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Introduction: Advances in knowledge about late effects of childhood cancer treatments have led to implement long-term follow-up care. This raises the question of the ethical issues involved in providing information to survivors, and in proposals for long-term follow-up consultations., Method: We conducted a two-part qualitative study: (1) A semi-directive interview survey to explore survivors' experiences of medical proposals for follow-up consultations; (2) The creation of a multidisciplinary ethical reflection group aimed at identifying the ethical issues associated with the systematization of follow-up care., Results: The study identified five key issues related to medical requests and the implementation of follow-up care: (1) The needs and expectations of former patients regarding information; (2) The temporality of after-cancer; (3) The ambivalence of categorizations in light of the diversity of post-cancer experiences; (4) The role of various professionals and the responsibility for follow-up; (5) The plurality of needs and proposed approaches., Discussion: In light of these issues, five areas of concern emerge: (1) Provide information about a risk in life after the disease? (2) When should follow-up be proposed? (3) The category of "former patients": relevant or problematic? (4) Who can or should assume the role and responsibility for follow-up? (5) The diversity of follow-up approaches: balancing standardization with reliance on informal networks., (Copyright © 2025 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Septins are a group of cytoskeletal GTP binding proteins which are involved in different cellular processes, like cell division, exocytosis and axon growth. Their function, especially in the nervous system, is not clear. In zebrafish 16 different septins are described and for some of them the expression in the brain is described. Interestingly, the expression pattern of several of them is highly specific. Here we describe the expression of sept10 and sept12 in the developing zebrafish brain and found that these show a very defined expression pattern. Interestingly, they show an overlap with a group, but not all proliferating PCNA positive cells in nervous tissue., Competing Interests: Declaration of competing interest There is no known conflict of interest for all authors., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Phototoxicity and skin cancer are severe adverse effects of the anti-fungal drug voriconazole (VOR). These adverse effects resemble those seen in xeroderma pigmentosum, caused by defective DNA nucleotide excision repair (NER), and we show that VOR decreases NER capacity. We show that VOR treatment does not perturb the expression of NER, or other DNA damage-related genes, but that VOR localizes to heterochromatin, in complexes containing histone acetyltransferase general control of amino-acid synthesis 5-like 2. Impairment of general control of amino-acid synthesis 5-like 2 binding to histone H3 reduced acetylation of H3, restricting damage-dependent chromatin unfolding, thereby reducing NER initiation. Restoration of H3 histone acetylation using histone deacetylase inhibitors, rescued VOR-induced NER repression, thus offering a preventive therapeutic option. These findings underline the importance of DNA damage-dependent chromatin remodeling as an important prerequisite of functional DNA repair., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Osteosarcoma stratification relies on clinical parameters and histological response. We developed a new personalized stratification using less invasive circulating tumor DNA (ctDNA) quantification., Patients and Methods: Plasma from patients homogeneously treated in the prospective protocol OS2006, at diagnosis, before surgery and end of treatment, were sequenced using low-passage whole-genome sequencing (lpWGS) for copy number alteration detection. We developed a prediction tool including ctDNA quantification and known clinical parameters to estimate patients' individual risk of event., Results: ctDNA quantification at diagnosis (diagCPA) was evaluated for 183 patients of the protocol OS2006. diagCPA as a continuous variable was a major prognostic factor, independent of other clinical parameters, including metastatic status [diagCPA hazard ratio (HR) = 3.5, P = 0.002 and 3.51, P = 0.012, for progression-free survival (PFS) and overall survival (OS)]. At the time of surgery and until the end of treatment, diagCPA was also a major prognostic factor independent of histological response (diagCPA HR = 9.2, P < 0.001 and 11.6, P < 0.001, for PFS and OS). Therefore, the addition of diagCPA to metastatic status at diagnosis or poor histological response after surgery improved the prognostic stratification of patients with osteosarcoma. We developed the prediction tool PRONOS to generate individual risk estimations, showing great performance ctDNA quantification at the time of surgery and the end of treatment still required improvement to overcome the low sensitivity of lpWGS and to enable the follow-up of disease progression., Conclusions: The addition of ctDNA quantification to known risk factors improves the estimation of prognosis calculated by our prediction tool PRONOS. To confirm its value, an external validation in the Sarcoma 13 trial is underway., (Copyright © 2023 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: Osteoporosis, characterized by loss of bone mineral density (BMD), is underscreened. Osteoporosis and low bone mass are diagnosed by a BMD T-score ≤ -2.5, and between -1.0 and -2.5, respectively, at the femoral neck or lumbar vertebrae (L1-4), using dual energy x-ray absorptiometry (DXA). The ability to estimate BMD at those anatomic sites from standard radiographs would enable opportunistic screening of low BMD (T-score < -1) in individuals undergoing x-ray for any clinical indication., Methods: Radiographs of the lumbar spine, thoracic spine, chest, pelvis, hand, and knee, with a paired DXA acquired within 1 year, were obtained from community imaging centers (62,023 x-ray-DXA pairs of patients). A software program called Rho was developed that uses x-ray, age, and sex as inputs, and outputs a score of 1 to 10 that corresponds with the likelihood of low BMD. The program's performance was assessed using receiver-operating characteristic analyses in three independent test sets, as follows: patients from community imaging centers (n = 3,729; 83% female); patients in the Canadian Multicentre Osteoporosis Study (n = 1,780; 71% female); and patients in the Osteoarthritis Initiative (n = 591; 50% female)., Results: The areas under the receiver-operating characteristic curves were 0.89 (0.87-0.90), 0.87 (0.85-0.88), and 0.82 (0.79-0.85), respectively, and subset analyses showed similar results for each sex, body part, and race., Conclusion: Rho can opportunistically screen patients at risk of low BMD (at femoral neck or L1-4) from radiographs of the lumbar spine, thoracic spine, chest, pelvis, hand, or knee., (Copyright © 2023 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Predicting the outward appearance of dogs via their DNA, also known as Canine DNA Phenotyping, is a young, emerging field of research in forensic genetics. The few previous studies published in this respect were restricted to the consecutive analysis of single DNA markers, a process that is time- and sample-consuming and therefore not a viable option for limited forensic specimens. Here, we report on the development and evaluation of a Massively Parallel Sequencing (MPS) based molecular genetic assay, the LASSIE MPS Panel. This panel aims to predict externally visible as well as skeletal traits, which include coat color, coat pattern, coat structure, tail morphology, skull shape, ear shape, eye color and body size from DNA using 44 genetic markers in a single molecular genetic assay. A biostatistical naïve Bayes classification approach was applied to identify the most informative marker combinations for predicting phenotypes. Overall, the predictive performance was characterized by a very high classification success for some of the trait categories, and high to moderate success for others. The performance of the developed predictive framework was further evaluated using blind samples from three randomly selected dog individuals, whose appearance was well predicted., Competing Interests: Declaration of Competing Interest The Agrigenomics Team at ThermoFisher Scientific (USA) supported the study by aiding primer design and providing primer pools., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Afghanistan has suffered through conflicts that have detrimentally impacted its health care systems. The countries' neurosurgeons have worked through wars and political upheavals to build solid practices and handle large caseloads with minimal supplies and almost no modern tools. Understanding the current state of neurosurgery in Afghanistan and the challenges faced by Afghan physicians and patients is critical to improving the country's healthcare capacity., Methods: To assess neurosurgery research in Afghanistan, searches were conducted in databases for articles originating from Afghanistan neurosurgeons and/or neurosurgery departments. We developed a 30-question English-language survey to assess the current state of neurosurgical capacity. Surveys were distributed to neurosurgeons throughout Afghanistan via email with the assistance of our English-speaking Afghan neurosurgical colleagues., Results: The neurosurgical disease burden of Afghanistan is poorly understood due to the lack of centralized and accessible databases. There are an estimated 124 neurosurgeons in the country based on modeled data. Surveys showed that government hospitals are poorly equipped, with private and military hospitals having access to slightly more modernized equipment but less accessible to the general population. The country lacks neurosurgery research with only 15 papers discovered through database searches deemed relevant to neurosurgery with Afghan affiliations., Conclusions: Afghanistan is facing existential humanitarian threats. Developing the country's neurosurgical capacity and general health care capabilities is crucial. Emphasis on training physicians and establishing communication routes, and aid deliverance with the country and its leaders is key to overcoming the many crises it faces., (Copyright © 2022 Elsevier Inc. All rights reserved.)

High-resolution STEM-EELS provides information about the composition of crystalline materials at the atomic scale, though a reliable quantitative chemical analysis is often hampered by zone axis conditions, where neighbouring atomic column intensities contribute to the signal at the probe position. In this work, we present a procedure to determine the concentration of two elements within equivalent atomic columns from EELS elemental maps - in our case barium and lanthanum within the A-sites of Ba 1.1 La 1.9 Fe 2 O 7 , a second order Ruddlesden-Popper phase. We took advantage of the large changes in the elemental distribution from column to column and introduced a technique, which substitutes inelastic scattering cross sections during the quantification step by using parameters obtained from the actual experiment. We considered channelling / de-channelling effects via inelastic multislice simulations and were thereby able to count occupancies in each atomic column. The EELS quantification results were then used as prior information during the Rietveld refinement in XRD measurements in order to differentiate between barium and lanthanum., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The goal of this study is to investigate the clinical presentation, treatment options, and outcomes of the patients with isolated ruptured paravisceral penetrating aortic ulcers (PV-PAU)., Methods: All patients presenting with acute aortic syndrome from 2015 to 2020 were screened, of which patients with isolated ruptured PV-PAU were included in this retrospective study. Study endpoints were the assessment of treatment options, technical success, and clinical outcome. Outcome measures included major perioperative complications and mortality., Results: Sixteen patients (11 men; median age 68; IQR 60 - 75 years) presented with isolated ruptured PV-PAU were included in this study. The median follow-up was 25 months (range 1 - 51). Ruptured PV-PAUs represented 12.3% of the ruptured aortic aneurysms in all locations. PV-PAUs were found in segment A (n = 8, 50%), segment B (n = 5, 31%), and segment C (n = 3, 19%). PV-PAUs showed a mean protrusion distance of 27±10 mm, a mean neck diameter of 21 ± 7 mm, and maximal aortic diameter of 50 ± 11 mm. Five patients (31%) showed hemodynamic instability on admission and needed intense fluid resuscitation. Of those, 2 patients needed urgent laparotomy with a fast transabdominal supraceliac aortic clamping, one needed an aortic balloon occlusion to obtain rapid aortic control. The open aortic repair was the most frequently performed surgery (11/16, 69%), followed by hybrid procedures (3/16) and parallel graft chimney technique (2/16). Two patients died during the follow-up, calculating for in-hospital and 1-year mortality rates of 6 - 12%, respectively. The postoperative morbidity rate was 31%. Postoperative complications included acute renal failure (31%), pneumonia (25%), and 1case of ischemic colitis (6%). No spinal cord ischemia was reported., Conclusions: Ruptured PV-PAU is a rare and challenging diagnostic and therapeutic entity. Open aortic repair seems to be a reliable option in treating patients with isolated ruptured PV-PAUs. Hybrid procedures and parallel stent-graft techniques can only be used in selected patients., (Copyright © 2021. Published by Elsevier Inc.)

Background: Radical cystectomy with pelvic lymph node dissection is the recommended treatment in non-metastatic muscle-invasive bladder cancer (MIBC). In randomised trials, robot-assisted radical cystectomy (RARC) showed non-inferior short-term oncological outcomes compared with open radical cystectomy (ORC). Data on intermediate and long-term oncological outcomes of RARC are limited., Objective: To assess the intermediate-term overall survival (OS) and recurrence-free survival (RFS) of patients with MIBC and high-risk non-MIBC (NMIBC) who underwent ORC versus RARC in clinical practice., Methods and Materials: A nationwide retrospective study in 19 Dutch hospitals including patients with MIBC and high-risk NMIBC treated by ORC (n = 1086) or RARC (n = 386) between January 1, 2012 and December 31, 2015. Primary and secondary outcome measures were median OS and RFS, respectively. Survival outcomes were estimated using Kaplan-Meier curves. A multivariable Cox regression model was developed to adjust for possible confounders and to assess prognostic factors for survival including clinical variables, clinical and pathological disease stage, neoadjuvant therapy and surgical margin status., Results: The median follow-up was 5.1 years (95% confidence interval ([95%CI] 5.0-5.2). The median OS after ORC was 5.0 years (95%CI 4.3-5.6) versus 5.8 years after RARC (95%CI 5.1-6.5). The median RFS was 3.8 years (95%CI 3.1-4.5) after ORC versus 5.0 years after RARC (95%CI 3.9-6.0). After multivariable adjustment, the hazard ratio for OS was 1.00 (95%CI 0.84-1.20) and for RFS 1.08 (95%CI 0.91-1.27) of ORC versus RARC. Patients who underwent ORC were older, had higher preoperative serum creatinine levels and more advanced clinical and pathological disease stage., Conclusion: ORC and RARC resulted in similar intermediate-term OS and RFS in a cohort of almost 1500 MIBC and high-risk NMIBC., Competing Interests: Conflict of interest All authors declare no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Food-safety measures are recommended to solid organ transplant (SOT) recipients. However, the burden of foodborne infections in SOT recipients has not been established. We describe the epidemiology and outcomes of bacterial foodborne infections in a nationwide cohort including 4405 SOT recipients in Switzerland between 2008 and 2018. Participants were prospectively followed for a median of 4.2 years with systematic collection of data on infections, and patient and graft-related outcomes. We identified 151 episodes of microbiologically confirmed bacterial foodborne infections occurring in median 1.6 years (IQR 0.58-3.40) after transplantation (131 [88%] Campylobacter spp. and 15 [10%] non-typhoidal Salmonella). The cumulative incidence of bacterial foodborne infections was 4% (95% CI 3.4-4.8). Standardized incidence rates were 7.4 (95% CI 6.2-8.7) and 4.6 (95% CI 2.6-7.5) for Campylobacter and Salmonella infections, respectively. Invasive infection was more common with Salmonella (33.3% [5/15]) compared to Campylobacter (3.2% [4/125]; p = .001). Hospital and ICU admission rates were 47.7% (69/145) and 4.1% (6/145), respectively. A composite endpoint of acute rejection, graft loss, or death occurred within 30 days in 3.3% (5/151) of cases. In conclusion, in our cohort bacterial foodborne infections were late post-transplant infections and were associated with significant morbidity, supporting the need for implementation of food-safety recommendations., (© 2021 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Hematotoxicity represents a frequent chimeric antigen receptor (CAR) T-cell-related adverse event and remains poorly understood. In this multicenter analysis, we studied patterns of hematopoietic reconstitution and evaluated potential predictive markers in 258 patients receiving axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) for relapsed/refractory large B-cell lymphoma. We observed profound (absolute neutrophil count [ANC] <100 cells per µL) neutropenia in 72% of patients and prolonged (21 days or longer) neutropenia in 64% of patients. The median duration of severe neutropenia (ANC < 500 cells per µL) was 9 days. We aimed to identify predictive biomarkers of hematotoxicity using the duration of severe neutropenia until day +60 as the primary end point. In the training cohort (n = 58), we observed a significant correlation with baseline thrombocytopenia (r = -0.43; P = .001) and hyperferritinemia (r = 0.54; P < .0001) on univariate and multivariate analysis. Incidence and severity of cytokine-release syndrome, immune effector cell-associated neurotoxicity syndrome, and peak cytokine levels were not associated with the primary end point. We created the CAR-HEMATOTOX model, which included markers associated with hematopoietic reserve (eg, platelet count, hemoglobin, and ANC) and baseline inflammation (eg, C-reactive protein and ferritin). This model was validated in independent cohorts, one from Europe (n = 91) and one from the United States (n = 109) and discriminated patients with severe neutropenia ≥14 days to <14 days (pooled validation: area under the curve, 0.89; sensitivity, 89%; specificity, 68%). A high CAR-HEMATOTOX score resulted in a longer duration of neutropenia (12 vs 5.5 days; P < .001) and a higher incidence of severe thrombocytopenia (87% vs 34%; P < .001) and anemia (96% vs 40%; P < .001). The score implicates bone marrow reserve and inflammation prior to CAR T-cell therapy as key features associated with delayed cytopenia and will be useful for risk-adapted management of hematotoxicity., (© 2021 by The American Society of Hematology.)

Background: Neurotrauma is a leading cause of morbidity and mortality around the world. Assessment of injury prevention and prehospital care for neurotrauma patients is necessary to improve care systems., Methods: A 29-question electronic survey was developed based on the Enhancing the Quality and Transparency Of health Research (EQUATOR) checklist to assess neurotrauma policies and laws related to safety precautions. The survey was distributed to members of World Health Organization regions that were considered to be experienced medical authorities in neurosurgery and traumatic brain injury., Results: There were 82 (39%) responses representing 46 countries. Almost all respondents (95.2%) were within the neurosurgical field. Of respondents, 40.2% were from high-income countries (HICs), and 59.8% were from low- and middle-income countries (LMICs). Motor vehicle accidents were reported as the leading cause of neurotrauma, followed by workplace injury and assault. Of respondents, 84.1% reported having a helmet law in their country. HICs (4.38 ± 0.78) were ranked more likely than LMICs (2.88 ± 1.34; P = 0.0001) to enforce helmet laws on a scale of 1-10. Effectiveness of helmet laws was rated as 3.94 ± 0.95 out of 10. Measures regarding prehospital care varied between HICs and LMICs. Patients in HICs were more likely to use public emergency ambulance transportation (81.8% vs. 42.9%; P = 0.0004). All prehospital personnel having emergency training was also reported to be more likely in HICs than LMICs (60.6% vs. 8.7%; P = 0.0001)., Conclusions: When injuries occur, timely access to neurosurgical care is critical. A focus on prehospital components of the trauma system is paramount, and policymakers can use the information presented here to implement and refine health care systems to ensure safe, timely, affordable, and equitable access to neurotrauma care., (Published by Elsevier Inc.)

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation (SOT). Most PTLD cases are associated with Epstein-Barr virus (EBV) infection. The role of antiviral prophylaxis or rituximab therapy for prevention of PTLD in SOT recipients is controversial. In a nationwide cohort, we assessed the incidence, presentation, and outcome of histologically proven PTLD. We included 4765 patients with a follow-up duration of 23 807 person-years (py). Fifty-seven PTLD cases were identified; 39 (68%) were EBV positive (EBV+ PTLD). Incidence rates for EBV+ PTLD at 1, 2, and 3 years posttransplant were 3.51, 2.24, and 1.75/1000 py and 0.44, 0.25, and 0.29/1000 py for EBV- PTLD. We did not find an effect of antiviral prophylaxis on early and late EBV+ PTLD occurrence (early EBV+ PTLD: SHR 0.535 [95% CI 0.199-1.436], p = .264; late EBV+ PTLD: SHR 2.213, [95% CI 0.751-6.521], p = .150). However, none of the patients (0/191) who received a rituximab-containing induction treatment experienced PTLD, but 57 of 4574 patients without rituximab induction developed PTLD. In an adjusted restricted mean survival time model, PTLD-free survival was significantly longer (0.104 years [95% CI 0.077-0.131]) in patients receiving rituximab as induction treatment. This study provides novel data on the association of rituximab induction and reduced risk for PTLD., (© 2020 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Solid organ transplant (SOT) recipients are exposed to respiratory viral infection (RVI) during seasonal epidemics; however, the associated burden of disease has not been fully characterized. We describe the epidemiology and outcomes of RVI in a cohort enrolling 3294 consecutive patients undergoing SOT from May 2008 to December 2015 in Switzerland. Patient and allograft outcomes, and RVI diagnosed during routine clinical practice were prospectively collected. Median follow-up was 3.4 years (interquartile range 1.61-5.56). Six hundred ninety-six RVIs were diagnosed in 151/334 (45%) lung and 265/2960 (9%) non-lung transplant recipients. Cumulative incidence was 60% (95% confidence interval [CI] 53%-69%) in lung and 12% (95% CI 11%-14%) in non-lung transplant recipients. RVI led to 17.9 (95% CI 15.7-20.5) hospital admissions per 1000 patient-years. Intensive care unit admission was required in 4% (27/691) of cases. Thirty-day all-cause case fatality rate was 0.9% (6/696). Using proportional hazard models we found that RVI (adjusted hazard ratio [aHR] 2.45; 95% CI 1.62-3.73), lower respiratory tract RVI (aHR 3.45; 95% CI 2.15-5.52), and influenza (aHR 3.57; 95% CI 1.75-7.26) were associated with graft failure or death. In this cohort of SOT recipients, RVI caused important morbidity and may affect long-term outcomes, underlying the need for improved preventive strategies., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Despite a high prevalence of angiodysplasia, no specific guidelines are available for the modalities of endoscopic exploration of gastrointestinal (GI) bleeding in von Willebrand disease (VWD). Whether VWD patients could benefit from video capsule endoscopy (VCE) looking for angiodysplasia eligible to endoscopic treatment or at high risk of bleeding is unknown., Objectives: To assess the diagnostic efficacy for angiodysplasia and the prognostic value of VCE on top of conventional endoscopy in VWD patients with GI bleeding., Patients/methods: A survey was sent to the 30 centers of the French-network on inherited bleeding disorders to identify VWD patients referred for endoscopic exploration of GI bleeding from January 2015 to December 2017. Data obtained included patient characteristics, VWD phenotype/genotype, GI bleeding pattern, results of endoscopic investigations, and medical management applied including endoscopic therapy. We assessed by Kaplan-Meier analysis the recurrence-free survival after the first GI bleeding event according to endoscopic categorization and, in patients with angiodysplasia, to the presence of small-bowel localizations on VCE exploration., Results: GI bleeding source localization was significantly improved when including VCE exploration (P < .01), even in patients without history of angiodysplasia (P < .05). Patients with angiodysplasia had more GI bleeding recurrences (P < .01). A lower recurrence-free survival was observed in patients with angiodysplasia (log-rank test, P = .02), and especially when lesions were located in the small bowel (log-rank test, P < .01), even after endoscopic treatment with argon plasma coagulation (log-rank test, P < .01)., Conclusion: VCE should be more systematically used in VWD patients with unexplained or recurrent GI bleeding looking for angiodysplasia eligible to endoscopic treatment or at high risk of relapse., (© 2020 International Society on Thrombosis and Haemostasis.)

The leptin receptor (Lepr) pathway is important for food intake regulation, energy expenditure, and body weight. Mutations in leptin and the Lepr have been shown to cause early-onset severe obesity in mice and humans. In studies with C57BL/6NCrl mice, we found a mouse with extreme obesity. To identify a putative spontaneous new form of monogenic obesity, we performed backcross studies with this mouse followed by a quantitative trait locus (QTL) analysis and sequencing of the selected chromosomal QTL region. We thereby identified a novel Lepr mutation (C57BL/6N-Lepr L536Hfs* 6-1NKB ), which is located at chromosome 4, exon 11 within the CRH2-leptin-binding site. Compared with C57BL/6N mice, Lepr L536Hfs* 6 develop early onset obesity and their body weight exceeds that of Lepr db/db mice at an age of 30 weeks. Similar to Lepr db/db mice, the Lepr L536Hfs* 6 model is characterized by hyperphagia, obesity, lower energy expenditure and activity, hyperglycemia, and hyperinsulinemia compared with C57BL/6N mice. Crossing Lepr db/wt with Lepr L536Hfs* 6/wt mice results in compound heterozygous Lepr L536Hfs* 6/db mice, which develop even higher body weight and fat mass than both homozygous Lepr db/db and Lepr L536Hfs* 6 mice. Compound heterozygous Lepr deficiency affecting functionally different regions of the Lepr causes more severe obesity than the parental homozygous mutations., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Global neurosurgery encompasses the social and surgical practices that effect the neurologic health of vulnerable and underserved populations in domestic and international resource-limited settings. Formal academic engagement in global neurosurgery is limited in residency programs. Here we explore the current status of global neurosurgery education in residency programs across the United States., Methods: We contacted 115 Accreditation Council for Graduate Medical Education-accredited residency programs in the United States to complete an 8-question electronic survey on global neurosurgery education. Questions were framed with binary "yes" or "no" answers to indicate presence of a global health activity. Respondents provided additional information if desired. Global education activity was categorized based on the number of resources attributed to global health activities: low (0-2), moderate (3-5), or high (6-8)., Results: Thirty-four residency programs completed the survey (29.6%). The majority of respondents reported offering funding for research and educational opportunities in global neurosurgery (n = 22). Programs tended to support global neurosurgery conferences (n = 20), periodic dedicated lectures (n = 15), and rotations in resource-constrained or marginalized communities domestically or abroad (n = 15). Some programs offer continuity clinics in marginalized settings (n = 10), supplementary reading material (n = 8), core curricula (n = 6), or a designated residency track in global neurosurgery (n = 3). The majority of residency programs had low-level engagement in global neurosurgery (n = 18), with only 3 programs having high levels of engagement., Conclusions: Formal global neurosurgery training is limited within US residency programs. With rising trends in the neurosurgical disease burden globally, it may benefit residency programs to develop training paths to equip the next generation of neurosurgeons to address such needs., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To define sepsis syndromes in high-HIV burden settings in the antiretroviral therapy (ART) era., Methods: We characterized a prospective cohort of adults presenting to a tertiary emergency department in Harare, Zimbabwe with suspected community-acquired sepsis using blood and urine cultures, urine tuberculosis lipoarabinomannan (TB LAM), and serum cryptococcal antigen (CrAg) testing. The primary outcome was 30-day all-cause mortality., Results: Of 142 patients enrolled 68% (n=96/142, 95% confidence interval (CI) [60-75%]) were HIV-positive, 41% (n=39/96, 95% CI [31-50%]) of whom were ART-naïve. Among HIV-positive patients, both opportunistic pathogens (TB LAM-positivity, 36%, 95% CI [24-48%]; CrAg-positivity, 15%, 95% CI [7-23%]) and severe non-AIDS infections (S. pneumoniae urine antigen-positivity 12%, 95% CI [4-20%]; bacteraemia 17% (n=16/96, 95% CI [9-24%]), of which 56% (n=9/16, 95% CI [30-80%]) were gram-negative organisms) were common. Klebsiella pneumoniae recovered from blood and urine was uniformly resistant to ceftriaxone, as were most Escherichia coli isolates. Acknowledging the power limitations of our study, we conclude that relative to HIV-negative patients, HIV-positive patients had modestly higher 30-day mortality (adjusted hazard ratio (HR) 1.88, 95% CI [0.78-4.55]; p=0.16, and 3.59, 95% CI [1.27-10.16], p=0.02) among those with and without viral suppression, respectively., Conclusion: Rapid point-of-care assays provide substantial clinically actionable information in the setting of suspected sepsis, even in areas with high ART coverage. Antimicrobial resistance to first-line antibiotics in high burden settings is a growing threat., (Published by Elsevier Ltd.)

Introduction: Survival of adolescents and young adults (AYA) with sarcoma is lower than in younger patients. The objective of this study was to describe the regional healthcare circuits, the differences in the management between adult, paediatric and mixed units and to assess the prognostic impact of compliance with clinical practice guidelines (CPGs) on overall survival (OS) and on relapse free survival (RFS)., Materials and Methods: Retrospective analysis of the management and long term follow-up of all 13-25 year old patients with a sarcoma diagnosed in the Rhône-Alpes area between 2000 and 2005., Results: 140 patients satisfied inclusion criteria and were selected. The majority of 13-25 year old patients were treated in paediatric units. Joint management resulted in a higher rate of discussion in multidisciplinary tumour board, inclusion in clinical trials, and fertility preservation. Non-compliance with guidelines was observed in 65% of cases. Overall compliance was not reported to correlate to survival. Compliance of radiotherapy with CPG's seemed associated with a better prognosis for OS (HR = 0.20, 95% CI = [0.10-0.40]; p < 0.0001) and RFS (HR = 0.18, 95% CI = [0.09-0.37; p < 0.0001) as well as compliance of surgery for OS (HR = 0.43, 95% CI = [0.23-0.81]; p = 0.01). Multivariate Cox regression analysis revealed other independent predictors of OS like age at diagnosis, stage and histological subtype., Conclusions: Management of AYA in joint units seems to improve the quality of care. Compliance of surgery and radiotherapy with CGP's seems to improve survival., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: On average 185 children are diagnosed each year in France with a cancer in their first year of life, representing 11 % of cancers diagnosed in children less than 15 years., Methods: A retrospective population-based observational study was conducted between 2000 and 2014 of all infants with a diagnosis of cancer using the National Registry of Childhood Cancers Database., Results: Out of 2760 cases of primary cancers in infancy, there were mainly neuroblastomas 30.1 %), central nervous system (CNS) tumors (16.1 %), leukemias (15.3 %), retinoblastomas (11.6 %), and Wilms tumors (6.9 %). Embryonal malignancies accounted for 55.2 % of cases. Most diagnoses showed a male excess, particularly for malignant gonadal germ-cell tumors (GCT) with a 17.5 sex-ratio. The annual incidence rate, 242.9 per million infants overall, was stable over the study period for all types of cancer. Most deaths occurred within the first month of life (70.8 % of deaths). The 5-year overall survival (5-y OS) was 81.0 % (95 %CI, 79.4-82.4) with large contrasts between diagnoses. The best 5-y OS (>85 %) were observed for retinoblastomas, carcinomas, nephroblastomas, GCT, neuroblastomas, and hepatoblastomas. Conversely, the lowest 5-y OS (<65 %) were observed for acute myeloid leukemias, CNS tumors, and lymphoid leukemias. We observed no substantial change over time (80.5 % [95 %CI, 77.7-82.9] in 2000-2004 and 82.6 % [95 %CI, 80.0-84.9] in 2010-2014) for all cancers combined. The same result has been found whatever the diagnostic group., Conclusion: Our results contribute to better understand these tumors by quantifying their impact on the French population and assessing the burden of some devastating infant cancers., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020. Published by Elsevier Ltd.)

The detection of new or enlarged white-matter lesions is a vital task in the monitoring of patients undergoing disease-modifying treatment for multiple sclerosis. However, the definition of 'new or enlarged' is not fixed, and it is known that lesion-counting is highly subjective, with high degree of inter- and intra-rater variability. Automated methods for lesion quantification, if accurate enough, hold the potential to make the detection of new and enlarged lesions consistent and repeatable. However, the majority of lesion segmentation algorithms are not evaluated for their ability to separate radiologically progressive from radiologically stable patients, despite this being a pressing clinical use-case. In this paper, we explore the ability of a deep learning segmentation classifier to separate stable from progressive patients by lesion volume and lesion count, and find that neither measure provides a good separation. Instead, we propose a method for identifying lesion changes of high certainty, and establish on an internal dataset of longitudinal multiple sclerosis cases that this method is able to separate progressive from stable time-points with a very high level of discrimination (AUC = 0.999), while changes in lesion volume are much less able to perform this separation (AUC = 0.71). Validation of the method on two external datasets confirms that the method is able to generalize beyond the setting in which it was trained, achieving an accuracies of 75 % and 85 % in separating stable and progressive time-points., (Copyright © 2019. Published by Elsevier Inc.)

Crime scene samples originating from domestic dogs such as hair, blood, or saliva can be probative as possible transfer evidence in human crime and in dog attack cases. In the majority of such cases canine DNA identification using short tandem repeat (STR) analysis is the method of choice, which demands, among others, a systematic survey of allele frequency data in the relevant dog populations. A set of 13 highly polymorphic canine STR markers was used to analyze samples of 1,184 dogs (including 967 purebred dogs) from the so-called DACH countries (Germany, Austria, Switzerland). This CaDNAP 13-STR panel has previously been validated for canine identification in a forensic context. Here, we present robust estimates of allele frequencies, which are essential to assess the weight of the evidence by estimating the probability of a matching DNA profile within the dog population under question, e.g. in the form of a random match probability (RMP). The geographical provenance of the tested dogs showed a negligible influence on the observed genotype variation. Therefore, we combined the STR data from all three countries into a single dog population sample (DPS). In contrast, pronounced genetic differentiation between dog breeds was found by principal component analysis and sub-structure analysis with the STRUCTURE software. These findings entailed the need to account for the effects of DPS breed composition on allele frequency estimates. A possible strategy, which was favored here, relies on collecting a DPS that is guided by the breed composition of the relevant dog population. In total, dogs from 166 different breeds were included in our DPS, 64 of them including at least 5 individuals (n = 771 dogs). Sampling reflected the abundance of breeds in the DACH countries with the following being the most common ones: German Shepherds (population frequency: 14.3%), Dachshunds (5.9%), Labrador Retrievers (3.9%), and Golden Retrievers (3.2%). The pedigree listing of the purebred dogs in our DPS ranked German Shepherds (DPS frequency 8.5%) first, followed by Labrador Retrievers (3.9%), Golden Retrievers (3%), and Dachshunds (2.5%). RMP values based on overall allele frequencies and accounting for substructure using F ST between breeds ranged between 10-13 and 10-14 and represent a conservative approach of RMP assessment., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Novel therapeutic regulators of uterine contractility are needed to manage preterm labor, induce labor and control postpartum hemorrhage. Therefore, we previously developed a high-throughput assay for large-scale screening of small molecular compounds to regulate calcium-mobilization in primary mouse uterine myometrial cells. The goal of this study was to select the optimal myometrial cells for our high-throughput drug discovery assay, as well as determine the similarity or differences of myometrial cells to vascular smooth muscle cells (VSMCs)-the most common off-target of current myometrial therapeutics. Molecular and pharmacological assays were used to compare myometrial cells from four sources: primary cells isolated from term pregnant human and murine myometrium, immortalized pregnant human myometrial (PHM-1) cells and immortalized non-pregnant human myometrial (hTERT-HM) cells. In addition, myometrial cells were compared to vascular SMCs. We found that the transcriptome profiles of hTERT-HM and PHM1 cells were most similar (r = 0.93 and 0.90, respectively) to human primary myometrial cells. Comparative transcriptome profiling of primary human myometrial transcriptome and VSMCs revealed 498 upregulated (p ≤ 0.01, log2FC≥1) genes, of which 142 can serve as uterine-selective druggable targets. In the high-throughput Ca 2+ -assay, PHM1 cells had the most similar response to primary human myometrial cells in OT-induced Ca 2+ -release (E max  = 195% and 143%, EC 50  = 30 nM and 120 nM, respectively), while all sources of myometrial cells showed excellent and similar robustness and reproducibility (Z' = 0.52 to 0.77). After testing a panel of 61 compounds, we found that the stimulatory and inhibitory responses of hTERT-HM cells were highly-correlated (r = 0.94 and 0.95, respectively) to human primary cells. Moreover, ten compounds were identified that displayed uterine-selectivity (≥5-fold E max or EC 50 compared to VSMCs). Collectively, this study found that hTERT-HM cells exhibited the most similarity to primary human myometrial cells and, therefore, is an optimal substitute for large-scale screening to identify novel therapeutic regulators of myometrial contractility. Moreover, VSMCs can serve as an important counter-screening tool to assess uterine-selectivity of targets and drugs given the similarity observed in the transcriptome and response to compounds., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

We tested a panel of 13 highly polymorphic canine short tandem repeat (STR) markers for dog breed assignment using 392 dog samples from the 23 most popular breeds in Austria, Germany, and Switzerland. This STR panel had originally been selected for canine identification. The dog breeds sampled in this study featured a population frequency ≥1% and accounted for nearly 57% of the entire pedigree dog population in these three countries. Breed selection was based on a survey comprising records for nearly 1.9 million purebred dogs belonging to more than 500 different breeds. To derive breed membership from STR genotypes, a range of algorithms were used. These methods included discriminant analysis of principal components (DAPC), STRUCTURE, GeneClass2, and the adegenet package for R. STRUCTURE analyses suggested 21 distinct genetic clusters. Differentiation between most breeds was clearly discernable. Fourteen of 23 breeds (61%) exhibited maximum mean cluster membership proportions of more than 0.70 with a highest value of 0.90 found for Cavalier King Charles Spaniels. Dogs of only 6 breeds (26%) failed to consistently show only one major cluster. The DAPC method yielded the best assignment results in all 23 declared breeds with 97.5% assignment success. The frequency-based assignment test also provided a high success rate of 87%. These results indicate the potential viability of dog breed prediction using a well-established and sensitive set of 13 canine STR markers intended for forensic routine use., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: The progesterone receptor modulator (PRM) mifepristone holds the potential to be developed for regular contraception. However, long-term treatment can cause thickening of the endometrium and PRM-associated endometrial changes (PAEC). The objective of this study was to explore the molecular expression of endometrium displaying PAEC after mifepristone treatment in order to understand the future implications of PAEC and safety of long-term use., Study Design: Endometrial biopsies were obtained from premenopausal women following 3 months of continuous mifepristone treatment. The biopsies were evaluated regarding occurrence of PAEC and followed up by a comparative analysis of gene expression in PAEC endometrium (n=7) with endometrium not displaying PAEC (n=4). Methods used included microarray analysis, Ingenuity Pathway Analysis (IPA) and real-time polymerase chain reaction., Results: Three genes relevant within endometrial function were up-regulated with PAEC: THY1 (p=.02), ADAM12 (p=.04) and TN-C (p=.04). The proliferation marker MKi67 was not altered (p=.31). None of the differentially regulated genes were involved in the endometrial cancer-signaling pathway (based on IPA knowledge database)., Conclusion: The genes altered in endometrium displaying PAEC after 3 months of mifepristone exposure are mainly involved in the structural architecture of tissue., Implications: PAEC features may be explained by the altered genes and their networks affecting tissue architecture although not involved in endometrial cancer signaling pathways, and thus, treatment with mifepristone at this dosage does not show any adverse effect at endometrial level., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Congenital neutropenias (CNs) are rare heterogeneous genetic disorders, with about 25% of patients without known genetic defects. Using whole-exome sequencing, we identified a heterozygous mutation in the SRP54 gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the SRP54 gene in 66 probands from the French CN registry. In total, we identified 23 mutated cases (16 sporadic, 7 familial) with 7 distinct germ line SRP54 mutations including a recurrent in-frame deletion (Thr117del) in 14 cases. In nearly all patients, neutropenia was chronic and profound with promyelocytic maturation arrest, occurring within the first months of life, and required long-term granulocyte colony-stimulating factor therapy with a poor response. Neutropenia was sometimes associated with a severe neurodevelopmental delay (n = 5) and/or an exocrine pancreatic insufficiency requiring enzyme supplementation (n = 3). The SRP54 protein is a key component of the ribonucleoprotein complex that mediates the co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). We showed that SRP54 was specifically upregulated during the in vitro granulocytic differentiation, and that SRP54 mutations or knockdown led to a drastically reduced proliferation of granulocytic cells associated with an enhanced P53-dependent apoptosis. Bone marrow examination of SRP54 -mutated patients revealed a major dysgranulopoiesis and features of cellular ER stress and autophagy that were confirmed using SRP54 -mutated primary cells and SRP54 knockdown cells. In conclusion, we characterized a pathological pathway, which represents the second most common cause of CN with maturation arrest in the French CN registry., (© 2018 by The American Society of Hematology.)

In 2015 and 2016 the Central Unit of the Dutch National Police created and submitted 21 cartridge case comparison tests as real cases to the Netherlands Forensic Institute (NFI), under supervision of the University of Twente (UT). A total of 53 conclusions were drawn in these 21 tests. For 31 conclusions the underlying ground truth was "positive", in the sense that it addressed a cluster of cartridge cases that was fired from the same firearm. For 22 conclusions the ground truth was "negative", in the sense that the cartridge cases were fired from different firearms. In none of the conclusions, resulting from examinations under casework conditions, misleading evidence was reported. All conclusions supported the hypothesis reflecting the ground truth. This article discusses the design and results of the tests in more detail., (Copyright © 2018 The Chartered Society of Forensic Sciences. Published by Elsevier B.V. All rights reserved.)

Clostridium difficile infection (CDI) is a leading cause of infectious diarrhea in solid organ transplant recipients (SOT). We aimed to assess incidence, risk factors, and outcome of CDI within the Swiss Transplant Cohort Study (STCS). We performed a case-control study of SOT recipients in the STCS diagnosed with CDI between May 2008 and August 2013. We matched 2 control subjects per case by age at transplantation, sex, and transplanted organ. A multivariable analysis was performed using conditional logistic regression to identify risk factors and evaluate outcome of CDI. Two thousand one hundred fifty-eight SOT recipients, comprising 87 cases of CDI and 174 matched controls were included. The overall CDI rate per 10 000 patient days was 0.47 (95% confidence interval ([CI] 0.38-0.58), with the highest rate in lung (1.48, 95% CI 0.93-2.24). In multivariable analysis, proven infections (hazard ratio [HR] 2.82, 95% CI 1.29-6.19) and antibiotic treatments (HR 4.51, 95% CI 2.03-10.0) during the preceding 3 months were independently associated with the development of CDI. Despite mild clinical presentations, recipients acquiring CDI posttransplantation had an increased risk of graft loss (HR 2.24, 95% CI 1.15-4.37; P = .02). These findings may help to improve the management of SOT recipients., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Introduction: In up to 20% of patients presenting with undescended testes, one or both are non-palpable. Whereas the most reliable means to exclude an abdominal testis is laparoscopy, there has been a lot of debate about the role of inguinal ultrasound (US) in detecting non-palpable inguinal testis. While we do not aim to add another paper claiming the benefits of US, we wanted to determine the excess capability of US to determine the correct surgical approach - inguinal or laparoscopy. In the light of avoiding unnecessary diagnostic laparoscopies, even the cost-effectiveness raised in many current papers might be called into question., Patients and Methods: Of a total of 684 boys who underwent surgery for undescended testes at our department between 2011 and 2014, in 58 (8.5%), one or both testes were neither palpable preoperatively nor under general anesthesia. These boys were examined by two experienced pediatric urologists clinically as well as by US. Besides the size of the contralateral testis, the presence of a testis in the inguinal channel was investigated. The additional impact of US over clinical exam and consideration of the size of the contralateral testis was assessed by means of intra-individual comparisons using Cochran-Q as well as McNemar tests., Results: Clinical exam without considering the size of the contralateral testis had a sensitivity of 9% (95% CI 2-24%) and a specificity of 100% (95% CI 86-100%) to accurately predict the surgical approach deemed appropriate postoperatively. The consideration of the size of the contralateral testis - taken as an isolated factor - accurately predicted the surgical approach with a sensitivity of 21% (95% CI 9-38%) and a specificity of 88% (95% CI 68-97%). Ultrasound accounted for a sensitivity of 53% (95% CI 35-70%) and a specificity of 100% (95% CI 86-100%). The addition of US increased the sensitivity to correctly predict an inguinal incision from 29% to 71% and specificity slightly increased from 88% to 92%. This difference is significant (p = 0.008) in the bilateral McNemar test (Figure)., Conclusion: Inguinal US of non-palpable testes and measurement of the contralateral testis are synergistic in predicting the surgical approach. The addition of ultrasound to a clinical exam, performed also under general anesthesia and by an experienced pediatric urologist significantly increases the prediction of the correct surgical approach. Our results translate into five boys needing an US of the NPT to prevent one laparoscopy. Whereas cost-effectiveness of US might be debatable in regard to different healthcare systems, it is proven to be an effective, non-harmful tool to avoid unnecessary diagnostic laparoscopies., (Copyright © 2017 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)