Discontinuous L-binding motifs in the transactivation domain of the vesicular stomatitis virus P protein are required for terminal de novo transcription initiation by the L protein.

The phospho- (P) protein, the co-factor of the RNA polymerase large (L) protein, of vesicular stomatitis virus (VSV, a prototype of nonsegmented negative-strand RNA viruses) plays pivotal roles in transcription and replication. However, the precise mechanism underlying the transcriptional transactivation by the P protein has remained elusive. Here, using an in vitro transcription system and a series of deletion mutants of the P protein, we mapped a region encompassing residues 51-104 as a transactivation domain (TAD) that is critical for terminal de novo initiation, the initial step of synthesis of the leader RNA and anti-genome/genome, with the L protein. Site-directed mutagenesis revealed that conserved amino acid residues in three discontinuous L-binding sites within the TAD are essential for the transactivation activity of the P protein or important for maintaining its full activity. Importantly, relative inhibitory effects of TAD point mutations on synthesis of the full-length leader RNA and mRNAs from the 3'-terminal leader region and internal genes, respectively, of the genome were similar to those on terminal de novo initiation. Furthermore, any of the examined TAD mutations did not alter the gradient pattern of mRNAs synthesized from internal genes, nor did they induce the production of readthrough transcripts. These results suggest that these TAD mutations impact mainly terminal de novo initiation but rarely other steps (e.g., elongation, termination, internal initiation) of single-entry stop-start transcription. Consistently, the mutations of the essential or important amino acid residues within the P TAD were lethal or deleterious to VSV replication in host cells. IMPORTANCE RNA-dependent RNA polymerase L proteins of nonsegmented negative-strand RNA viruses belonging to the Mononegavirales order require their cognate co-factor P proteins or their counterparts for genome transcription and replication. However, exact roles of these co-factor proteins in modulating functions of L proteins during transcription and replication remain unknown. In this study, we revealed that three discrete L-binding motifs within a transactivation domain of the P protein of vesicular stomatitis virus, a prototypic nonsegmented negative-strand RNA virus, are required for terminal de novo initiation mediated by the L protein, which is the first step of synthesis of the leader RNA as well as genome/anti-genome.

Clinical Significance of Background Parenchymal Enhancement in Breast Cancer Risk Stratification.

BACKGROUND: Background parenchymal enhancement (BPE) is an established breast cancer risk factor. However, the relationship between BPE levels and breast cancer risk stratification remains unclear. PURPOSE: To evaluate the clinical relationship between BPE levels and breast cancer risk with covariate adjustments for age, ethnicity, and hormonal status. STUDY TYPE: Retrospective. POPULATION: 954 screening breast MRI datasets representing 721 women divided into four cohorts: women with pathogenic germline breast cancer (BRCA) mutations (Group 1, N = 211), women with non-BRCA germline mutations (Group 2, N = 60), women without high-risk germline mutations but with a lifetime breast cancer risk of ≥20% using the Tyrer-Cuzick model (Group 3, N = 362), and women with <20% lifetime risk (Group 4, N = 88). FIELD STRENGTH/SEQUENCE: 3 T/axial non-fat-saturated T1, short tau inversion recovery, fat-saturated pre-contrast, and post-contrast T1-weighted images. ASSESSMENT: Data on age, body mass index, ethnicity, menopausal status, genetic predisposition, and hormonal therapy use were collected. BPE levels were evaluated by two breast fellowship-trained radiologists independently in accordance with BI-RADS, with a third breast fellowship-trained radiologist resolving any discordance. STATISTICAL TESTS: Propensity score matching (PSM) was utilized to adjust covariates, including age, ethnicity, menopausal status, hormonal treatments, and prior bilateral oophorectomy. The Mann-Whitney U test, chi-squared test, and univariate and multiple logistic regression analysis were performed, with an odds ratio (OR) and corresponding 95% confidence interval. Weighted Kappa statistic was used to assess inter-reader variation. A P value <0.05 indicated a significant result. RESULTS: In the assessment of BPE, there was substantial agreement between the two interpreting radiologists (κ = 0.74). Patient demographics were not significantly different between patient groups after PSM. The BPE of Group 1 was significantly lower than that of Group 4 and Group 3 among premenopausal women. In estimating the BPE level, the OR of gene mutations was 0.35. DATA CONCLUSION: Adjusting for potential confounders, the BPE level of premenopausal women with BRCA mutations was significantly lower than that of non-high-risk women. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 3.

Quantitative assessment of background parenchymal enhancement is associated with lifetime breast cancer risk in screening MRI.

OBJECTIVES: To compare the quantitative background parenchymal enhancement (BPE) in women with different lifetime risks and BRCA mutation status of breast cancer using screening MRI. MATERIALS AND METHODS: This study included screening MRI of 535 women divided into three groups based on lifetime risk: nonhigh-risk women, high-risk women without BRCA mutation, and BRCA1/2 mutation carriers. Six quantitative BPE measurements, including percent enhancement (PE) and signal enhancement ratio (SER), were calculated on DCE-MRI after segmentation of the whole breast and fibroglandular tissue (FGT). The associations between lifetime risk factors and BPE were analyzed via linear regression analysis. We adjusted for risk factors influencing BPE using propensity score matching (PSM) and compared the BPE between different groups. A two-sided Mann-Whitney U-test was used to compare the BPE with a threshold of 0.1 for multiple testing issue-adjusted p values. RESULTS: Age, BMI, menopausal status, and FGT level were significantly correlated with quantitative BPE based on the univariate and multivariable linear regression analyses. After adjusting for age, BMI, menopausal status, hormonal treatment history, and FGT level using PSM, significant differences were observed between high-risk non-BRCA and BRCA groups in PEFGT (11.5 vs. 8.0%, adjusted p = 0.018) and SERFGT (7.2 vs. 9.3%, adjusted p = 0.066). CONCLUSION: Quantitative BPE varies in women with different lifetime breast cancer risks and BRCA mutation status. These differences may be due to the influence of multiple lifetime risk factors. Quantitative BPE differences remained between groups with and without BRCA mutations after adjusting for known risk factors associated with BPE. CLINICAL RELEVANCE STATEMENT: BRCA germline mutations may be associated with quantitative background parenchymal enhancement, excluding the effects of known confounding factors. This finding can provide potential insights into the cancer pathophysiological mechanisms behind lifetime risk models. KEY POINTS: Expanding understanding of breast cancer pathophysiology allows for improved risk stratification and optimized screening protocols. Quantitative BPE is significantly associated with lifetime risk factors and differs between BRCA mutation carriers and noncarriers. This research offers a possible understanding of the physiological mechanisms underlying quantitative BPE and BRCA germline mutations.

Effect of sleep disturbance on biomarkers related to the development of adverse health outcomes: A systematic review of the human literature.

Literature suggests that unrestricted and undisturbed sleep is vital for basic human function and performance; however, it is unclear as to what amount of sleep disturbance leads to dysregulation in biomarkers, which may underscore the development of adverse health effects. This systematic review aims to identify the amount of sleep disturbance that contributes to biomarker changes as a potential precursor to the development of adverse health effects. English-language comparative studies available in PubMed, Cochrane Central, EMBASE, and CINAHL databases from 1 January 1980 to 31 July 2021 were searched. Where possible, random-effects meta-analyses were used to examine the effect of sleep disturbances on adverse health effects. The risk of bias of individual studies was assessed using the Cochrane Risk of Bias Tool and the Risk of Bias of Nonrandomised Studies - of Exposures instruments and the certainty of the body of evidence for each outcome was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. The search identified 92 primary studies reporting on blood pressure, hypertension, heart rate, cardiac arrhythmia, cardiac output, waist circumference, cortisol, adrenaline, noradrenaline, immune system markers, glucose, insulin, cholesterol, and triglyceride levels. Although some meta-analyses suggested there may be an association between sleep disturbances and certain outcomes, the certainty in the evidence was very low due to concerns with risk of bias, inconsistency across exposures, populations, and imprecision in the estimates of effects. Further research is needed to explore the point at which types, levels and duration of sleep disturbances may begin to increase the risk of developing adverse health outcomes to inform and tailor health interventions.

Temporarily implanted nitinol device versus prostatic urethral lift for minimally invasive surgical treatment of benign prostatic hyperplasia with lower urinary tract symptoms: a matching-adjusted indirect comparison.

INTRODUCTION: To evaluate the safety and efficacy of the temporarily implanted nitinol device (iTind) versus prostatic urethral lift (PUL) for minimally invasive surgical treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia in a matching-adjusted indirect comparison (MAIC). MATERIALS AND METHODS: Seven clinical trials were identified via a systematic literature review. Individual patient data from iTind trials and aggregated data from PUL trials were used in the MAIC. Safety and efficacy outcomes at 12 months post-treatment were compared between the adjusted iTind population and the pooled PUL population. RESULTS: iTind patients were significantly less likely than PUL patients to experience treatment-related adverse events within 3 months (25.0% vs. 79.8%; p < 0.001), including dysuria (17.8% vs. 34.7%; p = 0.001), hematuria (12.0% vs. 25.9%; p = 0.002), and pain (9.5% vs. 18.7%; p = 0.023). Rates of treatment-related adverse events from 3 to 12 months were also significantly lower among iTind than PUL patients (2.6% vs. 24.4%; p < 0.001). iTind and PUL efficacy outcomes were statistically equivalent on changes from baseline to 12 months on the International Prostate Symptom Score, quality of life, Qmax, post-void residual volume, and the Sexual Health Inventory for Men (all p > 0.05). CONCLUSIONS: This MAIC found superior safety and reduced risks of early and later treatment-related adverse events with iTind versus PUL. The 12-month efficacy was equivalent on subjective and objective urinary and sexual health metrics. This study finds that the iTind temporary device provides equivalent efficacy with lower adverse event risks versus the PUL permanent implants for patients with benign prostatic hyperplasia with lower urinary tract symptoms.

Physical activity interventions for cancer-related fatigue: A scoping review of randomized controlled trials from a Nursing Science Precision Health Model perspective.

BACKGROUND: The Nursing Science Precision Health (NSPH) Model has the potential to guide research on the development, testing, and targeting of interventions. PURPOSE: This scoping review examines the relationship between physical activity (PA) and cancer-related fatigue (CRF) within the context of the NSPH Model. METHODS: The Joanna Briggs Institute scoping review methodology and Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guided this review. We included randomized controlled trials in people with cancer that investigated PA interventions and measured change in CRF as an outcome. DISCUSSION: A total of 181 studies met the eligibility criteria. Over 20 different instruments were used to measure CRF. The most common PA interventions were strength training (48%), walking (36%), cycling (26%), and yoga (15%). A limited number of studies reported phenotypic characteristics (32/181, 17%) or biomarkers (31/181, 17%) associated with CRF. CONCLUSION: This scoping review identified the body of existing research exploring CRF and PA from a precision health perspective.

Epb41l5 interacts with Iqcb1 and regulates ciliary function in zebrafish embryos.

Erythrocyte protein band 4.1 like 5 (EPB41L5) is an adaptor protein beneath the plasma membrane that functions to control epithelial morphogenesis. Here we report a previously uncharacterized role of EPB41L5 in controlling ciliary function. We found that EPB41L5 forms a complex with IQCB1 (previously known as NPHP5), a ciliopathy protein. Overexpression of EPB41L5 reduced IQCB1 localization at the ciliary base in cultured mammalian epithelial cells. Conversely, epb41l5 knockdown increased IQCB1 localization at the ciliary base. epb41l5-deficient zebrafish embryos or embryos expressing C-terminally modified forms of Epb41l5 developed cilia with reduced motility and exhibited left-right patterning defects, an outcome of abnormal ciliary function. We observed genetic synergy between epb41l5 and iqcb1. Moreover, EPB41L5 decreased IQCB1 interaction with CEP290, another ciliopathy protein and a component of the ciliary base and centrosome. Together, these observations suggest that EPB41L5 regulates the composition of the ciliary base and centrosome through IQCB1 and CEP290.

Utilization and outcomes of extracorporeal CO2 removal (ECCO2 R): Systematic review and meta-analysis of arterio-venous and veno-venous ECCO2 R approaches.

INTRODUCTION: Extracorporeal carbon dioxide removal (ECCO2 R) provides respiratory support to patients suffering from hypercapnic respiratory failure by utilizing an extracorporeal shunt and gas exchange membrane to remove CO2 from either the venous (VV-ECCO2 R) or arterial (AV-ECCO2 R) system before return into the venous site. AV-ECCO2 R relies on the patient's native cardiac function to generate pressures needed to deliver blood through the extracorporeal circuit. VV-ECCO2 R utilizes a mechanical pump and can be used to treat patients with inadequate native cardiac function. We sought to evaluate the existing evidence comparing the subgroups of patients supported on VV and AV-ECCO2 R devices. METHODS: A literature search was performed to identify all relevant studies published between 2000 and 2019. Demographic information, medical indications, perioperative variables, and clinical outcomes were extracted for systematic review and meta-analysis. RESULTS: Twenty-five studies including 826 patients were reviewed. 60% of patients (497/826) were supported on VV-ECCO2 R. The most frequent indications were acute respiratory distress syndrome (ARDS) [69%, (95%CI: 53%-82%)] and chronic obstructive pulmonary disease (COPD) [49%, (95%CI: 37%-60%)]. ICU length of stay was significantly shorter in patients supported on VV-ECCO2 R compared to AV-ECCO2 R [15 (95%CI: 7-23) vs. 42 (95%CI: 17-67) days, p = 0.05]. In-hospital mortality was not significantly different [27% (95%CI: 18%-38%) vs. 36% (95%CI: 24%-51%), p = 0.26]. CONCLUSION: Both VV and AV-ECCO2 R provided clinically meaningful CO2 removal with comparable mortality.

Superficial angiomyxoma of the breast in a 16-year-old girl without carney's complex: A case report.

Superficial angiomyxoma (SA) is a rare benign soft-tissue tumor, arising sporadically or as the earliest manifestation of Carney's complex. When it arises sporadically, the breast is infrequently involved with only few cases reported in the literature. Key imaging findings include T2 signal hyperintensity on MRI and hypervascularity. In this study, we report the clinical, radiological, surgical, and histopathologic findings of a case of sporadic SA of the breast in a 16-year-old girl.

CRISPR/Cas9 knockouts reveal genetic interaction between strain-transcendent erythrocyte determinants of Plasmodium falciparum invasion.

During malaria blood-stage infections, Plasmodium parasites interact with the RBC surface to enable invasion followed by intracellular proliferation. Critical factors involved in invasion have been identified using biochemical and genetic approaches including specific knockdowns of genes of interest from primary CD34+ hematopoietic stem cells (cRBCs). Here we report the development of a robust in vitro culture system to produce RBCs that allow the generation of gene knockouts via CRISPR/Cas9 using the immortal JK-1 erythroleukemia line. JK-1 cells spontaneously differentiate, generating cells at different stages of erythropoiesis, including terminally differentiated nucleated RBCs that we term "jkRBCs." A screen of small-molecule epigenetic regulators identified several bromodomain-specific inhibitors that promote differentiation and enable production of synchronous populations of jkRBCs. Global surface proteomic profiling revealed that jkRBCs express all known Pfalciparum host receptors in a similar fashion to cRBCs and that multiple Pfalciparum strains invade jkRBCs at comparable levels to cRBCs and RBCs. Using CRISPR/Cas9, we deleted two host factors, basigin (BSG) and CD44, for which no natural nulls exist. BSG interacts with the parasite ligand Rh5, a prominent vaccine candidate. A BSG knockout was completely refractory to parasite invasion in a strain-transcendent manner, confirming the essential role for BSG during invasion. CD44 was recently identified in an RNAi screen of blood group genes as a host factor for invasion, and we show that CD44 knockout results in strain-transcendent reduction in invasion. Furthermore, we demonstrate a functional interaction between these two determinants in mediating Pfalciparum erythrocyte invasion.

Metabolic syndrome among adults living with sickle cell disease.

Metabolic syndrome (MetS) is a key risk factor for cardiovascular disease (CVD) incidence and all-cause mortality. MetS prevalence among adults with sickle cell disease (SCD) is not well known. We report initial findings from a cross-sectional study that examined MetS risk factors within a cohort of adults living with SCD. 50 adult SCD participants (ages 21-66 years; 72% female) completed demographic and health behavior surveys, health-related family and personal histories, and anthropometric and laboratory measurements. Descriptive and inferential statistics were used to summarize and compare CVD risk factors, stratified in separate analyses by SCD genotype and sex. Triglyceride, blood pressure, and fasting glucose levels were within normal limits. 78% of the cohort reported moderate to high physical activity. However, 46% of this cohort was overweight and dietary saturated fat intake exceeded both the national average (11%) and US Dietary Guidelines (<10%). 14.3% of the cohort fulfilled criteria for MetS with large waist circumference and reduced HDL levels prominently accounting for this status. We evaluated the prevalence of MetS in a cohort of adults living with SCD. Our findings suggest that increased attention to eating habits and physical activity may generate new approaches for decreasing cardiovascular morbidity in SCD.

Predictors of acute care utilization and acute pain treatment outcomes in adults with sickle cell disease: The role of non-hematologic characteristics and baseline chronic opioid dose.

Despite its rarity in the United States, sickle cell disease accounts for a disproportionate amount of healthcare utilization and costs. The majority of this is due to acute care for painful crises. A small subpopulation of patients accounts for most these costs due to frequent visits to emergency departments and acute care facilities. Previous investigations have found that these high utilizing patients are distinguished by both a more severe disease course and certain non-hematologic characteristics, which may include higher socioeconomic status and some psychiatric and psychological characteristics. This prospective observational cohort study was undertaken to test the ability of these characteristics to prospectively predict acute pain care outcomes, including visit frequency, total opioid doses, and pain improvement at the Johns Hopkins Sickle Cell Infusion Center (SCIC). Seventy-three participants were followed for 12 months and SCIC utilization and treatment outcomes were tabulated for 378 visits. Participants who visited the SCIC most frequently had markedly worse pain improvement despite higher within-visit opioid doses. Higher utilization was associated with indicators of greater illness severity, more aggressive treatment for sickle cell disease, higher baseline opioid doses, higher socioeconomic status, greater pain-related anxiety, and a history of psychiatric treatment. Overall, poor acute pain treatment response was associated with higher utilization and higher baseline opioid doses. The pattern of association between high utilization, poor acute care outcomes, and higher baseline opioid doses is discussed in terms of prior research and future directions.

Budget Impact of Next-Generation Sequencing for Molecular Assessment of Advanced Non-Small Cell Lung Cancer.

BACKGROUND: Genetic testing for nonsquamous advanced non-small cell lung cancer (aNSCLC) is recommended to guide first-line therapy. Activating mutations can be identified via single-gene testing or next-generation sequencing (NGS). OBJECTIVES: To evaluate the budget impact of NGS instead of single-gene testing for tissue-based molecular assessment of aNSCLC from the US health care payer perspective. METHODS: An annual cohort of newly diagnosed patients with nonsquamous aNSCLC in a hypothetical 1-million-member health care plan was evaluated using a Markov model over 5 years. Epidemiology and testing rates (EGFR, ALK, ROS1, BRAF, MET, HER2, and RET) were from the literature. Treatments were determined by available genetic information. Safety, progression, and survival with targeted therapy or chemotherapy were from randomized clinical trials. Single-gene testing and first-line and maintenance treatment costs were from RED BOOK and Medicare fee schedules; NGS testing, adverse event, and progression costs to payers were from the literature. RESULTS: Three hundred sixteen testing-eligible patients with aNSCLC were expected annually, of whom 179 undergo genetic testing. Of 57 patients expected to have activating mutations, single-gene testing identified 35, whereas NGS identified 54. NGS, instead of single-gene testing, decreased expected testing procedure-related costs to the health plan payer by $24,651. First-line and maintenance treatment costs increased by $842,205, offset by a $385,000 decrease in second-line treatment and palliative care costs. Over 5 years, total budget impact was $432,554 ($0.0072 per member per month). CONCLUSIONS: NGS is expected to identify more patients with activating mutations, thereby better enabling selection for targeted therapy and clinical trial enrollment. The budget impact to US payers is expected to be minimally cost-additive.

Symptomatic Avascular Necrosis: An Understudied Risk Factor for Acute Care Utilization by Patients with SCD.

OBJECTIVES: Sickle cell disease (SCD) is associated with high healthcare utilization rates and poor outcomes in a subset of patients, although the underlying factors that predict this phenotype are poorly understood. Prior studies suggest that comorbid avascular necrosis (AVN) contributes to high healthcare utilization. We sought to clarify whether AVN independently predicts acute care utilization in adults with SCD and to identify characteristics of those with AVN that predict higher utilization. METHODS: We reviewed the medical records of 87 patients with SCD with symptomatic AVN and compared acute care utilization and clinical characteristics with 87 sex- and age-matched patients with SCD without symptomatic AVN. Patients with ≥2 years of follow-up were included. Outcomes were compared using bivariate analysis and multivariate regression. RESULTS: Our study included 1381 follow-up years, with a median of 7 years per patient. The AVN cohort had greater median rates of urgent care visits (3.2/year vs 1.3/year; P = 0.0155), admissions (1.3/year vs 0.4/year; P = 0.0002), and admission days (5.1 days/year vs 1.8 days/year; P = 0.0007). History of high utilization (odds ratio [OR] 4.28; P = 0.001), acute chest syndrome (OR 3.12; P = 0.005), pneumonia (OR 3.20; P = 0.023), hydroxyurea therapy (OR 2.23; P = 0.0136), and long-term transfusion (OR 2.33; P = 0.014) were associated with AVN. In a median regression model, AVN, acute chest syndrome, and pneumonia were independently associated with greater urgent care visits and admissions. CONCLUSIONS: Symptomatic AVN was found to be an independent risk factor for acute care utilization in patients with SCD. Because this is a potentially modifiable factor, further studies are urgently needed to determine whether AVN prevention/early treatment interventions will alter utilization and improve outcomes for patients with SCD.

Societal cost-effectiveness analysis of the 21-gene assay in estrogen-receptor-positive, lymph-node-negative early-stage breast cancer in Japan.

BACKGROUND: Breast-cancer incidence and mortality have been increasing in Japan. Japanese-specific clinical validity and utility data for the 21-gene assay (Oncotype DX® Breast Cancer Assay; Genomic Health, Inc., Redwood City, USA) are now available. The objective of this study was to evaluate the cost-effectiveness of the 21-gene assay for the guidance of adjuvant chemotherapy decisions in estrogen-receptor-positive, lymph-node-negative, early-stage breast cancer patients, from the Japanese societal perspective. METHODS: The recurrence risk group distribution by the 21-gene assay result and the assay's influence on adjuvant chemotherapy recommendations were obtained from a study of 104 patients. A state-transition cohort (Markov) model tracked time from surgery until distant recurrence and from distant recurrence to death. Adjuvant chemotherapy benefit by 21-gene assay risk group was based on published clinical validation studies. Direct and indirect medical costs were obtained from the referral centers. Utilities associated with progression and chemotherapy-related adverse events were extracted from literature. Sensitivity analyses assessed the key drivers and robustness of the primary outcomes. RESULTS: The 21-gene assay identified 48% of patients as low-risk, 36% as intermediate-risk, and 16% as high-risk. Total acute chemotherapy-related costs decreased by ¥154,066 due to less adjuvant chemotherapy usage. In the high-risk group, adjuvant chemotherapy use increased 18%, leading to survival benefits. Chemotherapy use overall decreased by 19%. Monitoring costs increased by ¥3,744 but recurrence costs declined by ¥46,113 per patient. Use of the 21-gene assay increased quality-adjusted-life-years (QALYs) by 0.241 per patient on average; the net cost per QALY gained was ¥636,752 ($6,368). CONCLUSIONS: The 21-gene assay for women with estrogen-receptor-positive, lymph-node-negative, early-stage breast cancer is projected to be cost-effective in Japan.

Lives Saved Through Increasing Adherence to Follow-Up After Abnormal Cervical Cancer Screening Results.

OBJECTIVE: To model the potential number of cancers prevented and life-years saved over a range of adherence rates to cervical cancer screening, surveillance follow-up, and follow-up colposcopy that may result from removing financial barriers to these essential clinical services. METHODS: A previously validated decision-analytic Markov microsimulation model was used to evaluate the increase in adherence to screening, surveillance, and colposcopy after an abnormal cervical cancer screening result. For each incremental increase in adherence, we modeled the number of cervical cancer cases avoided, the stages at which the cancers were detected, the number of cervical cancer deaths avoided, and the number of life-years gained. RESULTS: Compared with current adherence rates, the model estimated that an optimized scenario of perfect screening, surveillance, and colposcopy adherence per 100,000 women currently eligible for screening in the United States was 128 (95% CI, 66-199) fewer cervical cancers detected (23%), 62 (95% CI, 7-120) fewer cervical cancer deaths (20%), and 2,135 (95% CI, 1,363-3,057) more life-years saved. Sensitivity analysis revealed that any increase in adherence led to clinically meaningful health benefits. CONCLUSION: The consequences of not attending routine screening or follow-up after an abnormal cervical cancer screening result are associated with preventable cervical cancer morbidity and premature mortality. Given the potential for the removal of consumer cost sharing to increase the use of necessary follow-up after abnormal screening results and to ultimately reduce cervical cancer morbidity and mortality, public and private payers should remove cost barriers to these essential services.

Multimodal Integrative Genomics and Pathology Analyses in Neoadjuvant Nivolumab Treatment for Intermediate and Locally Advanced Hepatocellular Carcinoma.

Introduction: Immunotherapy has resulted in pathologic responses in hepatocellular carcinoma (HCC), but the benefits and molecular mechanisms of neoadjuvant immune checkpoint blockade are largely unknown. Methods: In this study, we evaluated the efficacy and safety of preoperative nivolumab (anti-PD-1) in patients with intermediate and locally advanced HCC and determined the molecular markers for predicting treatment response. Results: Between July 2020 and November 2021, 20 treatment-naive HCC patients with intermediate and locally advanced tumors received preoperative nivolumab at 3 mg/kg for 3 cycles prior to surgical resection. Nineteen patients underwent surgical resection on trial. Seven (36.8%) of the 19 patients had major pathologic tumor necrosis (≥60%) in the post-nivolumab resection specimens, with 3 having almost complete (>90%) tumor necrosis. The tumor necrosis was hemorrhagic and often accompanied by increased or dense immune cell infiltrate at the border of the tumors. None of the patients developed major adverse reactions contradicting hepatectomy. RNA-sequencing analysis on both pre-nivolumab tumor biopsies and post-nivolumab resected specimens showed that, in cases with major pathologic necrosis, the proportion of CD8 T cells in the HCC tissues predominantly increased after treatment. Moreover, to investigate noninvasive biomarker for nivolumab response, we evaluated the copy number variation (CNV) using target-panel sequencing on plasma cell-free DNA of the patients and derived a CNV-based anti-PD-1 score. The score correlated with the extent of tumor necrosis and was validated in a Korean patient cohort with anti-PD-1 treatment. Conclusion: Neoadjuvant nivolumab demonstrated promising clinical activity in intermediate and locally advanced HCC patients. We also identified useful noninvasive biomarker predicting responsiveness.