Health State Utilities Associated with False-Positive Cancer Screening Results.

INTRODUCTION: Early cancer detection can significantly improve patient outcomes and reduce mortality rates. Novel cancer screening approaches, including multi-cancer early detection tests, have been developed. Cost-utility analyses will be needed to examine their value, and these models require health state utilities. The purpose of this study was to estimate the disutility (i.e., decrease in health state utility) associated with false-positive cancer screening results. METHODS: In composite time trade-off interviews using a 1-year time horizon, UK general population participants valued 10 health state vignettes describing cancer screening with true-negative or false-positive results. Each false-positive vignette described a common diagnostic pathway following a false-positive result suggesting lung, colorectal, breast, or pancreatic cancer. Every pathway ended with a negative result (no cancer detected). The disutility of each false positive was calculated as the difference between the true-negative and each false-positive health state, and because of the 1-year time horizon, each disutility can be interpreted as a quality-adjusted life-year decrement associated with each type of false-positive experience. RESULTS: A total of 203 participants completed interviews (49.8% male; mean age = 42.0 years). The mean (SD) utility for the health state describing a true-negative result was 0.958 (0.065). Utilities for false-positive health states ranged from 0.847 (0.145) to 0.932 (0.059). Disutilities for false positives ranged from - 0.031 to - 0.111 (- 0.041 to - 0.111 for lung cancer; - 0.079 for colorectal cancer; - 0.031 to - 0.067 for breast cancer; - 0.048 to - 0.088 for pancreatic cancer). CONCLUSION: All false-positive results were associated with a disutility. Greater disutility was associated with more invasive follow-up diagnostic procedures, longer duration of uncertainty regarding the eventual diagnosis, and perceived severity of the suspected cancer type. Utility values estimated in this study would be useful for economic modeling examining the value of cancer screening procedures.

Out-of-pocket cost by cancer stage at diagnosis in commercially insured patients in the United States.

AIMS: Out-of-pocket (OOP) costs may constitute a substantial financial burden to patients diagnosed with cancer. Earlier stage diagnosis and treatment of cancers may promote decreased morbidity and mortality, subsequently also lowering costs. To better understand costs experienced by patients with cancer, OOP costs by stage post-diagnosis were estimated. MATERIALS AND METHODS: A retrospective analysis was conducted using Optum's de-identified Integrated Claims-Clinical dataset with Enriched Oncology, which includes data from commercially insured members (June 1, 2015-July 31, 2020). Mean annual and cumulative OOP costs (co-pay + co-insurance + deductible) (2020 USD) were reported through a 3-year period post-cancer diagnosis among adult commercially insured members (not including Medicare Advantage members) diagnosed with staged breast, cervical, colorectal, lung, ovarian, or prostate cancer between January 1, 2016 and June 30, 2020 with continuous enrollment for ≥1-month post-diagnosis. RESULTS: A total of 7,494 eligible members were identified who were diagnosed with breast, cervical, colorectal, lung, ovarian, or prostate cancer. A greater proportion of OOP costs were incurred in year 1 post-diagnosis but remained relatively high through year 3 post-diagnosis. Cumulative mean OOP costs were as high as $35,243 (lung stage IV) per commercially insured patient by year 3 post-diagnosis and were generally higher among those diagnosed at later stages (III/IV) than those diagnosed at earlier stages (I/II) across all cancers. LIMITATIONS: Generalizability of these results is limited to those with commercial health insurance coverage. Additionally, cancer staging was dependent on accuracy of staging as recorded in the electronic medical record and as determined by Optum's proprietary algorithm using natural language processing. CONCLUSION: Cumulative mean OOP costs among commercially insured patients during the 3-year period post-cancer diagnosis were substantial and generally higher among those with later stage cancer diagnoses. Diagnosis of cancer at earlier stages may allow for more timely treatment and lessen patient OOP costs.

Patients diagnosed with cancer may face significant out-of-pocket costs (expenses that are not reimbursed by insurance) for care. However, lower costs may be achieved if the cancer is identified, diagnosed, and treated at earlier stages before the cancer tumor can grow or spread to other parts of the body. In this study, we examined patient out-of-pocket costs on an annual basis and over a 3-year period by cancer stage (I­IV) at diagnosis. Data were obtained from a large healthcare database (Optum's Claims-Clinical dataset with Enriched Oncology) that has administrative claims with out-of-pocket cost records as well as health records to determine cancer type and stage at diagnosis. Out-of-pocket costs recorded in the database included the co-pay, co-insurance, and deductible. Data from 7,494 adult patients with commercial insurance (not including Medicare Advantage) who were newly diagnosed with breast, cervical, colorectal, lung, ovarian, or prostate cancer between January 1, 2016 and June 30, 2020 were identified and analyzed. Patients incurred most of their out-of-pocket costs during the first year after a cancer diagnosis and these costs remained high for an additional 2 years. In general, patients diagnosed with cancer at later stages (III/IV) had a higher 3-year total out-of-pocket cost compared to those diagnosed at earlier stages (I/II) and this reached as high as $35,243 among patients diagnosed with stage IV lung cancer. Diagnosis of cancer at an earlier stage may reduce out-of-pocket costs for patients.

Maternal circulating miRNAs contribute to negative pregnancy outcomes by altering placental transcriptome and fetal vascular dynamics.

Circulating miRNAs the in blood are promising biomarkers for predicting pregnancy complications and adverse birth outcomes. Previous work identified 11 gestationally elevated maternal circulating miRNAs (HEamiRNAs) that predicted infant growth deficits following prenatal alcohol exposure and regulated epithelial-mesenchymal transition in the placenta. Here we show that a single intravascular administration of pooled murine-conserved HEamiRNAs to pregnant mice on gestational day 10 (GD10) attenuates umbilical cord blood flow during gestation, explaining the observed intrauterine growth restriction (IUGR), specifically decreased fetal weight, and morphometric indices of cranial growth. Moreover, RNAseq of the fetal portion of the placenta demonstrated that this single exposure has lasting transcriptomic changes, including upregulation of members of the Notch pathway (Dll4, Rfng, Hey1), which is a pathway important for trophoblast migration and differentiation. Weighted gene co-expression network analysis also identified chemokine signaling, which is responsible for regulating immune cell-mediated angiogenesis in the placenta, as an important predictor of fetal growth and head size. Our data suggest that HEamiRNAs perturb the expression of placental genes relevant for angiogenesis, resulting in impaired umbilical cord blood flow and subsequently, IUGR.

Blood-based tests for multicancer early detection (PATHFINDER): a prospective cohort study.

BACKGROUND: Multicancer early detection (MCED) blood tests can detect a cancer signal from circulating cell-free DNA (cfDNA). PATHFINDER was a prospective cohort study investigating the feasibility of MCED testing for cancer screening. METHODS: In this prospective cohort study done in oncology and primary care outpatient clinics at seven US health networks, a convenience sample of adults aged 50 years or older without signs or symptoms of cancer consented to MCED testing. We collected blood, analysed cfDNA, and returned results to participants' doctors. If a methylation signature indicative of cancer was detected, predicted cancer signal origin(s) informed diagnostic assessment. The primary outcome was time to, and extent of, diagnostic testing required to confirm the presence or absence of cancer. This trial is registered at ClinicalTrials.gov, NCT04241796, and is completed. FINDINGS: Between Dec 12, 2019, and Dec 4, 2020, we recruited 6662 participants. 4204 (63·5%) of 6621 participants with analysable results were women, 2417 (36·5%) were men, and 6071 (91·7%) were White. A cancer signal was detected in 92 (1·4%) of 6621 participants with analysable results. 35 (38%) participants were diagnosed with cancer (true positives) and 57 (62%) had no cancer diagnosis (false positives). Excluding two participants whose diagnostic assessments began before MCED test results were reported, median time to diagnostic resolution was 79 days (IQR 37-219): 57 days (33-143) in true-positive and 162 days (44-248) in false-positive participants. Most participants had both laboratory tests (26 [79%] of 33 with true-positive results and 50 [88%] of 57 with false-positive results) and imaging (30 [91%] of 33 with true-positive results and 53 [93%] of 57 with false-positive results). Fewer procedures were done in participants with false-positive results (17 [30%] of 57) than true-positive results (27 [82%] of 33) and few had surgery (one with a false-positive result and three with a true-positive result). INTERPRETATION: This study supports the feasibility of MCED screening for cancer and underscores the need for further research investigating the test's clinical utility. FUNDING: GRAIL.

Genetic influences on disease course and severity, 30 years after a clinically isolated syndrome.

Multiple sclerosis risk has a well-established polygenic component, yet the genetic contribution to disease course and severity remains unclear and difficult to examine. Accurately measuring disease progression requires long-term study of clinical and radiological outcomes with sufficient follow-up duration to confidently confirm disability accrual and multiple sclerosis phenotypes. In this retrospective study, we explore genetic influences on long-term disease course and severity; in a unique cohort of clinically isolated syndrome patients with homogenous 30-year disease duration, deep clinical phenotyping and advanced MRI metrics. Sixty-one clinically isolated syndrome patients [41 female (67%): 20 male (33%)] underwent clinical and MRI assessment at baseline, 1-, 5-, 10-, 14-, 20- and 30-year follow-up (mean age ± standard deviation: 60.9 ± 6.5 years). After 30 years, 29 patients developed relapsing-remitting multiple sclerosis, 15 developed secondary progressive multiple sclerosis and 17 still had a clinically isolated syndrome. Twenty-seven genes were investigated for associations with clinical outcomes [including disease course and Expanded Disability Status Scale (EDSS)] and brain MRI (including white matter lesions, cortical lesions, and brain tissue volumes) at the 30-year follow-up. Genetic associations with changes in EDSS, relapses, white matter lesions and brain atrophy (third ventricular and medullary measurements) over 30 years were assessed using mixed-effects models. HLA-DRB1*1501-positive (n = 26) patients showed faster white matter lesion accrual [+1.96 lesions/year (0.64-3.29), P = 3.8 × 10-3], greater 30-year white matter lesion volumes [+11.60 ml, (5.49-18.29), P = 1.27 × 10-3] and higher annualized relapse rates [+0.06 relapses/year (0.005-0.11), P = 0.031] compared with HLA-DRB1*1501-negative patients (n = 35). PVRL2-positive patients (n = 41) had more cortical lesions (+0.83 [0.08-1.66], P = 0.042), faster EDSS worsening [+0.06 points/year (0.02-0.11), P = 0.010], greater 30-year EDSS [+1.72 (0.49-2.93), P = 0.013; multiple sclerosis cases: +2.60 (1.30-3.87), P = 2.02 × 10-3], and greater risk of secondary progressive multiple sclerosis [odds ratio (OR) = 12.25 (1.15-23.10), P = 0.031] than PVRL2-negative patients (n = 18). In contrast, IRX1-positive (n = 30) patients had preserved 30-year grey matter fraction [+0.76% (0.28-1.29), P = 8.4 × 10-3], lower risk of cortical lesions [OR = 0.22 (0.05-0.99), P = 0.049] and lower 30-year EDSS [-1.35 (-0.87,-3.44), P = 0.026; multiple sclerosis cases: -2.12 (-0.87, -3.44), P = 5.02 × 10-3] than IRX1-negative patients (n = 30). In multiple sclerosis cases, IRX1-positive patients also had slower EDSS worsening [-0.07 points/year (-0.01,-0.13), P = 0.015] and lower risk of secondary progressive multiple sclerosis [OR = 0.19 (0.04-0.92), P = 0.042]. These exploratory findings support diverse genetic influences on pathological mechanisms associated with multiple sclerosis disease course. HLA-DRB1*1501 influenced white matter inflammation and relapses, while IRX1 (protective) and PVRL2 (adverse) were associated with grey matter pathology (cortical lesions and atrophy), long-term disability worsening and the risk of developing secondary progressive multiple sclerosis.

Cryptococcal meningoencephalitis in multiple sclerosis treated with fingolimod.

A 21-year-old woman with multiple sclerosis (taking regular fingolimod) developed sudden-onset severe headache with nausea and malaise. Neurological examination was normal and she was afebrile. Blood results showed lymphocytes 0.53 x 109/L and C reactive protein 19 mg/L. CT scan of head and venogram were normal. CSF showed an opening pressure of 33 cm H2O and an incidental light growth of Cryptococcus neoformans, confirmed with positive India Ink stain and a positive cryptococcal antigen (1:100). She was treated for cryptococcal meningoencephalitis with amphotericin and flucytosine. Her presenting symptoms had closely mimicked subarachnoid haemorrhage. This atypical presentation of cryptococcal CNS infection highlights the need for vigilance in immunosuppressed patients.

The relation of sarcopenia and disability in multiple sclerosis.

BACKGROUND: The relation of sarcopenia and disability in MS is unknown. OBJECTIVE: To investigate the relation of temporal muscle thickness (TMT) and disability. METHODS: A cohort of 132 people who presented with a clinically isolated syndrome (CIS) suggestive of MS at a mean age of 30.0 years, were prospectively followed clinically and with MRI over 30-years. TMT and expanded disability status scale (EDSS) were assessed at baseline, one- five- ten- fourteen- twenty- and thirty-year follow-up. RESULTS: At 30-years, 27 participants remained classified as having had a CIS, 34 converted to relapsing remitting MS, 26 to secondary progressive MS, and 16 had died due to MS. Using linear mixed effect models with subject nested in time, greater annualized TMT-thinning was seen in individuals who developed MS (-0.04 mm/a, 95%CI: -0.07 to -0.01, p = 0.023). In those who converted to MS, a thinner TMT was reached at 14- (p = 0.008), 20- (p = 0.002) and 30-years (p< 0.001). TMT was negatively correlated with EDSS at 20-years (R=-0.18, p = 0.032) and 30-years (R-0.244, p = 0.005). Longitudinally, TMT at earlier timepoints was not predictive for 30-year clinical outcomes. CONCLUSION: TMT thinning is accelerated in MS and correlated with disability in later disease stages, but is not predictive of future disability.

Population-Based Mini-Mental State Examination Norms in Adults of Mexican Heritage in the Cameron County Hispanic Cohort.

BACKGROUND: Accurately identifying cognitive changes in Mexican American (MA) adults using the Mini-Mental State Examination (MMSE) requires knowledge of population-based norms for the MMSE, a scale which has widespread use in research settings. OBJECTIVE: To describe the distribution of MMSE scores in a large cohort of MA adults, assess the impact of MMSE requirements on their clinical trial eligibility, and explore which factors are most strongly associated with their MMSE scores. METHODS: Visits between 2004-2021 in the Cameron County Hispanic Cohort were analyzed. Eligible participants were ≥18 years old and of Mexican descent. MMSE distributions before and after stratification by age and years of education (YOE) were assessed, as was the proportion of trial-aged (50-85- year-old) participants with MMSE <24, a minimum MMSE cutoff most frequently used in Alzheimer's disease (AD) clinical trials. As a secondary analysis, random forest models were constructed to estimate the relative association of the MMSE with potentially relevant variables. RESULTS: The mean age of the sample set (n = 3,404) was 44.4 (SD, 16.0) years old and 64.5% female. Median MMSE was 28 (IQR, 28-29). The percentage of trial-aged participants (n = 1,267) with MMSE <24 was 18.6% overall and 54.3% among the subset with 0-4 YOE (n = 230). The five variables most associated with the MMSE in the study sample were education, age, exercise, C-reactive protein, and anxiety. CONCLUSION: The minimum MMSE cutoffs in most phase III prodromal-to-mild AD trials would exclude a significant proportion of trial-aged participants in this MA cohort, including over half of those with 0-4 YOE.

Cancer incidence in immunocompromised patients: a single-center cohort study.

BACKGROUND: Diminished immune defense plays an important role in cancer development. Cancer risk in immunocompromised patients may differ. Identifying individuals with elevated cancer risk can inform strategies for routine cancer screening. This study aimed to understand and compare cancer incidence and risk in three patient groups: recipients of solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT); diagnosis of primary or secondary immunodeficiency disorder (PID/SID); and recipients of tumor necrosis factor inhibitor (TNF-i) therapy. METHODS: This retrospective cohort study used the University of Utah Health System database and Huntsman Cancer Institute tumor registry. Patients aged ≥18 years with SOT/HSCT, PID/SID or ≥ 3 months of TNF-i therapy were included. The date of transplant, diagnosis of PID/SID, or 1st TNF-i medication order date was defined as the index date. We calculated cumulative cancer incidence by Kaplan-Meier method. A Cox-proportional hazard regression model with a stepwise variable selection process was used to identify independent risk factors associated with the time to onset of a new primary cancer. RESULTS: In total, 13,887 patients were included which comprised of 2982 (21%) SOT/HSCT, 7542 (54%) PID/SID and 3363 (24%) patients receiving TNF-i. The mean (SD) age ranged from 46.8 (15) years - 50.4 (18.2) years. The proportion of white patients ranged from 72.3-84.8%. The estimated cumulative cancer incidence was 11.5% in the SOT/HSCT cohort, 14.3% in the PID/SID cohort, and 8.8% in the TNF-i cohort. The multivariable model adjusted for age, benign in-situ disease, Charlson Comorbidity Index, hypertension/cardiovascular disease/end stage renal disease, gender, race/ethnicity, and renal cyst as significant risk factors. The adjusted hazard ratios for cancer development in SOT/HSCT and PID/SID cohorts compared to the TNF-i cohort over the full follow-up period were 1.57 (95% CI: 1.16-2.13) and 2.14 (95% CI: 1.65-2.77), respectively. CONCLUSION: A significantly increased risk of cancer was observed in PID/SID patients and SOT/HSCT patients compared to TNF-i patients. Age ≥ 50 years, male gender, and clinical comorbidities were additional factors impacting cancer risk. PID/SID and SOT/HSCT patients may benefit from more intensive cancer screening.

"Can I exercise? Would it help? Would it not?": exploring the experiences of people with relapsing remitting multiple sclerosis engaging with physical activity during a relapse: a qualitative study.

PURPOSE: Physical activity (PA) has been found to be beneficial for people with multiple sclerosis (pwMS) outside of the relapse period. However, little is known about how people experience PA during a relapse. This study investigates the experiences of pwMS engaging with PA during a relapse. MATERIALS AND METHODS: The study followed an interpretivist approach, adopting a qualitative exploratory design. Semi-structured interviews were conducted with a purposive sample of 15 adults following a recent relapse. Transcripts were analysed in NVivo using framework analysis. RESULTS: The experiences of participants were synthesised in three overarching themes: "on the road to recovery", "getting active but fearing repercussions", and "self-directed versus guided recovery". Barriers to PA included: feeling unwell, physical limitations, concerns about causing deterioration, worries that others would recognise their disability, and lack of professional support. Facilitators included: awareness of the benefits of PA, access to exercise resources, individualised advice and support from practitioners, and PA pitched at the right level. CONCLUSIONS: Relapses can disrupt normal PA routines, making it challenging to return to PA. This article makes recommendations for supporting people to undertake PA, the timing and form of support, along with suggestions for further research exploring the safety of PA during a relapse. Implications for rehabilitationPeople with RRMS find it difficult to be physically active during a relapse.There are complex personal, social and environmental reasons why people find it hard to engage with physical activity (PA).Improved timely advice and customised support during a relapse can help reduce fears and enhance confidence with returning to PA.Physical activity recommendations should be tailored to individual's abilities to make them achievable, giving a sense of accomplishment and boosting motivation.

A Systematic Review of the Cost-Effectiveness of Cleft Care in Low- and Middle-Income Countries: What is Needed?

OBJECTIVE: The objective of this paper is to conduct a systematic review that summarizes the cost-effectiveness of cleft lip and/or palate (CL/P) care in low- and middle-income countries (LMICs) based on existing literature. DESIGN: We searched eleven electronic databases for articles from January 1, 2000 to December 29, 2020. This study is registered in PROSPERO (CRD42020148402). Two reviewers independently conducted primary and secondary screening, and data extraction. SETTING: All CL/P cost-effectiveness analyses in LMIC settings. PATIENTS, PARTICIPANTS: In total, 2883 citations were screened. Eleven articles encompassing 1,001,675 patients from 86 LMICs were included. MAIN OUTCOME MEASURES: We used cost-effectiveness thresholds of 1% to 51% of a country's gross domestic product per capita (GDP/capita), a conservative threshold recommended for LMICs. Quality appraisal was conducted using the Joanna Briggs Institute (JBI) checklist. RESULTS: Primary CL/P repair was cost-effective at the threshold of 51% of a country's GDP/capita across all studies. However, only 1 study met at least 70% of the JBI criteria. There is a need for context-specific cost and health outcome data for primary CL/P repair, complications, and existing multidisciplinary management in LMICs. CONCLUSIONS: Existing economic evaluations suggest primary CL/P repair is cost-effective, however context-specific local data will make future cost-effectiveness analyses more relevant to local decision-makers and lead to better-informed resource allocation decisions in LMICs.

Patient Preferences for Multi-Cancer Early Detection (MCED) Screening Tests.

BACKGROUND: Emerging blood-based multi-cancer early detection (MCED) tests can detect a variety of cancer types across stages with a range of sensitivity, specificity, and ability to predict the origin of the cancer signal. However, little is known about the general US population's preferences for MCED tests. OBJECTIVE: To quantify preferences for MCED tests among US adults aged 50-80 years using a discrete choice experiment (DCE). METHODS: To quantify preferences for attributes of blood-based MCED tests, an online DCE was conducted with five attributes (true positives, false negatives, false positives, likelihood of the cancer type unknown, number of cancer types detected), among the US population aged 50-80 years recruited via online panels and social media. Data were analyzed using latent class multinomial logit models and relative attribute importance was obtained. RESULTS: Participants (N = 1700) were 54% female, mean age 63.3 years. Latent class modeling identified three classes with distinct preferences for MCED tests. The rank order of attribute importance based on relative attribute importance varied by latent class, but across all latent classes, participants preferred higher accuracy (fewer false negatives and false positives, more true positives) and screenings that detected more cancer types and had a lower likelihood of cancer type unknown. Overall, 72% of participants preferred to receive an MCED test in addition to currently recommended cancer screenings. CONCLUSIONS: While there is significant heterogeneity in cancer screening preferences, the majority of participants preferred MCED screening and the accuracy of these tests is important. While the majority of participants preferred adding an MCED test to complement current cancer screenings, the latent class analyses identified a small (16%) and specific subset of individuals who value attributes differently, with particular concern regarding false-negative and false-positive test results, who are significantly less likely to opt-in.

Breast, Colorectal, Lung, Prostate, and Cervical Cancer Screening Prevalence in a Large Commercial and Medicare Advantage Plan, 2008-2020.

This study aimed to comprehensively assess breast, colorectal, cervical, lung, and prostate cancer screening rates and trends in the United States over time among individuals for whom screening is recommended by the United States Preventive Services Task Force (USPSTF). This retrospective study was conducted in two-year intervals from January 1, 2008 to February 29, 2020, using Optum's de-identified Clinformatics® Data Mart Database, which includes Medicare Advantage and commercially insured members. Screening-eligible individuals, who had not previously had the cancer being screened and met USPSTF criteria for screening, were identified at various time points within the study timeframe for relevant screening tests within five cancer types: breast, colorectal, cervical, lung, and prostate. In the 2020 analysis period, patients who were eligible for cancer screening included: breast: 1,620,588; colorectal: 2,763,736; cervical: 1,371,506; lung: 1,491,594; prostate: 1,126,249. Breast and cervical cancer screening prevalence rates were highest (64.4% and 63.8%, respectively), followed by colorectal (29.5%), prostate (11.7%), and lung (3.8%). Black/African American individuals and Hispanics had moderately low screening rates for cervical (58.6%) and breast (61.8%) cancer, respectively; Hispanics had the lowest screening rates for prostate cancer (6.1%). Those residing in the West had lower screening rates for breast (58.9%), cervical (62.1%), and prostate (5.6%) cancer. Screening rates remained stable over time for breast, colorectal, and lung cancer, and changed significantly for cervical (-9.5%, 2012-2020) and prostate (+7.3%, 2008-2020) cancer. Real-world cancer screening rates remain suboptimal and low, and efforts to increase screening uptake and reduce cancer health disparities remain critical.

Increased healthcare costs by later stage cancer diagnosis.

BACKGROUND: Cancer represents a significant source of disease burden in the United States (US), both clinically and economically. Diagnosis and treatment of cancer at earlier stages may reduce this burden. To better understand potential impacts of earlier diagnosis, healthcare costs among patients with cancer were assessed by cancer type and stage at diagnosis. METHODS: A retrospective analysis was conducted using Optum's de-identified Integrated Claims-Clinical data set with Enriched Oncology, which includes data from Medicare Advantage and commercially insured members. Adult members newly diagnosed with solid tumor cancers, cancer stage at diagnosis (diagnosed 1/1/2016-6/30/2020), and continuous enrollment for at least one month post diagnosis were identified. Patients with breast, cervical, colorectal, lung, ovarian, or prostate cancer were reported. Mean standardized costs (2020 USD) were calculated in each month on an annual and cumulative basis through four years post-cancer diagnosis. In each month, costs were calculated for those with continuous enrollment and no death reported in the month. Mean annual cost per patient was estimated by summing month one to 12 mean costs and stratifying by stage at cancer diagnosis; annual year one to four costs were summed to determine cumulative costs. RESULTS: Among members diagnosed 2016-2020 with breast, cervical, colorectal, lung, ovarian, or prostate cancer, 20,422 eligible members were identified. Mean costs increased by stage of diagnosis across all cancers at the annual and cumulative level through year four post diagnosis. Cumulative mean costs grew over time at a relatively similar rate across stages I to III and more dramatically in stage IV, except for cervical and lung cancer where the rate was relatively stable or slightly fluctuated across stages and ovarian cancer where stages III and IV both increased more sharply compared to stages I and II. CONCLUSIONS: Mean annual and cumulative healthcare costs through year four post cancer diagnosis were significantly higher among those diagnosed at later versus earlier cancer stages. The steeper increase in cumulative costs among those diagnosed in stage IV for many cancer types highlights the importance of earlier cancer diagnosis. Earlier cancer diagnosis may enable more efficient treatment, improve patient outcomes and reduce healthcare costs.

Productivity Loss and Indirect Costs for Patients Newly Diagnosed with Early- versus Late-Stage Cancer in the USA: A Large-Scale Observational Research Study.

BACKGROUND: The total economic burden of cancer reflects direct and indirect costs, including productivity loss due to employment change, absenteeism, and presenteeism of patients and caregivers. OBJECTIVE: This study estimated the magnitude of employment decrease, work absence (WA), short-term disability (STD), long-term disability (LTD), and associated indirect costs among employees newly diagnosed with metastatic versus non-metastatic cancer in the USA. METHODS: IBM® MarketScan® Commercial Claims and Encounters and Health and Productivity Management databases were used to identify employees aged 18-64 years and newly diagnosed with any cancer from 2009 to 2019. Proportions of patients with employment decrease, WA, STD, and LTD claims, and number of days missing from work were summarized by metastatic status during the first 12 months after diagnosis and the entire follow-up period. Subgroup analyses were conducted by age (< 50 years, ≥ 50 years) and cancer type (breast, lung, colon, pancreatic, and liver cancer). RESULTS: During the first year after diagnosis, compared to patients without metastases, significantly higher proportions of patients with metastases had employment decrease and STD or LTD claims (p < 0.001). The mean total number of days missing from work for patients with versus without metastases was 33.39 versus 14.91 (ratio = 2.40), 64.05 versus 27.15 (ratio = 2.36), and 105.93 versus 46.29 (ratio = 2.29) days within 3, 6, and 12 months after diagnosis, respectively. Estimates of indirect cost differences between the two groups ranged from $6,877 to $22,283 in the first year. CONCLUSION: Earlier detection of cancer may reduce productivity loss of patients and indirect costs by initiating treatment before cancer progresses to late stage.

Patient-Proxy and Societal Perspectives of Quality-of-Life Utilities in Children With Cleft Lip and Palate Managed With Surgical Repair vs No Repair in Ethiopia.

Importance: In Ethiopia, more than 70% of infants with cleft lip and/or palate (CL/P) lack access to surgery. Infants who are untreated can experience severe malnutrition and extreme social stigma resulting in abandonment. Utilities are standardized measures of health-related quality of life (HRQOL) that inform health care resource allocation. However, CL/P utilities are missing from low- and middle-income countries (LMICs). Objective: To elicit utilities for untreated and surgically treated children with CL/P with consideration for social determinants of health from patient-proxy and societal participants. Design, Setting, and Participants: This cross-sectional study used patient proxies and societal participants in Addis Ababa, Ethiopia, from July 1, 2019, to January 30, 2020. Eligible patient proxies were caregivers of children younger than 18 years with nonsyndromic CL/P who were untreated or received surgery. Proxies were necessary as most patients were 0 to 4 years old and cannot reliably self-report. Eligible societal participants were 18 years and older with no family history of CL/P. Exposures: Surgical treatment and social determinants of health. Main Outcomes and Measures: Participants measured utilities using the visual analog scale (VAS), time trade-off (TTO), and standard gamble (SG). Results: In this study, 312 patient proxies and 135 societal participants were recruited. Mean (SD) utilities for untreated CL/P ranged from 0.57 (0.23) to 0.70 (0.22) from patient proxies and from 0.35 (0.21) to 0.8 (0.23) from societal participants, depending on utility instrument and cleft type. Surgical treatment was associated with a better HRQOL from the patient-proxy perspective (VAS, 0.17; 95% CI, 0.09 to 0.26; TTO, 0.15; 95% CI, 0.05 to 0.25) from the societal perspective (VAS, 0.21; 95% CI, 0.16 to 0.26; TTO, 0.17; 95% CI, 0.13 to 0.22; SG, 0.11; 95% CI, 0.06 to 0.15). Social determinants of health that were associated with patient-proxy utilities were income above the national mean (VAS, 0.10; 95% CI, 0.02 to 0.17; TTO, 0.11; 95% CI, 0.02 to 0.20), and religion (Christian vs other: TTO, -0.10; 95% CI, -0.17 to -0.03). From the societal perspective, the association between treatment and utilities was smaller in females compared with males (TTO, -0.05; 95% CI, -0.10 to -0.01). Conclusions and Relevance: The findings of this study suggest that CL/P disease severity and surgical impact in Ethiopia were undervalued by previous estimates from high-income countries and were associated with social determinants of health. Utility studies from participants from LMICs are feasible and necessary for representing HRQOL in LMICs and addressing health inequalities.

Prenatal alcohol exposure contributes to negative pregnancy outcomes by altering fetal vascular dynamics and the placental transcriptome.

BACKGROUND: Prenatal alcohol exposure (PAE) has been shown to alter fetal blood flow in utero and is also associated with placental insufficiency and intrauterine growth restriction (IUGR), suggesting an underlying connection between perturbed circulation and pregnancy outcomes. METHODS: Timed-pregnant C57/BL6NHsd mice, bred in-house, were exposed by gavage on gestational day 10 (GD10) to ethanol (3 g/kg) or purified water, as a control. Pulse-wave Doppler ultrasound measurements for umbilical arteries and ascending aorta were obtained post-gavage (GD12, GD14, GD18) on 2 fetuses/litter. RNA from the non-decidual (labyrinthine and junctional zone) portion of placentas was isolated and processed for RNA-seq and subsequent bioinformatic analyses, and the association between transcriptomic changes and fetal phenotypes assessed. RESULTS: Exposure to ethanol in pregnant mice on GD10 attenuates umbilical cord blood flow transiently during gestation, and is associated with indices of IUGR, specifically decreased fetal weight and morphometric indices of cranial growth. Moreover, RNA-seq of the fetal portion of the placenta demonstrated that this single exposure has lasting transcriptomic changes, including upregulation of Tet3, which is associated with spontaneous abortion. Weighted gene co-expression network analysis (WGCNA) identified erythrocyte differentiation and homeostasis as important pathways associated with improved umbilical cord blood flow as gestation progresses. WGCNA also identified sensory perception of chemical stimulus/odorant and receptor activity as important pathways associated with cranial growth. CONCLUSION: Our data suggest that PAE perturbs the expression of placental genes relevant for placental hematopoiesis and environmental sensing, resulting in transient impairment of umbilical cord blood flow and, subsequently, IUGR.

Cost of cancer management by stage at diagnosis among Medicare beneficiaries.

OBJECTIVE: Estimate the annual cost of care in the 5 years following a cancer diagnosis for 17 invasive cancer types, by stage at diagnosis. METHODS: We used 2012-2016 data from the Surveillance, Epidemiology, and End Results (SEER) registry-Medicare claims database to examine cost of care among Medicare beneficiaries with a confirmed cancer diagnosis based on International Classification of Diseases for Oncology, Third Edition histology codes reported in SEER. Beneficiaries contributed to the annual cost calculations (Years 1-5) using their observed time after diagnosis. Beneficiaries were continuously enrolled in fee-for-service Medicare Parts A/B and Part D during follow-up. Total, inpatient, outpatient, and pharmacy cancer-related service costs were calculated. RESULTS: From 2012 to 2016, we identified 597,778 Medicare beneficiaries with incident cancer diagnosis within 5 years (Stage I, II, III, and IV: 32.6%, 33.4%, 15.9%, and 18.0%, respectively). In Year 1, mean (standard deviation) total costs for Stage I diagnoses varied from $7640 ($17,378) (prostate) to $94,636 ($117,636) (pancreas). Total costs increased by stage and reached $58,783 ($92,344) (prostate) to $156,982 ($175,009) (stomach) for Stage IV diagnoses in Year 1. Costs in Year 1 were significantly higher for Stage IV diagnoses than for earlier stages across all cancer types. In Years 2-5, total costs were lower than in Year 1 but continued to increase by stage. CONCLUSIONS: Beneficiaries diagnosed at later stages of cancer have higher costs of care (up to 7 times as much) than those diagnosed at earlier stages. Earlier cancer diagnosis may lead to more efficient treatment and decreased management cost.