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Visual speech cues from a speaker's talking face aid speech segmentation in adults, but despite the importance of speech segmentation in language acquisition, little is known about the possible influence of visual speech on infants' speech segmentation. Here, to investigate whether there is facilitation of speech segmentation by visual information, two groups of English-learning 7-month-old infants were presented with continuous speech passages, one group with auditory-only (AO) speech and the other with auditory-visual (AV) speech. Additionally, the possible relation between infants' relative attention to the speaker's mouth versus eye regions and their segmentation performance was examined. Both the AO and the AV groups of infants successfully segmented words from the continuous speech stream, but segmentation performance persisted for longer for infants in the AV group. Interestingly, while AV group infants showed no significant relation between the relative amount of time spent fixating the speaker's mouth versus eyes and word segmentation, their attention to the mouth was greater than that of AO group infants, especially early in test trials. The results are discussed in relation to the possible pathways through which visual speech cues aid speech perception.

To determine the efficacy of a new 2-week wait pathway that uses the faecal immunochemical test (FIT) in primary care to triage patients with high and low risk symptoms suspicious of colorectal cancer (CRC). This service improvement pilot follows 2017 National Institute for Health and Care Excellence guidance, that recommended using FIT to guide referral of patients with low risk, but not high risk symptoms, which continue to be referrred on the 2-week pathway.Patients with high- and low-risk CRC symptoms were tested with FIT and those with faecal haemoglobin (f-Hb) ≥9.5 μg haemoglobin/g faeces (hereafter μg/g) were referred to secondary care. Results were tracked and primary care prompted to refer if timely referral was not made.Between December 2019 and October 2020, 5672 patients presented to primary care with high and/or low risk symptoms warranting investigations. Of these, 622 (11%) patients were referred without a FIT, of whom 36 (5.8%) had CRC. The remaining 5050 patients had a FIT, of which 4187 (83%) were processed to produce a quantitative result. Of these, 1085 patients (25.9%) had an f-Hb ≥9.5 μg/g and of those, 982 patients (90.5%) were referred and 56 (5.7%) had CRC. A total of 3102 patients (74.1%) had an f-Hb9.5 μg/g, of which 456 (14.7%) were referred and three (0.7%) had CRC. A total of 97 cancers were diagnosed with a cancer prevalence of 1.7%.A 2-week wait pathway incorporating FIT as a triage tool can be implemented successfully in primary care to identify symptomatic patients at highest risk of CRC.

The optimal therapeutic strategy in nucleoside analogue (NA) experienced chronic hepatitis B (CHB) using peginterferon is still unclear; hence we explored a switch to or add-on peginterferon strategy versus continued NA.We conducted a randomized controlled trial of CHB patients on NA12 months with HBV DNA(-) randomized to switch or add-on peginterferon-alpha2b (1.5 μg/kg/weekly) for 48 weeks versus continuing NA (controls) (allocation 2:2:1; Clinicaltrial.gov: NCT01928511) in tertiary Singapore hospitals. The primary composite endpoint at week 72 was hepatitis B e antigen (HBeAg) loss or quantitative HBsAg (qHBsAg)1 log IU/mL reduction, and secondary endpoints were HBsAg loss, HBsAg seroconversion, qHBsAg200 IU/mL, qHBsAg100 IU/mL, HBV DNA(-), viral relapse, and safety. Analysis was by intention-to-treat (ITT).A total of 253 patients (controls 51, switch 103, add-on 99) were randomized. The primary ITT endpoint was achieved in 3.9% of controls, 33.3% of switch, and 26.7% of add-on (P.0001, switch/add-on versus controls). HBsAg loss occurred in 0% of controls, 7.8% of switch, and 10.1% of add-on (ITT, P.001, switch/add-on versus controls). HBeAg(+) patients on peginterferon had higher HBeAg loss than controls but poor HBsAg responses, whereas HBeAg(-) patients on peginterferon achieved better HBsAg responses than controls. Reduction in qHBsAg in HBeAg(+) was 0.14 log IU/mL versus 0.51 log IU/mL in HBeAg(-) (P.0001) in peginterferon-treated patients. Clinical relapse was higher in switch (13.6% overall, 27% in HBeAg(+)) versus 1% add-on and 0% controls. Adverse events were typically interferon-related symptoms, with one death (myocardial infarction unrelated to therapy).ITT analysis showed that either peginterferon strategies were superior to NA for the primary endpoint and HBsAg loss, but add-on peginterferon is preferred to switch due to improved safety and similar efficacy. ClincialTrials.gov number: NCT01928511.

BACKGROUND As many as 80% of children on the autism spectrum exhibit challenging behaviors (i.e., behaviors dangerous to the self or others, behaviors that interfere with learning and development, and/or behaviors that interfere with socialization) that can have a devastating impact on personal and family well-being, contribute to teacher burnout, and even require hospitalization. Evidence-based practices to reduce these behaviors emphasize identifying triggers (events or antecedents that lead to challenging behaviors), yet parents and teachers often report that challenging behaviors surface with little warning. Exciting recent advances in biometric sensing and mobile computing technology allow measurement of momentary emotion dysregulation using physiological indices. OBJECTIVE We present the framework and protocol for a pilot trial that will test a mobile digital mental health application, the KeepCalm app. School-based approaches to managing challenging behaviors in children on the autism spectrum are limited by three key factors: 1) children on the autism spectrum often have difficulties communicating their emotions; 2) it is challenging to implement evidence-based, personalized strategies for individual children in group settings; and 3) it is difficult for teachers to track which strategies are successful for each child. KeepCalm aims to address those barriers by 1) communicating children’s stress to their teachers using physiological signaling (emotion dysregulation detection); 2) supporting implementation of emotion regulation strategies via smartphone pop-up notifications of top strategies for each child per behavior (emotion regulation strategy implementation); and 3) easing the burden of tracking outcomes by providing the child’s educational team with a tool to track the most effective emotion regulation strategies for that child based on physiological stress reduction data (emotion regulation strategy evaluation). METHODS We will test KeepCalm with 20 educational teams of students on the autism spectrum with challenging behaviors (no exclusion based on IQ or speaking ability) in a pilot randomized waitlist-controlled field trial over a 3-month period. We will examine the usability, acceptability, feasibility, and appropriateness of KeepCalm as primary outcomes. Secondary preliminary efficacy outcomes include clinical decision support success, false positives/negatives of stress alerts, and reduction of challenging behaviors and emotion dysregulation. We will also examine technical outcomes, including the number of artifacts and the proportion of time children are engaged in high physical movement based on accelerometry data, test the feasibility of our recruitment strategies, and test the response rate and sensitivity to change of our measures, in preparation for a future fully powered large-scale randomized controlled trial. RESULTS The pilot trial will begin by September 2023. CONCLUSIONS Results will provide key data on important aspects of implementing KeepCalm in preschools and elementary schools and will provide preliminary data on its efficacy to reduce challenging behaviors and support emotion regulation in children on the autism spectrum. CLINICALTRIAL ClinicalTrials.gov ID: NCT05277194 (https://www.clinicaltrials.gov/ct2/show/NCT05277194)

Commercially available wearable biosensors have the potential to enhance psychophysiology research and digital health technologies for autism by enabling stress or arousal monitoring in naturalistic settings. However, such monitors may not be comfortable for children with autism due to sensory sensitivities. To determine the feasibility of wearable technology in children with autism age 8-12 years, we first selected six consumer-grade wireless cardiovascular monitors and tested them during rest and movement conditions in 23 typically developing adults. Subsequently, the best performing monitors (based on data quality robustness statistics), Polar and Mio Fuse, were evaluated in 32 children with autism and 23 typically developing children during a 2-h session, including rest and mild stress-inducing tasks. Cardiovascular data were recorded simultaneously across monitors using custom software. We administered the Comfort Rating Scales to children. Although the Polar monitor was less comfortable for children with autism than typically developing children, absolute scores demonstrated that, on average, all children found each monitor comfortable. For most children, data from the Mio Fuse (96%-100%) and Polar (83%-96%) passed quality thresholds of data robustness. Moreover, in the stress relative to rest condition, heart rate increased for the Polar, F(1,53) = 135.70, p

This article examines Wei Beihua's modernist works, which have receded into the shadows of Sinophone Malayan (Mahua) literary history, in relation to Indonesian poet Chairil Anwar, to excavate a neglected route of transculturation at the height of Southeast Asia's nationalist movements during the 1950s. Unlike Anwar's modernist poems that thrive in Indonesia, Wei Beihua's works were considered outliers during a period when realist literature was deemed an effective tool for social mobilization in postwar Malaya. Nonetheless, it is critical for us to recognize that Wei Beihua did not reject realism or underestimate the role of literature in nation building. This article argues that Wei Beihua's idea of modernism is premised on an artist's affective and self-reflexive engagement with realism, which gives rise to a dialectical tension. The tension between his advocacy of an artist's individualism, which is inspired by Anwar, and the impetus of responding to nationalism manifests in his meta-fictional short stories that reflect on the varying motivations behind art creation. His works offer a productive perspective to reconsider the modernist artist's role during revolution and “the limits of realism” of revolutionary works when art was deemed integral to nation building in postwar Southeast Asia.

Combined vaccine formulations targeting not only hemagglutinin but also other influenza virus antigens could form the basis for a universal influenza virus vaccine that has the potential to elicit long-lasting, broadly cross-reactive immune responses. Lipid nanoparticle (LNP)-encapsulated messenger RNA (mRNA) vaccines can be utilized to efficiently target multiple antigens with a single vaccine. Here, we assessed the immunogenicity and protective efficacy of nucleoside-modified mRNA-LNP vaccines that contain four influenza A group 2 virus antigens (hemagglutinin stalk, neuraminidase, matrix protein 2, and nucleoprotein) in mice. We found that all vaccine components induced antigen-specific cellular and humoral immune responses after administration of a single dose. While the monovalent formulations were not exclusively protective, the combined quadrivalent formulation protected mice from all challenge viruses, including a relevant H1N1 influenza virus group 1 strain, with minimal weight loss. Importantly, the combined vaccine protected from morbidity at a dose of 125 ng per antigen after a single vaccination in mice. With these findings, we confidently conclude that the nucleoside-modified mRNA-LNP platform can be used to elicit protection against a large panel of influenza viruses.

Mucosal vaccines and vaccines that block pathogen transmission are under-appreciated in vaccine development. However, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has shown that blocking viral transmission is an important attribute of efficient vaccines. Here, we investigated if recombinant influenza virus neuraminidase (NA) vaccines delivered at a mucosal site could protect from onward transmission of influenza B viruses in the guinea pig model. We tested four different scenarios in which sequential transmission was investigated in chains of four guinea pigs. The variables tested included a low and a high viral inoculum (104vs 105plaque forming units) in the initial donor guinea pig and variation of exposure/cohousing time (1 day vs 6 days). In three out of four scenarios – low inoculum-long exposure, low inoculum-short exposure and high inoculum-short exposure – transmission chains were efficiently blocked. Based on this data we believe an intranasal recombinant NA vaccine could be used to efficiently curtail influenza virus spread in the human population during influenza epidemics.ImportanceVaccines that can slow respiratory virus transmission in the population are urgently needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus. Here we describe how a recombinant neuraminidase-based influenza virus vaccines reduces transmission in vaccinated guinea pigs in an exposure-intensity based manner.

As severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infections continue, there is a substantial need for cost‐effective and large‐scale testing that utilizes specimens that can be readily collected from both symptomatic and asymptomatic individuals in various community settings. Although multiple diagnostic methods utilize nasopharyngeal specimens, saliva specimens represent an attractive alternative as they can rapidly and safely be collected from different populations. While saliva has been described as an acceptable clinical matrix for the detection of SARS‐CoV‐2, evaluations of analytic performance across platforms for this specimen type are limited. Here, we used a novel sensitive RT‐PCR/MALDI‐TOF mass spectrometry‐based assay (Agena MassARRAY®) to detect SARS‐CoV‐2 in saliva specimens. The platform demonstrated high diagnostic sensitivity and specificity when compared to matched patient upper respiratory specimens. We also evaluated the analytical sensitivity of the platform and determined the limit of detection of the assay to be 1562.5 copies/ml. Furthermore, across the five individual target components of this assay, there was a range in analytic sensitivities for each target with the N2 target being the most sensitive. Overall, this system also demonstrated comparable performance when compared to the detection of SARS‐CoV‐2 RNA in saliva by the cobas® 6800/8800 SARS‐CoV‐2 real‐time RT‐PCR Test (Roche). Together, we demonstrate that saliva represents an appropriate matrix for SARS‐CoV‐2 detection on the novel Agena system as well as on a conventional real‐time RT‐PCR assay. We conclude that the MassARRAY® system is a sensitive and reliable platform for SARS‐CoV‐2 detection in saliva, offering scalable throughput in a large variety of clinical laboratory settings.

OBJECTIVE The FACE-Q Craniofacial Module for children and young adults is a patient-reported outcome measure (PROM) designed to measure outcomes for patients aged 8 to 29 years with facial conditions. The aim of this study was to establish content validity of a relevant subset of the module for its use in orthodontic patients with malocclusion. SETTING AND SAMPLE POPULATION Experts in orthodontics were emailed and invited to provide feedback through a Research Electronic Data Capture survey. Patient feedback was obtained through cognitive interviews with patients aged 8 to 29 years recruited from a university-based orthodontic clinic in Canada. MATERIALS AND METHODS Expert opinion and patient interviews were used to obtain feedback on the content of 4 appearance (face, smile, teeth and jaws) and 1 function (eating and drinking) scales hypothesized to be relevant to orthodontic malocclusions, and to elicit new concepts. Interviews were audio-recorded, transcribed, and coded using a line-by-line approach. RESULTS Twenty-one experts and 15 patients participated. Expert feedback led us to drop 9, retain 40, revise 4 and add 16 new items. At the conclusion of cognitive interviews no items were dropped, 55 were retained, 5 were revised and 8 new items were added. The final set of 68 items demonstrated content validity for orthodontic patients. CONCLUSION Expert feedback and cognitive interviews enabled us to revise and refine 5 scales as part of the FACE-Q Craniofacial Module for use in orthodontic patients. These scales were included in the internationalfield-test of the FACE-Q Craniofacial Module.

Introduction Control status may be a useful tool to assess response to treatment at each clinical visit in COPD. Control status has demonstrated to have long-term predictive value for exacerbations, but there is no information about the short-term predictive value of the lack of control and changes in control status over time. Method Prospective, international, multicenter study aimed at describing the short-term (6 months) prognostic value of control status in patients with COPD. Patients with COPD were classified as controlled/uncontrolled at baseline and at 3,6-month follow-up visits using previously validated criteria of control. Moderate and severe exacerbation rates were compared between controlled and uncontrolled visits and between patients persistently controlled, uncontrolled and those changing control status over follow-up. Results A total of 267 patients were analyzed: 80 (29.8%) were persistently controlled, 43 (16%) persistently uncontrolled and 144 (53.7%) changed control status during follow-up. Persistently controlled patients were more frequently men, with lower (not increased) body mass index and higher FEV1(%). During the 6 months following an uncontrolled patient visit the odds ratio (OR) for presenting a moderate exacerbation was 3.41 (95% confidence interval (CI) 2.47–4.69) and OR = 4.25 (95%CI 2.48–7.27) for hospitalization compared with a controlled patient visit. Conclusions Evaluation of control status at each clinical visit provides relevant prognostic information about the risk of exacerbation in the next 6 months. Lack of control is a warning signal that should prompt investigation and action in order to achieve control status.

BACKGROUND AND AIM Real-world data on sofosbuvir/velpatasvir with and without ribavirin (SOF/VEL ± RBV), particularly among patients with genotype 3 (GT3) decompensated cirrhosis, prior treatment, coinfection, and hepatocellular carcinoma (HCC), are scarce. We aimed to assess the efficacy and safety of SOF/VEL ± RBV in a real-world setting that included both community and incarcerated GT3 hepatitis C virus (HCV) patients. METHODS We included all GT3 HCV patients treated with SOF/VEL ± RBV in our institution. The primary outcome measure was the overall sustained virological response 12 weeks after treatment (SVR12), reported in both intention-to-treat (ITT) and per-protocol analyses. The secondary outcome measures were SVR12 stratified by the presence of decompensated cirrhosis, prior treatment, HCC, and HIV/hepatitis C virus coinfection and the occurrence rate of serious adverse events requiring treatment cessation or hospitalization. RESULTS A total of 779 HCV patients were treated with 12 weeks of SOF/VEL ± RBV, of which 85% were treated during incarceration. Among the 530 GT3 HCV patients, 31% had liver cirrhosis, and 6% were treatment-experienced. The overall SVR12 for GT3 was 98.7% (95% confidence interval: 97.3%, 99.5%) and 99.2% (95% confidence interval: 98.1%, 99.8%) in ITT and per-protocol analyses, respectively. High SVR12 was also seen in ITT analysis among GT3 HCV patients with decompensated cirrhosis (88%), prior treatment (100%), HCC (100%), and HIV/hepatitis B virus coinfection (100%). Apart from one patient who developed myositis, no other serious adverse events were observed. CONCLUSION The SOF/VEL ± RBV is a safe and efficacious treatment option for GT3 HCV patients in a real-world setting. SOF/VEL with RBV may be considered for decompensated GT3 HCV patients.

Available online 15 April 2022 An auditory-visual speech benefit, the benefit that visual speech cues bring to auditory speech perception, is experienced from early on in infancy and continues to be experienced to an increasing degree with age. While there is both behavioural and neurophysiological evidence for children and adults, only behavioural evidence exists for infants –as no neurophysiological study has provided a comprehensive examination of the auditory- visual speech benefit in infants. It is also surprising that most studies on auditory-visual speech benefit do not concurrently report looking behaviour especially since the auditory-visual speech benefit rests on the assumption that listeners attend to a speaker’s talking face and that there are meaningful individual differences in looking behaviour. To address these gaps, we simultaneously recorded electroencephalographic (EEG) and eye-tracking data of 5-month-olds, 4-year-olds and adults as they were presented with a speaker in auditory-only (AO), visual- only (VO), and auditory-visual (AV) modes. Cortical tracking analyses that involved forward encoding models of the speech envelope revealed that there was an auditory-visual speech benefit [i.e., AV > ( A + V )], evident in 5-month-olds and adults but not 4-year-olds. Examination of cortical tracking accuracy in relation to looking behaviour, showed that infants’ relative attention to the speaker’s mouth (vs. eyes) was positively correlated with cortical tracking accuracy of VO speech, whereas adults’ attention to the display overall was negatively correlated with cortical tracking accuracy of VO speech. This study provides the first neurophysiological evidence of auditory-visual speech benefit in infants and our results suggest ways in which current models of speech processing can be fine-tuned. This research was funded by a doctoral scholarship to the first author funded by the MARCS Institute at Western Sydney University and the HEARing Cooperative Research Centre (CRC), and by HEARingCRC funding to the last author. The second author’s work is supported by the Basque Government through the BERC 2018–2021 program, and PIBA PI-2019–0054, and by the Spanish Ministry of Science and Innovation through the Ramon y Cajal Research Fellowship, PID2019– 105528GA-I00.

The public health burden caused by influenza virus infections is not adequately addressed with existing vaccines and antivirals. Identifying approaches that interfere with human-to-human transmission of influenza viruses remains a pressing need. The importance of neuraminidase (NA) activity for the replication and spread of influenza viruses led us to investigate whether broadly reactive human anti-NA monoclonal antibodies (MAbs) could affect airborne transmission of the virus using the guinea pig model. In that model, infection with recent influenza virus clinical isolates resulted in 100% transmission from inoculated donors to recipients in an airborne transmission setting. Anti-NA MAbs were administered either to the inoculated animals on days 1, 2, and 4 after infection or to the naive contacts on days 2 and 4 after donor infection. Administration of NA-1G01, a broadly cross-reactive anti-NA MAb, to either the donor or recipient reduced transmission of the A/New York City/PV02669/2019 (H1N1) and A/New York City/PV01148/2018 (H3N2) viruses. Administration of 1000-3C05, an anti-N1 MAb, to either the donor or recipient reduced transmission of A/New York City/PV02669/2019 (H1N1) virus but did not reduce transmission of A/New York City/PV01148 (H3N2) virus. Conversely, 229-2C06, an anti-N2 MAb, reduced transmission of A/New York City/PV01148 (H3N2) but did not impact transmission of A/New York City/PV02669/2019 (H1N1) virus. Our work demonstrates that anti-NA MAbs could be further developed into prophylactic or therapeutic agents to prevent influenza virus transmission to control viral spread. IMPORTANCE The burden of influenza remains substantial despite unremitting efforts to reduce the magnitude of seasonal influenza epidemics and prepare for pandemics. Although vaccination remains the mainstay of these efforts, current vaccines are designed to stimulate an immune response against the viral hemagglutinin. Interest in the role immunity against neuraminidase plays in influenza virus infection and transmission has recently surged. Human antibodies that bind broadly to neuraminidases of diverse influenza viruses and protect mice against lethal viral challenge have previously been characterized. Here, we show that three such antibodies inhibit the neuraminidase activity of recent isolates and reduce their airborne transmission in a guinea pig model. In addition to contributing to the accumulating support for incorporating neuraminidase as a vaccine antigen, these findings also demonstrate the potential of direct administration of anti-neuraminidase antibodies to individuals infected with influenza virus and to individuals for postexposure prophylaxis to prevent the spread of influenza virus.

The stalk of the influenza virus hemagglutinin (HA) is an attractive target for antibody-based universal influenza virus vaccine development. While antibodies that target this part of the virus can be neutralizing, it has been shown in recent years that Fc receptor-mediated effector functions are of significant importance for the protective effect of anti-stalk antibodies. Several assays to measure Fc-Fc receptor interaction-based effector functions like antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis exist, but they suffer from limitations such as low throughput and high run-to-run variability. Reporter assays for antibody-dependent cellular cytotoxicity based on reporter cells that express luciferase upon engagement of human FcγRIIIa with the Fc of antigen-bound antibodies have been developed as well. These reporter assays can be used in a higher throughput setting with limited run-to-run assay variability but since they express only one Fc receptor, their biological relevance is unclear. Here we optimized an antibody-dependent cellular cytotoxicity reporter assay to measure the activity of antibodies to the conserved stalk domain of H1 hemagglutinin. The assay was then correlated to a CD107a-based degranulation assay, and a strong and significant correlation could be observed. This data suggests that the FcγRIIIa-based reporter assay is a good substitute for functional assays, especially in settings where larger sample numbers need to be analyzed.

Background: Real world data (RWD) is increasingly relevant in breast cancer (BCa) as it is the most frequently diagnosed cancer. Developed world has seen improved breast cancer survival, however, RWDon BCa survival in Malaysia is still lacking. Aims and Objectives: This study aims to determine characteristics and survival of BCa patients from a single institute. Materials and Methods: Retrospective analysis of 168 BCa patients who were treated with at least one treatment modality in Beacon International Specialist Centre (BISC) from 2008-2012 was conducted. Patient characteristicsand treatments received were analysed descriptively to survival outcome.Vital status was obtained from the National Registry of Birth and Death (NRD) records. Observed survival rates wereestimated by Kaplan-Meier method and difference between groups by log-rank. Results: Of 143 eligible BCa patients,28 (19.6%) died during the study period. Five-year BCa specific survival rates were 100% for Stage I and II, 79.31% for stage III and 38.89% for Stage IV disease. In the multivariate analysis, higher stage at diagnosis, triple negative breast cancer with metastases and higher grade were associated with worse survival outcomes. The overall 5-year survival rate of BCa patients in BISC from 2008-2012 compares favourably to the survival data of developed countries. Conclusion: In conclusion, the overall 5-year survival rate of BCa patients in BISC compares favourably to the survival data of developed countries, as well as to other institutions.

Background and aim The prohibitively high cost of direct-acting antivirals (DAA) for hepatitis C virus (HCV) infection remains a barrier to treatment access in Singapore. We aimed to evaluate whether DAA as first-line therapy would be cost-effective for genotype 3 (GT3) HCV patients compared with pegylated interferon and ribavirin (PR). Methods A decision tree analysis was used to compare the costs and outcomes of DAA and PR as first-line therapy. Treatment effectiveness, defined as sustained virological response, was assessed using a retrospective cohort of treated GT3 HCV patients. Direct medical costs were estimated from the payer's perspective using billing information. We obtained health utilities from published literature. We performed extensive one-way sensitivity analyses and probabilistic sensitivity analyses to account for uncertainties regarding the model parameters. Results In base case analysis, first-line therapy with DAA and PR yielded quality-adjusted life years (QALYs) of 0.69 and 0.62 at a cost of USD 54 634 and USD 23 857, respectively. The resultant incremental cost-effectiveness ratio (ICER) (USD 449 232/QALY) exceeded the willingness-to-pay threshold (USD 53 302/QALY). The ICER was robust for uncertainties regarding the model parameters. The cost of DAA is the key factor influencing the cost-effectiveness of HCV treatment. At current price, DAA as first-line therapy is not cost-effective compared with PR, with or without consideration of retreatment. Threshold analysis suggested that DAA can be cost-effective if it costs less than USD 17 002 for a 12-week treatment course. Conclusion At current price, DAA as first-line therapy is not cost-effective compared with PR in GT3 HCV patients in Singapore.

SUMMARY N-acetyl-aspartyl-glutamate (NAAG) is a peptide-based neurotransmitter that has been extensively studied in many neurological diseases. In this study, we show a specific role of NAAG in cancer. We found that NAAG is more abundant in higher grade cancers and is a source of glutamate in cancers expressing glutamate carboxypeptidase II (GCPII), the enzyme that hydrolyzes NAAG to glutamate and N-acetyl-aspartate (NAA). Knocking down GCPII expression through genetic alteration or pharmacological inhibition of GCPII results in a reduction of both glutamate concentrations and cancer growth. Moreover, targeting GCPII in combination with glutaminase inhibition accentuates these effects. These findings suggest that NAAG serves as an important reservoir to provide glutamate to cancer cells through GCPII when glutamate production from other sources is limited. Thus, GCPII is a viable target for cancer therapy, either alone or in combination with glutaminase inhibition., In Brief Nguyen et al. show that NAAG is more abundant in higher grade cancers and a source of glutamate in cancers expressing GCPII, the enzyme that hydrolyzes NAAG to glutamate and NAA. The results suggest that GCPII is a viable target for cancer therapy, either alone or in combination with glutaminase inhibition., Graphical Abstract

Chronic hepatitis C infection is common among people with history of substance use. Liver fibrosis assessment is a barrier to linkage to care, particularly among those with history of substance users. The use of non-invasive scores can be helpful in predicting liver cirrhosis in the era of HCV elimination, especially in countries where transient elastography (TE) is not available. We compared the commonly used non-invasive scores with a novel non-invasive score in predicting liver cirrhosis in this population.HCV patients with history of substance use between 2011 and 2016 were analyzed. All patients had TE for liver fibrosis assessment. Clinical performance of established non-invasive scores for fibrosis assessment and novel score were compared. Youden's index was used to determine optimal cut-off of the novel score.A total of 579 patients were included. In multivariate logistic regression, cirrhosis on TE was associated with age (P = 0.002), aspartate aminotransferase (AST) (P = 0.004), and platelet count (P 0.001), but not alanine aminotransferase (ALT) (P = 0.896). These form the components of modified AST-to-platelet ratio index (APRI) score. Modified APRI was superior to APRI in predicting cirrhosis (AUROC, 0.796 vs. 0.770, P = 0.007), but not fibrosis-4 score (FIB-4) (P = 1.00). Modified APRI at cut-off of 4 has sensitivity, specificity and negative predictive value (NPV) of 94.4%, 26.9% and 92.6%, respectively, and at 19, has sensitivity, specificity and positive predictive value (PPV) of 33.3%, 96.2% and 77.1%, respectively. FIB-4 has a NPV and PPV of 88.6%, 41.8% and 78.5%, 77.6%, at cut-off of 1.45 and 3.25, respectively. Using the cut-off of 4 and 14 for modified APRI, 32.5% of patients can be correctly classified and misses out only 5.6% of cirrhosis patients.Modified APRI score is superior in predicting cirrhosis in HCV population, with 32.5% of the population being correctly classified using cut-off of 4 and 14. Further studies are required to validate the findings.