Blood–brain barrier water exchange measurements using contrast-enhanced ASL

A technique for quantifying regional blood–brain barrier (BBB) water exchange rates using contrast-enhanced arterial spin labelling (CE-ASL) is presented and evaluated in simulations and in vivo. The two-compartment ASL model describes the water exchange rate from blood to tissue, (Formula presented.), but to estimate (Formula presented.) in practice it is necessary to separate the intra- and extravascular signals. This is challenging in standard ASL data owing to the small difference in (Formula presented.) values. Here, a gadolinium-based contrast agent is used to increase this (Formula presented.) difference and enable the signal components to be disentangled. The optimal post-contrast blood (Formula presented.) ((Formula presented.)) at 3 T was determined in a sensitivity analysis, and the accuracy and precision of the method quantified using Monte Carlo simulations. Proof-of-concept data were acquired in six healthy volunteers (five female, age range 24–46 years). The sensitivity analysis identified the optimal (Formula presented.) at 3 T as 0.8 s. Simulations showed that (Formula presented.) could be estimated in individual cortical regions with a relative error (Formula presented.) % and coefficient of variation (Formula presented.) %; however, a high dependence on blood (Formula presented.) was also observed. In volunteer data, mean parameter values in grey matter were: arterial transit time (Formula presented.) s, cerebral blood flow (Formula presented.) mL blood/min/100 mL tissue and water exchange rate (Formula presented.) s−1. CE-ASL can provide regional BBB water exchange rate estimates; however, the clinical utility of the technique is dependent on the achievable accuracy of measured (Formula presented.) values

Non-Invasive MRI of Blood-Cerebrospinal Fluid Barrier Function

The blood-cerebrospinal fluid barrier (BCSFB) is a highly dynamic transport interface that serves brain homeostasis. To date, however, understanding of its role in brain development and pathology has been hindered by the absence of a non-invasive technique for functional assessment. Here we describe a method for non-invasive measurement of BSCFB function by using tracer-free MRI to quantify rates of water delivery from arterial blood to ventricular cerebrospinal fluid. Using this method, we record a 36% decrease in BCSFB function in aged mice, compared to a 13% decrease in parenchymal blood flow, itself a leading candidate biomarker of early neurodegenerative processes. We then apply the method to explore the relationship between BCSFB function and ventricular morphology. Finally, we provide proof of application to the human brain. Our findings position the BCSFB as a promising new diagnostic and therapeutic target, the function of which can now be safely quantified using non-invasive MRI

Rifampicin and clarithromycin (extended release) versus rifampicin and streptomycin for limited Buruli ulcer lesions: a randomised, open-label, non-inferiority phase 3 trial.

BACKGROUND: Buruli ulcer is a neglected tropical disease caused by Mycobacterium ulcerans infection that damages the skin and subcutis. It is most prevalent in western and central Africa and Australia. Standard antimicrobial treatment with oral rifampicin 10 mg/kg plus intramuscular streptomycin 15 mg/kg once daily for 8 weeks (RS8) is highly effective, but streptomycin injections are painful and potentially harmful. We aimed to compare the efficacy and tolerability of fully oral rifampicin 10 mg/kg plus clarithromycin 15 mg/kg extended release once daily for 8 weeks (RC8) with that of RS8 for treatment of early Buruli ulcer lesions. METHODS: We did an open-label, non-inferiority, randomised (1:1 with blocks of six), multicentre, phase 3 clinical trial comparing fully oral RC8 with RS8 in patients with early, limited Buruli ulcer lesions. There were four trial sites in hospitals in Ghana (Agogo, Tepa, Nkawie, Dunkwa) and one in Benin (Pobè). Participants were included if they were aged 5 years or older and had typical Buruli ulcer with no more than one lesion (caterories I and II) no larger than 10 cm in diameter. The trial was open label, and neither the investigators who took measurements of the lesions nor the attending doctors were masked to treatment assignment. The primary clinical endpoint was lesion healing (ie, full epithelialisation or stable scar) without recurrence at 52 weeks after start of antimicrobial therapy. The primary endpoint and safety were assessed in the intention-to-treat population. A sample size of 332 participants was calculated to detect inferiority of RC8 by a margin of 12%. This study was registered with ClinicalTrials.gov, NCT01659437. FINDINGS: Between Jan 1, 2013, and Dec 31, 2017, participants were recruited to the trial. We stopped recruitment after 310 participants. Median age of participants was 14 years (IQR 10-29) and 153 (52%) were female. 297 patients had PCR-confirmed Buruli ulcer; 151 (51%) were assigned to RS8 treatment, and 146 (49%) received oral RC8 treatment. In the RS8 group, lesions healed in 144 (95%, 95% CI 91 to 98) of 151 patients, whereas lesions healed in 140 (96%, 91 to 99) of 146 patients in the RC8 group. The difference in proportion, -0·5% (-5·2 to 4·2), was not significantly greater than zero (p=0·59), showing that RC8 treatment is non-inferior to RS8 treatment for lesion healing at 52 weeks. Treatment-related adverse events were recorded in 20 (13%) patients receiving RS8 and in nine (7%) patients receiving RC8. Most adverse events were grade 1-2, but one (1%) patient receiving RS8 developed serious ototoxicity and ended treatment after 6 weeks. No patients needed surgical resection. Four patients (two in each study group) had skin grafts. INTERPRETATION: Fully oral RC8 regimen was non-inferior to RS8 for treatment of early, limited Buruli ulcer and was associated with fewer adverse events. Therefore, we propose that fully oral RC8 should be the preferred therapy for early, limited lesions of Buruli ulcer. FUNDING: WHO with additional support from MAP International, American Leprosy Missions, Fondation Raoul Follereau France, Buruli ulcer Groningen Foundation, Sanofi-Pasteur, and BuruliVac

Emotional burnout of specialists in socio-occupational professions: contemporary views on the problem

Представлено сучасні підходи до проблеми вигорання у представників соціономічних професій у контексті емоційної праці, емоційного і когнітивного дисонансу. Проаналізовано й узагальнено наукову літературу з питань вигорання, визначено три основні його компоненти: емоційне і/або фізичне виснаження, зниження продуктивності праці і надмірна деперсоналізація. На основі аналізу визначень вигорання встановлено його зв’язок з емоційною працею (регуляцією і вираженням емоційних станів). Обстоюється думка, що фахівці соціономічних професій особливо вразливі до вигорання, оскільки тривалий час перебувають у стані, коли необхідно постійно контролювати свої емоції, брати на себе відповідальність і відчувати невизначеність, працюючи з іншими людьми. Емоційну працю розглянуто як предиктор вигорання у фахівців соціономічних професій. На основі аналізу літератури, присвяченої проблемам вигорання та емоційного дисонансу, висловлено припущення, що вимоги щодо емоційної праці зумовлюють різноманітність проявів синдрому виго-рання (у тому числі виснаження, цинізму, зниження продуктивності праці та погіршення самопочуття), а знання симптомів вигорання дало б змогу фахівцям соціономічних професій запобігти виникненню та загостренню цього стану.This article deals with the modern approaches to the problem of burnout of helping professionals in the context of emotional labor, emotional and cognitive dissonance. The burnout literature is reviewed, compared, and summarized. The definition of burnout is proposed including three components: emotional and/or physical exhaustion, lowered work productivity, and excessive depersonalization. Based on an analysis of the definitions of burnout, the paper focuses on the connec-tion of burnout and emotional work (regulation of feelings and emotional expression). It is also maintained a fact that helping professionals are especially vulnerable to burnout because of the necessity to control own emotions for a long time, to take responsibilities, and to feel uncertainties they encounter while working with others. The current study discussed emotional labor as a predictor of burnout of helping professionals. On the basis of the literature on burnout and emotional dissonance, the author of this article hypothesized that emotional job demands would explain variances of burnout (i.e., exhaustion and cynicism). Knowledge of abovementioned syndromes would help socionomy professionals to avoid emergence and aggravation of emotional burnout.Представлены современные подходы к проблеме выгорания у представителей социономических профессий в контексте эмоциональной труда, эмоционального и когнитивного диссонанса. Проанализированы и обобщены научную литературу по вопросам выгорания, определены три основные его компоненты: эмоциональное и / или физическое истощение, снижение производительности труда и чрезмерная деперсонализация. На основе анализа определений выгорания установлена ​​его связь с эмоциональной трудом (регуляцией и выражением эмоциональных состояний). Отстаивается мнение, что специалисты социономических профессий особенно уязвимы к выгоранию, поскольку длительное время находятся в состоянии, когда необходимо постоянно контролировать свои эмоции, брать на себя ответственность и чувствовать неопределенность, работая с другими людьми. Эмоциональный труд рассмотрен как предиктор выгорания у специалистов социономических профессий. На основе анализа литературы, посвященной проблемам выгорания и эмоционального диссонанса, высказано предположение, что требования по эмоциональной труда обусловливают разнообразие проявлений синдрома выгорания (в том числе истощения, цинизма, снижение производительности труда и ухудшение самочувствия), а знание симптомов выгорания позволило бы специалистам социономических профессий предотвратить возникновение и обострение этого состояния

Correlation of sonographically-determined residual urine volume with lower urinary tract symptoms in adult males at a tertiary hospital

Objective: To determine the correlation between the severity of LUTS as measured by the International Prostate Symptom Score (IPSS) and PVR urine volume measured by transabdominal ultrasound in patients with LUTS, and to determine the correlation between ‘feeling of incomplete bladder emptying and sonographically measured PVR urine volume. Design: Correlational cross-sectional study Setting: Ultrasound Unit of the Radiology Department and Urology Clinic of Korle Bu Teaching Hospital Participants: Male patients (n=256) aged 40 years or more and who presented to the urology department of Korle Bu Teaching Hospital with LUTS and gave their written consent were enrolled. The presence and severity of LUTS were evaluated using the IPSS. The PVR urine was measured using real-time transabdominal ultrasound scan. Main outcome measure: Severity of LUTS and Residual urine volume Results: The mean PVR urine volume was 84.5ml. Majority of respondents (57.3%, n=146) had PVR urine volume below 50ml with 27% (70 patients) having PVR urine volume above 100ml. PVR urine volume and total IPSS showed no statistically significant correlation. All age groups of respondents scored above 4 for quality of life (QoL). ‘Intermittency’ is the IPSS symptom which showed statistically significant correlation with PVR urine volume. PVR urine volume did not show a statistically significant correlation with the ‘feeling of incomplete emptying’. Conclusions: There was no statistically significant correlation between the total IPSS and PVR urine volume, thus residual urine volume does not correlate with severity of LUTS. The ‘feeling of incomplete emptying’ does not correlate with PVR urine volume

Non-invasive imaging of CSF-mediated brain clearance pathways via assessment of perivascular fluid movement with DTI MRI

The glymphatics system describes a CSF-mediated clearance pathway for the removal of potentially harmful molecules, such as amyloid beta, from the brain. As such, its components may represent new therapeutic targets to alleviate aberrant protein accumulation that defines the most prevalent neurodegenerative conditions. Currently, however, the absence of any non-invasive measurement technique prohibits detailed understanding of glymphatic function in the human brain and in turn, it's role in pathology. Here, we present the first non-invasive technique for the assessment of glymphatic inflow by using an ultra-long echo time, low b-value, multi-direction diffusion weighted MRI sequence to assess perivascular fluid movement (which represents a critical component of the glymphatic pathway) in the rat brain. This novel, quantitative and non-invasive approach may represent a valuable biomarker of CSF-mediated brain clearance, working towards the clinical need for reliable and early diagnostic indicators of neurodegenerative conditions such as Alzheimer's disease

Non-invasive MRI of brain clearance pathways using multiple echo time arterial spin labelling: an aquaporin-4 study

There is currently a lack of non-invasive tools to assess water transport in healthy and pathological brain tissue. Aquaporin-4 (AQP4) water channels are central to many water transport mechanisms, and emerging evidence also suggests that AQP4 plays a key role in amyloid-β (Aβ) clearance, possibly via the glymphatic system. Here, we present the first non-invasive technique sensitive to AQP4 channels polarised at the blood-brain interface (BBI). We apply a multiple echo time (multi-TE) arterial spin labelling (ASL) MRI technique to the mouse brain to assess BBI water permeability via calculation of the exchange time (Texw), the time for magnetically labelled intravascular water to exchange across the BBI. We observed a 31% increase in exchange time in AQP4-deficient (Aqp4-/-) mice (452 ± 90 ms) compared to their wild-type counterparts (343 ± 91 ms) (p = 0.01), demonstrating the sensitivity of the technique to the lack of AQP4 water channels. More established, quantitative MRI parameters: arterial transit time (δa), cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) detected no significant changes with the removal of AQP4. This clinically relevant tool may be crucial to better understand the role of AQP4 in water transport across the BBI, as well as clearance of proteins in neurodegenerative conditions such as Alzheimer's disease

Generalisability of deep learning models in low-resource imaging settings: A fetal ultrasound study in 5 African countries

Most artificial intelligence (AI) research have concentrated in high-income countries, where imaging data, IT infrastructures and clinical expertise are plentiful. However, slower progress has been made in limited-resource environments where medical imaging is needed. For example, in Sub-Saharan Africa the rate of perinatal mortality is very high due to limited access to antenatal screening. In these countries, AI models could be implemented to help clinicians acquire fetal ultrasound planes for diagnosis of fetal abnormalities. So far, deep learning models have been proposed to identify standard fetal planes, but there is no evidence of their ability to generalise in centres with limited access to high-end ultrasound equipment and data. This work investigates different strategies to reduce the domain-shift effect for a fetal plane classification model trained on a high-resource clinical centre and transferred to a new low-resource centre. To that end, a classifier trained with 1,792 patients from Spain is first evaluated on a new centre in Denmark in optimal conditions with 1,008 patients and is later optimised to reach the same performance in five African centres (Egypt, Algeria, Uganda, Ghana and Malawi) with 25 patients each. The results show that a transfer learning approach can be a solution to integrate small-size African samples with existing large-scale databases in developed countries. In particular, the model can be re-aligned and optimised to boost the performance on African populations by increasing the recall to $0.92 \pm 0.04$ and at the same time maintaining a high precision across centres. This framework shows promise for building new AI models generalisable across clinical centres with limited data acquired in challenging and heterogeneous conditions and calls for further research to develop new solutions for usability of AI in countries with less resources

High degree of prostate related LUTS in a prospective cross-sectional community study in Ghana (Mamprobi)

BACKGROUND: Changing voiding patterns, volume and frequency, may sometimes be mistaken for anxiety, stress or increase in fluid consumption. In the aging male population, the commencement of lower urinary tract symptoms (LUTS) may be silent and perceived as "normal" and unrelated to Benign prostatic enlargement (BPE). The purpose of the study was to determine the prevalence of apparently "silent LUTS" (perceived asymptomatic LUTS) in men in a Ghanaian Community as well as its underlying risk factors. METHODS: One hundred and eleven (111) men (40-70 years) were recruited from a community in Ghana. The International Prostate Symptoms Score (IPSS) questionnaire (administered in the local language and English) and ultrasonographic imaging of the prostate volume (PV) were utlized to collect data. IPSS score >7 plus PV > 30 cm3 was definitive of lower urinary tract symptoms. Eighty-one (81) participants were classified "LUTS Negative" (LN) and 30, "LUTS Positive" (LP). Risk factors i.e., cholesterol (CHOL), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), very low-density lipoprotein (VLDL), coronary risk (CR), BMI and Blood Pressure were also determined. RESULTS: The prevalence of LUTS using only IPSS definition alone was 42.3%. However, IPSS in combination with Prostate Volume gave a prevalence of 27.0%. LN subjects had enlarged prostate (41.98%) and LP, 100%. Quality of life (QoL) was better in the LUTS Negative than LUTS Positive group (p < 0.001). In the univariant analysis coronary risk, triglyceride and VLDL contributed to LUTS (p = 0.023, 0.22, 0.22, respectively). In a multivariant analysis HDL-C (p = 0.027), BMI (p = 0.047) and triglyceride (p = 0.019) significantly contributed to LUTS. CONCLUSIONS: The prevalence of LUTS (42.3%) is high. Components of Metabolic Syndrome- HDL-C, BMI, and coronary risk were associated with LUTS. This emphasizes the need for community education

Comparative efficacy of low-dose versus standard-dose azithromycin for patients with yaws: a randomised non-inferiority trial in Ghana and Papua New Guinea

Background: A dose of 30 mg/kg of azithromycin is recommended for treatment of yaws, a disease targeted for global eradication. Treatment with 20 mg/kg of azithromycin is recommended for the elimination of trachoma as a public health problem. In some settings, these diseases are co-endemic. We aimed to determine the efficacy of 20 mg/kg of azithromycin compared with 30 mg/kg azithromycin for the treatment of active and latent yaws. Methods: We did a non-inferiority, open-label, randomised controlled trial in children aged 6–15 years who were recruited from schools in Ghana and schools and the community in Papua New Guinea. Participants were enrolled based on the presence of a clinical lesion that was consistent with infectious primary or secondary yaws and a positive rapid diagnostic test for treponemal and non-treponemal antibodies. Participants were randomly assigned (1:1) to receive either standard-dose (30 mg/kg) or low-dose (20 mg/kg) azithromycin by a computer-generated random number sequence. Health-care workers assessing clinical outcomes in the field were not blinded to the patient's treatment, but investigators involved in statistical or laboratory analyses and the participants were blinded to treatment group. We followed up participants at 4 weeks and 6 months. The primary outcome was cure at 6 months, defined as lesion healing at 4 weeks in patients with active yaws and at least a four-fold decrease in rapid plasma reagin titre from baseline to 6 months in patients with active and latent yaws. Active yaws was defined as a skin lesion that was positive for Treponema pallidum ssp pertenue in PCR testing. We used a non-inferiority margin of 10%. This trial was registered with ClinicalTrials.gov, number NCT02344628. Findings: Between June 12, 2015, and July 2, 2016, 583 (65·1%) of 895 children screened were enrolled; 292 patients were assigned a low dose of azithromycin and 291 patients were assigned a standard dose of azithromycin. 191 participants had active yaws and 392 had presumed latent yaws. Complete follow-up to 6 months was available for 157 (82·2%) of 191 patients with active yaws. In cases of active yaws, cure was achieved in 61 (80·3%) of 76 patients in the low-dose group and in 68 (84·0%) of 81 patients in the standard-dose group (difference 3·7%; 95% CI −8·4 to 15·7%; this result did not meet the non-inferiority criterion). There were no serious adverse events reported in response to treatment in either group. The most commonly reported adverse event at 4 weeks was gastrointestinal upset, with eight (2·7%) participants in each group reporting this symptom. Interpretation: In this study, low-dose azithromycin did not meet the prespecified non-inferiority margin compared with standard-dose azithromycin in achieving clinical and serological cure in PCR-confirmed active yaws. Only a single participant (with presumed latent yaws) had definitive serological failure. This work suggests that 20 mg/kg of azithromycin is probably effective against yaws, but further data are needed