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Objectives We report the clinical, radiological, laboratory, and neuropathological findings in support of the first diagnosis of lethal, small-vessel cerebral vasculitis triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a pediatric patient. Patient description A previously healthy, 8-year-old Hispanic female presented with subacute onset left-sided weakness two weeks after a mild febrile illness. SARS-CoV-2 nasopharyngeal swab was positive. Magnetic resonance imaging (MRI) revealed an enhancing right frontal lobe lesion with significant vasogenic edema. Two brain biopsies of the lesion showed perivascular and intraluminal lymphohistiocytic inflammatory infiltrate consistent with vasculitis. Despite extensive treatment with immunomodulatory therapies targeting primary angiitis of the central nervous system, she experienced neurologic decline and died 93 days after presentation. SARS-CoV-2 testing revealed positive serum IgG and positive cerebrospinal fluid IgM. Comprehensive infectious, rheumatologic, hematologic/oncologic, and genetic evaluation did not identify an alternative etiology. Post-mortem brain autopsy remained consistent with vasculitis. Discussion This is the first pediatric presentation to suggest SARS-CoV-2 can lead to a fatal, post-infectious, inflammatory small-vessel cerebral vasculitis. Our case is unique in including supportive cerebrospinal fluid and post-mortem tissue analysis. While most children recover well from neurologic complications of SARS-CoV-2, we emphasize the potential mortality in a child with no risk factors for severe disease.

Background Diffuse intrinsic pontine glioma (DIPG) remains a clinico-radiologic diagnosis without routine tissue acquisition. Reliable imaging distinction between DIPG and other pontine tumors with potentially more favorable prognoses and treatment considerations is essential. Methods Cases submitted to the International DIPG registry (IDIPGR) with histopathologic and/or radiologic data were analyzed. Central imaging review was performed on diagnostic brain MRIs (if available) by two neuro-radiologists. Imaging features suggestive of alternative diagnoses included nonpontine origin, Results Among 286 patients with pathology from biopsy and/or autopsy, 23 (8%) had histologic diagnoses inconsistent with DIPG, most commonly nondiffuse low-grade gliomas and embryonal tumors. Among 569 patients with centrally-reviewed diagnostic MRIs, 40 (7%) were classified as non-DIPG, alternative diagnosis suspected. The combined analysis included 151 patients with both histopathology and centrally-reviewed MRI. Of 77 patients with imaging classified as characteristic of DIPG, 76 (99%) had histopathologic diagnoses consistent with DIPG (infiltrating grade II-IV gliomas). Of 57 patients classified as likely DIPG with some unusual imaging features, 55 (96%) had histopathologic diagnoses consistent with DIPG. Of 17 patients with imaging features suggestive of an alternative diagnosis, eight (47%) had histopathologic diagnoses inconsistent with DIPG (remaining patients were excluded due to nonpontine tumor origin). Association between central neuro-imaging review impression and histopathology was significant (p < 0.001), and central neuro-imaging impression was prognostic of overall survival. Conclusions The accuracy and important role of central neuro-imaging review in confirming the diagnosis of DIPG is demonstrated.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Post-marketing surveillance (PMS) is an important part of monitoring adverse events (AEs). AIMS: To report an analysis of PMS case safety reports for tofacitinib in patients with UC METHODS: Worldwide tofacitinib PMS reports received in the Pfizer safety database from 30 May 2018 (first regulatory approval) to 25 August 2020 were analysed. The type and estimated reporting rate (RR) of serious AEs of interest, including infection, gastrointestinal, vascular, respiratory, neoplasm and cardiac events, were reviewed. Patient-years of exposure (PY) was estimated based on worldwide sales data and the calculated daily regimens of tofacitinib 5 or 10 mg twice daily, immediate- or extended-release formulations. RESULTS: During the 27-month reporting period, worldwide post-marketing exposure to tofacitinib was 8916 PY. Overall, 4226 case reports were received and included 12 103 AEs, of which 1839 were serious AEs (SAEs). Among the cases reported, 1141 (27.0%) included an SAE and 18 (0.4%) were fatal. The RR (per 100 PY) for SAEs of interest by Medical Dictionary for Regulatory Activities System Organ Class were 3.28 for infections, 1.26 for vascular disorders, 0.74 for respiratory disorders, 0.55 for neoplasms and 0.50 for cardiac disorders. CONCLUSIONS: The types of AEs were consistent with those reported in tofacitinib clinical trials. Most reported AEs were non-serious. Limitations of PMS reports and reliance on estimated RRs due to lack of precise values for exposure, required for incidence rate calculation, should be considered when interpreting these results. ispartof: ALIMENTARY PHARMACOLOGY & THERAPEUTICS vol:55 issue:3 pages:302-310 ispartof: location:England status: published

OBJECTIVEThe aim of this study was to investigate diffusion tensor imaging (DTI), an objective and noninvasive neuroimaging technique, for its potential as an imaging biomarker to predict the need and timing of CSF diversion surgery in patients after prenatal myelomeningocele (MMC) repair.METHODSThis was a retrospective analysis of data based on 35 pediatric patients after prenatal MMC repair (gestational age at birth 32.68 ± 3.42 weeks, range 24–38 weeks; 15 females and 20 males). A logistic regression analysis was used to classify patients to determine the need for CSF diversion surgery. The model performance was compared between using the frontooccipital horn ratio (FOHR) alone and using the FOHR combined with DTI values (the genu of the corpus callosum [gCC] and the posterior limb of the internal capsule [PLIC]). For patients who needed to be treated surgically, timing of the procedure was used as the clinical outcome to test the predictive value of DTI acquired prior to surgery based on a linear regression analysis.RESULTSSignificantly lower fractional anisotropy (FA) values in the gCC (p = 0.014) and PLIC (p = 0.037) and higher mean diffusivity (MD) values in the gCC (p = 0.013) were found in patients who required CSF diversion surgery compared with those who did not require surgery (all p values adjusted for age). Based on the logistic regression analysis, the FOHR alone showed an accuracy of performance of 0.69 and area under the receiver operating characteristic curve (AUC) of 0.60. The performance of the model was higher when DTI measures were used in the logistic regression model (accuracy = 0.77, AUC = 0.84 for using DTI values in gCC; accuracy = 0.75, AUC = 0.84 for using DTI values in PLIC). Combining the DTI values of the gCC or PLIC and FOHR did not improve the model performance when compared with using the DTI values alone. In patients who needed CSF diversion surgery, significant correlation was found between DTI values in the gCC and the time interval between imaging and surgery (FA: ρ = 0.625, p = 0.022; MD: ρ = −0.6830, p = 0.010; both adjusted for age and FOHR).CONCLUSIONSThe authors’ data demonstrated that DTI could potentially serve as an objective biomarker differentiating patients after prenatal MMC repair regarding those who may require surgery for MMC-associated hydrocephalus. The predictive value for the need and timing of CSF diversion surgery is highly clinically relevant for improving and optimizing decision-making for the treatment of hydrocephalus in this patient population.

Seizures have sleep–wake and circadian patterns in various epilepsies and, in turn, disrupt sleep and circadian rhythms. The resultant sleep deprivation (SD) is an exacerbating factor for seizures that sets up a vicious cycle that can potentially lead to disease progression and even to epilepsy-related mortality. A variety of cellular or network electrophysiological changes and changes in expression of clock-controlled genes or other transcription factors underlie sleep–wake and circadian distribution of seizures, as well as the disruptions seen in both. A broad understanding of these mechanisms may help in designing better treatments to prevent SD-induced seizure exacerbation, disrupt the vicious cycle of disease progression, and reduce epilepsy-related mortality.

While autopsy-repository programs with a variety of pediatric central nervous system (CNS) tumor types are a critical resource for preclinical neuro-oncology research, few exist and there is no published guidance on how to develop one. The goal of this prospective Pediatric Brain Tumor Repository (PBTR) study was to develop such a program at Cincinnati Children’s Hospital Medical Center (CCHMC) and then publish the quantitative and experiential data as a guide to support the development of similar programs. Protocols and infrastructure were established—to educate oncologists and families, establish eligibility, obtain consent, address pre- and post-autopsy logistics (e.g., patient and tissue transportation), process and authenticate tissue samples, and collect and analyze data. Of the 129 pediatric CNS tumor patients at CCHMC who died between 2013 and 2018, 109 were eligible for our study. Of these, 74% (81 of 109) were approached for PBTR donation, and 68% (55 of 81) consented. In the final year of the study, approach and consent rates were 93% and 85%, respectively. Median time from death to autopsy (postmortem interval, PMI) was 10 h (range, 1.5–30). In the outpatient setting, PMI increased with distance (from the hospice/home where the patient died to CCHMC). In all patients, PMI appeared to be lower, when consent was obtained more than 24 h before death. Procurement of autopsy specimens need not be a barrier in neuro-oncology research. Regional centers, strict timing-of-consent, patient education, and dedicated staff are all needed to minimize PMI and, thereby, increase the value of the procured tissue for an array of basic and translational research applications.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors combined with immunotherapy have shown antitumour activity in preclinical studies. We aimed to assess the safety and activity of olaparib in combination with the PD-L1-inhibitor, durvalumab, in patients with germline BRCA1-mutated or BRCA2-mutated metastatic breast cancer.METHODS: The MEDIOLA trial is a multicentre, open-label, phase 1/2, basket trial of durvalumab and olaparib in solid tumours. Patients were enrolled into four initial cohorts: germline BRCA-mutated, metastatic breast cancer; germline BRCA-mutated, metastatic ovarian cancer; metastatic gastric cancer; and relapsed small-cell lung cancer. Here, we report on the cohort of patients with breast cancer. Patients who were aged 18 years or older (or aged 19 years or older in South Korea) with germline BRCA1-mutated or BRCA2-mutated or both and histologically confirmed, progressive, HER2-negative, metastatic breast cancer were enrolled from 14 health centres in the UK, the USA, Israel, France, Switzerland, and South Korea. Patients should not have received more than two previous lines of chemotherapy for metastatic breast cancer. Patients received 300 mg olaparib in tablet form orally twice daily for 4 weeks and thereafter a combination of olaparib 300 mg twice daily and durvalumab 1·5 g via intravenous infusion every 4 weeks until disease progression. Primary endpoints were safety and tolerability, and 12-week disease control rate. Safety was analysed in patients who received at least one dose of study treatment, and activity analyses were done in the full-analysis set (patients who received at least one dose of study treatment and were not excluded from the study). Recruitment has completed and the study is ongoing. This trial is registered with ClinicalTrials.gov, NCT02734004.FINDINGS: Between June 14, 2016, and May 2, 2017, 34 patients were enrolled and received both study drugs and were included in the safety analysis. 11 (32%) patients experienced grade 3 or worse adverse events, of which the most common were anaemia (four [12%]), neutropenia (three [9%]), and pancreatitis (two [6%]). Three (9%) patients discontinued due to adverse events and four (12%) patients experienced a total of six serious adverse events. There were no treatment-related deaths. 24 (80%; 90% CI 64·3-90·9) of 30 patients eligible for activity analysis had disease control at 12 weeks.INTERPRETATION: Combination of olaparib and durvalumab showed promising antitumour activity and safety similar to that previously observed in olaparib and durvalumab monotherapy studies. Further research in a randomised setting is needed to determine predictors of therapeutic benefit and whether addition of durvalumab improves long-term clinical outcomes compared with olaparib monotherapy.FUNDING: AstraZeneca.

Cyclin-dependent kinase-retinoblastoma (CDK-RB) pathway is dysregulated in some diffuse intrinsic pontine gliomas (DIPG). We evaluated safety, feasibility, and early efficacy of the CDK4/6-inhibitor ribociclib, administered following radiotherapy in newly-diagnosed DIPG patients. Following radiotherapy, eligible patients received ribociclib in 28-day cycles (350 mg/m2; 21 days on/7 days off). Feasibility endpoints included tolerability for at least 6 courses, and a less than 2-week delay in restarting therapy after 1 dose reduction. Early efficacy was measured by 1-year and median overall survival (OS). Patient/parent-by-proxy reported outcomes measurement information system (PROMIS) assessments were completed prospectively. The study included 10 evaluable patients, 9 DIPG and 1 diffuse midline glioma (DMG)—all 3.7 to 19.8 years of age. The median number of courses was 8 (range 3–14). Three patients required dose reduction for grade-4 neutropenia, and 1 discontinued therapy for hematological toxicity following course 4. The most common grade-3/4 toxicity was myelosuppression. After 2 courses, MRI evaluations in 4 patients revealed increased necrotic volume, associated with new neurological symptoms in 3 patients. The 1-year and median OS for DIPG was 89% and 16.1 months (range 10–30), respectively; the DMG patient died at 6 months post-diagnosis. Five patients donated brain tissue and tumor; 3 were RB+ . Ribociclib administered following radiotherapy is feasible in DIPG and DMG. Increased tumor necrosis may represent a treatment effect. These data warrant further prospective volumetric analyses of tumors with necrosis. Feasibility and stabilization findings support further investigation of ribociclib in combination therapies. NCT02607124.

ObjectivesTofacitinib is a Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ulcerative colitis, and has been investigated in psoriasis (PsO). Routine pharmacovigilance of an ongoing, open-label, blinded-endpoint, tofacitinib RA trial (Study A3921133; NCT02092467) in patients aged ≥50 years and with ≥1 cardiovascular risk factor identified a higher frequency of pulmonary embolism (PE) and all-cause mortality for patients receiving tofacitinib 10 mg twice daily versus those receiving tumour necrosis factor inhibitors and resulted in identification of a safety signal for tofacitinib. Here, we report the incidence of deep vein thrombosis (DVT), PE, venous thromboembolism (VTE; DVT or PE) and arterial thromboembolism (ATE) from the tofacitinib RA (excluding Study A3921133), PsA and PsO development programmes and observational studies. Data from an ad hoc safety analysis of Study A3921133 are reported separately within.MethodsThis post-hoc analysis used data from separate tofacitinib RA, PsO and PsA programmes. Incidence rates (IRs; patients with events per 100 patient-years’ exposure) were calculated for DVT, PE, VTE and ATE, including for populations stratified by defined baseline cardiovascular or VTE risk factors. Observational data from the US Corrona registries (including cardiovascular risk factor stratification), IBM MarketScan research database and the US FDA Adverse Event Reporting System (FAERS) database were analysed.Results12 410 tofacitinib-treated patients from the development programmes (RA: n=7964; PsO: n=3663; PsA: n=783) were included. IRs (95% CI) of thromboembolic events among the all tofacitinib cohorts’ average tofacitinib 5 mg and 10 mg twice daily treated patients for RA, respectively, were: DVT (0.17 (0.09–0.27) and 0.15 (0.09–0.22)); PE (0.12 (0.06–0.22) and 0.13 (0.08–0.21)); ATE (0.32 (0.22–0.46) and 0.38 (0.28–0.49)). Among PsO patients, IRs were: DVT (0.06 (0.00–0.36) and 0.06 (0.02–0.15)); PE (0.13 (0.02–0.47) and 0.09 (0.04–0.19)); ATE (0.52 (0.22–1.02) and 0.22 (0.13–0.35)). Among PsA patients, IRs were: DVT (0.00 (0.00–0.28) and 0.13 (0.00–0.70)); PE (0.08 (0.00–0.43) and 0.00 (0.00–0.46)); ATE (0.31 (0.08–0.79) and 0.38 (0.08–1.11)). IRs were similar between tofacitinib doses and generally higher in patients with baseline cardiovascular or VTE risk factors. IRs from the overall Corrona populations and in Corrona RA patients (including tofacitinib-naïve/biologic disease-modifying antirheumatic drug-treated and tofacitinib-treated) with baseline cardiovascular risk factors were similar to IRs observed among the corresponding patients in the tofacitinib development programme. No signals of disproportionate reporting of DVT, PE or ATE with tofacitinib were identified in the FAERS database.ConclusionsDVT, PE and ATE IRs in the tofacitinib RA, PsO and PsA programmes were similar across tofacitinib doses, and generally consistent with observational data and published IRs of other treatments. As expected, IRs of thromboembolic events were elevated in patients with versus without baseline cardiovascular or VTE risk factors, and were broadly consistent with those observed in the Study A3921133 ad hoc safety analysis data, although the IR (95% CI) for PE was greater in patients treated with tofacitinib 10 mg twice daily in Study A3921133 (0.54 (0.32–0.87)), versus patients with baseline cardiovascular risk factors treated with tofacitinib 10 mg twice daily in the RA programme (0.24 (0.13–0.41)).

BACKGROUND: To date, although neonatal infections with severe acute respiratory syndrome coronovirus 2 (SARS-CoV-2) have been described, none of these have been proven to be the result of vertical transmission of SARS-CoV-2. METHODS: We describe the probable vertical transmission of SARS-CoV-2 in a neonate born to a mother with coronavirus disease 2019 (COVID-19). RESULTS: Following cesarean section, the neonate was kept in strict isolation. Molecular tests for SARS-CoV-2 on respiratory samples, blood, and meconium were initially negative, but positive on a nasopharyngeal aspirate on the third day of life. On day 5, the neonate developed fever and coryza, which spontaneously resolved. Viral genomic analysis from the mother and neonate showed identical sequences except for 1 nucleotide. CONCLUSION: This report has important implications for infection control and clinical management of pregnant women with COVID-19 and their newborns.

Previous research into the inflammatory cell infiltrate of chronic hyperplastic candidosis (CHC) determined that the immune response is primarily composed of T cells, the majority of which are T helper (CD4+) cells. This present investigation used immunohistochemistry to further delineate the inflammatory cell infiltrate in CHC. Cells profiled were those expressing IL-17A cytokine, EBI3 and IL-12A subunits of the IL-35 cytokine, and FoxP3+ cells. Squamous cell papilloma (with Candida infection) and oral lichen planus tissues served as comparative controls to understand the local immune responses to Candida infection. The results demonstrated that Candida-induced inflammation and immune regulation co-exist in the oral mucosa of CHC and that high prevalence of cells expressing the EBI3 cytokine subunit may play an important role in this regulation. This balance between inflammation and immune tolerance toward invading Candida in the oral mucosa may be critical in determining progress of infection.

Rationale: Understanding the mechanisms that regulate arterial flow recovery is important to design treatment options for peripheral artery disease patients ineligible for invasive revascularization. Transcriptional orchestrators of this recovery process represent an appealing target for treatment design. We previously identified Prdm (positive regulatory domain-containing protein) 16 as an arterial-specific endothelial transcription factor but its in vivo role in arteries remains completely unknown. Objective: To unravel the role of Prdm16 in arteries under physiological and pathological conditions, more specifically during peripheral artery disease. Methods and Results: Within the vasculature, Prdm16 expression was strictly confined to arterial endothelial and smooth muscle cells. Heterozygous loss of Prdm16 caused a modest reduction of the inner arterial diameter and smooth muscle cell coating without compromising vasomotor function. Upon femoral artery ligation, Prdm16 +/− mice featured significantly impaired flow recovery to ischemic limbs. This impairment was recapitulated in mice with a Prdm16 deletion specifically in endothelial cells ( EC-Prdm16 −/− ) but not smooth muscle cells. Structural collateral remodeling was normal in both Prdm16 +/− and EC-Prdm16 −/− mice, but significant endothelial dysfunction postligation was present in EC-Prdm16 −/− mice as evidenced by impaired endothelial-dependent relaxation. Upon ligation, endothelial Prdm16 deficiency altered the expression of genes encoding endothelial cell function regulators, many related to nitric oxide bioavailability and Ca 2+ homeostasis. Accordingly, Prdm16 overexpression in cultured endothelial cells affected both total cellular Ca 2+ levels and store-operated Ca 2+ entry. Conclusions: We showed that Prdm16 is indispensable for arterial flow recovery under pathological challenge not because it affects structural remodeling but due to its role in maintaining endothelial function. It, therefore, represents an appealing target for designing novel therapeutic strategies for no-option patients with peripheral artery disease.

Background World Health Organization African region is wild poliovirus-free; however, outbreaks of vaccine-derived poliovirus type 2 (VDPV2) continue to expand across the continent including in Chad. We conducted a serological survey of polio antibodies in polio high-risk areas of Chad to assess population immunity against poliovirus and estimate the risk of future outbreaks. Methods This was a community-based, cross-sectional survey carried out in September 2019. Children between 12 and 59 months were randomly selected using GIS enumeration of structures. Informed consent, demographic and anthropometric data, vaccination history, and blood spots were collected. Seropositivity against all 3 poliovirus serotypes was assessed using a microneutralization assay at Centers for Disease Control and Prevention, Atlanta, GA, USA. Results Analyzable data were obtained from 236 out of 285 (82.8%) enrolled children. Seroprevalence of polio antibodies for serotypes 1, 2, and 3 was 214/236 (90.7%); 145/236 (61.4%); and 196/236 (86.2%), respectively. For serotype 2, the seroprevalence significantly increased with age (P = .004); chronic malnutrition was a significant risk factor for being type 2-seronegative. Interpretation Poliovirus type 2 seroprevalence in young children was considered insufficient to protect against the spread of paralytic diseases caused by VDPV2. Indeed, VDPV2 outbreaks were reported from Chad in 2019 and 2020. High-quality immunization response to these outbreaks is needed to prevent further spread.

The contribution of the gut microbiome to human health has long been established, with normal gut microbiota conferring protection against invasive pathogens. Antibiotics can disrupt the microbial balance of the gut, resulting in disease and the development of antimicrobial resistance. The effect of antibiotic administration route on gut dysbiosis remains under-studied to date, with conflicting evidence on the differential effects of oral and parenteral delivery. We have profiled the rat gut microbiome following treatment with commonly prescribed antibiotics (amoxicillin and levofloxacin), via either oral or intravenous administration. Fecal pellets were collected over a 13-day period and bacterial populations were analyzed by 16S rRNA gene sequencing. Significant dysbiosis was observed in all treatment groups, regardless of administration route. More profound dysbiotic effects were observed following amoxicillin treatment than those with levofloxacin, with population richness and diversity significantly reduced, regardless of delivery route. The effect on specific taxonomic groups was assessed, revealing significant disruption following treatment with both antibiotics. Enrichment of a number of groups containing known gut pathogens was observed, in particular, with amoxicillin, such as the family Enterobacteriaceae. Depletion of other commensal groups was also observed. The degree of dysbiosis was significantly reduced toward the end of the sampling period, as bacterial populations began to return to pretreatment composition. Richness and diversity levels appeared to return to pretreatment levels more quickly in intravenous groups, suggesting convenient parenteral delivery systems may have a role to play in reducing longer term gut dysbiosis in the treatment of infection.

Gastric neuroendocrine tumors (GNETs) are rare and subdivided into type I, type II, and type III. Types I and II are gastrin-dependent and are usually benign, whereas type III is gastrin-independent and more aggressive. Type I accounts for 70-80% of all GNETs. Most of them are asymptomatic and incidentally detected on endoscopy. It can sometimes present with iron and B12 deficiency, dyspepsia, and less commonly with an upper GI bleed. We present a case of type I GNET who came to the hospital with melena and esophagogastroduodenoscopy (EGD) showing a 3-cm bleeding polyp and histopathology revealing a well-differentiated neuroendocrine tumor with angioinvasion.

Summary Background The CNS manifestations of COVID-19 in children have primarily been described in case reports, which limit the ability to appreciate the full spectrum of the disease in paediatric patients. We aimed to identify enough cases that could be evaluated in aggregate to better understand the neuroimaging manifestations of COVID-19 in the paediatric population. Methods An international call for cases of children with encephalopathy related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and abnormal neuroimaging findings was made. Clinical history and associated plasma and cerebrospinal fluid data were requested. These data were reviewed by a central neuroradiology panel, a child neurologist, and a paediatric infectious diseases expert. The children were categorised on the basis of their time of probable exposure to SARS-CoV-2. In addition, cases were excluded when a direct link to SARS-CoV-2 infection could not be established or an established alternate diagnostic cause could be hypothesised. The accepted referral centre imaging data, from ten countries, were remotely reviewed by a central panel of five paediatric neuroradiologists and a consensus opinion obtained on the imaging findings. Findings 38 children with neurological disease related to SARS-CoV-2 infection were identified from France (n=13), the UK (n=8), the USA (n=5), Brazil (n=4), Argentina (n=4), India (n=2), Peru (n=1), and Saudi Arabia (n=1). Recurring patterns of disease were identified, with neuroimaging abnormalities ranging from mild to severe. The most common imaging patterns were postinfectious immune-mediated acute disseminated encephalomyelitis-like changes of the brain (16 patients), myelitis (eight patients), and neural enhancement (13 patients). Cranial nerve enhancement could occur in the absence of corresponding neurological symptoms. Splenial lesions (seven patients) and myositis (four patients) were predominantly observed in children with multisystem inflammatory syndrome. Cerebrovascular complications in children were less common than in adults. Significant pre-existing conditions were absent and most children had favourable outcomes. However, fatal atypical CNS co-infections developed in four previously healthy children infected with SARS-CoV-2. Interpretation Acute-phase and delayed-phase SARS-CoV-2-related CNS abnormalities are seen in children. Recurring patterns of disease and atypical neuroimaging manifestations can be found and should be recognised being as potentially due to SARS-CoV-2 infection as an underlying aetiological factor. Studies of paediatric specific cohorts are needed to better understand the effects of SARS-CoV-2 infection on the CNS at presentation and on long-term follow-up in children. Funding American Society of Pediatric Neuroradiology, University of Manchester (Manchester, UK). Video Abstract Neuroimaging manifestations in children with SARS-CoV-2 infection

The metabolic syndrome (MetS) is an escalating problem worldwide, causing left ventricular stiffening, an early characteristic of diastolic dysfunction for which no treatment exists. As diastolic dysfunction and stiffening in MetS patients are associated with increased circulating dipeptidyl peptidase-4 (DPP-4) levels, we investigated whether the clinically approved DPP-4 inhibitor linagliptin reduces left ventricular stiffness in MetS-induced cardiac disease. Sixteen-week-old obese ZSF1 rats, displaying the MetS and left ventricular stiffness, received linagliptin-supplemented or placebo diet for four weeks. Linagliptin significantly reduced obesity, hyperlipidaemia, and hyperglycaemia and improved left ventricular relaxation. This improved relaxation was related to decreased cardiac fibrosis and cardiomyocyte passive stiffness (Fpassive ). The reduced Fpassive was the result of titin isoform switching from the stiff N2B to the more flexible N2BA and increased phosphorylation of total titin and specifically its N2Bus region (S4080 and S3391). Importantly, DPP-4 directly cleaved titin in vitro, resulting in an increased Fpassive , which was prevented by simultaneous administration of linagliptin. In conclusion, linagliptin improves left ventricular stiffness in obese ZSF1 rats by preventing direct DPP4-mediated titin cleavage, as well as by modulating both titin isoform levels and phosphorylation. Reducing left ventricular stiffness by administering linagliptin might prevent MetS-induced early diastolic dysfunction in human. ispartof: Journal Of Cellular And Molecular Medicine vol:25 issue:2 ispartof: location:England status: Published online

Objective:Infective endocarditis remains a severe complication associated with a high morbidity and mortality in patients after heart valve replacement. Exploration of the pathogenesis is of high demand and we, therefore, present a competent model that allows studying bacterial adherence and the role of plasma fibrinogen in this process using a new in-house designed low-volume flow chamber. Three cardiac graft tissues used for pulmonary valve replacement have been tested under shear conditions to investigate the impact of surface composition on the adhesion events.Methods:Tissue pieces of cryopreserved homograft (non-decellularised), decellularised homograft and bovine pericardium patch were investigated for fibrinogen binding. Adherence of Staphylococcus aureus to these graft tissues was studied quantitatively under flow conditions in our newly fabricated chamber based on a parallel plates’ modality. The method of counting colony-forming units was reliable and reproducible to assess the propensity of different graft materials for bacterial attachment under shear.Results:Bacterial perfusions over all plasma-precoated tissues identified cryopreserved homograft with the lowest affinity for S. aureus compared to decellularised homograft presenting a significantly higher bacterial adhesion (p < 0.05), which was linked to a more avid fibrinogen binding (p < 0.01). Bovine pericardial patch, as a reference tissue in this study, was confirmed to be the most susceptible tissue graft for the bacterial adhesion, which was in line with our previous work.Conclusion:The two studied homograft tissues showed different levels of bacterial attachment, which might be postulated by the involvement of fibrinogen in the adhesion mechanism(s) shown previously for bovine tissues.

Recovered COVID19 patients often display cardiac dysfunction, even after a relatively mild infection. Here, we present the first histological description of cardiac SARS-CoV-2 infection. Within the heart, the ACE2 receptor is mostly expressed by pericytes. Using a COVID19 hamster model, we demonstrate SARS-CoV-2 is replicating in pericytes, and reduced pericyte density is present after infection. In healthy animals, pericytes recover; however, when metabolic comorbidities are present, they fail to recover. These latter animals present with cardiac fibrosis, cardiomyocyte hypertrophy, and early signs of diastolic dysfunction, resembling HFpEF. Biopsies from recovered COVID19 patients showed similar results, with pericyte loss being present.

Background Head and neck squamous cell carcinoma (HNSCC) is composed of a heterogeneous group of tumors arising trough environmental carcinogens or infection by human papillomavirus (HPV). Treatment interventions such as immunotherapy and targeted therapy have shown clinical benefit in HNSCC patients. Despite these encouraging results, resistance to treatment is still observed in the majority of patients. Additionally, clinical effectiveness of treatment options has also been shown to be associated with HPV status. Here we investigate the tumoral and peripheral landscape of HPV(-) vs. HPV(+) head and neck cancers to identify features able to expand treatment options for patients with Viral- and Carcinogen-Driven Head and Neck Cancer. Methods Biopsies and serum samples derived from 502 primary and metastatic HNSCC patients were leveraged for genomic, proteomic and immunochemistry evaluations. Tumor biopsies from HNSCC patients commercially obtained (n=143) or derived from patients enrolled in CP1108 trial (n=19, NCT01693562) were profiled by gene expression. Primary tumor biopsies (N=198) from HNSCC have been assessed by Whole Exome Sequence (WES). Expression of immune markers including CD8, NKp46 was evaluated by immunohistochemistry (IHC) on 186 and 214 tumors biopsies, respectively. The expression of 80 immune related soluble factors was evaluated in serum derived from n=285 patients of HNSCC enrolled in EAGLE (NCT02369874), a randomized, open-label, study assessing Durvalumab and Tremelimumab vs. Standard of Care (SoC). Statistical comparison between HPV(+) vs. HPV (-) samples were conducted using R software. Results Patients with HPV(-) vs. HPV(+) HNSCC were characterized by worse prognosis. Increased levels of immunosuppressive factors including VEGF (p=0.01), IL-8 (p=0.02), IL6 (p=0.07) and macrophages chemo attractive factor CCL4 (p=0.07) was observed in the serum of HPV(-) vs HPV(+) HNSCC patients. In the tumor microenvironment, higher mRNA expression of immune signatures associated with MDSC, Cancer Associated Fibroblast (CAF), and Metalloproteinase (MMP) was observed in HPV(-) vs. HPV (+) HNSCC patients. In contrast, HNSCC HPV(+) patients were characterized by increased mRNA expression of DC signatures and IFNg related genes (i.e. CXCL9). No differential infiltration of T and NK cells (CD8+ and NKp46+) were found in HPV (-) vs. HPV(+) patients. Enrichments of mutations in EGFR, and DNA repair genes (PMS1, POLK, ATM) was observed in HPV(+) patients. On the contrary, enrichments of mutations in TP53 was observed in HPV(-) patients. Conclusions Deep evaluation of tumoral and peripheral landscape of viral- versus carcinogen-driven HNSCC might help understanding differential outcome of treatments regimens in HPV(+) vs HPV (-) HNSCC thus leading to novel therapeutic interventions. Trial Registration NCT01693562,NCT02369874 Ethics Approval The study was approved by Astrazeneca. Consent Patients provided written consent to perform evalutions here described.

Study objectives Traumatic brain injury (TBI) results in sequelae that include posttraumatic epilepsy (PTE) and sleep‐wake disturbances. Here, we sought to determine whether sleep characteristics could predict development of PTE in a model of severe TBI. Methods Following controlled cortical impact (CCI) or sham injury (craniotomy only), CD‐1 mice were implanted with epidural electroencephalography (EEG) and nuchal electromyography (EMG) electrodes. Acute (1st week) and chronic (months 1, 2, or 3) 1‐week‐long video‐EEG recordings were performed after the injury to examine epileptiform activity. High‐amplitude interictal events were extracted from EEG using an automated method. After scoring sleep‐wake patterns, sleep spindles and EEG delta power were derived from nonrapid eye movement (NREM) sleep epochs. Brain CTs (computerized tomography) were performed in sham and CCI cohorts to quantify the brain lesions. We then employed a no craniotomy (NC) control to perform 1‐week‐long EEG recordings at week 1 and month 1 after surgery. Results Posttraumatic seizures were seen in the CCI group only, whereas interictal epileptiform activity was seen in CCI or sham. Sleep‐wake disruptions consisted of shorter wake or NREM bout lengths and shorter duration or lower power for spindles in CCI and sham. NREM EEG delta power increased in CCI and sham groups compared with NC though the CCI group with posttraumatic seizures had lower power at a chronic time point compared with those without. Follow‐up brain CTs showed a small lesion in the sham injury group suggesting a milder form of TBI that may account for their interictal activity and sleep changes. Significance In our TBI model, tracking changes in NREM delta power distinguishes between CCI acutely and animals that will eventually develop PTE, but further work is necessary to identify sleep biomarkers of PTE. Employing NC controls together with sham controls should be considered in future TBI studies.

We read with interest the recently published European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis (PsA) with pharmacological therapies1 and the associated systematic literature research (SLR)2; we welcome the clarity that they offer for patient care. We would like to bring three points to your readers’ attention to correct and clarify the narrative supporting Recommendation 7 (Janus kinase (JAK) inhibitors). Recommendation 7 states: “ … Our SLR indicated tofacitinib may have similar efficacy as the TNFi adalimumab for joint involvement, but numerically lower efficacy in skin psoriasis.1,15,72 … Safety signals exist for some infections, especially herpes zoster, as well as a recent signal for deep vein thrombosis especially with a high dose of tofacitinib which is not approved for PsA, but also the usual 5 mg twice daily dose particularly in those with cardiovascular risk factors and older patients.15,72,73” Regarding the statement: “ … as well as a recent signal for deep vein thrombosis especially with a high dose of tofacitinib which is not approved for PsA …”: We would like to respectfully correct this statement, as this signal was seen for pulmonary embolism (PE) rather than deep vein thrombosis (DVT); this was observed in the 10 mg twice daily dose of tofacitinib, …

Study objectivesTraumatic brain injury (TBI) results in sequelae that include post-traumatic epilepsy (PTE) and sleep-wake disturbances. Here we sought to determine whether sleep characteristics could predict development of PTE in a model of severe TBI.MethodsFollowing controlled cortical impact (CCI), sham injury (craniotomy only) or no craniotomy (NC), CD-1 mice were implanted with epidural electroencephalography (EEG) and nuchal electromyography (EMG) electrodes. Acute (1stweek) and chronic (months 1, 2 and 3 after injury) 1-week long video-EEG/EMG recordings were examined for epileptiform activity. We analyzed sleep-wake patterns manually and extracted high amplitude interictal events from EEG using an automated method. Sleep spindles and EEG delta power were derived from non-rapid eye movement (NREM) sleep epochs. Brain CTs (computerized tomography) were performed to quantify the extent of brain lesions in cohorts of sham and CCI.ResultsPosttraumatic seizures were seen with CCI, whereas interictal epileptiform activity as well as sleep-wake disruptions (shorter wake or NREM bout lengths, shorter duration or lower power for spindles, and increased NREM EEG delta power) were seen in CCI and sham groups. No sleep feature predicted PTE. Follow up brain CTs showed a small lesion in the sham injury group suggesting a milder form of TBI that may account for their interictal activity and sleep changes.ConclusionsIn our model, interictal epileptiform activity and sleep disruptions resulted from CCI and sham and thus, sham injury was not an optimal negative control. Further work is necessary to determine the relationship between sleep-wake disturbances and PTE.Statement of significanceTraumatic brain injury (TBI) results in sequelae such as post-traumatic seizures and sleep-wake disturbances but it is difficult to predict which individuals will develop these symptoms. Our study is novel in that we characterized epileptiform activity and multiple sleep characteristics in a mouse model of severe TBI (Controlled cortical impact-CCI) and explored whether any specific sleep disturbance can predict post-traumatic epilepsy. Specifically, post-traumatic seizures were seen after CCI only whereas epileptiform activity other than seizures as well as sleep-wake disruptions in mice that received a TBI and their sham injury controls. CT imaging showed that the sham injury group also had small brain lesions suggesting that a more optimal control in TBI research is to perform no craniotomy. No single sleep characteristic was predictive of post-traumatic epilepsy although NREM delta power was different in chronic recordings between TBI mice that developed seizures and those that did not. These studies are relevant to further research in TBI models, to develop a sleep biomarker for PTE. The work is also relevant to humans with TBI as monitoring sleep phenotypes may predict risk, but may also help develop therapies to prevent post-traumatic epilepsy.

The JAK2V617F point mutation has been implicated in the pathogenesis of the vast majority of myeloproliferative neoplasms (MPNs), but translocations involving JAK2 have increasingly been identified in patients with JAK2V617F-negativeMPNs. Here, we present a case of a patient diagnosed with JAK2V617F-negativepolycythemia vera (PV) that transformed to the MPN-blast phase. Cytogenetic and FISH analysis revealed a novel translocation of t(1;9)(p36;p24.1), causing a PEX14-JAK2 gene fusion product. The t(1;9)(p36;p24.1) represents a new addition to the list of known translocations involving JAK2that have been identified in hematologic malignancies. Although the prognostic and treatment implications of JAK2 translocations in MPNs have not been elucidated, positive outcomes have been described in case reports describing the use of JAK inhibitors in these patients. Further research into the role of JAK2 translocations in the pathogenesis and outcomes of hematologic malignancies is warranted.

Background Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of UC. In data analysed from a large, ongoing (data cut-off February 2019 [a]; database unlocked; data may be subject to change), post-authorisation safety study in patients with RA (≥50 years; ≥1 cardiovascular risk factor; enrolled on a stable dose of MTX), the incidence rate (IRs; unique patients with events per 100 pt-years [PY]) of pulmonary embolism (PE) in patients treated with tofacitinib 10mg BID (0.54 [95% CI] 0.32, 0.87]) was numerically higher compared with 5 mg BID (0.27 [0.12, 0.52]) and statistically different from TNFi (0.09 [0.02, 0.26]). Corresponding IRs for deep vein thrombosis (DVT) were 0.38 (0.20, 0.67), 0.30 (0.14, 0.55) and 0.18 (0.07, 0.39).1 UC is a known risk factor for DVT and PE. Subsequently, updates to the tofacitinib prescribing information have been made, with venous thromboembolism added as a warning and adverse drug reaction. Here, we provide an update on the incidence of DVT and PE in the tofacitinib UC clinical development programme, as of May 2019.2 Methods DVT and PE events were evaluated from 4 randomised placebo-controlled studies (Phase [P]2/P3 induction studies and P3 maintenance study) and an ongoing, open-label, long-term extension (OLE) study.3,4 Three cohorts were analysed: Induction, Maintenance and Overall (patients receiving tofacitinib 5 or 10mg BID in P2/P3/OLE studies; patients were categorised based on the average daily dose: predominant dose [PD] 5 or 10 mg BID). Results 1157 patients were evaluated for DVT and PE, with 2581 PY of tofacitinib exposure and up to 6.8 years’ treatment. In the Induction and Maintenance Cohorts, 2 patients had DVT and 2 had PE; all were receiving placebo at the time of the event (tables). In the Overall Cohort, DVT occurred in 1 pt and PE in 4 patients during the OLE study, after ≥7 months of treatment; all patients had received PD 10 mg BID (83% of Overall Cohort received PD 10 mg BID) and had other (non-UC) risk factors for venous thrombosis (tables). Conclusion IRs in the Overall Cohort have remained stable since the previously reported data cut.2 All of the events in tofacitinib patients (PD 10 mg BID) occurred during the OLE study and all had other (non-UC) risk factors for thromboembolic events. This analysis is limited by sample size and duration of drug exposure; further study is needed. [a] The tofacitinib 10mg BID arm of the study was discontinued in February 2019 and patients who re-consented and chose to remain in the study were switched to the 5 mg BID arm. References

Background Active inflammatory bowel disease increases the risk of adverse pregnancy outcomes. Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). As a small molecule, tofacitinib is likely to cross the placental barrier; however, information on the effects of tofacitinib on pregnancy outcomes is limited. We report pregnancy and newborn outcomes among patients in UC clinical studies with prenatal (maternal/paternal) exposure to tofacitinib. Methods Pregnancies with maternal/paternal exposure to tofacitinib were identified and outcomes reported in 5 tofacitinib UC interventional studies (up to March 2017). Outcomes from tofacitinib rheumatoid arthritis (RA), psoriasis, and psoriatic arthritis interventional studies, and RA noninterventional postapproval safety studies, spontaneous adverse event reporting, and registry data are also reported. Results Of 1157 patients enrolled in the UC interventional studies, 301 were women of childbearing age. Eleven cases of maternal exposure and 14 cases of paternal exposure to tofacitinib (doses of 5 mg or 10 mg twice daily) before/at the time of conception or during pregnancy were identified. Outcomes included 15 healthy newborns, no fetal deaths, no neonatal deaths, no congenital malformations, 2 spontaneous abortions, and 2 medical terminations. Outcomes across other tofacitinib studies and postmarketing cases were consistent, with a healthy newborn being the most common outcome and no fetal deaths. Conclusions Based on the limited data available, pregnancy and newborn outcomes among patients with prenatal (maternal/paternal) exposure to tofacitinib in UC studies appear similar to those reported for other tofacitinib clinical study populations and the general population.

Advances in next-generation sequencing technologies and the application of metagenomic approaches have fuelled an exponential increase in our understanding of the human gut microbiome. These approaches are now also illuminating features of the diverse and abundant collection of viruses (termed the virome) subsisting with the microbial ecosystems residing within the human holobiont. Here, we focus on the current and emerging knowledge of the human gut virome, in particular on viruses infecting bacteria (bacteriophage or phage), which are a dominant component of this viral community. We summarise current insights regarding the form and function of this ‘human gut phageome’ and highlight promising avenues for future research. In doing so, we discuss the potential for phage to drive ecological functioning and evolutionary change within this important microbial ecosystem, their contribution to modulation of host–microbiome interactions and stability of the community as a whole, as well as the potential role of the phageome in human health and disease. We also consider the emerging concepts of a ‘core healthy gut phageome’ and the putative existence of ‘viral enterotypes’ and ‘viral dysbiosis’.

There is no standard of care for cerebrospinal (CSF) diversion in children with diffuse intrinsic pontine glioma (DIPG), nor understanding of survival impact. We evaluated CSF diversion characteristics in children with DIPG to determine incidence, indications and potential impact on survival. Data was extracted from subjects registered in the International DIPG registry (IDIPGR). IDIPGR team personnel obtained clinical and radiographic data from the registry database and when appropriate, abstracted additional data from individual medical records. Univariable analyses were performed using the Fisher’s exact test or Wilcoxon rank sum test. Survival was estimated using the Kaplan-Meier method. Evaluable patients (n=457) met criteria for DIPG diagnosis by central radiology review. Ninety-two patients (20%) had permanent CSF diversion. Indications for permanent diversion were hydrocephalus (41%), hydrocephalus and clinical symptoms (35%), and clinical symptoms alone (3%). Those with permanent diversion were significantly younger at diagnosis than those without diversion (median 5.3 years vs 6.9 years, p=0.0002), otherwise no significant differences in gender, race, or treatment were found. The progression-free and overall survival of those with permanent CSF diversion compared to those without permanent diversion was 4.5 and 10.9 months vs 6.9 and 11.2 months, respectively (p=0.001, p= 0.4). There was no significant difference in overall survival in patients with or without permanent CSF diversion among a large cohort of DIPG patients. Patients without permanent diversion had significantly prolonged progression free survival compared to those with permanent diversion. The qualitative risks and benefits of permanent CSF diversion need to be further evaluated.

INTRODUCTION The role of diagnostic biopsy in diffuse intrinsic pontine glioma (DIPG) remains in question. Distinguishing radiographically between DIPG and other pontine tumors with more favorable prognosis and different therapy is critically important. METHODS Cases submitted to the International DIPG registry with histopathologic data were analyzed. Central imaging review was performed by two neuro-radiologists; all cases with imaging features or histopathology suggestive of alternative diagnoses were re-reviewed. Imaging features suggestive of alternative diagnoses included non-pontine origin, RESULTS Among 297 patients with pathology from biopsy and/or autopsy available, 27 (9%) had histologic diagnoses not consistent with DIPG, commonly embryonal tumors (n=9) and pilocytic astrocytomas (n=11). 163 patients had diagnostic MRI available for central neuroimaging review. Among 81 patients classified as characteristic of DIPG, 80 (99%) had histopathology consistent with DIPG (diffuse midline glioma, H3K27M-mutant, glioblastoma, anaplastic astrocytoma, diffuse astrocytoma). Among 63 patients classified as likely DIPG, but with unusual imaging features, 59 (94%) had histopathology consistent with DIPG. 19 patients had imaging features suggestive of another diagnosis, including 13 with non-pontine tumor origin; the remaining 6 all had histopathology not consistent with DIPG. Association between central imaging review and histopathology was significant (p CONCLUSIONS The important role and accuracy of central neuroimaging review in diagnosing or excluding DIPG is demonstrated. In patients with pontine tumors for which DIPG is felt unlikely radiographically, biopsy may be considered to guide diagnosis and treatment.

Established in April 2012, the mission of the IDIPGR is to provide secure integrated data sets including clinical, pathologic, radiologic and molecular genomics to the research community to promote hypothesis driven research. Over 600 data points per patient are securely stored on a CCHMC constructed web resource and domain using the open-source data mart development framework Harvest (PMID:24303304) (‘Links’). Genomic data is stored in the cloud-enabled VIVA platform and accessed through cross-platform integration and standardization algorithms for comparison across datasets. Features include source identification, data wrangling, and standardization of molecular and phenotypic data (2017), a web-enabled data mart that provides phenotype-genotype query/exploration, along with raw and processed data file downloads to authorized investigators (Harvest, 2017), additional tools for filtering and analysis of genomic datasets at the level of a phenotype, sample, gene, and variant (VIVA, 2017–2018), and uploaded digitized slides (Aperio, 2019). The IDIPGR Repository stores abstracted datasets for >1020 patients with DIPG/DMG, of whom 366 have tumor tissue available through biopsy and/or autopsy, and centrally reviewed and digitized specimens from 124 patients. The Repository contains >5000 radiology studies from >700 patients, with >550 patients centrally reviewed, and genomics data from 80 patients. Currently 27 IDIPGR approved projects utilize these datasets. The DIPG/DMG Registry constructed a robust database platform and integration system that provides the infrastructure to promote highly collaborative, international, hypothesis-driven research. Broadening collaboration among investigators for hypothesis-driven research studies will lead to better classification and more effective treatment of patients with DIPG and DMG.

PURPOSE: Some elderly patients (≥ 65 years old) with small-cell lung cancer (SCLC) do not receive chemotherapy likely because of fear of toxicity and uncertainty regarding benefits. Thus, we aimed to study real-world trends in utilization of antineoplastics over the years and predictors of utilization, survival, and Medicare expenditure in elderly patients with extensive-stage (ES) SCLC. PATIENTS AND METHODS: Using the linked SEER and Medicare database, we identified elderly patients with newly diagnosed ES-SCLC between 2001 and 2013. The Wald test was used to determine the significance of trends. Cox proportional hazards models were applied for survival analyses. We used SAS, version 9.4 (SAS Institute, Cary, NC). RESULTS: We identified 15,763 patients with newly diagnosed ES-SCLC. Approximately 6,838 patients (43.38%) received antineoplastics, and 8,925 patients (56.61%) received supportive care only. Every year since 2001, the percentage of patients receiving antineoplastics has decreased (45.8% v 36.6% in 2001 and 2013, respectively; Ptrend < .0001). Patients with advanced age ( P < .001), patients from high-poverty areas ( P < .001) or rural areas ( P = .005), patients with Charlson comorbidity index ≥ 3 ( P < .001), and non-Hispanic blacks ( P = .003) and Hispanics ( P = .001) were less likely to receive antineoplastics. Mean Medicare spending per patient decreased over the study period for patients treated with antineoplastics ($45,998 in 2001 and $35,053 in 2013; Ptrend < .001) and for those receiving supportive care only ($34,197 in 2001 and $25,265 in 2013; Ptrend < .001). CONCLUSION: Decreasing utilization of antineoplastics in elderly patients with ES-SCLC since 2001 could be partly secondary to higher comorbidities and physiologic age, leading to poor candidacy. Medicare expenditures decreased likely as a result of value-based treatment initiatives by the Centers for Medicaid and Medicare Services. However, expenditures are likely to increase with use of expensive novel agents.

In temporal lobe epilepsy, the ability of the dentate gyrus to limit excitatory cortical input to the hippocampus breaks down, leading to seizures. The dentate gyrus is also thought to help discriminate between similar memories by performing pattern separation, but whether epilepsy leads to a breakdown in this neural computation, and thus to mnemonic discrimination impairments, remains unknown. Here we show that temporal lobe epilepsy is characterized by behavioral deficits in mnemonic discrimination tasks, in both humans (females and males) and mice (C57Bl6 males, systemic low-dose kainate model). Using a recently developed assay in brain slices of the same epileptic mice, we reveal a decreased ability of the dentate gyrus to perform certain forms of pattern separation. This is due to a subset of granule cells with abnormal bursting that can develop independently of early EEG abnormalities. Overall, our results linking physiology, computation and cognition in the same mice advance our understanding of episodic memory mechanisms and their dysfunction in epilepsy.Significance StatementPeople with temporal lobe epilepsy (TLE) often have learning and memory impairments, sometimes occurring earlier than the first seizure, but those symptoms and their biological underpinnings are poorly understood. We focused on the dentate gyrus, a brain region that is critical to avoid confusion between similar memories and is anatomically disorganized in TLE. We show that both humans and mice with TLE experience confusion between similar situations. This impairment coincides with a failure of the dentate gyrus to disambiguate similar input signals because of pathological bursting in a subset of neurons. Our work bridges seizure-oriented and memory-oriented views of the dentate gyrus function, suggests a mechanism for cognitive symptoms in TLE and supports a long-standing hypothesis of episodic memory theories.

Heart failure (HF) is the most rapidly growing cardiovascular health burden worldwide. HF can be classified into three groups based on the percentage of the ejection fraction (EF): heart failure with reduced EF (HFrEF), heart failure with mid-range-also called mildly reduced EF- (HFmrEF), and heart failure with preserved ejection fraction (HFpEF). HFmrEF can progress into either HFrEF or HFpEF, but its phenotype is dominated by coronary artery disease, as in HFrEF. HFrEF and HFpEF present with differences in both the development and progression of the disease secondary to changes at the cellular and molecular level. While recent medical advances have resulted in efficient and specific treatments for HFrEF, these treatments lack efficacy for HFpEF management. These differential response rates, coupled to increasing rates of HF, highlight the significant need to understand the unique pathogenesis of HFrEF and HFpEF. In this review, we summarize the differences in pathological development of HFrEF and HFpEF, focussing on disease-specific aspects of inflammation and endothelial function, cardiomyocyte hypertrophy and death, alterations in the giant spring titin, and fibrosis. We highlight the areas of difference between the two diseases with the aim of guiding research efforts for novel therapeutics in HFrEF and HFpEF. ispartof: CELLS vol:9 issue:1 ispartof: location:Switzerland status: published

Heart failure with preserved ejection fraction (HFpEF) is a complex heterogeneous disease for which our pathophysiological understanding is still limited and specific prevention and treatment strategies are lacking. HFpEF is characterised by diastolic dysfunction and cardiac remodelling (fibrosis, inflammation, and hypertrophy). Recently, microvascular dysfunction and chronic low-grade inflammation have been proposed to participate in HFpEF development. Furthermore, several recent studies demonstrated the occurrence of generalized lymphatic dysfunction in experimental models of risk factors for HFpEF, including obesity, hypercholesterolaemia, type 2 diabetes mellitus (T2DM), hypertension, and aging. Here, we review the evidence for a combined role of coronary (micro)vascular dysfunction and lymphatic vessel alterations in mediating key pathological steps in HFpEF, including reduced cardiac perfusion, chronic low-grade inflammation, and myocardial oedema, and their impact on cardiac metabolic alterations (oxygen and nutrient supply/demand imbalance), fibrosis, and cardiomyocyte stiffness. We focus primarily on HFpEF caused by metabolic risk factors, such as obesity, T2DM, hypertension, and aging. ispartof: Basic Research In Cardiology vol:115 issue:4 ispartof: location:Germany status: published

Progenitor heterogeneity and identities underlying tumor initiation and relapse in medulloblastomas remain elusive. Utilizing single-cell transcriptomic analysis, we demonstrated a developmental hierarchy of progenitor pools in Sonic Hedgehog (SHH) medulloblastomas, and identified OLIG2-expressing glial progenitors as transit-amplifying cells at the tumorigenic onset. Although OLIG2+ progenitors become quiescent stem-like cells in full-blown tumors, they are highly enriched in therapy-resistant and recurrent medulloblastomas. Depletion of mitotic Olig2+ progenitors or Olig2 ablation impeded tumor initiation. Genomic profiling revealed that OLIG2 modulates chromatin landscapes and activates oncogenic networks including HIPPO-YAP/TAZ and AURORA-A/MYCN pathways. Co-targeting these oncogenic pathways induced tumor growth arrest. Together, our results indicate that glial lineage-associated OLIG2+ progenitors are tumor-initiating cells during medulloblastoma tumorigenesis and relapse, suggesting OLIG2-driven oncogenic networks as potential therapeutic targets.

BACKGROUND: Pediatric low-grade glioma (pLGG) is the most common CNS tumor of childhood. Progression-free survival (PFS) is much lower than overall survival emphasizing the need for alternative treatments. In addition, many children suffer functional morbidities such as visual and motor disturbances. Recently, there has been an appropriate prioritization of functional outcomes in children with pLGG. METHODS: We present the results of a PBTC phase II trial evaluating selumetinib, (AZD6244, ARRY-142886) a MEK-1/2 inhibitor, in children with recurrent/progressive pLGG on 2 strata, including visual outcomes. RESULTS: Stratum 3 enrolled Neurofibromatosis type 1 (NF1)-associated pLGG. Ten of 25 (40%) eligible patients had partial response (PR), 14/25 (56%) had stable disease (SD) and 1/25 (4%) had progressive disease (PD); 2-year PFS was 96+4%. Ten patients with optic pathway glioma (OPG) were evaluable for visual acuity (VA) at baseline and 1 year. VA improved in 2/10 patients (20%) and was stable in 8/10 (80%). One patient (10%) had improvement in visual fields (VF) and 9 patients (90%) had stable VF. Stratum 4 included patients with non-NF1-associated recurrent/progressive hypothalamic and OPG. Five of 25 (20%) eligible patients had PR, 16/25 (64%) had SD and 4 (16%) had PD; 2-year PFS was 78+8.5%. Nineteen of 25 patients were evaluable for VA. VA improved in 4/19 patients (21%), was stable in 13/19 (68%) and worsened in 2/19 (11%). Five patients (26%) had improved VF and 14 (74%) had stable VF. The most common toxicities included grade 1/2 CPK elevation, diarrhea, hypoalbuminemia and rash. Rare grade 3 toxicities included elevated CPK, rash and paronychia. CONCLUSIONS: Selumetinib was tolerable and effective in treating children with NF1-associated and sporadic recurrent/progressive hypothalamic and OPG based upon radiographic response and PFS. Twenty-seven of 29 (93%) evaluable patients had stable or improved vision based on VA and VF testing.

ObjectivesTo analyse adverse events (AEs) of special interest across tofacitinib clinical programmes in rheumatoid arthritis (RA), psoriatic arthritis (PsA), ulcerative colitis (UC) and psoriasis (PsO), and to determine whether the incidence rates (IRs; unique patients with events per 100 patient-years) of these events are consistent across diseases.MethodsThe analysis included data from patients exposed to ≥1 dose of tofacitinib in phase 1, 2, 3 or 3b/4 clinical trials and long-term extension (LTE) studies (38 trials) in RA (23 trials), PsA (3 trials), UC (5 trials) and PsO (7 trials). All studies were completed by or before July 2019, except for one ongoing UC LTE study (data cut-off May 2019). IRs were obtained for AEs of special interest.Results13 567 patients were included in the analysis (RA: n=7964; PsA: n=783; UC: n=1157; PsO: n=3663), representing 37 066 patient-years of exposure. Maximum duration of exposure was 10.5 years (RA). AEs within the ‘infections and infestations’ System Organ Class were the most common in all diseases. Among AEs of special interest, IRs were highest for herpes zoster (non-serious and serious; 3.6, 1.8, 3.5 and 2.4 for RA, PsA, UC and PsO, respectively) and serious infections (2.5, 1.2, 1.7 and 1.3 for RA, PsA, UC and PsO, respectively). Age-adjusted and sex-adjusted mortality ratios (weighted for country) were ≤0.2 across cohorts.ConclusionsThe tofacitinib safety profile in this analysis was generally consistent across diseases and with longer term follow-up compared with previous analyses.

Understanding the interaction between humans and mosquitoes is a critical area of study due to the phenomenal burdens on public health from mosquito-transmitted diseases. In this study, we conducted the first genome-wide association studies (GWAS) of self-reported mosquito bite reaction size (n = 84,724), itchiness caused by bites (n = 69,057), and perceived attractiveness to mosquitoes (n = 16,576). In total, 15 independent significant (P

The purpose of this collective review is to study the techniques, usage, methods, and clinical results of functional electrical stimulation applied to the peroneal nerve in the treatment of dropped foot. When stimulation is applied through surface electrodes, clinical reports have documented the therapeutic and orthotic benefits of functional electrical stimulation. Clinical trials are now being undertaken in which implantable electrodes are being used to stimulate the peroneal nerve in patients with dropped foot.

Background Platelet Endothelial Aggregation Receptor-1 (PEAR1) is a transmembrane platelet receptor that amplifies the activation of the platelet fibrinogen receptor (αIIbβ3) during platelet aggregation. In man, Pear1 polymorphisms are associated with changes in platelet aggregability. In this report, we characterized Pear1 expression and function in murine platelets. Methods Pear1 phosphorylation and signaling, platelet aggregation, α-degranulation and clot retraction were studied in WT and Pear1 −/− platelets. The function of Pear1 in haemostasis and thrombosis was studied in a mouse tail vein bleeding and ferric chloride-induced mesenteric thrombosis model. Results Mature murine platelets express Pear1 on their membrane and clustering of Pear1 by anti-Pear1 antibodies triggered platelet aggregation. Pear1 was weakly phosphorylated during collagen-induced murine platelet aggregation and was translocated to the cytoskeleton. Absence of murine Pear1 impaired dextran sulfate-induced platelet aggregation, but did not impact collagen-, AYPGK and ADP-induced platelet aggregation, coupled to a lower Pear1 expression in murine than in human platelets and to weaker Pear1-mediated downstream signaling. Neither clot retraction nor α-degranulation was affected in Pear1 −/− mice. Likewise, in vivo tests like the tail vein bleeding time and thrombus formation in mesenteric veins were similar in WT and Pear1 −/− mice. Conclusion Murine platelet Pear1 shares a number of characteristics with human platelet PEAR1. Nevertheless, murine Pear1 contributes less to platelet function as does human PEAR1 and does not overtly impact haemostasis and thrombosis in mice.

OBJECTIVE The purpose of this study was to investigate white matter (WM) structural abnormalities using diffusion tensor imaging (DTI) in children with hydrocephalus before CSF diversionary surgery (including ventriculoperitoneal shunt insertion and endoscopic third ventriculostomy) and during the course of recovery after surgery in association with neuropsychological and behavioral outcome. METHODS This prospective study included 54 pediatric patients with congenital hydrocephalus (21 female, 33 male; age range 0.03–194.5 months) who underwent surgery and 64 normal controls (30 female, 34 male; age range 0.30–197.75 months). DTI and neurodevelopmental outcome data were collected once in the control group and 3 times (preoperatively and at 3 and 12 months postoperatively) in the patients with hydrocephalus. DTI measures, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) values were extracted from the genu of the corpus callosum (gCC) and the posterior limb of internal capsule (PLIC). Group analysis was performed first cross-sectionally to quantify DTI abnormalities at 3 time points by comparing the data obtained in the hydrocephalus group for each of the 3 time points to data obtained in the controls. Longitudinal comparisons were conducted pairwise between different time points in patients whose data were acquired at multiple time points. Neurodevelopmental data were collected and analyzed using the Adaptive Behavior Assessment System, Second Edition, and the Bayley Scales of Infant Development, Third Edition. Correlation analyses were performed between DTI and behavioral measures. RESULTS Significant DTI abnormalities were found in the hydrocephalus patients in both the gCC (lower FA and higher MD, AD, and RD) and the PLIC (higher FA, lower AD and RD) before surgery. The DTI measures in the gCC remained mostly abnormal at 3 and 12 months after surgery. The DTI abnormalities in the PLIC were significant in FA and AD at 3 months after surgery but did not persist when tested at 12 months after surgery. Significant longitudinal DTI changes in the patients with hydrocephalus were found in the gCC when findings at 3 and 12 months after surgery were compared. In the PLIC, trend-level longitudinal changes were observed between preoperative findings and 3-month postoperative findings, as well as between 3- and 12-month postoperative findings. Significant correlation between DTI and developmental outcome was found at all 3 time points. Notably, a significant correlation was found between DTI in the PLIC at 3 months after surgery and developmental outcome at 12 months after surgery. CONCLUSIONS The data showed significant WM abnormality based on DTI in both the gCC and the PLIC in patients with congenital hydrocephalus before surgery, and the abnormalities persisted in both the gCC and the PLIC at 3 months after surgery. The DTI values remained significantly abnormal in the gCC at 12 months after surgery. Longitudinal analysis showed signs of recovery in both WM structures between different time points. Combined with the significant correlation found between DTI and neuropsychological measures, the findings of this study suggest that DTI can serve as a sensitive imaging biomarker for underlying neuroanatomical changes and postsurgical developmental outcome and even as a predictor for future outcomes.

Summary Background No evidence-based guidelines are available for the definitive diagnosis or directed treatment of most blast-associated traumatic brain injuries, partly because the underlying pathology is unknown. Moreover, few neuropathological studies have addressed whether blast exposure produces unique lesions in the human brain, and if those lesions are comparable with impact-induced traumatic brain injury. We aimed to test the hypothesis that blast exposure produces unique patterns of damage, differing from that associated with impact-induced, non-blast traumatic brain injuries. Methods In this post-mortem case series, we investigated several features of traumatic brain injuries, using clinical histopathology techniques and markers, in brain specimens from male military service members with chronic blast exposures and from those who had died shortly after severe blast exposures. We then compared these results with those from brain specimens from male civilian (ie, non-military) cases with no history of blast exposure, including cases with and without chronic impact traumatic brain injuries and cases with chronic exposure to opiates, and analysed the limited associated clinical histories of all cases. Brain specimens had been archived in tissue banks in the USA. Findings We analysed brain specimens from five cases with chronic blast exposure, three cases with acute blast exposure, five cases with chronic impact traumatic brain injury, five cases with exposure to opiates, and three control cases with no known neurological disorders. All five cases with chronic blast exposure showed prominent astroglial scarring that involved the subpial glial plate, penetrating cortical blood vessels, grey–white matter junctions, and structures lining the ventricles; all cases of acute blast exposure showed early astroglial scarring in the same brain regions. All cases of chronic blast exposure had an antemortem diagnosis of post traumatic stress disorder. The civilian cases, with or without history of impact traumatic brain injury or a history of opiate use, did not have any astroglial scarring in the brain regions analysed. Interpretation The blast exposure cases showed a distinct and previously undescribed pattern of interface astroglial scarring at boundaries between brain parenchyma and fluids, and at junctions between grey and white matter. This distinctive pattern of scarring may indicate specific areas of damage from blast exposure consistent with the general principles of blast biophysics, and further, could account for aspects of the neuropsychiatric clinical sequelae reported. The generalisability of these findings needs to be explored in future studies, as the number of cases, clinical data, and tissue availability were limited. Funding Defense Health Program of the United States Department of Defense.

Objective: We report an unusual case of masticator space foreign body in a patient presenting with otorrhea and granulation tissue within the external auditory canal (EAC). Methods: Case report. Results: A 16-month-old male presented with fever, unilateral otorrhea, facial swelling, leukocytosis, and granulation tissue within the EAC that failed to respond to conventional medical treatment. Computed tomography scan showed EAC and middle ear opacification and soft tissue swelling involving the masticator space. Given concerns for malignancy, biopsies of tissue within the EAC and of a newly detected right buccal mass were performed, revealing granulation tissue. Concern persisted for neoplasm, however, and magnetic resonance imaging was obtained, showing a masticator space foreign body and possible osteomyelitis of the mandible and pterygoid plates. The patient underwent urgent operative removal of a 3 cm crayon fragment from the masticator space and debridement of granulation tissue arising from a small defect at the inferior medial cartilaginous EAC. He likely sustained foreign body injury several weeks earlier upon falling from standing height while biting a crayon. Postoperatively, he was observed in hospital on intravenous antibiotics and improved significantly. He has since fully recovered. Conclusion: Masticator space foreign bodies may present with erosion and granulation tissue of the EAC.

Video-electroencephalography (VEEG) is an invaluable tool for the differentiation of psychogenic nonepileptic seizures (PNES) from epileptic seizures (ES). This paper (i) evaluates the demographics of patients undergoing VEEGs at the Princess Alexandra Hospital from July 1 2017 to July 1 2019 and identifies those subsequently diagnosed with PNES, (ii) determines the delay in PNES diagnosis and proportion of PNES patients on antiepileptic drugs (AEDs) prior to a VEEG, and (iii) determines the proportion of PNES patients who subsequently ceased their AEDs. Of the 94 patients in the study group, 51 were female and 43 were male. In total, 22 (23%) of VEEGs were consistent with epilepsy (ES), 25 (26%), with PNES, 5 (5%) mixed (PNES and ES), 5 (5%) with other types of events, and 37 were nondiagnostic. Two patients with non-diagnostic VEEGs were subsequently treated as PNES at the treating clinician's discretion. Regarding AEDs, 62 of the patients were on at least one agent at the time of VEEG recording. The mean durations of AED therapy and diagnostic delay for patients subsequently diagnosed with PNES were six years and seven years, respectively. Of these, the majority had their AEDs subsequently weaned/ceased. This study highlights the value of VEEG in diagnostic differentiation of epileptic from nonepileptic events, thereby preventing unnecessary AED therapy for patients with PNES. The results are consistent with previous studies in the literature evaluating VEEG clinical outcomes.

Oncolytic viruses (OV) are defined by their intrinsic or engineered tropism for tumor cells. Understanding the drivers of susceptibility to infection as well as the downstream intracellular signaling and immune activation profile is critical in identifying the patients that will respond to OV therapy. Newcastle Disease Virus (NDV) is a negative stranded RNA avian paramyxovirus, here modified to encode human GM-CSF or IL-12. Patient derived xenografts (PDX) can more accurately reflect the genetic, epigenetic, and architectural heterogeneity of human tumors and were therefore selected to model the in vivo activity of NDV:GM-CSF. Eighty-nine independent models derived from patients with Bladder, Colorectal, Head and Neck, Kidney, Liver, Lung, Ovarian, Pancreatic, and Breast tumors were studied. Mice were dosed intravenously with NDV:GM-CSF, monitored for pharmacodynamic and pharmacokinetic changes 48 hours after the first dose, and followed for tumor growth inhibition. Objective response was observed in 68% of treated mice, with responses observed in all indications. Using total stranded RNAseq, we were able to assess changes in human tumor, murine immune infiltrate, and viral RNA. Results showed that NDV:GM-CSF treatment leads to increases in transcripts of inflammatory chemokines and cytokines such as RANTES and CXCL9, with induction directly correlated to level of viral replication. Additionally, we saw increases in NKp46 and IL-12R, markers of NK cells. To assess if IL-12 would augment immune activation, we treated surgically resected human tumors with NDV:IL-12. NDV:IL-12 was capable of infecting tumor cells, generating IL-12 protein, and driving a strong IFNγ response. Here we show that NDV can infect a wide variety of human tumors across multiple indications and drive a potent immune activation which can be modulated by transgenes. This data provides insight into what types of tumors could be treated with NDV:GM-CSF or NDV:IL-12. Citation Format: Nicholas M. Durham, Kelly McGlinchey, Shannon Burke, Todd Creasy, Nicola Rath, Noel Monks, Ravinder Tammali, Kevin Schifferli, Nick Holoweckyj, Susie Hayes, Emma Jones, Elizabeth J. Kelly, Danielle Carroll, James Harper, Katie Streicher. Newcastle Disease Virus in human derived tumors: Understanding immune recruitment and activation via virally delivered IL-12 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5544.

Summary Objective Manual detection of spike‐wave discharges (SWDs) from electroencephalography (EEG) records is time intensive, costly, and subject to inconsistencies/biases. In addition, manual scoring often omits information on SWD confidence/intensity, which may be important for the investigation of mechanistic‐based research questions. Our objective is to develop an automated method for the detection of SWDs in a mouse model of absence epilepsy that is focused on the characteristics of human scoring of preselected events to establish a confidence‐based, continuous‐valued scoring. Methods We develop a support vector machine (SVM)–based algorithm for the automated detection of SWDs in the γ2R43Q mouse model of absence epilepsy. The algorithm first identifies putative SWD events using frequency‐ and amplitude‐based peak detection. Four humans scored a set of 2500 putative events identified by the algorithm. Then, using predictors calculated from the wavelet transform of each event and the labels from human scoring, we trained an SVM to classify (SWD/nonSWD) and assign confidence scores to each event identified from 60, 24‐hour EEG records. We provide a detailed assessment of intra‐ and interrater scoring that demonstrates advantages of automated scoring. Results The algorithm scored SWDs along a continuum that is highly correlated with human confidence and that allows us to more effectively characterize ambiguous events. We demonstrate that events along our scoring continuum are temporally and proportionately correlated with abrupt changes in spectral power bands relevant to normal behavioral states including sleep. Significance Although there are automated and semi‐automated methods for the detection of SWDs in humans and rats, we contribute to the need for continued development of SWD detection in mice. Our results demonstrate the value of viewing detection of SWDs as a continuous classification problem to better understand “ground truth” in SWD detection (ie, the most reliable features agreed upon by humans that also correlate with objective physiologic measures).