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Summary Oral papillary lesions represent a variety of developmental and neoplastic conditions. Early diagnoses of different papillary lesions are challenging for oral medicine specialists. Malignant acanthosis nigricans (MAN) is a rare cutaneous disorder and a potential marker of underlying hidden tumours. It is characterized by papillary lesions that always involve the oral mucosa. In oral medicine specialities, MAN is not well understood. When the early signs of MAN are extensive oral lesions and slight cutaneous pigmentation without obvious florid cutaneous papillomatosis, the diagnosis can be incorrect or delayed. Oral medicine specialists should ask affected patients to provide details of their medical history and conduct a timely systemic examination.

Toothpaste tablets are claimed as a sustainable oral care solution because of their plastic-free concept and ability to deliver the same health benefits as toothpaste cream without harming the environment. Various studies on the environmental impacts related to toothpaste packaging have been conducted; however, far too little attention has been paid to toothpaste ingredients. Life cycle assessment was employed to evaluate the impacts between cleaning teeth with toothpaste cream and tablets. The functional unit of brushing teeth for 2 min twice a day for 6 months was compared within a cradle-to-grave system boundary. The study was conducted in the context of toothpaste manufacturing and domestic consumption in Thailand. Results show that using toothpaste tablets remarkably contributes to a higher score than applying toothpaste cream, accounting for 188 and 163 millipoints, respectively. About 65% of the total impact is from the use phase, and 20% is from ingredient production. The damage to human health is the biggest concern (10.358 × 10−6 DALY). Sugar alcohols, magnesium stearate, and polyvidone are inactive ingredients in the tablets that cause serious human health problems. Toothpaste manufacturers should reconsider ingredient substitution and redesign an appropriate amount and form of the tablet to mitigate the abovementioned impacts.

ObjectiveTo test the hypothesis that cerebral blood flow (CBF) assessed with arterial spin labelling (ASL) MRI is increased and standardised neurological examination is altered in infants with neonatal opioid withdrawal syndrome (NOWS) compared with those without.DesignProspective cohort study.SettingLevel IV neonatal intensive care unit and outpatient primary care centre.ParticipantsInfants with NOWS receiving pharmacological treatment and unexposed controls matched for gestational age at birth and post-menstrual age at MRI.Main outcomesCBF assessed by ASL on non-sedated 3-Tesla MRI and standardised Hammersmith Neonatal Neurological Examination (HNNE) within 14 days of birth.ResultsThirty infants with NOWS and 31 control infants were enrolled and included in the final analysis. Global CBF across the brain was higher in the NOWS group compared with controls (14.2 mL/100 g/min±5.5 vs 10.7 mL/100 g/min±4.3, mean±SD, Cohen’s d=0.72). HNNE total optimality score was lower in the NOWS group compared with controls (25.9±3.6 vs 28.4±2.4, mean±SD, Cohen’s d=0.81). A penalised logistic regression model including both CBF and HNNE items discriminated best between the two groups.ConclusionsIncreased cerebral perfusion and neurological examination abnormalities characterise infants with NOWS compared with those without intrauterine drug exposure and suggest prenatal substance exposure affects fetal brain development. Identifying neurological and neuroimaging characteristics of infants with NOWS can contribute to understanding mechanisms underlying later outcomes and to designing potential new treatments.

Hypertension is a potent cardiovascular risk factor with deleterious end-organ effects and is especially prevalent among patients with chronic kidney disease. The SPRINT (Systolic Blood Pressure Intervention Trial) enrolled patients at an elevated cardiac risk including patients with mild to moderate chronic kidney disease and found that an intensive systolic blood pressure goal of

Pediatric imaging use and payment trends in accountable care organizations (ACOs) are seldom studied but are important for health policy decisions and resource allocation. To evaluate patterns of advanced imaging use and associated payments over a 7-year period at a large ACO in the USA serving a Medicaid population. We reviewed paid claims data from 2011 through 2017 from an ACO, analyzing the MRI, CT and US use trends and payments from emergency department (ED) and outpatient encounters. We defined “utilization rate” as the number of advanced imaging procedures per 100 enrolled children per calendar year. Average yearly utilization and payments trends were analyzed using Pearson correlation. Across 7 years, 186,552 advanced imaging procedures were performed. The average overall utilization rate was 6.99 (95% confidence interval [CI]: 6.9–7.1). In the ED this was 2.7 (95% CI: 2.6–2.8) and in outpatients 4.3 (95% CI: 4.2–4.3). The overall utilization rate grew by 0.7% yearly (P=0.077), with US growing the most at 4.0% annually (P=0.0005), especially in the ED in the US, where it grew 10.8% annually (P=0.000019). The overall payments were stable from 2011 to 2017, with outpatient MRI seeing the largest payment decrease at 1.8% (P=0.24) and ED US showing the most growth at 3.3% (P=0.00016). Head CT and abdominal US were the two most common procedures. Over the study period, advanced imaging utilization at this large pediatric ACO serving the Medicaid population increased, especially with US use in the ED. Overall payments related to advanced imaging remained stable over this period.

Context An inverse relationship between brown adipose tissue (BAT) and obesity has previously been reported in older children and adults but is unknown in young children. Objective We investigated the influence of BAT in thermoneutral condition on adiposity and metabolic profile in Asian preschool children. Design, Setting, and Participants A total of 198 children aged 4.5 years from a prospective birth cohort study, Growing Up in Singapore Towards Healthy Outcomes (GUSTO) were successfully studied with water-fat magnetic resonance imaging of the supraclavicular and axillary fat depot (FDSA). Regions within FDSA with fat-signal-fraction between 20% and 80% were considered BAT, and percentage BAT (%BAT; 100*BAT volume/ FDSA volume) was calculated. Main Outcome Measures Abdominal adipose tissue compartment volumes, ectopic fat in the soleus muscle and liver, fatty liver index, metabolic syndrome scores, and markers of insulin sensitivity. Results A 1% unit increase in %BAT was associated with lower body mass index, difference (95% CI), −0.08 (−0.10, −0.06) kg/m2 and smaller abdominal adipose tissue compartment volumes. Ethnicity and sex modified these associations. In addition, each unit increase in %BAT was associated with lower ectopic fat at 4.5 years in the liver, −0.008% (−0.013%, −0.003%); soleus muscle, −0.003% (−0.006%, −0.001%) of water content and lower fatty liver index at 6 years. Conclusions Higher %BAT is associated with a more favorable metabolic profile. BAT may thus play a role in the pathophysiology of obesity and related metabolic disorders. The observed ethnic and sex differences imply that the protective effect of BAT may vary among different groups.

Background: In the Phase III SOLAR-1 trial (NCT02437318), ALP (PI3Kα inhibitor) + fulvestrant (FUL) significantly improved progression-free survival vs FUL alone in patients (pts) with HR+/HER2− advanced breast cancer with PIK3CA mutations (André et al. N Engl J Med. 2019;380:1929-1940). Hyperglycemia was identified as an expected adverse event (AE) with ALP and was the most frequent grade (G) 3/4 AE in SOLAR-1 (G3, 32.7%; G4, 3.9%). A protocol amendment was implemented during the study to provide additional detailed guidance on hyperglycemia and rash management. Additionally, conditions at baseline such as prediabetic or diabetic glycemic status, body mass index (BMI) ≥30, and age ≥75 years have been identified as risk factors for ALP-induced hyperglycemia. Here we present a case report highlighting 4 examples of early intervention and different management approaches for ALP-induced hyperglycemia in SOLAR-1. Methods: According to the protocol, glycemic status was assessed at baseline and over time using fasting plasma glucose and glycated hemoglobin. Hyperglycemia was regularly assessed per the National Cancer Institute CTCAE v4.03. In addition to concomitant medications for hyperglycemia, dose interruptions or reductions by one level were recommended for both G3 and G4 hyperglycemia, per protocol. If G4 hyperglycemia had not improved within 24 hours and confounding factors could be excluded, pts should be permanently discontinued from ALP. Pts from this case report were selected on the basis of hyperglycemia events of interest to the community: (1) not well controlled on metformin alone; (2) required hospitalization; (3) no risk factors for hyperglycemia at baseline; (4) no action taken at initial presentation of hyperglycemia. Results: In SOLAR-1, 284 pts were randomized to ALP + FUL and 187 (66%) developed hyperglycemia; 163 of these pts received concomitant medications for hyperglycemia, and most received metformin as part of their treatment (87%). Three cases exhibited examples of early intervention for ALP-induced hyperglycemia. The first pt was prediabetic and had a BMI >30. She presented with G2 hyperglycemia on day 8 and received metformin and a DPP-4 inhibitor but then had a G3 event 2 weeks later, managed by an ALP dose interruption. Another G2 event led to addition of an SGLT2 inhibitor and a sulfonylurea, which allowed her to stay on ALP treatment (>43.3 mo). The second pt was prediabetic and had a BMI >30. She had G3 hyperglycemia leading to hospitalization on day 8, started metformin, and then received rescue insulin. She continued to be managed with dose adjustments of metformin and addition of a sulfonylurea until disease progression (11.2 mo). The third pt had a normal glycemic status at baseline and a BMI 40.5 mo). A case example of late intervention for ALP-induced hyperglycemia was a pt who had a normal glycemic status at baseline and a BMI Citation Format: Ingrid Mayer, Azeez Farooki, Hope S. Rugo, Hiroji Iwata, Eva Ciruelos, Mario Campone, Sibylle Loibl, Pierfranco Conte, Dejan Juric, Farhat Ghaznawi, Ines Lorenzo, Huilin Hu, Fiorenza Gaudenzi, Fabrice Andre. Early intervention for and management of alpelisib (ALP)-induced hyperglycemia: Case studies from the phase III SOLAR-1 trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-35.

BackgroundTo investigate the serum level of hepcidin and its relationship with cardiovascular disease (CVD) in maintenance hemodialysis (MHD) patients.MethodsBlood was obtained from 75 MHD patients before undergoing hemodialysis and 20 healthy controls. Serum hepcidin, advanced oxidation protein products (AOPP) and interleukin (IL)-6 were measured by enzyme-linked immunosorbant assay (ELISA). Spearman correlation, and binary logistic regression linear regression analyses were used to assess the relationship between serum hepcidin and other parameters.ResultsThe serum level of hepcidin, AOPP and IL-6 was significantly up-regulated in MHD patients compared with the control (P < 0.05). Furthermore, serum hepcidin levels in patients with CVD were higher than those in patients without CVD (P < 0.05). In all MHD patients, serum hepcidin level was correlated positively with erythropoietin (EPO) dose per week (ρ = 0.251, P = 0.030), EPO resistance index (ρ = 0.268, P = 0.020), ferritin (ρ = 0.814, P < 0.001), transferin saturation (TSAT, ρ = 0.263, P = 0.023), AOPP (ρ = 0.280, P = 0.049), high sensitive C reactive protein (ρ = 0.151, P = 0.006), IL-6 (ρ = 0.340, P = 0.003) and left ventricular mass index (LVMI, ρ = 0.290, P = 0.033). Moreover, it was negatively correlated with serum pre-albumin (ρ = −0.266, P = 0.021), total iron-binding capacity (TIBC, ρ = −0.458, P < 0.001), unsaturated iron-binding capacity (UIBC, ρ = −0.473, P < 0.001) and transferrin (ρ = −0.487, P < 0.001). Linear regression analysis showed that ferritin (β = 0.708, P < 0.001), TIBC (β = −0.246, P = 0.032) and IL-6 (β = 0.209, P = 0.041) were independently associated with hepcidin. Results of binary logistic regression analysis suggested that higher serum hepcidin level (>249.2 ng/mL) was positively and independently related to CVD (OR = 1.32, 95% CI [1.20–9.56], P = 0.043).ConclusionsSerum hepcidin level is associated with CVD in MHD patients, indicating that hepcidin may be a novel biomarker and therapeutic target for CVD.

Purpose Three commonly used classifications for thumb polydactyly are the Wassel-Flatt, Rotterdam, and Chung. The ideal classification system would have high validity and reliability and be descriptive of the thumb anomaly. The purposes of this investigation were to (1) compare the inter- and intrarater reliability of these 3 classifications when applied to a large sample of patients enrolled in the Congenital Upper Limb Differences (CoULD) Registry and (2) determine the prevalence of radial polydactyly types when using the various classifications in a North American population. Methods Inter- and intrarater reliability were determined using 150 cases of radial polydactyly presented in a Web-based format to 7 raters in 3 rounds, a preliminary training round and 2 observation rounds. Raters classified each case according to the Wassel-Flatt, Rotterdam, and Chung classifications. Inter- and intrarater reliability were evaluated with the intraclass correlation coefficient (ICC) calculated using 2-way random measures with perfect agreement. Results For Wassel-Flatt, both the interrater (ICC, 0.93) and the intrarater reliability (ICC, 0.91) were excellent. The Rotterdam classification had excellent reliability for both interrater reliability (ICC, 0.98) and intrarater reliability (ICC, 0.94), when considering type alone. Interrater analysis of the additional subtypes demonstrated a wide range of reliabilities. The Chung classification had good interrater (ICC, 0.88) and intrarater reliability (ICC, 0.77). Within the Wassel-Flatt classification, the most frequent unclassifiable thumb was a type IV hypoplastic thumb as classified by the Rotterdam classification. Conclusions The Wassel-Flatt and Rotterdam classifications for radial polydactyly have excellent inter- and intrarater reliability. Despite its simplicity, the Chung classification was less reliable in comparison. The Chung and Rotterdam classification systems capture the hypoplastic subtypes that are unclassifiable in the Wassel-Flatt system. Addition of the hypoplastic subtype to the Wassel-Flatt classification (eg, Wassel-Flatt type IVh) would maintain the highest reliability and classify over 90% of thumbs deemed unclassifiable in the Wassel-Flatt system. Clinical relevance The Wassel-Flatt and Rotterdam classifications have excellent inter-and intrarater reliability for the hand surgeon treating thumb polydactyly. Addition of a hypoplastic subtype to the Wassel-Flatt (Type 4h) allows classification of most previously unclassifiable thumbs.

Yu Hu,1,* Ying Zhang,2,* Meng Ding,2 Ruisi Xu2 1Department of Pathology, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin, People’s Republic of China; 2Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Meng Ding; Ruisi XuChina-Japan Union Hospital of Jilin University, Changchun 130033, Jilin, People’s Republic of ChinaEmail dingmeng@jlu.edu.cn; xuruisi@jlu.edu.cnBackground: Colorectal cancer (CRC), characterized by high mortality and incidence rate, is one of the most common types of rectum tumors in the gastrointestinal tract worldwide. An increasing number of investigations indicated that long noncoding RNAs (lncRNAs) have been implicated in the growth of a wide range of cancers. Although it has obtained general acceptance that lncRNA LINC00511 plays a significant role in numerous cancers, the regulatory mechanism of LINC00511 in CRC still needs to be explored.Materials and Methods: Bioinformatics analysis and a wide range of experiments of sphere formation assay, cell proliferation assay, RT-qPCR, colony formation assay, Transwell assay and Western blot assays investigated the function and mechanism of LINC00511 in CRC tissues and cells.Results: Our results manifested that the expression level of LINC00511 was obviously upregulated in CRC tissues and cells and it accelerated CRC development through facilitating cell proliferation, metastasis and stemness. Molecular mechanism exploration uncovered that LINC00511 acted as a ceRNA competing with NFIA to bind with miR-29c-3p. Through rescue experiments, we discovered that NFIA upregulation partly counteracted the inhibitive effect induced by LINC00511 silencing on CRC progression.Conclusion: These results revealed that LINC00511 participated in the progression of CRC by targeting the LINC00511/miR-29c-3p/NFIA axis, indicating that LINC00511 may be a potential therapeutic target for CRC treatment.Keywords: LINC00511, miR-29c-3p, NFIA, colorectal cancer

Intracytoplasmic sperm injection (ICSI), microinjection of a single spermatozoon into an oocyte, is a routine procedure in assisted reproduction programs. This procedure uses fine control of small bore microinjection needles and precise volume control via hydraulic syringe pumps. In many early experiments mercury is placed within the injection system because its high surface tension in the system facilitates the injection procedure. However, mercury is cytotoxic and therefore alternative fluids or approaches are needed. Here we examine the main properties of mercury and their impact on the various aspects of ICSI. We conclude that the small momentum diffusivity of mercury is the most important contributing factor that facilitates the ICSI procedures.

BACKGROUND Stack-of-radial multiecho gradient-echo MRI is promising for free-breathing liver R2* quantification and may benefit children. PURPOSE To validate stack-of-radial MRI with self-gating motion compensation in phantoms, and to evaluate it in children. STUDY TYPE Prospective. PHANTOMS Four vials with different R2* driven by a motion stage. SUBJECTS Sixteen pediatric patients with suspected nonalcoholic fatty liver disease or steatohepatitis (five females, 13 ± 4 years, body mass index 29.2 ± 8.6 kg/m2 ). FIELD STRENGTH/SEQUENCES Stack-of-radial, and 2D and 3D Cartesian multiecho gradient-echo sequences at 3T. ASSESSMENT Ungated and gated stack-of-radial proton density fat fraction (PDFF) and R2* maps were reconstructed without and with self-gating motion compensation. Stack-of-radial R2* measurements of phantoms without and with motion were validated against reference 2D Cartesian results of phantoms without motion. In subjects, free-breathing stack-of-radial and reference breath-hold 3D Cartesian were acquired. Subject inclusion for statistical analysis and region of interest placement were determined independently by two observers. STATISTICAL TESTS Phantom results were fitted with a weighted linear model. Demographic differences between excluded and included subjects were tested by multivariate analysis of variance. PDFF and R2* measurements were compared using Bland-Altman analysis. Interobserver agreement was assessed by the intraclass correlation coefficient (ICC). RESULTS Ungated stack-of-radial R2* inside moving phantom vials showed a significant positive bias of 64.3 s-1 (P 0.31). Subject inclusion decisions for statistical analysis from two observers were consistent. No significant differences were found between four excluded and 12 included subjects (P = 0.14). Compared to breath-hold Cartesian, ungated and gated free-breathing stack-of-radial exhibited mean R2* differences of 18.5 s-1 and 3.6 s-1 . Mean PDFF differences were 1.1% and 1.0% for ungated and gated measurements, respectively. Interobserver agreement was excellent (ICC for PDFF = 0.99, ICC for R2* = 0.90; P

Corneal transplantation surgery faces several fundamental problems, including graft failure, especially in complicated cases, and a marked shortage of human donor corneas. The purpose of this revie...

Background Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) account for an increasing proportion of liver disease in the Asia-Pacific region. Many areas in the region are experiencing epidemics of metabolic syndrome among rapidly ageing populations. Aims To estimate using modelling the growth in NAFLD populations, including cases with significant fibrosis that are most likely to experience advanced liver disease and related mortality. Methods A disease progression model was used to summarise and project fibrosis progression among the NAFLD populations of Hong Kong, Singapore, South Korea and Taiwan. For each area, changes in the adult prevalence of obesity was used to extrapolate long-term trends in NAFLD incidence. Results In the areas studied, prevalent NAFLD cases were projected to increase 6%-20% during 2019-2030, while prevalent NASH cases increase 20%-35%. Incident cases of hepatocellular carcinoma are projected to increase by 65%-85%, while incident decompensated cirrhosis cases increase 65%-100% by 2030. Likewise, NAFLD-related mortality is projected to increase between 65% and 100% from 2019 to 2030. NAFLD disease burden is expected to increase alongside rising trends in metabolic syndrome and obesity among populations in the region. This leads to more cases of advanced liver disease and associated mortality. Conclusions Preventing the growth of diabetic and obese populations will be a key factor in reducing ongoing increases in NAFLD-related disease burden in the Asia-Pacific region.

The benefit and harm of three-field lymphadenectomy for oesophageal cancer are still unknown. The aim of this study was to compare overall survival and morbidity and mortality between three- and two-field lymphadenectomy in patients with oesophageal squamous cell carcinoma.Between March 2013 and November 2016, patients with squamous cell carcinoma of the middle or distal oesophagus were assigned randomly to open oesophagectomy with three-field (cervical-thoracic-abdominal) or two-field (thoracic-abdominal) lymphadenectomy. No chemo(radio) therapy was given before surgery. This paper reports on the secondary outcomes of the study: pathology and surgical complications.Some 400 patients were randomized, 200 in each group. A median of 37 (i.q.r. 30-49) lymph nodes were dissected in the three-field group, compared with 24 (18-30) in the two-field group (P0·001). Some 43 of 200 patients (21·5 per cent) in the three-field group had cervical lymph node metastasis. More patients in the three-field group had pN3 disease: 21 of 200 (10·5 per cent) versus 10 of 200 (5·0 per cent) (P = 0·040). The rate and severity of postoperative complications were comparable between the two groups, except that six patients in the three-field arm needed reintubation compared with none in the two-field group (3·0 versus 0 per cent; P = 0·030). The 90-day mortality rate was 0 per cent in the three-field group and 0·5 per cent (1 patient) in the two-field group (P = 1·000).Oesophagectomy with three-field lymphadenectomy increased the number of lymph nodes dissected and led to stage migration owing to a 21·5 per cent rate of cervical lymph node metastasis. Postoperative complications were largely comparable between two- and three-field lymphadenectomy. Registration number: NCT01807936 ( https://www.clinicaltrials.gov).El beneficio y los daños potenciales de la linfadenectomía en tres campos (three-field, 3-FLD) en el cáncer de esófago aún se desconoce. El objetivo de este estudio fue comparar la supervivencia global y la morbilidad y mortalidad entre la linfadenectomía en tres campos (3-FLD) y la linfadenectomía en dos campos (two-field lymphadenectomy, 2-FLD) en pacientes con carcinoma escamoso de esófago. MÉTODOS: Entre marzo de 2013 y noviembre de 2016, pacientes con carcinoma escamoso del tercio medio y distal del esófago fueron asignados de forma aleatoria a esofaguectomía abierta con linfadenectomía 3-FLD (cervical-torácica-abdominal) o 2-FLD (torácica-abdominal). No se administró quimioterapia o quimiorradioterapia antes de la cirugía. Este estudio describe los resultados secundarios: datos de la anatomía patología y complicaciones quirúrgicas.Se aleatorizaron un total de 400 pacientes a linfadenectomía 3-FLD y 2-FLD (200 pacientes en cada grupo). En el grupo de 3-FLD se disecaron una mediana (rango) de 37 (30-49) ganglios linfáticos en comparación con 24 (18-30) en el grupo de 2-FLD (P0,001). Un total de 43 de 200 (21,5%) pacientes en el grupo 3-FLD presentaron metástasis en los ganglios linfáticos (lymph node metastasis, LNM) cervicales. Más pacientes en el grupo 3-FLD presentaron un estadio de la enfermedad pN3 en comparación con el grupo 2-FLD: 21 de 200 (10,5%) versus 10 de 200 (5,0%), P = 0,040). La tasa y gravedad de las complicaciones postoperatorias fue comparable en ambos grupos, aparte de 6 pacientes en la rama 3-FLD que necesitaron reintubación (3,0%) en comparación con ninguno en el grupo 2-FLD (P = 0,030). La mortalidad a los 90 días fue del 0% en 3-FLD y del 0,5% (1 paciente en el grupo 2-FLD (P = 1,000). CONCLUSIÓN: La esofaguectomía con 3-FLD aumenta el número de ganglios linfáticos y conduce a una migración del estadio debido a la tasa de LNM cervicales del 21,5%. Las complicaciones postoperatorias fueron similares entre las linfadenectomías 3-FLD y 2-FLD.

BACKGROUND AND PURPOSE: Spiral MR imaging has several advantages compared with Cartesian MR imaging that can be leveraged for added clinical value. A multicenter multireader study was designed to compare spiral with standard-of-care Cartesian postcontrast structural brain MR imaging on the basis of relative performance in 10 metrics of image quality, artifact prevalence, and diagnostic benefit. MATERIALS AND METHODS: Seven clinical sites acquired 88 total subjects. For each subject, sites acquired 2 postcontrast MR imaging scans: a spiral 2D T1 spin-echo, and 1 of 4 routine Cartesian 2D T1 spin-echo/TSE scans (fully sampled spin-echo at 3T, 1.5T, partial Fourier, TSE). The spiral acquisition matched the Cartesian scan for scan time, geometry, and contrast. Nine neuroradiologists independently reviewed each subject, with the matching pair of spiral and Cartesian scans compared side-by-side, and scored on 10 image-quality metrics (5-point Likert scale) focused on intracranial assessment. The Wilcoxon signed rank test evaluated relative performance of spiral versus Cartesian, while the Kruskal-Wallis test assessed interprotocol differences. RESULTS: Spiral was superior to Cartesian in 7 of 10 metrics (flow artifact mitigation, SNR, GM/WM contrast, image sharpness, lesion conspicuity, preference for diagnosing abnormal enhancement, and overall intracranial image quality), comparable in 1 of 10 metrics (motion artifacts), and inferior in 2 of 10 metrics (susceptibility artifacts, overall extracranial image quality) related to magnetic susceptibility (P < .05). Interprotocol comparison confirmed relatively higher SNR and GM/WM contrast for partial Fourier and TSE protocol groups, respectively (P < .05). CONCLUSIONS: Spiral 2D T1 spin-echo for routine structural brain MR imaging is feasible in the clinic with conventional scanners and was preferred by neuroradiologists for overall postcontrast intracranial evaluation.

Context Evidence has shown that essential nutrients are highly correlated with the occurrence of esophageal cancer (EC). However, findings from observational studies on the associations between dietary carbohydrate, salt consumption, and the risk of EC remain controversial. Objective The aim of this study was to conduct a systematic review and meta-analysis to confirm the associations of dietary carbohydrate and salt consumption with EC risk. Data Source Various electronic databases (PubMed, MEDLINE, Embase, Google Scholar, Cochrane Library, Chinese Electronic Periodical Services, and China Knowledge Resource Integrated) were searched up until January 31, 2019. Data Extraction Data related to patient characteristics and study characteristics were extracted by 2 independent reviewers. The risk ratio reported as relative risk (RR) or odds ratio (OR) was extracted, and random-effects models were performed to estimate the summary risk ratio. Results In total, 26 studies were included in this analysis, of which 12 studies, including 11 case-control studies and 1 cohort study, examined dietary carbohydrates, and 18 studies, including 16 case-control studies and 2 cohort studies, examined dietary salt. The pooled OR showed that dietary carbohydrate intake was inversely related to EC risk (OR = 0.62; 95% confidence interval [CI], 0.50–0.77), but positive correlations between dietary salt intake and the risk of EC were supported by the recruited case-control studies (OR = 1.97; 95% CI, 1.50–2.61) and cohort studies (RR = 1.04; 95% CI, 1.00–1.08). Conclusions Salt is an essential nutrient for body functions and biochemical processes. Providing health education and management regarding proper use of salt in daily foods and labeling the amount of sodium in manufactured products to reduce the risk of developing EC should be more appropriately performed in the general population.

Summary: Background: We undertook a Grand Challenges in Global Eye Health prioritisation exercise to identify the key issues that must be addressed to improve eye health in the context of an ageing population, to eliminate persistent inequities in health-care access, and to mitigate widespread resource limitations. Methods: Drawing on methods used in previous Grand Challenges studies, we used a multi-step recruitment strategy to assemble a diverse panel of individuals from a range of disciplines relevant to global eye health from all regions globally to participate in a three-round, online, Delphi-like, prioritisation process to nominate and rank challenges in global eye health. Through this process, we developed both global and regional priority lists. Findings: Between Sept 1 and Dec 12, 2019, 470 individuals complete round 1 of the process, of whom 336 completed all three rounds (round 2 between Feb 26 and March 18, 2020, and round 3 between April 2 and April 25, 2020) 156 (46%) of 336 were women, 180 (54%) were men. The proportion of participants who worked in each region ranged from 104 (31%) in sub-Saharan Africa to 21 (6%) in central Europe, eastern Europe, and in central Asia. Of 85 unique challenges identified after round 1, 16 challenges were prioritised at the global level; six focused on detection and treatment of conditions (cataract, refractive error, glaucoma, diabetic retinopathy, services for children and screening for early detection), two focused on addressing shortages in human resource capacity, five on other health service and policy factors (including strengthening policies, integration, health information systems, and budget allocation), and three on improving access to care and promoting equity. Interpretation: This list of Grand Challenges serves as a starting point for immediate action by funders to guide investment in research and innovation in eye health. It challenges researchers, clinicians, and policy makers to build collaborations to address specific challenges. Funding: The Queen Elizabeth Diamond Jubilee Trust, Moorfields Eye Charity, National Institute for Health Research Moorfields Biomedical Research Centre, Wellcome Trust, Sightsavers, The Fred Hollows Foundation, The Seva Foundation, British Council for the Prevention of Blindness, and Christian Blind Mission. Translations: For the French, Spanish, Chinese, Portuguese, Arabic and Persian translations of the abstract see Supplementary Materials section.

International audience; Isosorbide isomerisation is a known reaction that can proceed over Ru and Ni-based heterogeneous catalysts. As a rule, an exogenous H2 pressure (40–100 bar) is required, even though H2 does not participate stoichiometrically in the reaction. By marrying experiments with DFT computations, we ascribe the role of H2 in isosorbide isomerisation to a coverage effect on the catalyst surface. We demonstrate the possibility of conducting the reaction at a low H2 pressure either in the presence of an inert gas to increase H2 solubility in an underlying solvent or using 2-propanol as a hydrogen donor. This might benefit the economy and safety of a potential industrial process.

Background There is no consensus nor recommendation for the surgical management of a minimally dilated adjacent aortic segment, such as the proximal aortic arch, at the time of proximal aortic aneurysm repair. Consequently, clinical equipoise exists regarding whether to extend the proximal aortic aneurysm repair to include the proximal aortic arch, by performing a hemiarch replacement, to mitigate the future risk of aortic aneurysm-related events in the proximal aortic arch. We hypothesized that additional hemiarch replacement to excise a non- or minimally aneurysmal proximal aortic arch does not have clinical benefit in patients undergoing proximal aortic aneurysm repair. Purpose To compare the long-term survival and freedom from aortic-arch reoperation in patients undergoing proximal aortic aneurysm repair with and without additional hemiarch replacement. Methods A retrospective review was performed of all patients undergoing proximal aortic aneurysm repair at our Aortic Center between 2005 and 2019. Inclusion criteria included all patients with a diagnosed root or ascending aortic aneurysm undergoing root or ascending aortic replacement with or without hemiarch replacement. Exclusion criteria were Age Results Hemiarch patients had a significantly lower 10-year survival rate (86.7%; 95% CI, 79.2–94.8 in non-hemiarch vs 81.9%; 95% CI, 75.9–88.3 in hemiarch; P=0.005). There was no significant difference in 10- year cumulative incidence of aortic-arch reintervention (0.7%; 95% CI, 0.3–1.9 in non-hemiarch vs 0.69%; 95% CI, 0.17–2.75 in hemiarch; P=0.99). Hemiarch patients had higher rates of in-hospital mortality (1% in non-hemiarch vs 4% in hemiarch; P Conclusions Proximal aortic aneurysm repair with additional hemiarch was associated with higher mortality without a decrease in aortic-arch reintervention rates compared to isolated proximal aortic aneurysm repair. Furthermore, aortic arch reintervention rate was extremely low. These data call for caution in adding hemiarch replacement at the time of proximal aortic aneurysm repair. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institute of Heath (NIH) 5T35HL007616-40 grant Matched Cohort: KM Survival CurveMatched Cohort: Cumulative Incidence

SummaryT cell exhaustion is a major impediment to anti-tumor immunity. However, it remains elusive how other immune cells in the tumor microenvironment (TME) contribute to this dysfunctional state. Here we show that the biology of tumor-associated macrophages (TAM) and exhausted T cells (Tex) in the TME is extensively linked. We demonstrate thatin vivodepletion of TAM reduces exhaustion programs in tumor-infiltrating CD8+T cells and reinvigorates their effector potential. Reciprocally, transcriptional and epigenetic profiling reveals that Texexpress factors that actively recruit monocytes to the TME and shape their differentiation. Using lattice light sheet microscopy, we show that TAM and CD8+T cells engage in unique long-lasting antigen-specific synaptic interactions that fail to activate T cells, but prime them for exhaustion, which is then accelerated in hypoxic conditions. Spatially resolved sequencing supports a spatiotemporal self-enforcing positive feedback circuit that is aligned to protect rather than destroy a tumor.Graphical Abstract

Venom peptides are potent and selective modulators of voltage-gated ion channels that regulate neuronal function both in health and in disease. We previously identified the spider venom peptide Tap1a from the Venezuelan tarantula Theraphosa apophysis that targeted multiple voltage-gated sodium and calcium channels in visceral pain pathways and inhibited visceral mechano-sensing neurons contributing to irritable bowel syndrome. In this work, alanine scanning and domain activity analysis revealed Tap1a inhibited sodium channels by binding with nanomolar affinity to the voltage-sensor domain II utilising conserved structure-function features characteristic of spider peptides belonging to family NaSpTx1. In order to speed up the development of optimized NaV-targeting peptides with greater inhibitory potency and enhanced in vivo activity, we tested the hypothesis that incorporating residues identified from other optimized NaSpTx1 peptides into Tap1a could also optimize its potency for NaVs. Applying this approach, we designed the peptides Tap1a-OPT1 and Tap1a-OPT2 exhibiting significant increased potency for NaV1.1, NaV1.2, NaV1.3, NaV1.6 and NaV1.7 involved in several neurological disorders including acute and chronic pain, motor neuron disease and epilepsy. Tap1a-OPT1 showed increased potency for the off-target NaV1.4, while this off-target activity was absent in Tap1a-OPT2. This enhanced potency arose through a slowed off-rate mechanism. Optimized inhibition of NaV channels observed in vitro translated in vivo, with reversal of nocifensive behaviours in a murine model of NaV-mediated pain also enhanced by Tap1a-OPT. Molecular docking studies suggested that improved interactions within loops 3 and 4, and C-terminal of Tap1a-OPT and the NaV channel voltage-sensor domain II were the main drivers of potency optimization. Overall, the rationally designed peptide Tap1a-OPT displayed new and refined structure-function features which are likely the major contributors to its enhanced bioactive properties observed in vivo. This work contributes to the rapid engineering and optimization of potent spider peptides multi-targeting NaV channels, and the research into novel drugs to treat neurological diseases.

OBJECTIVE This study aimed to examine whether total, regional, and organ fat predicts bone marrow adipose tissue (BMAT) fat content and to explore whether BMAT fat content differs by sex among Latino youth. METHODS Latino youth (n = 86; age 13.6 [1.4] years, 62% male) with obesity (BMI percentile = 98.5% [1.2%]) underwent a dual-energy x-ray absorptiometry scan to assess body composition and a magnetic resonance imaging scan to determine abdominal adiposity, liver fat, and vertebral BMAT fat content in the thoracic (average of T8-T12) and lumbar (average of L1-L5) spine. RESULTS Male youth exhibited significantly greater thoracic (male youth = 30.8% [1.4%] vs. female youth = 24.5% [2.1%], p = 0.027) and lumbar (male youth = 36.3% [1.5%] vs. female youth = 30.2% [2.2%], p = 0.038) BMAT fat content compared with female youth. Visceral adipose tissue was a significant predictor of thoracic (β = 0.434, t[86] = 3.016, p = 0.003) and lumbar (β = 0.389, t[86] = 2.677, p = 0.009) BMAT fat content, explaining 8.9% and 6.9% of the variance, respectively. Liver fat was a significant predictor of both thoracic (β = 0.487, t[86] = 4.334, p < 0.001) and lumbar (β = 0.436, t[86] = 3.793, p < 0.001) BMAT fat content, explaining 17.6% and 13.8% of the variance, respectively. CONCLUSIONS Male youth had significantly greater thoracic and lumbar BMAT fat content than female youth. Greater BMAT fat content is associated with greater liver fat and visceral adipose tissue among youth with obesity. Further investigation of the mechanistic underpinnings of BMAT may help to differentiate its metabolic and bone-related functions.

ObjectiveFungal keratitis is a major ophthalmic public health problem, particularly in low-income and middle-income countries. The options for treating fungal keratitis are limited. Our study aimed to describe the outcomes of using chlorhexidine 0.2% eye-drops as additional treatment in the management of patients with recalcitrant fungal keratitis.MethodsThis study was nested within a large cohort study of people presenting with microbial keratitis in Uganda. We enrolled patients with recalcitrant fungal keratitis not improving with topical natamycin 5% and commenced chlorhexidine 0.2%. Follow-up was scheduled for 3 months and 1 year. The main outcome measures were healing, visual acuity and scar size at final follow-up.ResultsThirteen patients were followed in this substudy. The patients were aged 27–73 years (median 43 years). Filamentous fungi were identified by microscopy of corneal scrape samples in all cases. Isolated organisms included Aspergillus spp, Fusarium spp, Candida spp, Bipolaris spp and Acremoninum spp. At the final follow-up, nine patients (75%) had healed; three had vision of better than 6/18. Three patients lost their eyes due to infection. In the remaining nine cases, corneal scarring was variable ranging from 4.6 to 9.4 mm (median 6.6 mm, IQR 5.9–8.0 mm); of these five had dense scars, three had moderate scars and one had a mild scar. None of the patients demonstrated signs of chlorhexidine toxicity during the follow-up.ConclusionChlorhexidine 0.2% was found to be a useful sequential adjunctive topical antifungal in cases of fungal keratitis not responding to natamycin 5%, which warrants further evaluation.

To demonstrate the long-range effects of CD8+ T cell–secreted interferon-γ on bystander tumor cells, two studies now use mosaic models of antigen loss in tumors combined with intravital imaging. Factors that influence the length scale of diffusible signals could shape disease progression in cancer and autoimmunity.

More than 100 attendees from Australia, Austria, Belgium, Canada, China, Germany, Hong Kong, Indonesia, Japan, Malaysia, the Netherlands, the Philippines, Republic of Korea, Singapore, Sweden, Switzerland, the United Kingdom, and the United States convened in Singapore for the 2019 ISMRM-sponsored workshop on MRI of Obesity and Metabolic Disorders. The scientific program brought together a multidisciplinary group of researchers, trainees, and clinicians and included sessions in diabetes and insulin resistance; an update on recent advances in water–fat MRI acquisition and reconstruction methods; with applications in skeletal muscle, bone marrow, and adipose tissue quantification; a summary of recent findings in brown adipose tissue; new developments in imaging fat in the fetus, placenta, and neonates; the utility of liver elastography in obesity studies; and the emerging role of radiomics in population-based “big data” studies. The workshop featured keynote presentations on nutrition, epidemiology, genetics, and exercise physiology. Forty-four proffered scientific abstracts were also presented, covering the topics of brown adipose tissue, quantitative liver analysis from multiparametric data, disease prevalence and population health, technical and methodological developments in data acquisition and reconstruction, newfound applications of machine learning and neural networks, standardization of proton density fat fraction measurements, and X-nuclei applications. The purpose of this article is to summarize the scientific highlights from the workshop and identify future directions of work.

INTRODUCTION: Metastasis is a fundamentally physical process in which cells deform through narrow gaps and generate forces to invade surrounding tissues. While it is commonly thought that increased cell deformability is an advantage for invading cells, we previously found that more invasive pancreatic ductal adenocarcinoma (PDAC) cells are stiffer than less invasive PDAC cells. Here we investigate potential mechanisms of the simultaneous increase in PDAC cell stiffness and invasion, focusing on the contributions of myosin II, Arp2/3, and formins. METHOD: We measure cell invasion using a 3D scratch wound invasion assay and cell stiffness using atomic force microscopy (AFM). To determine the effects of actin- and myosin-mediated force generation on cell stiffness and invasion, we treat cells with pharmacologic inhibitors of myosin II (blebbistatin), Arp2/3 (CK-666), and formins (SMIFH2). RESULTS: We find that the activity of myosin II, Arp2/3, and formins all contribute to the stiffness of PDAC cells. Interestingly, we find that the invasion of PDAC cell lines is differentially affected when the activity of myosin II, Arp2/3, or formins is inhibited, suggesting that despite having similar tissue origins, different PDAC cell lines may rely on different mechanisms for invasion. CONCLUSIONS: These findings deepen our knowledge of the factors that regulate cancer cell mechanotype and invasion, and incite further studies to develop therapeutics that target multiple mechanisms of invasion for improved clinical benefit. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12195-019-00603-1) contains supplementary material, which is available to authorized users.

The effect of molecular crowding on the structure and function of Escherichia coli prolyl-transfer RNA synthetase (Ec ProRS), a member of the aminoacyl-transfer RNA synthetase family, has been investigated using a combined experimental and theoretical method. Ec ProRS is a multidomain enzyme; coupled-domain dynamics are essential for efficient catalysis. To gain insight into the mechanistic detail of the crowding effect, kinetic studies were conducted with varying concentrations and sizes of crowders. In parallel, spectroscopic and quantum chemical studies were employed to probe the “soft interactions” between crowders and protein side chains. Finally, the dynamics of the dimeric protein was examined in the presence of crowders using a long-duration (70 ns) classical molecular dynamic simulations. The results of the simulations revealed a shift in the conformational ensemble, which is consistent with the preferential exclusion of cosolutes. The “soft interactions” model of the crowding effect also explained the alteration in kinetic parameters. In summary, the study found that the effects of molecular crowding on both conformational dynamics and catalytic function are correlated in the multidomain Ec ProRS, an enzyme that is central to protein synthesis in all living cells. This study affirmed that large and small cosolutes have considerable impacts on the structure, dynamics, and function of modular proteins and therefore must be considered for stabilizing protein-based pharmaceuticals and industrial enzymes.

The ability to recognize others' emotions based on vocal emotional prosody follows a protracted developmental trajectory during adolescence. However, little is known about the neural mechanisms supporting this maturation. The current study investigated age-related differences in neural activation during a vocal emotion recognition (ER) task. Listeners aged 8 to 19 years old completed the vocal ER task while undergoing functional magnetic resonance imaging. The task of categorizing vocal emotional prosody elicited activation primarily in temporal and frontal areas. Age was associated with a) greater activation in regions in the superior, middle, and inferior frontal gyri, b) greater functional connectivity between the left precentral and inferior frontal gyri and regions in the bilateral insula and temporo-parietal junction, and c) greater fractional anisotropy in the superior longitudinal fasciculus, which connects frontal areas to posterior temporo-parietal regions. Many of these age-related differences in brain activation and connectivity were associated with better performance on the ER task. Increased activation in, and connectivity between, areas typically involved in language processing and social cognition may facilitate the development of vocal ER skills in adolescence.

Magnetic resonance spectroscopic imaging helps to determine abnormal brain tissue conditions by evaluating metabolite concentrations. Although a powerful technique, it is underutilized in routine clinical studies because of its long scan times. In this study, we evaluated the feasibility of scan time reduction in metabolic imaging using compressed-sensing-based MR spectroscopic imaging in pediatric patients undergoing routine brain exams. We retrospectively evaluated compressed-sensing reconstructions in MR spectroscopic imaging datasets from 20 pediatric patients (11 males, 9 females; average age: 5.4±4.5 years; age range: 3 days to 16 years). We performed retrospective under-sampling of the MR spectroscopic imaging datasets to simulate accelerations of 2-, 3-, 4-, 5-, 7- and 10-fold, with subsequent reconstructions in MATLAB. Metabolite maps of N-acetylaspartate, creatine, choline and lactate (where applicable) were quantitatively evaluated in terms of the root-mean-square error (RMSE), peak amplitudes and total scan time. We used the two-tailed paired t-test along with linear regression analysis to statistically compare the compressed-sensing reconstructions at each acceleration with the fully sampled reference dataset. High fidelity was maintained in the compressed-sensing MR spectroscopic imaging reconstructions from 50% to 80% under-sampling, with the RMSE not exceeding 3% in any dataset. Metabolite intensities and ratios evaluated on a voxel-by-voxel basis showed no statistically significant differences and mean metabolite intensities showed high correlation compared to the fully sampled reference dataset up to an acceleration factor of 5. Compressed-sensing MR spectroscopic imaging has the potential to reduce MR spectroscopic imaging scan times for pediatric patients, with negligible information loss.

Magnetic resonance imaging (MRI) is a powerful radiologic tool with the ability to generate a variety of proton-based signal contrast from tissues. Owing to this immense flexibility in signal generation, new MRI techniques are constantly being developed, tested, and optimized for clinical utility. In addition, the safe and nonionizing nature of MRI makes it a suitable modality for imaging in children. In this review article, we summarize a few of the most popular advances in MRI techniques in recent years. In particular, we highlight how these new developments have affected brain, spine, and neuromuscular imaging and focus on their applications in pediatric patients. In the first part of the review, we discuss new approaches such as multiphase and multidelay arterial spin labeling for quantitative perfusion and angiography of the brain, amide proton transfer MRI of the brain, MRI of brachial plexus and lumbar plexus nerves (i.e., neurography), and T2 mapping and fat characterization in neuromuscular diseases. In the second part of the review, we focus on describing new data acquisition strategies in accelerated MRI aimed collectively at reducing the scan time, including simultaneous multislice imaging, compressed sensing, synthetic MRI, and magnetic resonance fingerprinting. In discussing the aforementioned, the review also summarizes the advantages and disadvantages of each method and their current state of commercial availability from MRI vendors.

T1-weighted post-contrast MRI is essential in brain protocols. We demonstrate the feasibility and utility of a 3D non-Cartesian radial acquisition in children.To compare bulk motion artifacts, image quality, and lesion conspicuity in 3D T1-weighted post-contrast brain MRI between a new fat-suppressed radial gradient-echo and a traditional non-fat-suppressed inversion-recovery Cartesian gradient-echo sequence.Images from 53 patients acquired at 3 Tesla were compared. Three radiologists rated the images in three categories, including the presence of bulk motion and whether it impacted diagnosis, whether one sequence was preferred over the other in overall image quality and conspicuity of vascular structures and lesions, and whether diagnosis was possible if only the new fat-suppressed radial acquisition was obtained.The Fleiss' kappa for inter-rater agreement was 0.67 for bulk motion and 0.54 for sequence preference. Of the 53 cases, 56% were identified to have significant motion on conventional imaging, while only 13% had motion artifacts on the radial acquisition (p 0.05). There were no cases where motion was seen on the radial acquisition but not on conventional imaging. Both sequences were equally preferred in 87% of the cases. All radiologists agreed that the radial approach had lower gray-white matter contrast than the conventional inversion-recovery method, but preferred the former for making diagnosis in uncooperative patients.We demonstrate the potential utility of a fat-suppressed 3D T1-weighted post-contrast brain gradient-echo sequence in children. The technique is useful in non-sedate pediatric imaging due to its reduced sensitivity to bulk motion.

AIM To evaluate the association between volume ratio of the mucus pool and tumour response to neoadjuvant therapy in patients with mucinous rectal adenocarcinoma (MC). MATERIALS AND METHODS The volume of the mucus pool and whole tumour on pre-therapeutic T2-weighted magnetic resonance imaging (MRI) of 79 patients was measured using semi-automated software. Mucus pool volume, whole tumour volume, and volume ratio of the mucus pool were compared to tumour response and tumour and lymph node downstaging after neoadjuvant therapy using receiver operating characteristic curve (ROC) and multivariate logistic regression analysis. RESULTS After preoperative neoadjuvant therapy of rectal MC, the rate of pathological complete response, tumour downstaging, tumour response, and lymph node downstaging were 9%, 48%, 39% and 58%, respectively. Tumour downstaging more frequently occurred in patients with a mucus pool volume ratio of at least 68.3% (area under the ROC curve [AUC], 0.793 with 95% confidence interval [CI]: 0.693–0.893), and at least 62.1% for identifying those with a higher tumour response with an AUC of 0.739 (95% CI: 0.630–0.847). CONCLUSION A higher volume ratio of mucus pool in patients with MC may be related to more tumour downstaging and therapy response, and therefore, could serve as an independent imaging biomarker for predicting tumour response to neoadjuvant therapy.

Background: Basal-like breast cancer (BLBC) have poor prognosis. Molecular similarities have been reported between BLBC and high grade serous ovarian cancer (HGSOC). To date, there have been no prognostic biomarkers specifically developed for BLBC or HGSOC that can provide risk stratification and inform treatment selections. In this study, we utilized RNA-seq data available from The Cancer Genome Atlas (TCGA) project to develop molecular signatures for risk stratification in BLBC, and further validated these signatures in HGSOC RNA-seq data from TCGA. Methods: Raw count of RNA-seq data were downloaded from TCGA for 190 BLBC and 374 HGSOC patients. The datasets were annotated with 56963 Ensembl gene IDs. Excluding 31375 gene IDs with no greater than 10 counts in at least 90% of the samples, totally 25228 unique Ensembl gene IDs were used. Progression-free interval (PFI) is the primary study endpoint. Analyses of differentially expressed genes were performed using 3 bioconductor packages: DESEq2, edgeR and voom/limma. Signatures based on commonly identified genes among the 3 analytic methods were established using weighted linear combination of gene expression levels. Their performance was evaluated in the BLBC and HGSOC datasets using Kaplan-Meier survival analysis with log-rank tests and Cox proportional hazard regressions. Results: Among 190 TNBC patients, 18 had recurrences within 2 years and 40 showed no recurrences for at least 5 years. These patients were used as recurrent vs. non-recurrent cases for differential expression analysis. 307 and 343 genes were differentially expressed based on adjusted p value threshold 0.05 and 0.01 in DESeq2 and edgeR analysis, respectively. voom/limma identified no genes differentially expressed based on adjusted p values, but 228 genes had unadjusted p values < 0.01 and were used in the following analysis. Taken together, 63, 58 and 21 genes were commonly identified by DESeq2/edgeR, DESeq2/limma and edgeR/limma analysis, respectively. All 3 signatures were able to significantly stratify the TNBC full dataset (n=190) using either 20-, 50- or 80-percentile as the cut-points. When evaluated in HGSOC patients using 80-percentile cut-point, both 63- and 58-gene signatures were able to significantly stratify patients into different risk groups (HR 2.16, 95% CI: 1.4-3.34, p < 0.001; HR 2.06, 95% CI: 1.36-3.11, p < 0.001). Multivariate Cox regression adjusting for age, grade and stage showed 63- and 58-gene signatures remained to be statistically significant in stratifying HGSOC patients (p = 0.0005 and 0.001, respectively). Conclusion: Gene signatures were specifically identified to prognosticate BLBC patients based on RNA-seq data from TCGA project. Which were able to classify HGSOC patients into differential risk groups. With further validations, these signatures may provide additional prognostic tools for clinicians to better manage triple-negative breast cancer that mostly overlap with BLBC, and HGSOC patients who are difficult-to-treat currently. Disclaimer The views expressed in this article are those of the authors and do not reflect the official policy of the department of Army/Navy/Air Force, Department of Defense, or U.S. government. Citation Format: Hu H, Zhang Y, Liu J, Raj-Kumar P-K, Yang H, Lee M, Kovatich AJ, Shriver CD. Development and validation of prognostic gene signatures for basal-like breast cancer and high grade serous ovarian cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-12.

MRI methods that have reduced sensitivity to motion are attractive in pediatric applications. In spine imaging, physiologic motion such as respiration and cerebrospinal fluid pulsation can hamper diagnostic image quality. We compare a 3D T1-weighted non-Cartesian radial acquisition with a conventional Cartesian 2D turbo-spin-echo (TSE) acquisition in axial post-contrast spine imaging at 3T. Thirty-two patients (mean age 12.2 ± 5.3 years) scheduled for routine clinical spine exams with contrast were enrolled. Three pediatric neuroradiologists compared the two sequences and assessed the presence of motion, the conspicuity of nerve roots, and whether one of the sequences was preferred in visualizing pathology using Likert scales. The Fleiss’ kappa statistic for inter-rater agreement was 0.29 (95% confidence interval, 0.15–0.43) for the presence of motion, 0.30 (0.21–0.38) for conspicuity, and 0.37 (0.19–0.55) for sequence preference. Radial images were less sensitive to motion than TSE (p

BACKGROUND AND PURPOSE: Carotid web was recognized as a cause of ischemic stroke. We sought to determine the clinical and imaging profiles of patients with a carotid web as well as its association with TIA. MATERIALS AND METHODS: A retrospective review of carotid CT angiography studies and brain MR imaging in patients with TIA during the past 3 years (n = 135) was performed to determine the presence of carotid webs by 2 experienced neuroradiologists according to previously published criteria. Demographics and clinical and imaging characteristics are shown by descriptive statistics for patients with an identified carotid web. The agreement in the detection of carotid webs between 2 neuroradiologists was examined using κ statistics. RESULTS: There were 12 (8.9%) carotid webs at the symptomatic bifurcation and 1 carotid web (0.7%) at the asymptomatic bifurcation, and no hyperintensity was seen on DWI of these 12 patients. Eight of these 12 (75%) patients with a carotid web were women. None of the 12 patients with a carotid web had major risk factors or other causes of TIA. Fair-to-good interobserver agreement (κ = 0.87) was seen for diagnosing a carotid web with CT angiography. The rate (10/12, 83.3%) of short-term recurrent episodes of TIA in patients with TIA with a carotid web was significantly higher than that of patients without a carotid web (15/123, 12.2%) (P < .001). CONCLUSIONS: The incidence of carotid web in patients with TIA was 8.9%. There is an association between carotid web and patients with TIA without other identified risks. Carotid web may be an underestimated risk factor for TIA.

Lung cancer (LC) is the highest lethality in all tumors. Non-small cell lung cancer (NSCLC) accounts for about 80% of all LC. Acanthopanax senticosus polysaccharide (ASPS) is extracted from the root of Acanthopanax senticosus (AS). Herein, we examined the effect and molecular mechanism of ASPS on NSCLC. The proliferation, invasion and migration of NCI-H520 cells were detected by cell counting kit-8 (CCK-8), transwell assay and wound healing assay, respectively. The epithelial-mesenchymal transition (EMT) and Wnt/β-catenin pathway-related factors were evaluated using quantitative real-time PCR (QRT-PCR) and western blot assay. Our results observed that ASPS significantly decreased the proliferation of cells at 24 and 48 h. Moreover, ASPS markedly repressed the invasion and migration capacities of cells in a concentration-dependent manner. Besides, ASPS obviously down-regulated the levels of matrix metalloproteinase-2 (MMP-2), MMP-9, fibronectin 1 (FN1), vimentin, wnt3a, phosphorylated-glycogen synthase kinase 3β (p-GSK3β) and cyclin D1, whereas, up-regulating E-cadherin level. The level of GSK3β was not changed in the different groups. ASPS conspicuously inhibited the abilities of proliferation and metastasis in human non-small cell lung cancer cell line NCI-H520 possibly by suppressing Wnt/β-catenin pathway mediated-EMT.

Aim This study aimed to assess the effects of daily sedation interruption on the mechanical ventilation duration and relevant outcomes in mechanically ventilated patients in the intensive care unit (ICU). Background Previously, three meta-analyses on the association of daily sedation interruption with the mechanical ventilation duration have reported conflicting findings, and these did not support current guideline recommendations that daily sedation interruption can be routinely used in mechanically ventilated adult ICU patients. Design This was a systematic review and meta-analysis of randomized controlled studies. Data sources Data were from PubMed, Embase, Cochrane Library, CINAHL, ProQuest dissertation and theses, Airiti Library, China National Knowledge Infrastructure, Wanfang Data Chinese, Science Direct and PsycINFO databases. Review methods Two reviewers independently assessed, extracted and appraised the included studies. Then, pooled estimates were calculated using a random-effects model. Results In total, 45 studies involving 5493 participants were included. Compared with controls, daily sedation interruption significantly reduced the mechanical ventilation duration, ICU stay length, sedation duration, and tracheostomy and ventilator-associated pneumonia risks (all p ≤ 0.001). Moreover, the Acute Physiology and Chronic Health Evaluation II score and study quality were significant moderators. Conclusion Daily sedation interruption could substantially reduce the duration of mechanical ventilation, particularly when it was applied to patients with high disease severity. Summary statement What is already known about this topic? Daily sedation interruption has been associated with reductions in excessive sedation and excessive use of sedative agents. The findings on the effects of daily sedation interruption on the mechanical ventilation duration have been inconsistent. What this paper adds? Daily sedation interruption could effectively reduce the mechanical ventilation duration, intensive care unit stay length, sedation duration, and tracheostomy and ventilator-associated pneumonia risks in intensive care unit patients. Applying daily sedation interruption to patients with high disease severity yielded a larger reduction in the mechanical ventilation duration. The implications of this paper: There is a need to adopt daily sedation interruption as routine care to reduce the mechanical ventilation duration, especially in higher disease severity population.

Background Hepatitis C virus (HCV) is one of the main causes of liver fibrosis, chronic hepatitis, and liver cirrhosis. The aim of this study is to determine the prevalence of HCV, age-dependent prevalence and genotypes distribution in a large number of clinical samples in Sichuan area of China. Methods In the past five years from 2014 to 2018, a total number of 4,508 individuals received the serum HCV-RNA analysis in the Sichuan Provincial People's Hospital. Viral nucleic acid was extracted from the serum samples and amplified using COBAS AmpliPre/COBAS TaqMan Detection Platform. Five HCV genotypes (1b, 2a, 3a, 3b, and 6a) of serum samples from 469 HCV positive individuals collected from 2016 to 2018 were analyzed using the PCR-fluorescence probe technique. Results A total of 1,668 individuals had positive results by high precision HCV-RNA quantitative technique, corresponding to a crude prevalence of 37.0% (95% confidence interval: 33.6 - 40.3%). The majority of HCV positive individuals were aged over 41 years, accounting for 80.7% (1,346/1,668, CI: 72.3 - 87.1%). Among the nine age groups, the 41 - 50-year age group had the highest HCV prevalence of 29.8% (497/1,668, CI: 25.6 - 32.3%). Of the 469 HCV-RNA positive serum samples collected in 2016 - 2018, genotype 1b was the most frequent type found in 357 individuals, corresponding to a prevalence of 76.1% (CI: 72.3 - 80.0%). Conclusions Positive rates of HCV in the years of 2014 to 2018 showed a downward trend year by year, of which a majority of positive cases were aged over 41 years. HCV was distributed with multi-genotype features while genotype 1b yielded a very high prevalence in the Sichuan area. The results have potential for prevention and treatment of HCV infection, as well as epidemiological research.

Although infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has pleiotropic and systemic effects in some individuals1-3, many others experience milder symptoms. Here, to gain a more comprehensive understanding of the distinction between severe and mild phenotypes in the pathology of coronavirus disease 2019 (COVID-19) and its origins, we performed a whole-blood-preserving single-cell analysis protocol to integrate contributions from all major immune cell types of the blood-including neutrophils, monocytes, platelets, lymphocytes and the contents of the serum. Patients with mild COVID-19 exhibit a coordinated pattern of expression of interferon-stimulated genes (ISGs)3 across every cell population, whereas these ISG-expressing cells are systemically absent in patients with severe disease. Paradoxically, individuals with severe COVID-19 produce very high titres of anti-SARS-CoV-2 antibodies and have a lower viral load compared to individuals with mild disease. Examination of the serum from patients with severe COVID-19 shows that these patients uniquely produce antibodies that functionally block the production of the ISG-expressing cells associated with mild disease, by activating conserved signalling circuits that dampen cellular responses to interferons. Overzealous antibody responses pit the immune system against itself in many patients with COVID-19, and perhaps also in individuals with other viral infections. Our findings reveal potential targets for immunotherapies in patients with severe COVID-19 to re-engage viral defence.

BACKGROUND: Proton density fat fraction (PDFF) estimated by using chemical shift–encoded (CSE) MRI is an accepted imaging biomarker of hepatic steatosis. This work aims to promote standardized use of CSE MRI to estimate PDFF. PURPOSE: To assess the accuracy of CSE MRI methods for estimating PDFF by determining the linearity and range of bias observed in a phantom. MATERIALS AND METHODS: In this prospective study, a commercial phantom with 12 vials of known PDFF values were shipped across nine U.S. centers. The phantom underwent 160 independent MRI examinations on 27 1.5-T and 3.0-T systems from three vendors. Two three-dimensional CSE MRI protocols with minimal T1 bias were included: vendor and standardized. Each vendor’s confounder-corrected complex or hybrid magnitude-complex based reconstruction algorithm was used to generate PDFF maps in both protocols. The Siemens reconstruction required a configuration change to correct for water-fat swaps in the phantom. The MRI PDFF values were compared with the known PDFF values by using linear regression with mixed-effects modeling. The 95% CIs were calculated for the regression slope (ie, proportional bias) and intercept (ie, constant bias) and compared with the null hypothesis (slope = 1, intercept = 0). RESULTS: Pooled regression slope for estimated PDFF values versus phantom-derived reference PDFF values was 0.97 (95% CI: 0.96, 0.98) in the biologically relevant 0%–47.5% PDFF range. The corresponding pooled intercept was −0.27% (95% CI: −0.50%, −0.05%). Across vendors, slope ranges were 0.86–1.02 (vendor protocols) and 0.97–1.0 (standardized protocol) at 1.5 T and 0.91–1.01 (vendor protocols) and 0.87–1.01 (standardized protocol) at 3.0 T. The intercept ranges (absolute PDFF percentage) were −0.65% to 0.18% (vendor protocols) and −0.69% to −0.17% (standardized protocol) at 1.5 T and −0.48% to 0.10% (vendor protocols) and −0.78% to −0.21% (standardized protocol) at 3.0 T. CONCLUSION: Proton density fat fraction estimation derived from three-dimensional chemical shift–encoded MRI in a commercial phantom was accurate across vendors, imaging centers, and field strengths, with use of the vendors’ product acquisition and reconstruction software. © RSNA, 2021 See also the editorial by Dyke in this issue.

Intestinal epithelial cells (IEC) are important parts of the mucosal barrier, whose function can be impaired upon various injury factors such as lipopolysaccharide. Although food-derived exosomes are preventable against intestinal barrier injuries, there have been few studies on the effect of yak milk-derived exosomes and the underlying mechanism that remains poorly understood. This study aimed to characterize the effect of exosomal proteins derived from yak and cow milk on the barrier function of IEC-6 treated with lipopolysaccharide and the relevant mechanism involved. Proteomics study revealed 392 differentially expressed proteins, with 58 higher expressed and 334 lower expressed in yak milk-derived exosomes than those in cow exosomes. Additionally, the top 20 proteins with a relatively consistent higher expression in yak milk exosomes than cow milk exosomes were identified. Protein CD46 was found to be a regulator for alleviating inflammatory injury of IEC-6. In vitro assay of the role of yak milk exosomes on survival of IEC-6 in inflammation by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide assay confirmed the effectiveness of yak milk exosomes to increase IEC-6 survival up to 18% for 12 h compared with cow milk exosomes (up to 12%), indicating a therapeutic effect of yak milk exosomes in the prevention of intestinal inflammation. Furthermore, yak and cow milk exosomes were shown to activate the PI3K/AKT/C3 signaling pathway, thus promoting IEC-6 survival. Our findings demonstrated an important relationship between yak and cow milk exosomes and intestinal inflammation, facilitating further understanding of the mechanisms of inflammation-driven epithelial homeostasis. Interestingly, compared with cow milk exosomes, yak milk exosomes activated the PI3K/AKT/C3 signaling pathway more to lower the incidence and severity of intestine inflammation, which might represent a potential innovative therapeutic option for intestinal inflammation.

Peter A Fasching,1 Thomas E Delea,2 Yen-Shen Lu,3 Richard De Boer,4 Sara A Hurvitz,5 Aaron Moynahan,2 David Chandiwana,6 Brad Lanoue,6 Huilin Hu,6 Astrid Thuerigen,7 Joyce O’Shaughnessy8 1University Hospital Erlangen, Comprehensive Cancer Center Erlangen—EMN, Department of Gynecology and Obstetrics, Friedrich-Alexander University Erlangen—Nuremberg, Erlangen, Germany; 2Policy Analysis Inc. (PAI), Brookline, MA, USA; 3National Taiwan University Hospital, Taipei, Taiwan; 4Peter MacCallum Cancer Centre, Victoria, Australia; 5University of California, Los Angeles, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA; 6Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 7Novartis Pharma AG, Basel, Switzerland; 8Department of Medical Oncology, Baylor University Medical Center, Texas Oncology and US Oncology Network, Dallas, TX, USACorrespondence: Peter A FaschingUniversity Hospital Erlangen, Comprehensive Cancer Center Erlangen—EMN, Department of Gynecology and Obstetrics, Friedrich-Alexander University Erlangen, Maximiliansplatz 2, Erlangen, 91054, GermanyEmail peter.fasching@uk-erlangen.dePurpose: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) plus endocrine therapy are recommended for first-line treatment of hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) advanced breast cancer (ABC). However, not all CDK4/6i trials have reported significant overall survival (OS) benefit, and there have been no head-to-head trials. Two trials have reported OS outcomes in first-line patients: MONALEESA-3 reported significant OS benefit with first- or second-line ribociclib plus fulvestrant (RIB+FUL) versus placebo plus fulvestrant (PBO+FUL), while PALOMA-1 reported no significant OS benefit for palbociclib plus letrozole (PAL+LET) versus LET in first-line postmenopausal patients. Matched-adjusted indirect comparisons (MAICs) are an established method for comparing efficacy of treatments from different trials. We used an MAIC to compare first-line patients from MONALEESA-3 and PALOMA-1.Patients and Methods: An unanchored MAIC of progression-free survival (PFS) and OS in first-line patients with HR+/HER2− ABC treated with RIB+FUL versus PAL+LET was conducted using individual patient data from MONALEESA-3 and aggregated data from PALOMA-1. To match patients in PALOMA-1, patients in MONALEESA-3 were limited to those with no prior endocrine therapy for ABC and no (neo) adjuvant LET ≤ 12 months before enrollment. PFS and OS were compared using Kaplan–Meier estimators and Cox regression.Results: A total of 329 and 178 patients from RIB+FUL and PBO+FUL arms, respectively, of MONALEESA-3 were matched to 84 and 81 patients from PAL+LET and LET arms of PALOMA-1. After weighting, OS was significantly longer for RIB+FUL versus PAL+LET (hazard ratio [HR], 0.50; 95% CI, 0.32– 0.77; p = 0.0020). PFS favored RIB+FUL versus PAL+LET, although the difference was not statistically significant (HR, 0.77; 95% CI, 0.54– 1.10; p = 0.1553).Conclusion: Using MAIC to adjust for trial differences, OS comparisons favored RIB+FUL over PAL+LET as first-line treatment in postmenopausal patients with HR+/HER2− ABC. These exploratory results suggest a significant increase in OS benefit with RIB treatment compared with PAL.Keywords: MONALEESA-3, PALOMA-1, overall survival, CDK4/6 inhibitor

While SARS-CoV-2 infection has pleiotropic and systemic effects in some patients, many others experience milder symptoms. We sought a holistic understanding of the severe/mild distinction in COVID-19 pathology, and its origins. We performed a whole-blood preserving single-cell analysis protocol to integrate contributions from all major cell types including neutrophils, monocytes, platelets, lymphocytes and the contents of serum. Patients with mild COVID-19 disease display a coordinated pattern of interferon-stimulated gene (ISG) expression across every cell population and these cells are systemically absent in patients with severe disease. Severe COVID-19 patients also paradoxically produce very high anti-SARS-CoV-2 antibody titers and have lower viral load as compared to mild disease. Examination of the serum from severe patients demonstrates that they uniquely produce antibodies with multiple patterns of specificity against interferon-stimulated cells and that those antibodies functionally block the production of the mild disease-associated ISG-expressing cells. Overzealous and auto-directed antibody responses pit the immune system against itself in many COVID-19 patients and this defines targets for immunotherapies to allow immune systems to provide viral defense., One Sentence Summary: In severe COVID-19 patients, the immune system fails to generate cells that define mild disease; antibodies in their serum actively prevents the successful production of those cells.