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Hajnal Zsuzsanna Balla,1 Yang Cao,2,3 Jakob O Ström1,4 1Department of Neurology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 2Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden; 3Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 4Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, SwedenCorrespondence: Jakob O StrömDepartment of Neurology, Faculty of Medicine and Health, Örebro University Hospital, Örebro, 701 85, SwedenTel +46 196021000Email jakob.strom@oru.seIntroduction: Cardiovascular events and infections are common in the acute phase after stroke. It has been suggested that these complications may be associated with excessive sympathetic activation due to the stroke, and that beta-adrenergic antagonists (beta-blockers) therefore may be beneficial.Aim: The aim of the current meta-analysis was to investigate the association between beta-blocker treatment in acute stroke and the three outcomes: mortality, functional outcome and post-stroke infections.Methods: A literature search was performed using the keywords stroke, cerebrovascular disorders, adrenergic beta-antagonists, treatment outcome and mortality. Randomized clinical trials and observational studies were eligible for data extraction. Heterogeneity was investigated using I2 statistics. Random effect model was used when heterogeneity presented among studies; otherwise, a fixed-effect model was used. Publication bias was assessed using Egger’s test and by visually inspecting funnel plots.Results: A total of 20 studies were eligible for at least one of the three outcomes. Two of the included studies were randomized controlled trials and 18 were observational studies. Quality assessments indicated that the risk of bias was moderate. The meta-analysis found no significant association between treatment with beta-blockers and any of the three outcomes. The studies analyzed for the outcomes mortality and infection were heterogeneous, while studies analyzed for functional outcome were homogeneous. The articles analyzed for mortality showed signs of publication bias.Conclusion: The lack of significant effects in the current meta-analysis, comprising more than 100,000 patients, does not support the proposed beneficial effects of beta-blockers in the acute phase of stroke.Keywords: stroke, beta-blockers, mortality, outcome, infection

Abstract Background ST-elevation myocardial infarction (STEMI) patients have risk factors and co-morbidities and require procedures predisposing to healthcare acquired infections (HAIs). As few data exist on the extent and consequences of infections among these patients, the prevalence, predictors, and potential complications of major infections among hospitalized STEMI patients at all Florida acute care hospitals during 2006 were analyzed. Methods Sociodemographic characteristics, risk factors, co-morbidities, procedures, complications, and mortality were analyzed from hospital discharge data for 11, 879 STEMI patients age ≥18 years. We used multivariable logistic regression modeling to examine and adjust for multiple potential predictors of any infection, bloodstream infection (BSI), pneumonia, surgical site infection (SSI), and urinary tract infection (UTI). Results There were 2, 562 infections among 16.6% of STEMI patients; 6.2% of patients had ≥2 infections. The most prevalent HAIs were UTIs (6.0%), pneumonia (4.6%), SSIs (4.1%), and BSIs (2.6%). Women were at 29% greater risk, Blacks had 23% greater risk, and HAI risk increased 11% with each 5 year increase in age. PCI was the only protective major procedure (OR 0.81, 95% CI, 0.69-0.95, p < .05). HAI lengthened hospital stays. STEMI patients with a BSI were almost 5 times more likely (31.3% vs. 6.5%, p < .0001), and those with pneumonia were 3 times more likely (19.6% vs. 6.5%, p < .0001) to die before discharge. Conclusions The protective effect of PCI on risk of infection is likely mediated by its many benefits, including reduced length of hospitalizations.

Abstract Background An estimated 1 in 3 American adults will have diabetes by the year 2050. Nationally, South Carolina ranks 10th in cases of diagnosed diabetes compared to other states. In adults, type 2 diabetes (T2DM) accounts for approximately 90-95% of all diagnosed cases of diabetes. Clinically, provider and health system factors account for < 10% of the variance in major diabetes outcomes including hemoglobin A1c (HbA1c), lipid control, and resource use. Use of telemonitoring systems offer new opportunities to support patients with T2DM while waiting to be seen by their health care providers at actual office visits. A variety of interventions testing the efficacy of telemedicine interventions have been conducted, but the outcomes have yielded equivocal results, emphasizing the shortage of controlled, randomized trials in this area. This study provides a unique opportunity to address this gap in the literature by optimizing two strategies that have been shown to improve glycemic control, while simultaneously implementing clinical outcomes measures, using a sufficient sample size, and offering health care delivery to rural, underserved and low income communities with T2DM who are seen at Federally Qualified Health Centers (FQHCs) in coastal South Carolina. Methods We describe a four-year prospective, randomized clinical trial, which will test the effectiveness of technology-assisted case management in low income rural adults with T2DM. Two-hundred (200) male and female participants, 18 years of age or older and with an HbA1c ≥ 8%, will be randomized into one of two groups: (1) an intervention arm employing the innovative FORA system coupled with nurse case management or (2) a usual care group. Participants will be followed for 6-months to ascertain the effect of the interventions on glycemic control. Our primary hypothesis is that among indigent, rural adult patients with T2DM treated in FQHC's, participants randomized to the technology-assisted case management intervention will have significantly greater reduction in HbA1c at 6 months of follow-up compared to usual care. Discussion Results from this study will provide important insight into the effectiveness of technology-assisted case management intervention (TACM) for optimizing diabetes care in indigent, rural adult patients with T2DM treated in FQHC's. Trial Registration National Institutes of Health Clinical Trials Registry (http://ClinicalTrials.gov identifier# NCT01373489

Abstract Background African Americans with Type 2 diabetes (T2DM) have higher prevalence of diabetes, poorer metabolic control, and greater risk for complications and death compared to American Whites. Poor outcomes in African Americans with T2DM can be attributed to patient, provider, and health systems level factors. Provider and health system factors account for Methods/Design We describe an ongoing four-year randomized clinical trial, using a 2 × 2 factorial design, which will test the efficacy of separate and combined telephone-delivered, diabetes knowledge/information and motivation/behavioral skills training interventions in high risk African Americans with poorly controlled T2DM (HbA1c ≥ 9%). Two-hundred thirty-two (232) male and female African-American participants, 18 years of age or older and with an HbA1c ≥ 9%, will be randomized into one of four groups for 12-weeks of phone interventions: (1) an education group, (2) a motivation/skills group, (3) a combined group or (4) a usual care/general health education group. Participants will be followed for 12-months to ascertain the effect of the interventions on glycemic control. Our primary hypothesis is that among African Americans with poorly controlled T2DM, patients randomized to the combined diabetes knowledge/information and motivation/behavioral skills training intervention will have significantly greater reduction in HbA1c at 12 months of follow-up compared to the usual care/general health education group. Discussion Results from this study will provide important insight into how best to deliver diabetes education and skills training in ethnic minorities and whether combined knowledge/information and motivation/behavioral skills training is superior to the usual method of delivering diabetes education for African Americans with poorly controlled T2DM. Trial registration National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov identifier# NCT00929838).

Background: Due to the rapid growth of the world´s oldest population, the number of older persons with stroke is expected to rise. Knowledge of stroke etiology is essential to offer personalized and equal health care across age groups. The present systematic review aimed to investigate the prevalence of etiological subtypes of ischemic and hemorrhagic stroke in older compared to younger people., Methods: MEDLINE, Embase, Cochrane, Epistemonikos, and Cinahl were systematically searched for studies regarding etiological classification in people ≥80 years compared to those <80 years with ischemic or hemorrhagic stroke., Results: Out of 28 441 identified articles, eight met the inclusion criteria. In total, 8223 individuals were included in meta-analyses, of whom 2997 were 80 years or older. We demonstrated a higher prevalence of cardioembolic stroke in people ≥80 years OR 1.68 (95% CI, 1.12-2.53). Small vessel disease was significantly less common in older people OR .64 (95% CI, .50-.81). Regarding large vessel disease, no statistically significant difference between the two groups was shown OR 1.05 (95% CI, .77-1.43)., Conclusion: In people ≥80 years, cardioembolic stroke is more common, and small vessel disease less common compared to people <80 years. Overall, the results have to be interpreted with caution due to few studies. Large studies using validated classification systems are needed., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: To perform a meta-analysis on how the admissions of stroke and transient ischemic attack (TIA) changed during the Corona Virus infection-19 (COVID-19) pandemic and evaluate if the effect was depending on stroke severity., Methods: Observational cohort studies comparing the number of stroke and/or TIA admissions during a period of the pandemic compared to a period before the pandemic were identified in PubMed and Embase. After excluding studies with overlapping populations and studies without satisfactory case ascertainment, data was extracted and meta-analyzed., Findings: A total of 59 studies were included. During the pandemic, there was a decrease in admissions of ischemic stroke (admission rate ratio (ARR) = 0.77, 95% confidence interval (CI): 0.72, 0.82), intracerebral hemorrhage (ARR = 0.79, 95% CI: 0.70, 0.90) and TIA (ARR = 0.66, 95% CI: 0.58, 0.75). Albeit admission rates of both mild (ARR = 0.61, 95% CI: 0.49, 0.77) and severe (ARR = 0.82, 95% CI = 0.71, 0.95) strokes decreased, milder strokes decreased more (proportion ratio (PR) = 0.76, 95% CI: 0.65, 0.89)., Discussion: Potential causes for the admission reduction could be strict prioritizations within the health care, patients' fear of acquiring COVID-19, or decreased access to health care due to lockdowns., Conclusion: During the COVID-19 pandemic, there was a reduction in admissions of stroke and TIA, possibly caused by reluctance to seek medical care., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Atrial fibrillation (AF) is a major risk factor for ischaemic stroke and transient ischaemic attack (TIA), and AF detection can be challenged by asymptomatic and paroxysmal presentation. Long-term ECG monitoring after ischaemic stroke or TIA is recommended by all major societies in cardiology and cerebrovascular medicine as a secondary prophylactic measure. However, data on stroke reduction are lacking, and the recommendations show significant diversity., Methods and Analysis: AF SPICE is a multicentre, national, investigator-initiated, randomised, parallel-group, register-based trial comparing extended ECG monitoring versus standard ECG monitoring in patients admitted with ischaemic stroke or TIA, with a composite endpoint of stroke, all-cause-mortality and intracerebral bleeding. Patients aged ≥70 years without previous AF will be randomised 1:1 to control (standard ECG monitoring) or intervention (extended ECG monitoring). In the control arm, patients will undergo 48±24 hours (ie, a range of 24-72 hours) of continuous ECG monitoring according to national recommendations. In the intervention arm, patients will undergo 14+14 days of continuous ECG monitoring 3 months apart using an ECG patch device, which will provide an easy-accessed, well-tolerated 14-day continuous ECG recording. All ECG patch recordings will be read in a core facility. In cases of AF detection, oral anticoagulation will be recommended if not contraindicated. A pilot phase has been concluded in 2022, which will transcend into the main trial during 2023-2026, including approximately 30 stroke units. The sample size was calculated to be 3262 patients. The primary outcome will be collected from register data during a 36-month follow-up., Ethics and Dissemination: Ethical approval has been provided by the Swedish Ethical Review Authority, reference 2021-02770. The trial will be conducted according to the ethical principles of the Declaration of Helsinki and national regulatory standards. Positive results from the study have the potential for rapid dissemination in clinical practice., Trial Registration Number: NCT05134454., Competing Interests: Competing interests: JE has received consultant or lecture fees from Roche Diagnostics, Pfizer, Bristol Myers Squibb, Boehringer Ingelheim, Piotrode and Philips, as well as research grants from the Swedish Research Council, the Swedish Heart & Lung Foundation, the Swedish Innovation Agency and the Stockholm Region. KS, EI and ER report no disclosures. ES reports consultant or lecture fees from Bayer, Bristol-Myers Squibb, Pfizer, Boehringer-Ingelheim, Johnson & Johnson and Merck Sharp & Dome, as well as research grants from the Swedish Research Council, the Swedish Heart & Lung Foundation, the Åke Wibergs Foundation and CIMED. BN reports Data Safety Monitoring Board fees from Astra Zeneca. MvE is the chairman of Riksstroke, the Swedish Stroke Register. KH, WG, JOS, SS and ME report no disclosures. SÅ reports lecture fees paid to the institution from Bristol-Myers Squibb, Pfizer and Boehringer-Ingelheim and is a member of the steering committee of Riksstroke, the Swedish Stroke Register. PW reports consulting fees, fees as a Clinical Events Committee member and unrestricted grants from Abbott. PW is a member of the steering committee of Riksstroke, the Swedish Stroke Register., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Purpose: Testosterone analysis in hair allows for retrospective evaluation of endogenous testosterone concentrations, but studies devoted to investigating confounders in hair testosterone analysis have hitherto been scarce. The current study examined the stability of testosterone concentrations between two hair samples collected three months apart and investigated two potential confounding factors: natural hair colour and cosmetic hair treatments., Methods: Testosterone was analysed with an in-house radioimmunoassay with a limit of detection adequate for the purpose., Results: The testosterone concentrations from the two samplings, at baseline and three months later, had an intra-individual correlation of moderate strength (rho = 0.378, p<0.001, n = 146). Hair treatment, such as colouring or bleaching, seemed to increase testosterone concentrations (p = 0.051, n = 191, and in a paired analysis in a subset of the cohort p = 0.005, n = 24), while no effect of natural colour in untreated hair (p = 0.133) could be detected., Conclusion: The current results suggest that cosmetic hair treatments need to be considered in hair testosterone analyses and demonstrate the utility of a radioimmunoassay to reliably measure testosterone concentrations in small hair samples in women., Competing Interests: “JOS received advisory board fees from Bayer Pharmaceuticals during 2016 and 2019, but the advisory boards were not in any way related to the subject of the current paper. JKP, ISP, ET and EI have no relevant financial or non-financial interests to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials.”, (Copyright: © 2023 Preinbergs et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Testosterone is thought to be incorporated in growing hair strands so that specific hair segments reflect average free hormone concentrations from the corresponding time period. However, the exact mechanisms of hormone integration in scalp hair have not yet been established and it is not known how testosterone is stored in the hair segments over time. The aim of this study was to investigate the stability of testosterone concentrations in hair as it grows and to determine if segmental hair analysis can be used as a retrospective testosterone diary. Thirty men and 40 women provided two hair samples and 16 saliva samples during a period of three months. Hair growth between the two samplings was measured. Hair samples were cut into 10 mm segments resulting in three segments from the first sampling and six segments from the second sampling. Hair samples were pulverised and extracted with methanol. Hair testosterone concentrations were analysed using an in-house radioimmunoassay. Salivary testosterone was analysed using a commercial enzyme-linked immunosorbent assay (Demeditec). The results demonstrated that there is a degree of segmental hormone conservation over time (rho = 0.405-0.461, p < 0.001, n = 66-67), but also highlighted three potential confounders. Firstly, testosterone concentrations were higher in distal hair segments (mean concentration ratio most distal by most scalp-near was 1.55, SD 0.70), which may be due to continuous hormone integration from sebum and changes in hair matrix composition. Secondly, more frequent hair washing stunted the increase in testosterone concentrations in distal segments (rho = -0.404, p =  < 0.001, n = 66). And lastly, intra- and inter- individual variability in hair growth rate influenced the temporal resolution along the hair, although mean growth rate was indeed 30.0 mm for three months. In a multiple regression model the biological sex, natural hair colour, and relationship status were significant explanatory variables to hair testosterone concentrations. The current results indicate that repeated hair sampling near the hair roots during a study may be preferable to analysing concentration changes between proximal and distal segments within the same hair sample. Also, hair testosterone analysis needs to be adjusted for sex and the natural hair colour., (© 2023. Springer Nature Limited.)

Rationale and Aims: The Quality of Dyadic Relationships is a self-assessment scale used to evaluate various aspects of relationship quality. Psychometric evaluation by the developers of the instrument has led to a nontested amended version. Further psychometric testing is thus warranted, and the aim of this study was to evaluate homogeneity, construct validity (in terms of concurrent, discriminant and known-groups validity) and any floor and ceiling effects of the Quality of Dyadic Relationships., Methods: Forty-seven cohabitant couples (47 women with a mean age of 30.0 years and 47 men with a mean age of 31.5 years) answered the Quality of Dyadic Relationships, the Relationship Assessment Scale (to test concurrent validity) and the Perceived Stress Scale (to test discriminant validity). Homogeneity (internal consistency) was calculated by Cronbach's alpha. Concurrent and discriminant validity were estimated as correlations between Quality of Dyadic Relationships and the other instruments. Assessment of known-groups validity was based on the variables of parental status and gender. Floor and ceiling effects were evaluated according to frequency distribution., Results: The overall homogeneity was good with acceptable Cronbach's alpha values (α > 0.70) for all subscales but dyadic sexuality. Concurrent validity and discriminant validity were found. Known-groups validity was indicated by significant differences between individuals with different parental status on the total QDR index, where the ones without children scored higher. No difference between the genders was found. No significant floor effects were found, but a significant ceiling effect was found in the subscale dyadic sensuality, with 27.7% of respondents scoring maximum., Conclusion: In all, the QDR showed promising psychometric properties and may be used for screening and follow-up purposes. However, it can benefit from further development, as suggested by the ceiling effect in the subscale dyadic sensuality and the low internal consistency in the subscale dyadic sexuality., (© 2020 The Authors. Scandinavian Journal of Caring Sciences published by John Wiley & Sons Ltd on behalf of Nordic College of Caring Science.)

Extensive research has been devoted to developing methods for assessing core body temperature, and to determine which method is most accurate. A number of wireless dermal thermometers for home use are presently available, but their relation to core body temperature and suitability for use in clinical research has hitherto not been assessed. The current study aimed to evaluate such thermometers by comparing them to the results of a rectal thermometer. Four wireless dermal thermometers for home use (FeverSmart, iThermonitor, Quest Temp Sitter, and Thermochron iButton) were applied to 15 patients during 24 h, and rectal temperature was measured at four occasions. Pearson correlation revealed moderate correlation for the Feversmart (r = 0.75), iThermonitor (r = 0.79), and Thermochron iButton (r = 0.71) systems. The Quest Temp Sitter system malfunctioned repeatedly, and the correlation (r = 0.29) for this method should therefore be assessed with caution. All dermal thermometers rendered lower average temperatures than Terumo c405 (Feversmart -0.70 ± 0.65 °C; iThermonitor -0.77 ± 0.53 °C, Quest Temp Sitter -1.18 ± 0.66 °C, and Thermochron iButton -0.87 ± 0.65 °C). Sensitivity of the dermal thermometers for detecting core temperatures ≥38.0 °C was low, ranging from 0.33 to 0.6, but improved to 0.60 to 0.80 after adjusting temperatures by the methods' average deviation from rectal temperature. The results from the dermal thermometers tested here showed an insufficient correlation to core temperature to be used for core temperature monitoring in clinical research and practice. Unfortunately, other options for non-invasive temperature measurements are few. The two thermometers with the least unsatisfactory performance profile in our evaluations were the Feversmart and iThermonitor systems.

Background: It has not yet been established whether men in heterosexual relationships adapt their hormone levels to their female partner's menstrual cycle to allocate reproductive resources to the period when the female is actually fertile., Aim: This prospective observational study tested the hypothesis that some males have peaks in testosterone or acne (a possible biomarker for androgen activity) near their partners' ovulation, whereas other males display the opposite pattern., Methods: 48 couples supplied menstrual cycle data, male salivary samples, and a protocol of daily activities for 120 days. Daily saliva samples were analyzed for testosterone concentrations by enzyme-linked immunosorbent assay. The main hypothesis was tested by analyzing whether each individual male's testosterone/acne response to ovulation (either an increase or a decrease in comparison to the individual's average levels) was stable over time. To do this, we analyzed the Spearman correlation between individually normalized periovulatory testosterone and acne during the first half of the study versus the second half of the study., Outcomes: Correlation between each male individual's periovulatory testosterone and acne patterns during the first half of the study versus the second half of the study., Results: No predictability in the male individuals' testosterone (Spearman's rho = -0.018, P = .905) or acne (Spearman's rho = -0.036, P = .862) levels during ovulation was found., Clinical Translation: The study being "negative," there is no obvious translational potential in the results., Strengths and Limitations: The main strength of this study lies in the excellent compliance of the study participants and the large number of sampling timepoints over several menstrual cycles, thereby allowing each male individual to be his own control subject. A limitation is that samples were only obtained in the morning; however, including later timepoints would have introduced a number of confounders and would also have hampered the study's feasibility., Conclusions: The current results strongly indicate that male morning testosterone levels neither increase nor decrease in response to the partner's ovulation. This discordance to previous laboratory studies could indicate either that (i) the phenomenon of hormonal adaptation of men to women does not exist and earlier experimental studies should be questioned, (ii) that the phenomenon is short-lived/acute and wanes if the exposure is sustained, or (iii) that the male testosterone response may be directed toward other women than the partner. Ström JO, Ingberg E, Slezak JK, et al. Male Testosterone Does Not Adapt to the Partner's Menstrual Cycle. J Sex Med 2018;15:1103-1110., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Fever after stroke is common, and often caused by infections. In the current study, we aimed to test the hypothesis that pneumonia, urinary tract infection and all-cause fever (thought to include at least some proportion of endogenous fever) have different predicting factors, since they differ regarding etiology., Methods: PubMed was searched systematically for articles describing predictors for post-stroke pneumonia, urinary tract infection and all-cause fever. A total of 5294 articles were manually assessed; first by title, then by abstract and finally by full text. Data was extracted from each study, and for variables reported in 3 or more articles, a meta-analysis was performed using a random effects model., Results: Fifty-nine articles met the inclusion criteria. It was found that post-stroke pneumonia is predicted by age OR 1.07 (1.04-1.11), male sex OR 1.42 (1.17-1.74), National Institutes of Health Stroke Scale (NIHSS) OR 1.07 (1.05-1.09), dysphagia OR 3.53 (2.69-4.64), nasogastric tube OR 5.29 (3.01-9.32), diabetes OR 1.15 (1.08-1.23), mechanical ventilation OR 4.65 (2.50-8.65), smoking OR 1.16 (1.08-1.26), Chronic Obstructive Pulmonary Disease (COPD) OR 4.48 (1.82-11.00) and atrial fibrillation OR 1.37 (1.22-1.55). An opposite relation to sex may exist for UTI, which seems to be more common in women., Conclusions: The lack of studies simultaneously studying a wide range of predictors for UTI or all-cause fever calls for future research in this area. The importance of new research would be to improve our understanding of fever complications to facilitate greater vigilance, monitoring, prevention, diagnosis and treatment.

Background: Stroke is among the leading causes of death and disability. Although intense research efforts have provided promising treatment options in animals, most clinical trials in humans have failed and the therapeutic options are few. Several factors have been suggested to explain this translational difficulty, particularly concerning methodology and study design. Consistent infarcts and low mortality might be desirable in some, but not all, studies. Here, we aimed to investigate whether the use of laser Doppler flowmetry (LDF) and the occlusion time (60 vs. 45 min) affected outcome variability and mortality in a rat stroke model. Eighty ovariectomized female Wistar rats were subjected to ischemic stroke using intraluminal filament middle cerebral artery occlusion with or without LDF and with occlusion times of 45 or 60 min. Outcome was evaluated by triphenyl tetrazolium chloride staining of brain slices to measure infarct size and a modified sticky tape test., Results: Neither LDF nor occlusion times of 45 versus 60 min significantly affected mortality, outcome variability or outcome severity., Conclusions: Due to the unexpectedly high mortality and variability the statistical power was very low and thus the results were inconclusive.

The concentrations of testosterone deposited in hair during hair growth may provide a retrospective reflection of the concentrations of bioactive testosterone in plasma. The objective of this study was to develop a radioimmunoassay with a sufficiently low limit of detection to measure the testosterone-like immunoreactivity in smaller hair samples (5 mg) than used in earlier studies, and to compare three different extraction procedures. The competitive radioimmunoassay consisted of a polyclonal antiserum (immunogen testosterone-7α-BSA) and a radioligand synthesised from testosterone-3-CMO-histamine. The within-assay and total coefficients of variation in the working range was 3% and 4.5%, respectively. The limit of detection was 0.87 pg/mL, which is equivalent to 0.12 pg/mg testosterone in 5 mg of hair. The concentration of testosterone-like immunoreactivity in hair samples was 1.23 (SD 0.47) pg/mg in women and 2.67 (SD 0.58) pg/mg in men (pulverised hair). Significantly improved precision was found when pulverised hair was used compared to non-pulverised hair. Our data indicate that pulverisation of the hair prior to hormone extraction is crucial. Detection limits fit for the intended purpose are achievable with 5 mg samples of hair.

Background: Growing evidence indicates that elevated body temperature after stroke is associated with unfavorable outcome. The aim of the current study was to investigate which factors predict temperature elevation within 48 h of stroke onset. Specifically, we hypothesized that temperature elevation would be associated with stroke symptom severity and that hemorrhagic stroke would cause a more pronounced temperature increase compared to ischemic stroke., Methods: The medical records of 400 stroke patients were retrospectively reviewed. Multiple linear regression analysis was used to determine which factors were associated with elevated body temperature., Results: Several factors were significantly associated with peak body temperature (the highest recorded body temperature) within 48 h of stroke onset: stroke severity measured by the National Institutes of Health Stroke Scale (NIHSS) (regression coefficient; (RC) 0.022), female gender (RC 0.157), tympanic/non-rectal temperature reading (RC -0.265), swallowing difficulties (RC 0.335), intubation (RC 0.470), antipyretic treatment (RC 0.563), and C-reactive protein > 50 or signs of infection at admission (RC 0.298). Contrary to our expectations, patients with intracerebral hemorrhage did not have higher peak body temperatures than patients with ischemic stroke., Conclusions: In conclusion, temperature elevation within the first 48 h of stroke onset is common, can be partially predicted using information at admission and is strongly associated with stroke severity. The strong association with stroke severity may, at least partly, explain the previously described association between post-stroke temperature elevation and unfavorable outcome.

Introduction: Measuring testosterone concentrations is of interest both in clinical situations and for research, the latter expanding rapidly during recent years. An increased demand for convenient methods has prompted a number of companies to develop enzyme-linked immunosorbent assay (ELISA) kits to measure testosterone concentrations in saliva. However, the inter-comparability of kits from different manufacturers have yet to be determined., Aim of Study: The aim of this study was to compare commercially available ELISA kits from four different manufacturers (Salimetrics, IBL, DRG and Demeditec)., Methods: Saliva was collected from 50 participants (25 men and 25 women). Each sample was analysed by the four ELISA kits., Results: The correlations between the ELISA kits from Demeditec, DRG and Salimetrics were moderate to high with r-values > .77; however, proportional errors between the methods calls for caution. The ELISA kit from IBL malfunctioned and no results from this kit was obtained., Conclusions: Results from studies using the ELISA kits from Demeditec, DRG and Salimetrics are generally comparable; however, translation using the formulae presented in the current study could increase the accuracy of these comparisons.

Objectives: To investigate at what age preterm infants develop a salivary cortisol circadian rhythm and identify whether it is dependent on gestational age and/or postnatal age. To evaluate whether salivary cortisol circadian rhythm development is related to behavioral regularity. To elucidate salivary cortisol levels in preterm infants during the first year of life., Methods: This prospective, longitudinal study included 51 preterm infants. 130 healthy full-term infants served as controls. Monthly salivary cortisol levels were obtained in the morning (07:30-09:30), at noon (10:00-12:00), and in the evening (19:30-21:30), beginning at gestational age week 28-32 and continuing until twelve months corrected age. Behavioral regularity was studied using the Baby Behavior Questionnaire., Results: A salivary cortisol circadian rhythm was established by one month corrected age and persisted throughout the first year. The preterm infants showed a cortisol pattern increasingly more alike the full-term infants as the first year progressed. The preterm infants increase in behavioral regularity with age but no correlation was found between the development of salivary cortisol circadian rhythm and the development of behavior regularity. The time to establish salivary cortisol circadian rhythm differed between preterm and full-term infants according to postnatal age (p = 0.001) and was dependent on gestational age. Monthly salivary cortisol levels for preterm infants from birth until twelve months are presented. Additional findings were that topical corticosteroid medication was associated with higher concentrations of salivary cortisol (p = 0.02) and establishment of salivary cortisol circadian rhythm occurred later in infants treated with topical corticosteroid medication (p = 0.02)., Conclusions: Salivary cortisol circadian rhythm is established by one month corrected age in preterm infants. Establishment of salivary cortisol circadian rhythm is related to gestational age rather than to postnatal age. Salivary cortisol circadian rhythm development is not related to behavioral regularity.

Background: In the absence of active management, the stroke risk after a transient ischemic attack (TIA) may be high. Almost 10 years ago, the results of the EXPRESS and SOS-TIA studies called for a more rapid management of TIA patients. The purpose of this study was to investigate the other stroke risks in the longer term, after the implementation of a more active approach to TIA. We also wanted to assess the predictive value of the ABCD2 score in this context., Methods: Riksstroke is the national stroke registry in Sweden. Data from Riksstroke's TIA module, and the national cause-of-death register, for the years 2011 and 2012 were used in this study. Stroke occurrence was monitored via Riksstroke. Cox's regression was used for risk evaluation. The predictive value of the ABCD2 score was assessed by calculating the area under the receiver operating characteristics curve., Results: A total of 15,068 TIA episodes occurred in 14,102 patients. The follow-up time varied between 0 and 819 days, with an average of 417 days. The mortality for all TIA patients during the follow-up time was 7.1%. Of the unique patients, 545 had one or more strokes (3.9%), corresponding to 34 events per 1,000 person years. Significant risk factors for stroke were: age, previous TIA, atrial fibrillation (AF), oral anticoagulant (OAC) treatment, hypertension treatment, and the ABCD2 items speech impairment, unilateral weakness, and diabetes mellitus. The ABCD2 score correlated with a subsequent stroke, but its predictive value was low., Conclusion: The risk of stroke is low after the acute phase of a TIA, probably lower than in previous studies. This may be due to better secondary prevention in recent years. Several risk factors predict stroke, notably hypertensive treatment, which may be inadequate; and AF, where OACs may be under-used. It is difficult to identify the role of the ABCD2 score in clinical practice., (© 2016 S. Karger AG, Basel.)

Background: Transient ischemic attack (TIA) constitutes a major risk factor for stroke, making TIA patients an important group for secondary intervention. The aim of this study was to account for risk factor prevalence in TIA patients and analyze the association between TIA characteristics and risk factors., Methods: We included 20,871 TIA events in 19,872 patients who were registered in the Swedish Riksstroke registry during the years 2010 through 2012. Data from other Swedish registers were used for comparison. The following variables were analyzed: age, sex, diabetes mellitus, atrial fibrillation (AF), cigarette smoking, and antihypertensive treatment., Results: Compared to the general population (based on data retrieved from Sweden's national public health survey 'Health on equal terms'), TIA patients more often had diabetes mellitus (prevalence ratio, PR = 2.3), AF without oral anticoagulants (OAC) (PR = 2.8), and AF on OAC (PR = 1.6). Blood pressure medication was less prevalent among TIA patients than in the general population (PR = 0.57). Increasing age was associated with longer attacks., Conclusions: The fact that diabetes mellitus, atrial fibrillation, and smoking are more common in TIA patients than in the general population suggests that these factors are risk factors for TIA, even if causal relations cannot be proven. The relation between increasing age and longer attacks possibly reflects an increased proportion of embolic TIAs, or impaired recovery ability. Our results also suggest a significant proportion of untreated hypertension cases in the population., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Although hundreds of promising substances have been tested in clinical trials, thrombolysis currently remains the only specific pharmacological treatment for ischemic stroke. Poor quality, e.g. low statistical power, in the preclinical studies has been suggested to play an important role in these failures. Therefore, it would be attractive to use animal models optimized to minimize unnecessary mortality and outcome variability, or at least to be able to power studies more exactly by predicting variability and mortality given a certain experimental setup. The possible combinations of methodological parameters are innumerous, and an experimental comparison of them all is therefore not feasible. As an alternative approach, we extracted data from 334 experimental mouse stroke articles and, using a hypothesis-driven meta-analysis, investigated the method parameters' impact on infarct size variability and mortality. The use of Swiss and C57BL6 mice as well as permanent occlusion of the middle cerebral artery rendered the lowest variability of the infarct size while the emboli methods increased variability. The use of Swiss mice increased mortality. Our study offers guidance for researchers striving to optimize mouse stroke models.

The majority of the numerous animal studies of the effects of estrogens on cerebral ischemia have reported neuroprotective results, but a few have shown increased damage. Differences in hormone administration methods, resulting in highly different 17β-estradiol levels, may explain the discrepancies in previously reported effects. The objective of the present study was to test the hypothesis that it is the delivered dose per se, and not the route and method of administration, that determines the effect, and that high doses are damaging while lower doses are protective. One hundred and twenty ovariectomized female Wistar rats (n = 40 per group) were randomized into three groups, subcutaneously administered different doses of 17β-estradiol and subjected to transient middle cerebral artery occlusion. The modified sticky tape test was performed after 24 h and the rats were subsequently sacrificed for infarct size measurements. In contrast to our hypothesis, a significant negative correlation between 17β-estradiol dose and infarct size was found (p = 0.018). Thus, no support was found for the hypothesis that 17β-estradiol can be both neuroprotective and neurotoxic merely depending on dose. In fact, on the contrary, the findings indicate that the higher the dose of 17β-estradiol, the smaller the infarct.

Background and Purpose: Stroke incidence may be on the decline in high-income countries. There may have been a shift from severe forms of cerebrovascular disease to less severe forms. No study regarding transient ischemic attack (TIA) incidence has been performed in Sweden since the 1980s., Methods: We used 2011 and 2012 data from the Swedish stroke register. A large proportion of Sweden's 72 hospitals took part in the TIA register, meaning that 63 (2011) and 66 (2012) percent of the entire population were studied., Results: The number of TIA-cases was 13,880. The number of first ever TIA cases was 9098, 4,675 in men, and 4,423 in women, comprising 66% of all TIAs. The crude overall IR for first ever TIA was 74 per 100,000. The age- and sex-standardized IRs were 73 per 100,000 when standardized to the European population of 2013, and 47 per 100,000 when standardized to the European population 1976., Conclusions: The TIA incidence in Sweden is high, and no decline is seen when compared with previous studies. Better prevention may have caused a shift from severe forms of cerebrovascular disease to less severe forms. For demographic reasons, the health services will most likely face an increasing number of TIA patients in the coming years., (© 2016 S. Karger AG, Basel.)

Background: The elevated body swing test (EBST) is a behavioral test used to evaluate experimental stroke in rodents. The basic idea is that when the animal is suspended vertically by the tail, it will swing its head laterally to the left or right depending on lesion side. In a previous study from our lab using the EBST after middle cerebral artery occlusion (MCAo), rats swung contralateral to the infarct day 1 post-MCAo, but ipsilateral day 3 post-MCAo. This shift was unexpected and prompted us to perform the present study. First, the literature was systematically reviewed to elucidate whether a similar shift had been noticed before, and if consensus existed regarding swing direction. Secondly, an experiment was conducted to systematically investigate the suggested behavior. Eighty-three adult male and female Sprague-Dawley rats were subjected to MCAo or sham surgery and the EBST was performed up to 7 days after the lesion., Results: Both experimentally and through systematic literature review, the present study shows that the direction of biased swing activity in the EBST for rodents after cerebral ischemia can differ and even shift over time in some situations. The EBST curve for females was significantly different from that of males after the same occlusion time (p = 0.023)., Conclusions: This study highlights the importance of adequate reporting of behavioral tests for lateralization and it is concluded that the EBST cannot be recommended as a test for motor asymmetry after MCAo in rats.

Background: Cortisol concentrations in plasma display a circadian rhythm in adults and children older than one year. Earlier studies report divergent results regarding when cortisol circadian rhythm is established. The present study aims to investigate at what age infants develop a circadian rhythm, as well as the possible influences of behavioral regularity and daily life trauma on when the rhythm is established. Furthermore, we determine age-related reference intervals for cortisol concentrations in saliva during the first year of life., Methods: 130 healthy full-term infants were included in a prospective, longitudinal study with saliva sampling on two consecutive days, in the morning (07:30-09:30), noon (10:00-12:00) and evening (19:30-21:30), each month from birth until the infant was twelve months old. Information about development of behavioral regularity and potential exposure to trauma was obtained from the parents through the Baby Behavior Questionnaire and the Life Incidence of Traumatic Events checklist., Results: A significant group-level circadian rhythm of salivary cortisol secretion was established at one month, and remained throughout the first year of life, although there was considerable individual variability. No correlation was found between development of cortisol circadian rhythm and the results from either the Baby Behavior Questionnaire or the Life Incidence of Traumatic Events checklist. The study presents salivary cortisol reference intervals for infants during the first twelve months of life., Conclusions: Cortisol circadian rhythm in infants is already established by one month of age, earlier than previous studies have shown. The current study also provides first year age-related reference intervals for salivary cortisol levels in healthy, full-term infants.

Background: In 2010, the Swedish Stroke Register (Riksstroke; RS) established a module for transient ischemic attacks (RS-TIA). We report a diagnostic validation study of patients included in RS-TIA., Methods: During the first year, 7,825 patients were registered at 59 out of 74 Swedish hospitals. A time-based TIA definition was applied. A sample of 180 patients (30 patients each from 6 hospitals), with a similar distribution of age and sex as in RS-TIA, was prepared. Two independent observers assessed medical records for quality of documentation and assigned a diagnosis of likely, possible, unlikely TIA or ischemic stroke, according to prespecified criteria., Results: The 2 observers agreed in 77% of cases that the event was a likely or possible TIA, in 3% that the event was an ischemic stroke, and in 2% that the event was an unlikely TIA. The observers disagreed in 8% of patients on TIA vs. ischemic stroke, and in 11% on a vascular vs. non-vascular cause. Quality of documentation was fair., Conclusions: There was interobserver agreement on diagnosis of TIA in the majority of patients included in RS-TIA. Diagnostic accuracy may be further improved by more systematic documentation of symptoms and signs., (© 2015 S. Karger AG, Basel.)

Background: Although most animal stroke studies have demonstrated potent neuroprotective effects of estrogens, there are a number of articles reporting the opposite. In 2009, we made the case that this dichotomy was related to administered estrogen dose. Several other suggestions for the discordant results have also been propagated, including the age of the experimental animals and the length of hypoestrogenicity prior to estrogen administration. These two suggestions have gained much popularity, probably because of their kinship with the window of opportunity hypothesis, which is commonly used to explain the analogous dichotomy among human studies. We were therefore encouraged to perform an updated meta-analysis, and to improve it by including all relevant variables in a large multiple regression model, where the impact of confounders could be controlled for., Results: The multiple regression model revealed an indisputable impact of estrogen administration mode on the effects of estrogens in ischemic stroke. Subcutaneous slow-release pellets differed from the injection and silastic capsule treatments in terms of impact of estrogens on ischemic stroke, showing that the first mentioned were more prone to render estrogens damaging. Neither the use of elderly animals nor the adoption of longer wash-out periods influenced estrogens' effects on experimental ischemic stroke in rats., Conclusions: We conclude that the discordant results regarding estrogens' effects in rat models of ischemic stroke are a consequence of differences in estrogen administration modes. These results are not only of importance for the ongoing debate regarding menopausal hormone therapy, but also have an important bearing on experimental stroke methodology and the apparent translational roadblock for suggested stroke interventions.

The recent claim that stimulated platelets activate the intrinsic pathway of coagulation by the release of polyphosphates has been considered a breakthrough in hemostasis research. In little more than 3 years, the original publication by Müller et al has been cited >100 times. However, none of the citing articles has sought to independently validate this potentially paradigm-shifting concept. To this end, we performed extensive experimentation in vitro and in vivo in an attempt to verify the claim that factor XII (FXII) is primarily activated by stimulated platelets. In contrast to the original assertion, platelet-derived polyphosphates were found to be weak activators of FXII, with a FXIIa-generating activity of <10% compared with equivalent concentrations of kaolin. Using different coagulation assays, it was shown that platelet contribution to whole blood coagulation was unrelated to the generation of activated FXII in vitro. Additionally, key results used to verify the hypothesis in the original study in vivo were found to be irreproducible. We conclude that platelet-derived polyphosphates are not physiologically relevant activators of FXII.

Background: Even though more than 600 stroke treatments have been shown effective in preclinical studies, clinically proven treatment alternatives for cerebral infarction remain scarce. Amongst the reasons for the discrepancy may be methodological shortcomings, such as high mortality and outcome variability, in the preclinical studies. A common approach in animal stroke experiments is that A) focal cerebral ischemia is inflicted, B) some type of treatment is administered and C) the infarct sizes are assessed. However, within this paradigm, the researcher has to make numerous methodological decisions, including choosing rat strain and type of surgical procedure. Even though a few studies have attempted to address the questions experimentally, a lack of consensus regarding the optimal methodology remains., Methods: We therefore meta-analyzed data from 502 control groups described in 346 articles to find out how rat strain, procedure for causing focal cerebral ischemia and the type of filament coating affected mortality and infarct size variability., Results: The Wistar strain and intraluminal filament procedure using a silicone coated filament was found optimal in lowering infarct size variability. The direct and endothelin methods rendered lower mortality rate, whereas the embolus method increased it compared to the filament method., Conclusions: The current article provides means for researchers to adjust their middle cerebral artery occlusion (MCAo) protocols to minimize infarct size variability and mortality.

Background: Leukotrienes are potent inflammatory mediators, which in a number of studies have been found to be associated with ischemic stroke pathology: gene variants affecting leukotriene synthesis, including the FLAP (ALOX5AP) gene, have in human studies shown correlation to stroke incidence, and animal studies have demonstrated protective properties of various leukotriene-disrupting drugs. However, no study has hitherto described a significant effect of a genetic manipulation of the leukotriene system on ischemic stroke. Therefore, we decided to compare the damage from focal cerebral ischemia between wild type and FLAP knockout mice. Damage was evaluated by infarct staining and a functional test after middle cerebral artery occlusion in 20 wild type and 20 knockout male mice., Results: Mortality-adjusted median infarct size was 18.4 (3.2-76.7) mm3 in the knockout group, compared to 72.0 (16.7-174.0) mm3 in the wild type group (p < 0.0005). There was also a tendency of improved functional score in the knockout group (p = 0.068). Analysis of bone marrow cells confirmed that knockout animals had lost their ability to form leukotrienes., Conclusions: Since the local inflammatory reaction after ischemic stroke is known to contribute to the brain tissue damage, the group difference seen in the current study could be a consequence of a milder inflammatory reaction in the knockout group. Our results add evidence to the notion that leukotrienes are important in ischemic stroke, and that blocked leukotriene production ameliorates cerebral damage.

Estrogens are a family of female sexual hormones with an exceptionally wide spectrum of effects. When rats and mice are used in estrogen research they are commonly ovariectomized in order to ablate the rapidly cycling hormone production, replacing the 17β-estradiol exogenously. There is, however, lack of consensus regarding how the hormone should be administered to obtain physiological serum concentrations. This is crucial since the 17β-estradiol level/administration method profoundly influences the experimental results. We have in a series of studies characterized the different modes of 17β-estradiol administration, finding that subcutaneous silastic capsules and per-oral nut-cream Nutella are superior to commercially available slow-release pellets (produced by the company Innovative Research of America) and daily injections in terms of producing physiological serum concentrations of 17β-estradiol. Amongst the advantages of the nut-cream method, that previously has been used for buprenorphine administration, is that when used for estrogen administration it resembles peroral hormone replacement therapy and is non-invasive. The subcutaneous silastic capsules are convenient and produce the most stable serum concentrations. This video article contains step-by-step demonstrations of ovariectomy and 17β-estradiol hormone replacement by silastic capsules and peroral Nutella in rats and mice, followed by a discussion of important aspects of the administration procedures.

Background: A complication of a silastic dural substitute is described, which appeared after 32 years-by far the longest latency period reported in the literature., Methods: Case report and literature review., Results: In 1971, a 20-year old woman suffered from an acute subdural haematoma and a temporal cerebral contusion due to a motorbike accident. She underwent an operation with evacuation of these and the dura was mended with a silastic duraplasty. Thirty-two years later she deteriorated with increased memory problems and dysphasia. CT revealed an expanding haemorrhagic mass around the previous duraplasty, which demanded surgery with removal of the silastic dural implant and evacuation of the haemorrhagic mass. Although the haemorrhagic mass enveloped the silastic implant, a contribution of the acrylate flap cannot be ruled out. Bacteriological cultures revealed Acinetobacter spp. in the CSF. Adequate post-operative antibiotic treatment was administered. The patient slowly improved, but the complication represented a major setback in her long-term cognitive and communicative functions., Conclusions: This case widens the previously reported time-frame of late complications by 60%, from 20 to 32 years, and will hopefully serve to increase the awareness of late infections and haemorrhages induced by silastic dural implants, thereby improving diagnosis and treatment in future cases.

The use of animal models, especially the rat, is crucial for elucidating the biological effects and mechanisms of the widely used hormone 17beta-oestradiol. Unfortunately, there is a lack of consensus on optimal means of obtaining and maintaining physiological 17beta-oestradiol concentrations in plasma and this may be the reason for the varying results in several studies, including the disagreement on whether 17beta-oestradiol is neuroprotective or not. Very few studies have been devoted to investigating the characteristics and biological relevance of different methods of 17beta-oestradiol administration. We therefore ovariectomized 75 Sprague-Dawley rats and, following a 2-week washout period, administered 17beta-oestradiol using three different methods; daily injections (10 microg 17beta-oestradiol/kg), slow-release pellets (0.25 mg 60 day-release pellets, 0.10 mg 90 day-release pellets) and silastic capsules (with/without washout periods) (silastic laboratory tubing, inner/outer diameter: 1.575/3.175 mm, filled with 20 mm columns of 180 microg 17beta-oestradiol/mL sesame oil). A further 45 animals were used as ovariectomized and native controls studied in different parts of the oestrous cycle. Silastic capsules produced concentrations of 17beta-oestradiol within the physiological range 4-5 weeks independently of whether a prior washout period was included or not. The slow-release pellets, irrespective of dose or release period, resulted in initial concentrations an order of magnitude above physiological concentrations during the first 2 weeks followed by a substantial decrease. Daily injections resulted in increasing 17beta-oestradiol concentrations, but within physiological levels. Silastic capsules are conveniently manufactured and used and are superior to pellets and injections in reliably producing long-term 17beta-oestradiol concentrations within the physiological range.