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As part of its role in the World Health Organization’s (WHO) Global Influenza Surveillance and Response System (GISRS), the WHO Collaborating Centre for Reference and Research on Influenza in Melbourne received a record total of 9,266 human influenza positive samples during 2019. Viruses were analysed for their antigenic, genetic and antiviral susceptibility properties. Selected viruses were propagated in qualified cells or embryonated hen’s eggs for potential use in seasonal influenza virus vaccines. In 2019, influenza A(H3N2) viruses predominated over influenza A(H1N1)pdm09 and B viruses, accounting for a total of 51% of all viruses analysed. The majority of A(H1N1)pdm09, A(H3N2) and influenza B viruses analysed at the Centre were found to be antigenically similar to the respective WHO recommended vaccine strains for the Southern Hemisphere in 2019. However, phylogenetic analysis indicated that a significant proportion of circulating A(H3N2) viruses had undergone genetic drift relative to the WHO recommended vaccine strain for 2019. Of 5,301 samples tested for susceptibility to the neuraminidase inhibitors oseltamivir and zanamivir, four A(H1N1)pdm09 viruses showed highly reduced inhibition with oseltamivir, one A(H1N1)pdm09 virus showed highly reduced inhibition with zanamivir and three B/Victoria viruses showed highly reduced inhibition with zanamivir.

OBJECTIVE. One central question pertaining to mammography quality relates to discerning the optimal recall rate to maximize cancer detection while minimizing unnecessary downstream diagnostic imaging and breast biopsies. We examined the trade-offs for higher recall rates in terms of biopsy recommendations and cancer detection in a single large health care organization. MATERIALS AND METHODS. We included 2D analog, 2D digital, and 3D digital (tomosynthesis) screening mammography examinations among women 40–79 years old performed between January 1, 2005, and December 31, 2017, with cancer follow-up through 2018. There were 36, 67, and 38 radiologists who read at least 1000 2D analog examinations, 2D digital examinations, and 3D tomosynthesis examinations, respectively, who were included in these analyses. Using logistic regression with marginal standardization, we estimated radiologist-specific mean recall (abnormal interpretations/1000 mammograms), biopsy recommendation, cancer detection (screening-detected in situ and invasive cancers/1000 mammograms), and minimally invasive cancer detection rates while adjusting for differences in patient characteristics. RESULTS. Among 1,060,655 screening mammograms, the mean recall rate was 10.7%, the cancer detection rate was 4.0/1000 mammograms, and the biopsy recommendation rate was 1.60%. Recall rates between 7% and 9% appeared to maximize cancer detection while minimizing unnecessary biopsies. CONCLUSION. The results of this investigation are in contrast to those of a recent study suggesting appropriateness of higher recall rates. The “sweet spot” for optimal cancer detection appears to be in the recall rate range of 7–9% for both 2D digital mammography and 3D tomosynthesis. Too many women are being called back for diagnostic imaging, and new benchmarks could be set to reduce this burden.

Recently a series of papers was introduced describing on “how to do” certain techniques. More specifically we published on how to perform strain imaging using the transcutaneous and endoscopic ultrasound approach and shear wave elastography (SWE). In the first part we describe how to optimize the examination technique, discussing normal values, pitfalls, artefacts and specific tips for applying SWE to specific organs (liver, breast, thyroid, salivary glands) as part of a diagnostic US examination. In part II, the use of SWE in the pancreas, spleen, kidney, prostate, scrotum, musculoskeletal system, lymph nodes and future developments are discussed.

The 12q13-q14 chromosomal region is recurrently amplified in 25% of fusion-positive (FP) rhabdomyosarcoma (RMS) cases and is associated with a poor prognosis. To identify amplified oncogenes in FP RMS, we compared the size, gene composition, and expression of 12q13-q14 amplicons in FP RMS with those of other cancer categories (glioblastoma multiforme, lung adenocarcinoma, and liposarcoma) in which 12q13-q14 amplification frequently occurs. We uncovered a 0.2 Mb region that is commonly amplified across these cancers and includes CDK4 and 6 other genes that are overexpressed in amplicon-positive samples. Additionally, we identified a 0.5 Mb segment that is only recurrently amplified in FP RMS and includes 4 genes that are overexpressed in amplicon-positive RMS. Among these genes, only serine hydroxymethyltransferase 2 (SHMT2) was overexpressed at the protein level in an amplicon-positive RMS cell line. SHMT2 knockdown in amplicon-positive RMS cells suppressed growth, transformation, and tumorigenesis, whereas overexpression in amplicon-negative RMS cells promoted these phenotypes. High SHMT2 expression reduced sensitivity of FP RMS cells to SHIN1, a direct SHMT2 inhibitor, but sensitized cells to pemetrexed, an inhibitor of the folate cycle. In conclusion, our study demonstrates that SHMT2 contributes to tumorigenesis in FP RMS and that SHMT2 amplification predicts differential response to drugs targeting this metabolic pathway.

Indeterminate renal masses are a common clinical problem. CEUS has several advantages to characterize both cystic and solid renal masses including thin slice thickness, excellent background subtraction, and real-time imaging with a high frame rate. The ultrasound contrast agents are not nephrotoxic and can be used in patients with renal insufficiency and obstruction. The Bosniak classification has been developed for use in CT and MRI. A CEUS Bosniak classification has not yet been developed. This meta-analysis reviews the results of renal mass characterization using Lumason/Sonovue in characterizing renal solid and cystic masses. For complex cystic renal lesions (419 patients; 436 lesions), the pooled sensitivity and specificity of CEUS were 95% (95% CI: 91%, 99%) and 84% (95% CI: 77%, 90%) and for solid lesions (331 patients; 341 lesions), the pooled sensitivity and specificity of CEUS were 98% (95% CI: 95%, 100%) and 78% (95% CI: 68%, 88%), respectively.

The non-pharmaceutical interventions implemented to slow the spread of SARS-CoV-2 have had consequences on the transmission of other respiratory viruses, most notably paediatric respiratory syncytial virus (RSV) and influenza. At the beginning of 2020, lockdown measures in the southern hemisphere led to a winter season with a marked reduction in both infections. Intermittent lockdowns in the northern hemisphere also appeared to interrupt transmission during winter 2020/21. However, a number of southern and northern hemisphere countries have now seen delayed RSV peaks. We examine the implications of these unpredictable disease dynamics for health service delivery in Europe, such as paediatric hospital and intensive care bed space planning, or palivizumab prophylaxis. We discuss the challenges for RSV vaccine trials and influenza immunisation campaigns, and highlight the considerable research opportunities that have arisen with the SARS-CoV-2 pandemic. We argue that the rapid advances in viral whole genome sequencing, phylogenetic analysis, and open data sharing during the pandemic are applicable to the ongoing surveillance of RSV and influenza. Lastly, we outline actions to prepare for forthcoming influenza seasons and for future implementation of RSV vaccines.

BACKGROUND AND OBJECTIVE Influenza virus (FLU), rhinovirus (RV) and respiratory syncytial virus (RSV) are the most common acute respiratory infections worldwide. Infection can cause severe health outcomes, while therapeutic options are limited, primarily relieving symptoms without attenuating the development of lesions or impaired lung function. We therefore examined the inflammatory response to these infections with the intent to identify common components that are critical drivers of immunopathogenesis and thus represent potential therapeutic targets. METHODS BALB/c mice were infected with FLU, RV or RSV, and lung function, airway inflammation and immunohistopathology were measured over a 10-day period. Anti-IL-17A mAb was administered to determine the impact of attenuating this cytokine's function on the development and severity of disease. RESULTS All three viruses induced severe airway constriction and inflammation at 2 days post-infection (dpi). However, only FLU induced prolonged inflammation till 10 dpi. Increased IL-17A expression was correlated with the alterations in lung function and its persistence. Neutralization of IL-17A did not affect the viral replication but led to the resolution of airway hyperresponsiveness. Furthermore, anti-IL-17A treatment resulted in reduced infiltration of neutrophils (in RV- and FLU-infected mice at 2 dpi) and lymphocytes (in RSV-infected mice at 2 dpi and FLU-infected mice at 10 dpi), and attenuated the severity of immunopathology. CONCLUSION IL-17A is a common pathogenic molecule regulating disease induced by three prevalent respiratory viruses. Targeting the IL-17A pathway may provide a unified approach to the treatment of these respiratory infections alleviating both inflammation-induced lesions and difficulties in breathing.

Background: PAX-fusion negative rhabdomyosarcoma (FN RMS) is driven by alterations in the RAS/MAP kinase pathway and is partially responsive to MEK inhibition. Overexpression of IGF1R and its ligands is also observed in FN RMS. Preclinical and clinical studies have suggested that IGF1R is itself an important target in FN RMS. Our previous studies revealed preclinical efficacy of the MEK1/2 inhibitor, trametinib, and an IGF1R inhibitor, BMS75807, but this combination was not pursued clinically due to excessive toxicity in preclinical murine models. Here, we sought to identify a combination of an MEK1/2 inhibitor and IGF1R inhibitor that would be better tolerated in murine models and effective in both cell line and patient derived xenograft models of RAS-mutant FN RMS. Methods: Using proliferation and apoptosis assays, we studied the factorial effects of trametinib and ganitumab (AMG 479), a monoclonal antibody with specificity for human and murine IGF1R, in a panel of RAS-mutant FN RMS cell lines. The molecular mechanism of the observed synergy was determined using conventional and capillary immunoassays. The efficacy and tolerability of the combination was assessed using a panel of RAS-mutated cell-line and patient-derived RMS xenograft models. Results: Treatment with trametinib and ganitumab resulted in synergistic cellular growth inhibition in all cell lines tested and inhibition of tumor growth in five out of six models of RAS-mutant RMS. Evidence suggests that the combination had little effect on body weight loss, thrombocytopenia, neutropenia, or hyperinsulinemia in tumor-bearing SCID beige mice. Mechanistically, ganitumab treatment prevented the AKT phosphorylation that is induced by MEK inhibition alone. Therapeutic response to the combination was observed in models with an intact PI3K/PTEN axis. Conclusions: We demonstrate that combined trametinib and ganitumab is effective in a genomically diverse panel of RAS-mutated FN RMS preclinical models. The trametinib/ganitumab combination also likely has an improved tolerability profile compared to other IGF1R/MEK inhibitor combinations. These data support testing this combination in a phase I/II clinical trial for pediatric patients with relapsed or refractory RAS-mutated FN RMS. Citation Format: Marielle E. Yohe, Katie E. Hebron, Xiaolin Wan, Jacob S. Roth, David J. Liewehr, Nancy E. Sealover, Stacey Stauffer, Olivia Feehan-Nelson, Wenyue Sun, Kristine A. Isanogle, Christina M. Robinson, Amy James, Parirokh Awasthi, Priya Shankarappa, Xiaoling Liu, Haiyan Lei, Donna Butcher, Roberta Smith, Elijah F. Edmonson, Jin-Qui Chen, Noemi Kedei, Cody S. Peer, Jack F. Shern, W. Douglas Figg, Lu Chen, Matthew D. Hall, Simone Difillipantonio, Frederic G. Barr, Robert L. Kortum, Angelina V. Vaseva, Javed Khan. Therapeutic efficacy of trametinib and ganitumab in RAS-mutated rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr IA023.

We recently developed a fluorescence in situ hybridization probe set for evaluating suspicious biliary and pancreatic duct strictures (PB-FISH). We aimed to determine whether PB-FISH results in biliary brush cytology specimens are associated with outcomes of patients with cholangiocarcinoma (CCA).We performed a retrospective study of patients with CCA tested by PB-FISH from January 2015 to August 2018. CCA was stratified by primary sclerosing cholangitis (PSC) into those with (PSC CCA) or without PSC ( de novo CCA). PB-FISH results were categorized as polysomy (gain of multiple loci), nonpolysomy (single locus gain, single locus gain with 9p21 loss, homozygous 9p21 loss, tetrasomy), and disomy (no abnormalities). Overall survival (OS) was estimated using Kaplan-Meier methods and compared between the PB-FISH results using log-rank tests. Cox models were adjusted for age, sex, CA 19-9, cytology results, source of brushing sample, and treatments.Characteristics of 264 eligible patients (median age 60.4; range 18-92) were comparable for patients with PB-FISH polysomy vs nonpolysomy vs disomy. The median OS was similar between disomy, nonpolysomy, and polysomy in the overall population (22.7 vs 22.7 vs 20.3 months, respectively). For de novo CCA, both polysomy and nonpolysomy were associated with worse OS compared with disomy (polysomy: hazard ratio [HR] = 2.09, 95% confidence interval [CI] = 1.14-3.83; nonpolysomy: HR = 2.4, 95% CI = 0.54-2.46; P = 0.027). For PSC CCA, neither polysomy nor nonpolysomy were significantly associated with worse OS (polysomy: 0.90, 95% CI = 0.47-1.75; nonpolysomy: HR = 1.78, CI = 0.71-4.49; P = 0.27).PB-FISH alterations are associated with worse survival in de novo CCA, though statistical significance was lost when adjusting for confounding variables.

Background The controversial hypothesis that recalled immunological memory limits responses to variant virus strains has been revived by recent reports linking poor vaccine effectiveness against A(H3N2) influenza viruses with prior vaccination. The impact of memory induced by prior infection is rarely considered, and is difficult to ascertain because infections are often sub-clinical. This study investigates influenza vaccine immunogenicity among participants who had been monitored for 9 years for clinical influenza infection or seroconversion. Methods In 2007, 269 households from Ha Nam, Viet Nam commenced ongoing monitoring for influenza infection. In 2016, 72 adult participants with documented prior A(H3N2) infection and 28 without infection received trivalent inactivated influenza vaccine for the first time. Serological responses were assessed by hemagglutination inhibition assay against 40 A(H3N2) viruses spanning 1968-2018. Effects of prior infection were determined by comparing geometric mean titres and titre rises. Generalized additive and lowess models were used to fit, and compare, titre landscapes across strains. Findings Participants with documented prior A(H3N2) virus infection had higher pre-vaccine titres against strains circulating since 2004 compared to those without prior infection. Moreover, they had higher titre rises on days 7, 14, 21 and 280 post-vaccination against vaccine and subsequently circulating strains. Accordingly, 1/72 versus 4/28 of vaccinees with and without documented prior infection experienced illness due to A(H3N2) in the season after vaccination (p = 0.021). The range of A(H3N2) virus clades recognized by vaccine-induced antibodies was associated with the clade that last caused infection, indicating that recalled immunity drove antibody production against shared epitopes. Interpretation These results suggest that immunological memory from prior infection drives and shapes antibody production induced by inactivated influenza vaccine, and underpins the capacity for vaccine to induce sufficient antibody for protection.

To assess chronic liver disease (CLD) using multiparametric US in a private practice setting in a cohort of patients with increased skin-to-liver distance. 110 consecutive patients with increased skin-to-liver distance scheduled for US assessment of CLD were reviewed for study completion time, liver stiffness values (LS), attenuation imaging, and shear wave dispersion slope. The ROI was placed 2 cm below the liver capsule. The study included patients with NAFLD/NASH (68), hepatitis C (30), prior Fontan surgery (1), elevated liver function tests (5), alcohol abuse (3), hepatitis B (2), and primary biliary cirrhosis (1). IQR/M values were obtained. Comparison of less experienced sonographers (LES) and more experienced sonographers (MES) were evaluated through Student’s t test for independent data. Pearson coefficient r of correlation among quantitative variables was calculated. The mean time to perform the exam was 129.7 ± 62.1 s. There was a statistically significant difference between LES and MES. The mean IQR/M for LS was 12.3 ± 5.5% m/s. Overall, in a cohort of difficult patients, 4.5% of LS values were not reliable. Fat quantification using attenuation imaging had a mean value of 0.60 ± 0.15 dB/cm/MHz (range 0.35–0.98 cm/dB/MHz) with an IQR/M of 14.7 ± 9.2%. Less reliable measurements of steatosis were obtained in 4.5% of patients. The mean shear wave dispersion slope was 12.74 ± 4.05 (m/s)/kHz (range 7.7–27.5 (m/s)/kHz) with an IQR/M of 38.7 ± 20.2% (range 3–131%). 20.9% of patients had values suggestive of compensated advanced chronic liver disease (cACLD). Multiparametric US can provide assessment of CLD in less than 3 min in most patients and identify patients at risk for cACLD.

We recently introduced a series of papers describing how to do certain techniques. This article is the first part of a review of shear wave elastography (SWE). It reports the principles and interpretation of the technique and describes how to optimize it. Normal values, pitfalls and artefacts for the examination of liver, breast. thyroid and salivary gland with shear wave elastography are presented. The manuscript provides specific tips for applying SWE as part of a diagnostic US examination.

Background Concerns over gadolinium (Gd) retention encourage the use of lower Gd doses. However, lower Gd doses may compromise imaging performance. Higher relaxivity gadobenate may be suited to reduced dose protocols. Purpose To compare 0.05 mmol/kg and 0.1 mmol/kg gadobenate in patients undergoing enhanced MRI of the central nervous system (CNS). Study type Retrospective, multicenter. Population Three hundred and fifty-two patients receiving 0.05 (n = 181) or 0.1 (n = 171) mmol/kg gadobenate. Field strength/sequences 1.5 T and 3.0 T/precontrast and postcontrast T1-weighted spin echo/fast spin echo (SE/FSE) and/or gradient echo/fast field echo (GRE/FFE); precontrast T2-weighted FSE and T2-FLAIR. Assessment Images of patients with extra-axial lesions at 1.5 T or any CNS lesion at 3.0 T were reviewed by three blinded, independent neuroradiologists for qualitative (lesion border delineation, internal morphology visualization, contrast enhancement; scores from 1 = poor to 4 = excellent) and quantitative (lesion-to-brain ratio [LBR], contrast-to-noise ratio [CNR]; SI measurements at regions-of-interest on lesion and normal parenchyma) enhancement measures. Noninferiority of 0.05 mmol/kg gadobenate was determined for each qualitative endpoint if the lower limit of the 95% confidence interval (CI) for the difference in precontrast + postcontrast means was above a noninferiority margin of -0.4. Statistical tests Student's t-test for comparison of mean qualitative endpoint scores, Wilcoxon signed rank test for comparison of LBR and CNR values; Wilcoxon rank sum test for comparison of SI changes. Tests were significant for P Results The mean change from precontrast to precontrast + postcontrast was significant for all endpoints. Readers 1, 2, and 3 evaluated 304, 225, and 249 lesions for 0.05 mmol/kg gadobenate, and 382, 309, and 298 lesions for 0.1 mmol/kg gadobenate. The lower limit of the 95% CI was above -0.4 for all comparisons. Significantly, higher LBR and CNR was observed with the higher dose. Data conclusion 0.05 mmol/kg gadobenate was noninferior to 0.1 mmol/kg gadobenate for lesion visualization. Evidence level 2 TECHNICAL EFFICACY: Stage 3.

Using data from five long-term field sites measuring soil moisture, we show the limitations of using soil moisture observations alone to constrain modelled hydrological fluxes. We test a land surface model, MESH/CLASS, with two configurations: one where the soil hydraulic properties are determined using a pedotransfer function (the texture-based calibration) and one where they are assigned directly (the hydraulic properties-based calibration). The hydraulic properties-based calibration outperforms the texture-based calibration in terms of reproducing changes in soil moisture storage within a 1.6 m deep profile at each site, but both perform reasonably well, especially in the summer months. When the models are constrained using observations of changes in soil moisture, the predicted hydrological fluxes are subject to very large uncertainties associated with equifinality. The uncertainty is larger for the hydraulic properties-based calibration, even though the performance was better. We argue that since the pedotransfer functions constrain the model parameters in the texture-based calibrations in an unrealistic way, the texture-based calibration underestimates the uncertainty in the fluxes. We recommend that reproducing observed cumulative changes in soil moisture storage should be considered a necessary but insufficient criterion of model success. Additional sources of information are needed to reduce uncertainties, and these could include improved estimation of the soil hydraulic properties and direct observations of fluxes, particularly evapotranspiration.

Prior to the beginning of the World Meteorological Organization's (WMO) Solid Precipitation Inter-Comparison Experiment (SPICE, 2013–2015), two precipitation measurement intercomparison sites were established in Saskatchewan to help assess the systematic bias in the automated gauge measurement of solid precipitation and the impact of wind on the undercatch of snow. Caribou Creek, located in the southern boreal forest, and Bratt's Lake, located in the southern plains, are a contribution to the international SPICE project but also to examine national and regional issues in measuring solid precipitation, including regional assessment of wind bias in precipitation gauges and windshield configurations commonly used in Canadian monitoring networks. Overlapping with WMO-SPICE, the Changing Cold Regions Network (CCRN) Special Observation and Analysis Period (SOAP) occurred from 2014 to 2015, involving other enhanced observations and cold regions research projects in the same geographical domain as the Saskatchewan SPICE sites. Following SPICE, the two Saskatchewan sites continued to collect core meteorological data (temperature, humidity, wind speed, etc.) as well as precipitation observations via several automated gauge configurations, including the WMO automated reference and the Meteorological Service of Canada's (MSC) network gauges. In addition, manual snow surveys to collect snow cover depth, density, and water equivalent were completed over the duration of the winter periods at the northern Caribou Creek site. Starting in the fall of 2013, the core intercomparison precipitation and ancillary data continued to be collected through the winter of 2017. Automated observations were obtained at a temporal resolution of 1 min, subjected to a rigorous quality control process, and aggregated to a resolution of 30 min. The manual snow surveys at Caribou Creek were typically performed every second week during the SPICE field program with monthly surveys following the end of the SPICE intercomparison period. The Saskatchewan SPICE data are available at https://doi.org/10.18164/63773b5b-5529-4b1e-9150-10acb84d59f0 (Smith and Yang, 2018). The data collected at the Saskatchewan SPICE sites will continue to be useful for transfer function testing, numerical weather prediction and hydrological forecasting verification, ground truth for remote-sensing applications, as well as providing reference precipitation measurements for other concurrent research applications in the cold regions.

OBJECTIVES Paragangliomas have unique features in the mediastinum, in part due to their location. Because of their paucity, they have not been thoroughly investigated. We studied the clinical, pathological, immunohistochemical and molecular features of mediastinal paragangliomas. METHODS Immunohistochemistry, next-generation sequencing mutation panel and the Oncoscan assay were performed. RESULTS Twenty-four patients with mediastinal paraganglioma (7 men, 29.2%) had a median age of 45.5 years (19.8–72.2). Twenty-one (87.5%) paragangliomas were completely resected. Six (of 24, 25.0%) tumours were considered metastatic. Mitotic activity occurred in 11 (of 24, 45.8%) paragangliomas. Programmed death-ligand 1 (PD-L1) (n = 23) was expressed in 6 (26%) patients in 10% (n = 2) and 1% (n = 4) of tumour cells, respectively. SDHB expression was lost in 19 (of 22, 86.4%) cases. ATRX expression was lost in 11 (of 23, 47.8%) cases. Next-generation sequencing revealed a single pathogenic mutation in 10 (of 19) specimens including SDHB (n = 4), SDHD (n = 6), SDHC (n = 1), ATRX (n = 1), and ≥2 mutations in 2 cases [SDHC and TERT (n = 1); SDHB, ATRX and TP53 (n = 1)]. Germline mutation analysis revealed the same succinate dehydrogenase mutation (or lack thereof) as identified in the paraganglioma in 11 (of 12) cases. During a median follow-up (n = 21) of 4.8 years (0.8–14.9), 3 patients developed metastases; 4 patients died, at least 1 of disease. CONCLUSIONS Mediastinal paragangliomas can be associated with morbidity and mortality. Many mediastinal paragangliomas have been reported to be associated with syndromes such as multiple endocrine neoplasia, von Hippel-Lindau or succinate dehydrogenase syndrome with mutation profiles dominated by alterations in genes associated with these syndromes.

Strain ratio (SR) is a semiquantitative parameter in differentiating benign from malignant tumors in breast ultrasound elastography. Currently, SR is computed manually and, thus, user dependent. The objective of this study was to evaluate the performance of a new tool assist strain ratio (ASR) and determine how it performs compared with an expert sonologist.Ninety-one patients scheduled for breast biopsy were included in this institutional review board-approved/Health Insurance Portability and Accountability Act-compliant study. For manual strain ratio (MSR), fat and lesion were manually outlined, whereas for ASR, the clinician indicated the lesion center and the fat-to-lesion ratio is computed automatically. Three measurements were obtained for each lesion. The same raw data were used to calculate the MSR and ASR.The SR thresholds to differentiate benign from malignant tumors were determined using the Youden index. For MSR, the cutoff was 2.7, and for ASR was 2.8. The MSR showed a sensitivity of 88%, specificity of 64%, accuracy of 77%, positive predictive value of 72%, and negative predictive value of 92.1%. Corresponding ASR showed a sensitivity of 86%, specificity of 76%, accuracy of 81%, positive predictive value of 79%, and negative predictive value of 84%. The areas under the curve for the MSR and ASR were 0.83 and 0.85, respectively. The average coefficients of variation for the MSR and ASR measurements were 43% and 30%, respectively.Assist strain ratio demonstrated similar diagnostic performance compared with MSR. In addition, the coefficient of variation of ASR is lower, implying lower intraoperator dependency. Thus, ASR may aid less-experienced scanners in obtaining improved results.

Both strain elastography and shear wave elastography have been shown to have high sensitivity and specificity for characterizing breast lesions as benign or malignant. Training is important for both strain and shear wave elastography. The unique feature of benign lesions measuring smaller on elastography than B-mode imaging and malignant lesions appearing larger on elastography is an important feature for characterization of breast masses. There are several artifacts which can contain diagnostic information or alert to technique problems. Both strain and shear wave elastography continue to have improvements and new techniques will soon be available for clinical use that may provide additional diagnostic information. This paper reviews the present state of breast elastography and discusses future techniques that are not yet in clinical practice.

A modified synthesis method for aqueous nanoparticle printing inks, based upon vacuum-assisted solvent removal, is reported. Poly(3-hexylthiophene):phenyl C61 butyric acid methyl ester nanoparticle inks were prepared via this modified miniemulsion method, leading to both an improvement in photoactive layer morphology and a substantial reduction in the ink fabrication time. A combination of UV-visible spectroscopy, photoluminescence spectroscopy and scanning transmission X-ray microscopy measurements revealed a nanoparticle morphology comprising highly intermixed donor-acceptor domains. Consistent with these measurements, dynamic mechanical thermal analysis of the nanoparticles showed a glass transition temperature (Tg) of 104 °C, rather than a pure polymer phase or pure fullerene phase Tg. Together the spectroscopy, microscopy and thermomechanical data indicate that rapid solvent removal generates a more blended nanoparticle morphology. As such, this study highlights a new experimental lever for optimising nanostructure in the photoactive layer of nanoparticulate organic photovoltaic devices by enabling highly intermixed donor-acceptor architectures to be built from customised nanoparticulate inks.

Obesity can increase the severity of influenza infection. Data are limited regarding immune responses to influenza vaccination in obese children. We aimed to investigate the impact of obesity on quadrivalent influenza vaccine responses in children. Children with obesity (body mass index (BMI) ≥ 95th percentile for age and gender) and children without obesity (BMI < 95th percentile) were enrolled in the study. Blood samples were collected before, 1, and 6 months after influenza vaccination, to measure antibody responses by haemagglutination inhibition (HI) assay. Vaccine immunogenicity outcomes were compared between children with and without obesity. Forty-four children (mean age 13.3 ± 2.1 years, 18 males and 14 with obesity) completed the 6-month study. More than 90% of the participants with and without obesity had seroprotective antibody titres (HI ≥ 40) at both 1 and 6 months following vaccination for each of the four influenza strains (A/H3N2, A/H1N1, B/(Victoria) and B/(Yamagata)). Influenza-specific geometric mean titres at baseline, 1, and 6 months post-vaccination were similar between children with and without obesity for all influenza vaccine strains. Children with and without obesity have robust, sustained antibody responses over 6 months to the quadrivalent influenza vaccine.

There are 3 methods of interpreting breast strain elastography: the elastographic-to-B-mode length ratio (E/B), a 5-point color scale (5P), and the strain ratio (SR). This meta-analysis assessed which method is superior to the others. A systematic search of the medical literature was performed in July 2017. Studies were eligible for inclusion if they fulfilled the following criteria: (1) had biopsy-proven or long-term stability as the reference standard; (2) used either the E/B, 5P, or SR to interpret results; and (3) had at least 50 cases. A total of 220 records were retrieved; 60 full-text articles were examined, and 46 were included in the meta-analysis. Publication years ranged from 2007 and 2017. The quality of studies was generally high. The mean age of women was 48 years; 12,398 lesions (4242 malignant) were analyzed. For the 5P method, the sensitivity was 77%; specificity, 87%; positive likelihood ratio (LR), 5.3; and negative LR, 0.24. For the SR method, sensitivity was 87%; specificity, 81%; positive LR, 4.8; and negative LR, 0.16. For the E/B method, sensitivity was 96%; specificity, 88%; positive LR, 7.1; and negative LR, 0.03. Of the 3 methods, the E/B had the highest sensitivity, and the E/B and 5P had the highest specificity. With a negative LR of 0.03, the E/B method can downgrade lesions with a pretest probability of 50% to a 2% probability of malignancy.

International audience; Live bird market surveillance for avian influenza viruses in Cambodia in 2015 has led to the detection of two 7:1 reassortant influenza A(H5N1) clade 2.3.2.1c viruses. These reassortant strains, designated A/duck/Cambodia/ Z564W35M1/2015 and A/chicken/Cambodia/Z850W49M1/2015, both contained a single gene (PB1 and matrix gene, respectively) from concurrently circulating A(H9N2) influenza viruses. All other viral genes from both isolates clustered with A(H5N1) clade 2.3.2.1 viruses. Continued and prolonged co-circulation of influenza A(H5N1) and A(H9N2) viruses in Cambodian live bird markets may present a risk for the emergence of novel influenza reassortant viruses with negative agricultural and/or public health implications.

OBJECTIVES The BI-RADS© classification provides a standardized way to describe ultrasound findings in breast cancer diagnostics. However, there is little information regarding which BI-RADS© descriptors are most strongly associated with malignancy, to better distinguish BI-RADS© 3 (follow-up imaging) and 4 (diagnostic biopsy) breast masses. METHODS Patients were recruited as part of an international, multicenter trial (NCT02638935). The trial enrolled 1294 women (6 excluded) categorized as BI-RADS© 3 or 4 upon routine B-mode ultrasound examination. Ultrasound images were evaluated by three expert physicians according to BI-RADS©. All patients underwent histopathological confirmation (reference standard). We performed univariate and multivariate analyses (chi-square test, logistic regression, and Krippendorff's alpha). RESULTS Histopathologic evaluation showed malignancy in 368 of 1288 masses (28.6%). Upon performing multivariate analysis, the following descriptors were significantly associated with malignancy (P

BACKGROUND/OBJECTIVES: Rhabdomyosarcoma (RMS) is characterized by the expression of the myogenic regulatory protein MYOD1. Histologic types include alveolar, embryonal (ERMS), and spindle cell sclerosing RMS (SRMS). SRMS harbors MYOD1 mutations in a subset of adult cases in association with poor prognosis. DESIGN/METHODS: To study the level of MYOD1 protein expression and its clinical significance, we have analyzed variable numbers of pediatric (

International audience; Nanoengineered, eco-friendly, solution-processable electroactive materials are in demand for the growing field of printed electronics, and these material requirements can be achieved by the development of waterborne colloidal dispersions. Functionality in these composite materials can be tuned by thermodynamically modifying the material nanomorphology, often by creation of kinetically stabilized aqueous nanoparticle dispersions. In this work we demonstrate that the internal structure of organic nanoparticles is controlled by the surface energy difference between the polymeric donor material and the non-fullerene acceptor (NFA) material. Nanoparticles of the following donor–acceptor combinations, suitable for printed organic photovoltaics, have been synthesized: TQ1:N2200, TQ1:PNDIT10, P3HT:N2200, P3HT: o-IDTBR and P3HT:eh-IDTBR. Advanced synchrotron-based X-ray spectroscopy and microscopy are used to correlate the formation of core–shell nanoparticle morphology to the material surface energy. We subse- quently present a viable avenue for customizing the blended nanoparticle structure into (i) core–shell, (ii) molecularly intermixed, or (iii) inverted shell–core structures. Our results showed that TQ1:PNDIT10 and P3HT:o-IDTBR nanoparticles were comprised of a donor-richshell andan NFA-richcore, however, interestingly we show a reversal to the inverse NFA shell/donor core structure for TQ1:N2200, P3HT:N2200 and P3HT:eh-IDTBR nanoparticles, driven by the low surface energy of N2200 (23.7 mJ m?2)and eh-IDTBR (18.3 mJ m?2). This article is the first report of a flipped nanoparticle core–shell morphology comprising an NFA-rich shell for the miniemulsion synthesis route. The composition of the shells and cores was able to be controlled by the differential mismatch in the surface energy of the donor and acceptor materials, with DGsurface 4 0, DGsurface =0,and DGsurface o 0 for acceptor core–donor shell, molecularly intermixed, and acceptor shell–donor core, respectively. Accordingly, we introduce an entirely overlooked new figure of merit (FoM) for customizing nanoparticulate colloidal inks: tunable surface energy of non-fullerene-based semiconductors. The establishment of this FoM opens up electroactive material design to a wide range of functional printing applications with varying device and ink structure requirements, thereby reshaping the nanoengineering toolkit for waterborne colloidal dispersions and hence printed electronics.

Solar-Induced chlorophyll Fluorescence (SIF) provides a powerful proxy for determining forest gross primary production (GPP), particularly in evergreen ecosystems where traditional measures of gree...

A new printable organic semiconducting material combination as a tissue equivalent photodetector for indirect X-ray detection is demonstrated in this work. The device exhibits a higher optical-to-electrical conversion efficiency than any other reported printable organic systems for X-ray photodetection while also operating efficiently with zero applied bias. Complete X-ray detectors fabricated by coupling the photodiode with a plastic scintillator are among the first flexible and fully tissue equivalent X-ray detectors capable of operating without external bias. The response to X-rays is energy independent between 50 keV and 1.2 MeV, with a detection sensitivity equivalent to inorganic direct X-ray detectors and one of the fastest temporal responses ever reported for organic X-ray detectors. The materials can be printed into arrays with a pixel pitch of 120 μm, providing 2D spatial detection. The devices are found to be highly stable with respect to time, mechanical flexing, and large (5 kGy) radiation doses. The new materials and fully tissue equivalent X-ray detectors reported here provide stable, printable, flexible, and tissue equivalent detectors with a high radiolucency that are ideally suited for wearable applications, where simultaneous monitoring and high transmission of the X-ray absorbed dose into the human body is required.

New ultrasound methods that can be used to quantitatively assess liver fat content have recently been developed. These quantitative ultrasound (QUS) methods are based on the analysis of radiofrequency echoes detected by the transducer, allowing calculation of parameters for quantifying the fat in the liver. In this position paper, after a section dedicated to the importance of quantifying liver steatosis in patients with non-alcoholic fatty liver disease and another section dedicated to the assessment of liver fat with magnetic resonance, the current clinical studies performed using QUS are summarized. These new methods include spectral-based techniques and techniques based on envelope statistics. The spectral-based techniques that have been used in clinical studies are those estimating the attenuation coefficient and those estimating the backscatter coefficient. Clinical studies that have used tools based on the envelope statistics of the backscattered ultrasound are those performed by using the acoustic structure quantification or other parameters derived from it, such as the normalized local variance, and that performed by estimating the speed of sound. Experts' opinions are reported.

Although seasonal influenza viruses circulate globally, prevention and treatment occur at the level of regions, cities, and communities. At these scales, the timing, duration and magnitude of epidemics vary substantially, but the underlying causes of this variation are poorly understood. Here, based on analyses of a 15-year city-level dataset of 18,250 laboratory-confirmed and antigenically-characterised influenza virus infections from Australia, we investigate the effects of previously hypothesised environmental and virological drivers of influenza epidemics. We find that anomalous fluctuations in temperature and humidity do not predict local epidemic onset timings. We also find that virus antigenic change has no consistent effect on epidemic size. In contrast, epidemic onset time and heterosubtypic competition have substantial effects on epidemic size and composition. Our findings suggest that the relationship between influenza population immunity and epidemiology is more complex than previously supposed and that the strong influence of short-term processes may hinder long-term epidemiological forecasts., Seasonal influenza epidemics vary in timing and size, but the causes of the variation remain unclear. Here, the authors analyse a 15-year city-level data set, and find that fluctuations in climatic factors do not predict onset timing, and that while antigenic change does not have a consistent effect on epidemic size, the timing of onset and heterosubtypic competition do.

The coronavirus disease pandemic was declared in March 2020, as the southern hemisphere’s winter approached. Australia expected co-circulation of severe acute respiratory syndrome coronavirus 2, influenza and other seasonal respiratory viruses. However, influenza notifications were 7,029 (March–September) compared with an average 149,832 for the same period in 2015–2019*, despite substantial testing. Restrictions on movement within and into Australia may have temporarily eliminated influenza. Other respiratory pathogens also showed remarkably changed activity in 2020.

BACKGROUND Molecular parameters have been incorporated into the 2016 WHO Classification of CNS Tumors and subsequent cIMPACT-NOW updates to facilitate clinical management of glioma patients. However, there have been few reports of the overall clinical utility of comprehensive genetic testing in adult glioma patients. We report the results of sequencing and chromosomal microarray analysis of adult gliomas seen at the Mayo Clinic and through the Mayo Clinic Laboratories (MCL) reference practice. METHODS A consecutive series of 379 Mayo Clinic adult glioma patients were consented to receive targeted next generation sequencing and chromosomal microarray analysis, regardless of standard clinical ordering practices. Known diagnostic, prognostic, and predictive alterations were annotated for each case. These results were compared to the larger MCL reference practice of 2400 adult glioma samples that received one or both tests clinically. RESULTS Of the consecutive Mayo Clinic cases, 67% had alterations that fell into at least one of the diagnostic, prognostic, and/or predictive categories. Molecular testing generated diagnostic, prognostic, and predictive information in 44%, 34%, and 36% of cases, respectively. Diagnostically, molecular testing mainly aided in arriving at a final integrated diagnosis, and only a small number of cases (n= 5; 1%) had a change in diagnosis. The consecutive cases represent the typical distribution of adult glioma types (47% IDH-wildtype glioblastoma/astrocytoma, 22% IDH-mutant astrocytoma/glioblastoma, 13% IDH-mutant 1p/19q-codeleted oligodendroglioma, and 18% other tumor types). The MCL practice is enriched in tumors with atypical molecular patterns (37% IDH-wildtype glioblastoma/astrocytoma, 17% IDH-mutant astrocytoma/glioblastoma, 18% IDH-mutant 1p/19q-codeleted oligodendroglioma, and 29% other tumor types). CONCLUSIONS Molecular testing provides useful diagnostic, prognostic, and predictive information for the clinical management of adult glioma patients. While the current guidelines for ordering molecular testing are effective for diagnostic purposes, additional prognostic and predictive information can be gleaned from comprehensive molecular testing of adult gliomas.

Objectives Sclerosing pneumocytomas are rare pulmonary neoplasms that are typically benign. However, rare patients experience progressive disease, and therapy targeting specific genetic underpinnings could be an attractive therapeutic option. Recent studies have found recurrent AKT 1 mutations in sclerosing pneumocytoma, but little is known about whether oncogenic fusion genes may also be present. Methods To better understand the genetic background, 10 sclerosing pneumocytomas were subjected to next-generation sequencing cancer mutation panel testing (n = 9) and/or RNA sequencing (n = 3). The patients were all women (average age, 47 years; range, 17-74 years). Results Eight patients had solitary sclerosing pneumocytomas, while one had two tumors, and one had many bilateral tumors. Recurrent mutations were noted in genes involved in the mTOR pathway, including AKT1, PIK3R1, and PTEN. AKT1 alterations were particularly common, present in 78%. No recurrent genetic fusions were identified. The patient in our study with multiple bilateral lesions was treated with the mammalian target of rapamycin (mTOR) inhibitor everolimus, with no objective radiographic evidence of treatment response after 4 months. Conclusions Our data further support that abnormal activation of the mTOR pathway is a consistent genetic event in sclerosing pneumocytoma. This warrants further exploration to determine if mTOR pathway inhibitors may be effective in patients with metastatic or recurrent disease.

Respiratory syncytial virus (RSV) is a common cause of acute respiratory disease worldwide, especially in young children. The World Health Organization (WHO) has initiated an RSV Surveillance Pilot program that aims to perform worldwide RSV surveillance, requiring the development of reliable and rapid molecular methods to detect and identify RSV. A duplex real-time RT-PCR assay developed for simultaneous detection of both A and B subtypes of RSV was included as part of this program. This duplex assay targeted a conserved region of the RSV polymerase gene and was validated for analytical sensitivity, specificity, reproducibility and clinical performance with a wide range of respiratory specimens. The assay was highly specific for RSV and did not react with non-RSV respiratory pathogens, including the SARS-CoV-2 virus.

The interior of western Canada, like many similar cold mid- to high-latitude regions worldwide, is undergoing extensive and rapid climate and environmental change, which may accelerate in the coming decades. Understanding and predicting changes in coupled climate–land–hydrological systems are crucial to society, yet limited by lack of understanding of changes in cold region process responses and interactions, along with their representation in most current generation land surface and hydrological models. It is essential to consider the underlying processes and base predictive models on the proper physics, especially under conditions of non-stationarity where the past is no longer a reliable guide to the future and system trajectories can be unexpected. These challenges were forefront in the recently completed Changing Cold Regions Network (CCRN), which assembled and focused a wide range of multi-disciplinary expertise to improve the understanding, diagnosis, and prediction of change over the cold interior of western Canada. CCRN advanced knowledge of fundamental cold region ecological and hydrological processes through observation and experimentation across a network of highly instrumented research basins and other sites. Significant efforts were made to improve the functionality and process representation, based on this improved understanding, within the fine-scale Cold Regions Hydrological Modelling (CRHM) platform and the large-scale Modélisation Environmentale Communautaire (MEC) – Surface and Hydrology (MESH) model. These models were, and continue to be, applied under past and projected future climates, and under current and expected future land and vegetation cover configurations to diagnose historical change and predict possible future hydrological responses. This second of two articles synthesizes the nature and understanding of cold region processes and Earth system responses to future climate, as advanced by CCRN. These include changing precipitation and moisture feedbacks to the atmosphere; altered snow regimes, changing balance of snowfall and rainfall, and glacier loss; vegetation responses to climate and the loss of ecosystem resilience to wildfire and disturbance; thawing permafrost and its influence on landscapes and hydrology; groundwater storage and cycling, and its connections to surface water; and stream and river discharge as influenced by the various drivers of hydrological change. Collective insights, expert elicitation, and model application are used to provide a synthesis of this change over the CCRN region for the late-21st century.

Peatlands and forests cover large areas of the boreal biome and are critical for global climate regulation. They also regulate regional climate through heat and water vapour exchange with the atmosphere. Understanding how land-atmosphere interactions in peatlands differ from forests may therefore be crucial for modelling boreal climate system dynamics and for assessing climate benefits of peatland conservation and restoration. To assess the biophysical impacts of peatlands and forests on peak growing season air temperature and humidity, we analysed surface energy fluxes and albedo from 35 peatlands and 37 evergreen needleleaf forests-the dominant boreal forest type-and simulated air temperature and vapour pressure deficit (VPD) over hypothetical homogeneous peatland and forest landscapes. We ran an evapotranspiration model using land surface parameters derived from energy flux observations and coupled an analytical solution for the surface energy balance to an atmospheric boundary layer (ABL) model. We found that peatlands, compared to forests, are characterized by higher growing season albedo, lower aerodynamic conductance, and higher surface conductance for an equivalent VPD. This combination of peatland surface properties results in a similar to 20% decrease in afternoon ABL height, a cooling (from 1.7 to 2.5 degrees C) in afternoon air temperatures, and a decrease in afternoon VPD (from 0.4 to 0.7 kPa) for peatland landscapes compared to forest landscapes. These biophysical climate impacts of peatlands are most pronounced at lower latitudes (similar to 45 degrees N) and decrease toward the northern limit of the boreal biome (similar to 70 degrees N). Thus, boreal peatlands have the potential to mitigate the effect of regional climate warming during the growing season. The biophysical climate mitigation potential of peatlands needs to be accounted for when projecting the future climate of the boreal biome, when assessing the climate benefits of conserving pristine boreal peatlands, and when restoring peatlands that have experienced peatland drainage and mining.

Vaccine development has been hampered by the long lead times and the high cost required to reach the market. The 2020 pandemic, caused by a new coronavirus (SARS-CoV-2) that was first reported in late 2019, has seen unprecedented rapid activity to generate a vaccine, which belies the traditional vaccine development cycle. Critically, much of this progress has been leveraged off existing technologies, many of which had their beginnings in influenza vaccine development. This commentary outlines the most promising of the next generation of non-egg-based influenza vaccines including new manufacturing platforms, structure-based antigen design/computational biology, protein-based vaccines including recombinant technologies, nanoparticles, gene- and vector-based technologies, as well as an update on activities around a universal influenza vaccine.

As part of its role in the World Health Organization’s (WHO) Global Influenza Surveillance and Response System (GISRS), the WHO Collaborating Centre for Reference and Research on Influenza in Melbourne received a total of 2,393 human influenza positive samples between 1 January 2020 and 31 December 2021 (2020: n = 2,021 samples; 2021: n = 372 samples). Viruses were analysed for their antigenic, genetic and antiviral susceptibility properties. Selected viruses were propagated in qualified cells or embryonated hen’s eggs for potential use in seasonal influenza virus vaccines. During 2020–2021, influenza A viruses (A(H1N1)pdm09 in 2020 and A(H3N2) in 2021) predominated over influenza B viruses. In 2020, the majority of A(H1N1)pdm09, A(H3N2) and influenza B viruses analysed at the Centre were found to be antigenically similar to the respective WHO recommended vaccine strains for the southern hemisphere in 2020. In 2021, the majority of A(H1N1)pdm09 and A(H3N2) viruses were found to be antigenically distinct relative to the WHO recommended vaccine strains for the southern hemisphere in 2021. Of the influenza B viruses analysed at the Centre, 46.7% were found to be antigenically distinct to the respective WHO recommended vaccine strains. Of 1,538 samples tested for susceptibility to the neuraminidase inhibitors oseltamivir and zanamivir (in 2020, n = 1,374; in 2021, n = 164), two A(H1N1)pdm09 viruses showed highly reduced inhibition against oseltamivir, and one A(H1N1)pdm09 virus showed highly reduced inhibition against zanamivir. All of these samples were received in 2020.

BACKGROUND: Pulmonary endothelial damage has been shown to precede the development of emphysema in animals, and vascular changes in humans have been observed in COPD and emphysema. RESEARCH QUESTION: Is intraparenchymal vascular pruning associated with longitudinal progression of emphysema on CT imaging or decline in lung function over 5 years? STUDY DESIGN AND METHODS: The Genetic Epidemiology of COPD Study enrolled ever smokers with and without COPD from 2008 through 2011. The percentage of emphysema-like lung, or “percent emphysema,” was assessed at baseline and after 5 years on noncontrast CT imaging as the percentage of lung voxels < –950 Hounsfield units. An automated CT imaging-based tool assessed and classified intrapulmonary arteries and veins. Spirometry measures are postbronchodilator. Pulmonary arterial pruning was defined as a lower ratio of small artery volume (< 5 mm(2) cross-sectional area) to total lung artery volume. Mixed linear models included demographics, anthropomorphics, smoking, and COPD, with emphysema models also adjusting for CT imaging scanner and lung function models adjusting for clinical center and baseline percent emphysema. RESULTS: At baseline, the 4,227 participants were 60 ± 9 years of age, 50% were women, 28% were Black, 47% were current smokers, and 41% had COPD. Median percent emphysema was 2.1 (interquartile range, 0.6-6.3) and progressed 0.24 percentage points/y (95% CI, 0.22-0.26 percentage points/y) over 5.6 years. Mean FEV(1) to FVC ratio was 68.5 ± 14.2% and declined 0.26%/y (95% CI, –0.30 to –0.23%/y). Greater pulmonary arterial pruning was associated with more rapid progression of percent emphysema (0.11 percentage points/y per 1-SD increase in arterial pruning; 95% CI, 0.09-0.16 percentage points/y), including after adjusting for baseline percent emphysema and FEV(1). Arterial pruning also was associated with a faster decline in FEV(1) to FVC ratio (–0.04%/y per 1-SD increase in arterial pruning; 95% CI, –0.008 to –0.001%/y). INTERPRETATION: Pulmonary arterial pruning was associated with faster progression of percent emphysema and more rapid decline in FEV(1) to FVC ratio over 5 years in ever smokers, suggesting that pulmonary vascular differences may be relevant in disease progression. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov

Objectives Contrast enhanced ultrasound (CEUS) is now broadly used clinically for liver lesion detection and characterization. Obstacles to the efforts to quantify perfusion with CEUS have been the lack of a standardized approach and undocumented reproducibility. The use of multiple scanners and different analysis software packages compounds the degree of variability. Our objectives were to standardize a CEUS-based approach for quantification of perfusion-related parameters of liver lesions and to evaluate the variability of bolus transit parameters (rise time [RT], mean transit time [MTT], peak intensity, and area under the curve) obtained from various clinical ultrasound scanners and analysis software. Materials and methods Bolus transit as a way of evaluating perfusion has been investigated both in vivo and in vitro in the past but without establishing its reproducibility. We developed a tissue flow phantom that produces time-intensity curves very similar to those extracted from clinical cine loops of liver lesions. We evaluated the variability of the bolus transit parameters with 4 commercial scanners (Philips iU22, Philips EPIQ, GE LOGIQ E9, and Siemens Acuson Sequoia) and 3 different analysis software packages in multiple trials (15 per scanner). Results The variability (coefficient of variation) from repeated trials and while using a single scanner and software was less than 8% for RT, less than 12% for MTT, less than 49% for peak intensity, and less than 50% for area under the curve. Currently, it is not possible to directly compare amplitude values from different scanners and analysis software packages owing to the arbitrary linearization algorithm used among manufacturers; however, it is possible for time parameters (RT and MTT). The variability when using a different scanner with the same analysis software package was less than 9% for RT and less than 21% for MTT. The variability when using a different analysis software with the same scanner was less than 9% for RT and less than 15% for MTT. In all the evaluations we have performed, RT is the least variable parameter, while MTT is only slightly more variable. Conclusions The present study will lay the groundwork for multicenter patient evaluations with CEUS quantification of perfusion-related parameters with the bolus transit technique. When using the protocol and method developed here, it is possible to perform perfusion quantification on different scanners and analysis software and be able to compare the results. The current work is the first study that presents a comparison of bolus transit parameters derived from multiple systems and software packages.

Seasonal influenza virus A/H3N2 is a major cause of death globally. Vaccination remains the most effective preventative. Rapid mutation of hemagglutinin allows viruses to escape adaptive immunity. This antigenic drift necessitates regular vaccine updates. Effective vaccine strains need to represent H3N2 populations circulating one year after strain selection. Experts select strains based on experimental measurements of antigenic drift and predictions made by models from hemagglutinin sequences. We developed a novel influenza forecasting framework that integrates phenotypic measures of antigenic drift and functional constraint with previously published sequence-only fitness estimates. Forecasts informed by phenotypic measures of antigenic drift consistently outperformed previous sequence-only estimates, while sequence-only estimates of functional constraint surpassed more comprehensive experimentally-informed estimates. Importantly, the best models integrated estimates of both functional constraint and either antigenic drift phenotypes or recent population growth., eLife digest Vaccination is the best protection against seasonal flu. It teaches the immune system what the flu virus looks like, preparing it to fight off an infection. But the flu virus changes its molecular appearance every year, escaping the immune defences learnt the year before. So, every year, the vaccine needs updating. Since it takes almost a year to design and make a new flu vaccine, researchers need to be able to predict what flu viruses will look like in the future. Currently, this prediction relies on experiments that assess the molecular appearance of flu viruses, a complex and slow approach. One alternative is to examine the virus's genetic code. Mathematical models try to predict which genetic changes might alter the appearance of a flu virus, saving the cost of performing specialised experiments. Recent research has shown that these models can make good predictions, but including experimental measures of the virus’ appearance could improve them even further. This could help the model to work out which genetic changes are likely to be beneficial to the virus, and which are not. To find out whether experimental data improves model predictions, Huddleston et al. designed a new forecasting tool which used 25 years of historical data from past flu seasons. Each forecast predicted what the virus population might look like the next year using the previous year's genetic code, experimental data, or both. Huddleston et al. then compared the predictions with the historical data to find the most useful data types. This showed that the best predictions combined changes from the virus's genetic code with experimental measures of its appearance. This new forecasting tool is open source, allowing teams across the world to start using it to improve their predictions straight away. Seasonal flu infects between 5 and 15% of the world's population every year, causing between quarter of a million and half a million deaths. Better predictions could lead to better flu vaccines and fewer illnesses and deaths.

Hyper-Kamiokande is the next generation underground water Cherenkov detector that builds on the highly successful Super-Kamiokande experiment. The detector which has an 8.4~times larger effective volume than its predecessor will be located along the T2K neutrino beamline and utilize an upgraded J-PARC beam with 2.6~times beam power. Hyper-K's low energy threshold combined with the very large fiducial volume make the detector unique, that is expected to acquire an unprecedented exposure of 3.8~Mton$\cdot$year over a period of 20~years of operation. Hyper-Kamiokande combines an extremely diverse science program including nucleon decays, long-baseline neutrino oscillations, atmospheric neutrinos, and neutrinos from astrophysical origins. The scientific scope of this program is highly complementary to liquid-argon detectors for example in sensitivity to nucleon decay channels or supernova detection modes. Hyper-Kamiokande construction has started in early 2020 and the experiment is expected to start operations in 2027. The Hyper-Kamiokande collaboration is presently being formed amongst groups from 19 countries including the United States, whose community has a long history of making significant contributions to the neutrino physics program in Japan. US physicists have played leading roles in the Kamiokande, Super-Kamiokande, EGADS, K2K, and T2K programs., 6 pages, prepared as Snowmass2021 LOI

In adults with chronic liver diseases, ultrasound and magnetic resonance shear wave elastography (SWE) can replace liver biopsy in several clinical scenarios. Several guidelines on the use of ultrasound SWE for the adult population have been published. However, the number of publications in the pediatric population is limited, and available guidelines on SWE do not specifically address pediatric chronic liver diseases. In this article, we review the literature on the use of SWE for pediatric chronic liver diseases and provide expert opinion on how to use SWE, both ultrasound and magnetic resonance techniques, in the pediatric population.

Objective The FUSION-X-US-II prototype was developed to combine 3D automated breast ultrasound (ABUS) and digital breast tomosynthesis in a single device. We evaluated the performance of ABUS and tomosynthesis in a single examination in a clinical setting. Methods In this prospective feasibility study, digital breast tomosynthesis and ABUS were performed using the FUSION-X-US-II prototype without any change of the breast position in patients referred for clarification of breast lesions with an indication for tomosynthesis. The tomosynthesis and ABUS images of the prototype were interpreted independently from the clinical standard by a breast diagnostics specialist. Any detected lesion was classified using BI-RADS® scores, and results of the standard clinical routine workup (gold standard) were compared to the result of the separate evaluation of the prototype images. Image quality was rated subjectively and coverage of the breast was measured. Results One hundred one patients received both ABUS and tomosynthesis using the prototype. The duration of the additional ABUS acquisition was 40 to 60 s. Breast coverage by ABUS was approximately 80.0%. ABUS image quality was rated as diagnostically useful in 86 of 101 cases (85.1%). Thirty-three of 34 malignant breast lesions (97.1%) were identified using the prototype. Conclusion The FUSION-X-US-II prototype allows a fast ABUS scan in combination with digital breast tomosynthesis in a single device integrated in the clinical workflow. Malignant breast lesions can be localized accurately with direct correlation of ABUS and tomosynthesis images. The FUSION system shows the potential to improve breast cancer screening in the future after further technical improvements. Key Points • The FUSION-X-US-II prototype allows the combination of automated breast ultrasound and digital breast tomosynthesis in a single device without decompression of the breast. • Image quality and coverage of ABUS are sufficient to accurately detect malignant breast lesions. • If tomosynthesis and ABUS should become part of breast cancer screening, the combination of both techniques in one device could offer practical and logistic advantages. To evaluate a potential benefit of a combination of ABUS and tomosynthesis in screening-like settings, further studies are needed.