, as well as internal and external validity of the HSSC-8, an HIV stigma scale for children with HIV infection, measuring disclosure concerns, negative self-image, and concerns with public attitudes. The present study shows that different aspects of HIV stigma can be assessed among children with HIV in the age group 8–18

Development of a 12-item short version of the HIV stigma scale

BACKGROUND: Valid and reliable instruments for the measurement of enacted, anticipated and internalised stigma in people living with HIV are crucial for mapping trends in the prevalence of HIV-related stigma and tracking the effectiveness of stigma-reducing interventions. Although longer instruments exist, e.g., the commonly used 40-item HIV Stigma Scale by Berger et al., a shorter instrument would be preferable to facilitate the inclusion of HIV stigma in more and broader surveys. Therefore, the aim of this work was to develop a substantially shorter, but still valid, version of the HIV Stigma Scale. METHODS: Data from a psychometric evaluation of the Swedish 40-item HIV Stigma Scale were reanalysed to create a short version with 12 items (three from each of the four stigma subscales: personalised stigma, disclosure concerns, concerns with public attitudes and negative self-image). The short version of the HIV stigma scale was then psychometrically tested using data from a national survey investigating stigma and quality of life among people living with HIV in Sweden (n = 880, mean age 47.9 years, 26% female). RESULTS: The hypothesized factor structure of the proposed short version was replicated in exploratory factor analysis without cross loadings and confirmatory factor analysis supported construct validity with high standardised effects (>0.7) of items on the intended scales. The χ(2) test was statistically significant (χ(2) = 154.2, df = 48, p 0.4 for all items, with a variation indicating that the broadness of the concept of stigma had been captured. All but two aspects of HIV-related stigma that the instrument is intended to cover were captured by the selected items in the short version. The aspects that did not lose any items were judged to have acceptable psychometric properties. The short version of the instrument showed higher floor and ceiling effects than the full-length scale, indicating a loss of sensitivity in the short version. Cronbach's α for the subscales were all >0.7. CONCLUSIONS: Although being less sensitive in measurement, the proposed 12-item short version of the HIV Stigma Scale has comparable psychometric properties to the full-length scale and may be used when a shorter instrument is needed

Novel Assay of Metformin Levels in Patients With Type 2 Diabetes and Varying Levels of Renal Function: Clinical recommendations

AbstractObjective: To study trough levels of metformin in serum and its intra individual variation in patients using a newly developed assay. Research Design and Methods: Trough serum levels of metformin was measured once using Liquid Chromatography Tandem Mass Spectrometry (LcMSMS) in 137 type 2 diabetes patients with varying renal function (99 men) and followed repeatedly during two months in 20 patients (16 men) with estimated GFR (eGFR) below 60 ml/min/1.73 m(2) body surface. Results: Patients with eGFR >60, 30-60, and <30 ml/min/1.73 m(2) had a median trough metformin concentration of 4.5 mumol/l (range 0.1-20.7, n=107), 7.71 mumol/l (0.12-15.15, n=21), and 8.88 mumol/l (5.99-18.60, n=9), respectively. The median intraindividual overall coefficient of variation (CV) was 29.4 % (range 9,8-74,2). Conclusions: Determination of serum metformin with the LCMSMS technique is useful in patients on metformin treatment. Few patients had values over 20 mumol/L. Metformin measurement is less suitable for dose titration

Sexual Dysfunction and Reproductive Concerns in Young Men Diagnosed With Testicular Cancer: An Observational Study

INTRODUCTION: The survival rates for testicular cancer are excellent; still, there is a lack of knowledge regarding important survivorship issues, such as sexual dysfunction and reproductive concerns. AIM: The aim of this study was to investigate the prevalence and predictors of sexual dysfunction and reproductive concerns and the potential association between these issues in young men ∼2 years after a diagnosis of testicular cancer. METHODS: Data were collected from 111 men (response rate = 50%) diagnosed with testicular cancer at age 16-39. Patients were identified via the Swedish National Quality Registry for Testicular Cancer and approached with a survey, including standardized measures of sexual function, reproductive concerns, body image, and health-related quality of life. The survey was sent to participants approximately 2 years after their cancer diagnosis. Clinical variables were collected from the registry. Predictors were identified by multivariable linear regression analyses. MAIN OUTCOME MEASURES: The main outcomes were sexual function, assessed with the Patient-Reported Outcomes Measurement Information System Sexual Function and Satisfaction measure version 2.0, and reproductive concerns, assessed with the Reproductive Concerns After Cancer scale. RESULTS: Sexual dysfunction was reported by 26% of men, and a high level of reproductive concerns was reported by 28%. Lower satisfaction with sex life was associated with older age (β = -0.41), negative body image (β = -0.42), not having a partner (β = 4.8), and dissatisfaction with sex life before cancer (β = 8.31). Negative body image was associated with reproductive concerns in the dimensions of fertility potential (β = 0.06), partner disclosure (β = 0.08), and child's health (β = 0.07), whereas having had fertility preservation predicted higher levels of concerns with regard to personal health (β = 0.52) and achieving pregnancy (β = 0.53). Clinical variables did not predict either sexual function or reproductive concerns. CLINICAL IMPLICATIONS: Our results show that the majority of young men diagnosed with testicular cancer do not report sexual dysfunction or reproductive concerns 2 years after diagnosis. A sizeable minority, however, does report dysfunction or reproductive concerns, which should be recognized in the follow-up care of this population. STRENGTHS & LIMITATIONS: A strength of the study is the use of high-quality registry data and validated instruments. The lack of Swedish norms for sexual function and reproductive concerns is a possible limitation. CONCLUSION: A subgroup of young men treated for testicular cancer report sexual dysfunction or reproductive concerns approximately 2 years after diagnosis. Factors associated with these issues seem to mainly be psychological, rather than medical, nature. Ljungman L, Eriksson LE, Flynn KE, et al. Sexual Dysfunction and Reproductive Concerns in Young Men Diagnosed With Testicular Cancer: An Observational Study. J Sex Med 2019;16:1049-1059

Systemic exosomal siRNA delivery reduced alpha-synuclein aggregates in brains of transgenic mice.

Alpha-synuclein (α-Syn) aggregates are the main component of Lewy bodies, which are the characteristic pathological feature in Parkinson's disease (PD) brain. Evidence that α-Syn aggregation can be propagated between neurones has led to the suggestion that this mechanism is responsible for the stepwise progression of PD pathology. Decreasing α-Syn expression is predicted to attenuate this process and is thus an attractive approach to delay or halt PD progression. We have used α-Syn small interfering RNA (siRNA) to reduce total and aggregated α-Syn levels in mouse brains. To achieve widespread delivery of siRNAs to the brain we have peripherally injected modified exosomes expressing Ravies virus glycoprotein loaded with siRNA. Normal mice were analyzed 3 or 7 days after injection. To evaluate whether this approach can decrease α-Syn aggregates, we repeated the treatment using transgenic mice expressing the human phosphorylation-mimic S129D α-Syn, which exhibits aggregation. In normal mice we detected significantly reduced α-Syn messenger RNA (mRNA) and protein levels throughout the brain 3 and 7 days after treatment with RVG-exosomes loaded with siRNA to α-Syn. In S129D α-Syn transgenic mice we found a decreased α-Syn mRNA and protein levels throughout the brain 7 days after injection. This resulted in significant reductions in intraneuronal protein aggregates, including in dopaminergic neurones of the substantia nigra. This study highlights the therapeutic potential of RVG-exosome delivery of siRNA to delay and reverse brain α-Syn pathological conditions

Identification of storage conditions stabilizing extracellular vesicles pre

Extracellular vesicles (EVs) play a key role in many physiological and pathophysiological processes and hold great potential for therapeutic and diagnostic use. Despite significant advances within the last decade, the key issue of EV storage stability remains unresolved and under investigated. Here, we aimed to identify storage conditions stabilizing EVs and comprehensively compared the impact of various storage buffer formulations at different temperatures on EVs derived from different cellular sources for up to 2 years. EV features including concentration, diameter, surface protein profile and nucleic acid contents were assessed by complementary methods, and engineered EVs containing fluorophores or functionalized surface proteins were utilized to compare cellular uptake and ligand binding. We show that storing EVs in PBS over time leads to drastically reduced recovery particularly for pure EV samples at all temperatures tested, starting already within days. We further report that using PBS as diluent was found to result in severely reduced EV recovery rates already within minutes. Several of the tested new buffer conditions largely prevented the observed effects, the lead candidate being PBS supplemented with human albumin and trehalose (PBS-HAT). We report that PBS-HAT buffer facilitates clearly improved short-term and long-term EV preservation for samples stored at -80°C, stability throughout several freeze-thaw cycles, and drastically improved EV recovery when using a diluent for EV samples for downstream applications

Efficacy of a Web-Based Psychoeducational Intervention for Young Adults With Fertility-Related Distress Following Cancer (Fex-Can): Randomized Controlled Trial

Background: Threatened fertility following cancer diagnosis in the reproductive age may severely impact emotional and psychosocial well-being in survivorship. Effective web-based interventions for fertility-related distress have been lacking. Objective: This study aims to test whether the Fertility and Sexuality following Cancer (Fex-Can) intervention is superior to standard care in reducing fertility-related distress and related psychosocial outcomes in young adults with cancer. Methods: This randomized controlled trial evaluated a 12-week, web-based, automated self-help intervention for fertility-related distress following cancer—Fex-Can Fertility. Individuals were identified via Swedish national quality registries, and those reporting fertility-related distress 1.5 years after diagnosis were invited. A total of 100 women and 24 men (aged 19-40 years) answered self-administered surveys at baseline (T0), directly after the intervention (T1), and 3 months later (T2). The main outcome was fertility-related distress, which was measured by using the 6-dimension Reproductive Concerns After Cancer (RCAC) scale. The secondary outcomes were health-related quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire), emotional distress (Hospital Anxiety and Depression Scale), fertility-related knowledge, and fertility self-efficacy. In addition, the intervention group (IG) reported self-perceived changes in problems related to fertility after cancer (T1). 2-tailed t tests and linear mixed models, including intention-to-treat and subgroup analyses, were performed to compare the effects of the intervention with those of standard care. Results: Although 62% (31/50) of the participants in the IG stated that their concerns about fertility were fewer after the intervention, there were few statistically significant group differences in the main outcome (RCAC) at T1 and T2. Compared with controls, the IG rated lower distress concerning the dimension child’s health at T2 (P=.003; effect size [ES]=0.64). This difference was maintained when adding group and time interactions (intention-to-treat: P=.003; ES=0.58). The IG also had better self-perceived cancer-related fertility knowledge at T1 (P=.05; ES=0.35) and T2 (P=.01; ES=0.42) than the control group. Subgroup analyses based on dose or adherence and baseline RCAC scores did not substantially alter these results. Overall, the use of the web-based program was low. Conclusions: The Fex-Can intervention had small to moderate positive effects on cancer-related fertility knowledge and distress related to child’s health. The lack of group differences in other dimensions of fertility distress and related secondary outcomes contrasted with reports on self-perceived improvement after the intervention. The Fex-Can Fertility program may be a useful complement to routine psychosocial support in the clinical care of young women and men with cancer. Trial Registration: ISRCTN Registry 36621459; https://www.isrctn.com/ISRCTN3662145

Differential item functioning for items in Berger's HIV Stigma Scale: an analysis of cohorts from the Indian, Swedish, and US contexts

PURPOSE: To examine whether items in Berger's HIV Stigma Scale function differently with persons of different age, gender, and cultural backgrounds. METHODS: Secondary data from cohorts, collected in South India (n = 250), Sweden (n = 193), and the US (n = 603) were reanalyzed to evaluate DIF within, between, and across these cohorts. All participants had answered the revised version of the HIV stigma scale consisting of 32 items forming the subscales Personalized stigma, Disclosure concerns, Concerns about public attitudes, and Negative self-image. Differential Item Functioning (DIF) for these items was assessed using hybrid ordinal regression-IRT technique. When DIF was detected, the cumulative impact of DIF on individual subscale scores was evaluated. RESULTS: DIF was detected for 9 items within, between, or across cohorts, but the DIF was negligible in general. Detected DIF between the Swedish and Indian cohorts had a cumulative salient impact on individual scores for the subscale Disclosure Concerns; Disclosure concerns were overestimated in the Swedish cohort and both over- and underestimated in the Indian cohort. CONCLUSIONS: The items in the 32-item version of the HIV stigma scale did not seem to be particularly prone to present DIF. The DIF between the Indian and Swedish cohort for items in the subscale Disclosure Concerns could, however, result in both type I and type II errors if scores should be compared between the Indian and Swedish cohort