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BACKGROUND AND PURPOSE Progressive multifocal leukoencephalopathy (PML) constitutes a severe disease with increasing incidence, mostly in the context of immunosuppressive therapies. A detailed understanding of immune response in PML appears critical for the treatment strategy. The aim was a comprehensive immunoprofiling and radiological characterization of magnetic resonance imaging (MRI) defined PML variants. METHODS All biopsy-confirmed PML patients (n = 15) treated in our department between January 2004 and July 2019 were retrospectively analysed. Data from MRI, histology as well as detailed clinical and outcome data were collected. The MRI-defined variants of classical (cPML) and inflammatory (iPML) PML were discriminated based on the intensity of gadolinium enhancement. In these PML variants, intensity and localization (perivascular vs. parenchymal) of inflammation in MRI and histology as well as the cellular composition by immunohistochemistry were assessed. The size of the demyelinating lesions was correlated with immune cell infiltration. RESULTS Patients with MRI-defined iPML showed a stronger intensity of inflammation with an increased lymphocyte infiltration on histological level. Also, iPML was characterized by a predominantly perivascular inflammation. However, cPML patients also demonstrated certain inflammatory tissue alterations. Infiltration of CD163-positive microglia and macrophage (M/M) subtypes correlated with PML lesion size. CONCLUSIONS The non-invasive MRI-based discrimination of PML variants allows for an estimation of inflammatory tissue alterations, although exhibiting limitations in MRI-defined cPML. The association of a distinct phagocytic M/M subtype with the extent of demyelination might reflect disease progression.

Purpose: We present seven cases of advanced cancer patients who initially underwent tumor testing utilizing smaller, panel-based tests, followed by a variety of therapeutic treatments which ultimately resulted in progression of their disease. These cases demonstrate the value of utilizing WES/RNA seq and characterization following disease progression in these patients and the determination of clinically targetable alterations as well as acquired resistance mutations. Materials and Methods: All patients are part of an IRB approved observational study. WES and RNA sequencing were performed, using GEM ExTra® on tumor and blood samples obtained during routine clinical care. To accurately determine somatic versus germline alterations the test was performed with paired normal testing from peripheral blood. Results: The presented cases demonstrate the clinical impact of actionable findings uncovered using GEM ExTra® in patients with advanced disease who failed many rounds of treatment. Unique alterations were identified resulting in newly identified potential targeted therapies, mechanisms of resistance, and variation in the genomic characterization of the primary versus the metastatic tumor. Conclusions: Taken together our results demonstrate that GEM ExTra® maximizes detection of actionable mutations, thus allowing for appropriate treatment selection for patients harboring both common and rare genomic alterations.

Initial reports of a clinical response in patients treated with the radioligand [177Lu]-PSMA-617 for castration-resistant prostate cancer (CRPC) are promising, despite known inter- and intrapatient heterogeneity. In metastatic CRPC, we examined the association of baseline immunohistochemical (IHC) expression of prostate-specific membrane antigen (PSMA) in a single lesion and responsiveness to [177Lu]-PSMA-617 therapy, measured as the PSMA maximum standardized uptake value (SUVmax). Between 2015 and 2020, 19 patients with multiple metastases underwent single-lesion biopsy, [68Ga]-PSMA positron emission tomography (PET) imaging, and treatment with [177Lu]-PSMA-617. A monoclonal anti-PSMA antibody was used to semiquantitatively assess PSMA IHC in the biopsy specimen. Imaging evaluation of the biopsied single lesion and overall response was performed according to Positron Emission Tomography Response Criteria in Solid Tumors. The PSMA IHC histoscore correlated positively with pretreatment same-site PSMA SUVmax (rs = 0.6). Nine patients had imaging after three cycles of [177Lu]-PSMA-617 and were included in the lesion-specific analysis. Of these, five patients (55.6%) had an SUVmax response at the biopsy site, but three experienced overall progression. The histoscore was unable to predict the lesion-specific change in SUVmax (95% confidence interval [CI] −44.2 to 69.2) or PSA (95% CI−125.2 to 17.2). There was no correlation between single-lesion SUVmax and overall progression (rs = 0.1) on [68Ga]-PSMA PET imaging. Additional studies need to interrogate the clinical consequence of PSMA expression heterogeneity in metastases and the association with response to [177Lu]-PSMA-671. Patient summary Treatment with a radioactive binding molecule called [177Lu]-PSMA-617 for men with prostate cancer resistant to castration (CRPC) is showing promise. We investigated the association between the presence of PSMA protein in metastatic lesions at biopsy and response to [177Lu]-PSMA-617 among men with metastatic CRPC. We found that assessment of PSMA presence at biopsy is not a reliable predictor of response to [177Lu]-PSMA-617. Additional studies are needed to better determine which CRPC metastatic sites will respond to this therapy.

Background and purpose This was an investigation of treatment expectations and of the perception of therapy in adult patients with 5q-associated spinal muscular atrophy (5q-SMA) receiving nusinersen. Methods A prospective, non-interventional observational study of nusinersen treatment in adult 5q-SMA patients was conducted at nine SMA centers in Germany. The functional status, treatment expectations and perceived outcomes were assessed using the Amyotrophic Lateral Sclerosis Functional Rating Scale—extended (ALS-FRS-ex), the Measure Yourself Medical Outcome Profile (MYMOP2), the Treatment Satisfaction Questionnaire for Medication (TSQM-9) and the Net Promoter Score (NPS). Results In all, 151 patients were included with a median age of 36 years (15–69 years). SMA type 3 (n = 90, 59.6%) prevailed, followed by type 2 (33.8%) and type 1 (6.6%). In SMA types 1–3, median ALS-FRS-ex scores were 25, 33 and 46 (of 60 scale points), respectively. MYMOP2 identified distinct treatment expectations: head verticalization (n = 13), bulbar function (n = 16), arm function (n = 65), respiration (n = 15), trunk function (n = 34), leg function (n = 76) and generalized symptoms (n = 77). Median symptom severity decreased during nusinersen treatment (median observational period 6.1 months, 0.5–16 months) from 3.7 to 3.3 MYMOP2 score points (p < 0.001). The convenience of drug administration was critical (49.7 of 100 TSQM-9 points, SD 22); however, the overall treatment satisfaction was high (74.3, SD 18) and the recommendation rating very positive (NPS +66). Conclusions Nusinersen was administered across a broad range of ages, disease durations and motor function deficits. Treatment expectations were highly differentiated and related to SMA type and functional status. Patient-reported outcomes demonstrated a positive perception of nusinersen therapy in adult patients with 5q-SMA., publishedVersion

Background The incidence of spinal cord gliomas, particularly in adults is low, and the role of chemotherapy has remained unclear. Methods We performed a multicenter, retrospective study of 21 patients diagnosed with spinal cord glioma who received chemotherapy at any time during the disease course. Benefit from chemotherapy was estimated by magnetic resonance imaging. Data on radiotherapy were taken into consideration. Results Thirteen patients were diagnosed with astrocytic gliomas World Health Organization (WHO) grades 1-4, the remaining eight patients with ependymomas WHO grades 1 or 3. Most patients had more than one neurosurgical intervention. Median age at time of first chemotherapy was 33 years (range 21-67 years). Seven patients had chemotherapy combined with radiotherapy as first-line treatment. Two patients had chemoradiotherapy at recurrence, without prior tumor-specific treatment beyond surgery. One patient received chemotherapy alone as first-line treatment and 2 patients had chemotherapy alone at recurrence, without prior treatment. Nine patients had received radiation therapy at an earlier time and chemotherapy was given at time of further recurrences. Best responses in astrocytomas were as follows: chemotherapy alone—2 stable disease (SD) and 3 progressive disease (PD); chemoradiotherapy—1 complete response, 3 SD, and 4 PD. Best responses in ependymomas were as follows: chemotherapy alone—1 partial response, 5 SD, and 1 PD; chemoradiotherapy—1 SD. Conclusions Spinal cord gliomas represent a heterogeneous group of tumors. Survival outcomes in response to chemotherapy in adult spinal cord glioma patients vary substantially, but individual patients appear to derive benefit from chemotherapy.

Purpose Classification and treatment of WHO grade II/III gliomas have dramatically changed. Implementing molecular markers into the WHO classification raised discussions about the significance of grading and clinical trials showed overall survival (OS) benefits for combined radiochemotherapy. As molecularly stratified treatment data outside clinical trials are scarce, we conducted this retrospective study. Methods We identified 343 patients (1995–2015) with newly diagnosed WHO grade II/III gliomas and analyzed molecular markers, patient characteristics, symptoms, histology, treatment, time to treatment failure (TTF) and OS. Results IDH-status was available for all patients (259 mutant, 84 IDH1-R132H-non-mutant). Molecular subclassification was possible in 173 tumors, resulting in diagnosis of 80 astrocytomas and 93 oligodendrogliomas. WHO grading remained significant for OS in astrocytomas/IDH1-R132H-non-mutant gliomas (p p = 0.27). Chemotherapy (and temozolomide in particular) showed inferior OS compared to radiotherapy in astrocytomas (median 6.1/12.1 years; p = 0.03) and oligodendrogliomas (median 13.2/not reached (n.r.) years; p = 0.03). While radiochemotherapy improved TTF in oligodendroglioma (median radiochemotherapy n.r./chemotherapy 3.8/radiotherapy 7.3 years; p p Conclusion This is one of the largest retrospective, real-life datasets reporting treatment and outcome in low-grade gliomas incorporating molecular markers. Current histologic grading features remain prognostic in astrocytomas while being insignificant in oligodendroglioma with interfering treatment effects. Chemotherapy (temozolomide) was less effective than radiotherapy in both astrocytomas and oligodendrogliomas while radiochemotherapy showed the highest TTF in oligodendrogliomas.

THE Incidence of the first behavioural oestrus (puberty) in 28 ewe lambs was investigated to determine the effect of the plane of nutrition on it. The ewes were randomly alloted and reared on two planes of nutrition: one exclusively on roughage (grazing and bay) the second roughage supplemented with concentrate at the rate of 454g a day from weaning to puberty. The ewe lambs were checked for standing heat with two vasectomised rams twice daily - mornings and evenings. The age and body weight at puberty and the average daily gain from weaning to puberty In unsupplemented ewes were 339.5 ± 7.8 days, 14.6 ± 0.9kg and 29.4 ± 4.7g respectively. The corresponding figures for the supplemented ewes were 262.0 ± 16.2 days, 16.2 ± 0.7kg and 73.0 ± 6.6g. The ewe lambs born as singles attained puberty at a younger age but lambs fed supplemented concentrate ration had a significantly higher growth rate and attained puberty at a significantly younger age and higher body weight than ewe lambs fed on roughage only. The durations of early postpuberal oestrus and oestrous cycle were 41.03 ± 2.94 hours and 18.00 ± 0.63 days respectively.

Rodent progressive cardiomyopathy (PCM) encompasses a constellation of microscopic findings commonly seen as a spontaneous background change in rat and mouse hearts. Primary histologic features of PCM include varying degrees of cardiomyocyte degeneration/necrosis, mononuclear cell infiltration, and fibrosis. Mineralization can also occur. Cardiotoxicity may increase the incidence and severity of PCM, and toxicity-related morphologic changes can overlap with those of PCM. Consequently, sensitive and consistent detection and quantification of PCM features are needed to help differentiate spontaneous from test article-related findings. To address this, we developed a computer-assisted image analysis algorithm, facilitated by a fully convolutional network deep learning technique, to detect and quantify the microscopic features of PCM (degeneration/necrosis, fibrosis, mononuclear cell infiltration, mineralization) in rat heart histologic sections. The trained algorithm achieved high values for accuracy, intersection over union, and dice coefficient for each feature. Further, there was a strong positive correlation between the percentage area of the heart predicted to have PCM lesions by the algorithm and the median severity grade assigned by a panel of veterinary toxicologic pathologists following light microscopic evaluation. By providing objective and sensitive quantification of the microscopic features of PCM, deep learning algorithms could assist pathologists in discerning cardiotoxicity-associated changes.

BACKGROUND There are still only a few therapeutic strategies to improve taste sensation, which is part of oral health and quality of life. OBJECTIVE Therefore, here we aimed to investigate gustatory functions of healthy subjects performing mechanical tongue cleaning (MTC), an easy-to-perform oral hygiene procedure, to demonstrate taste changes and to describe possible negative side effects. METHODS Prior to and 14 days following MTC with an Orabrush® , the following tests were conducted in 65 healthy participants including both non-smokers (n = 50, 76.9%) and smokers (n = 15, 23.1%): 'taste strips' test, the Winkel Tongue Coating Index (WTCI), and subjective self-assessment. RESULTS Among non-smokers, subjective self-assessments of gustatory function (P

The CeTeG/NOA-09 trial showed a survival benefit for combined CCNU/TMZ therapy in MGMT-promoter-methylated glioblastoma patients (quantitative methylation-specific PCR [qMSP] ratio > 2). Here, we report on the prognostic value of the MGMT promoter methylation ratio determined by qMSP and evaluate the concordance of MGMT methylation results obtained by qMSP, pyrosequencing (PSQ) or DNA methylation arrays (MGMT-STP27). A potential association of qMSP ratio with survival was analyzed in the CeTeG/NOA-09 trial population (n = 129; log-rank tests, Cox regression analyses). The concordance of MGMT methylation assays (qMSP, PSQ and MGMT-STP27) was evaluated in 76 screened patients. Patients with tumors of qMSP ratio > 4 showed superior survival compared to those with ratios 2-4 (P = .0251, log-rank test). In multivariate analysis, the qMSP ratio was not prognostic across the study cohort (hazard ratio [HR] = 0.88; 95% CI: 0.72-1.08). With different cutoffs for qMSP ratio (4, 9, 12 or 25), the CCNU/TMZ benefit tended to be larger in subgroups with lower ratios (eg, for cutoff 9: HR 0.32 for lower subgroup, 0.73 for higher subgroup). The concordance rates with qMSP were 94.4% (PSQ) and 90.2% (MGMT-STP27). Discordant results were restricted to tumors with qMSP ratios ≤4 and PSQ mean methylation rate ≤25%. Despite a shorter survival in MGMT-promoter-methylated patients with lower methylation according to qMSP, these patients had a benefit from combined CCNU/TMZ therapy, which even tended to be stronger than in patients with higher methylation rates. With acceptable concordance rates, decisions on CCNU/TMZ therapy may also be based on PSQ or MGMT-STP27.

Background Children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) are at high risk for invasive fungal disease (IFD). Methods This multicenter, randomized, open-label trial planned to enroll 560 children and adolescents (3 months to Results A planned futility analysis demonstrated a low rate of IFD in the comparator triazole arm, so the trial was closed early. A total of 290 eligible patients, with a median age of 9.5 years (range 0.3–20.7), were randomized to caspofungin (n = 144) or a triazole (n = 146; fluconazole, n = 100; voriconazole, n = 46). The day 42 cumulative incidence of proven or probable IFD was 1.4% (95% confidence interval [CI], 0.3%–5.4%) in the caspofungin group vs 1.4% (95% CI, 0.4%–5.5%) in the triazole group (P = .99, log-rank test). When stratified by specific triazole, there was no significant difference in proven or probable IFD at day 42 between caspofungin vs fluconazole (1.0%, 95% CI, 0.1%–6.9%, P = .78) or caspofungin vs voriconazole (2.3%, 95% CI, 0.3%–15.1%, P = .69). Conclusions In pediatric HCT patients, prophylaxis with caspofungin did not significantly reduce the cumulative incidence of early proven or probable IFD compared with triazoles. Future efforts to decrease IFD-related morbidity and mortality should focus on later periods of risk. Trial Registration NCT01503515.

Purpose ERGO2 is the first randomized clinical trial on a calorically restricted ketogenic diet (KD) and intermittent fasting (KD-IF) in addition to reirradiation for recurrent malignant gliomas. Methods and Materials Fifty patients were randomized 1:1 to reirradiation combined with either a calorically unrestricted diet or KD-IF. The KD-IF schedule included 3 days of KD (21-23 kcal/kg/d), followed by 3 days of fasting and again 3 days of KD. Primary endpoint was progression-free survival (PFS) at 6 months (PFS6). Secondary endpoints were PFS, local PFS, overall survival (OS), frequency of epileptic seizures, rate of ketosis and quality of life. Results Four patients quit the trial before treatment and 3 patients stopped KD-IF prematurely. Of the 20 patients who completed KD-IF, 17 patients developed ketosis at day 6 and glucose levels declined significantly. KD-IF was well-tolerated with a modest weight loss of –2.1 ± 1.8 kg. No severe adverse events attributable to the diet occurred. PFS6 was not significantly different between the 2 groups (KD-IF: 20%; calorically unrestricted diet: 16%). Similarly, no difference in PFS, local PFS6, or OS was observable. Explorative analysis revealed that patients in the KD-IF group who had a glucose level of less than the median (83.5 mg/dL) on day 6 had significantly longer PFS and OS compared with those above the median (P Conclusions KD-IF is feasible and effective in inducing ketosis in heavily pretreated patients with recurrent glioma. However, the short schedule reported here failed to increase the efficacy of reirradiation. Clinicaltrials.gov number NCT01754350.

Mucormycosis is one of the most complicated to diagnose and treat invasive fungal diseases. Diagnostic techniques have not significantly advanced in years, and recent international consensus treatment guidelines offer some insight into the current best approaches to treating this deadly invasive mold.

PURPOSE To develop a clinical practice guideline for systemic antifungal prophylaxis in pediatric patients with cancer and hematopoietic stem-cell transplantation (HSCT) recipients. METHODS Recommendations were developed by an international multidisciplinary panel that included a patient advocate. We conducted a systematic review of systemic antifungal prophylaxis in children and adults with cancer and HSCT recipients. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to make strong or weak recommendations and to classify level of evidence as high, moderate, low, or very low. The panel considered directness of the data to pediatric patients. RESULTS There were 68 randomized trials included in the systematic review, of which 6 (9%) were conducted in a solely pediatric population. Strong recommendations were made to administer systemic antifungal prophylaxis to children and adolescents receiving treatment of acute myeloid leukemia, to those undergoing allogeneic HSCT pre-engraftment, and to those receiving systemic immunosuppression for graft-versus-host disease treatment. A strong recommendation was made to administer a mold-active agent with an echinocandin or a mold-active azole when systemic antifungal prophylaxis is warranted. For children younger than 13 years of age, an echinocandin, voriconazole, or itraconazole is suggested. Posaconazole may also be used in those age 13 years or older. A strong recommendation against routine administration of amphotericin as systemic antifungal prophylaxis was made. CONCLUSION We developed a clinical practice guideline for systemic antifungal prophylaxis administration in pediatric patients with cancer and HSCT recipients. Implementation and assessment of guideline-concordant rates and impacts are important future steps.

Purposes We present the first in-human brain PET imaging data of the new α4β2 nicotinic acetylcholine receptor (nAChR)–targeting radioligand (+)-[18F]Flubatine. Aims were to develop a kinetic modeling-based approach to quantify (+)-[18F]Flubatine and compare the data of healthy controls (HCs) and patients with Alzheimer’s disease (AD); to investigate the partial volume effect (PVE) on regional (+)-[18F]Flubatine binding; and whether (+)-[18F]Flubatine binding and cognitive test data respective β-amyloid radiotracer accumulation were correlated. Methods We examined 11 HCs and 9 mild AD patients. All subjects underwent neuropsychological testing and [11C]PiB PET/MRI examination. (+)-[18F]Flubatine PET data were evaluated using full kinetic modeling and regional as well as voxel-based analyses. Results With 270-min p.i., the unchanged parent compound amounted to 97 ± 2%. Adequate fits of the time-activity curves were obtained with the 1 tissue compartment model (1TCM). (+)-[18F]Flubatine distribution volume (binding) was significantly reduced in bilateral mesial temporal cortex in AD patients compared with HCs (right 10.6 ± 1.1 vs 11.6 ± 1.4, p = 0.049; left 11.0 ± 1.1 vs 12.2 ± 1.8, p = 0.046; one-sided t tests each). PVE correction increased not only (+)-[18F]Flubatine binding of approximately 15% but also standard deviation of 0.4–70%. Cognitive test data and (+)-[18F]Flubatine binding were significantly correlated in the left anterior cingulate, right posterior cingulate, and right parietal cortex (r > 0.5, p 18F]Flubatine binding and [11C]PiB standardized uptake value ratios were negatively correlated in several regions; whereas in HCs, a positive correlation between cortical (+)-[18F]Flubatine binding and [11C]PiB accumulation in the white matter was found. No adverse event related to (+)-[18F]Flubatine occurred. Conclusion (+)-[18F]Flubatine is a safe and stable PET ligand. Full kinetic modeling can be realized by 1TCM without metabolite correction. (+)-[18F]Flubatine binding affinity was high enough to detect group differences. Of interest, correlation between white matter β-amyloid PET uptake and (+)-[18F]Flubatine binding indicated an association between white matter integrity and availability of α4β2 nAChRs. Overall, (+)-[18F]Flubatine showed favorable characteristics and has therefore the potential to serve as α4β2 nAChR–targeting PET ligand in further clinical trials.

Posttraumatic Stress Disorder (PTSD) is common in the United States, with a prevalence of nearly 8% in the general population and between 10%-30% in veterans. Despite how common PTSD is, inpatient providers may not be familiar with its manifestations or feel comfortable taking care of patients who may exhibit symptoms related to it. In our combined experience as VA-based hospital medicine care providers, we have cared for thousands of patients hospitalized for a primary medical condition who also have PTSD as a comorbidity. We have noticed in our practices that we only focus our attention on PTSD if a related problem arises during a patient’s hospitalization (eg, confrontations with the care team or high levels of anxiety). We contend that a more proactive approach could lead to better care, but little evidence about best practices exists to inform the interdisciplinary team how to optimally care for hospitalized medical patients with PTSD. In this narrative review, we present a synthesis of existing literature, describe how trauma-informed care could be used to guide the approach to patients with PTSD, and generate ideas for changes that inpatient providers could implement now, such as engaging patients to prevent PTSD exacerbations and promoting better sleep in the hospital.

To evaluate a novel fully automated mitral valve analysis software platform for cardiac computer tomography angiography (CCTA)-based structural heart therapy procedure planning. The study included 52 patients (25 women; mean age, 66.9 ± 12.4 years) who had undergone CCTA prior to transcatheter mitral valve replacement (TMVR) or surgical mitral valve intervention (replacement or repair). Therapeutically relevant mitral valve annulus parameters (projected area, circumference, trigone-to-trigone (T-T) distance, anterior-posterior (AP) diameter, and anterolateral-posteromedial (AL-PM) diameter) were measured. Results of the fully automated mitral valve analysis software platform with and without manual adjustments were compared with the reference standard of a user-driven measurement program (3mensio, Pie Medical Imaging). Measurements were compared between the fully automated software, both with and without manual adjustment, and the user-driven program using intraclass correlation coefficients (ICC). A secondary analysis included the time to obtain all measurements. Fully automated measurements showed a good to excellent agreement (circumference, ICC = 0.70; projected area, ICC = 0.81; T-T distance, ICC = 0.64; AP, ICC = 0.62; and AL-PM diameter, ICC = 0.78) compared with the user-driven analysis. There was an excellent agreement between fully automated measurement with manual adjustments and user-driven analysis regarding circumference (ICC = 0.91), projected area (ICC = 0.93), T-T distance (ICC = 0.80), AP (ICC = 0.78), and AL-PM diameter (ICC = 0.79). The time required for mitral valve analysis was significantly lower using the fully automated software with manual adjustments compared with the standard assessment (134.4 ± 36.4 s vs. 304.3 ± 77.7 s) (p < 0.01). The fully automated mitral valve analysis software, when combined with manual adjustments, demonstrated a strong correlation compared with the user-driven software while reducing the total time required for measurement. • The novel software platform allows for a fully automated analysis of mitral valve structures. • An excellent agreement was found between the fully automated measurement with manual adjustments and the user-driven analysis. • The software showed quicker measurement time compared with the standard analysis of the mitral valve.

Cryptosporidium spp. are protozoan parasites that cause enteric infection in a wide range of mammals, including humans. The raccoon (Procyon lotor) is an invasive species in many parts of the world and studies have shown that they can be infected with Cryptosporidium spp. both outside and in their original distribution area. The aim of the present study was to determine the presence of Cryptosporidium spp. antigens in the faeces of raccoons in Luxembourg. Using an enzyme-linked immunosorbent assay (ELISA), we tested 81 faeces samples, collected between 2014 and 2018, for the presence of Cryptosporidium spp. coproantigens. Samples with an optical density equal to or greater than 0.15% were considered positive. Antigens were detected in 12.35% (10/81; 95% CI 6.68–21.26) of the tested samples. There was no significant difference in the prevalence of Cryptosporidium spp. infection between the sexes and age categories. Cryptosporidium spp.-positive raccoons were found in 7 of the 12 Luxembourg administrative districts (Clervaux, Diekirch, Echternach, Mersch, Remich, Vianden and Wiltz). The results show that Cryptosporidium infections are not uncommon in Luxembourg raccoons and suggest possible transmission of Cryptosporidium by raccoons.

Introduction Cystoscopy and transurethral resection are the current reference standard tests to diagnose and histologically confirm non–muscle-invasive bladder cancer (NMIBC). In other tumor entities (ie, colon carcinoma, cervical cancer), DNA methylation markers have been approved as diagnostic tests with high diagnostic power. In our case-control study, we used an approved molecular cervical cancer diagnostics test that includes 6 DNA methylation markers (GynTect) for the detection of bladder cancer. Patients and Methods We included samples from 40 patients with bladder cancer and 34 control subjects. In a pilot study, we analyzed DNA methylation in 38 tumor tissues and 4 healthy ureters using methylation-specific polymerase chain reaction. Subsequently, we determined the sensitivity and specificity of the GynTect for the detection of bladder cancer in urine sediments from 40 patients with bladder cancer and 30 control subjects with benign prostatic hyperplasia or urolithiasis. Results The markers showed very different methylation rates in the NMIBC tissues, ranging from 2.6% to 78.9%. No methylation of any of the markers was detectable in the healthy ureters. Using the urine sediments from the patients with cancer and control subjects, we found surprisingly high sensitivity and specificity for the GynTect assay (60% and 96.7%, respectively). The application of different algorithms for evaluation of the markers included in GynTect resulted in a sensitivity of ≤ 90% and specificity of ≤ 100%. Conclusion The GynTect assay, originally designed for cervical cancer diagnostics, showed unexpectedly high diagnostic accuracy for bladder cancer detection. The inclusion of additional methylation markers might allow for the development of a suitable diagnostic marker set based on the GynTect test for NMIBC diagnostics.

BACKGROUND: Neurofibroma/schwannoma hybrid nerve sheath tumors (N/S HNSTs) are neoplasms associated with larger nerves that occur sporadically and in the context of schwannomatosis or neurofibromatosis type 2 or 1. Clinical management of N/S HNSTs is challenging, especially for large tumors, and established systemic treatments are lacking. METHODS: We used next-generation sequencing and array-based DNA methylation profiling to determine the clinically actionable genomic and epigenomic landscapes of N/S HNSTs. RESULTS: Whole-exome sequencing within a precision oncology program identified an activating mutation (p.Asp769Tyr) in the catalytic domain of the ERBB2 receptor tyrosine kinase in a patient with schwannomatosis-associated N/S HNST, and targeted treatment with the small-molecule ERBB inhibitor lapatinib led to prolonged clinical benefit and a lasting radiographic and metabolic response. Analysis of a multicenter validation cohort revealed recurrent ERBB2 mutations (p.Leu755Ser, p.Asp769Tyr, p.Val777Leu) in N/S HNSTs occurring in patients who met diagnostic criteria for sporadic schwannomatosis (3 of 7 patients), but not in N/S HNSTs arising in the context of neurofibromatosis (6 patients) or outside a tumor syndrome (1 patient), and showed that ERBB2-mutant N/S HNSTs cluster in a distinct subgroup of peripheral nerve sheath tumors based on genome-wide DNA methylation patterns. CONCLUSION: These findings uncover a key biological feature of N/S HNSTs that may have important diagnostic and therapeutic implications. FUNDING: This work was supported by grant H021 from DKFZ-HIPO, the University Cancer Center Frankfurt, and the Frankfurt Research Funding Clinician Scientist Program.

Background O6-methylguanine DNA-methyl transferase (MGMT) promoter methylation status is predictive for alkylating chemotherapy, but there are non-benefiting subgroups. Methods This is the long-term update of NOA-08 (NCT01502241), which compared efficacy and safety of radiotherapy (RT, n = 176) and temozolomide (TMZ, n = 193) at 7/14 days in patients >65 years old with anaplastic astrocytoma or glioblastoma. DNA methylation patterns and copy number variations were assessed in the biomarker cohort of 104 patients and in an independent cohort of 188 patients treated with RT+TMZ-containing regimens in Heidelberg. Results In the full NOA-08 cohort, median overall survival (OS) was 8.2 [7.0–10.0] months for TMZ treatment versus 9.4 [8.1–10.4] months for RT; hazard ratio (HR) = 0.93 (95% CI: 0.76–1.15) of TMZ versus RT. Median event-free survival (EFS) [3.4 (3.2–4.1) months vs 4.6 (4.2–5.0) months] did not differ, with HR = 1.02 (0.83–1.25). Patients with MGMT methylated tumors had markedly longer OS and EFS when treated with TMZ (18.4 [13.9–24.4] mo and 8.5 [6.9–13.3] mo) versus RT (9.6 [6.4–13.7] mo and 4.8 [4.3–6.2] mo, HR 0.44 [0.27–0.70], P < 0.001 for OS and 0.46 [0.29–0.73], P = 0.001 for EFS). Patients with glioblastomas of the methylation classes receptor tyrosine kinase I (RTK I) and mesenchymal subgroups lacked a prognostic impact of MGMT in both cohorts. Conclusion MGMT promoter methylation is a strong predictive biomarker for the choice between RT and TMZ. It indicates favorable long-term outcome with initial TMZ monotherapy in patients with MGMT promoter-methylated tumors primarily in the RTK II subgroup.

The dorsal raphe (DR) nucleus is involved in a myriad of physiological functions, such as the control of sleep-wake cycle, motivation, pain, energy balance, and food intake. We have previously demonstrated that in ad libitum fed rats the intra-DR administration of phenylephrine, an α-1 receptor agonist, does not affect food intake, whereas clonidine, an α-2 receptor agonist, potently stimulates food intake. These results indicated that in fed rats an increased adrenergic tonus blocked food intake, since the activation of α-2 auto-receptors, which decreases pre-synaptic release of adrenaline/noradrenaline, affected food intake. Thus, in this study we assessed whether the response to adrenergic stimuli would differ after overnight fasting, a situation of low adrenergic activity in the DR. Intra-DR administration of adrenaline and noradrenaline blocked food intake evoked by overnight fasting. Similarly, phenylephrine administration decreased hunger-induced food intake. These changes in food intake were accompanied by changes in other behaviors, such as increased immobility time and feeding duration. On the other hand, intra-DR administration of clonidine did not affect food-intake or associated behaviors. These results further support the hypothesis that in fed animals, increased adrenergic tonus in DR neurons inhibiting feeding, while in fasted rats the adrenergic tonus decreases and favors food intake. These data indicate a possible mechanism through which adrenergic input to the DRN contributes to neurobiology of feeding.

Background and Purpose: Clinical fluctuations in ischemic stroke symptoms are common, but fluctuations before hospital arrival have not been previously characterized. Methods: A standardized qualitative assessment of fluctuations before hospital arrival was obtained in an observational study that enrolled patients with mild ischemic stroke symptoms (National Institutes of Health Stroke Scale [NIHSS] score of 0–5) present on arrival to hospital within 4.5 hours of onset, in a subset of 100 hospitals participating in the Get With The Guidelines–Stroke quality improvement program. The number of fluctuations, direction, and the overall improvement or worsening was recorded based on reports from the patient, family, or paramedics. Baseline NIHSS on arrival and at 72 hours (or discharge if before) and final diagnosis and stroke subtype were collected. Outcomes at 90 days included the modified Rankin Scale, Barthel Index, Stroke Impact Scale 16, and European Quality of Life. Prehospital fluctuations were examined in relation to hospital NIHSS change (admission to 72 hours or discharge) and 90-day outcomes. Results: Among 1588 participants, prehospital fluctuations, consisting of improvement, worsening, or both were observed in 35.5%: 25.1% improved once, 5.3% worsened once, and 5.1% had more than 1 fluctuation. Those who improved were less likely and those who worsened were more likely to receive alteplase. Those who improved before hospital arrival had lower change in the hospital NIHSS than those who did not fluctuate. Better adjusted 90-day outcomes were noted in those with prehospital improvement compared to those without any fluctuations. Conclusions: Fluctuations in neurological symptoms and signs are common in the prehospital setting. Prehospital improvement was associated with better 90-day outcomes, controlling for admission NIHSS and alteplase treatment. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT 02072681.

Background Invasive candidiasis is the most common invasive fungal disease in children and adolescents, but there are limited pediatric-specific antifungal effectiveness data. We compared the effectiveness of echinocandins to triazoles or amphotericin B formulations (triazole/amphotericin B) as initial directed therapy for invasive candidiasis. Methods This multinational observational cohort study enrolled patients aged >120 days and Results Seven-hundred and fifty invasive candidiasis episodes were identified. After exclusions, 541 participants (235 in the echinocandin group and 306 in the triazole/amphotericin B group) remained. Crude failure rates at 14 days for echinocandin and triazole/amphotericin B groups were 9.8% (95% confidence intervals [CI]: 6.0% to 13.6%) and 13.1% (95% CI: 9.3% to 16.8%), respectively. The adjusted 14-day risk difference between echinocandin and triazole/amphotericin B groups was −7.1% points (95% CI: −13.1% to −2.4%), favoring echinocandins. The risk difference was −0.4% (95% CI: −7.5% to 6.7%) at 30 days. Conclusions In children with invasive candidiasis, initial directed therapy with an echinocandin was associated with reduced failure rate at 14 days but not 30 days. These results may support echinocandins as initial directed therapy for invasive candidiasis in children and adolescents. Clinical Trials Registration NCT01869829.

A 13-year-old male neutered mixed-breed dog with a history of gallbladder mucocele and urolithiasis was evaluated by ultrasound. Two hyperechoic, linear foreign bodies with no distal acoustic shadowing were detected in the urinary bladder and urethra. Following the ultrasound examination, the patient underwent cystoscopy, and two single hairs were found and successfully retrieved. Considering that urinary bladder foreign bodies may be a source for urinary tract infection and can act as a nidus for urocystolith formation, removal is recommended. This is the first published report describing ultrasonographic diagnosis of a hair foreign body in the canine urinary bladder and urethra.

Purpose The prospective, randomized ERGO2 trial investigated the effect of calorie-restricted ketogenic diet and intermittent fasting (KD-IF) on re-irradiation for recurrent brain tumors. The study did not meet its primary endpoint of improved progression-free survival in comparison to standard diet (SD). We here report the results of the quality of life/neurocognition and a detailed analysis of the diet diaries. Methods 50 patients were randomized 1:1 to re-irradiation combined with either SD or KD-IF. The KD-IF schedule included 3 days of ketogenic diet (KD: 21–23 kcal/kg/d, carbohydrate intake limited to 50 g/d), followed by 3 days of fasting and again 3 days of KD. Follow-up included examination of cognition, quality of life and serum samples. Results The 20 patients who completed KD-IF met the prespecified goals for calorie and carbohydrate restriction. Substantial decreases in leptin and insulin and an increase in uric acid were observed. The SD group, of note, had a lower calorie intake than expected (21 kcal/kg/d instead of 30 kcal/kg/d). Neither quality of life nor cognition were affected by the diet. Low glucose emerged as a significant prognostic parameter in a best responder analysis. Conclusion The strict caloric goals of the ERGO2 trial were tolerated well by patients with recurrent brain cancer. The short diet schedule led to significant metabolic changes with low glucose emerging as a candidate marker of better prognosis. The unexpected lower calorie intake of the control group complicates the interpretation of the results. Clinicaltrials.gov number: NCT01754350; Registration: 21.12.2012.

Background Bacteremia and other invasive bacterial infections are common among children with cancer receiving intensive chemotherapy and in pediatric recipients of hematopoietic stem cell transplantation (HSCT). Systemic antibacterial prophylaxis is one approach that can be used to reduce the risk of these infections. Our purpose was to develop a clinical practice guideline (CPG) for systemic antibacterial prophylaxis administration in pediatric patients with cancer and those undergoing HSCT. Methods An international and multidisciplinary panel was convened with representation from pediatric hematology/oncology and HSCT, pediatric infectious diseases (including antibiotic stewardship), nursing, pharmacy, a patient advocate, and a CPG methodologist. The panel used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to generate recommendations based on the results of a systematic review of the literature. Results The systematic review identified 114 eligible randomized trials of antibiotic prophylaxis. The panel made a weak recommendation for systemic antibacterial prophylaxis for children receiving intensive chemotherapy for acute myeloid leukemia and relapsed acute lymphoblastic leukemia (ALL). Weak recommendations against the routine use of systemic antibacterial prophylaxis were made for children undergoing induction chemotherapy for ALL, autologous HSCT and allogeneic HSCT. A strong recommendation against its routine use was made for children whose therapy is not expected to result in prolonged severe neutropenia. If used, prophylaxis with levofloxacin was recommended during severe neutropenia. Conclusions We present a CPG for systemic antibacterial prophylaxis administration in pediatric cancer and HSCT patients. Future research should evaluate the long-term effectiveness and adverse effects of prophylaxis., This clinical practice guideline presents recommendations for systemic antibacterial prophylaxis administration in pediatric cancer and hematopoietic stem cell transplantation patients. The recommendations were developed by an international panel based on the results of a systematic review of 114 randomized trials.

Objective Evaluate the MR distribution of inflammatory sacroiliac joint changes in axial spondyloarthritis phenotypes, including Ankylosing Spondylitis (AS) and non-radiographic Axial Spondyloarthritis (nrAxSpA). Methods A retrospective review of 94 patients seen for treatment of axial spondyloarthritis (SpA) who underwent sacroiliac joint MRI between January 2011 and December 2015 was performed. MR images from 68 patients (20 with AS and 48 with nrAxSpA) were reviewed independently by two radiologists. Images were scored on presence of active inflammatory and chronic structural lesions. These lesions were further categorized as unilateral, bilateral and asymmetric, or bilateral and symmetric. Results No statistically significant difference was found in the distribution (laterality or symmetry) of bone marrow edema or sclerosis between the AS and nr-axSpA groups. Osseous erosions were more commonly bilateral symmetric in AS than nr-axSpA (11/20 vs. 8/48, p = 0.01). No statistically significant difference was noted between bone marrow edema scores in the AS and nr-axSpA subgroups (2.6 vs 3.3, p = 0.514). Patients with AS had a significantly higher fat metaplasia score compared to patients with nr-axSpA (7.3 vs 1.1, p = 0.001). Patients with nr-axSpA had a higher mean score for erosions (11.6 vs 4.2, p = 0.001). Only patients classified as AS were found to have bony ankylosis. Inter-observer reliability was strong to excellent. Conclusion Ankylosing spondylitis findings at the sacroiliac joints are classically described as bilateral and symmetric on radiographs. Our study demonstrates that distribution on MRI at an individual time point is variable. The variable distribution should be considered when radiologists evaluate MRI exams of AS patients.

Aims: The purpose of this international survey was to describe the impact of current practices and techniques of caesarean section on the neonatal Apgar score in the Czech Republic (CZE) and Slovakia (SVK). Methods: All Czech and Slovak departments that provide obstetric anaesthesia were invited to participate in a one-month (November 2015) prospective study that monitored in details all peripartum anaesthetic practices, delivered by anaesthesiologists. Participating centers recorded all data on-line in the CLADE-IS database (Masaryk University, CZE). Results and Discussions. We collected data of 10119 women who delivered 10226 newborns. A caesarean section was recorded in 25.1% of deliveries (CZE 23.2%; SVK 30%). General anaesthesia was used for caesarean section in 37.5% of the cases (CZE 40%, SVK 33%). There was no statistically significant difference in the Apgar score lower than 7 in the 1, 5 or 10 min in groups of general and regional anaesthesia for caesarean section, when only elective sections of in-term babies with birth weight over 2500 g were analyzed. We found no statistically significant differences in the Apgar score in newborns of women intubated for caesarean section in rocuronium (n=21; 2.2%) and suxamethonium (n=889; 93%). Conclusion: We found no difference in neonatal outcomes in groups of general and regional anaesthesia for caesarean section when only out-of-risk newborns were analyzed. The risk factors were identified as follows: an acute caesarean section, preterm babies, birth weight less than 2 500 g, born in perinatological center and multiple pregnancy - second baby. Trial Registration: ClinicalTrials.gov (ID: NCT02380586) https://clinicaltrials.gov/ct2/show/NCT02380586

The enzyme O6-methylguanine-DNA methyltransferase (MGMT) is an important component of the DNA repair machinery. MGMT removes O6-methylguanine from the DNA by transferring the methyl group to a cysteine residue in its active site. Recently, we detected the single nucleotide polymorphism (SNP) rs12917 (C/T) in the MGMT sequence adjacent to the active site in Hodgkin lymphoma (HL) cell line KM-H2. We now investigated whether this SNP is also present in other HL cell lines and patient samples. Furthermore, we asked whether this SNP might have an impact on metabolic response in 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography ([18F]FDG-PET), and on overall treatment outcome based on follow-up intervals of at least 34 months. We determined the frequency of this MGMT polymorphism in 5 HL cell lines and in 29 pediatric HL (PHL) patients. The patient cohort included 17 female and 12 male patients aged between 4 and 18 years. After characterization of the sequence, we tested a possible association between rs12917 and age, gender, Ann Arbor stage, treatment group, metabolic response following two courses of OEPA (vincristine, etoposide, prednisone, and doxorubicin) chemotherapy, radiotherapy indication, and relapse status. We detected the minor T allele in four of five HL cell lines. 11/29 patients carried the minor T allele whereas 18/29 patients showed homozygosity for the major C allele. Interestingly, we observed significantly better metabolic response in PHL patients carrying the rs12917 C allele resulting in a lower frequency of radiotherapy indication. MGMT polymorphism rs12917 seems to affect chemotherapy response in PHL. The prognostic value of this polymorphism should be investigated in a larger patient cohort.

Infections and graft-versus-host disease (GVHD) have historically resulted in high mortality among children undergoing umbilical cord blood transplantation (UCBT). However, recent advances in clinical practice have likely improved outcomes of these patients. We conducted a retrospective cohort study of children (18years of age) undergoing UCBT at Duke University between January 1, 1995 and December 31, 2014. We compared 2-year all-cause and cause-specific mortality during 3 time periods based on year of transplantation (1995 to 2001, 2002 to 2007, and 2008 to 2014). We used multivariable Cox regression to identify demographic and UCBT characteristics that were associated with all-cause mortality, transplantation-related mortality, and death from invasive aspergillosis after adjustment for time period. During the 20-year study period 824 children underwent UCBT. Two-year all-cause mortality declined from 48% in 1995 to 2001 to 30% in 2008 to 2014 (P = .0002). White race and nonmalignant UCBT indications were associated with lower mortality. Black children tended to have a higher risk of death for which GVHD (18% versus 11%; P = .06) or graft failure (9% versus 3%; P = .01) were contributory than white children. Comparing 2008 to 2014 with 1995 to 2001, more than half (59%) of the reduced mortality was attributable to a reduction in infectious mortality, with 45% specifically related to reduced mortality from invasive aspergillosis. Antifungal prophylaxis with voriconazole was associated with lower mortality from invasive aspergillosis than low-dose amphotericin B lipid complex (hazard ratio, .09; 95% confidence interval, .01 to .76). With the decline in mortality from invasive aspergillosis, adenovirus and cytomegalovirus have become the most frequentinfectious causes of death in children after UCBT. Advances in clinical practice over the past 20years improved survival of children after UCBT. Reduced mortality from infections, particularly invasive aspergillosis, accounted for the largest improvement in survival and was associated with use of voriconazole for antifungal prophylaxis.

Cell-free DNA (cfDNA) harboring mutations has been found in patients with diseases. Experimental studies have shown that cfDNA can be transmitted, leading to transformations in the host. In the present study, we evaluated whether bone allograft material contains cfDNA and whether this foreign cfDNA can be released into the patient’s blood circulation. Plasma samples were collected preoperatively and postoperatively on the same day, at 5 weeks, and 4 months from 25 women who received bone allograft material (test group) from male donors and from 10 women who were treated with autologous graft (control group, only pre- and postoperative samples were collected). DNA was quantified and characterized in bone material and plasma samples by quantitative PCR with primers specific for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Y chromosome and gel electrophoresis. DNA in bone material was digested by different concentrations of DNase I. We detected between 1 and 1.8 μg cfDNA fragments at a length around 601 base pairs (bp) and smaller in each 100 mg allograft. Treatment of the allograft with DNase I completely degraded the longer but not the shorter DNA 90-bp fragments. Y-DNA was not detected in the patients’ bloodstream at any time during the treatment and follow-up, but elevated levels of circulating cfDNA could be measured immediately postoperatively. Our results suggest that a transmission of DNA from allografts used for alveolar ridge reconstruction in humans is unlikely. The observed increase in circulating cfDNA in allograft and autograft patients immediately postoperatively may be elicited by the surgical procedure. The results support the safety of allograft materials. The results suggest that human allograft materials seem not to release DNA into the blood since we did not measure Y-DNA with our technique.

Summary Background There is an urgent need for more effective therapies for glioblastoma. Data from a previous unrandomised phase 2 trial suggested that lomustine-temozolomide plus radiotherapy might be superior to temozolomide chemoradiotherapy in newly diagnosed glioblastoma with methylation of the MGMT promoter. In the CeTeG/NOA-09 trial, we aimed to further investigate the effect of lomustine-temozolomide therapy in the setting of a randomised phase 3 trial. Methods In this open-label, randomised, phase 3 trial, we enrolled patients from 17 German university hospitals who were aged 18–70 years, with newly diagnosed glioblastoma with methylated MGMT promoter, and a Karnofsky Performance Score of 70% and higher. Patients were randomly assigned (1:1) with a predefined SAS-generated randomisation list to standard temozolomide chemoradiotherapy (75 mg/m 2 per day concomitant to radiotherapy [59–60 Gy] followed by six courses of temozolomide 150–200 mg/m 2 per day on the first 5 days of the 4-week course) or to up to six courses of lomustine (100 mg/m 2 on day 1) plus temozolomide (100–200 mg/m 2 per day on days 2–6 of the 6-week course) in addition to radiotherapy (59–60 Gy). Because of the different schedules, patients and physicians were not masked to treatment groups. The primary endpoint was overall survival in the modified intention-to-treat population, comprising all randomly assigned patients who started their allocated chemotherapy. The prespecified test for overall survival differences was a log-rank test stratified for centre and recursive partitioning analysis class. The trial is registered with ClinicalTrials.gov, number NCT01149109. Findings Between June 17, 2011, and April 8, 2014, 141 patients were randomly assigned to the treatment groups; 129 patients (63 in the temozolomide and 66 in the lomustine-temozolomide group) constituted the modified intention-to-treat population. Median overall survival was improved from 31·4 months (95% CI 27·7–47·1) with temozolomide to 48·1 months (32·6 months–not assessable) with lomustine-temozolomide (hazard ratio [HR] 0·60, 95% CI 0·35–1·03; p=0·0492 for log-rank analysis). A significant overall survival difference between groups was also found in a secondary analysis of the intention-to-treat population (n=141, HR 0·60, 95% CI 0·35–1·03; p=0·0432 for log-rank analysis). Adverse events of grade 3 or higher were observed in 32 (51%) of 63 patients in the temozolomide group and 39 (59%) of 66 patients in the lomustine-temozolomide group. There were no treatment-related deaths. Interpretation Our results suggest that lomustine-temozolomide chemotherapy might improve survival compared with temozolomide standard therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. The findings should be interpreted with caution, owing to the small size of the trial. Funding German Federal Ministry of Education and Research.

Our lab has previously shown that patients with early glaucoma have longer vection latencies than controls. We attempted to explain this finding using a combined index of structure and function (CSFI), as proposed by Medeiros and colleagues. The CSFI estimates the proportion of retinal ganglion cell loss.Roll and circular vection were evoked using a back-projected screen (experiment 1) and the Oculus Rift system (experiment 2). Vection latency and duration were measured using a button response box. In experiment 1, tilt angles were measured with a tilt sensor, whereas subjective tilt was determined using a joystick attached to a protractor. In experiment 2, subjective vection strength was rated on a 1 to 10 scale. These measurements were compared with the CSFI, which utilizes visual field and optical coherence tomography data.For experiment 1 we tested 22 patients (mean age, 70.3±6 y) with glaucoma and 18 controls (mean age, 54.6±9 y); and for experiment 2 we tested 24 patients (mean age, 71.1 ±5 y) and 23 controls (mean age 61.4±10 y), but not all patients experienced vection. In both experiments, vection latency was significantly longer for patients than for controls (smallest P=0.02). The CSFI was not related to vection latency, duration, or objective and subjective measures of vection strength (smallest P=0.06) in either experiment.Two experiments have replicated the finding that vection responses are longer in patients with glaucoma than in controls; however, the CSFI is not related to vection responses.

Background Diffuse low-grade gliomas (DLGGs) are rare and incurable tumors. Whereas maximal safe, functional-based surgical resection is the first-line treatment, the timing and choice of further treatments (chemotherapy, radiation therapy, or combined treatments) remain controversial. Methods An online survey on the management of DLGG patients was sent to 28 expert centers from the European Low-Grade Glioma Network (ELGGN) in May 2015. It contained 40 specific questions addressing the modalities of use of chemotherapy in these patients. Results The survey demonstrated a significant heterogeneity in practice regarding the initial management of DLGG patients and the use of chemotherapy. Interestingly, radiation therapy combined with the procarbazine, CCNU (lomustine), and vincristine regimen has not imposed itself as the gold-standard treatment after surgery, despite the results of the Radiation Therapy Oncology Group 9802 study. Temozolomide is largely used as first-line treatment after surgical resection for high-risk DLGG patients, or at progression. Conclusions The heterogeneity in the management of patients with DLGG demonstrates that many questions regarding the postoperative strategy and the use of chemotherapy remain unanswered. Our survey reveals a high recruitment potential within the ELGGN for retrospective or prospective studies to generate new data regarding these issues.

The Lancet Countdown: tracking progress on health and climate change was established to provide an independent, global monitoring system dedicated to tracking the health dimensions of the impacts of, and the response to, climate change. The Lancet Countdown tracks 41 indicators across five domains: climate change impacts, exposures, and vulnerability; adaptation, planning, and resilience for health; mitigation actions and health co-benefits; finance and economics; and public and political engagement. This report is the product of a collaboration of 27 leading academic institutions, the UN, and intergovernmental agencies from every continent. The report draws on world-class expertise from climate scientists, ecologists, mathematicians, geographers, engineers, energy, food, livestock, and transport experts, economists, social and political scientists, public health professionals, and. doctors. The Lancet Countdown’s work builds on decades of research in this field, and was first proposed in the 2015 Lancet Commission on health and climate change,1 which documented the human impacts of climate change and provided ten global recommendations to respond to this public health emergency and secure the public health benefits available (panel 1).

Bacterial vaginosis (BV) is one of the most common vaginal infections that affects hundreds of millions of women of reproductive age, worldwide. Traditional treatment strategies, such as oral and topical antibiotics, have shown efficacy against BV, but frequent recurrence of infection and the development of antibiotic-resistant bacteria remain as significant challenges. Alternatively, recent progress in understanding immune, microbiological, and metabolic interactions in the vaginal microbiota has prompted the consideration of administering probiotic organisms to restore and maintain vaginal health within the context of BV prevention and treatment. Given this, the objective of this review is to discuss existing and potential alternative approaches to deliver, and to potentially sustain the delivery of probiotics, to prevent and/or treat BV infections. First, a brief overview is provided regarding the probiotic species and combinatorial probiotic strategies that have shown promise in the treatment of BV and in restoring female reproductive health. Additionally, the advantages and challenges associated with current oral and intravaginal probiotic delivery platforms are discussed. Lastly, we present emerging and promising alternative dosage forms, such as electrospun fibers and 3D bioprinted scaffolds, that may be adapted as new strategies to intravaginally deliver probiotic organisms. Graphical abstract.

BACKGROUND Novel therapies are needed in newly diagnosed glioblastoma as nearly all patients experience recurrence following standard-of-care radiotherapy (RT) + temozolomide (TMZ), including patients with tumors with methylated MGMT promoter, a positive prognostic factor and predictor of benefit with TMZ. Here, we report the final analysis of progression-free survival (PFS), overall survival (OS), and safety from an international randomized, single-blind phase-3 study of nivolumab (NIVO)+RT+TMZ in patients with newly diagnosed glioblastoma with methylated/indeterminate MGMT promoter (CheckMate 548; NCT02667587). METHODS Patients (N=716) aged ≥ 18y were randomized 1:1 regardless of tumor PD-L1 expression to NIVO (240 mg Q2W×8, then 480 mg Q4W) + RT (60 Gy over 6 weeks) + TMZ (75 mg/m2 QD during RT, then 4-week break, then 150–200 mg/m2 QD on days 1–5 of every 28-day cycle for 6 cycles) or placebo (PBO)+RT+TMZ. The dual-primary endpoints were PFS by blinded independent central review and OS, both overall and without baseline corticosteroids. RESULTS As of December 22, 2020, median PFS was 10.6 months (95% CI, 8.9–11.8) with NIVO+RT+TMZ and 10.3 months (95% CI, 9.7–12.5) with PBO+RT+TMZ (HR, 1.06 [95% CI, 0.90–1.25]). Median OS was 28.9 months (95% CI, 24.4–31.6) with NIVO+RT+TMZ and 32.1 months (95% CI, 29.4–33.8) with PBO+RT+TMZ (HR, 1.10 [95% CI, 0.91–1.33]). Among patients without baseline corticosteroids, median OS was 31.3 months (95% CI, 28.6–34.8) with NIVO+RT+TMZ and 33.0 months (95% CI, 31.0–35.1) with PBO+RT+TMZ (HR, 1.12 [95% CI, 0.87–1.43]). Grade 3–4 treatment-related adverse events were 52.4% and 33.6% with NIVO+RT+TMZ and PBO+RT+TMZ, respectively. CONCLUSIONS NIVO added to RT+TMZ did not improve survival in patients with newly diagnosed glioblastoma with methylated/indeterminate MGMT promoter. No new safety signals were observed with NIVO. The role of immunotherapy in this treatment landscape remains an area for further investigation.

Background and AimsThe host receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small intestine. Our aim was to study colonic ACE2 expression in Crohn’s disease (CD) and non-inflammatory bowel disease (non-IBD) controls. We hypothesized that the colonic expression levels of ACE2 impacts CD course.MethodsWe examined the expression of colon ACE2 using RNA-seq and quantitative (q) RT-PCR from 69 adult CD and 14 NIBD control patients. In a subset of this cohort we validated ACE2 protein expression and localization in formalin-fixed, paraffin-embedded matched colon and ileal tissues using immunohistochemistry. The impact of increased ACE2 expression in CD for the risk of surgery was evaluated by a multivariate regression analysis and a Kaplan-Meier estimator. To provide critical support for the generality of our findings, we analyzed previously published RNA-seq data from two large independent cohorts of CD patients.ResultsColonic ACE2 expression was significantly higher in a subset of adult CD patients (ACE2-high CD). IHC in a sampling of ACE2-high CD patients confirmed high ACE2 protein expression in the colon and ileum compared to ACE2-low CD and NIBD patients. Notably, we found that ACE2-high CD patients are significantly more likely to undergo surgery within 5 years of diagnosis, with a Cox regression analysis finding that high ACE2 levels is an independent risk factor (OR 2.18; 95%CI, 1.05-4.55; p=0.037).ConclusionIncreased intestinal expression of ACE2 is associated with deteriorated clinical outcomes in CD patients. These data point to the need for molecular stratification that may impact CD disease-related outcomes.

Background: In brain tumor surgery, injury to cerebellar connectivity pathways can induce a neurodegenerative disease called hypertrophic olivary degeneration (HOD), along with a disabling clinical syndrome. In children, cerebellar mutism syndrome (CMS) is another consequence of damage to cerebello&ndash, thalamo&ndash, cortical networks. The goal of this study was to compare paravermal trans-cerebellar to other more midline or lateral operative approaches in their risk of causing HOD on MR-imaging and CMS. Methods: We scanned our neurosurgical database for patients with surgical removal of pilocytic astrocytoma, ependymoma and medulloblastoma in the posterior fossa. Fifty patients with a mean age of 22.7 (&plusmn, 16.9) years were identified and analyzed. Results: HOD occurred in n = 10/50 (20%) patients within four months (median), always associated with contralateral dentate nucleus (DN)-lesions (p &lt, 0.001). Patients with paravermal trans-cerebellar approach significantly more often developed HOD (7/11, 63.6%) when compared to other approaches (3/39, 7.7%, p &lt, 0.001). Injury to the DN occurred more frequently after a paravermal approach (8/11 vs. 13/39 patients, 0.05). CMS was described for n = 12/50 patients (24%). Data indicated no correlation of radiological HOD and CMS development. Conclusions: A paravermal trans-cerebellar approach more likely causes HOD due to DN-injury when compared to more midline or lateral approaches. HOD is a radiological indicator for surgical disruption of cerebellar pathways involving the DN. Neurosurgeons should consider trajectories and approaches in the planning of posterior fossa surgery that spare the DN, whenever feasible.

Although invasive aspergillosis is the most common invasive mold infection, mucormycosis and other non-Aspergillus opportunistic mold infections are increasingly associated with significant morbidity and mortality among highly immunocompromised patients. Early clinical suspicion is critically important to accurately distinguish, diagnose, and appropriately treat these rapidly progressive infections. Their relative rarity compared with other infections in these patient populations makes diagnosis and treatment challenging owing to the lack of large-scale available data, and therefore, current clinical outcomes remain far from ideal.

Background and purpose Systemic molecular radiotherapy utilizes internal irradiation by radionuclide-labeled tumor-targeting agents with the potential to destroy (micro-)metastases. However, doses that are applicable in solid tumors do not reach the levels nessecary for tumor control. Thus, the combination of molecular and external radiotherapy is a promising treatment strategy, as enhanced tumor doses can be delivered with and without minor overlapping toxicities. Here, we combined a 90Y-labeled anti-EGFR antibody (Cetuximab) with clinically relevant fractionated radiotherapy in a preclinical trial using head and neck squamous cell carcinoma xenograft tumors. Materials and methods To model 90Y-Cetuximab uptake for treatment schedule optimization, FaDu-bearing mice were injected with near-infrared-labeled-Cetuximab at different time points during radiotherapy with differing doses. Cetuximab uptake was longitudinally followed by in vivo-optical imaging. Tumor control probability experiments with fractionated radiotherapy (30 fx, 6 weeks, 8 dose groups/ arm) in combination with 90Y-Cetuximab were performed to test the curative potential. Results Imaging of near-infrared-labeled-Cetuximab uptake revealed that low to moderate external beam doses can enhance antibody uptake. Using the optimized schedule, combination of molecular and external radiotherapy using 90Y-Cetuximab at a dose that did not result in permanent tumor inactivation in previous experiments, led to substantially increased tumor control compared to radiotherapy alone. Conclusion Our results indicate that combination of radiolabeled therapeutics with clinically relevant fractionated radiotherapy has a remarkable potential to improve curative treatment outcome. Application of some radiation dose prior to injection may improve drug uptake and enable patient stratification and treatment personalization via a corresponding PET-tracer during therapy.

Purpose: This prospective trial investigates the association of time to recurrence (TTR) in glioblastoma with [11C]methionine (MET) tracer uptake before postoperative radiochemotherapy (RCT) aiming to guide radiotherapy boost regions. Experimental Design: Between 2013 and 2016, 102 patients with glioblastoma were recruited. RCT was performed with concurrent and adjuvant temozolomide to a total dose of 60 Gy. Tumor residues in postresection PET and MRI were together defined as gross tumor volumes for radiotherapy treatment planning. [11C]methionine (MET)-PET/MRI was performed before RCT and at each follow-up. Results: The primary hypothesis of a longer TTR for patients without increased tracer accumulation in postoperative MET-PET was confirmed in 89 patients. With 18.9 months (95% confidence interval, 9.3–28.5 months), median TTR was significantly (P < 0.001) longer for patients without (n = 29, 32.6%) as compared with 6.3 months (3.6–8.9) for patients with MET accumulation (n = 60, 67.4%) in pre-RCT PET. Although MRI often did not detect all PET-positive regions, an unfavorable impact of residual tumor in postsurgical MRI (n = 38, 42.7%) on TTR was observed [4.6 (4.2–5.1) vs. 15.5 months (6.0–24.9), P < 0.001]. Significant multivariable predictors for TTR were MRI positivity, PET-positive volume, and O6-methylguanine DNA methyltransferase (MGMT) hypermethylation. Conclusions: Postsurgical amino acid PET has prognostic value for TTR after RCT in glioblastoma. Because of the added value of the metabolic beyond the pure structural information, it should complement MRI in radiotherapy planning if available with reasonable effort, at least in the context of maximal therapy. Furthermore, the spatial correlation of regions of recurrence with PET-positive volumes could provide a bioimaging basis for further trials, for example, testing local radiation dose escalation.

Objective The association of body mass index (BMI) and all-cause mortality is controversial, frequently referred to as a paradox. Whether the cause is metabolic factors or statistical biases is still controversial. We assessed the association of BMI and all-cause mortality considering a wide range of comorbidities and baseline mortality risk. Methods Retrospective cohort study of Olmsted County residents with at least one BMI measurement between 2000–2005, clinical data in the electronic health record and minimum 8 year follow-up or death within this time. The cohort was categorized based on baseline mortality risk: Low, Medium, Medium-high, High and Very-high. All-cause mortality was assessed for BMI intervals of 5 and 0.5 Kg/m2. Results Of 39,739 subjects (average age 52.6, range 18–89; 38.1% male) 11.86% died during 8-year follow-up. The 8-year all-cause mortality risk had a “U” shape with a flat nadir in all the risk groups. Extreme BMI showed higher risk (BMI Conclusions There is a complex association between BMI and all-cause mortality when evaluated including comorbidities and baseline mortality risk. In general, comorbidities are better predictors of mortality risk except at extreme BMIs. In patients with no or few comorbidities, BMI seems to better define mortality risk. Aggressive management of comorbidities may provide better survival outcome for patients with body mass between normal and moderate obesity.

Introduction. Neurons with long neurites are physiologically remarkable, as they need to transport newly synthesized proteins and organelles (e.g. mitochondria) from the soma over long distances to the synapses, which is essential for neuronal homeostasis. Via adaptor proteins, which walk on microtubules, organelles find their target place. Next to microtubules, the neuronal cytoskeleton consists of neurofilaments, and actin: neurofilaments regulate axonal caliber, and actin is involved in the neuronal shape (Eira et al. 2016, Hoffman et al. 1984). A misbalance or dysfunction of cytoskeletal components might contribute to neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). Neurofilament light chain (NfL) is an established biomarker for ALS (Bacioglu et al. 2016). Here, we study the human cytoskeletal components during aging. As a model we chose sensory neurons which possess long processes and axon endings can be accessed easily by skin biopsies. In this study we focus on the expression levels of microtubules, neurofilaments, and actin in skin biopsies of healthy individuals. Furthermore, we analyze the axonal diameter. Methods. Skin biopsies (thigh and ankle) of 27 men (mean age 54.2 ± 18.9 a, from 24 a to 79 a) were PFA-fixed and cut. Fluorescent immunostaining for non-phosphorylated neurofilament heavy chain (npNfH), betaIII-tubulin, and actin was performed. Images of the dermis were acquired by confocal microscopy. At least 20 axons per healthy individual were analyzed for the mean gray values and diameter. Statistics were calculated using GraphPad Prism (V9). This study was approved by the local ethics committee. Participants gave informed written consent. Results. Cytoskeletal components (npNfH, betaIII-tubulin, actin) drastically increased with age. NpNfH increased 2.7-fold from 24- to 75-year-old individuals. Actin showed a change of 3.8-fold from the youngest to the 62-year-old controls (peak, maximum values), whereas betaIII-tubulin levels increased 3.2-fold from the 24- to the 75-year-old healthy individuals. Sensory axon caliber increased 2.2-fold from the 29- (1.35 µm) to the 78/79-year old (2.97 µm) controls which results in a 4.9-fold increase of the cross-sectional area of the axons. Statistical analysis (Mann-Whitney U test) showed highly significant results between each staining/caliber and age (p Discussion. Our results suggest an age-driven “ossification” of the axonal cytoskeleton in peripheral sensory axons, which might influence cytoskeletal functionality and axonal caliber. The age-dependent increase in caliber can be explained by the higher expression of neurofilaments, which mainly regulate the diameter of axons (Costa et al. 2018). These findings are in accordance with the increased susceptibility of aged individuals to neurodegenerative diseases. The results reported here will be validated in a second independent cohort (27 men, age 26 to 74). We further plan the analysis of length dependency as biopsies were obtained from thigh and ankle.

BackgroundMucormycosis is a difficult to diagnose rare disease with high morbidity and mortality. Diagnosis is often delayed, and disease tends to progress rapidly. Urgent surgical and medical intervention is lifesaving. Guidance on the complex multidisciplinary management has potential to improve prognosis, but approaches differ between health care settings.MethodsFrom January 2018, authors from 33 countries in all United Nations regions analysed the published evidence on mucormycosis management and provided consensus recommendations addressing differences between the regions of the world as part of the “One World One Guideline” initiative of the European Confederation of Medical Mycology (ECMM). The author group based in 17 time zones, relied on electronic media including video tutorial on methodology, and central document repository with several daily updates.FindingsSigns and symptoms of mucormycosis depend on organ patterns and underlying conditions. Diagnostic management does not differ greatly between world regions. Upon suspicion of mucormycosis appropriate imaging is strongly recommended to document extent of disease and is followed by strongly recommended surgical intervention. First-line treatment with high-dose liposomal amphotericin B is strongly recommended, while intravenous isavuconazole and intravenous or delayed release tablet posaconazole are recommended with moderate strength. Both triazoles are strongly recommended salvage treatments. Amphotericin B deoxycholate is recommended against, because of substantial toxicity, but may be the only option in resource limited settings.InterpretationManagement of mucormycosis depends on recognising disease patterns and on early diagnosis. Limited availability of contemporary treatments burdens patients in low and middle income settings. Areas of uncertainty were identified and future research directions specified.