Absolute quantitative and base-resolution sequencing reveals comprehensive landscape of pseudouridine across the human transcriptome.

Pseudouridine (Ψ) is one of the most abundant modifications in cellular RNA. However, its function remains elusive, mainly due to the lack of highly sensitive and accurate detection methods. Here, we introduced 2-bromoacrylamide-assisted cyclization sequencing (BACS), which enables Ψ-to-C transitions, for quantitative profiling of Ψ at single-base resolution. BACS allowed the precise identification of Ψ positions, especially in densely modified Ψ regions and consecutive uridine sequences. BACS detected all known Ψ sites in human rRNA and spliceosomal small nuclear RNAs and generated the quantitative Ψ map of human small nucleolar RNA and tRNA. Furthermore, BACS simultaneously detected adenosine-to-inosine editing sites and N1-methyladenosine. Depletion of pseudouridine synthases TRUB1, PUS7 and PUS1 elucidated their targets and sequence motifs. We further identified a highly abundant Ψ114 site in Epstein-Barr virus-encoded small RNA EBER2. Surprisingly, applying BACS to a panel of RNA viruses demonstrated the absence of Ψ in their viral transcripts or genomes, shedding light on differences in pseudouridylation across virus families.

Characterisation of HBV and co-infection with HDV and HIV through spatial transcriptomics.

Background and aims: The intrahepatic processes associated with chronic hepatitis B (CHB), especially in the context of hepatitis delta virus (HDV) and HIV co-infection, require a better understanding. Spatial transcriptomics can provide new insights into the complex intrahepatic biological processes, guiding new personalised treatments. Our aim is to evaluate this method characterising the intrahepatic transcriptional landscape, cellular composition and biological pathways in liver biopsy samples from patients with hepatitis B virus (HBV) and HDV or HIV co-infection. Method: The NanoString GeoMx digital spatial profiling platform was employed to assess expression of HBV surface antigen and CD45 in formalin-fixed paraffin-embedded (FFPE) biopsies from three treatment-naïve patients with chronic HBV and HDV or HIV co-infection. The GeoMx Human Whole Transcriptome Atlas assay quantified the expression of genes enriched in specific regions of interest (ROIs). Cell type proportions within ROIs were deconvoluted using a training matrix from the human liver cell atlas. A weighted gene correlation network analysis evaluated transcriptomic signatures across sampled regions. Results: Spatially discrete transcriptomic signatures and distinct biological pathways were associated with HBV infection/disease status and immune responses. Shared features including 'cytotoxicity' and 'B cell receptor signalling' were consistent across patients, suggesting common elements alongside individual traits. HDV/HBV co-infection exhibited upregulated genes linked to apoptosis and immune cell recruitment, whereas HIV/HBV co-infection featured genes related to interferon response regulation. Varied cellular characteristics and immune cell populations, with an abundance of γδT cells in the HDV/HBV sample, were observed within analysed regions. Transcriptional differences in hepatocyte function suggest disrupted metabolic processes in HDV/HBV co-infection potentially impacting disease progression. Conclusion: This proof-of-principle study shows the value of this platform in investigating the complex immune landscape, highlighting relevant host pathways to disease pathogenesis.

Primary splenic multicystic peritoneal mesothelioma in a young healthy male.

Multicystic peritoneal mesothelioma (BMPM) is a rare, usually benign tumor that arises from peritoneal mesothelial cells that most commonly occurs in women of reproductive age. Pathogenesis of these tumors is thought to come from chronic inflammation from prior surgery, endometriosis, trauma, or recurrent peritonitis. Here we report a case of primary splenic BMPM in a 20-year-old male with no past medical or surgical history and without any typical risk factors for this condition. He underwent an open splenectomy without complication. Pathology revealed an 18 × 4 × 11 cm3 spleen with a cyst occupying 75% of the splenic surface. Sections revealed a multilocular cyst with trabeculated walls and immunohistochemical staining positive for cytokeratin (AE1/AE3) consistent with BMPM. One year post operatively he remains asymptomatic; however, his interval computed tomography (CT) scan revealed several sub centimeter nodules that either represents small splenules or neoplastic implants. These will be followed with close interval imaging.

Economic evaluation of supplemental breast cancer screening modalities to mammography or digital breast tomosynthesis in women with heterogeneously and extremely dense breasts and average or intermediate breast cancer risk in US healthcare.

OBJECTIVE: To evaluate the cost-effectiveness of supplemental breast imaging modalities for women with heterogeneously and extremely dense breasts and average or intermediate risk of breast cancer (BC) in the USA, and analyze capacity requirements for supplemental magnetic resonance imaging (MRI) and contrast-enhanced mammography (CEM). METHODS: Clinical and economic outcomes for supplemental imaging modalities including full- and abbreviated-protocol MRI (Fp-MRI, Ab-MRI), CEM, and ultrasound (U/S) as add-on to x-ray mammography (XM) or digital breast tomosynthesis (DBT), were compared to XM or DBT alone, in a decision tree linked to a Markov chain validated by comparison with a microsimulation analysis. A Delphi panel supplemented model input parameters from the literature. A capacity model evaluated the number of additional daily scans and scanners required for Fp-MRI and CEM. RESULTS: Compared to XM or DBT alone, all supplemental imaging protocols were cost-effective. Both Fp- and Ab-MRI, and to a lesser extent CEM and U/S, yielded superior clinical outcomes to XM or DBT. Compared to XM alone, U/S and Ab-MRI had the lowest incremental cost-effectiveness ratios (ICER). For U/S, the ICER was $23,394 for the average-risk population and $13,241 for the intermediate-risk population. For CEM, the ICER was $38,423 and $23,772, respectively. For the extremely dense subpopulation with intermediate risk, supplemental screening requirements could be accommodated by conducting one Fp-MRI scan per day per existing general scanner. CONCLUSIONS: While ultrasound had the lowest ICER, MRI and CEM demonstrated the best clinical outcomes, compared to XM or DBT alone for women with dense breasts and intermediate and high risk. Existing MRI scanner capacity has the potential to meet most of the supplemental screening needs of this population.

Performance of Supplemental Imaging Modalities for Breast Cancer in Women With Dense Breasts: Findings From an Umbrella Review and Primary Studies Analysis.

Breast cancer screening performance of supplemental imaging modalities by breast density and breast cancer risk has not been widely studied, and the optimal choice of modality for women with dense breasts remains unclear in clinical practice and guidelines. This systematic review aimed to assess breast cancer screening performance of supplemental imaging modalities for women with dense breasts, by breast cancer risk. Systematic reviews (SRs) in 2000 to 2021, and primary studies in 2019 to 2021, on outcomes of supplemental screening modalities (digital breast tomography [DBT], MRI (full/abbreviated protocol), contrast enhanced mammography (CEM), ultrasound (hand-held [HHUS]/automated [ABUS]) in women with dense breasts (BI-RADS C&D) were identified. None of the SRs analyzed outcomes by cancer risk. Meta-analysis of the primary studies was not feasible due to lack of studies (MRI, CEM, DBT) or methodological heterogeneity (ultrasound); therefore, findings were summarized narratively. For average risk, a single MRI trial reported a superior screening performance (higher cancer detection rate [CDR] and lower interval cancer rate [ICR]) compared to HHUS, ABUS and DBT. For intermediate risk, ultrasound was the only modality assessed, but accuracy estimates ranged widely. For mixed risk, a single CEM study reported the highest CDR, but included a high proportion of women with intermediate risk. This systematic review does not allow a complete comparison of supplemental screening modalities for dense breast populations by breast cancer risk. However, the data suggest that MRI and CEM might generally offer superior screening performance versus other modalities. Further studies of screening modalities are urgently required.

"I don't have chronic back pain anymore": Patient Experiences in Pain Reprocessing Therapy for Chronic Back Pain.

In a recently published randomized controlled trial, two-thirds of the patients receiving a novel psychological treatment, pain reprocessing therapy (PRT), reported elimination or near-elimination of chronic back pain. The mechanisms of PRT and related treatments remain poorly understood but are hypothesized to center on pain reappraisal, fear reduction, and exposure-potentiated extinction. Here, we investigated treatment mechanisms from the participants' perspective. A sample of 32 adults with chronic back pain who received PRT completed semi-structured posttreatment interviews about their treatment experiences. The interviews were analyzed with multiphase thematic analysis. The analyses identified 3 major themes reflecting participants' understanding of how PRT led to pain relief: 1) reappraisal to reduce fear of pain, which included guiding participants to relate to pain as a helpful indicator, overcoming pain-related fear and avoidance, and reconceptualizing pain as a "sensation;" 2) the link between pain, emotions, and, stress, which included gaining insight into these connections and resolving difficult emotions; and 3) social connections, which included patient-provider alliance, therapist belief in the treatment model, and peer models of recovery from chronic pain. Our findings support the hypothesized mechanisms of PRT centered on pain reappraisal and fear reduction, but also highlight additional processes from the participants' perspective, including a focus on emotions and relationships. This study underscores the value of qualitative research methods in illuminating the mechanisms of novel pain therapies. PERSPECTIVE: This article presents participants' perspectives on their experience engaging in a novel psychotherapy for chronic pain, PRT. Through pain reappraisal, linking pain, emotions, and stress, and connecting with their therapist and peers, many participants reported an elimination or near-elimination of their chronic back pain with therapy.

Evaluation of health economic impact of initial diagnostic modality selection for colorectal cancer liver metastases in suspected patients in China, Japan and the USA.

AIMS: To compare cost offsets and contributing factors (false-negative rates and confirmatory imaging requirements, potentially leading to longer waiting times for diagnosis) as well as long-term cost effectiveness associated with the diagnostic and treatment pathways for colorectal cancer liver metastases (CRCLM) in the US, Japan, and China according to initial imaging modality used. Gadoxetate disodium (ethoxylbenzyl-diethylenetriaminepentaacetic acid)-enhanced magnetic resonance imaging (EOB-MRI) was compared to multidetector computed tomography (MDCT), extracellular contrast media enhanced-MRI (ECCM-MRI) (the US and China only) and contrast-enhanced ultrasound (CEUS). MATERIALS AND METHODS: Decision tree models were developed to simulate the clinical pathway, from first diagnostic test to initial treatment decision, based on local clinical guidelines and validated by experts. Input data were derived from the literature (up to 31st December 2020) as well as from interviews with local experts. A Markov model extension was built to evaluate the number of false-negative patients and associated costs, over a lifetime horizon. RESULTS: The decision-tree models showed that, increasing proportionate use of initial EOB-MRI resulted in a cost-offset per patient (excluding false-negative patients) in all countries (USD 201 for the US, JPY 6,284 for Japan and CNY 446 for China) driven by reductions in follow-on diagnostic procedures and unnecessary treatment. The use of EOB-MRI was also associated with a shorter average waiting time to a final diagnosis and treatment decision compared to MDCT, ECCM-MRI and CEUS. The Markov model showed that with an increase in EOB-MRI use, there are fewer false-negative diagnoses over a lifetime horizon. In all three countries, the incremental cost-effectivenes ratio (ICER) was below standard willingness-to-pay thresholds. CONCLUSION: The findings of these models demonstrate that use of EOB-MRI early in the diagnostic pathway for CRCLM results in short-term cost savings, as well as being cost effective in the long term.

BT595, a 10% Human Normal Immunoglobulin, for Replacement Therapy of Primary Immunodeficiency Disease: Results of a Subcohort Analysis in Children.

PURPOSE: To assess the efficacy, pharmacokinetics, and safety of a new, highly purified 10% IVIg (BT595, Yimmugo®) administered in children with PID. METHODS: This was an open-label, prospective, uncontrolled, multicenter Phase III pivotal trial. Among the 67 subjects in the trial were 18 pediatric patients aged 2 to 17 years with diagnosis of PID included in this analysis. They received doses between 0.2 and 0.8 g/kg body weight for approximately 12 months at intervals of either 3 or 4 weeks. Dosage and dosing interval were based on each patient's pre-trial infusion schedule. The rates of acute serious bacterial infections (SBI), secondary efficacy, safety, and pharmacokinetic outcomes were evaluated. RESULTS: No SBI occurred in the pediatric population. Two hundred sixty infusions were administered to the 18 pediatric patients. The mean (SD) IgG trough level was 8.55 (1.67) g/L at baseline and 8.84 (2.17) g/L at the follow-up visit after the last BT595 infusion. At the single infusions respectively, the average mean IgG trough levels ranged between 8.52 and 10.58 g/L. More than 85% of all infusions administered were not associated with any infusional AE (start during or within 72 h post-infusion). None of the severe or serious AEs were related to the investigational medicinal product (IMP). No premedication was used. Thirteen children reached a maximum infusion rate between > 2.0 and 8 mL/kg/h; no AE with an onset during the infusion occurred at these infusion rates. CONCLUSION: BT595 is effective, convenient, well tolerated, and safe for the treatment of children with PID. TRIAL REGISTRATION: EudraCT: 2015-003652-52; NCT02810444, registered June 23, 2016.

A course in medical device design & commercialization for medical students pursuing surgical fields.

BACKGROUND: The modern surgeon faces an ever-changing landscape of procedural innovation. The demands of present-day healthcare highlight the importance of successfully developing new medical devices and technologies. This effort requires multidisciplinary collaborations of professionals ranging from manufacturers and engineers to researchers and healthcare providers. Surgeons regularly interact with complex equipment and user interfaces without substantial formal education on their design and development. The objective of this study was to ascertain the impact of a 10-week BME course into a medical school curriculum on surgery-bound students' knowledge of product design and gauge their ability to develop an actual product to meet a real need in a surgical field. METHODS: A Medical Device Design and Commercialization co-enrolled elective course was offered to medical students at a single institution. Five students with an expressed surgical and procedural interest were enrolled. At the beginning of the course, they were tasked with developing a product to meet a clinical need they observed. At the conclusion of the course, students filled out a questionnaire about their level of comfort and knowledge of the material using a 5-point Likert scale. This survey was administered to a control group of medical students who did not take the course. RESULTS: The BME student cohort was able to successfully identify a post-operative need, develop a prototype of a novel device, and present their product to attending surgeons. A total of 35 survey entries were received: five from the experimental group and 30 from the comparison group. The experimental group scored higher than the comparison group for all survey questions and reached the level of statistical significance in 13 of the 15 questions (p < 0.05). Survey respondents reported similar degrees of knowledge and comfort in recognizing unmet needs in a hospital setting and formulating a comprehensive statement describing them. CONCLUSION: The principles of biomedical engineering are integral to advancing the field of surgery. Presently, a small cohort of medical students/residents successfully acquired and applied basic BME concepts in a relatively short period of time relative to other training paradigms. Our findings also suggest medical students recognize unmet needs in the hospital setting, and those who completed a BME course felt more able to take steps to meet those needs. Early integration of biomedical engineering principles in medical training may help produce more innovative and well-rounded surgeons.

Evaluation of a National Quality Improvement Collaborative for Improving Cancer Screening.

Importance: Cancer screening deficits during the first year of the COVID-19 pandemic were found to persist into 2021. Cancer-related deaths over the next decade are projected to increase if these deficits are not addressed. Objective: To assess whether participation in a nationwide quality improvement (QI) collaborative, Return-to-Screening, was associated with restoration of cancer screening. Design, Setting, and Participants: Accredited cancer programs electively enrolled in this QI study. Project-specific targets were established on the basis of differences in mean monthly screening test volumes (MTVs) between representative prepandemic (September 2019 and January 2020) and pandemic (September 2020 and January 2021) periods to restore prepandemic volumes and achieve a minimum of 10% increase in MTV. Local QI teams implemented evidence-based screening interventions from June to November 2021 (intervention period), iteratively adjusting interventions according to their MTVs and target. Interrupted time series analyses was used to identify the intervention effect. Data analysis was performed from January to April 2022. Exposures: Collaborative QI support included provision of a Return-to-Screening plan-do-study-act protocol, evidence-based screening interventions, QI education, programmatic coordination, and calculation of screening deficits and targets. Main Outcomes and Measures: The primary outcome was the proportion of QI projects reaching target MTV and counterfactual differences in the aggregate number of screening tests across time periods. Results: Of 859 cancer screening QI projects (452 for breast cancer, 134 for colorectal cancer, 244 for lung cancer, and 29 for cervical cancer) conducted by 786 accredited cancer programs, 676 projects (79%) reached their target MTV. There were no hospital characteristics associated with increased likelihood of reaching target MTV except for disease site (lung vs breast, odds ratio, 2.8; 95% CI, 1.7 to 4.7). During the preintervention period (April to May 2021), there was a decrease in the mean MTV (slope, -13.1 tests per month; 95% CI, -23.1 to -3.2 tests per month). Interventions were associated with a significant immediate (slope, 101.0 tests per month; 95% CI, 49.1 to 153.0 tests per month) and sustained (slope, 36.3 tests per month; 95% CI, 5.3 to 67.3 tests per month) increase in MTVs relative to the preintervention trends. Additional screening tests were performed during the intervention period compared with the prepandemic period (170 748 tests), the pandemic period (210 450 tests), and the preintervention period (722 427 tests). Conclusions and Relevance: In this QI study, participation in a national Return-to-Screening collaborative with a multifaceted QI intervention was associated with improvements in cancer screening. Future collaborative QI endeavors leveraging accreditation infrastructure may help address other gaps in cancer care.

17ß-Oestradiol Protects from Hepatitis C Virus Infection through Induction of Type I Interferon.

BACKGROUND AND AIMS: Sex hormones are widely recognised to act as protective factors against several viral infections. Specifically, females infected by the hepatitis C virus display higher clearance rates and reduced disease progression than those found in males. Through modulation of particle release and spread, 17ß-oestradiol controls HCV's life cycle. We investigated the mechanism(s) behind oestrogen's antiviral effect. METHODS: We used cell culture-derived hepatitis C virus in in vitro assays to evaluate the effect of 17ß-oestradiol on the innate immune response. Host immune responses were evaluated by enumerating gene transcripts via RT-qPCR in cells exposed to oestrogen in the presence or absence of viral infection. Antiviral effects were determined by focus-forming unit assay or HCV RNA quantification. RESULTS: Stimulation of 17ß-oestradiol triggers a pre-activated antiviral state in hepatocytes, which can be maintained for several hours after the hormone is removed. This induction results in the elevation of several innate immune genes, such as interferon alpha and beta, tumour necrosis factor, toll-like receptor 3 and interferon regulatory factor 5. We demonstrated that this pre-activation of immune response signalling is not affected by a viral presence, and the antiviral state can be ablated using an interferon-alpha/beta receptor alpha inhibitor. Finally, we proved that the oestrogen-induced stimulation is essential to generate an antiviral microenvironment mediated by activation of type I interferons. CONCLUSION: Resulting in viral control and suppression, 17ß-oestradiol induces an interferon-mediated antiviral state in hepatocytes. Oestrogen-stimulated cells modulate the immune response through secretion of type I interferon, which can be countered by blocking interferon-alpha/beta receptor alpha signalling.

Evaluating information loss in the National Cancer Database from cases lost to follow-up.

BACKGROUND AND OBJECTIVES: Cancer registries must focus on data capture which returns value while reducing resource burden with minimal loss of data. Identifying the optimum length of follow-up data collection for patients with cancer achieves this goal. METHODS: A two-step analysis using entropy calculations to assess information gain for each follow-up year, and second-order differences to compare survival outcomes between the defined follow-up periods and lifetime follow-up. A total of 391 567 adult cases, deidentified in the National Cancer Database and diagnosed in 1989. Comparisons examined a subset of 61 908 lung cancer cases, 48 387 colon and rectal cancer cases, and 64 134 breast cancer cases in adults. A total of 4133 pediatric cases were diagnosed in 1989 examining 1065 leukemia cases and 494 lymphoma cases. RESULTS: Annual increases in information gain fell below 1% after 16 years of follow-up for adult cases and 9 years for pediatric cases. Comparison of second-order differences showed 62% of the comparisons were similar between 15 years and lifetime follow-up when examining restricted mean survival time. In addition, 90% of the comparisons were statistically similar when comparing hazard ratios. CONCLUSIONS: Survival analysis using 15 years postdiagnosis follow-up showed minimal differences in information gain compared to lifetime follow-up.

Evaluation of the health economic impact of initial diagnostic modality selection in patients suspected of having HCC in China and the USA.

AIMS: To compare relative costs associated with the diagnostic pathways for hepatocellular carcinoma (HCC) in the US and China according to the initial imaging modality used. Gadoxetate disodium (ethoxylbenzyl-diethylenetriaminepentaacetic acid)-enhanced magnetic resonance imaging (EOB-MRI) was compared to contrast-enhanced multidetector computed tomography (MDCT), extracellular contrast media enhanced-MRI (ECCM-MRI) and contrast-enhanced ultrasound (CEUS). MATERIALS AND METHODS: Decision tree models were developed to simulate the clinical pathway, based on local clinical guidelines, and validated by experts. Input data were derived from the literature (up to 31 December 2020) as well as from interviews with local experts. RESULTS: The models showed that compared to alternative initial imaging modalities, EOB-MRI was associated with higher diagnostic accuracy (fewer false-positive and fewer false-negative results). Increasing proportionate use of EOB-MRI resulted in a cost offset per patient (excluding false-negative patients) in both the US (USD 337) and China (CNY 1,443), driven by reductions in scan costs and unnecessary treatment costs. The use of EOB-MRI was also associated with a shorter average waiting time for a final diagnosis and treatment decision for patients compared to MDCT, ECCM-MRI, and CEUS. CONCLUSION: The findings of these models demonstrate that EOB-MRI is the most accurate and rapid imaging modality for the diagnosis of HCC in the US and China, resulting in cost offsets that may benefit the healthcare system.

Efficacy, safety and pharmacokinetics of a new 10% normal human immunoglobulin for intravenous infusion, BT595, in children and adults with primary immunodeficiency disease.

BACKGROUND AND OBJECTIVES: To evaluate the efficacy, safety and pharmacokinetics of a new, highly purified 10% IVIg (BT595, Yimmugo®) administered in children and adults with Primary immunodeficiency diseases (PID). MATERIALS AND METHODS: Prospective, uncontrolled, multicentre Phase III trial. Patients aged 2 to <76 years with PID were switched from their pre-trial IVIg replacement therapy to BT595. In all, 67 patients (49 adults, 18 children) received doses between 0.2 and 0.8 g/kg body weight for approximately 12 months at intervals of 3 or 4 weeks. Dosing and dosing intervals were based on each patient's pre-trial infusion schedule. The primary end point was the rate of acute serious bacterial infections (SBIs); secondary efficacy, safety and pharmacokinetic outcomes were also evaluated. RESULTS: The primary efficacy end point was met, and the unadjusted SBI rate was 0.01 per subject-year (adjusted SBI rate 0.015 per subject-year, with an upper limit of the one-sided 99% confidence interval of 0.151). A single adult patient experienced one event classified as an SBI. All secondary end points, including those related to infections, supported the efficacy. Infusion rates were increased up to 8 ml/kg/h. Overall, 8% of infusions were associated with ≥1 infusional adverse event (AE) (start during or within 72 h post-infusion), comprising mainly headache (2.4%), fatigue (0.9%) and nausea (0.5%). There were no infusional AEs at infusion rates of >4.0 ml/kg/h, and only one patient required a single premedication. The observed patterns, severity and frequency of treatment-emergent adverse events are consistent with the established safety profile for IVIgs and did not show clinically relevant differences between all age groups. CONCLUSION: BT595 is effective, safe and well tolerated for treating patients with PID.

A national quality improvement study identifying and addressing cancer screening deficits due to the COVID-19 pandemic.

BACKGROUND: Cancer-related deaths over the next decade are expected to increase due to cancer screening deficits associated with the coronavirus disease 2019 (COVID-19) pandemic. Although national deficits have been quantified, a structured response to identifying and addressing local deficits has not been widely available. The objectives of this report are to share preliminary data on monthly screening deficits in breast, colorectal, lung, and cervical cancers across diverse settings and to provide online materials from a national quality improvement (QI) study to help other institutions to address local screening deficits. METHODS: This prospective, national QI study on Return-to-Screening enrolled 748 accredited cancer programs in the United States from April through June 2021. Local prepandemic and pandemic monthly screening test volumes (MTVs) were used to calculate the relative percent change in MTV to describe the monthly screening gap. RESULTS: The majority of facilities reported monthly screening deficits (colorectal cancer, 80.6% [n = 104/129]; cervical cancer, 69.0% [n = 20/29]; breast cancer, 55.3% [n = 241/436]; lung cancer, 44.6% [n = 98/220]). Overall, the median relative percent change in MTV ranged from -17.7% for colorectal cancer (interquartile range [IQR], -33.6% to -2.8%), -6.8% for cervical cancer (IQR, -29.4% to 1.7%), -1.6% for breast cancer (IQR, -9.6% to 7.0%), and 1.2% for lung cancer (IQR, -16.9% to 19.0%). Geographic differences were not observed. There were statistically significant differences in the percent change in MTV between institution types for colorectal cancer screening (P = .02). CONCLUSION: Cancer screening is still in need of urgent attention, and the screening resources made available online may help facilities to close critical gaps and address screenings missed in 2020. LAY SUMMARY: Question: How can the effects of the coronavirus disease 2019 pandemic on cancer screening be mitigated? FINDINGS: When national resources were provided, including methods to calculate local screening deficits, 748 cancer programs promptly enrolled in a national Return-to-Screening study, and the majority identified local screening deficits, most notably in colorectal cancer. Using these results, 814 quality improvement projects were initiated with the potential to add 70,000 screening tests in 2021. Meaning: Cancer screening is still in need of urgent attention, and the online resources that we provide may help to close critical screening deficits.

Inhibition of the master regulator of Listeria monocytogenes virulence enables bacterial clearance from spacious replication vacuoles in infected macrophages.

A hallmark of Listeria (L.) monocytogenes pathogenesis is bacterial escape from maturing entry vacuoles, which is required for rapid bacterial replication in the host cell cytoplasm and cell-to-cell spread. The bacterial transcriptional activator PrfA controls expression of key virulence factors that enable exploitation of this intracellular niche. The transcriptional activity of PrfA within infected host cells is controlled by allosteric coactivation. Inhibitory occupation of the coactivator site has been shown to impair PrfA functions, but consequences of PrfA inhibition for L. monocytogenes infection and pathogenesis are unknown. Here we report the crystal structure of PrfA with a small molecule inhibitor occupying the coactivator site at 2.0 Å resolution. Using molecular imaging and infection studies in macrophages, we demonstrate that PrfA inhibition prevents the vacuolar escape of L. monocytogenes and enables extensive bacterial replication inside spacious vacuoles. In contrast to previously described spacious Listeria-containing vacuoles, which have been implicated in supporting chronic infection, PrfA inhibition facilitated progressive clearance of intracellular L. monocytogenes from spacious vacuoles through lysosomal degradation. Thus, inhibitory occupation of the PrfA coactivator site facilitates formation of a transient intravacuolar L. monocytogenes replication niche that licenses macrophages to effectively eliminate intracellular bacteria. Our findings encourage further exploration of PrfA as a potential target for antimicrobials and highlight that intra-vacuolar residence of L. monocytogenes in macrophages is not inevitably tied to bacterial persistence.

Twenty-Five Years of Cancer Follow-Up; Is the Data Worth the Effort?

BACKGROUND: Substantial resources are dedicated to long-term follow-up within cancer registries; however, the completeness of these data is poorly characterized. Our objectives were to quantify long-term cancer follow-up data completeness and the effort required to collect these data using the National Cancer Database (NCDB). METHODS: To quantify data completeness, patients diagnosed with cancer in 1989 were identified in the NCDB and loss to follow-up rates were assessed for 25 years after diagnosis. To quantify data collection effort, patients diagnosed from 1989 to 2014 who were alive and eligible for follow-up in 2014 were identified and the effort to perform patient follow-up was obtained via a survey of tumor registrars. The effort to perform follow-up beyond various intervals after diagnosis was calculated. RESULTS: In total, 484,201 patients at 958 hospitals were diagnosed with cancer in 1989. After 5 years, 6.5% of patients were lost to follow-up (13.1% of living patients), 50.3% were deceased, and 43.2% had ongoing follow-up. After 15 years, 22.9% were lost to follow-up (68.7% of living patients), 66.7% were deceased, and 10.5% had ongoing follow-up. By 25 years, loss to follow-up increased to 28.6% (93.7% of living patients), 69.5% were deceased, and 1.9% had ongoing follow-up. In 2014, 522,838 h were spent performing follow-up for 2,091,353 patients at 1456 hospitals who were >15 years from their initial cancer diagnosis. CONCLUSIONS: While 5-year follow-up is excellent in the NCDB, loss to follow-up increases over time. The impact of curtailing data collection is under investigation and follow-up duration requirements will be re-evaluated.

What Are the Risk Factors for Infection After Operative Treatment of Peritalar Fracture Dislocations?

OBJECTIVE: To assess the risk factors associated with deep infection after operative treatment of peritalar fracture dislocations. DESIGN: A retrospective study was performed to identify patients who had operative treatment of a peritalar fracture dislocation over an 11-year period (2008-2019). SETTING: Level 1 trauma center. PARTICIPANTS: Patients were identified by review of all surgical billing that included open reduction of peritalar dislocation. Minimum follow-up for inclusion was 3 months or the outcome of interest. A total of 178 patients were identified, and 154 patients met inclusion criteria. MAIN OUTCOME: The primary outcome was deep infection, defined as return to the operating room for debridement with positive cultures. RESULTS: A total of 19 (12.3%) patients developed a postoperative deep infection. The most common associated fractures were talus (47%), calcaneus (33%), and fibula (9%) fractures. The infected group was significantly older (47.2 vs. 39.5 years, P = 0.03). Patients undergoing operative management for peritalar fracture dislocations with current smoking were found to have significantly higher odds of postoperative deep infection (74 vs. 34%, adjusted odds ratio = 7.4, 95% confidence interval, 2.3-24.1, P = 0.001). There was a significantly higher risk of infection in patients with a Gustilo-Anderson type 3 open fracture (32 vs. 12%, adjusted odds ratio = 5.7, 95% confidence interval, 1.6-20.3, P = 0.007). The infected group had high rates of below knee amputation when compared with the group without infection (47 vs. 1%, P < 0.001). CONCLUSION: In our retrospective study, risk factors for infection after peritalar fracture dislocation included older age, smoking, and Gustilo-Anderson type 3 open fracture. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.