Severe postpartum hemorrhage and the risk of adverse maternal outcome: A comparative analysis of two population-based studies in France and the Netherlands.

Objectives: Among women with severe PPH (sPPH) in France and the Netherlands, we compared incidence of adverse maternal outcome (major obstetric hemorrhage (≥2.5L blood loss) and/or hysterectomy and/or mortality) by mode of delivery. Second, we compared use and timing of resuscitation and transfusion management, second-line uterotonics and uterine-sparing interventions (intra-uterine tamponade, compression sutures, vascular ligation, arterial embolization) by mode of delivery. Methods:  Secondary analysis of two population-based studies of women with sPPH in France and the Netherlands. Women were selected by a harmonized definition for sPPH: (total blood loss ≥ 1500 ml) AND (blood transfusion of ≥ 4 units packed red blood cells and/or multicomponent blood transfusion). Findings: Incidence of adverse maternal outcome after vaginal birth was 793/1002, 9.1 % in the Netherlands versus 88/214, 41.1 % in France and 259/342, 76.2% versus 160/270, 59.3% after cesarean. Hemostatic agents such as fibrinogen were administered less frequently (p < 0.001) in the Netherlands (vaginal birth: 83/1002, 8.3% versus 105/2014, 49.5% in France; cesarean: 47/342, 13.7% and 152/270, 55.6%). Second-line uterotonics were started significantly later after PPH-onset in the Netherlands than France (vaginal birth: 46 versus 25 min; cesarean: 45 versus 18 min). Uterine-sparing interventions were less frequently (p < 0.001) applied in the Netherlands after vaginal birth (394/1002,39.3 %, 134/214, 62.6%) and cesarean (133/342, 38.9 % and 155/270, 57.4%), all initiated later after onset of refractory PPH in the Netherlands. Interpretation: Incidence of adverse maternal outcome was higher among women with sPPH in the Netherlands than France regardless mode of birth. Possible explanatory mechanisms are earlier and more frequent use of second-line uterotonics and uterine-sparing interventions in France compared to the Netherlands.

Binational confidential enquiry of maternal deaths due to postpartum hemorrhage in France and the Netherlands: Lessons learned through the perspective of a different context of care.

OBJECTIVE: To learn lessons for maternity care by scrutinizing postpartum hemorrhage management (PPH) in cases of PPH-related maternal deaths in France and the Netherlands. METHODS: In this binational Confidential Enquiry into Maternal Deaths (CEMD), 14 PPH-related maternal deaths were reviewed by six experts from the French and Dutch national maternal death review committees regarding cause and preventability of death, clinical care and healthcare organization. Improvable care factors and lessons learned were identified. CEMD practices and PPH guidelines in France and the Netherlands were compared in the process. RESULTS: For France, new insights were primarily related to organization of healthcare, with lessons learned focusing on medical leadership and implementation of (surgical) checklists. For the Netherlands, insights were mainly related to clinical care, emphasizing hemostatic surgery earlier in the course of PPH and reducing the third stage of labor by prompter manual removal of the placenta. Experts recommended extending PPH guidelines with specific guidance for women refusing blood products and systematic evaluation of risk factors. The quality of CEMD was presumed to benefit from enhanced case finding, also through non-obstetric sources, and electronic reporting of maternal deaths to reduce the administrative burden. CONCLUSION: A binational CEMD revealed opportunities for improvement of care beyond lessons learned at the national level.

Safe shortening of antibiotic treatment duration for complicated Staphylococcus aureus bacteraemia (SAFE trial): protocol for a randomised, controlled, open-label, non-inferiority trial comparing 4 and 6 weeks of antibiotic treatment.

INTRODUCTION: A major knowledge gap in the treatment of complicated Staphylococcus aureus bacteraemia (SAB) is the optimal duration of antibiotic therapy. Safe shortening of antibiotic therapy has the potential to reduce adverse drug events, length of hospital stay and costs. The objective of the SAFE trial is to evaluate whether 4 weeks of antibiotic therapy is non-inferior to 6 weeks in patients with complicated SAB. METHODS AND ANALYSIS: The SAFE-trial is a multicentre, non-inferiority, open-label, parallel group, randomised controlled trial evaluating 4 versus 6 weeks of antibiotic therapy for complicated SAB. The study is performed in 15 university hospitals and general hospitals in the Netherlands. Eligible patients are adults with methicillin-susceptible SAB with evidence of deep-seated or metastatic infection and/or predictors of complicated SAB. Only patients with a satisfactory clinical response to initial antibiotic treatment are included. Patients with infected prosthetic material or an undrained abscess of 5 cm or more at day 14 of adequate antibiotic treatment are excluded. Primary outcome is success of therapy after 180 days, a combined endpoint of survival without evidence of microbiologically confirmed disease relapse. Assuming a primary endpoint occurrence of 90% in the 6 weeks group, a non-inferiority margin of 7.5% is used. Enrolment of 396 patients in total is required to demonstrate non-inferiority of shorter antibiotic therapy with a power of 80%. Currently, 152 patients are enrolled in the study. ETHICS AND DISSEMINATION: This is the first randomised controlled trial evaluating duration of antibiotic therapy for complicated SAB. Non-inferiority of 4 weeks of treatment would allow shortening of treatment duration in selected patients with complicated SAB. This study is approved by the Medical Ethics Committee VUmc (Amsterdam, the Netherlands) and registered under NL8347 (the Netherlands Trial Register). Results of the study will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NL8347 (the Netherlands Trial Register).

Offering women a choice in induction of labour: a prospective cohort study.

PURPOSE: To evaluate women's choice in the method of labour induction between oral misoprostol, PGE2 pessary and the Foley catheter. To compare women's satisfaction according to their choice and to identify factors associated with patient satisfaction. METHODS: We conducted a comparative, prospective cohort study of 520 women who chose their preferred method for labour induction, in a French tertiary hospital, from July 2019 to October 2020. Before and after the delivery, they were asked to argue their choice and to evaluate their satisfaction through the use of questionnaires. The primary outcome was global level of satisfaction. RESULTS: Of the 520 women included, 67.5% of women chose oral misoprostol compared to 21% PGE2 pessary and 11.5% Foley catheter. Regarding global satisfaction, we found no significant difference between the three groups: 78.4%, 68.8% and 71.2% (p = 0.107) for, respectively, oral misoprostol, PGE2 pessary and Foley catheter. Factors that seem to improve women's satisfaction were nulliparity (aOR = 2.03, 95% CI [1.19-3.53]), delivery within 24 h after the start of induction (aOR = 3.46, 95% CI [2.02-6.14]) and adequate information (aOR = 4.21, 95% CI [1.869.64]). Factors associated with lower satisfaction rates were postpartum haemorrhage (aOR = 0.51, 95% CI [0.30-0.88]) and caesarean section (aOR = 0.31, 95% CI [0.17-0.54]). CONCLUSION: Women satisfaction rates were not different between the three methods, when chosen by the patients themselves. These finding should encourage caregivers to promote shared decision making when possible. TRIAL REGISTRATION: The protocol was approved by the French ethics committee for research in obstetrics and gynaecology (CEROG, reference number 2019-OBS-0602) on 1st June 2019.

De novo mutations in children born after medical assisted reproduction.

STUDY QUESTION: Are there more de novo mutations (DNMs) present in the genomes of children born through medical assisted reproduction (MAR) compared to spontaneously conceived children? SUMMARY ANSWER: In this pilot study, no statistically significant difference was observed in the number of DNMs observed in the genomes of MAR children versus spontaneously conceived children. WHAT IS KNOWN ALREADY: DNMs are known to play a major role in sporadic disorders with reduced fitness such as severe developmental disorders, including intellectual disability and epilepsy. Advanced paternal age is known to place offspring at increased disease risk, amongst others by increasing the number of DNMs in their genome. There are very few studies reporting on the effect of MAR on the number of DNMs in the offspring, especially when male infertility is known to be affecting the potential fathers. With delayed parenthood an ongoing epidemiological trend in the 21st century, there are more children born from fathers of advanced age and more children born through MAR every day. STUDY DESIGN, SIZE, DURATION: This observational pilot study was conducted from January 2015 to March 2019 in the tertiary care centre at Radboud University Medical Center. We included a total of 53 children and their respective parents, forming 49 trios (mother, father and child) and two quartets (mother, father and two siblings). One group of children was born after spontaneous conception (n = 18); a second group of children born after IVF (n = 17) and a third group of children born after ICSI combined with testicular sperm extraction (ICSI-TESE) (n = 18). In this pilot study, we also subdivided each group by paternal age, resulting in a subgroup of children born to younger fathers (<35 years of age at conception) and older fathers (>45 years of age at conception). PARTICIPANTS/MATERIALS, SETTING, METHODS: Whole-genome sequencing (WGS) was performed on all parent-offspring trios to identify DNMs. For 34 of 53 trios/quartets, WGS was performed twice to independently detect and validate the presence of DNMs. Quality of WGS-based DNM calling was independently assessed by targeted Sanger sequencing. MAIN RESULTS AND THE ROLE OF CHANCE: No significant differences were observed in the number of DNMs per child for the different methods of conception, independent of parental age at conception (multi-factorial ANOVA, f(2) = 0.17, P-value = 0.85). As expected, a clear paternal age effect was observed after adjusting for method of conception and maternal age at conception (multiple regression model, t = 5.636, P-value = 8.97 × 10-7), with on average 71 DNMs in the genomes of children born to young fathers (<35 years of age) and an average of 94 DNMs in the genomes of children born to older fathers (>45 years of age). LIMITATIONS, REASONS FOR CAUTION: This is a pilot study and other small-scale studies have recently reported contrasting results. Larger unbiased studies are required to confirm or falsify these results. WIDER IMPLICATIONS OF THE FINDINGS: This pilot study did not show an effect for the method of conception on the number of DNMs per genome in offspring. Given the role that DNMs play in disease risk, this negative result is good news for IVF and ICSI-TESE born children, if replicated in a larger cohort. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Netherlands Organisation for Scientific Research (918-15-667) and by an Investigator Award in Science from the Wellcome Trust (209451). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Circulating tumour cells to drive the use of neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer.

BACKGROUND: Guidelines recommend neoadjuvant chemotherapy (NAC) for the treatment of nonmetastatic muscle-invasive bladder cancer (MIBC). NAC is, however, underutilized in practice because of its associated limited overall survival (OS) benefit and significant treatment-related toxicity. We hypothesized that the absence of circulating tumour cells (CTCs) identifies MIBC patients with such a favourable prognosis that NAC may be withheld. PATIENTS AND METHODS: The CirGuidance study was an open-label, multicentre trial that included patients with clinical stage T2-T4aN0-N1M0 MIBC, scheduled for radical cystectomy. CTC-negative patients (no CTCs detectable using the CELLSEARCH system) underwent radical surgery without NAC; CTC-positive patients (≥1 detectable CTCs) were advised to receive NAC, followed by radical surgery. The primary endpoint was the 2-year OS in the CTC-negative group with a prespecified criterion for trial success of ≥75% (95% confidence interval (CI) ±5%). RESULTS: A total of 273 patients were enrolled. Median age was 69 years; median follow-up was 36 months. The primary endpoint of 2-year OS in the CTC-negative group was 69.5% (N = 203; 95% CI 62.6%-75.5%). Two-year OS was 58.2% in the CTC-positive group (N = 70; 95% CI 45.5%-68.9%). CTC-positive patients had a higher rate of cancer-related mortality [hazard ratio (HR) 1.61, 95% CI 1.05-2.45, P = 0.03] and disease relapse (HR 1.87, 95% CI 1.28-2.73, P = 0.001) than CTC-negative patients. Explorative analyses suggested that CTC-positive patients who had received NAC (n = 22) survived longer than CTC-positive patients who had not (n = 48). CONCLUSION: The absence of CTCs in MIBC patients was associated with improved cancer-related mortality and a lower risk of disease relapse after cystectomy; however, their absence alone does not justify to withhold NAC. Exploratory analyses suggested that CTC-positive MIBC patients might derive more benefit from NAC. TRIAL REGISTRATION: Netherlands Trial Register NL3954; https://www.trialregister.nl/trial/3954.

A de novo paradigm for male infertility.

De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p-value = 1.00 × 10-5) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p-value = 5.01 × 10-4) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p-value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility.

Pulvinar and pubic cartilage measurements to refine universal ultrasound screening for developmental dysplasia of the hip: Data from 1896 infant hips.

PURPOSE: Screening modalities for Developmental Dysplasia of the Hip (DDH) and indications for treatment of mild forms remain controversial. Ultrasound (US) measurement of the pubofemoral distance (PFD > 6 mm, composed of the pubic cartilage and the pulvinar) can avoid late diagnoses of DDH. A thick pubic cartilage may nevertheless lead to false positives. The purpose of this study was to establish standard measurements of pubic cartilage and pulvinar, through universal US screening, to lower false positive results and thus any overtreatment. METHODS: This is a single-center observational prospective study conducted from December 2016 to January 2018, on infants who underwent universal US screening for DDH. The only inclusion criterion was an adjusted age between 4 and 12 weeks when US was realized. PFD measurement was made using the Couture and Tréguier method. In addition, thicknesses of pubic cartilage and pulvinar were measured on the same US section, in millimeters. RESULTS: Nine hundred and forty-eight patients, representing 1896 hips, were included. The average value of pubic cartilage thickness was 1.25 mm ±â€¯0.58 mm, with an upper threshold of 2.39 mm (+1.96σ). The average value of pulvinar thickness was 2.67 mm ±â€¯0.78 mm, with an upper threshold of 4.20 mm (+1.96σ). We found high inter-observer reproducibility in pubic cartilage measurements. CONCLUSION: Systematic measurements of pubic cartilage and pulvinar may refine therapeutic decision by identifying false positives. Patients with increased PFD due to a thick pubic cartilage >2,39 mm, without an associated pulvinar enlargement (<4,20 mm), could be therefore only monitored and not overtreated.

[An unvaccinated man with a painful arm and jaw]. / Een ongevaccineerde man met een pijnlijke arm en kaak.

BACKGROUND: Clostridium tetani is a gram-positive spore-forming bacterium that produces toxins and grows under anaerobic conditions. Infections with this bacterium can lead to local or generalised forms of tetanus. CASE DESCRIPTION: An 83-year-old man presented to the acute cardiac care unit with a painful left arm and jaw. Because the patient had a hypertonic left arm and was unable to open his mouth fully, the neurologist was consulted. The patient had been to the emergency department 9 days earlier for an infected wound after falling in the garden. He had not been actively or passively immunised against tetanus at that time. On inquiry, it appeared that the patient had also not been vaccinated as a child. We made a clinical diagnosis of tetanus. The patient was admitted and treated with tetanus immunoglobulin, metronidazole, diazepam and painkillers. He was also administered tetanus toxoid and the wound was cleaned. After 1 month and 7 months, the patient was again administered tetanus toxoid. CONCLUSION: Patients with a wound that may have come into contact with road grime, dirt or manure, should always be asked for their vaccination status, especially people from high-risk groups, such as the elderly.

Exome sequencing reveals novel causes as well as new candidate genes for human globozoospermia.

STUDY QUESTION: Can exome sequencing identify new genetic causes of globozoospermia? SUMMARY ANSWER: Exome sequencing in 15 cases of unexplained globozoospermia revealed deleterious mutations in seven new genes, of which two have been validated as causing globozoospermia when knocked out in mouse models. WHAT IS KNOWN ALREADY: Globozoospermia is a rare form of male infertility characterised by round-headed sperm and malformation of the acrosome. Although pathogenic variants in DPY19L2 and SPATA16 are known causes of globozoospermia and explain up to 70% of all cases, genetic causality remains unexplained in the remaining patients. STUDY DESIGN, SIZE, DURATION: After pre-screening 16 men for mutations in known globozoospermia genes DPY19L2 and SPATA16, exome sequencing was performed in 15 males with globozoospermia or acrosomal hypoplasia of unknown aetiology. PARTICIPANTS/MATERIALS, SETTING, METHOD: Targeted next-generation sequencing and Sanger sequencing was performed for all 16 patients to screen for single-nucleotide variants and copy number variations in DPY19L2 and SPATA16. After exclusion of one patient with DPY19L2 mutations, we performed exome sequencing for the 15 remaining subjects. We prioritised recessive and X-linked protein-altering variants with an allele frequency of <0.5% in the population database GnomAD in genes with an enhanced expression in the testis. All identified candidate variants were confirmed in patients and, where possible, in family members using Sanger sequencing. Ultrastructural examination of semen from one of the patients allowed for a precise phenotypic characterisation of abnormal spermatozoa. MAIN RESULTS AND ROLE OF CHANCE: After prioritisation and validation, we identified possibly causative variants in eight of 15 patients investigated by exome sequencing. The analysis revealed homozygous nonsense mutations in ZPBP and CCDC62 in two unrelated patients, as well as rare missense mutations in C2CD6 (also known as ALS2CR11), CCIN, C7orf61 and DHNA17 and a frameshift mutation in GGN in six other patients. All variants identified through exome sequencing, except for the variants in DNAH17, were located in a region of homozygosity. Familial segregation of the nonsense variant in ZPBP revealed two fertile brothers and the patient's mother to be heterozygous carriers. Paternal DNA was unavailable. Immunohistochemistry confirmed that ZPBP localises to the acrosome in human spermatozoa. Ultrastructural analysis of spermatozoa in the patient with the C7orf61 mutation revealed a mixture of round heads with no acrosomes (globozoospermia) and ovoid or irregular heads with small acrosomes frequently detached from the sperm head (acrosomal hypoplasia). LIMITATIONS, REASONS FOR CAUTION: Stringent filtering criteria were used in the exome data analysis which could result in possible pathogenic variants remaining undetected. Additionally, functional follow-up is needed for several candidate genes to confirm the impact of these mutations on normal spermatogenesis. WIDER IMPLICATIONS OF THE FINDINGS: Our study revealed an important role for mutations in ZPBP and CCDC62 in human globozoospermia as well as five new candidate genes. These findings provide a more comprehensive understanding of the genetics of male infertility and bring us closer to a complete molecular diagnosis for globozoospermia patients which would help to predict the success of reproductive treatments. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by The Netherlands Organisation for Scientific Research (918-15-667); National Health and Medical Research Council of Australia (APP1120356) and the National Council for Scientific Research (CONICET), Argentina, PIP grant 11220120100279CO. The authors have nothing to disclose.

Antibiotic treatment for 6 days versus 12 days in patients with severe cellulitis: a multicentre randomized, double-blind, placebo-controlled, non-inferiority trial.

OBJECTIVES: To investigate whether antibiotic treatment of 6 days' duration is non-inferior to treatment for 12 days in patients hospitalized for cellulitis. METHODS: This multicentre, randomized, double-blind, placebo-controlled, non-inferiority trial enrolled adult patients hospitalized for severe cellulitis who were treated with intravenous flucloxacillin. At day 6 participants with symptom improvement who were afebrile were randomized between an additional 6 days of oral flucloxacillin or placebo in a 1:1 ratio, stratified for diabetes and hospital. The primary outcome was cure by day 14, without relapse by day 28. Secondary outcomes included a modified cure assessment and relapse rate by day 90. RESULTS: Between August 2014 and June 2017, 151 of 248 included participants were randomized. The intention-to-treat population consisted of 76 and 73 participants allocated to 12 and 6 days of antibiotic therapy, respectively (mean age 62 years, 67% males, 24% diabetics); 38/76 (50.0%) and 36/73 (49.3%) were cured in the 12- and 6-day groups respectively (ARR 0.7 percentage points, 95%CI: -15.0 to 16.3). Cure rates were 56/76 (73.7%) and 49/73 (67.1%) with the modified cure assessment (ARR 6.6, 95%CI: -8.0 to 20.8). After initial cure without relapse, day 90 relapse rates were higher in the 6-day group (6% versus 24%, p < 0.05). CONCLUSIONS: Given the wide confidence intervals, we can neither confirm nor refute our hypothesis that 6 days of therapy is non-inferior to 12 days of therapy. However, a 6-day course resulted in significantly more frequent relapses by day 90. These findings require confirmation in future studies.

The burden of depression and anxiety among medical students in South Africa: A cross-sectional survey at the University of Cape Town.

BACKGROUND: Depressive and anxiety disorders occur at very high rates among medical students. For instance, an international review and meta-analysis estimated the overall pooled crude prevalence of depression or depressive symptoms at 27.2%. However, South African (SA) data are very limited. OBJECTIVES: To determine rates of depression and anxiety among medical students and to examine the associations with various sociodemographic variables (biological sex, gender identity, household income, ethnicity, and clinical v. pre-clinical students). We also examined whether the 'mini-semester' of 2017 resulting from the 2016 'Fees Must Fall' student protests was associated with increased depression/anxiety. METHODS: The study was a cross-sectional electronic survey conducted in the Faculty of Health Sciences, University of Cape Town, using an anonymous, self-administered online questionnaire. The questionnaire included basic sociodemographic questions, the Patient Health Questionnaire-9 and the Hospital Anxiety and Depression Scale. RESULTS: The sample consisted of 473 medical students, 333 (70.4%) female and 140 (29.6%) male. Based on ethnic self-identification, 165 (35.6%) were black, 144 (31.1%) white, 88 (19%) coloured, 52 (11.2%) Indian and 8 (1.7%) Asian. There were 239 pre-clinical students (50.5%) and 234 clinical students (49.5%). Of the sample, 36.4% were above the cut-off for major depressive disorder and 45.9% for anxiety disorder. Reported rates of disorders diagnosed by a health professional were 25.0% for depressive disorder and 20.5% for anxiety disorder, and 28.1% of all students were receiving psychotropic medication. Female sex was associated with both depression (prevalence ratio (PR) 3.7; p<0.001) and anxiety diagnoses (PR 4.7; p<0.001). None of the other sociodemographic characteristics showed significant associations. Interestingly, students who undertook the 2017 mini-semester showed an increased rate of depression (PR 2.1; p<0.05) and anxiety diagnoses (PR 2.1; p<0.05). CONCLUSIONS: Nearly one in four students reported depression/anxiety diagnoses and were on psychotropic medication, significantly more than age-based expectations. Even more screened positive for risk of depression/anxiety. Our findings indicate that medical students, particularly females, are at a significantly increased risk of depression and anxiety disorders. Results suggest that the 2016 student protests may have had a direct impact on the mental state of students. Multidisciplinary efforts should be targeted at initiatives to strengthen mental wellbeing and institutional culture around mental health. These efforts may help build resilience in the next generation of health professionals in SA ahead of work in an overburdened health and health education system.

Correction to: Implementing a hospital-wide protocol for Staphylococcus aureus bacteremia.

The article "Implementing a hospital-wide protocol for Staphylococcus aureus bacteremia", written by K. Bolhuis, L. J. Bakker, J. T. Keijer, and P. J. de Vries was originally published electronically on 31 May 2018 with incorrect copyright line in the publisher's internet portal.

Recurrence quantification analysis of resting state EEG signals in autism spectrum disorder - a systematic methodological exploration of technical and demographic confounders in the search for biomarkers.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a worldwide prevalence of 1-2%. In low-resource environments, in particular, early identification and diagnosis is a significant challenge. Therefore, there is a great demand for 'language-free, culturally fair' low-cost screening tools for ASD that do not require highly trained professionals. Electroencephalography (EEG) has seen growing interest as an investigational tool for biomarker development in ASD and neurodevelopmental disorders. One of the key challenges is the identification of appropriate multivariate, next-generation analytical methodologies that can characterise the complex, nonlinear dynamics of neural networks in the brain, mindful of technical and demographic confounders that may influence biomarker findings. The aim of this study was to evaluate the robustness of recurrence quantification analysis (RQA) as a potential biomarker for ASD using a systematic methodological exploration of a range of potential technical and demographic confounders. METHODS: RQA feature extraction was performed on continuous 5-second segments of resting state EEG (rsEEG) data and linear and nonlinear classifiers were tested. Data analysis progressed from a full sample of 16 ASD and 46 typically developing (TD) individuals (age 0-18 years, 4802 EEG segments), to a subsample of 16 ASD and 19 TD children (age 0-6 years, 1874 segments), to an age-matched sample of 7 ASD and 7 TD children (age 2-6 years, 666 segments) to prevent sample bias and to avoid misinterpretation of the classification results attributable to technical and demographic confounders. A clinical scenario of diagnosing an unseen subject was simulated using a leave-one-subject-out classification approach. RESULTS: In the age-matched sample, leave-one-subject-out classification with a nonlinear support vector machine classifier showed 92.9% accuracy, 100% sensitivity and 85.7% specificity in differentiating ASD from TD. Age, sex, intellectual ability and the number of training and test segments per group were identified as possible demographic and technical confounders. Consistent repeatability, i.e. the correct identification of all segments per subject, was found to be a challenge. CONCLUSIONS: RQA of rsEEG was an accurate classifier of ASD in an age-matched sample, suggesting the potential of this approach for global screening in ASD. However, this study also showed experimentally how a range of technical challenges and demographic confounders can skew results, and highlights the importance of probing for these in future studies. We recommend validation of this methodology in a large and well-matched sample of infants and children, preferably in a low- and middle-income setting.

Renal artery embolization in a child with delayed hemodynamic instability from penetrating knife wound.

Penetrating laceration injury in the pediatric population may present as an acute or delayed life-threatening injury. Although emergent intra-arterial embolization is commonly utilized in adults, few cases have been reported for children. Surgical treatment for severe renal laceration injuries may require complete nephrectomy; an unfortunate outcome for a pediatric patient if a renal-preserving alternative is feasible. We present a case of penetrating renal laceration in a 10-year-old boy treated with intra-arterial embolization of the lacerated dominant renal artery and subsequent renal perfusion by an uninjured accessory renal artery allowing for renal preservation.

Implementing a hospital-wide protocol for Staphylococcus aureus bacteremia.

Staphylococcus aureus bacteraemia (SAB) is associated with high-mortality and complication rates. A multidisciplinary approach is needed to predict, detect and treat complications. In this pre- and post-intervention study, we investigated the effects of a hospital-wide protocol for diagnosis, classification and treatment of SAB. It was hypothesized that complications and endocarditis would be better identified and treated. Medical records of SAB patients admitted in 2011 and 2012 (pre) were analysed. In 2013, a protocol, describing risk factors, diagnostic classification and recommended treatment, was implemented. In 2014 and 2015 (post), SAB patients were followed prospectively. Transthoracic (TTE) or transoesophageal cardiac ultrasound (TEE) was chosen following a decision tree. A resident internal medicine acted as contact person. Pre-intervention, 98 patients were eligible for analysis compared to 85 patients post-intervention. Age and number of risk factors were slightly higher post-intervention; other baseline characteristics were similar. Most SAB-patients were classified as complicated (89 and 82% pre- and post-intervention, respectively). Follow-up blood cultures drawn within 2 days after initiating treatment increased from 51 to 85%. Cardiac ultrasounds increased from 44 to 83% for TTE and 13 to 24% for TEE. Endocarditis was more frequently diagnosed (4 vs. 12%). Additionally, duration of antibiotic therapy increased. The 3-month mortality did not change significantly (33% pre-intervention vs. 35% post-intervention; p > 0.05). Introduction of a hospital-wide protocol for SAB management increased standard of care, created awareness among clinicians to properly classify SAB, search for endocarditis and adapt duration of antibiotic treatment. Mortality did not decrease.

Reduce bladder cancer recurrence in patients treated for upper urinary tract urothelial carcinoma: The REBACARE-trial.

BACKGROUND: Following radical nephro-ureterectomy for urothelial carcinoma of the upper urinary tract (UUT), the reported bladder recurrence rate of urothelial carcinoma is 22-47%. A single intravesical instillation of chemotherapy within 10 days following nephro-ureterectomy has the potential to decrease the risk of a bladder recurrence significantly. Despite recommendation by the European Association of Urology guideline to administer a single instillation postoperatively, the compliance rate is low because the risk of extravasation of chemotherapy. AIM: To reduce the risk of bladder cancer recurrence by a single intravesical instillation of Mitomycin immediately (within 3 h) before radical nephro-ureterectomy or partial ureterectomy. METHODS: Adult patients (age ≥ 18 years) with a (suspicion of a) urothelial carcinoma of the UUT undergoing radical nephro-ureterectomy or partial ureterectomy will be eligible and will receive a single intravesical instillation of Mitomycin within 3 h before surgery. In total, 170 patients will be included in this prospective, observational study. Follow-up will be according to current guidelines. RESULTS: The primary endpoint is the bladder cancer recurrence rate up to two years after surgery. Secondary endpoints are: a) the compliance rate; b) oncological outcome; c) possible side-effects; d) the quality of life; e) the calculation of costs of a single neoadjuvant instillation with Mitomycin and f) molecular characterization of UUT tumors and intravesical recurrences. CONCLUSIONS: A single intravesical instillation of Mitomycin before radical nephro-ureterectomy or partial ureterectomy may reduce the risk of a bladder recurrence in patients treated for UUT urothelial carcinoma and will circumvent the disadvantages of current therapy.

Effect of everolimus on skin lesions in patients treated for subependymal giant cell astrocytoma and renal angiomyolipoma: final 4-year results from the randomized EXIST-1 and EXIST-2 studies.

BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disorder associated with tumour growth in various organs, including the brain, kidneys, heart and skin. Cutaneous lesions are prevalent manifestations of TSC, occurring in up to 90% of patients. Oral mammalian target of rapamycin inhibitors, such as everolimus, is believed to be effective for treatment of TSC-associated lesions because they act on the underlying disease pathophysiology. OBJECTIVE: We evaluated the long-term effect of oral everolimus on TSC-associated skin lesions as a secondary objective in the phase III studies EXIST-1 (NCT00789828) and EXIST-2 (NCT00790400) after approximately 4 years of treatment. MATERIALS AND METHODS: Everolimus was dosed 4.5 mg/m2 /day (titrated to trough 5-15 ng/mL) in patients with TSC-associated subependymal giant cell astrocytoma in EXIST-1, and 10 mg/day initially in adult patients with TSC- or sporadic lymphangioleiomyomatosis-associated renal angiomyolipoma in EXIST-2. Following positive results from the core phase, remaining patients were offered open-label everolimus in an extension. Skin lesion response rate was the proportion of patients achieving complete or partial clinical response. RESULTS: A total of 105 patients in EXIST-1 and 107 in EXIST-2 received everolimus and had ≥1 skin lesion at baseline. Skin lesion response rate (95% confidence interval) was 58.1% (48.1-67.7%) in EXIST-1 and 68.2% (58.5-76.9%) in EXIST-2; most were partial responses. At week 192 (EXIST-1: n = 55; EXIST-2: n = 56), 69% and 66% had a response. Most common drug-related adverse event was stomatitis (41-45%). CONCLUSION: Oral everolimus improved TSC-related skin lesions, with responses sustained over 4 years of treatment in EXIST-1 and EXIST-2.

An unusual causative pathogen of sepsis after a cat bite: Anaerobiospirillum succiniciproducens.

A 40-year-old woman with a history of liver cirrhosis presented with septic shock caused by an Anaerobiospirillum succiniciproducens bacteraemia after a cat bite. A. succiniciproducens sepsis can develop after a cat or dog bite, especially in immunocompromised hosts, or might occur after translocation from the gut flora. It is a potentially lethal infection.