The Japanese Esophageal Society classification for prediction of superficial esophageal squamous cell neoplasia invasion depth: Validation in a Western population.

BACKGROUND: The Japan Esophageal Society proposed the JES microvessel classification to assess eligibility of early esophageal squamous cell neoplasia (ESCN) for endoscopic resection based on intrapapillary capillary loop assessment. We aimed to assess its diagnostic reproducibility and accuracy in Western ESCN patients. METHODS: Intrapapillary capillary loops on endoscopic images of Western ESCN lesions (n = 113) collected between 2010 and 2022 were assessed by nine endoscopists, including three Japanese expert endoscopists, three Western expert endoscopists, and three residents-in-training, and graded according to the JES microvessel classification where microvessel type A corresponds with normality or low-grade intraepithelial neoplasia, and microvessel types B1, B2, and B3 correspond with high-grade intraepithelial neoplasia or invasion into the lamina propria, muscularis mucosae or superficial submucosa, and deep submucosa, respectively. Outcomes included overall accuracy in predicting ESCN invasion depth and interobserver agreement. RESULTS: Good interobserver agreement was observed among expert endoscopists (Krippendorf's alpha 0.64, 95% CI 0.57-0.70), while agreement was moderate among residents-in-training (Krippendorf's alpha 0.58, 95% CI 0.52-0.72). Overall accuracy of the JES microvessel classification was 53% (95% CI 42-63), 52% (95% CI 41-62), and 44% (95% CI 34-55) for Japanese endoscopists, Western endoscopists, and residents-in-training, respectively. Sensitivity and specificity for vessel type A, B1, B2, and B3 across assessors were 0%-50% and 89%-100%, 55%-64% and 66%-77%, 42%-71% and 60%-76%, and 10%-24% and 92%-97%, respectively. Negative predictive value ranged between 80% and 85% for B3 vessels. CONCLUSION: Overall accuracy of the JES microvessel classification in Western ESCN patients is low, though absence of B3 vessels as assessed by experienced endoscopists may predict superficial ESCN amenable to endoscopic resection. TRIAL REGISTRY: www.trialregister.nl; NL8897 (6-9-2020).

Radiation protection in CT-guided interventions: does real-time dose visualisation lead to a reduction in radiation dose to participating radiologists? A single-centre evaluation.

AIM: To evaluate if real-time dose visualisation during computed tomography (CT)-guided interventions leads to a reduction in radiation dose to participating radiologists. MATERIALS AND METHODS: The individual radiation dose radiologists are exposed to during CT interventions was measured using dedicated dosimeters (RaySafe i2-system, Unfors RaySafe GmbH, Billdal, Sweden) worn over the usual radiation protective apron. Initially, only the total radiation dose was measured, without visualisation (control group). In the following study period, the radiation dose was shown to participants on a live screen in real-time (experimental group). In both groups, the dose was recorded in 1-second intervals. The results collected were evaluated by comparison using descriptive statistics and mixed-effect models. In particular, the variables experience, gender, role, and position during the intervention were analysed. RESULTS: In total, 517 measurements of 304 interventions (n=249 with and n=268 without live screen) performed by 29 radiologists acting as interventionalists or assistants were analysed. All CT-guided interventions were performed percutaneously, the majority of which (n=280) were microwave ablations (MWA). Radiation doses in the group without visualisation were comparable with usual dose rates for the corresponding intervention type. The mean total radiation dose was reduced by 58.1% (11.6 versus 4.86 µSv) in the experimental group (p=0.034). The highest reduction of 78.5% (15.55 versus 3.35 µSv) was observed in radiologists with the role of assistant (p=0.002). Sub-analysis showed significant dose reduction (p<0.0001) for the use of live screen in general; considering all variables, the role "assistant" alone had a statistically significant influence (p=0.002). CONCLUSION: The real-time visualisation of active radiation dose during CT interventions leads to a relevant reduction in radiation dose to participating radiologists.

Hospital-based antimicrobial stewardship in Denmark, Greenland and the Faroe Islands - current landscape and barriers.

OBJECTIVES: To describe the current organization and implementation of formalized, multi-disciplinary hospital-based antimicrobial stewardship (AMS) structures in Denmark, the Faroe Islands and Greenland. METHODS: A structured electronic questionnaire was sent to all trainees and specialists in clinical microbiology (N=207) and infectious diseases (N=260), as well as clinical pharmacists (N=20) and paediatricians (N=10) with expertise in infectious diseases. The survey had 30 multiple-choice, rating-scale, and open-ended questions based on an international consensus checklist for hospital AMS, adapted to a Danish context. RESULTS: Overall, 145 individual responses representing 20 hospitals were received. Nine hospitals (45%) reported a formal AMS strategy, eight (40%) a formal organizational multi-disciplinary structure and a multi-disciplinary AMS team, and six (30%) a designated professional as a leader of the AMS team. A majority of hospitals reported access to updated guidelines (80%) and regularly monitored and reported the quantity of antibiotics prescribed (70% and 65%, respectively). Only one hospital (5%) reported a dedicated, sustainable and sufficient AMS budget, three hospitals (15%) audited courses of therapy for specific agents/clinical conditions and four hospitals (20%) had a document clearly defining roles, procedures of collaboration and responsibilities for AMS. A total of 42% of all individual respondents had received formal AMS training. Main barriers were a lack of financial resources (52%), a lack of mandate from the hospital management (30%) and AMS not being a priority (18%). CONCLUSIONS: Core elements important for multi-disciplinary hospital-based AMS can be strengthened in Danish hospitals. Funding, clear mandates, prioritization from the hospital management and the implementation of multi-disciplinary AMS structures may help close the identified gaps.

Ethnic endotypes in paediatric atopic dermatitis depend on immunotype, lipid composition and microbiota of the skin.

BACKGROUND: Atopic dermatitis (AD) endotypes differ with ethnicity. We examined the skin microbiota, cytokine and lipid profiles in Greenlandic Inuit and Danish children with AD. METHODS: Twenty-five Inuit children with AD and 25 Inuit control children were clinically examined and compared to previously collected data from 25 Danish children with AD. Skin tape strips and skin swabs were collected from lesional and non-lesional skin. Levels of cutaneous immune biomarkers, free sphingoid bases and their (glycosyl)ceramides were analysed. Skin swabs were analysed with 16S rRNA and tuf gene for characterization of bacterial species communities. RESULTS: Bacterial ß-diversity was significantly different between Inuit and Danish AD skin, in both lesional (p < 0.001) and non-lesional (p < 0.001) AD skin, and there was a higher relative abundance of Staphylococcus aureus in Danish compared to Inuit lesional (53% vs. 8%, p < 0.01) and non-lesional skin (55% vs. 5%, p < 0.001). Danish AD children had a higher α-diversity than Inuit children in non-lesional (p < 0.05) but not in lesional skin. Significantly higher levels of type 2 immunity cytokine interleukin (IL)-4 (p < 0.05) and IL-5 (p < 0.01) were identified in Inuit compared to Danish AD children. In contrast, IL-33 (p < 0.01) was higher in Danish lesional and non-lesional AD skin. Higher levels of long-chain glucosylceramide (GlcCER)[S](d26:1) were found in lesional (p < 0.001) and non-lesional (p < 0.001) Inuit skin compared with Danish AD skin. NMF levels were similar in Inuit and Danish AD skin. CONCLUSION: Skin microbiota, cytokine and lipid composition differed significantly between Inuit and Danish children with AD and showed a stronger type 2 immune signature in Inuit children.

Five-Year Follow-Up of a Slowly Resorbable Biosynthetic P4HB Mesh (Phasix) in VHWG Grade 3 Incisional Hernia Repair.

Objective: To assess the 5-year recurrence rate of incisional hernia repair in Ventral Hernia Working Group (VHWG) 3 hernia with a slowly resorbable mesh. Summary Background Data: Incisional hernia recurs frequently after initial repair. In potentially contaminated hernia, recurrences rise to 40%. Recently, the biosynthetic Phasix mesh has been developed that is resorbed in 12-18 months. Resorbable meshes might be a solution for incisional hernia repair to decrease short- and long-term (mesh) complications. However, long-term outcomes after resorption are scarce. Methods: Patients with VHWG grade 3 incisional midline hernia, who participated in the Phasix trial (Clinilcaltrials.gov: NCT02720042) were included by means of physical examination and computed tomography (CT). Primary outcome was hernia recurrence; secondary outcomes comprised of long-term mesh complications, reoperations, and abdominal wall pain [visual analogue score (VAS): 0-10]. Results: In total, 61/84 (72.6%) patients were seen. Median follow-up time was 60.0 [interquartile range (IQR): 55-64] months. CT scan was made in 39 patients (68.4%). A recurrence rate of 15.9% (95% confidence interval: 6.9-24.8) was calculated after 5 years. Four new recurrences (6.6%) were found between 2 and 5 years. Two were asymptomatic. In total, 13/84 recurrences were found. No long-term mesh complications and/or interventions occurred. VAS scores were 0 (IQR: 0-2). Conclusions: Hernia repair with Phasix mesh in high-risk patients (VHWG 3, body mass index >28) demonstrated a recurrence rate of 15.9%, low pain scores, no mesh-related complications or reoperations for chronic pain between the 2- and 5-year follow-up. Four new recurrences occurred, 2 were asymptomatic. The poly-4-hydroxybutyrate mesh is a safe mesh for hernia repair in VHWG 3 patients, which avoids long-term mesh complications like pain and mesh infection.

Gene-nutrient interactions that impact magnesium homeostasis increase risk for neural tube defects in mice exposed to dolutegravir.

In 2018, data from a surveillance study in Botswana evaluating adverse birth outcomes raised concerns that women on antiretroviral therapy (ART) containing dolutegravir (DTG) may be at increased risk for neural tube defects (NTDs). The mechanism of action for DTG involves chelation of Mg2+ ions in the active site of the viral integrase. Plasma Mg2+ homeostasis is maintained primarily through dietary intake and reabsorption in the kidneys. Inadequate dietary Mg2+ intake over several months results in slow depletion of plasma Mg2+ and chronic latent hypomagnesemia, a condition prevalent in women of reproductive age worldwide. Mg2+ is critical for normal embryonic development and neural tube closure. We hypothesized that DTG therapy might slowly deplete plasma Mg2+ and reduce the amount available to the embryo, and that mice with pre-existing hypomagnesemia due to genetic variation and/or dietary Mg2+ insufficiency at the time of conception and initiation of DTG treatment would be at increased risk for NTDs. We used two different approaches to test our hypothesis: 1) we selected mouse strains that had inherently different basal plasma Mg2+ levels and 2) placed mice on diets with different concentrations of Mg2+. Plasma and urine Mg2+ were determined prior to timed mating. Pregnant mice were treated daily with vehicle or DTG beginning on the day of conception and embryos examined for NTDs on gestational day 9.5. Plasma DTG was measured for pharmacokinetic analysis. Our results demonstrate that hypomagnesemia prior to conception, due to genetic variation and/or insufficient dietary Mg2+ intake, increases the risk for NTDs in mice exposed to DTG. We also analyzed whole-exome sequencing data from inbred mouse strains and identified 9 predicted deleterious missense variants in Fam111a that were unique to the LM/Bc strain. Human FAM111A variants are associated with hypomagnesemia and renal Mg2+ wasting. The LM/Bc strain exhibits this same phenotype and was the strain most susceptible to DTG-NTDs. Our results suggest that monitoring plasma Mg2+ levels in patients on ART regimens that include DTG, identifying other risk factors that impact Mg2+ homeostasis, and correcting deficiencies in this micronutrient might provide an effective strategy for mitigating NTD risk.

Development of placental lesions after recovery from COVID-19 during pregnancy: case-control study.

OBJECTIVE: To study whether the occurrence and type of placental lesions vary according to the time of onset of COVID-19 in pregnant women. DESIGN: Case-control study. SETTING: Departments of Gynaecology-Obstetrics and Pathology, Strasbourg University Hospital, France. POPULATION: Cases were 49 placentas of women with COVID-19. Controls were 50 placentas from women who had a past history of molar pregnancy. COVID-19 placentas were categorised based on whether birth occurred at more or less than 14 days post-infection. METHODS: Comparison between case and controls. MAIN OUTCOME MEASURES: Maternal and neonatal outcomes were recorded. Macroscopic and microscopic examination of the placentas was performed. RESULTS: The rate of vascular complications was higher in the COVID groups than in the controls (8 [16.3%] versus 1 [2%], p = 0.02). Signs of fetal (22[44.9%] versus 13 [26%], p = 0.05) and maternal (44 [89.8%] versus 36 [72.0%], p = 0.02) vascular malperfusion and signs of inflammation (11 [22.4%] versus 3 [6.0%], p = 0.019) were significantly more common in the COVID-19 groups than in the control group. Fetal malperfusion lesions (9 [39.1%] versus 13 [50.0%], p = 0.45) and placental inflammation (4 [17.4%] versus 7 [26.9%], p = 0.42) rates were not significantly different between the two COVID-19 groups. Chronic villitis was significantly more common when the delivery occurred >14 days after infection than in the group that delivered <14 days after infection (7 [26.9%] versus 1 [4.4%], p = 0.05). CONCLUSIONS: Our study suggests that SARS-COV-2 induces placental lesions that evolve after disease recovery, especially with the development of inflammatory lesions, such as chronic villitis.

[Inguinal hernia operations-Always outpatient?] / Leistenhernienoperationen ­ immer ambulant?

Inguinal hernia operations represent the most frequent operations overall with 300,000 interventions annually in Germany, Austria and Switzerland (DACH region). Despite the announced political willingness and the increasing pressure from the legislator to avoid costly inpatient treatment by carrying out as many outpatient operations as possible, outpatient treatment has so far played a subordinate role in the DACH region. The Boards of the specialist societies the German Hernia Society (DHG), the Surgical Working Group Hernia (CAH of the DHG), the Austrian Hernia Society (ÖHG) and the Swiss Working Group Hernia Surgery (SAHC) make inroads into this problem, describe the initial position and assess the current situation.

Arthroscopic versus Open Distal Hemitrapeziectomy without Interposition: 2-Year Results of a Randomized Controlled Trial.

BACKGROUND: Distal hemitrapeziectomy is suggested as an alternative for total trapeziectomy for carpometacarpal thumb joint osteoarthritis, when the scaphotrapeziotrapezoidal joint is unaffected. This can be performed as an arthroscopic or open procedure, with suggested advantages for the less invasive arthroscopic technique. To determine which technique has better outcome on subjective and objective measures, the authors performed a prospective, randomized, controlled trial. METHODS: The authors randomized 90 thumbs in the open ( n = 45) and arthroscopic ( n = 45) groups and evaluated results preoperatively and at 3-, 12- and 24-month follow-up. The primary outcome was the Patient-Rated Wrist and Hand Evaluation (PRWHE) to assess pain and function. Also, the authors evaluated pinch, grip, and range of motion, together with return to work, satisfaction, and complications. RESULTS: Full follow-up was obtained in 62 thumbs (open group, n = 32; arthroscopic group, n = 30). For both groups, the PRWHE improved from preoperatively to 12- and 24-month follow-up. Also, grip power, key pinch, and tip pinch improved at final follow-up for both groups. Between groups, there were no clinically important differences between PRWHE, power of grip or pinch, and range of motion. Operation time was shorter for the open group; also, return to work was slightly shorter after open surgery. Satisfaction was comparable between groups. CONCLUSIONS: This study shows good functional improvement and pain reduction obtained with a hemitrapeziectomy. No arthroscopic benefits could be substantiated in the results. Because of shorter operation time for the open procedure, and because of equal outcomes compared to the arthroscopic technique, we prefer open hemitrapeziectomy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I.

[Single dose of misoprostol for abortion until 9 weeks of gestation]. / Efficacité d'une dose unique de misoprostol pour les interruptions volontaires de grossesse jusqu'à 9 semaines d'aménorrhée.

OBJECTIVES: The primary objective was to compare the efficacy of a single-dose misoprostol for abortion before 7 weeks of gestation and between 7 and 9 weeks of gestation. The secondary objectives were to compare the amount of misoprostol required for complete expulsion, the need for endo-uterine aspiration, and to assess pain and patient experience in these two groups. METHODS: This was a single-centre prospective observational study conducted at the University Hospitals of Strasbourg from 1st October 2019 to 31st December 2020. RESULTS: A total of 306 patients were included, 150 in the group before 7 weeks of gestation and 156 in the group between 7 and 9 weeks of gestation. There was no significant difference in the success rate of the single dose of misoprostol between the two groups with 34.7 and 37.8% respectively (P=0.63). After taking painkillers, there is no difference in terms of pain relief (EN ≤ 4 for 92 et 95% of patients P=0.37). CONCLUSION: The single dose of misoprostol for in-hospital abortion is as effective between 7 and 9 weeks of gestation as it is before 7. By extension, therefore, we would suggest that there should be no difference in efficacy between home abortions before 7 weeks of gestation and between 7 and 9 weeks of gestation and therefore suggest that home abortions can be performed up to 9 weeks of gestation without fear of a decrease in the rate of complete expulsion and the efficacy of analgesia, with potentially less use of misoprostol compared with the hospital setting.

Into the Blue: First in Man Data on Diving Physiology in Fontan Patients.

Swimming and diving are popular recreational activities. As congenital heart disease, especially patients with univentricular hearts after Fontan palliation are thought to have reduced physiologic capacities for compensation of submersion-associated physiologic demands, current guidelines put restraints on this group of patients. Although these restrictions on doctoral advice place a significant burden on affected patients, it is especially interesting that these guideline recommendations are merely based on physiologic assumptions, i.e., expert consensus. A recent study by Paech et al. presented the first in vivo data on the effects of immersion in Fontan patients, stating no major adverse events in their study group as well as comparable physiologic adaption as reported in the literature for healthy people. Yet, submersion was not reflected in this study, and the current study therefore aimed to conduct a first study for the evaluation of the effects of submersion and apnea diving in Fontan patients. A control group of healthy adults as well as patients recruited from the Heart Center Leipzig, Department of pediatric cardiology underwent a standardized diving protocol including a static as well as dynamic apnea phase. Physiologic data were recorded. This study presents the first structured data on diving physiology in Fontan patients compared to healthy probands. There were no adverse events. The physiologic response to diving seems to be comparable between healthy probands and Fontan patients. Although, healthy probands did reach a much better performance, the basic mechanisms of physiologic adaption seem comparable.

Oxygen-enriched air reduces breathing gas consumption over air.

Owing to the unfamiliar environment, recreational and professional diving is confronted with several challenges. Usage of self-contained under-water breathing apparatuses during the dive provides the indispensable breathing gas supply for the diver. Instead of air, oxygen-enriched breathing gases (EANx or nitrox) are used with increasing frequency. Unfortunately, their usage implies negative effects because the elevated oxygen partial pressure (pO2) increases oxidative stress. As a result, the increased formation of reactive oxygen species exerts negative effects on the central nervous system, lungs, vasculature and eyes. However, these disadvantages can be avoided if appropriate rules are followed, e.g. a pO2<1.4 bar. EANx breathing gases have, on the other hand, major advantages as they help reducing narcotic nitrogen effects and bubble formation. Several land-based studies had proven a reduced ventilation of exercising subjects if EANx was used instead of air. As breathing gas is the most valuable under-water good, we wanted to translate the on-land results into under-water results. Appropriate studies now demonstrate a novel EANx property as under-water ventilation is also reduced with EANx. In this short communication, we present this additional advantage of EANx-breathing. This benefit seems to be of particular importance as it delays unforeseen running-out-of-gas and thus, contributes to further improving diving safety.

[Medical strategy for abortions between 14 and 16 weeks of gestation]. / Interruption volontaire de grossesse entre 14 et 16 semaines d'aménorrhée : place de la technique médicamenteuse.

OBJECTIVE: To adapt the protocols for the management of voluntary termination of pregnancy following the new law extending the practice to 16 weeks of gestation. MATERIAL AND METHOD: A systematic review of the literature in French and English concerning the management of patients requesting medically induced abortion was performed on PubMed, Cochrane Library and on the recommendations of international learned societies. RESULTS: The efficacy of the medical method is greater than 95% when the protocols are adapted to the gestational age. The combination of mifepristone and misoprostol currently represents the "gold standard" of drug-based management. Mifepristone 200mg is sufficient, followed 24 to 48hours later by misoprostol 800µg administered sublingually or buccally. After the first dose, 400µg should be administered every 3hours buccally or sublingually until expulsion. Adverse effects (digestive and thermoregulatory disorders) during medical abortion are usually mild and short-lived. An anti-emetic treatment should be proposed as a prophylactic measure. For pain, ibuprofen is the analgesic treatment of choice, with the addition of level 2 analgesics if necessary. CONCLUSION: Medical abortion is a safe and effective method up to 16 weeks of gestation, provided that the protocols, which differ according to gestational age, are respected. Women must be informed of the advantages and disadvantages of the methods according to the term and the side effects, which will allow them to choose the method that fits them best.

3D-printed simulator for nasopharyngeal swab collection for COVID-19.

OBJECTIVES: Diagnosis of COVID-19 is essential to prevent the spread of SARS-CoV-2. Nasopharyngeal swabs (NPS) remain the gold standard in screening, although associated with false negative results (up to 30%). We developed a 3D simulator of the nasal and pharyngeal cavities for the learning and improvement of NPS collection. PATIENTS AND METHODS: Simulator training sessions were carried out in 11 centers in France. A questionnaire assessing the simulator was administered at the end of the sessions. The study population included both healthcare workers (HCW) and volunteers from the general population. RESULTS: Out of 589 participants, overall satisfaction was scored 9.0 [8.9-9.1] on a scale of 0 to 10 with excellent results in the 16 evaluation items of each category (HCWs and general population, NPS novices and experienced). The simulator was considered very realistic (95%), easy to use (97%), useful to understand the anatomy (89%) and NPS sampling technique (93%). This educational tool was considered essential (93%). Participants felt their future NPS would be more reliable (72%), less painful (70%), easier to perform (88%) and that they would be carried out more serenely (90%). The mean number of NPS conducted on the simulator to feel at ease was two; technical fluency with the simulator can thus be acquired quickly. CONCLUSION: Our simulator, whose 3D printing can be reproduced freely using a permanent open access link, is an essential educational tool to standardize the learning and improvement of NPS collection. It should enhance virus detection and thus contribute to better pandemic control.

Slowly resorbable biosynthetic mesh: 2-year results in VHWG grade 3 hernia repair.

INTRODUCTION: Information on the long-term performance of biosynthetic meshes is scarce. This study analyses the performance of biosynthetic mesh (Phasix™) over 24 months. METHODS: A prospective, international European multi-center trial is described. Adult patients with a Ventral Hernia Working Group (VHWG) grade 3 incisional hernia larger than 10 cm2, scheduled for elective repair, were included. Biosynthetic mesh was placed in sublay position. Short-term outcomes included 3-month surgical site occurrences (SSO), and long-term outcomes comprised hernia recurrence, reoperation, and quality of life assessments until 24 months. RESULTS: Eighty-four patients were treated with biosynthetic mesh. Twenty-two patients (26.2%) developed 34 SSOs, of which 32 occurred within 3 months (primary endpoint). Eight patients (11.0%) developed a hernia recurrence. In 13 patients (15.5%), 14 reoperations took place, of which 6 were performed for hernia recurrence (42.9%), 3 for mesh infection (21.4%), and in 7 of which the mesh was explanted (50%). Compared to baseline, quality of life outcomes showed no significant difference after 24 months. Despite theoretical resorption, 10.7% of patients reported presence of mesh sensation in daily life 24 months after surgery. CONCLUSION: After 2 years of follow-up, hernia repair with biosynthetic mesh shows manageable SSO rates and favorable recurrence rates in VHWG grade 3 patients. No statistically significant improvement in quality of life or reduction of pain was observed. Few patients report lasting presence of mesh sensation. Results of biosynthetic mesh after longer periods of follow-up on recurrences and remodeling will provide further valuable information to make clear recommendations. TRIAL REGISTRATION: Registered on clinicaltrials.gov (NCT02720042), March 25, 2016.

Development of a prognostic risk model for clear cell renal cell carcinoma by systematic evaluation of DNA methylation markers.

BACKGROUND: Current risk models for renal cell carcinoma (RCC) based on clinicopathological factors are sub-optimal in accurately identifying high-risk patients. Here, we perform a head-to-head comparison of previously published DNA methylation markers and propose a potential prognostic model for clear cell RCC (ccRCC). PATIENTS AND METHODS: Promoter methylation of PCDH8, BNC1, SCUBE3, GREM1, LAD1, NEFH, RASSF1A, GATA5, SFRP1, CDO1, and NEURL was determined by nested methylation-specific PCR. To identify clinically relevant methylated regions, The Cancer Genome Atlas (TCGA) was used to guide primer design. Formalin-fixed paraffin-embedded (FFPE) tissue samples from 336 non-metastatic ccRCC patients from the prospective Netherlands Cohort Study (NLCS) were used to develop a Cox proportional hazards model using stepwise backward elimination and bootstrapping to correct for optimism. For validation purposes, FFPE ccRCC tissue of 64 patients from the University Hospitals Leuven and a series of 232 cases from The Cancer Genome Atlas (TCGA) were used. RESULTS: Methylation of GREM1, GATA5, LAD1, NEFH, NEURL, and SFRP1 was associated with poor ccRCC-specific survival, independent of age, sex, tumor size, TNM stage or tumor grade. Moreover, the association between GREM1, NEFH, and NEURL methylation and outcome was shown to be dependent on the genomic region. A prognostic biomarker model containing GREM1, GATA5, LAD1, NEFH and NEURL methylation in combination with clinicopathological characteristics, performed better compared to the model with clinicopathological characteristics only (clinical model), in both the NLCS and the validation population with a c-statistic of 0.71 versus 0.65 and a c-statistic of 0.95 versus 0.86 consecutively. However, the biomarker model had limited added prognostic value in the TCGA series with a c-statistic of 0.76 versus 0.75 for the clinical model. CONCLUSION: In this study we performed a head-to-head comparison of potential prognostic methylation markers for ccRCC using a novel approach to guide primers design which utilizes the optimal location for measuring DNA methylation. Using this approach, we identified five methylation markers that potentially show prognostic value in addition to currently known clinicopathological factors.

ViBiBa: Virtual BioBanking for the DETECT multicenter trial program - decentralized storage and processing.

BACKGROUND: Liquid Biopsy (LB) in the form of e.g., circulating tumor cells (CTCs) is a promising non-invasive approach to support current therapeutic cancer management. However, the proof of clinical utility of CTCs in informing therapeutic decision-making for e.g., breast cancer in clinical trials and associated translational research projects is facing the issues of low CTC positivity rates and low CTC numbers - even in the metastasized situation. To compensate for this dilemma, clinical CTC trials are designed as large multicenter endeavors with decentralized sample collection, processing and storage of products, making data management highly important to enable high-quality translational CTC research. AIM: In the DETECT clinical CTC trials we aimed at developing a custom-made, browser-based virtual database to harmonize and organize both decentralized processing and storage of LB specimens and to enable the collection of clinically meaningful LB sample. METHODS: ViBiBa processes data from various sources, harmonizes the data and creates an easily searchable multilayered database. RESULTS: An open-source virtual bio-banking web-application termed ViBiBa was created, which automatically processes data from multiple non-standardized sources. These data are automatically checked and merged into one centralized databank and are providing the opportunity to extract clinically relevant patient cohorts and CTC sample collections. SUMMARY: ViBiBa, which is a highly flexible tool that allows for decentralized sample storage of liquid biopsy specimens, facilitates a solution which promotes collaboration in a user-friendly, federalist and highly structured way. The source code is available under the MIT license from https://vibiba.com or https://github.com/asperciesl/ViBiBa.

Atopic dermatitis among children and adolescents in the Arctic region - a systematic review and meta-analysis.

The prevalence of atopic dermatitis (AD) varies across the globe, and the clinical phenotype with racial background and ethnicity. AD in the Arctic region has only been scarcely studied. We performed a systematic review and meta-analysis to examine the prevalence, clinical manifestations and risk factors for AD among children and adolescents in the Arctic. Three medical databases PubMed, Embase and Web of Science were screened. All studies published between 1990 to 2020 with epidemiologic data on AD in children and adolescents in the Arctic region, were included. Data were extracted and a meta-analysis was performed to obtain pooled proportions and incidences with 95% confidence intervals (CI). We identified 21 studies from 8 different Arctic regions with 31 403 participants. The cumulative incidence of AD was 23% (95% CI 20-26) and 1-year prevalence was 19% (95% CI 15-25). The incidence of AD was higher in the Arctic parts of Scandinavia and lower in Greenland and Russia. Children of indigenous descent had a slightly lower incidence of AD (19%, 95% CI 13-26) compared to the overall population. The dominant phenotype of AD was mild to moderate flexural dermatitis with facial involvement. Asthma and allergic rhinitis were common and observed in 20-30% of children with AD. In conclusion, AD is highly prevalent in the Arctic, but varies between regions and races. Indigenous children living in less urbanized countries appear to have a slightly lower risk of AD. Future studies should confirm this and examine whether this correlation relates to behavioural differences or genetic signature.

Human myelomeningocele risk and ultra-rare deleterious variants in genes associated with cilium, WNT-signaling, ECM, cytoskeleton and cell migration.

Myelomeningocele (MMC) affects one in 1000 newborns annually worldwide and each surviving child faces tremendous lifetime medical and caregiving burdens. Both genetic and environmental factors contribute to disease risk but the mechanism is unclear. This study examined 506 MMC subjects for ultra-rare deleterious variants (URDVs, absent in gnomAD v2.1.1 controls that have Combined Annotation Dependent Depletion score ≥ 20) in candidate genes either known to cause abnormal neural tube closure in animals or previously associated with human MMC in the current study cohort. Approximately 70% of the study subjects carried one to nine URDVs among 302 candidate genes. Half of the study subjects carried heterozygous URDVs in multiple genes involved in the structure and/or function of cilium, cytoskeleton, extracellular matrix, WNT signaling, and/or cell migration. Another 20% of the study subjects carried heterozygous URDVs in candidate genes associated with gene transcription regulation, folate metabolism, or glucose metabolism. Presence of URDVs in the candidate genes involving these biological function groups may elevate the risk of developing myelomeningocele in the study cohort.

Shouldice standard 2020: review of the current literature and results of an international consensus meeting.

INTRODUCTION: For many years the Shouldice technique was the gold standard for inguinal hernia repair. Nowadays mesh repair has been proven to entail better results in randomized trials. Since the first publication 1953 the Repair has been described in detail in many textbooks, articles and You Tube videos. It appears that the original technique is used almost exclusively in the Shouldice Hospital in Thornhill/ Canada and despite the success of the Shouldice Hospital many surgeons inexplicably modify this original technique in their daily practice. In the last couple of years there appears to be an increasing interest in pure tissue repairs for various reasons, often fear of mesh-related pain. The aim of the study was to review the current evidence and to define an updated standard with key principles of the Shouldice repair. METHODS: Because of unpublished evidence regarding many operative details the organizing group decided to create a technical update via a consensus meeting with 13 international designated hernia surgeons from six countries. In preparation of the meeting a review of the current literature regarding Shouldice repair was done by the organizing group. A questionnaire was prepared and sent to all participants before the meeting to get an independent answer on all critical aspects. RESULTS: All questions regarding a detailed standard of the operation technique could be outlined. As result of the consensus meeting the participants have formulated all key-points of preparation/dissection and repair of the Shouldice technique. For 5 of 6 critical technical surgical steps a strong consensus could be defined in the group. There was no consensus among the group regarding the cremaster resection and the ideal indication for Shouldice repair. CONCLUSION: After a 75-year history of the Shouldice repair the technique should continue to merit consideration by all hernia surgeons. After this consensus meeting a clear binding standard of the Shouldice technique for all interested surgeons is proposed.