Quantitative assessment of multiple pathogen exposure and immune dynamics at scale.

IMPORTANCE: Serology reveals exposure to pathogens, as well as the state of autoimmune and other clinical conditions. It is used to evaluate individuals and their histories and as a public health tool to track epidemics. Employing a variety of formats, studies nearly always perform serology by testing response to only one or a few antigens. However, clinical outcomes of new infections also depend on which previous infections may have occurred. We developed a high-throughput serology method that evaluates responses to hundreds of antigens simultaneously. It can be used to evaluate thousands of samples at a time and provide a quantitative readout. This tool will enable doctors to monitor which pathogens an individual has been exposed to and how that changes in the future. Moreover, public health officials could track populations and look for infectious trends among large populations. Testing many potential antigens at a time may also aid in vaccine development.

Evaluating high-cost technologies - no need to throw the baby out with the bathwater.

INTRODUCTION: Evidence generation for the health technology assessment (HTA) of a new technology is a long and expensive process with no guarantees that the health technology will be adopted and implemented into a health-care system. This would suggest that there is a greater risk of failure for a company developing a high-cost technology and therefore incentives (such as increasing the funding available for research or additional market exclusivity) may be needed to encourage development of such technologies as has been seen with many high-cost orphan drugs. AREAS COVERED: This paper discusses some of the key issues relating to the evaluation of high-cost technologies through the use of existing HTA processes and what the challenges will be going forward. EXPERT OPINION: We propose that while the current HTA process is robust, its evolution into accommodating the incorporation of real-world data and evidence alongside a life-cycle HTA approach should better enable developers to produce the evidence required on effectiveness and cost-effectiveness. This should lead to reduced decision uncertainty for HTA agencies to make adoption decisions in a more timely and efficient manner. Furthermore, budget impact analysis remains important in understanding the actual financial impact on health-care systems and budgets outside of the cost-effectiveness framework used to aid decision-making.

Defining the condensate landscape of fusion oncoproteins.

Fusion oncoproteins (FOs) arise from chromosomal translocations in ~17% of cancers and are often oncogenic drivers. Although some FOs can promote oncogenesis by undergoing liquid-liquid phase separation (LLPS) to form aberrant biomolecular condensates, the generality of this phenomenon is unknown. We explored this question by testing 166 FOs in HeLa cells and found that 58% formed condensates. The condensate-forming FOs displayed physicochemical features distinct from those of condensate-negative FOs and segregated into distinct feature-based groups that aligned with their sub-cellular localization and biological function. Using Machine Learning, we developed a predictor of FO condensation behavior, and discovered that 67% of ~3000 additional FOs likely form condensates, with 35% of those predicted to function by altering gene expression. 47% of the predicted condensate-negative FOs were associated with cell signaling functions, suggesting a functional dichotomy between condensate-positive and -negative FOs. Our Datasets and reagents are rich resources to interrogate FO condensation in the future.

Photodynamic Diagnosis-guided Transurethral Resection of Bladder Tumour in Participants with a First Suspected Diagnosis of Intermediate- or High-risk Non-muscle-invasive Bladder Cancer: Cost-effectiveness Analysis Alongside a Randomised Controlled Trial.

Background: Recurrence of non-muscle-invasive bladder cancer (NMIBC) is common after transurethral resection of bladder tumour (TURBT). Photodynamic diagnosis (PDD) may reduce recurrence. PDD uses a photosensitiser in the bladder that causes the tumour to fluoresce to guide resection. PDD provides better diagnostic accuracy and allows more complete tumour resection. Objective: To estimate the economic efficiency of PDD-guided TURBT (PDD-TURBT) in comparison to white light-guided TURNT (WL-TURBT) in individuals with a suspected first diagnosis of NMIBC at intermediate or high risk of recurrence on the basis of routine visual assessment before being scheduled for TURBT. Design setting and participants: This is a health economic evaluation alongside a pragmatic, open-label, parallel-group randomised trial from a societal perspective. A total of 493 participants (aged ≥16 yr) were randomly allocated to PDD-TURBT (n = 244) or WL-TURBT (n = 249) in 22 UK National Health Service hospitals. Outcome measurements and statistical analysis: Cost effectiveness ratios were based on the use of health care resources associated with PDD-TURBT and WL-TURBT and quality-adjusted life years (QALYs) gained within the trial. Uncertainties in key parameters were assessed using sensitivity analyses. Results and limitations: On the basis of the use of resources driven by the trial protocol, the incremental cost effectiveness of PDD-TURBT in comparison to WL-TURBT was not cost saving. At 3 yr, the total cost was £12 881 for PDD-TURBT and £12 005 for WL-TURBT. QALYs at three years were 2.087 for PDD-TURBT and 2.094 for WL-TURBT. The probability that PDD-TURBT is cost effective was never >30% above the range of societal cost-effectiveness thresholds. Conclusions: There was no evidence of a difference in either costs or QALYs over 3-yr follow-up between PDD-TURBT and WL-TURBT in individuals with suspected intermediate- or high-risk NMIBC. PDD-TURBT is not supported for the management of primary intermediate- or high-risk NMIBC. Patient summary: We assessed overall costs for two approaches for removal of bladder tumours in noninvasive cancer and measured quality-adjusted life years gained for each. We found that use of a photosensitiser in the bladder was not more cost effective than use of white light only during tumour removal.

A qualitative interview study applying the COM-B model to explore how hospital-based trainers implement antimicrobial stewardship education and training in UK hospital-based care.

BACKGROUND: Antimicrobial resistance (AMR) is a major global health threat caused by the inappropriate use of antimicrobials in healthcare and other settings. Antimicrobial stewardship (AMS) is a broad multi-component health services intervention that promotes and monitors the judicious use of antimicrobials to preserve their future effectiveness. A main component of AMS is education and training (E&T). However, there are often discrepancies in how such interventions are implemented and delivered in hospital-based care. The aim of this study was to explore the factors influencing the implementation of AMS E&T in UK hospitals. METHODS: Semi-structured interviews were carried out with AMS E&T trainers in UK hospitals. The interview schedule was developed using the Capability, Opportunity, Motivation = Behaviour (COM-B) model. Participants were identified via professional networks and social media. Interviews were analysed using inductive thematic analysis, followed by deductive analysis using the COM-B model as a framework. RESULTS: A total of 34 participants (26 antimicrobial pharmacists, 3 nurses, 1 advanced clinical practitioner, 2 infectious disease consultants, 1 microbiologist and 1 clinical scientist). responsible for designing, implementing and evaluating AMS E&T in UK hospitals (five from Northern Ireland, four from Wales, two from Scotland and 23 from England) took part in virtual interviews. Key themes were: (1) The organisational context, including system-level barriers to AMS included competing organisational targets (Reflective motivation and physical opportunity) and the impact of the COVID-19 pandemic on activity (Physical opportunity); (2) Healthcare professionals' roles and the wider multi-disciplinary team, such that AMS roles were defined and addressed poorly in E&T (Social opportunity); and (3) The individual perception of the need for AMS E&T in hospital-based care, manifest in a perceived lack of conviction of the wider threat of AMR and the resulting need for AMS E&T (Reflective motivation). CONCLUSION: This study has identified factors influencing implementation of AMS E&T in UK hospitals and further identified where implemented, AMS E&T did not address real-world challenges. Current AMS E&T needs to be optimised to elicit practice change, with recommendations including training and engaging the wider work-force and drawing upon theoretically-informed intervention development frameworks to inform AMS E&T to better target AMS behaviour change.

Herpes Simplex Virus-1 ICP27 Nuclear Export Signal Mutants Exhibit Cell Type-Dependent Deficits in Replication and ICP4 Expression.

Herpes simplex virus type-1 (HSV-1) protein ICP27 is an essential immediate early (IE) protein that promotes the expression of viral early (E) and late (L) genes via multiple mechanisms. Our understanding of this complex regulatory protein has been greatly enhanced by the characterization of HSV-1 mutants bearing engineered alterations in the ICP27 gene. However, much of this analysis has been performed in interferon-deficient Vero monkey cells. Here, we assessed the replication of a panel of ICP27 mutants in several other cell types. Our analysis shows that mutants lacking ICP27's amino (N)-terminal nuclear export signal (NES) display a striking cell type-dependent growth phenotype, i.e., they grow semi-permissively in Vero and some other cells but are tightly blocked for replication in primary human fibroblasts and multiple human cell lines. This tight growth defect correlates with a failure of these mutants to replicate viral DNA. We also report that HSV-1 NES mutants are deficient in expressing the IE protein ICP4 at early times postinfection. Analysis of viral RNA levels suggests that this phenotype is due, at least in part, to a defect in the export of ICP4 mRNA to the cytoplasm. In combination, our results (i) show that ICP27's NES is critically important for HSV-1 replication in many human cells, and (ii) suggest that ICP27 plays a heretofore unappreciated role in the expression of ICP4. IMPORTANCE HSV-1 IE proteins drive productive HSV-1 replication. The major paradigm of IE gene induction, developed over many years, involves the parallel activation of the five IE genes by the viral tegument protein VP16, which recruits the host RNA polymerase II (RNAP II) to the IE gene promoters. Here, we provide evidence that ICP27 can enhance ICP4 expression early in infection. Because ICP4 is required for transcription of viral E and L genes, this finding may be relevant to understanding how HSV-1 enters and exits the latent state in neurons.

Clinical and cost effectiveness of endoscopic bipolar radiofrequency ablation for the treatment of malignant biliary obstruction: a systematic review.

Background: Early evidence suggests that using radiofrequency ablation as an adjunct to standard care (i.e. endoscopic retrograde cholangiopancreatography with stenting) may improve outcomes in patients with malignant biliary obstruction. Objectives: To assess the clinical effectiveness, cost-effectiveness and potential risks of endoscopic bipolar radiofrequency ablation for malignant biliary obstruction, and the value of future research. Data sources: Seven bibliographic databases, three websites and seven trials registers were searched from 2008 until 21 January 2021. Review methods: The study inclusion criteria were as follows: patients with biliary obstruction caused by any form of unresectable malignancy; the intervention was reported as an endoscopic biliary radiofrequency ablation to ablate malignant tissue that obstructs the bile or pancreatic ducts, either to fit a stent (primary radiofrequency ablation) or to clear an obstructed stent (secondary radiofrequency ablation); the primary outcomes were survival, quality of life or procedure-related adverse events; and the study design was a controlled study, an observational study or a case report. Risk of bias was assessed using Cochrane tools. The primary analysis was meta-analysis of the hazard ratio of mortality. Subgroup analyses were planned according to the type of probe, the type of stent (i.e. metal or plastic) and cancer type. A de novo Markov model was developed to model cost and quality-of-life outcomes associated with radiofrequency ablation in patients with primary advanced bile duct cancer. Insufficient data were available for pancreatic cancer and secondary bile duct cancer. An NHS and Personal Social Services perspective was adopted for the analysis. A probabilistic analysis was conducted to estimate the incremental cost-effectiveness ratio for radiofrequency ablation and the probability that radiofrequency ablation was cost-effective at different thresholds. The population expected value of perfect information was estimated in total and for the effectiveness parameters. Results: Sixty-eight studies (1742 patients) were included in the systematic review. Four studies (336 participants) were combined in a meta-analysis, which showed that the pooled hazard ratio for mortality following primary radiofrequency ablation compared with a stent-only control was 0.34 (95% confidence interval 0.21 to 0.55). Little evidence relating to the impact on quality of life was found. There was no evidence to suggest an increased risk of cholangitis or pancreatitis, but radiofrequency ablation may be associated with an increase in cholecystitis. The results of the cost-effectiveness analysis were that the costs of radiofrequency ablation was £2659 and radiofrequency ablation produced 0.18 quality-adjusted life-years, which was more than no radiofrequency ablation on average. With an incremental cost-effectiveness ratio of £14,392 per quality-adjusted life-year, radiofrequency ablation was likely to be cost-effective at a threshold of £20,000 per quality-adjusted life-year across most scenario analyses, with moderate uncertainty. The source of the vast majority of decision uncertainty lay in the effect of radiofrequency ablation on stent patency. Limitations: Only 6 of 18 comparative studies contributed to the survival meta-analysis, and few data were found concerning secondary radiofrequency ablation. The economic model and cost-effectiveness meta-analysis required simplification because of data limitations. Inconsistencies in standard reporting and study design were noted. Conclusions: Primary radiofrequency ablation increases survival and is likely to be cost-effective. The evidence for the impact of secondary radiofrequency ablation on survival and of quality of life is limited. There was a lack of robust clinical effectiveness data and, therefore, more information is needed for this indication. Future work: Future work investigating radiofrequency ablation must collect quality-of-life data. High-quality randomised controlled trials in secondary radiofrequency ablation are needed, with appropriate outcomes recorded. Study registration: This study is registered as PROSPERO CRD42020170233. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 7. See the NIHR Journals Library website for further project information.

The bile and pancreatic ducts transport fluids to the intestines to help people digest their food properly. Some types of cancer can cause these ducts to become totally or partially blocked. We wanted to know if endoscopic radiofrequency ablation is safe and works well to treat people who have one of these blockages that cannot be removed by surgery. Radiofrequency ablation burns away a blockage by hitting it with radio waves. Endoscopic means that the radio waves are directed to the blockage using a thin, tube-like wire with a camera at the end. During radiofrequency ablation, a person might have a small tube called a stent put into their bile or pancreatic duct to keep it open or to replace an already blocked stent.

We searched for research studies that looked at (1) whether or not radiofrequency ablation was able to remove blockages from the ducts, (2) if radiofrequency ablation allowed people to live longer, (3) if patients had a better quality of life after radiofrequency ablation, (4) if radiofrequency ablation caused any side effects and (5) how much it costs to treat people with radiofrequency ablation.

We found that treatment with radiofrequency ablation before giving a person a stent helped them to live a little longer with their cancer. We did not find any evidence that radiofrequency ablation increased pain or swelling in the bile duct or pancreatic duct. Radiofrequency ablation might cause more swelling in the gall bladder than having a stent without radiofrequency ablation, but there was not enough research available for us to be certain of this.

Radiofrequency ablation before inserting a stent could be a safe option to add to treatment of bile and pancreatic duct blockages caused by cancer. There is limited research evidence and so we are unable to recommend radiofrequency ablation as a treatment for standard clinical practice.

An empirical analysis of American Passenger's willingness to fly in commercial airplanes after vaccination against COVID-19.

Although several studies have explored the effects of the pandemic on aviation, little remains known about whether members of the public are willing to fly again after they have been vaccinated. The current study uses the Health Belief Model (HBM) to fill this missing gap by manipulating the following variables: 1) whether or not the participant is vaccinated; 2) whether or not airlines require that all passengers and crew receive vaccinations; 3) length of flight; 4) destination; and 5) the number of passengers. The data from 678 participants revealed that willingness to fly is much higher if the participants themselves have been vaccinated, if the airlines require all passengers to be vaccinated, if the flight is short, if the destination is domestic, and if the number of passengers is low. These findings did not appear to differ as a function of flying business versus pleasure. We discuss the practical implications of these data as airlines struggle to bring back their customer base.

Economic evaluations of interventions to prevent and control health-care-associated infections: a systematic review.

Almost 9 million health-care-associated infections have been estimated to occur each year in European hospitals and long-term care facilities, and these lead to an increase in morbidity, mortality, bed occupancy, and duration of hospital stay. The aim of this systematic review was to review the cost-effectiveness of interventions to limit the spread of health-care-associated infections), framed by WHO infection prevention and control core components. The Embase, National Health Service Economic Evaluation Database, Database of Abstracts of Reviews of Effects, Health Technology Assessment, Cinahl, Scopus, Pediatric Economic Database Evaluation, and Global Index Medicus databases, plus grey literature were searched for studies between Jan 1, 2009, and Aug 10, 2022. Studies were included if they reported interventions including hand hygiene, personal protective equipment, national-level or facility-level infection prevention and control programmes, education and training programmes, environmental cleaning, and surveillance. The British Medical Journal checklist was used to assess the quality of economic evaluations. 67 studies were included in the review. 25 studies evaluated methicillin-resistant Staphylococcus aureus outcomes. 31 studies evaluated screening strategies. The assessed studies that met the minimum quality criteria consisted of economic models. There was some evidence that hand hygiene, environmental cleaning, surveillance, and multimodal interventions were cost-effective. There were few or no studies investigating education and training, personal protective equipment or monitoring, and evaluation of interventions. This Review provides a map of cost-effectiveness data, so that policy makers and researchers can identify the relevant data and then assess the quality and generalisability for their setting.

Practitioner and digitally delivered interventions for reducing hazardous and harmful alcohol consumption in people not seeking alcohol treatment: a systematic review and network meta-analysis.

AIM: To compare the effectiveness of practitioner versus digitally delivered interventions for reducing hazardous and harmful alcohol consumption. DESIGN: Systematic review and network meta-analysis comprising comprehensive search for randomised controlled trials, robust screening and selection methods and appraisal with the Cochrane Risk of Bias tool. Network meta-analyses were conducted in Stata using random effects, frequentist models. The confidence in network meta-analysis (CINeMA) tool was used to assess confidence in effect sizes. SETTING: Online or community or health settings where the intervention was immediately accessible without referral. PARTICIPANTS: Non treatment-seeking hazardous or harmful drinkers. MEASUREMENTS: Primary outcome was mean difference in alcohol consumption (g/wk); secondary outcome was number of single high intensity drinking episodes. Baseline consumption was analysed as a covariate. FINDINGS: Of 201 included trials (94 753 participants), 152 reported a consumption outcome that could be converted to grams/week; 104 reported number of single high intensity drinking episodes. At 1 and 6 months, practitioner delivered interventions reduced consumption more than digitally delivered interventions (1 month: -23 g/wk (95% CI, -43 to -2); 6 months: -14 g/wk [95% CI, -25 to -3]). At 12 months there was no evidence of difference between practitioner and digitally delivered interventions (-6 g/wk [95% CI, -24 to 12]). There was no evidence of a difference in single high intensity drinking episodes between practitioner and digitally delivered interventions at any time point. Effect sizes were small, but could impact across a population with relatively high prevalence of hazardous and harmful drinking. Heterogeneity was a concern. Some inconsistency was indicated at 1 and 6 months, but little evidence was apparent at 12 months. CONCLUSION: Practitioner delivered interventions for reducing hazardous and harmful alcohol consumption are more effective than digitally delivered interventions up to 6 months; at 12 months there is no evidence of a difference.

The effect of the endoscopic device Endocuff™/Endocuff vision™ on quality standards in colonoscopy: A systematic review and meta-analysis of randomized trials.

AIM: The adenoma detection rate (ADR) is an important quality measure, with a high ADR reflecting high-quality colonoscopy. This systematic review and meta-analysis aimed to assess the effects of Endocuff™/Endocuff Vision™-assisted colonoscopy (EAC) versus standard colonoscopy (SC) on ADR and other clinical, patient and resource-use outcomes. METHOD: MEDLINE, EMBASE, Web of Science, Scopus and the Cochrane Central Register of Controlled Trials were searched for full papers reporting randomized studies comparing EAC with SC. The primary outcome was ADR. Secondary outcomes comprised key polyp/adenoma detection, procedure-related, patient-related and health economic measures. Random effects meta-analyses provided pooled estimates of outcomes [risk ratio (RR) or mean difference (MD), with 95% confidence intervals (CI)]. RESULTS: Twelve parallel-group randomized controlled trials (RCTs) and three crossover RCTs with data on 9140 patients were included. EAC significantly increased the ADR (RR 1.18, 95% CI 1.09-1.29), mean adenomas per procedure (MAP) (MD 0.19, 95% CI 0.06-0.33), polyp detection rate (PDR) (RR 1.20, 95% CI 1.10-1.30) and mean polyps per procedure (MPP) (MD 0.39, 95% CI 0.14-0.63) versus SC. EAC significantly increased segmental PDR versus SC in the sigmoid (RR 2.02, 95% CI 1.64-2.49), transverse (RR 1.63, 95% CI 1.09-2.42), ascending (RR 1.74, 95% CI 1.26-2.41) and caecal segments (RR 1.91, 95% CI 1.29-2.82). Procedure-related variables did not differ between arms. There were insufficient data for meta-analysis of health economic or patient-centred outcomes. CONCLUSIONS: EAC increased ADR, MAP, PDR and MPP versus SC without detrimental effects on procedure measures. Cost-effectiveness and patient experience data are lacking and would be valuable to inform practice recommendations.

Oral nutritional interventions in frail older people who are malnourished or at risk of malnutrition: a systematic review.

BACKGROUND: Malnutrition worsens the health of frail older adults. Current treatments for malnutrition may include prescribed oral nutritional supplements, which are multinutrient products containing macronutrients and micronutrients. OBJECTIVE: To assess the effectiveness and cost-effectiveness of oral nutritional supplements (with or without other dietary interventions) in frail older people who are malnourished or at risk of malnutrition. DATA SOURCES: MEDLINE, EMBASE, Cochrane Library, Scopus, CINAHL (Cumulative Index to Nursing and Allied Health Literature) and grey literature were searched from inception to 13 September 2021. REVIEW METHODS: A systematic review and meta-analysis was conducted to evaluate the effectiveness and cost-effectiveness of oral nutritional supplements in frail older people (aged ≥ 65 years) who are malnourished or at risk of malnutrition (defined as undernutrition as per National Institute for Health and Care Excellence guidelines). Meta-analysis and network meta-analysis were undertaken, where feasible, along with a narrative synthesis. A cost-effectiveness review was reported narratively. A de novo model was developed using effectiveness evidence identified in the systematic review to estimate the cost-effectiveness of oral nutritional supplements. RESULTS: Eleven studies (n = 822 participants) were included in the effectiveness review, six of which were fully or partly funded by industry. Meta-analyses suggested positive effects of oral nutritional supplements compared with standard care for energy intake (kcal) (standardised mean difference 1.02, 95% confidence interval 0.15 to 1.88; very low quality evidence) and poor mobility (mean difference 0.03, p < 0.00001, 95% confidence interval 0.02 to 0.04; very low quality evidence) but no evidence of an effect for body weight (mean difference 1.31, 95% confidence interval -0.05 to 2.66; very low quality evidence) and body mass index (mean difference 0.54, 95% confidence interval -0.03 to 1.11; very low quality evidence). Pooled results for other outcomes were statistically non-significant. There was mixed narrative evidence regarding the effect of oral nutritional supplements on quality of life. Network meta-analysis could be conducted only for body weight and grip strength; there was evidence of an effect for oral nutritional supplements compared with standard care for body weight only. Study quality was mixed; the randomisation method was typically poorly reported. One economic evaluation, in a care home setting, was included. This was a well-conducted study showing that oral nutritional supplements could be cost-effective. Cost-effectiveness analysis suggested that oral nutritional supplements may only be cost-effective for people with lower body mass index (< 21 kg/m2) using cheaper oral nutritional supplements products that require minimal staff time to administer. LIMITATIONS: The review scope was narrow in focus as few primary studies used frailty measures (or our proxy criteria). This resulted in only 11 included studies. The small evidence base and varied quality of evidence meant that it was not possible to determine accurate estimates of the effectiveness or cost-effectiveness of oral nutritional supplements. Furthermore, only English-language publications were considered. CONCLUSIONS: Overall, the review found little evidence of oral nutritional supplements having significant effects on reducing malnutrition or its adverse outcomes in frail older adults. FUTURE WORK: Future research should focus on independent, high-quality, adequately powered studies to investigate oral nutritional supplements alongside other nutritional interventions, with longer-term follow-up and detailed analysis of determinants, intervention components and cost-effectiveness. STUDY REGISTRATION: This study is registered as PROSPERO CRD42020170906. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 51. See the NIHR Journals Library website for further project information.

WHAT WAS THE QUESTION?: Malnutrition, in the form of undernutrition, is very common in frail older people. Dietary advice is recommended (e.g. adding nutrients to meals) for older adults who are malnourished, while powdered or liquid supplements (oral nutritional supplements) can be prescribed to those who are malnourished or at risk of becoming malnourished. In this study, we reviewed previous studies to see if oral nutritional supplements (as a form of dietary support) work at reducing malnutrition in frail older adults and whether or not they are value for money. WHAT DID WE DO?: We searched for studies up to September 2021 on frail older people who were at risk of malnutrition or were malnourished in care homes, hospitals or the community in any country. We included studies that measured malnutrition and the consequences of malnutrition, quality of life, survival, costs and hospitalisations. We assessed the difference in malnutrition between those receiving oral nutritional supplements and those receiving usual care or other dietary (or nutritional) interventions. We also looked at the value for money of oral nutritional supplements. WHAT DID WE FIND?: We found 12 studies (11 studies looking at whether the supplements worked and one study looking at value for money). Most of which were of low quality, and many were funded by industry. Studies often did not report on longer-term effects, or how older people felt about the supplements. There was no clear or strong evidence that oral nutritional supplements worked or were value for money in reducing malnutrition or its consequences (such as the ability to perform everyday tasks). WHAT DOES THIS MEAN?: There is weak evidence for oral nutritional supplements in frail older adults. Future high-quality studies should be independent, assess longer-term effects, and have better reporting on factors that influence the impacts of oral nutritional supplements.

Photodynamic versus white-light-guided resection of first-diagnosis non-muscle-invasive bladder cancer: PHOTO RCT.

BACKGROUND: Around 7500 people are diagnosed with non-muscle-invasive bladder cancer in the UK annually. Recurrence following transurethral resection of bladder tumour is common, and the intensive monitoring schedule required after initial treatment has associated costs for patients and the NHS. In photodynamic diagnosis, before transurethral resection of bladder tumour, a photosensitiser that is preferentially absorbed by tumour cells is instilled intravesically. Transurethral resection of bladder tumour is then conducted under blue light, causing the photosensitiser to fluoresce. Photodynamic diagnosis-guided transurethral resection of bladder tumour offers better diagnostic accuracy than standard white-light-guided transurethral resection of bladder tumour, potentially reducing the chance of subsequent recurrence. OBJECTIVE: The objective was to assess the clinical effectiveness and cost-effectiveness of photodynamic diagnosis-guided transurethral resection of bladder tumour. DESIGN: This was a multicentre, pragmatic, open-label, parallel-group, non-masked, superiority randomised controlled trial. Allocation was by remote web-based service, using a 1 : 1 ratio and a minimisation algorithm balanced by centre and sex. SETTING: The setting was 22 NHS hospitals. PARTICIPANTS: Patients aged ≥ 16 years with a suspected first diagnosis of high-risk non-muscle-invasive bladder cancer, no contraindications to photodynamic diagnosis and written informed consent were eligible. INTERVENTIONS: Photodynamic diagnosis-guided transurethral resection of bladder tumour and standard white-light cystoscopy transurethral resection of bladder tumour. MAIN OUTCOME MEASURES: The primary clinical outcome measure was the time to recurrence from the date of randomisation to the date of pathologically proven first recurrence (or intercurrent bladder cancer death). The primary health economic outcome was the incremental cost per quality-adjusted life-year gained at 3 years. RESULTS: We enrolled 538 participants from 22 UK hospitals between 11 November 2014 and 6 February 2018. Of these, 269 were allocated to photodynamic diagnosis and 269 were allocated to white light. A total of 112 participants were excluded from the analysis because of ineligibility (n = 5), lack of non-muscle-invasive bladder cancer diagnosis following transurethral resection of bladder tumour (n = 89) or early cystectomy (n = 18). In total, 209 photodynamic diagnosis and 217 white-light participants were included in the clinical end-point analysis population. All randomised participants were included in the cost-effectiveness analysis. Over a median follow-up period of 21 months for the photodynamic diagnosis group and 22 months for the white-light group, there were 86 recurrences (3-year recurrence-free survival rate 57.8%, 95% confidence interval 50.7% to 64.2%) in the photodynamic diagnosis group and 84 recurrences (3-year recurrence-free survival rate 61.6%, 95% confidence interval 54.7% to 67.8%) in the white-light group (hazard ratio 0.94, 95% confidence interval 0.69 to 1.28; p = 0.70). Adverse event frequency was low and similar in both groups [12 (5.7%) in the photodynamic diagnosis group vs. 12 (5.5%) in the white-light group]. At 3 years, the total cost was £12,881 for photodynamic diagnosis-guided transurethral resection of bladder tumour and £12,005 for white light. There was no evidence of differences in the use of health services or total cost at 3 years. At 3 years, the quality-adjusted life-years gain was 2.094 in the photodynamic diagnosis transurethral resection of bladder tumour group and 2.087 in the white light group. The probability that photodynamic diagnosis-guided transurethral resection of bladder tumour was cost-effective was never > 30% over the range of society's cost-effectiveness thresholds. LIMITATIONS: Fewer patients than anticipated were correctly diagnosed with intermediate- to high-risk non-muscle-invasive bladder cancer before transurethral resection of bladder tumour and the ratio of intermediate- to high-risk non-muscle-invasive bladder cancer was higher than expected, reducing the number of observed recurrences and the statistical power. CONCLUSIONS: Photodynamic diagnosis-guided transurethral resection of bladder tumour did not reduce recurrences, nor was it likely to be cost-effective compared with white light at 3 years. Photodynamic diagnosis-guided transurethral resection of bladder tumour is not supported in the management of primary intermediate- to high-risk non-muscle-invasive bladder cancer. FUTURE WORK: Further work should include the modelling of appropriate surveillance schedules and exploring predictive and prognostic biomarkers. TRIAL REGISTRATION: This trial is registered as ISRCTN84013636. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 40. See the NIHR Journals Library website for further project information.

Around 7500 people are diagnosed with early-stage bladder cancer in the UK each year. Early bladder cancer is contained within the bladder and has not yet invaded the bladder's muscle wall or spread elsewhere in the body. The cancer will return (recur) in around half of people after initial treatment and they have to attend hospital for regular check-ups, with costs to both them and the NHS. The first step in treating early bladder cancer is surgery to remove the tumour. This surgery is normally performed under white light. Photodynamic diagnosis is a new technique in which a liquid is put into the patient's bladder before surgery and a blue light is used during the operation. This causes the bladder cancer to fluoresce so that it can be seen more easily by the surgeon. The Photodynamic versus white-light-guided resection of first diagnosis non-muscle-invasive bladder cancer ( PHOTO ) trial aimed to find out whether or not using photodynamic diagnosis at initial surgery would reduce how often the cancer recurred and whether or not this could reduce the cost of treating early bladder cancer. A total of 538 people with early bladder cancer who had a medium to high chance of their cancer returning after treatment were enrolled in the PHOTO trial. They were included in one of two treatment groups, at random: 269 had photodynamic surgery and 269 had standard white-light surgery. People in both groups were monitored regularly for any recurrences, with further treatment as appropriate. After 3 years, 4 out of 10 people in each group had a recurrence of their bladder cancer. We found no difference between the treatment groups in the number of people with recurrences. We found no evidence of a benefit to patients, and the total costs of photodynamic surgery were higher than those of standard white light. We therefore recommend that it is no longer used in the treatment of this group of patients.

Effectiveness and cost-effectiveness of oral nutritional supplements in frail older people who are malnourished or at risk of malnutrition: a systematic review and meta-analysis.

BACKGROUND: Current management of malnutrition can include prescribed oral nutritional supplements (ONS); however, there is uncertainty whether these supplements are effective in people who are older (≥65 years) and frail. We assessed the effectiveness, cost-effectiveness, and adherence and acceptability of ONS in frail older people who are malnourished or at risk of malnutrition. METHODS: In this systematic review and meta-analysis, five bibliographic databases (MEDLINE, EMBASE, Cochrane Library, Scopus, and CINAHL) and grey literature sources were searched from inception to Sept 13, 2021, to identify studies assessing the effectiveness and cost-effectiveness of ONS (with or without other dietary interventions) in frail older people who are malnourished or at risk of malnutrition. Multiple reviewers independently did study screening, data extraction, and risk of bias assessment. Quality was assessed using version 1.0 of the Cochrane risk of bias tool for randomised controlled trials (RCTs), and the BMJ Drummond checklist was used to assess the quality of the included cost-effectiveness study. A meta-analysis was done for the effectiveness review; for the other reviews, a narrative synthesis approach was used. This systematic review and meta-analysis was registered on PROSPERO, CRD42020170906. FINDINGS: Of 8492 records retrieved and screened, we included 11 RCTs involving 822 participants, six of which were fully or partly funded by industry. For the majority of the outcomes for which meta-analyses were possible (11/12), Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) assessments suggested that the evidence was of very low certainty. Results suggested that ONS might have a slightly positive effect on energy (kcal) intake (standardised mean difference 1·02 [95% CI 0·15 to 1·88]; I2=87%; four studies), protein intake (standardised mean difference 1·67 [-0·03 to 3·37; I2=97%; four studies), and mobility (mean difference 0·03 [0·02 to 0·04]; I2=0%; four studies), compared with standard care. Narrative syntheses suggested that the effect of ONS on quality of life, compared with standard care, was mixed. In the identified studies, there was very little information related to active components, determinants, or acceptability of interventions. One economic evaluation, done in a care home setting, showed that ONS could be cost-effective. INTERPRETATION: We found little evidence of ONS reducing malnutrition or its associated adverse outcomes in older people who are frail. High-quality, non-industry-funded, adequately powered studies reporting on short-term and long-term health outcomes, determinants, and participant characteristics are needed. FUNDING: UK National Institute of Health and Care Research (NIHR) Health Technology Assessment (NIHR128729).

The genomic landscape of pediatric acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Here, using whole-genome, exome and transcriptome sequencing of 2,754 childhood patients with ALL, we find that, despite a generally low mutation burden, ALL cases harbor a median of four putative somatic driver alterations per sample, with 376 putative driver genes identified varying in prevalence across ALL subtypes. Most samples harbor at least one rare gene alteration, including 70 putative cancer driver genes associated with ubiquitination, SUMOylation, noncoding transcripts and other functions. In hyperdiploid B-ALL, chromosomal gains are acquired early and synchronously before ultraviolet-induced mutation. By contrast, ultraviolet-induced mutations precede chromosomal gains in B-ALL cases with intrachromosomal amplification of chromosome 21. We also demonstrate the prognostic significance of genetic alterations within subtypes. Intriguingly, DUX4- and KMT2A-rearranged subtypes separate into CEBPA/FLT3- or NFATC4-expressing subgroups with potential clinical implications. Together, these results deepen understanding of the ALL genomic landscape and associated outcomes.

Special Issue "Replication and Spread of Alphaherpesviruses".

Alphaherpesviruses, one of three sub-families of the Herpesviridae, are of keen interest to biomedical scientists for several reasons [...].

Effects of vaccination status in the United States on willingness to undergo surgery during a pandemic: A prospective survey study.

PURPOSE OF THE RESEARCH: Modifiable and non-modifiable patient and hospital characteristics may affect willingness to undergo surgery during a pandemic. We hypothesized that vaccination of hospital staff and patients, type of surgery, and length of stay, would affect willingness to undergo a surgical procedure. 2006 adult participants in the United States were recruited electronically using Amazon's ® Mechanical Turk ® and answered a 26-item survey in English about hypothetical surgery, manipulating requirements for: staff vaccination, patient vaccination, surgical urgency, and time in hospital. They also answered questions about their opinions about vaccination, personal vaccination status, and demographics. PRINCIPLE RESULTS: Participants are more willing to undergo surgery if they have been vaccinated, if staff vaccinations are required, and if surgery is lifesaving and outpatient. MAJOR CONCLUSIONS: Willingness to undergo surgery varies with hospital staff and patient vaccination. This may inform policies for vaccination, boosters, and resource allocation.