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Graphical Abstract Abstract Studies evaluating pregnancy outcomes after assisted reproductive treatment (ART) in women with high-normal (2.5–4.5 mIU/L) thyroid-stimulating hormone (TSH) levels are conflicting, possibly due to different patient charactistics and subfertility indications. The aim of this study was to examine the hypothesis that high-normal compared to low-normal TSH levels are associated with adverse implications for pregnancy outcomes in conventional in vitro fertilization (IVF)-treated women. Therefore, we analyzed retrospectively the characteristics and pregnancy outcomes of 949 subfertile women with TSH 0.3–4.5 mIU/L, treated with conventional IVF between January 2008 and March 2012. Demographic and baseline characteristics were compared between groups of patients based on TSH quartiles, using one-way Anova, Kruskal–Wallis ANOVA and chi-square test. Women with high-normal quartile TSH were significantly more likely to be primary subfertile (P = 0.01), with a higher prevalence of unexplained subfertility and with 15% fewer live births after IVF compared to lower TSH quartiles (P = 0.02). In secondary subfertile women with high-normal TSH, male factor subfertility prevailed (P = 0.01), with more live births (P = 0.01). When analyzing primary and secondary subfertile women as one group, these differences failed to be observed, showing no differences in cumulative pregnancy outcomes of IVF between TSH quartiles (I: 0.3–1.21 mIU/L; II: 1.22–1.68 mIU/L; III: 1.69–2.31 mIU/L; IV: 2.32–4.5 mIU/L). In conclusion, primary subfertile women predominate in the high-normal TSH quartile, associated with significantly fewer live births in a subgroup of primary unexplained subfertile women (9%; n = 87/949), while in secondary subfertile women, dominated by male factor subfertility, high-normal TSH is associated with more live births. Lay summary Thyroid hormones are required for all cell processes in the body. An underactive thyroid gland, in which insufficient thyroid hormones are produced and thyroid-stimulating hormone (TSH) rises, is associated with a lower chance of pregnancy. It is not yet clear above which TSH level, 4.5 or also 2.5 mIU/L, this lower probability occurs. Therefore, in 949 couples treated with conventional IVF, we examined whether high-normal TSH levels (TSH: 2.5–4.5 mIU/L) compared to low normal TSH levels (0.3–2.5 mIU/L) affect the live birth rate. We found that women who were trying to become pregnant for the first time, especially without any other cause, that is unexplained subfertility, were more likely to have higher TSH levels. These women had a much lower chance of having a baby compared to women with low-normal TSH levels.

Optimal selection of systemic therapy in older adults with psoriasis can be challenging, due to sparse evidence-based guidance. This multicentre retrospective study investigated the safety of systemic therapy with causality assessment in a real-world cohort of older adults (≥ 65 years) with psoriasis. Data from 6 hospitals on (serious) adverse events were collected, causality assessment performed and incidence rate ratios calculated. Potential predictors for adverse events-occurrence were studied using multivariable logistic regression analysis. In total, 117 patients with 176 treatment episodes and 390 patient-years were included, comprising 115 (65.3%) and 61 (34.7%) treatment episodes with conventional systemic therapy and biologics/apremilast, respectively. After causality assessment, 232 of 319 (72.7%) adverse events remained and were analysed further, including 12 serious adverse events. No significant differences in incidence rate ratios were found between the systemic treatment types. In regression analysis, increasing age was associated with causality assessed adverse events-occurrence (odds ratio 1.195; p=0.022). Comorbidity, polypharmacy, and treatment type were not associated with causality assessed adverse events-occurrence. In conclusion, increasing age was associated with a higher causality assessed adverse events-occurrence. Causality assessed serious adverse events were rare, reversible and/or manageable in clinical practice. In conclusion, the safety profile of systemic antipsoriatic therapy within this population is reassuring.

Contains fulltext : 282870.pdf (Publisher’s version ) (Open Access) BACKGROUND: Psoriasis is a common inflammatory disease in any age group, but also in older patients (≥ 65 years of age). Since older patients are often excluded from clinical trials, limited data specifically on this growing population are available, e.g. regarding the safety and performance of biological treatment. AIMS: We aimed to give insight into this specific population by comparing the drug survival and safety of biologics in older patients with that in younger patients. METHODS: In this real-world observational study, data from 3 academic and 15 non-academic centers in The Netherlands were extracted from the prospective BioCAPTURE registry. Biologics included in this study were tumor necrosis factor (TNF)-α, interleukin (IL)-17, IL-12/23, and IL-23 inhibitors. Patients were divided into two age groups: ≥ 65 years and

Lacticaseibacillus rhamnosus GR-1 (LGR-1) (previously classified as Lactobacillus rhamnosus GR-1) is the most researched probiotic strain for women's health. Its various urogenital health effects, including a reduction in the recurrence of bacterial vaginosis and urinary-tract infection, are well documented. The strain has also been safely used by HIV-positive subjects, a portion of whom have reported reduced diarrhea and increased CD4 counts. Unlike most probiotic strains used for urogenital health, LGR-1 has been extensively studied for its properties, including its genomic and metabolic traits and its surface properties. This review aims to highlight the totality of research performed with LGR-1, to act as a rigorous scientific benchmark for probiotic microbes, especially for application to women's health.

Supplemental Digital Content is available in the text, Objective: Cross-sectional studies, including one from our NOVICE cohort [Neurological Visual and Cognitive performance in children with treated perinatally acquired HIV (PHIV) compared with matched HIV-negative controls], have revealed that the brains of children with PHIV have lower white matter and grey matter volumes, more white matter hyperintensities (WMH) and poorer white matter integrity. This longitudinal study investigates whether these differences change over time. Methods: We approached all NOVICE participants to repeat MRI after 4.6 ± 0.3 years, measuring total white matter and grey matter volume, WMH volume and white matter integrity, obtained by T1-weighted, fluid-attenuated inversion recovery (FLAIR) and diffusion tensor imaging (DTI), respectively. We compared rates of change between groups using multivariable linear mixed effects models, adjusted for sex and age at enrolment. We investigated determinants of developmental deviation, and explored associations with cognitive development. Results: Twenty out of 31 (65%) PHIV-positive, and 20 out of 37 (54%) HIV-negative participants underwent follow-up MRI. Groups did not significantly differ in terms of age and sex. Over time, we found no statistically different changes between groups for white matter and WMH volumes, and for white matter integrity (P > 0.1). Total grey matter volume decreased significantly less in PHIV [group∗time 10 ml, 95% confidence interval −1 to 20, P = 0.078], but this difference in rate of change lost statistical significance after additional adjustment for height (group∗time 9 ml, 95% confidence interval −2 to 20, P = 0.112). We found no HIV-associated determinants for potential reduced grey matter pruning, nor associations with cognitive development. Conclusion: While using long-term antiretroviral treatment, structural brain development of adolescents growing up with perinatally acquired HIV appears largely normal.

Young people perinatally infected with HIV (pHIV) are at risk of a lowered health-related quality of life (HRQOL). Previous evaluation of the NeurOlogical, VIsual and Cognitive performance in HIV-infected Children (NOVICE)-cohort showed no difference in HRQOL between pHIV and matched HIV-uninfected controls (HIV-), yet a higher percentage of pHIV had impaired HRQOL. The aim of this study is to compare the change over time in HRQOL of pHIV to HIV- over a 5-year period. We used the Pediatric Quality of Life Inventory (PedsQL)™ 4.0 to repeat HRQOL assessment. High PedsQL scores indicate good HRQOL. Fifteen/33 (45.5%) pHIV and 17/37 (45.9%) HIV- completed both assessments. At the first assessment, the mean age was 13.1 years (range 8.0–18.4). PHIV scored higher than HIV- on Emotional functioning and on Total scale score. After five years, the mean age was 17.6 years (range 12.1–22.8). PHIV scored higher than HIV- on all scales, except Social functioning. PHIV did not differ significantly from the Dutch norm on either time-point. LMEM showed no difference in change over time for any of the PedsQL scales. In this study, young people with pHIV receiving high-quality health care, including monitoring of HRQOL, remain to experience a good HRQOL.

Telehealth is an important tool utilized to provide remote clinical care and has increased in prevalence during the coronavirus disease of 2019 (COVID-19) pandemic. It allows providers to conduct safe, timely, and high-quality ambulatory care for patients without increasing risk of disease exposure for both parties. Major organizations including the Centers for Disease Control and Prevention and American College of Obstetrics and Gynecology have released recommendations encouraging the use of telehealth systems for patient care. In obstetrics and gynecology, practice of telehealth has not been commonplace and no practical procedural guidelines have been published. The authors have created such guidelines for use of telehealth in a moderate-risk academic generalist practice in response to the COVID-19 pandemic. This document highlights the process to determine which obstetrics and gynecology patients are candidates for telehealth, the frequency of follow-up, and the technical aspects of designing and delivering a de novo telehealth system. The guidelines were vital in providing structure amid a sudden transition in an academic setting while ensuring patient and provider safety.

Background Patient suitability for magnetic resonance-guided high intensity focused ultrasound (MRgHIFU) therapy of pelvic tumors is currently assessed by visual estimation of the proportion of tumor that can be reached by the device’s focus (coverage). Since it is important to assess whether enough energy reaches the tumor to achieve ablation, a methodology for estimating the proportion of the tumor that can be ablated (treatability) was developed. Predicted treatability was compared against clinically achieved thermal ablation. Methods MR Dixon sequence images of five patients with recurrent gynecological tumors were acquired during their treatment. Acousto-thermal simulations were performed using k-Wave for three exposure points (the deepest and shallowest reachable focal points within the tumor, identified from tumor coverage analysis, and a point halfway in-between) per patient. Interpolation between the resulting simulated ablated tissue volumes was used to estimate the maximum treatable depth and hence, tumor treatability. Predicted treatability was compared both to predicted tumor coverage and to the clinically treated tumor volume. The intended and simulated volumes and positions of ablated tissues were compared. Results Predicted treatability was less than coverage by 52% (range: 31–78%) of the tumor volume. Predicted and clinical treatability differed by 9% (range: 1–25%) of tumor volume. Ablated tissue volume and position varied with beam path length through tissue. Conclusion Tumor coverage overestimated patient suitability for MRgHIFU therapy. Employing patient-specific simulations improved treatability assessment. Patient treatability assessment using simulations is feasible.

Objective To document longitudinal symptom, quality-of-life and imaging response in patients with recurrent gynecological tumors treated with magnetic resonance guided high intensity focused ultrasound (MRgHIFU), and compare changes in patients with intra- versus extra-pelvic lesions. Methods Eleven symptomatic patients with painful recurrent gynecological tumors were treated with MRgHIFU (Profound Sonalleve) in a prospective single center study (NCT02714621). Pain scores, analgesic intake and quality-of-life metrics, whole tumor volume, and perfused tumor volume from Gadolinium-enhanced T1W imaging documented before and up to 90 days after treatment were compared between patients with intra- and extra-pelvic tumors. Results Two of five patients with intra-pelvic and three of six patients with extra-pelvic tumors were classified as responders (>2 point reduction in NRS pain score without analgesia increase or a > 25% reduction in analgesic use). Cohort reductions in worst pain scores were not significant for either group. Emotional functioning for the whole cohort improved, although physical functioning did not. Ablative thermal temperatures were achieved in three patients with extra-pelvic tumors, but in none whose tumors were intra-pelvic. Pain response did not correlate with thermal dose. Tumor volume increased by 18% immediately post-treatment in the extra-pelvic but not in the intra-pelvic group. Ratio of perfused to whole lesion volume decreased by >20% by day 30 in extra-pelvic, but not intra-pelvic tumors although at day 30 both extra-pelvic and intra-pelvic tumors increased in volume. Conclusion MRgHIFU treatments can be delivered safely to patients with recurrent gynecological tumors. Extra-pelvic tumors responded better than intra-pelvic tumors and showed immediate swelling and reduction in perfused volume by day 30.

Background Sub-ablative heat induces pleiotropic biological effects in cancer cells, activating programmed cell death or survival processes. These processes decide the fate of the heated cell. This study investigates these and assesses whether heat, in combination with HSP90 inhibition, augments cell death and induces a pro-immune phenotype in these cells. Methods HCT116 and HT29 cells were subjected to thermal doses (TID) of 60 and 120CEM43 using a PCR thermal cycler. HSP90 was inhibited with NVP-AUY922. Viability was assessed using the MTT assay. Cellular ATP and HSP70 release were assessed using ATP and Enzyme-linked Immunosorbent assays, respectively. Flow cytometry and immunoblotting were used to study the regulation of biomarkers associated with the heat shock response, the cell cycle, and immunogenic and programmed cell death. Results Exposure of HCT116 and HT29 cells to TIDs of 60 and 120CEM43 decreased their viability. In addition, treatment with 120CEM43 increased intracellular HSP70 and the percentage of HCT116/HT29 cells in the G2/M cell cycle phase, ATP release and Calreticulin/HSP70/HSP90 exposure in the plasma membrane, while downregulating CD47 compared to sham-exposed cells. When combined with NVP-AUY922, treatment of HCT116/HT29 cells with 120CEM43 resulted in a synergistic decrease of cell viability associated with the induction of apoptosis. Also, the combined treatments increased Calreticulin exposure, CD47 downregulation, and HSP70 release compared to the sham-exposed cells. Conclusion Sub-ablative heating can act synergistically with the clinically relevant HSP90 inhibitor NVP-AUY922 to induce a pro-immunogenic form of cell death in colon cancer cells.

In view of the challenges of the current coronavirus (COVID-19) pandemic and to protect both patients and ultrasound providers (physicians, sonographers, allied professionals), ISUOG has compiled the following expert-opinion-based guidance for the performance of ultrasound investigations in pregnancy and for gynecological indications.

Background Patient suitability for magnetic resonance-guided high intensity focused ultrasound (MRgHIFU) ablation of pelvic tumors is initially evaluated clinically for treatment feasibility using referral images, acquired using standard supine diagnostic imaging, followed by MR screening of potential patients lying on the MRgHIFU couch in a ‘best-guess’ treatment position. Existing evaluation methods result in ≥40% of referred patients being screened out because of tumor non-targetability. We hypothesize that this process could be improved by development of a novel algorithm for predicting tumor coverage from referral imaging. Methods The algorithm was developed from volunteer images and tested with patient data. MR images were acquired for five healthy volunteers and five patients with recurrent gynaecological cancer. Subjects were MR imaged supine and in oblique-supine-decubitus MRgHIFU treatment positions. Body outline and bones were segmented for all subjects, with organs-at-risk and tumors also segmented for patients. Supine images were aligned with treatment images to simulate a treatment dataset. Target coverage (of patient tumors and volunteer intra-pelvic soft tissue), i.e. the volume reachable by the MRgHIFU focus, was quantified. Target coverage predicted from supine imaging was compared to that from treatment imaging. Results Mean (±standard deviation) absolute difference between supine-predicted and treatment-predicted coverage for 5 volunteers was 9 ± 6% (range: 2–22%) and for 4 patients, was 12 ± 7% (range: 4–21%), excluding a patient with poor acoustic coupling (coverage difference was 53%). Conclusion Prediction of MRgHIFU target coverage from referral imaging appears feasible, facilitating further development of automated evaluation of patient suitability for MRgHIFU.

The therapeutic application of heat is very effective in cancer treatment. Both hyperthermia, i.e., heating to 39-45 degrees C to induce sensitization to radiotherapy and chemotherapy, and thermal ablation, where temperatures beyond 50 degrees C destroy tumor cells directly are frequently applied in the clinic. Achievement of an effective treatment requires high quality heating equipment, precise thermal dosimetry, and adequate quality assurance. Several types of devices, antennas and heating or power delivery systems have been proposed and developed in recent decades. These vary considerably in technique, heating depth, ability to focus, and in the size of the heating focus. Clinically used heating techniques involve electromagnetic and ultrasonic heating, hyperthermic perfusion and conductive heating. Depending on clinical objectives and available technology, thermal therapies can be subdivided into three broad categories: local, locoregional, or whole body heating. Clinically used local heating techniques include interstitial hyperthermia and ablation, high intensity focused ultrasound (HIFU), scanned focused ultrasound (SFUS), electroporation, nanoparticle heating, intraluminal heating and superficial heating. Locoregional heating techniques include phased array systems, capacitive systems and isolated perfusion. Whole body techniques focus on prevention of heat loss supplemented with energy deposition in the body, e.g., by infrared radiation. This review presents an overview of clinical hyperthermia and ablation devices used for local, locoregional, and whole body therapy. Proven and experimental clinical applications of thermal ablation and hyperthermia are listed. Methods for temperature measurement and the role of treatment planning to control treatments are discussed briefly, as well as future perspectives for heating technology for the treatment of tumors.

In view of the rapid spread of the Omicron variant of concern (VOC) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1, the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) has decided to revise its position statements on use of personal protective equipment for the safe performance of obstetric and gynecological ultrasound2, 3, particularly in relation to the protection of healthcare workers. The World Health Organization (WHO) recommendation on mask use by healthcare workers, issued on 22 December 2021, states that ‘…the Omicron variant is spreading significantly faster than the Delta variant in countries with documented community transmission, with a doubling time between 1.5–3 days. Preliminary, unpublished data show a reduction in neutralizing titres against Omicron suggesting a level of immune evasion and an important reduction in vaccine effectiveness against infection and symptomatic disease for Omicron compared to Delta’4. ISUOG previously recommended the use of fit-approved masks or respirators (FFP2, FFP3, NIOSH-approved N95 or other equivalent or higher-level certified respirator) for the ultrasound examination of patients with suspected or confirmed SARS-CoV-2 infection3 or in the event of widespread community transmission2. The latest WHO recommendation on mask use by healthcare workers1 states that ‘A respirator… should be worn by health workers along with other personal protective equipment (PPE) – a gown, gloves and eye protection – before entering a room where there is a patient with suspected or confirmed COVID-19 … in care settings where ventilation is known to be poor or cannot be assessed or the ventilation system is not properly maintained…’. This applies to the rooms in which ultrasound scans are typically performed. In light of the growing number of SARS-CoV-2 infections and in particular the highly infectious Omicron VOC, the USA Centers for Disease Control and Prevention has predicted and provided strategies to limit the effects of healthcare staff shortages5. Patients do not undergo routinely polymerase chain reaction or lateral flow testing prior to ultrasound assessment for obstetric or gynecological indications, nonetheless, a high number of asymptomatic cases are to be expected in the context of the SARS-CoV-2 epidemic caused by the Omicron VOC6. On this basis, ISUOG now recommends that fit-approved masks or respirators should be worn routinely in ultrasound clinics and departments to limit the risk of infection for practitioners performing obstetric and gynecological ultrasound scans, in addition to preventive measures including hand hygiene, patient mask-wearing2-4 and vaccination7, 8. The recommendation can be adapted locally based on community prevalence and transmissibility of the current and future variants of SARS-CoV-2.

RNA editing by the adenosine deaminase ADAR1 prevents innate immune responses to endogenous RNAs. In ADAR1-deficient cells, unedited self RNAs form base-paired structures that resemble viral RNAs and inadvertently activate the cytosolic RIG-I-like receptor (RLR) MDA5, leading to an antiviral type I interferon (IFN) response. Mutations in ADAR1 cause Aicardi-Goutieres Syndrome (AGS), an autoinflammatory syndrome characterized by chronic type I IFN production. Conversely, ADAR1 loss and the consequent type I IFN production restricts tumor growth and potentiates the activity of some chemotherapeutics. Here, we show that another RIG-I-like receptor, LGP2, also has an essential role in the induction of a type I IFN response in ADAR1-deficient human cells. This requires the canonical function of LGP2 as an RNA sensor and facilitator of MDA5-dependent signaling. Furthermore, we show that the sensitivity of tumor cells to ADAR1 loss requires LGP2 expression. Finally, type I IFN induction in tumor cells depleted of ADAR1 and treated with some chemotherapeutics fully depends on LGP2 expression. These findings highlight a central role for LGP2 in self RNA sensing with important clinical implications.

Contains fulltext : 287312.pdf (Publisher’s version ) (Open Access) BACKGROUND: Evidence-based guidance in older adults (≥65 years) with psoriasis is sparse and undertreatment might be present. OBJECTIVES: To assess prescribing patterns, comfort levels, barriers and needs of dermatologists when treating older adults with systemic antipsoriatic therapy. METHODS: A mixed-methods design was used including a survey among all Dutch dermatologists and residents, followed by semi-structured interviews. RESULTS: Most of the survey respondents applied systemic treatment to the same extent in older versus younger patients (n = 49; 67.1%) and weren't reluctant prescribing systemic therapy (n = 50; 68.5%) in older adults. However, 26% (n = 19) of the respondents treated older adults less often with systemic therapy compared to younger patients and 68.1% (n = 49) performed additional actions in older adults, e.g. intensified monitoring or dose reduction. Based on the survey and interviews (n = 10), the main reasons for these age-based treatment differences were comorbidity, comedication, and fear of adverse events. More evidence-based guidance, education, and time to assess older adults were identified as most important needs, especially regarding frailty screening. CONCLUSIONS: Age-based treatment differences in and reluctance to treating older adults with systemic antipsoriatic therapy were common. There is a need for more evidence-based guidance, education, and consultation time, to improve treatment in this growing population.

Objectives: The aim of this study was to analyze the fertility outcome in intracytoplasmic sperm injection (ICSI)-treated women across normal range thyroid-stimulating hormone (TSH) levels. Published results are inconclusive about optimal TSH levels and fertility. Design: This is a retrospective cohort study in 752 ICSI-treated women with predominantly severe male factor subfertility, starting treatment between the first of January 2008 and the first of March 2012 with a follow-up until 2014. Participants/Materials, Setting, Methods: Women aged 22–45 years with TSH 0.3–4.5 mIU/L without thyroid hormone substitution were included in Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands, an iodine-sufficient area. Demographic and baseline characteristics were compared between groups of patients based on TSH, using one-way ANOVA, Kruskal-Wallis ANOVA, and χ2 test. The patient was the unit of analysis: all cumulative cycles per patient were analyzed up to and including the first ongoing pregnancy. The primary outcome was a cumulative live birth rate. Clinical pregnancy rate, pregnancy loss, and ongoing pregnancy rate were secondary outcomes. The χ2 test and logistic regression were used to compare interquartile groups while adjusting for confounders. Logistic regression was used with the natural logarithm of TSH as a continuous predictor. Primary and secondary subfertile women were analyzed separately. Results: Analysis of the total cohort (n = 752) showed no difference in fertility outcomes across the normal TSH range. The cumulative live birth rate for the 4 groups of primary subfertile women (n = 455) was 76% in the upper TSH quartile compared to 56%, 60%, and 59% in the lower TSH quartiles. Limitations: Levels of thyroxine and presence of thyroid autoimmunity were not measured in this retrospective cohort study. Conclusions: The observation that a higher live birth rate was found in primary subfertile ICSI-treated women with high but allegedly normal TSH levels contributes to the hypothesis that in certain subfertile women in addition to a male factor, female factors such as subtle hypothyroidism and/or thyroid autoimmunity may play a role in keeping them from conception, which can be overcome by the process of ICSI.

Tree-like structures such as retinal images are widely studied in computer-aided diagnosis systems for large-scale screening programs. Despite several segmentation and tracking methods proposed in the literature, there still exist several limitations specifically when two or more curvilinear structures cross or bifurcate, or in the presence of interrupted lines or highly curved blood vessels. In this paper, we propose a novel approach based on multi-orientation scores augmented with a contextual affinity matrix, which both are inspired by the geometry of the primary visual cortex (V1) and their contextual connections. The connectivity is described with a five-dimensional kernel obtained as the fundamental solution of the Fokker-Planck equation modelling the cortical connectivity in the lifted space of positions, orientations, curvatures and intensity. It is further used in a self-tuning spectral clustering step to identify the main perceptual units in the stimuli. The proposed method has been validated on several easy and challenging structures in a set of artificial images and actual retinal patches. Supported by quantitative and qualitative results, the method is capable of overcoming the limitations of current state-of-the-art techniques.

Ultrasound safety is of particular importance in fetal and neonatal scanning. Fetal tissues are vulnerable and often still developing, the scanning depth may be low, and potential biological effects have been insufficiently investigated. On the other hand, the clinical benefit may be considerable. The perinatal period is probably less vulnerable than the first and second trimesters of pregnancy, and ultrasound is often a safer alternative to other diagnostic imaging modalities. Here we present step-by-step procedures for obtaining clinically relevant images while maintaining ultrasound safety. We briefly discuss the current status of the field of ultrasound safety, with special attention to the safety of novel modalities, safety considerations when ultrasound is employed for research and education, and ultrasound of particularly vulnerable tissues, such as the neonatal lung. This CME is prepared by ECMUS, the safety committee of EFSUMB, with contributions from OB/GYN clinicians with a special interest in ultrasound safety. Die Sicherheit des Ultraschalls ist bei der Untersuchung von Foten und Neugeborenen von besonderer Bedeutung. Fetales Gewebe ist empfindlich und befindet sich meist noch in der Entwicklung, die Eindringtiefe kann gering sein und mogliche biologische Effekte sind nur unzureichend untersucht worden. Andererseits kann der klinische Nutzen betrachtlich sein. In der Perinatalperiode ist der Fotus wohl weniger gefahrdet als im ersten und zweiten Trimester der Schwangerschaft, und Ultraschall ist haufig eine sicherere Alternative verglichen mit anderen diagnostischen bildgebenden Verfahren. Hier stellen wir Schritt fur Schritt das Vorgehen vor, um klinisch relevante Bilder zu erhalten und gleichzeitig die Ultraschallsicherheit zu gewahrleisten. Wir erortern kurz den aktuellen Stand auf dem Gebiet der Ultraschallsicherheit, mit besonderem Augenmerk auf der Sicherheit neuer Modalitaten, Uberlegungen zur Sicherheit beim Einsatz von Ultraschall in Forschung und Ausbildung sowie die Sonografie besonders gefahrdeter Gewebe, wie z. B. der neonatalen Lunge. Diese CME-Arbeit wurde von ECMUS, dem Sicherheitsausschuss der EFSUMB, unter Mitwirkung von Gynakologen mit besonderem Interesse an der Ultraschallsicherheit erstellt.

Background Fatigue is common among adults living with human immunodeficiency virus (HIV) as well as children with a chronic disease (CCD). Fatigue can have disastrous effects on health status, including health related quality of life (HRQOL). Even so, fatigue is underexplored in children and adolescents perinatally infected with HIV (PHIV+) in the Netherlands. The objective of this observational study is to explore fatigue in PHIV+ and its association with their HRQOL. Methods We measured HRQOL and fatigue using the Pediatric Quality of Life Inventory™ (PedsQL 4.0) and the PedsQL Multidimensional Fatigue Scale (MFS). The PedsQL MFS encompasses three subscales: general fatigue, sleep/rest fatigue and cognitive fatigue, and a total fatigue score. We compared outcomes of PHIV+ children and adolescents in the Amsterdam University Medical Centre with three groups: 1) HIV-uninfected controls (HIV-) matched for age, sex, region of birth, socioeconomic status and adoption status, 2) CCD, and 3) the general Dutch population. Within the PHIV+ group we explored associations between fatigue and HRQOL. Results We enrolled 14 PHIV+ (median age 10.2 years [IQR 9.2–11.4]) and 14 HIV-. Compared to CCD, PHIV+ significantly reported less general fatigue (mean difference 13.0, 95% CI 1.3 to 24.8). PHIV+ did not score significantly different on any of the other PedsQL MFS scales compared to HIV-, CCD or the general Dutch population. PHIV children scored relatively low on the cognitive fatigue scale in comparison to HIV-uninfected matched controls, CCD and the general population, although these differences did not reach significance. Among PHIV+, a lower score on total fatigue, general fatigue and cognitive fatigue was associated with a lower HRQOL score. Conclusions The results of this study suggest that PHIV children and adolescents do not experience more symptoms of fatigue than their healthy peers. However, PHIV children and adolescents may be more likely to experience cognitive fatigue. Fatigue in PHIV also appears to be associated with children’s HRQOL. Further research should confirm these exploratory findings.

Improved training for translational scientists is important to help address the waste of resources and irreproducibility of research outcomes in current translational medicine. However, there are a lack of training programs that cover the full range of knowledge and skills translational scientists need to develop, and many translational research training programs struggle to develop competency frameworks and assessment tools. Entrustable professional activities (EPAs) have been successfully implemented to link competencies with everyday practice in training health care professionals but have not yet been developed for research training. The purpose of the current study was to develop EPAs for translational scientists that could be used for their training and assessment and help increase the transparency and reproducibility of research outcomes and methods by providing best practices for translational research.In 2019, a modified Delphi technique, preceded by a focus group held in 2018 using a nominal group technique, was used to reach consensus on EPA titles and content among an international panel of 22 translational experts. Mean, standard deviation, and level of agreement were calculated after each round. Consensus was defined as ≥ 80% agreement.Consensus was reached on 89% of the items after the first round and 100% after the second round. The final list of EPAs consists of 17 EPAs divided over 7 sections.The concept of EPAs is new to the field of research training. The 17 EPA titles and their descriptions developed in this study may be used as a framework for improved training for translational scientists with the ultimate goal to contribute to closing the gap between bench and bedside, reducing resource waste in science, and increasing the reproducibility of research outcomes.

Stay-at-home orders, physical distancing, face masks and other non-pharmaceutical interventions (NPIs) do not only impact COVID-19, but also the dynamics of various other infectious diseases. Bronchiolitis is a clinically diagnosed viral infection of the lower respiratory tract, and causes a yearly seasonal wave of admissions in paediatric wards worldwide. We counted 92,5% less bronchiolitis hospitalisations in Antwerp before the expected end of the peak this year (of which only 1 RSV positive), as compared to the last 3 years. Furthermore, there was a >99% reduction in the number of registered RSV cases in Belgium. Conslusion: The 2020 winter bronchiolitis peak is hitherto nonexistent, but we fear a 'delayed' spring/summer bronchiolitis peak when most NPIs will be relaxed and pre-pandemic life restarts. What is known? Bronchiolitis causes a yearly seasonal wave of admissions in paediatric departments worldwide. Non-pharmaceutical interventions (NPIs) do not only impact COVID-19, but also the dynamics of various other infectious diseases. What is new? The 2020 winter bronchiolitis peak is hitherto nonexistent. A 'delayed' spring or summer bronchiolitis peak could happen when most NPIs will be relaxed and pre-pandemic life restarts.

A key feature of vocal ontogeny in a variety of taxa with extensive vocal repertoires is a developmental pattern in which vocal exploration is followed by a period of category formation that results in a mature species-specific repertoire. Vocal development preceding the adult repertoire is often called ‘babbling’, a term used to describe aspects of vocal development in species of vocal-learning birds, some marine mammals, some New World monkeys, some bats and humans. The paper summarizes the results of research on babbling in examples from five taxa and proposes a unifying definition facilitating their comparison. There are notable similarities across these species in the developmental pattern of vocalizations, suggesting that vocal production learning might require babbling. However, the current state of the literature is insufficient to confirm this suggestion. We suggest directions for future research to elucidate this issue, emphasizing the importance of (i) expanding the descriptive data and seeking species with complex mature repertoires where babbling may not occur or may occur only to a minimal extent; (ii) (quasi-)experimental research to tease apart possible mechanisms of acquisition and/or self-organizing development; and (iii) computational modelling as a methodology to test hypotheses about the origins and functions of babbling.This article is part of the theme issue ‘Vocal learning in animals and humans’.

Psoriasis management in the rapidly expanding geriatric population can be complex due to frailty, comorbidities, comedication and limited available data on treating older psoriasis patients.1 Previous studies reported comparable disease severity in patients ≥65 years old (≥65yo) and patients

Viral infections continue to cause considerable morbidity and mortality around the world. Recent rises in these infections are likely due to complex and multifactorial external drivers, including climate change, the increased mobility of people and goods and rapid demographic change to name but a few. In parallel with these external factors, we are gaining a better understanding of the internal factors associated with viral immunity. Increasingly the gastrointestinal (GI) microbiome has been shown to be a significant player in the host immune system, acting as a key regulator of immunity and host defense mechanisms. An increasing body of evidence indicates that disruption of the homeostasis between the GI microbiome and the host immune system can adversely impact viral immunity. This review aims to shed light on our understanding of how host-microbiota interactions shape the immune system, including early life factors, antibiotic exposure, immunosenescence, diet and inflammatory diseases. We also discuss the evidence base for how host commensal organisms and microbiome therapeutics can impact the prevention and/or treatment of viral infections, such as viral gastroenteritis, viral hepatitis, human immunodeficiency virus (HIV), human papilloma virus (HPV), viral upper respiratory tract infections (URTI), influenza and SARS CoV-2. The interplay between the gastrointestinal microbiome, invasive viruses and host physiology is complex and yet to be fully characterized, but increasingly the evidence shows that the microbiome can have an impact on viral disease outcomes. While the current evidence base is informative, further well designed human clinical trials will be needed to fully understand the array of immunological mechanisms underlying this intricate relationship.

ObjectivesTo describe the clinical characteristics, treatment response and genetic findings in a large cohort of patients with undefined systemic autoinflammatory diseases (SAIDs).MethodsClinical and genetic data from patients with undefined SAIDs were extracted from the Eurofever registry, an international web-based registry that retrospectively collects clinical information on patients with autoinflammatory diseases.ResultsThis study included 187 patients. Seven patients had a chronic disease course, 180 patients had a recurrent disease course. The median age at disease onset was 4.3 years. Patients had a median of 12 episodes per year, with a median duration of 4 days. Most commonly reported symptoms were arthralgia (n=113), myalgia (n=86), abdominal pain (n=89), fatigue (n=111), malaise (n=104) and mucocutaneous manifestations (n=128). In 24 patients, relatives were affected as well. In 15 patients, genetic variants were found in autoinflammatory genes. Patients with genetic variants more often had affected relatives compared with patients without genetic variants (p=0.005). Most patients responded well to non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, colchicine and anakinra. Complete remission was rarely achieved with NSAIDs alone. Notable patterns were found in patients with distinctive symptoms. Patients with pericarditis (n=11) were older at disease onset (33.8 years) and had fewer episodes per year (3.0/year) compared with other patients. Patients with an intellectual impairment (n=8) were younger at disease onset (2.2 years) and often had relatives affected (28.6%).ConclusionThis study describes the clinical characteristics of a large cohort of patients with undefined SAIDs. Among these, patients with pericarditis and intellectual impairment appear to comprise distinct subsets.

Thermal ablation is a form of hyperthermia in which oncologic control can be achieved by briefly inducing elevated temperatures, typically in the range 50-80°C, within a target tissue. Ablation modalities include high intensity focused ultrasound, radiofrequency ablation, microwave ablation, and laser interstitial thermal therapy which are all capable of generating confined zones of tissue destruction, resulting in fewer complications than conventional cancer therapies. Oncologic control is contingent upon achieving predefined coagulation zones; therefore, intraoperative assessment of treatment progress is highly desirable. Consequently, there is a growing interest in the development of ablation monitoring modalities. The first section of this review presents the mechanism of action and common applications of the primary ablation modalities. The following section outlines the state-of-the-art in thermal dosimetry which includes interstitial thermal probes and radiologic imaging. Both the physical mechanism of measurement and clinical or pre-clinical performance are discussed for each ablation modality. Thermal dosimetry must be coupled with a thermal damage model as outlined in Section 4. These models estimate cell death based on temperature-time history and are inherently tissue specific. In the absence of a reliable thermal model, the utility of thermal monitoring is greatly reduced. The final section of this review paper covers technologies that have been developed to directly assess tissue conditions. These approaches include visualization of non-perfused tissue with contrast-enhanced imaging, assessment of tissue mechanical properties using ultrasound and magnetic resonance elastography, and finally interrogation of tissue optical properties with interstitial probes. In summary, monitoring thermal ablation is critical for consistent clinical success and many promising technologies are under development but an optimal solution has yet to achieve widespread adoption.

ObjectivesMajor ECG abnormalities have been associated with increased risk of cardiovascular disease (CVD) burden in asymptomatic populations. However, sex differences in occurrence of major ECG abnormalities have been poorly studied, particularly across ethnic groups. The objectives were to investigate (1) sex differences in the prevalence of major and, as a secondary outcome, minor ECG abnormalities, (2) whether patterns of sex differences varied across ethnic groups, by age and (3) to what extent conventional cardiovascular risk factors contributed to observed sex differences.DesignCross-sectional analysis of population-based study.SettingMulti-ethnic, population-based Healthy Life in an Urban Setting cohort, Amsterdam, the Netherlands.Participants8089 men and 11 369 women of Dutch, South-Asian Surinamese, African Surinamese, Ghanaian, Turkish and Moroccan origin aged 18–70 years without CVD.Outcome measuresAge-adjusted and multivariable logistic regression analyses were performed to study sex differences in prevalence of major and, as secondary outcome, minor ECG abnormalities in the overall population, across ethnic groups and by age-groups (18–35, 36–50 and >50 years).ResultsMajor and minor ECG abnormalities were less prevalent in women than men (4.6% vs 6.6% and 23.8% vs 39.8%, respectively). After adjustment for conventional risk factors, sex differences in major abnormalities were smaller in ethnic minority groups (OR ranged from 0.61 in Moroccans to 1.32 in South-Asian Surinamese) than in the Dutch (OR 0.49; 95% CI 0.36 to 0.65). Only in South-Asian Surinamese, women did not have a lower odds than men (OR 1.32; 95% CI 0.96 to 1.84). The pattern of smaller sex differences in ethnic minority groups was more pronounced in older than in younger age-groups.ConclusionsThe prevalence of major ECG abnormalities was lower in women than men. However, sex differences were less apparent in ethnic minority groups. Conventional risk factors did not contribute substantially to observed sex differences.

Fundus photography has been widely used for inspecting eye disorders by ophthalmologists or computer algorithms. Biomarkers related to retinal vessels plays an essential role to detect early diabetes. To quantify vascular biomarkers or the corresponding changes, an accurate artery and vein classification is necessary. In this work, we propose a new framework to boost local vessel classification with a global vascular network model using graph convolution. We compare our proposed method with two traditional state-of-the-art methods on a testing dataset of 750 images from the Maastricht Study. After incorporating global information, our model achieves the best accuracy of 86.45% compared to 85.5% from convolutional neural networks (CNN) and 82.9% from handcrafted pixel feature classification (HPFC). Our model also obtains the best area under receiver operating characteristic curve (AUC) of 0.95, compared to 0.93 from CNN and 0.90 from HPFC. The new classification framework has the advantage of easy deployment on top of local classification features. It corrects the local classification error by minimizing global classification error and it brings free additional classification performance.

Background Early prehospital recognition of critical conditions such as ST‐segment–elevation myocardial infarction (STEMI) has prognostic relevance. Current international electrocardiographic STEMI thresholds are predominantly based on individuals of Western European descent. However, because of ethnic electrocardiographic variability both in health and disease, there is a need to reevaluate diagnostic ST‐segment elevation thresholds for different populations. We hypothesized that fulfillment of ST‐segment elevation thresholds of STEMI criteria (STE‐ECGs) in apparently healthy individuals is ethnicity dependent. Methods and Results HELIUS (Healthy Life in an Urban Setting) is a multiethnic cohort study including 10 783 apparently healthy subjects of 6 different ethnicities (African Surinamese, Dutch, Ghanaian, Moroccan, South Asian Surinamese, and Turkish). Prevalence of STE‐ECGs across ethnicities, sexes, and age groups was assessed with respect to the 2 international STEMI thresholds: sex and age specific versus sex specific. Mean prevalence of STE‐ECGs was 2.8% to 3.4% (age/sex‐specific and sex‐specific thresholds, respectively), although with large ethnicity‐dependent variability. Prevalences in Western European Dutch were 2.3% to 3.0%, but excessively higher in young (45% STE‐ECGs. Conclusions The accuracy of diagnostic tests partly relies on background prevalence in healthy individuals. In apparently healthy subjects, there is a highly variable ethnicity‐dependent prevalence of ECGs with ST‐segment elevations exceeding STEMI thresholds. This has potential consequences for STEMI evaluations in individuals who are not of Western European descent, putatively resulting in adverse outcomes with both over‐ and underdiagnosis of STEMI.

Background In the prehospital triage of patients presenting with symptoms suggestive of acute myocardial ischemia, reliable myocardial ischemia detection in the electrocardiogram (ECG) is pivotal. Due to large interindividual variability and overlap between ischemic and nonischemic ECG‐patterns, incorporation of a previous elective (reference) ECG may improve accuracy. The aim of the current study was to explore the potential value of serial ECG analysis using subtraction electrocardiography. Methods SUBTRACT is a multicenter retrospective observational study, including patients who were prehospitally evaluated for acute myocardial ischemia. For each patient, an elective previously recorded reference ECG was subtracted from the ambulance ECG. Patients were classified as myocardial ischemia cases or controls, based on the in‐hospital diagnosis. The diagnostic performance of subtraction electrocardiography was tested using logistic regression of 28 variables describing the differences between the reference and ambulance ECGs. The Uni‐G ECG Analysis Program was used for state‐of‐the‐art single‐ECG interpretation of the ambulance ECG. Results In 1,229 patients, the mean area‐under‐the‐curve of subtraction electrocardiography was 0.80 (95%CI: 0.77–0.82). The performance of our new method was comparable to single‐ECG analysis using the Uni‐G algorithm: sensitivities were 66% versus 67% (p‐value > .05), respectively; specificities were 80% versus 81% (p‐value > .05), respectively. Conclusions In our initial exploration, the diagnostic performance of subtraction electrocardiography for the detection of acute myocardial ischemia proved equal to that of state‐of‐the‐art automated single‐ECG analysis by the Uni‐G algorithm. Possibly, refinement of both algorithms, or even integration of the two, could surpass current electrocardiographic myocardial ischemia detection.

For multimodality therapies such as the combination of hyperthermia and radiation, quantification of biological effects is key for dose prescription and response prediction. Tumour spheroids have a microenvironment that more closely resembles that of tumours in vivo and may thus be a superior in vitro cancer model than monolayer cultures. Here, the response of tumour spheroids formed from two established human cancer cell lines (HCT116 and CAL27) to single and combination treatments of radiation (0–20 Gy), and hyperthermia at 47 °C (0–780 CEM43) has been evaluated. Response was analysed in terms of spheroid growth, cell viability and the distribution of live/dead cells. Time-lapse imaging was used to evaluate mechanisms of cell death and cell detachment. It was found that sensitivity to heat in spheroids was significantly less than that seen in monolayer cultures. Spheroids showed different patterns of shrinkage and regrowth when exposed to heat or radiation: heated spheroids shed dead cells within four days of heating and displayed faster growth post-exposure than samples that received radiation or no treatment. Irradiated spheroids maintained a dense structure and exhibited a longer growth delay than spheroids receiving hyperthermia or combination treatment at (thermal) doses that yielded equivalent levels of clonogenic cell survival. We suggest that, unlike radiation, which kills dividing cells, hyperthermia-induced cell death affects cells independent of their proliferation status. This induces microenvironmental changes that promote spheroid growth. In conclusion, 3D tumour spheroid growth studies reveal differences in response to heat and/or radiation that were not apparent in 2D clonogenic assays but that may significantly influence treatment efficacy.

Study Design Basic research (cross-sectional). Introduction Dupuytren disease can cause disabling contractures of the finger joints. After partial fasciectomy, postoperative hand splinting helps to maintain extension range of motion. Purpose of the Study To measure how the contraction forces of the finger on the splint change over time. Methods Subjects who were treated for Dupuytren contracture with partial fasciectomy were invited to participate in this study. Force sensors were placed in their dorsal extension splint, and the applied force was measured continually for several weeks. Results Eleven subjects (aged 59-75 years) with the metacarpophalangeal (8) or proximal interphalangeal (3) as their most severely affected finger joint participated. Each night, the measured force consistently decreased to reach a plateau after about 3 hour (adaptation time, 2.55; 95% confidence interval, 0.2-31.8 hours). The time to reach this plateau decreased with time after surgery (≈5%/day, P = .0005, R2 = 0.08). Discussion and Conclusions The observed rate of decrease in the measured force indicates a tissue adaptation time of approximately 3 hours.

IL-1 mediated auto-inflammatory diseases are characterised by episodes of unexplained fever, generalized and localized inflammation. The characteristic symptoms predominantly result from exaggerated activation of innate immune pathways. However, in some patients with typical IL-1 mediated diseases, chronic disease manifestations develop in the absence of acute inflammation, suggesting the involvement of adaptive immune pathways. We discuss clinical observations as well as novel insights in how chronic activation of innate immune pathways can lead to auto-immune disease features in patients with auto-inflammatory diseases and how we need to better understand these sequelae in order to improve treatment strategies.

The skin and its microbiota serve as physical barriers to prevent invasion of pathogens. Skin damage can be a consequence of illness, surgery, and burns. The most effective wound management strategy is to prevent infections, promote healing, and prevent excess scarring. It is well established that probiotics can aid in skin healing by stimulating the production of immune cells, and they also exhibit antagonistic effects against pathogens via competitive exclusion of pathogens. Our aim was to conduct a review of recent literature on the efficacy of using probiotics against pathogens that cause wound infections. In this integrative review, we searched through the literature published in the international following databases: PubMed, ScienceDirect, Web of Science, and Scopus using the search terms “probiotic” AND “wound infection.” During a comprehensive review and critique of the selected research, fourteenin vitrostudies, 8 animal studies, and 19 clinical studies were found. Two of thesein vitrostudies also included animal studies, yielding a total of 39 articles for inclusion in the review. The most commonly used probiotics for all studies were well-known strains of the speciesLactobacillus plantarum,Lactobacillus casei,Lactobacillus acidophilus, andLactobacillus rhamnosus.Allin vitrostudies showed successful inhibition of chosen skin or wound pathogens by the selected probiotics. Within the animal studies on mice, rats, and rabbits, probiotics showed strong opportunities for counteracting wound infections. Most clinical studies showed slight or statistically significant lower incidence of surgical site infections, foot ulcer infection, or burn infections for patients using probiotics. Several of these studies also indicated a statistically significant wound healing effect for the probiotic groups. This review indicates that exogenous and oral application of probiotics has shown reduction in wound infections, especially when used as an adjuvant to antibiotic therapy, and therefore the potential use of probiotics in this field remains worthy of further studies, perhaps focused more on typical skin inhabitants as next-generation probiotics with high potential.

Background and objectives: The automatic classification of retinal blood vessels into artery and vein (A/V) is still a challenging task in retinal image analysis. Recent works on A/V classification mainly focus on the graph analysis of the retinal vasculature, which exploits the connectivity of vessels to improve the classification performance. While they have overlooked the importance of pixel-wise classification to the final classification results. This paper shows that a complicated feature set is efficient for vessel centerline pixels classification. Methods: We extract enormous amount of features for vessel centerline pixels, and apply a genetic-search based feature selection technique to obtain the optimal feature subset for A/V classification. Results: The proposed method achieves an accuracy of 90.2%, the sensitivity of 89.6%, the specificity of 91.3% on the INSPIRE dataset. It shows that our method, using only the information of centerline pixels, gives a comparable performance as the techniques which use complicated graph analysis. In addition, the results on the images acquired by different fundus cameras show that our framework is capable for discriminating vessels independent of the imaging device characteristics, image resolution and image quality. Conclusion: The complicated feature set is essential for A/V classification, especially on the individual vessels where graph-based methods receive limitations. And it could provide a higher entry to the graph-analysis to achieve a better A/V labeling.

Objective: In this paper, we propose a robust, efficient, and automatic reconnection algorithm for bridging interrupted curvilinear skeletons in ophthalmologic images. Methods: This method employs the contour completion process, i.e., mathematical modeling of the direction process in the roto-translation group $SE(2) \equiv \mathbb {R}^2 \rtimes S^1$ to achieve line propagation/completion. The completion process can be used to reconstruct interrupted curves by considering their local consistency. An explicit scheme with finite-difference approximation is used to construct the three-dimensional (3-D) completion kernel, where we choose the Gamma distribution for time integration. To process structures in $SE(2)$ , the orientation score framework is exploited to lift the 2-D curvilinear segments into the 3-D space. The propagation and reconnection of interrupted segments are achieved by convolving the completion kernel with orientation scores via iterative group convolutions. To overcome the problem of incorrect skeletonization of 2-D structures at junctions, a 3-D segment-wise thinning technique is proposed to process each segment separately in orientation scores. Results: Validations on 4 datasets with different image modalities show that our method achieves an average success rate of $95.24\%$ in reconnecting $40\,457$ gaps of sizes from $7 \times 7$ to $39 \times 39$ , including challenging junction structures. Conclusion: The reconnection approach can be a useful and reliable technique for bridging complex curvilinear interruptions. Significance: The presented method is a critical work to obtain more complete curvilinear structures in ophthalmologic images. It provides better topological and geometric connectivities for further analysis.

It remains uncertain whether nebulization of mucolytics with bronchodilators should be applied for clinical indication or preventively in intensive care unit (ICU) patients receiving invasive ventilation. To determine if a strategy that uses nebulization for clinical indication (on-demand) is noninferior to one that uses preventive (routine) nebulization. Randomized clinical trial enrolling adult patients expected to need invasive ventilation for more than 24 hours at 7 ICUs in the Netherlands. On-demand nebulization of acetylcysteine or salbutamol (based on strict clinical indications, n = 471) or routine nebulization of acetylcysteine with salbutamol (every 6 hours until end of invasive ventilation, n = 473). The primary outcome was the number of ventilator-free days at day 28, with a noninferiority margin for a difference between groups of -0.5 days. Secondary outcomes included length of stay, mortality rates, occurrence of pulmonary complications, and adverse events. Nine hundred twenty-two patients (34% women; median age, 66 (interquartile range [IQR], 54-75 years) were enrolled and completed follow-up. At 28 days, patients in the on-demand group had a median 21 (IQR, 0-26) ventilator-free days, and patients in the routine group had a median 20 (IQR, 0-26) ventilator-free days (1-sided 95% CI, -0.00003 to ∞). There was no significant difference in length of stay or mortality, or in the proportion of patients developing pulmonary complications, between the 2 groups. Adverse events (13.8% vs 29.3%; difference, -15.5% [95% CI, -20.7% to -10.3%]; P

Despite effective combination anti-retroviral therapy (cART), perinatally HIV infected (PHIV) adolescents still experience cognitive complications. We previously reported higher cerebral blood flow (CBF) in basal ganglia and white matter (WM) in PHIV children compared to matched controls. In healthy children CBF is associated with cognitive domains. To determine longitudinal changes in CBF and its impact on cognitive complications, we measured CBF—using arterial spin labeling—in 21 PHIV adolescents and 23 controls matched for age, sex and socio-economic status twice with a mean follow-up of 4.6 years. We explored associations between CBF changes and WM micro- and macrostructural markers and cognitive domains using linear mixed models. The median age at follow-up was comparable between PHIV adolescents 17.4y (IQR:15.3–20.7) and controls 16.2y (IQR:15.6–19.1). At baseline, PHIV had higher CBF in the caudate nucleus and putamen. CBF development was comparable in gray matter (GM), WM and subcortical regions in both groups. In our cohort, we found that over time an increase of GM CBF was associated with an increase of visual motor function (p = 0.043) and executive function (p = 0.045). Increase of CBF in the caudate nucleus, putamen and thalamus was associated with an increase processing speed (p = 0.033, 0.036, 0.003 respectively) and visual motor function (p = 0.023, 0.045, 0.003 respectively). CBF development is relatively normal in PHIV adolescents on cART. CBF decline is associated with cognitive impairment, irrespective of HIV status.

Pulsed high-intensity focused ultrasound (pHIFU) uses acoustic pressure to physically disrupt tumours. The aim of this study was to investigate whether pHIFU can be used in combination with immune checkpoint inhibitors (ICIs) to enhance survival of tumour-bearing animals. Murine orthotopic pancreatic KPC tumours were exposed both to a grid of pHIFU lesions (peak negative pressure = 17 MPa, frequency = 1.5 MHz, duty cycle = 1%, 1 pulse s−1, duration = 25 s) and to anti-CTLA-4/anti-PD-1 antibodies. Acoustic cavitation was detected using a weakly focused passive sensor. Tumour dimensions were measured with B-mode ultrasound before treatment and with callipers post-mortem. Immune cell subtypes were quantified with immunohistochemistry and flow cytometry. pHIFU treatment of pancreatic tumours resulted in detectable acoustic cavitation and increased infiltration of CD8+T cells in the tumours of pHIFU and pHIFU + ICI-treated subjects compared with sham-exposed subjects. Survival of subjects treated with pHIFU + ICI was extended relative to both control untreated subjects and those treated with either pHIFU or ICI alone. Subjects treated with pHIFU + ICI had increased levels of CD8+IFNγ+T cells, increased ratios of CD8+IFNγ+to CD3+CD4+FoxP3+and CD11b+Ly6G+cells, and decreased CD11chighcells in their tumours compared with controls. These results provide evidence that pHIFU combined with ICI may have potential for use in pancreatic cancer therapy.

Thermo-radiosensitisation is a promising approach for treatment of radio-resistant tumours such as those containing hypoxic subregions. Response prediction and treatment planning should account for tumour response heterogeneity, e.g. due to microenvironmental factors, and quantification of the biological effects induced. 3D tumour spheroids provide a physiological in vitro model of tumour response and a systems oncology framework for simulating spheroid response to radiation and hyperthermia is presented. Using a cellular automaton model, 3D oxygen diffusion, delivery of radiation and/or hyperthermia were simulated for many ($${\bf{1}}{{\bf{0}}}^{{\bf{4}}}{\boldsymbol{-}}{\bf{1}}{{\bf{0}}}^{{\bf{7}}}$$ 1 0 4 − 1 0 7 ) individual cells forming a spheroid. The iterative oxygen diffusion model was compared to an analytical oxygenation model and simulations were calibrated and validated against experimental data for irradiated (0–10 Gy) and/or heated (0–240 CEM43) HCT116 spheroids. Despite comparable clonogenic survival, spheroid growth differed significantly following radiation or hyperthermia. This dynamic response was described well by the simulation ($${{\bf{R}}}^{{\bf{2}}}$$ R 2 > 0.85). Heat-induced cell death was implemented as a fast, proliferation-independent process, allowing reoxygenation and repopulation, whereas radiation was modelled as proliferation-dependent mitotic catastrophe. This framework stands out both through its experimental validation and its novel ability to predict spheroid response to multimodality treatment. It provides a good description of response where biological dose-weighting based on clonogenic survival alone was insufficient.

Aims/hypothesis Retinal microvascular diameters are biomarkers of cardio-metabolic risk. However, the association of (pre)diabetes with retinal microvascular diameters remains unclear. We aimed to investigate the association of prediabetes (impaired fasting glucose or impaired glucose tolerance) and type 2 diabetes with retinal microvascular diameters in a predominantly white population. Methods In a population-based cohort study with oversampling of type 2 diabetes (N = 2876; n = 1630 normal glucose metabolism [NGM], n = 433 prediabetes and n = 813 type 2 diabetes, 51.2% men, aged 59.8 ± 8.2 years; 98.6% white), we determined retinal microvascular diameters (measurement unit as measured by retinal health information and notification system [RHINO] software) and glucose metabolism status (using OGTT). Associations were assessed with multivariable regression analyses adjusted for age, sex, waist circumference, smoking, systolic blood pressure, lipid profile and the use of lipid-modifying and/or antihypertensive medication. Results Multivariable regression analyses showed a significant association for type 2 diabetes but not for prediabetes with arteriolar width (vs NGM; prediabetes: β = 0.62 [95%CI −1.58, 2.83]; type 2 diabetes: 2.89 [0.69, 5.08]; measurement unit); however, there was a linear trend for the arteriolar width across glucose metabolism status (p for trend = 0.013). The association with wider venules was not statistically significant (prediabetes: 2.40 [−1.03, 5.84]; type 2 diabetes: 2.87 [−0.55, 6.29], p for trend = 0.083; measurement unit). Higher HbA1c levels were associated with wider retinal arterioles (standardised β = 0.043 [95% CI 0.00002, 0.085]; p = 0.050) but the association with wider venules did not reach statistical significance (0.037 [−0.006, 0.080]; p = 0.092) after adjustment for potential confounders. Conclusions/interpretation Type 2 diabetes, higher levels of HbA1c and, possibly, prediabetes, are independently associated with wider retinal arterioles in a predominantly white population. These findings indicate that microvascular dysfunction is an early phenomenon in impaired glucose metabolism. Electronic supplementary material The online version of this article (10.1007/s00125-020-05146-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Objective: Systemic juvenile idiopathic arthritis (JIA) is a multifactorial autoinflammatory disease with a historically poor prognosis. With current treatment regimens, approximately half of patients still experience active disease after 1 year of therapy. This study was undertaken to evaluate a treat-to-target approach using recombinant interleukin-1 receptor antagonist (rIL-1Ra; anakinra) as first-line monotherapy to achieve early inactive disease and prevent damage. Methods: In this single-center, prospective study, patients with new-onset systemic JIA with an unsatisfactory response to nonsteroidal antiinflammatory drugs received rIL-1Ra monotherapy according to a treat-to-target strategy. Patients with an incomplete response to 2 mg/kg rIL-1Ra subsequently received 4 mg/kg rIL-1Ra or additional prednisolone, or switched to alternative therapy. For patients in whom inactive disease was achieved, rIL-1Ra was tapered after 3 months and subsequently stopped. Results: Forty-two patients, including 12 who had no arthritis at disease onset, were followed up for a median of 5.8 years. The median time to achieve inactive disease was 33 days. At 1 year, 76% had inactive disease, and 52% had inactive disease while not receiving medication. High neutrophil counts at baseline and a complete response after 1 month of rIL-1Ra were highly associated with inactive disease at 1 year. After 5 years of follow-up, 96% of the patients included had inactive disease, and 75% had inactive disease while not receiving medication. Articular or extraarticular damage was reported in

Objective: To assess the feasibility of targeting recurrent gynaecological tumours with MR guided high intensity focused ultrasound (MRgHIFU). Methods: 20 patients with recurrent gynaecological tumours were prospectively scanned on a Philips/Profound 3 T Achieva MR/ Sonalleve HIFU system. Gross tumour volume (GTV) and planning target volume (PTV) were delineated on T 2W and diffusion-weighted imaging (DWI). Achievable treatment volumes that (i) assumed bowel and/or urogenital tract preparation could be used to reduce risk of damage to organs-at-risk (TVoptimal), or (ii) assumed no preparations were possible (TVno-prep) were compared with PTV on virtual treatment plans. Patients were considered treatable if TVoptimal ≥ 50 % PTV. Results: 11/20 patients (55%) were treatable if preparation strategies were used: nine had central pelvic recurrences, two had tumours in metastatic locations. Treatable volume ranged from 3.4 to 90.3 ml, representing 70 ± 17 % of PTVs. Without preparation, 6/20 (30%) patients were treatable (four central recurrences, two metastatic lesions). Limiting factors were disease beyond reach of the HIFU transducer, and bone obstructing tumour access. DWI assisted tumour outlining, but differences from T 2W imaging in GTV size (16.9 ± 23.0%) and PTV location (3.8 ± 2.8 mm in phase-encode direction) limited its use for treatment planning. Conclusions: Despite variation in size and location within the pelvis, ≥ 50 % of tumour volumes were considered targetable in 55 % patients while avoiding adjacent critical structures. A prospective treatment study will assess safety and symptom relief in a second patient cohort. Advances in knowledge: Target size, location and access make MRgHIFU a viable treatment modality for treating symptomatic recurrent gynaecological tumours within the pelvis.

High-intensity focused ultrasound (HIFU) is a non-invasive method of selective placental vascular occlusion, providing a potential therapy for conditions such as twin–twin transfusion syndrome. In order to translate this technique into human studies, evidence of prolonged fetal recovery and maintenance of a healthy fetal physiology following exposure to HIFU is essential. At 116 ± 2 days gestation, 12 pregnant ewes were assigned to control ( n = 6) or HIFU vascular occlusion ( n = 6) groups and anaesthetized. Placental blood vessels were identified using colour Doppler ultrasound; HIFU-mediated vascular occlusion was performed through intact maternal skin (1.66 MHz, 5 s duration, in situ I SPTA 1.8–3.9 kW cm −2 ). Unidentifiable colour Doppler signals in targeted vessels following HIFU exposure denoted successful occlusion. Ewes and fetuses were then surgically instrumented with vascular catheters and transonic flow probes and recovered from anaesthesia. A custom-made wireless data acquisition system, which records continuous maternal and fetal cardiovascular data, and daily blood sampling were used to assess wellbeing for 20 days, followed by post-mortem examination. Based on a comparison of pre- and post-treatment colour Doppler imaging, 100% (36/36) of placental vessels were occluded following HIFU, and occlusion persisted for 20 days. All fetuses survived. No differences in maternal or fetal blood pressure, heart rate, heart rate variability, metabolic status or oxygenation were observed between treatment groups. There was evidence of normal fetal maturation and no evidence of chronic fetal stress. There were no maternal injuries and no placental vascular haemorrhage. There was both a uterine and fetal burn, which did not result in any obstetric or fetal complications. This study demonstrates normal long-term recovery of fetal sheep from exposure to HIFU-mediated placental vascular occlusion and underlines the potential of HIFU as a potential non-invasive therapy in human pregnancy.

* Abbreviations: ABP — : American Board of Pediatrics GH — : global health MOC — : maintenance of certification PIM — : performance-improvement module QI — : quality improvement Global health (GH), defined as issues that transcend national boundaries and a call for actions by key stakeholders to determine the well-being of all people,1 is an expanding field. In 2014, 25% of active pediatric-training programs had dedicated GH tracks, and 66% had faculty identified to lead GH efforts for their training programs.2 Those traveling abroad for GH experiences as trainees are likely to remain involved later in their careers in varying capacities.3,4 GH also includes pediatricians engaged locally with immigrant or refugee communities in the United States. Engagement in GH activities takes various forms, from clinical care to advocacy, research, and policy making.5 As with other niche areas of pediatrics, GH practitioners may wrestle with issues relevant to their unique areas of practice, including incorporating GH activities into professional requirements and development.6 Challenges include maintaining clinical skills relevant for the US setting or skills relevant for short-term trips internationally, balancing between staying current with US medicine and practicing in a resource-limited sphere, finding continued learning activities relevant to the practice of pediatrics internationally, and charting a career path in this field. Thus, there is a growing population of board-certified pediatricians who may want or need to incorporate a GH focus into their maintenance of certification … Address correspondence to Tonya Arscott-Mills, MD, MPH, Botswana-University of Pennsylvania Partnership, PO Box 45498, Riverwalk, Gaborone, Botswana. E-mail: tonyaarscottmillsbup{at}gmail.com