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Background: Patients treated for early stage breast cancer (BC) have a 30% lifetime risk of developing metastatic disease. Numerous studies have demonstrated that dormant bone marrow disseminated tumor cells (DTCs) are independently associated with risk of recurrence and death, yet interventions targeting these cells are lacking. The PENN-SURMOUNT (Surveillance Markers of Utility for Recurrence after (Neo)adjuvant Therapy) Screening Study was launched in 2016 to screen high risk BC survivors for DTCs using bone marrow aspirate (BMA) and identify eligible DTC positive patients for clinical trials. Given the novelty of this approach, we concurrently developed and pilot tested a PRO measurement strategy to study how the screening method of BMA and disclosure of DTC results impacts early-stage BC patients. Methods: PENN-SURMOUNT is a single center prospective, longitudinal cohort study examining BM and blood biomarkers of MRD among patients within 5 years of BC diagnosis who have high risk criteria (positive axillary nodes, triple negative biology, ER+ with Oncotype Dx ≥ 25 and/or high risk Mammaprint, or pathologic residual disease after neoadjuvant chemotherapy). From May 2019 – August 2021, we recruited patients on SURMOUNT to complete PRO surveys at baseline (T0), after BMA (T1), and after disclosure of DTC results (T2). Surveys were administered in paper form initially, then electronic form starting Feb 2021. PRO survey instruments were selected through literature review, followed by consensus among multidisciplinary clinical and research experts and patient advocates. PRO measures assess recurrence distress (Quality of Life in Adult Cancer Survivors, QLACS), illness intrusiveness (Illness Intrusiveness Ratings Scale, IIRS), and decision making (Decision Regret Scale). Additional survey items assess tolerability of the BMA and patients’ risk perception and cognitive understanding after DTC results disclosure. Descriptive statistics summarize PRO survey compliance and responses at T0, T1, and T2 in the total population and the population who reported longitudinal data for T2. Results: 61 of 66 eligible patients on the SURMOUNT trial enrolled in the PRO pilot study and completed a baseline survey, of which 47 (77%) tested negative for DTCs. Mean completion rates were 0.92 at T0, 0.85 at T1, and 0.56 at T2. After electronic survey implementation, completion rates increased to 0.94 (T0), 0.97 (T1) and 0.81 (T2). At T0, 36 (59%) patients reported a high risk perception of developing BC recurrence at 5 years and 42 (69%) during their lifetime. Mean T0 recurrence distress using the QLACS subscale was 14.6 (SD 6.3) out of possible score 4-28, compared to an expected mean of 11.42 (SD 5.48) in a general survivorship population. Mean T0 illness intrusiveness was 27.3 (SD 13.9) out of possible score 13-91. At T1, approximately 85% of patients agreed that they correctly understood the purpose of the bone marrow procedure and what the procedure would entail. 44 (72%) of patients reported a maximum pain score Citation Format: Tara Kaufmann, Patrick Chang, Shoshana Rosenberg, Elizabeth Frank, Brian Hobbs, Lauren J. Bayne, Isoris Nivar, Brooke L. Goodspeed, Killian M. Rohn, Emily M. Kugler, Kevin Fox, Susan Domchek, Angela Bradbury, Payal Shah, Hayley Knollman, Rachel C. Jankowitz, Igor Makhlin, Amy S. Clark, Lewis A. Chodosh, Angela DeMichele, Katherine Goodfellow. Pilot study of a patient-reported outcome (PRO) measurement strategy to determine impact of screening for minimal residual disease (MRD) in high-risk breast cancer survivors [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-08-01.

Field studies were conducted to assess the efficacy of physical weed management of Palmer amaranth management in cucumber, peanut, and sweetpotato. Treatments were arranged in a 3 × 4 factorial in which the first factor included a treatment method of electrical, mechanical, or hand-roguing Palmer amaranth control and the second factor consisted of treatments applied when Palmer amaranth was approximately 0.3, 0.6, 0.9, or 1.2 m above the crop canopy. Four wk after treatment (WAT), the electrical applications controlled Palmer amaranth at least 27 percentage points more than the mechanical applications when applied at the 0.3- and 0.6-m timings. At the 0.9- and 1.2-m application timings 4 WAT, electrical and mechanical applications controlled Palmer amaranth by at most 87%. Though hand removal generally resulted in the greatest peanut pod count and total sweetpotato yield, mechanical and electrical control resulted in similar yield to the hand-rogued plots, depending on the treatment timing. With additional research to provide insight into the optimal applications, there is potential for electrical control and mechanical control to be used as alternatives to hand removal. Additional studies were conducted to determine the effects of electrical treatments on Palmer amaranth seed production and viability. Treatments consisted of electricity applied to Palmer amaranth at first visible inflorescence, 2 wk after first visible inflorescence (WAI) or 4 WAI. Treatments at varying reproductive maturities did not reduce the seed production immediately after treatment. However, after treatment, plants primarily died and ceased maturation, reducing seed production assessed at 4 WAI by 93% and 70% when treated at 0 and 2 WAI, respectively. Treatments did not have a negative effect on germination or seedling length.

We performed a comprehensive systematic review and meta-analysis comparing initiation of full solid diet (FSD) versus stepwise diet to better define the management of patients with mild acute pancreatitis (AP).Electronic databases were searched through August 2, 2021 for trials comparing initial FSD versus stepwise advancement in patients with mild AP on length of hospital stay (LOHS). We stratified by whether diet was initiated early (within 24 h or immediately upon presence of bowel sounds).We identified seven RCTs that compared LOHS in AP patients who received initial oral intake with solid diet versus stepwise diet. Across the studies a total of 305 patients were randomized to immediate FSD and 308 patients to sequential advancement. Patients who were initiated on a FSD had a significant reduction in total LOHS (Standardized Mean Difference (SMD) -0.52 [95% CI -0.69, -0.36]). There was no difference in post refeeding abdominal pain, tolerance of diet, or necessity to cease diet between the two groups. Sub-analysis of three studies that initiated FSD early reduced total LOHS (OR -0.95 [95% CI -1.26, -0.65]) compared to those who received graded diet advancement as well as higher likelihood of tolerating the assigned diet (OR 6.8 [95% CI 1.2, 39.2]).Our meta-analysis shows that initiation of FSD reduces total LOHS in patients with mild AP and does not increase post refeeding abdominal pain. Though additional high-quality studies are needed, these findings support initial solid diet for AP and consideration of feeding within the first 24 h.

Background Indonesia still has the highest maternal mortality rate (MMR) compared to other countries in Southeast Asia. In Indonesia, most maternal deaths occur before, during, or after delivery. Therefore, Indonesia’s government has rolled out various health insurance schemes so they have access to maternal healthcare services. This review aims to evaluate the impact of health insurance on maternal health care in Indonesia.Methods All searches for relevant studies were performed in PubMed, Science Direct, Cochrane, and Garuda databases. This review focuses on RCT or observational study, and only articles written in English and Indonesian were retrieved. The main outcome was the utilization of maternal services and patient satisfaction.Results A total of 140,555 participants were enrolled with ten studies that met the inclusion criteria. Of these, seven studies reported on National Health Insurance (NHI) and the remaining reported on Local Health Insurance (LHI). Both NHI and LHI studies showed that insurance increases the use of maternal health care services significantly, including antenatal, delivery, and postnatal care services. Only two studies reported patient satisfaction. The LHI study showed that insurance increases the patient’s level of satisfaction significantly. On the other hand, the NHI study showed there is no difference between NHI and non-NHI patients’ levels of satisfaction. This was due to complicated procedures and long examination times for NHI users.Conclusion The implementation of health insurance appears to increase the utilization of maternal health care services, although the result on patients’ satisfaction is inconsistent between NHI and LHI studies.

BACKGROUND Many patients with inflammatory bowel disease (IBD) also have symptoms of depression. Both IBD and depression are associated with high healthcare utilization. In this cross-sectional study of population-based data, we sought to better characterize the impact of comorbid depression on hospitalizations of IBD patients. METHODS We used the 2016-2018 National Inpatient Sample (NIS) from the United States Department of Health and Human Services to identify hospitalizations with IBD and depression using ICD-10 codes. ICD-10 codes also identified confirmed complications of IBD, such as rectal bleed, fistula, abscess, or intestinal obstruction. Hospitalizations for suicidal intent were excluded from our analysis. Health outcomes including length of stay (LOS), total cost, and complications of IBD were compared between IBD patients with and without depression. Patients with confirmed discharges were captured and survival curves were compared for time to discharge. Statistical analysis was performed using STATA, including two-sample t-testing and logistic regression (significance, p RESULTS Over three years, 129,011 hospitalizations for IBD were isolated. Of these, 2,124 hospitalizations (1.65%) were recognized to have both IBD and depression. Lengths of hospitalization for IBD patients with depression were longer than those without (mean LOS [95% CI]: 7.52 [7.06-7.98] vs. 5.28 [5.24-5.32], p CONCLUSIONS While IBD patients with depression demonstrated lengthier hospitalizations compared to IBD patients without depression, the higher inpatient cost and complications from the latter group may reflect diagnostic, procedural, or surgical management of active disease. While major limitations of this administrative database include identification of hospitalizations instead of individual patients, as well as possibly underreporting or lower recognition of depression during hospitalization, our findings suggest that management of comorbid depression may reduce the length of stay in hospitalized patients with IBD.

Mailed stool testing programs increase colorectal cancer (CRC) screening in diverse settings, but whether uptake differs by key demographic characteristics is not well-studied and has health equity implications.To examine the uptake and equity of the first cycle of a mailed stool test program implemented over a 3-year period in a Central Texas Federally Qualified Health Center (FQHC) system.Retrospective cohort study within a single-arm intervention.Patients in an FQHC aged 50-75 at average CRC risk identified through electronic health records (EHR) as not being up to date with screening.Mailed outreach in English/Spanish included an introductory letter, free-of-charge fecal immunochemical test (FIT), and lab requisition with postage-paid mailer, simple instructions, and a medical records update postcard. Patients were asked to complete the FIT or postcard reporting recent screening. One text and one letter reminded non-responders. A bilingual patient navigator guided those with positive FIT toward colonoscopy.Proportions of patients completing mailed FIT in response to initial cycle of outreach and proportion of those with positive FIT completing colonoscopy; comparison of whether proportions varied by demographics and insurance status obtained from the EHR.Over 3 years, 33,606 patients received an initial cycle of outreach. Overall, 19.9% (n = 6672) completed at least one mailed FIT, 5.6% (n = 374) tested positive during that initial cycle, and 72.5% (n = 271 of 374) of those with positive FIT completed a colonoscopy. Hispanic/Latinx, Spanish-speaking, and uninsured patients were more likely to complete mailed FIT compared with white, English-speaking, and commercially insured patients. Spanish-speaking patients were more likely to complete colonoscopy after positive FIT compared with English-speaking patients.Mailed FIT outreach with patient navigation implemented in an FQHC system was effective in equitably reaching patients not up to date for CRC screening.

To estimate the effects of an inpatient initiative to decrease opioid use among women admitted to labor and delivery.We created a multimodal pain power plan with standard therapeutic postpartum activity goals rather than pain goals, tiered order sets with scheduled administration of nonsteroidal antiinflammatory drugs (NSAIDs), and embedded changes into the electronic health record. Before the multimodal pain power plan launch, pain was assessed on a 10-point scale; women received NSAIDs for pain levels of 3 or less and opioids for pain levels higher than 3. For this analysis, we included women who delivered at 5 hospitals in the 10 months before and 12 months after the multimodal pain power plan launch. Women with prior substance use disorder or complicated deliveries were excluded and we stratified analyses into women who delivered vaginally compared with by cesarean. Opioid use was converted to morphine milligram equivalent (MME). Women rated pain control in 24-hour blocks using individually ascertained cutoffs. A multivariable regression analysis was performed, and adjusted odds ratios are reported.We compared the 6,892 women who delivered 10 months before the pain power plan launch to the 7,527 who delivered in the 12 months after the launch. The mean cohort age was 29.6±6.0 years; the majority (75%) were white. Risk of opioid use decreased by 26% among women who delivered vaginally (risk ratio [RR] 0.74; 95% CI [0.68, 0.81]) and 18% among women who delivered by cesarean (RR 0.82; 95% CI [0.72, 0.92]). Among women who received opioids, mean MME use decreased 21% (RR 0.79; 95% CI [0.70, 0.88]) and 54% (RR 0.46; 95% CI [0.35, 0.61]) in the vaginal and cesarean delivery groups, respectively. Fewer women reported acceptable pain levels, with decreases of 82-69% (P.01) and 82-74% (P.01) in the vaginal and cesarean delivery groups, respectively. Within the postlaunch cesarean delivery group, women also reported that they were less likely to have their pain well controlled on the Hospital Consumer Assessment of Healthcare Providers and Systems questionnaires (82% vs 62%, P.01).A standardized multimodal pain power plan reduced opioid use among a large cohort of women admitted to labor and delivery in Central Texas. Despite meeting functional goals, some women reported increased pain during their hospital stay.

SummaryDuring most of 2020, the COVID-19 pandemic gave rise to considerable and growing numbers of hospitalizations across most of the U.S. Typical COVID-19 hospitalization data, including length of stay, intensive care unit (ICU) use, mechanical ventilation (Vent), and in-hospital mortality provide clearly interpretable health care endpoints that can be compared across population strata. They capture the resources consumed for the care of COVID-19 patients, and analysis of these endpoints can be used for resource planning at the local level. Yet, hospitalization data embody novel features that require careful statistical treatment to be useful in this context. Specifically, statistical models must meet three goals: (i) They should mesh with and inform mathematical epidemiologic or agent-based models of the COVID-19 experience in the population. (ii) They need to handle administrative censoring of hospitalization experience when data are extracted and downloaded for a given patient before that patient’s hospitalization experience has terminated. And, (iii) models need to handle risks for competing events, the occurrence of one blocking the possibility of the other(s). For example, live discharge from the hospital “competes with” (i.e., blocks) in-hospital mortality. We have adapted approaches from the survival analysis literature to address these challenges in order to better understand and quantify the population experience in hospital with respect to length of stay, ICU, Vent use and so on. Using hospitalization data from a large U.S. metropolitan region, in this report, we show how standard techniques from survival analysis can be brought to bear to address these challenges and yield interpretable results. In the breakout/discussion, we will discuss formulation, estimation and inference, and interpretation of competing risks models.

T cell receptor (TCR)-engineered T cells are a promising approach to cell therapy for cancer. TCRs targeting public tumor associated antigens (TAAs) offer the widest potential coverage of patients within and across tumor types. TAA-specific TCRs, however, are rare in the blood and when detected are frequently of low affinity due to negative selection of high-affinity self-antigen reactive T cells in the thymus. Here, we present a TCR discovery platform based on in vitro generation of T cells from human pluripotent stem cells (PSCs) using the previously described artificial thymic organoid (ATO) system. We hypothesized that ATO-derived T cells offer several advantages for TCR discovery including a novel TCR repertoire and the absence of negative selection against TAAs during T cell development. Sequencing of the TCR repertoire of polyclonal CD8+ T cells generated from a HLA-A*02:01+ PSC line confirmed low junctional diversity at both the TCR beta and alpha loci, consistent with our previous finding of low TdT expression during T cell development from PSCs and an enrichment for germline-like TCRs. We then interrogated this novel TCR repertoire for reactivity against two well-described HLA-A2-restricted epitopes of NY-ESO-1 and WT1, reactivities to which are rare in the blood. Following co-culture with artificial APCs, a surprisingly high frequency of antigen-specific T cells was detected by MHC-tetramer staining. From these, high frequency TCR clonotypes were functionally validated by reconstitution in Jurkat TCR-reporter cells. Interestingly, from a single experimental run multiple antigen-specific TCRs were validated (5 out of 10 tested clonotypes for NY-ESO-1, and 2 out of 5 for WT1). This finding was reproducible across independent experimental runs, yielding further validated TCRs against these targets. To benchmark relative TCR affinities, we compared a panel of 5 ATO-derived NY-ESO-1 TCRs with 4 blood-derived TCRs with the same specificity, as well as the affinity-enhanced 1G4 TCR. ATO-derived TCRs showed not only superior performance to their blood derived counterparts in peptide dilution assays, but TCRs were identified with equivalent or superior cytotoxicity to 1G4, including against cell lines with endogenous NY-ESO-1 expression. Comparative in vivo anti-tumor efficacy studies are in process. A similarly high level of specificity and cytotoxicity was observed for ATO-derived WT1-specific TCRs. Finally, we demonstrate proof-of-concept identification of TCRs specific to a prostate-specific antigen for which high quality TCRs have remained elusive. In conclusion, the PSC ATO TCR-discovery platform efficiently identifies high-affinity TAA-specific TCRs, including against previously intractable targets. Considering the potential for MHC modularity of this in vitro system, this approach may theoretically enable rapid discovery of therapeutic TCRs based on any designated peptide/MHC-I combination. Citation Format: Chloe S. Wang, Suwen Li, Zhiyuan Mao, Olivia Zhou, Carlos Botero, William Satyadi, Patrick Chang, Sang Pil Yoo, Ho-Chung Chen, Shawn Lopez, Jami McLaughlin, Amélie Montel-Hagen, Owen N. Witte, Gay M. Crooks, Christopher S. Seet. PSC-derived T cells as a novel source of tumor antigen-specific T cell receptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3604.

BACKGROUND: Mailed fecal immunochemical testing (FIT) can increase colorectal cancer (CRC) screening rates, including for vulnerable patients, but its cost-effectiveness is unclear. OBJECTIVE: We sought to examine the effectiveness and cost-effectiveness of the initial cycle of our mailed FIT program from November 2017 to July 2019 in a federally qualified health center (FQHC) system in Central Texas. DESIGN: Single group intervention and economic analysis PARTICIPANTS: Eligible patients were those ages 50–75 who had been seen recently in a system practice and were not up to date with screening. INTERVENTION: The program mailing packet included an introductory letter in plain language, the FIT itself, easy to read instructions, and a postage-paid lab mailer, supplemented with written and text messaging reminders. MAIN MEASURES: We measured effectiveness based on completion of mailed FIT and cost-effectiveness in terms of cost per person screened. Costs were measured using detailed micro-costing techniques from the perspective of a third-party payer and expressed in 2019 US dollars. Direct costs were based on material supply costs and detailed observations of labor required, valued at the wage rate. KEY RESULTS: Of the 22,838 eligible patients who received program materials, mean age was 59.0, 51.5% were female, and 43.9% were Latino. FIT were successfully completed by 19.2% (4395/22,838) patients at an average direct cost of $5275.70 per 500-patient mailing. Assuming completed tests from the mailed intervention represent incremental screening, the direct cost per patient screened, compared with no intervention, was $54.83. Incorporating start-up and indirect costs increases total costs to $7014.45 and cost per patient screened to $72.90. Alternately, assuming 2.5% and 5% screening without the intervention increased the direct (total) cost per patient screened to $60.03 ($80.80) and $67.05 ($91.47), respectively. CONCLUSIONS: Mailed FIT is an effective and cost-effective population health strategy for CRC screening in vulnerable patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11606-021-06691-y.

Defective autophagy is associated with chronic inflammation. Loss-of-function of the core autophagy gene Atg16l1 increases risk for Crohn’s disease by enhancing innate immunity in macrophages. However, autophagy also mediates clearance of intracellular pathogens. These divergent observations prompted a re-evaluation of ATG16L1 in antimicrobial immunity. In this study, we found that loss of Atg16l1 in macrophages enhanced the killing of virulent Shigella flexneri (S.flexneri), an enteric bacterium that resides within the cytosol by escaping all membrane-bound compartments. Quantitative multiplexed proteomics revealed that ATG16L1 deficiency significantly upregulated proteins involved in the glutathione-mediated antioxidant response to compensate for elevated oxidative stress, which also promoted S.flexneri killing. Consistently, myeloid cell-specific deletion of Atg16l1 accelerated bacterial clearance in vivo. Finally, pharmacological modulation of oxidative stress by suppression of cysteine import conferred enhanced microbicidal properties to wild type macrophages. These findings demonstrate that control of oxidative stress by ATG16L1 regulates antimicrobial immunity against intracellular pathogens.Impact statementMaculins et al utilize multiplexed mass spectrometry to show that loss of the autophagy gene Atg16l1 in macrophages enhances antimicrobial immunity against intracellular pathogens via the oxidative stress response.

We implement and test kernel averaging Non-Uniform Fast Fourier Transform (NUFFT) methods to enhance the performance of correlation and covariance estimation on asynchronously sampled event-data using the Malliavin-Mancino Fourier estimator. The methods are benchmarked for Dirichlet and Fej\'{e}r Fourier basis kernels. We consider test cases formed from Geometric Brownian motions to replicate synchronous and asynchronous data for benchmarking purposes. We consider three standard averaging kernels to convolve the event-data for synchronisation via over-sampling for use with the Fast Fourier Transform (FFT): the Gaussian kernel, the Kaiser-Bessel kernel, and the exponential of semi-circle kernel. First, this allows us to demonstrate the performance of the estimator with different combinations of basis kernels and averaging kernels. Second, we investigate and compare the impact of the averaging scales explicit in each averaging kernel and its relationship between the time-scale averaging implicit in the Malliavin-Mancino estimator. Third, we demonstrate the relationship between time-scale averaging based on the number of Fourier coefficients used in the estimator to a theoretical model of the Epps effect. We briefly demonstrate the methods on Trade-and-Quote (TAQ) data from the Johannesburg Stock Exchange to make an initial visualisation of the correlation dynamics for various time-scales under market microstructure., Comment: 29 pages, 15 figures, 3 tables, 10 algorithms, link to our supporting Julia code: https://github.com/CHNPAT005/PCEPTG-MM-NUFFT; v3: Accepted submitted version for SISC

Time and the choice of measurement time scales is fundamental to how we choose to represent information and data in finance. This choice implies both the units and the aggregation scales for the resulting statistical measurables used to describe a financial system. It also defines how we measure the relationship between different traded instruments. As we move from high-frequency time scales, when individual trade and quote events occur, to the mesoscales when correlations emerge in ways that can conform to various latent models; it remains unclear what choice of time and sampling rates are appropriate to faithfully capture system dynamics and asset correlations for decision making. The Epps effect is the key phenomenology that couples the emergence of correlations to the choice of sampling time scales. Here we consider and compare the Epps effect under different sampling schemes in order to contrast three choices of time: calendar time, volume time and trade time. Using a toy model based on a Hawkes process, we are able to achieve simulation results that conform well with empirical dynamics. Concretely, we find that the Epps effect is present under all three definitions of time and that correlations emerge faster under trade time compared to calendar time, whereas correlations emerge linearly under volume time., Comment: 15 pages, 13 figures. Link to our supporting Julia code: https://github.com/CHNPAT005/PCRBTG-VT. Accepted: Physica A

The ability to generate T cells from self-renewing pluripotent stem cells (PSC) has the potential to transform the current practice of autologous T cell immunotherapy into universal off-the-shelf products. However, differentiation of human PSCs into mature, conventional T cells has been challenging with existing methods. We report that a 3D artificial thymic organoid (PSC-ATO) system induced efficient differentiation of human embryonic stem cell and induced pluripotent stem cell-derived mesoderm progenitors to mature, functional T cells with a diverse T cell receptor (TCR) repertoire. This continuous culture system supported both hematopoietic specification and terminal differentiation to naïve CD3+CD8αβ+ and CD3+CD4+ conventional T cells. Introduction of an MHC class I-restricted TCR in PSCs produced naïve, antigen-specific cytotoxic CD8αβ+ T cells which lacked endogenous TCR Vβ expression. Functional assays and RNA sequencing aligned PSC-derived T cells with primary naïve CD8+ T cells. The PSC-ATO system presented here is an efficient platform for generating functional, mature T cells from human PSCs.